melphalan and Multiple-Myeloma

The development of therapy-related myeloid neoplasms (t-MN) is a rare complication that can occur in myeloma patients treated primarily with novel therapies. To better understand t-MNs in this context, we reviewed 66 such patients and compared them with a control group of patients who developed t-MN after cytotoxic therapies for other malignancies. The study group included 50 men and 16 women, with a median age of 68 years (range, 48-86 years). Therapies included proteasome inhibitors, immunomodulatory agents, and high-dose melphalan-based autologous stem cell transplantation (HDM-ASCT) in 64 (97%), 65 (98.5%), and 64 (97%) patients, respectively; 29 (43.9%) patients were exposed to other cytotoxic drugs besides HDM. The latency interval from therapy to t-MN was 4.9 years (range, 0.6-21.9 years). Patients who received HDM-ASCT in addition to other cytotoxic therapies had a longer latency period to t-MN compared with patients who only received HDM-ASCT (6.1 vs 4.7 years, P = .009). Notably, 11 patients developed t-MN within 2 years. Therapy-related myelodysplastic syndrome was the most common type of neoplasm (n = 60), followed by therapy-related acute myeloid leukemia (n = 4) and myelodysplastic syndrome/myeloproliferative neoplasm (n = 2). The most common cytogenetic aberrations included complex karyotypes (48.5%), del7q/-7 (43.9%), and/or del5q/-5 (40.9%). The most frequent molecular alteration was TP53 mutation, in 43 (67.2%) patients and the sole mutation in 20 patients. Other mutations included DNMT3A, 26.6%; TET2, 14.1%; RUNX1, 10.9%; ASXL1, 7.8%; and U2AF1, 7.8%. Other mutations in less than 5% of cases included SRSF2, EZH2, STAG2, NRAS, SETBP, SF3B1, SF3A1, and ASXL2. After a median follow-up of 15.3 months, 18 patients were alive and 48 died. The median overall survival after the diagnosis of t-MN in the study group was 18.4 months. Although the overall features are comparable to the control group, the short interval to t-MN (<2 years) underscores the unique vulnerable status of myeloma patients.

Topics: Aged; Aged, 80 and over; Female; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid, Acute; Male; Melphalan; Middle Aged; Multiple Myeloma; Myelodysplastic Syndromes; Myelodysplastic-Myeloproliferative Diseases; Pregnancy; Transplantation, Autologous

Treatment outcomes of multiple myeloma (MM) have dramatically improved in the past 20 years. The IFM/DFCI group reported that triplet induction (bortezomib, lenalidomide, and dexamethasone), followed by up-front high-dose melphalan and autologous stem cell transplantation (HDM/ASCT) and maintenance therapy, demonstrated a median progression-free survival (PFS) of 50 months. Therefore, up-front HDM/ASCT is considered standard care even in the era of novel agents. Daratumumab, lenalidomide, and dexamethasone have also been reported to prolong PFS for newly diagnosed transplant-ineligible MM. Quadruplet induction, including anti-CD38 antibody, will be approved even for transplant-eligible MM soon. Conversely, the success of chimeric antigen receptor T-cell therapy revealed that cellular immunotherapy may play an important role in treating MM. This review discussed the current standard of care and future perspectives for transplant-eligible MM.

Topics: Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Hematopoietic Stem Cell Transplantation; Humans; Lenalidomide; Melphalan; Multiple Myeloma; Transplantation, Autologous

Cancer is an uncontrolled expansion of atypical cells in the body. These unusual cells are labelled as cancerous or malignant cells. Melphalan, an anticancer drug which is imperatively recognized under the class of alkylating agents. It exhibits broad spectrum antitumor activity, as observed in ovarian cancer, breast cancer, etc. However, it is mainly utilized in the management of multiple myeloma. Several studies across the globe suggest that resistance to melphalan is the major concern that leads to relapsed myeloma. In the present paper, several pivotal approaches to compensate resistance associated with melphalan have been discussed. Numerous chemical and formulation developments concerning melphalan to enhance its salient characteristics and targeted profile have also been portrayed. The rationale of the current article also summarizes the recent analytical methods, structure-activity relationship, pharmacokinetics, interactions, potential adverse effects along with medicinal updates of melphalan. Special attention is also laid on their synthetic developments viz. melphalan derivatives, conjugates and prodrugs along with encouraging insights and research findings.

Topics: Antineoplastic Agents, Alkylating; Drug Resistance, Neoplasm; Humans; Melphalan; Multiple Myeloma; Prodrugs; Structure-Activity Relationship

High-dose melphalan supported by autologous transplantation has been the standard of care for eligible patients with newly diagnosed multiple myeloma (MM) for >25 years. Several randomized clinical trials have recently reaffirmed the strong position of transplantation in the era of proteasome inhibitors and immunomodulatory drugs combinations, demonstrating a significant reduction of progression or death in comparison with strategies without transplantation. Immunotherapy is currently changing the paradigm of MM management, and daratumumab is the first-in-class human monoclonal antibody targeting CD38 approved in the setting of newly diagnosed MM. Quadruplets have become the new standard in transplantation programs, but outcomes remain heterogeneous, with various response depth and duration. The development of sensitive and specific tools for disease prognostication allows the consideration of strategies adaptive to dynamic risk. This review discusses the different options available for the treatment of transplantation-eligible patients with MM in frontline setting.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Humans; Melphalan; Multiple Myeloma; Proteasome Inhibitors; Transplantation, Autologous

The objective of this article was to review existing data of melflufen (Pepaxto) as an additional treatment option for heavily pretreated relapsed and refractory multiple myeloma.. A PubMed search was completed using the search terms melphalan flufenamide; melflufen; melflufen AND relapsed refractory multiple myeloma; melphalan flufenamide and relapsed refractory multiple myeloma between January 1, 2013, and October 18, 2021. Additional information was obtained from the National Institutes of Health Clinical Trial Registry, Federal Drug Administration (FDA) web updates, and Pepaxto prescribing information.. Clinical trials including melflufen in relapsed refractory multiple myeloma and trials related to safety and clinical pharmacology were included.. The findings of this review show melflufen in combination with dexamethasone can be used as a treatment option for patients with relapsed and refractory multiple myeloma who have previously received greater than 4 previous lines of therapy, and documented resistance to a proteosome inhibitor, an anti-CD38 monoclonal antibody, and an immunomodulator.. Melflufen in combination with dexamethasone is a reasonable option for patients with relapsed and refractory multiple myeloma who have received at least 4 previous lines of therapy and considered ineligible for autologous stem cell transplant. Further clinical utilization in earlier lines of therapy is under review, pending the in-depth safety analysis by the FDA.. The FDA approval of melflufen in combination with dexamethasone provides an additional therapy option for patients with heavily pretreated relapsed and refractory multiple myeloma.

Topics: Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Humans; Melphalan; Multiple Myeloma; Peptides; Phenylalanine

For patients with multiple myeloma who are eligible for high-dose melphalan therapy and autologous stem cell transplant (ASCT), the strategy of maintenance with low-dose lenalidomide therapy has become the current standard of care. However, this strategy is not curative, and many unanswered questions remain regarding the optimization of lenalidomide-based maintenance therapy.. In this review, we evaluate the current data supporting the use of lenalidomide maintenance, either alone or in combination, following ASCT. We provide an overview of the management of lenalidomide-associated toxicities as well as address the unresolved topics of optimal treatment duration and use of minimal residual disease assessment.. While single-agent lenalidomide maintenance is a current standard of care, a one-size-fits-all approach to maintenance therapy is not optimal. The rapidly evolving landscape of multiple myeloma therapy in conjunction with ongoing clinical trials should enable a future where an individualized approach based on disease characteristics, response to induction and ASCT (or even non-ASCT consolidation approaches such as CAR T-cell therapy or bispecific antibodies), as well as patient preferences will influence the use of lenalidomide maintenance.

Topics: Antineoplastic Combined Chemotherapy Protocols; Hematopoietic Stem Cell Transplantation; Humans; Lenalidomide; Melphalan; Multiple Myeloma; Transplantation, Autologous

Pooled analyses of four single-arm phase 1 and 2 studies (NCT01816971, NCT02405364, NCT01029054, NCT01402284) investigated the clinical effectiveness of carfilzomib-lenalidomide-dexamethasone (KRd) in newly diagnosed multiple myeloma (NDMM). Patients who did (Cohort 1;

Topics: Antineoplastic Combined Chemotherapy Protocols; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Dexamethasone; Humans; Lenalidomide; Melphalan; Multiple Myeloma; Oligopeptides

The use of autologous stem cell transplantation (ASCT) in multiple myeloma (MM) is the standard of care in patients who are deemed transplantation eligible. Novel therapies, namely immunomodulatory drugs, proteasome inhibitors, and monoclonal antibodies, have revolutionized the treatment algorithm for MM but have not yet resulted in a cure. To achieve long-lasting disease control in MM, a high-dose conditioning regimen followed by ASCT continues to be an essential part of the management of transplantation-eligible patients with MM. High-dose (or conditioning) regimens are preparative chemotherapy-based regimens used before ASCT. High-dose melphalan is the most commonly used regimen in MM treatment. This clinical review provides an evidence-based summary to guide practicing hematologists/oncologists in the various high-dose regimens used before ASCT in MM treatment. We highlight the use of single-agent melphalan along with various combination-based high-dose regimens with their clinical efficacy. Various dosing schedules and modifications, timing of administration, and novel drugs-based combination regimens are discussed.

Topics: Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Multiple Myeloma; Transplantation Conditioning; Transplantation, Autologous

Oral oncolytic treatments (OOTs) have improved the prognosis of patients with multiple myeloma (MM). However, the effectiveness of these therapies is undermined by poor adherence. We aimed to characterize the real-world adherence to, and persistence with, OOTs for MM.. MEDLINE, EMBASE, and the International Pharmaceutical abstracts databases were searched for relevant observational studies published in English up to November 21, 2021. This was supplemented by manual searches of abstracts from the annual meetings of the American Society of Hematology, the American Society for Clinical Oncology, and the European Hematology Association as well as screening the references of included articles. Random-effects meta-analysis was performed.. Following screening of 11,557 articles, 19 studies involving 27,129 patients in 8 countries (France, the US, Germany, Italy, the UK, Brazil, South Korea, and Belgium) prescribed OOTs (lenalidomide, thalidomide, pomalidomide, panobinostat, ixazomib, and melphalan) for MM were included. The overall pooled proportion of adherent patients was 67.9% (95% confidence interval [CI]: 57.1%-77.8%). The pooled proportion of adherent patients was higher in self-reported questionnaire-based studies compared to those using prescription/dispensing data (81.6% vs. 61.0%; P-value for difference = .08). Across 5 studies involving 15,363 patients, a pooled proportion of 35.8% (95% CI: 22.0-50.9) discontinued treatment. Factors reported to be associated with nonadherence included increasing age, higher comorbidity, polypharmacy, and a lack of social support.. In patients with MM, adherence to and persistence with OOTs remains suboptimal. To achieve desired clinical outcomes, interventions to improve adherence and minimize discontinuation may be warranted.

Topics: Humans; Lenalidomide; Medication Adherence; Melphalan; Multiple Myeloma; Panobinostat; Pharmaceutical Preparations; Thalidomide

Despite therapeutic advances and improved patient outcomes in recent years, multiple myeloma (MM) remains a mostly incurable hematologic malignancy. Patients with relapsed/refractory MM (RRMM), especially those with triple-class-refractory disease or poor-prognostic features, have substantially unmet needs for new therapies with novel mechanisms of action. Melphalan flufenamide (melflufen) is the first alkylating peptide-drug conjugate that targets aminopeptidases to show efficacy and manageable safety, in combination with dexamethasone, in patients with RRMM who had received at least 4 prior lines of therapy, including at least 1 immunomodulatory drug, at least 1 proteasome inhibitor and at least 1 anti-CD38 monoclonal antibody, and received accelerated approval by the U.S. Food and Drug Administration (FDA) in early 2021 for use in this patient population. Initial analyses of the phase III OCEAN study data led to melflufen being voluntarily withdrawn from the U.S. market in late 2021, but subsequent analyses have prompted the manufacturer to rescind its voluntary withdrawal to allow further discussions with the U.S. FDA and the regulatory review with the European Medicines Agency (EMA) is also ongoing. Here, we provide a review of the novel mechanism of action and pharmacokinetics of melflufen, as well as key efficacy and safety from clinical studies that supported its initial approval, and discuss the nuances of the OCEAN study data. Melflufen demonstrates the potential of novel peptide-drug conjugates to positively impact the treatment landscape in RRMM.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Humans; Melphalan; Multiple Myeloma; Phenylalanine

Topics: Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Humans; Melphalan; Multicenter Studies as Topic; Multiple Myeloma; Randomized Controlled Trials as Topic

The introduction of whole genome and exome sequencing partnered with advanced bioinformatic pipelines has allowed the comprehensive characterization of mutational processes (i.e., mutational signatures) in individual cancer patients. Studies focusing on multiple myeloma have defined several mutational processes, including a recently identified mutational signature (called "SBS-MM1") directly caused by exposure to high-dose melphalan (i.e., autologous stem cell transplant). High-dose melphalan exposure increases both the overall and nonsynonymous mutational burden detected between diagnosis and relapse by ~10-20%. Nevertheless, most of these mutations are acquired within the heterochromatin and late-replicating regions, rarely involving key myeloma driver genes. In this review, we summarize key studies that made this discovery possible, and we discuss potential clinical implications.

Topics: Humans; Melphalan; Multiple Myeloma; Mutagenesis; Mutagens; Mutation; Neoplasm Proteins

Despite recent therapeutic advances, multiple myeloma (MM) patients experience relapses as they become resistant to various classes and combinations of treatment. Melphalan (L-PAM) is an ageless drug. However, its use in the autologous stem cell transplantation (ASCT) setting and the innovative quadruplet regimen as well as daratumumab, bortezomib, and prednisone make this old drug current yet. Melflufen is a peptide-conjugated alkylator belonging to a novel class of compounds, representing an overcoming of L-PAM in terms of mechanism of action and effectiveness. The improved melflufen cytotoxicity is related to aminopeptidase activity, notably present in normal and neoplastic cells and remarkably heavily overexpressed in MM cells. Upon entering a cell, melflufen is cleaved by aminopeptidases, ultimately releasing the L-PAM payload and eliciting further the inflow and cleavage of the conjugated peptide. This virtuous loop persists until all extracellular melflufen has been utilized. The aminopeptidase-driven accumulation results in a 50-fold increase in L-PAM cell enrichment as compared with free alkylator. This condition produces selective cytotoxicity, increased on-target cell potency, and decreased off-target cell toxicity, ultimately overcoming resistance pathways triggered by previous treatments, including alkylators. Due to its distinct mechanism of action, melflufen plus dexamethasone as a doublet, and in combination with other novel drugs, has the potential to be beneficial for a broad range of patients with relapsed/refractory (RR) MM in third- or even in second-line therapy. The safety profile of melflufen has been consistent across studies, and no new safety concerns have been identified when melflufen was administered in doublet and triplet combinations. Based on growing clinical evidence, melflufen could be not only a good addition in the fight against RRMM but also a drug with a very favorable tolerability profile.

Topics: Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Drug Resistance, Neoplasm; Humans; Melphalan; Multiple Myeloma; Phenylalanine

In this review, we discuss the most important aspects of the role of high-dose melphalan (HDM) and autologous stem-cell transplantation (ASCT) in the treatment of multiple myeloma (MM).. Almost 40 years after the publication of the first study on safety and efficacy of HDM and ASCT in MM patients, and despite the introduction of several drugs and combinations with various targets on the plasma cell and the surrounding microenvironment, HDM-ASCT still stands as a standard of care for the upfront treatment of newly diagnosed MM patients. Indeed, all attempts to replace HDM-ASCT with novel-agent-based, non-transplant strategies have failed to demonstrate their efficacy, at least in terms of progression-free survival.. Despite such a long history in MM, a number of open issues regarding HDM-ASCT still exist, from the choice between using transplant in first-line therapy or at relapse to the use of tandem HDM-ASCT in high-risk patients. With the introduction of more and more effective multidrug regimens and of novel immunotherapeutic approaches, the challenge between transplant and non-transplant is not over yet.

Topics: Antineoplastic Agents, Alkylating; Humans; Melphalan; Multiple Myeloma; Randomized Controlled Trials as Topic; Stem Cell Transplantation

For patients with newly diagnosed multiple myeloma (NDMM) who are transplant ineligible, bortezomib-melphalan-prednisone (VMP) demonstrated superior efficacy based on the VISTA trial. In subsequent trials, twice-weekly bortezomib was limited to the first cycle or completely replaced with once-weekly bortezomib to reduce toxicity. Following a systematic literature review, the efficacy and safety of modified VMP schedules (pooled data from the once-weekly bortezomib VMP arm of the GIMEMA trial and the VMP arm of the ALCYONE trial) were compared to the VISTA schedule using naïve and unanchored matching-adjusted indirect comparison (MAIC). Median progression-free survival was similar between VISTA and modified VMP (20.7 months [95% CI, 18.4-24.3] vs 19.6 months [95% CI, 18.8-21.0]). Peripheral neuropathy was significantly reduced with modified VMP versus VISTA VMP (all grades: naïve, 32.1% vs 46.8% and MAIC, 32.1% vs 46.7%; both

Topics: Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Humans; Melphalan; Multiple Myeloma; Prednisone; Treatment Outcome

Established treatments for transplant-ineligible (TNE) patients with newly diagnosed multiple myeloma (NDMM) include melphalan and prednisone (MP) combined with either bortezomib (VMP) or thalidomide (MPT), or lenalidomide plus low-dose dexamethasone (Rd). New treatments for TNE NDMM include Rd plus bortezomib (RVd) and daratumumab plus VMP (VMP + D), daratumumab plus lenalidomide and dexamethasone (D + Rd). Relative efficacy of these treatments was compared using a network meta-analysis. Eight trials identified by a systematic literature review were included in the primary analysis; hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS) were used. Rd was superior to other MP-based regimens for OS and PFS. There was strong evidence that, compared with Rd, both D + Rd and RVd improved PFS (HR 0.57; 95% credible interval (CrI) 0.43, 0.73 and HR 0.72; 95% CrI 0.56, 0.91, respectively). However, there was strong evidence only for RVd in respect to OS (HR 0.72; 95% CrI 0.52, 0.96).

Topics: Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Humans; Lenalidomide; Melphalan; Multiple Myeloma; Network Meta-Analysis; Thalidomide; Treatment Outcome

The changing landscape of treatment options for multiple myeloma has led to a higher proportion of patients achieving deep, long-lasting responses to therapy. With the associated improvement in overall survival, the development of subsequent second malignancies has become of increased significance. The risk of second malignancy after multiple myeloma is affected by a combination of patient-, disease- and therapy-related risk factors. This review discusses recent data refining our knowledge of these contributing factors, including current treatment modalities which increase risk (i.e. high-dose melphalan with autologous stem cell transplant and lenalidomide maintenance therapy). We highlight emerging data towards individualized risk- and response-adapted treatment strategies and discuss key areas requiring future research.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Clinical Trials as Topic; Disease-Free Survival; Drug Administration Schedule; Hematopoietic Stem Cell Transplantation; Humans; Lenalidomide; Maintenance Chemotherapy; Melphalan; Multiple Myeloma; Neoplasm, Residual; Neoplasms, Second Primary; Risk Factors; Thalidomide; Transplantation, Autologous

State of the art treatment for myeloma involves using 3-drug combinations incorporating immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs). Clinical trials for 4-drug combinations incorporating monoclonal antibodies added to IMiD and PI based backbones are underway. Recent retrospective analyses show that patients who attain MRD negativity have similar long term outcomes regardless of early or delayed high dose melphalan with autologous stem cell support (HDM-ASCT). Given HDM-ASCT toxicity, not "overtreating" would be beneficial. Short of data from future prospective clinical trials addressing the question of the role of HDM-ASCT in MRD negative patients, varying expert opinions inherently arise. In this paper, we present the historical context of HDM-ASCT and data supporting 3-drug combinations. We then propose that a viable option for patients who reach MRD negativity is to transition to maintenance therapy directly without early HDM-ASCT, and reserving stem cell harvest to cases where HDM-ASCT is a possibility at relapse.

Topics: Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Drug Administration Schedule; Hematopoietic Stem Cell Transplantation; Humans; Lenalidomide; Melphalan; Multiple Myeloma; Neoplasm, Residual; Oligopeptides; Risk Factors; Survival Analysis; Thalidomide; Transplantation, Autologous

Over the course of the past decade-plus, the therapy of newly diagnosed multiple myeloma has seen incredible advances in the domains of diagnostic evaluation, active medical therapy, and response evaluation. This manuscript reviews the evaluation and management of newly diagnosed active multiple myeloma, with a focus on major clinical trials and IMWG recommendations. The paper describes a current approach for the initial evaluation and workup for patients with putative active myeloma, with consideration towards potential MRD-directed therapeutic approaches and future clinical trials, and then discusses management with a focus on induction regimens with attention primarily to modern three and four-drug combinations for transplant-eligible and transplant-ineligible patients, and those with organ dysfunction. Finally, this article briefly reviews minimal residual disease directed therapy approaches, primarily in the context of whether eligible patients should be referred for high dose chemotherapy and autologous stem cell rescue. Maintenance therapy for both transplant eligible and ineligible patients is discussed elsewhere in this issue.

Topics: Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Bortezomib; Clinical Trials as Topic; Cyclophosphamide; Dexamethasone; Drug Administration Schedule; Hematopoietic Stem Cell Transplantation; Humans; Lenalidomide; Melphalan; Multiple Myeloma; Neoplasm, Residual; Oligopeptides; Plasma Cells; Survival Analysis; Thalidomide; Transplantation, Autologous

Recent advances in multiple myeloma include numerous approvals of novel therapies with unprecedented efficacy, a rapid and sustained tempo of new drug development, and further refinements to prognostication to include minimal residual disease (MRD) testing and improved risk stratification. The upfront use of immunomodulatory drug and proteasome inhibitor combinations followed by maintenance has resulted in transformative clinical benefit. Four-drug regimens incorporating monoclonal antibodies are reporting unprecedented rates of complete response and MRD negativity in the absence of intensification. In the context of these advances, the added value of high-dose melphalan with autologous stem-cell transplant (HDM-ASCT) is a key question. From a safety standpoint, HDM-ASCT is associated with both acute toxicities that reduce quality of life and long-term toxicities that may limit life expectancy for some patients. The present review discusses the recent advances in induction therapy, the impact of these advances on HDM-ASCT, the evolving role of MRD testing and the short- and long-term risks of HDM-ASCT. Recognising that prospective data remains limited, we suggest that HDM-ASCT not be considered mandatory for eligible newly diagnosed patients who are treated with highly efficacious regimens and achieve deep responses, but rather be held in reserve without early exposure to the clinical and genomic toxicity inherent to this approach.

Topics: Hematopoietic Stem Cell Transplantation; Humans; Immunologic Factors; Melphalan; Multiple Myeloma; Neoplasm, Residual; Proteasome Inhibitors; Transplantation, Autologous

Multiple myeloma (MM) is a chronically managed blood cancer with a median age of 69 years at the time of diagnosis. Although high dose melphalan and autologous stem cell transplantation (ASCT) remains a standard of care for eligible patients, more than half of the newly diagnosed MM patients are deemed ineligible due to comorbidities or complications of the disease by itself. In this setting, where ASCT is deemed inappropriate, patients could still achieve durable and deep responses if given the appropriate treatment plan. The key concepts of optimizing induction and maintenance strategies while minimizing side-effects are discussed in this review, especially in the context of employing novel agent combinations. It is important to understand the balance between safety and efficacy for each regimen, utilizing maintenance strategy and the best supportive care measures (bone health, infection prevention, and treatment, pain management, etc.). Here, we examine the evidence behind each of those principles and review results from clinical trials for transplant-ineligible (TI) MM.

Topics: Aged; Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Multiple Myeloma; Transplantation, Autologous

The overall survival of patients with multiple myeloma has improved with the advent of novel agents; however, multiple myeloma remains incurable. Combinations of standard-of-care agents such as immunomodulators, proteasome inhibitors, and anti-CD38 monoclonal antibodies are increasingly used in earlier lines of therapy. Patients with disease that is refractory to multiple novel agents represent a population with high unmet medical need and for whom therapies with new mechanisms of action could be beneficial. Melphalan flufenamide (melflufen) has demonstrated encouraging activity in patients with relapsed and refractory multiple myeloma.. This review provides an overview of the mechanism of action of melflufen, a first-in-class peptide-drug conjugate that targets aminopeptidases and rapidly delivers alkylating agents into tumor cells. It reviews key Phase I and II clinical trial data for melflufen in combination with dexamethasone as well as in triplet combinations with daratumumab or bortezomib. The safety profile of melflufen, which is characterized primarily by clinically manageable hematologic adverse events, is described.. Melflufen has potential to fill a gap in the myeloma treatment landscape by providing a new mechanism of action with clinically meaningful efficacy and a favorable safety profile in patients refractory to multiple novel agents.

Topics: Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Humans; Melphalan; Multiple Myeloma; Phenylalanine; Recurrence; Survival Rate

CD38 antibodies were first evaluated in extensively pretreated patients with multiple myeloma (MM). Currently, there are 3 CD38 antibody-based regimens approved for the treatment of both transplant-eligible (daratumumab plus bortezomib-thalidomide-dexamethasone [D-VTd]) and transplant-ineligible (daratumumab plus lenalidomide-dexamethasone [D-Rd] or daratumumab plus bortezomib-melphalan-prednisone [D-VMP]) patients with newly diagnosed MM (NDMM). The phase 3 studies that evaluated these regimens uniformly showed that the addition of daratumumab to backbone regimens improved the depth of response, which translated into improved progression-free survival and also overall survival in 2 of the studies. Importantly, elderly patients age 75 years or older benefit from these regimens, indicating that these regimens have an acceptable safety profile. Although the number of patients with high-risk cytogenetics was relatively small, these patients also experienced benefit from the addition of daratumumab to standard-of-care regimens, but poor risk conferred by the cytogenetic aberrations is not completely abrogated. Altogether, daratumumab-based regimens have high anti-MM activity and a favorable toxicity profile and therefore represent new standards of care for patients with NDMM.

Topics: ADP-ribosyl Cyclase 1; Aged; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Dexamethasone; Humans; Lenalidomide; Male; Melphalan; Membrane Glycoproteins; Multiple Myeloma; Neoplasm Proteins; Thalidomide

The significant advances made in the treatment of multiple myeloma (MM) have allowed for a paradigm shift away from the early use of high-dose melphalan with autologous stem cell transplant (HDM-ASCT). In 2015 alone, the US Food and Drug Administration (FDA) approved 4 novel drugs for MM. Novel drugs and regimens have shown unprecedented efficacy, which has increased the tempo of new drug development. Furthermore, the FDA recently approved a diagnostic test to detect minimal residual disease (MRD) that will allow community clinicians to conduct real-time testing of MRD. Most importantly, frontline regimens based on immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs) have shown a large clinical benefit. The next era has begun, as several 4-drug combinations that include monoclonal antibodies are being evaluated in clinical trials in the attempt to replace HDM-ASCT in the treatment of MM. We and others have therefore questioned the need for early HDM-ASCT, especially in light of the possible complications. HDM-ASCT is associated not only with acute toxicities-cytopenia, infection, and even death-but also an increased risk of developing secondary cancers. This article discusses the historic context of HDM-ASCT, the modern role of HDM-ASCT given the availability of highly sensitive MRD testing, and the likely future of quadruplet treatment. In summary, patients who attain deep responses using IMiD- and PI-based regimens may not require early HDM-ASCT. A delayed approach to this treatment is acceptable, and might be preferred by patients.

Topics: Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Multiple Myeloma; Myeloablative Agonists; Prognosis; Time-to-Treatment; Transplantation Conditioning; Transplantation, Autologous

To evaluate the role of high-dose melphalan plus autologous stem-cell transplantation (ASCT) as consolidation therapy for patients with newly diagnosed multiple myeloma (NDMM) in the era of novel agents, we undertook this meta-analysis. Medline, Embase, the Cochrane controlled trials register, the SCI, ASH, EHA, and ASCO were searched for clinical trials including high-dose chemotherapy plus ASCT for patients with NDMM. Finally, we identified four RCTs of ASCT versus novel agents based consolidations, and 10 single-arm prospective trials of ASCT alone. Pooled analysis indicated that response quality improved further after ASCT in the era of novel agents (≥CR rates of 13% pre-ASCT versus 29% post-ASCT,

Topics: Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Dose-Response Relationship, Drug; Hematopoietic Stem Cell Transplantation; Humans; Lenalidomide; Melphalan; Multiple Myeloma; Progression-Free Survival; Randomized Controlled Trials as Topic; Transplantation, Autologous

High-dose melphalan (HDMel) is the most common conditioning chemotherapy regimen for autologous stem cell transplantation (SCT) in patients affected by multiple myeloma (MM). No consensus exists for the emetogenicity or prophylaxis of chemotherapy-induced nausea and vomiting (CINV) in this regimen.. Data on the incidence and efficacy/safety of CINV prophylaxis among patients affected by MM undergoing autologous SCT with the HDMel regimen was extracted from electronic databases and analyzed.. Eleven studies involving multiple CINV prophylaxis regimens were identified and included. No consensus on HDMel emetogenicity was reached, but most studies summarized the emetogenicity as moderate-high risk. An aprepitant-based three-drug regimen (aprepitant + serotonin receptor antagonist (5HT3RA) + dexamethasone) showed better efficacy than a two-drug regimen (5HT3RA + dexamethasone) for CINV prevention without increasing the frequency in adverse events.. The aprepitant-based three-drug regimen should be the regimen of choice for CINV prophylaxis for MM patients undergoing autologous SCT with HDMel conditioning.

Topics: Adult; Antiemetics; Antineoplastic Agents, Alkylating; Aprepitant; Dexamethasone; Female; Hematopoietic Stem Cell Transplantation; Humans; Induction Chemotherapy; Male; Melphalan; Multiple Myeloma; Nausea; Quality of Life; Serotonin Antagonists; Transplantation Conditioning; Transplantation, Autologous; Vomiting

Decision making for patients with multiple myeloma (MM) not transplant eligible (NTE) is complicated by a lack of head-to-head comparisons of standards of care, the increase in the choice of treatment modalities, and the promising results that are rapidly evolving from studies with novel regimens. To support evidence-based decision making, we performed a network meta-analysis for NTE MM patients that synthesizes direct and indirect evidence and enables a comparison of all treatments. Relevant randomized clinical trials were identified by a systematic literature review in EMBASE®, MEDLINE®, MEDLINE®-in-Process and the Cochrane Central Register of Controlled Trials for January 1999 to March 2016. Efficacy outcomes [i.e. the hazard ratio (HR) and 95% confidence interval (95%CI) for progression-free survival] were extracted and synthesized in a random effects network-meta analysis. In total, 24 studies were identified including 21 treatments. According to the network-meta analysis, the HR for progression-free survival was favorable for all NTE MM treatments compared to dexamethasone (HR: 0.19-0.90). Daratumumab-bortezomib-melphalan-prednisone and bortezomib-melphalan-prednisone-thalidomide with bortezomib-thalidomide maintenance were identified as the most effective treatments (HR: 0.19, 95%CI: 0.08-0.45 and HR: 0.22, 95%CI: 0.10-0.51, respectively). HR and 95%CI for currently recommended treatments, bortezomib-lenalidomide-dexamethasone, bortezomib-melphalan-prednisone, and lenalidomide-dexamethasone compared to dexamethasone, were 0.31 (0.16-0.59), 0.39 (0.20-0.75), and 0.44 (0.29-0.65), respectively. In addition to identifying the most effective treatment options, we illustrate the additional value and evidence of network meta-analysis in clinical practice. In the current treatment landscape, the results of network meta-analysis may support evidence-based decisions and ultimately help to optimize treatment and outcomes of NTE MM patients.

Topics: Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Dexamethasone; Hematopoietic Stem Cell Transplantation; Humans; Lenalidomide; Maintenance Chemotherapy; Melphalan; Multiple Myeloma; Network Meta-Analysis; Prednisone; Thalidomide; Treatment Outcome

Intravenous daratumumab (DARZALEX

Topics: ADP-ribosyl Cyclase 1; Antibodies, Monoclonal; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Clinical Trials, Phase III as Topic; Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Membrane Glycoproteins; Multiple Myeloma; Prednisone; Randomized Controlled Trials as Topic; Transplantation Conditioning

Therapy-related myeloid neoplasms (t-MN), including therapy-related acute myeloid leukaemia and myelodysplastic syndrome, are second primary malignancies (SPM) that are of growing importance as patients with plasma cell disorders (PCD) such as multiple myeloma (MM) are living longer with more effective therapies. Both patient-specific and treatment-specific factors likely impact the risk of t-MN development after diagnosis and treatment of PCD. Alkylating chemotherapy, especially melphalan, has been strongly tied to the risk of t-MN. More recently, there has been a shift away from long-term alkylating therapies to immunomodulatory agents and high-dose therapy with autologous stem cell transplant (HD-ASCT). This shift has led to improved survival and long-term outcomes for most MM patients. However, the risks of t-MN remain despite the improved efficacy of these treatments, and patients who develop t-MN have a poor prognosis. Understanding the risk factors predisposing MM patients to t-MN can thus help to tailor individualized therapy to maximize anti-myeloma efficacy and minimize the risks of t-MN.

Topics: Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid, Acute; Melphalan; Multiple Myeloma; Myelodysplastic Syndromes; Neoplasms, Second Primary; Prognosis; Risk Factors; Transplantation, Autologous

Many new regimens have been applied to newly diagnosed transplant-ineligible multiple myeloma, but no head-to-head research has been performed to compare the efficacy of these treatments. Currently lenalidomide plus dexamethasone (Rd) is one of the standard treatments. Our aim was to make a comparison of these treatments to Rd by a network meta-analysis. We performed a systematic review and network meta-analysis. We searched PubMed, Embase, and the Cochrane Library for articles published from January 1, 1988, to April 26, 2018, as well as research presented at 5 international conferences (American Society of Clinical Oncology, American Society of Hematology, European Hematology Association, European Society of Medical Oncology, and International Myeloma Working Group) between January 2015 and December 2018. Our interest outcomes were hazard ratios (HRs) for progression-free survival (PFS) and overall survival (OS). Bayesian fixed-effects mixed-treatment comparisons were used for this study. A total of 23 articles describing 10,401 participants were included for this network meta-analysis. Lenalidomide and dexamethasone plus daratumumab (HR, 0.57; 95% credible interval [CrI], 0.43-0.73), daratumumab plus bortezomib, melphalan, and prednisone (HR, 0.59; 95% CrI, 0.36-0.91), and the combination of bortezomib with lenalidomide and dexamethasone (RVd) (HR, 0.72, 95% CrI, 0.56-0.90) all showed significant effect compared to Rd for PFS. RVd demonstrated significant benefit compared to Rd (HR, 0.72; 95% CrI, 0.53-0.96) for OS. Our study results suggested that lenalidomide and dexamethasone plus daratumumab; daratumumab plus bortezomib, melphalan, and prednisone; and RVd showed better efficacy than Rd in PFS; and RVd showed better efficacy than Rd in OS in patients with newly diagnosed transplant-ineligible multiple myeloma in the absence of head-to-head research.

Topics: Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Dexamethasone; Humans; Lenalidomide; Melphalan; Multiple Myeloma; Stem Cell Transplantation; Thalidomide; Treatment Outcome

Multiple myeloma (MM) is an incurable disease characterized by clonal plasma cell proliferation and overproduction of monoclonal paraprotein, hypercalcemia, renal failure, anemia, osteolytic bone lesions, and infections. Melphalan, a nitrogen mustard, is an alkylating agent synthesized in 1953, and it has been used in multiple myeloma therapy for fifty years. Although novel agents have been introduced in the past few decades improving prognosis of the disease, melphalan still maintains a crucial role in the treatment of MM acting both as cytotoxic agent through damage to DNA, and as immunostimulatory drug by inhibiting Interleukin-6, as well as interaction with dendritic cells, and immunogenic effects in tumor microenvironment. Areas covered: This review focuses on available data about melphalan pharmacology and its role in clinical practice. Expert opinion: Melphalan remains crucial in therapy of multiple myeloma because of its good manageability, safety profile, efficacy, and economic sustainability. These characteristics make it pivotal also for new regimens in combination with novel agents.

Topics: Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Humans; Interleukin-6; Melphalan; Molecular Structure; Multiple Myeloma; Myeloma Proteins; Prognosis

The introduction of new drugs with less severe toxicity profiles than those of conventional antimyeloma agents allowed the evaluation of continuous therapy compared with fixed duration therapy. In transplant-eligible patients, consolidation therapy with bortezomib or bortezomib-based regimens showed significant progression-free survival (PFS) benefit in cytogenetic standard-risk patients and to a lesser extent, high-risk patients. Continuous therapy with lenalidomide maintenance treatment after autologous stem cell transplantation resulted in a significant survival gain. In transplant noneligible patients, continuous lenalidomide-dexamethasone therapy improved survival over fixed duration melphalan-prednisone-thalidomide. The concept of prolonged treatment in elderly patients is supported by some other studies, but most of them revealed a gain in PFS only. Young patients with unfavorable prognosis show a greater willingness to accept long-term treatment, whereas the readiness to undergo such treatments and the benefits therefrom decline with increasing age and decreasing fitness, rendering fixed duration therapy a suitable option in elderly frail patients.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Consolidation Chemotherapy; Disease-Free Survival; Humans; Melphalan; Multiple Myeloma; Prednisone; Survival Rate; Thalidomide; Time Factors

Multiple myeloma is the second most frequent hematological disease. The introduction of melphalan as high-dose therapy followed by autologous hematopoietic cell transplantation (HDT/ASCT) for young patients and the availability of novel agents for young and elderly patients with multiple myeloma have dramatically changed the perspective of treatment. However, further research is necessary if we want definitively to cure the disease. Treatment goals for transplant-eligible and non-transplant-eligible patients should be to prolong survival by achieving the best possible response while ensuring quality of life. For young patients, HDT-ASCT is a standard of care for treatment, and its efficacy has been enhanced and challenged by the new drugs. For elderly patients, treatment options were once limited to alkylators, but new upfront treatment combinations based on novel agents (proteasome inhibitors and immunomodulatory drugs) combined or not with alkylators have significantly improved outcomes. Extended treatment of young and elderly patients improves the quality and duration of clinical responses; however, the optimal scheme, appropriate doses, and duration of long-term therapy have not yet been fully determined. This review summarizes progress in the treatment of patients with newly diagnosed multiple myeloma, addressing critical questions such as the optimal induction, early vs late ASCT, consolidation and/or maintenance for young patients, and how we can choose the best treatment option for non-transplant-eligible patients.

Topics: Age Factors; Autografts; Disease-Free Survival; Hematopoietic Stem Cell Transplantation; Humans; Immunologic Factors; Melphalan; Multiple Myeloma; Proteasome Inhibitors; Quality of Life; Survival Rate

In 2015, there is a large body of evidence demonstrating that minimal residual disease (MRD) negativity after therapy is a powerful predictor of progression-free survival and overall survival in multiple myeloma. On the basis of available data, we believe MRD provides a meaningful endpoint for regulatory purposes, academic studies, and a valuable prognostic evaluation of individual patients in the clinical setting. Similar to what has been shown in acute and chronic lymphocytic leukemia, based on emerging data, the prognostic impact of MRD in multiple myeloma appears to be independent of induction therapy received. This fact raises fundamental questions regarding best possible treatment strategies (e.g., fixed number of cycles versus response adapted number of cycles) as well as optimal treatment modalities (e.g., newer effective but less intense combination therapies versus high dose melphalan followed by autologous stem cell transplantation), in particular for patients newly diagnosed with multiple myeloma.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Flow Cytometry; Hematopoietic Stem Cell Transplantation; Humans; Induction Chemotherapy; Melphalan; Multiple Myeloma; Neoplasm, Residual; Plasma Cells; Prognosis; Remission Induction; Survival Analysis; Transplantation, Autologous

The purpose of this study was to compare approved first-line therapies for patients with multiple myeloma.. A systematic literature search for phase III randomized controlled trials (RCTs) comparing first-line chemotherapies approved in Germany and recommended by guidelines at the time of study design was conducted. Random-effects meta-analysis (MA) was used for direct and the Bucher method for adjusted indirect treatment comparison.. One RCT comparing melphalan and prednisone plus bortezomib (VMP) vs. melphalan and prednisone (MP) and six RCTs comparing MP plus thalidomide (MPT) vs. MP were analysed. For MPT vs. MP, an individual patient data (IPD) MA was used for sensitivity analyses. VMP and MPT were superior to MP regarding efficacy endpoints (VMP vs. MP, overall survival (OS): hazard ratio (HR) 0.70, 95 % confidence interval (CI) 0.57-0.86; progression-free survival (PFS): HR 0.56, 0.39-0.79; complete response (CR), risk-ratio (RR) for non-response: 0.70, 0.65-0.75; MPT vs.. HR 0.83, 0.66-1.03; PFS: HR 0.67, 0.56-0.81; CR, RR for non-response 0.92, 0.88-0.95); but had a higher risk of developing any grade 3-4 adverse events (AEs) (VMP vs. MP: RR 1.13, 1.06-1.20; MPT vs. MP: RR 2.06, 1.43-2.98). The indirect comparison of VMP vs. MPT via MP showed a statistically not significant advantage for VMP regarding survival outcomes (OS: HR 0.85, 0.63-1.14; PFS: HR 0.83, 0.56-1.23) and a significant advantage regarding CR (RR for non-response 0.76, 0.70-0.83) and AEs (RR 0.55, 0.38-0.80). Treatment comparisons using results of IPD MA yielded similar effect sizes.. VMP and MPT seem more effective than MP, VMP was superior to MPT regarding response criteria and AEs. Our results may best be confirmed by a head-to-head trial of VMP vs. MPT.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Clinical Trials, Phase III as Topic; Germany; Humans; Melphalan; Multiple Myeloma; Prednisone; Randomized Controlled Trials as Topic; Thalidomide

Thalidomide is an immunomodulatory and anti-angiogenic drug that has shown promise in patients with myeloma. Trials comparing efficacy of standard melphalan and prednisone (MP) therapy with MP plus thalidomide (MPT) in transplant-ineligible or elderly patients with multiple myeloma (MM) have provided conflicting evidence. This meta-analysis aimed to determine the efficacy and toxicity of thalidomide in previously untreated elderly patients with myeloma.. Medline, the Cochrane Controlled Trials register, conference proceedings of the American Society of Hematology (1995-2014), the American Society of Clinical Oncology (1995-2014), and CBM, VIP, and CNKI databases were searched for randomized control trials with the use of the medical subject headings "MM " and "thalidomide ". Trials were assessed by two reviewers for eligibility. Meta-analysis was conducted using a fixed effects model. Sensitivity analysis was performed to test the robustness of the findings.. Overall, seven trials were identified, covering a total of 1821 subjects. The summary hazard ratio (thalidomide vs. control) was 0.82 (95% confidence interval [CI]: 0.72-0.94) for overall survival (OS), and 0.65 (95% CI: 0.58-0.73) for progression-free survival, in favor of thalidomide treated group. The risk ratio of complete response with induction thalidomide was 3.48 (95% CI: 2.24-5.41). A higher rate of III/IV adverse events were observed in MPT arm compared with the MP arm. However, analysis of sub-groups administering anticoagulation as venous thromboembolism prophylaxis suggested no difference in relative risk of thrombotic events between two arms (RR = 1.47, 95% CI: 0.43-5.07, P = 0.54). Further analysis of trials on the treatment effects of MPT versus MP on adverse events-related mortality showed no statistical difference between two arms (RR = 1.24, 95% CI: [0.95-1.63], P = 0.120).. Thalidomide appears to improve the OS of elderly and/or transplant-ineligible patients with MM when it is added to standard MP therapy.

Topics: Disease-Free Survival; Humans; Immunosuppressive Agents; Melphalan; Multiple Myeloma; Prednisone; Thalidomide

The advent of the immunomodulatory drugs thalido-mide, lenalidomide, and pomalidomide; the proteasome inhib-itors bortezomib, carfilzomib, and ixazomib; the histone deacet-ylase inhibitor panobinostat; and the monoclonal antibodies elotuzumab and daratumumab has led to dramatic improvements in outcomes for patients with multiple myeloma. Along with progress in nontransplant therapy have come questions regarding the continued role of high-dose melphalan (HDM) supported by autologous stem cell transplant (ASCT) in the treatment of multiple myeloma. Emerging evidence from phase 3 studies demonstrates that consolidation therapy with HDM/ASCT further improves depth of response and progression-free survival in the context of modern therapy for multiple myeloma. Moreover, unprecedented survival data from ongoing phase 3 studies of patients treated with modern myeloma therapy followed by HDM/ASCT in first-line or second-line therapy reaffirm single and tandem HDM/ASCT as important standards of care for eligible patients. Herein, we review the evolving role of HDM/ASCT for the treatment of patients with newly diagnosed or relapsed multiple myeloma.

Topics: Antineoplastic Agents, Alkylating; Combined Modality Therapy; Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Multiple Myeloma; Transplantation, Autologous

Although there have been many definitions for high-risk (HR) myeloma, most recent consensus for classifying risk in patients with newly diagnosed multiple myeloma (NMM) comes from the International Myeloma Working Group. This recently published revised International Staging System includes del(17p) or t(4;14) by fluorescence in situ hybridization, β-2 microglobulin, albumin, and lactate dehydrogenase. These elements should be captured in all NMM patients. The optimal treatments for HR myeloma have not been fully worked out; therefore, these patients should be considered for clinical trials. Outside of the trial setting for those patients who are not eligible for autologous stem cell transplantation (ASCT), a regimen with bortezomib, but not thalidomide, should be considered, with a duration of therapy of at least 1 year. The regimen with the best results to date is bortezomib, melphalan, and predisone. A nonthalidomide maintenance could also be considered. In patients who are eligible for ASCT, an induction regimen with bortezomib and an immunomodulatory drug should be administered for 3 to 6 months followed by 2 ASCTs. Finally, a consolidation/maintenance regimen containing at least 1 year of bortezomib should be administered followed by maintenance thereafter. For patient convenience, an oral agent that is not thalidomide could be prescribed as maintenance. Finally, in patients with HR myeloma, allogeneic SCT may be associated with reasonable outcomes, but this too will require further research.

Topics: Autografts; Bortezomib; Humans; Melphalan; Multiple Myeloma; Neoplasm Staging; Risk Factors; Stem Cell Transplantation; Time Factors

Multiple myeloma (MM) remains an incurable malignancy. Approximately 37% of patients with plasma cell myeloma are over the age of 75 and the median age of diagnosis is 70. The management approach to over 70s differs from younger patients, as treatment goals may vary and underlying co-morbidities and expected treatment related toxicities have to be taken into account. Individualisation of management is important, aiming to achieve the best response whilst minimising adverse events. A proportion of patients will be unable to tolerate any treatment with palliation being appropriate. Age alone should not be a barrier to treatment however, with some fit patients over the age of 70 potentially benefitting from intensive treatment options including high dose chemotherapy with autologous stem cell rescue. Comprehensive geriatric assessment is indicated in the over 70s; this should be employable in a clinic outpatient setting to make it feasible. Outcomes of this assessment potentially help physicians' choice of therapy. For decades the combination of Melphalan and prednisolone was the standard of care for older MM patients. Over the last ten years, newer drugs and combinations have improved therapeutic options for patients but are yet to demonstrate vast improvement in overall survival in this cohort.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Autografts; Bone Density Conservation Agents; Bortezomib; Comorbidity; Cyclophosphamide; Dexamethasone; Diphosphonates; Fractures, Compression; Geriatric Assessment; Humans; Lenalidomide; Melphalan; Multiple Myeloma; Palliative Care; Stem Cell Transplantation; Thalidomide; Vertebroplasty

Topics: Dexamethasone; Humans; Melphalan; Multiple Myeloma; Recurrence; Thalidomide

The availability of novel drugs with different and innovative mechanisms of action such as proteasome inhibitors such as bortezomib and immunomdulatory agents as thalidomide and lenalidomide have changed the landscape of the treatment of patients with newly diagnosed multiple myeloma, allowing the development of several new therapeutic regimens both for transplant-eligible and -ineligible patients. Among these new agents, lenalidomide has become one of the most commonly used in these patients. In this article, we review the current state-of-the-art of different induction and maintenance lenalidomide-containing regimens administered in transplant-eligible and -ineligible patients with newly diagnosed multiple myeloma. We also discuss the safety profile and potential long-term side effects of this drug and analyze its utility in certain subgroups of patients like those with high-risk disease or different degrees of renal impairment.

Topics: Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Dexamethasone; Humans; Induction Chemotherapy; Lenalidomide; Maintenance Chemotherapy; Melphalan; Multiple Myeloma; Neoplasms, Second Primary; Prednisone; Renal Insufficiency; Risk Factors; Stem Cell Transplantation; Thalidomide

Lenalidomide (Revlimid(®)) is a second-generation immunomodulatory drug structurally related to thalidomide, with improved efficacy and tolerability, for which the label in the EU was recently expanded to include continuous therapy in patients with previously untreated multiple myeloma not eligible for stem-cell transplantation. In randomized, controlled clinical trials, continuous lenalidomide therapy, either in combination with dexamethasone (FIRST trial) or as maintenance monotherapy following induction with melphalan/prednisone/lenalidomide (MM-015 trial), significantly improved progression-free survival (PFS) compared with induction therapy alone (with non-lenalidomide- or lenalidomide-containing regimens) in patients with newly diagnosed multiple myeloma not eligible for stem-cell transplantation. The improvements in PFS with continuous lenalidomide were reflected in improved health-related quality-of-life measures. An overall survival benefit was observed in the FIRST trial, but not in the MM-015 trial. Continuous lenalidomide and continuous thalidomide regimens displayed similar efficacy, but lenalidomide was associated with significantly less toxicity than thalidomide. Continuous use of lenalidomide did not appear to negatively impact on the drug's tolerability and did not increase the incidence of neutropenia or second primary malignancy compared with shorter-term use. The incidence of most adverse events began to reduce after about 18 months of therapy. In conclusion, continuous lenalidomide regimens provide an effective longer-term treatment option in patients with newly diagnosed multiple myeloma ineligible for stem-cell transplantation.

Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Humans; Lenalidomide; Melphalan; Multiple Myeloma; Prednisone; Stem Cell Transplantation; Thalidomide; Treatment Outcome

The development of novel agents has markedly improved the prognosis of multiple myeloma(MM). However, salvage therapies for patients with MM that is refractory to novel agents and conventional chemotherapies have not been established. Herein, we describe successful treatments for such patients with the combination of clarithromycin, lenalidomide, and lowdose dexamethasone(BiRd)with or without melphalan and prednisolone(MP). Although its duration was relatively short, the remission is important in terms of the salvage strategy until the second generation of novel agents becomes available.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Clarithromycin; Dexamethasone; Female; Humans; Lenalidomide; Male; Melphalan; Multiple Myeloma; Prednisolone; Recurrence; Thalidomide

Multiple myeloma is the second most frequent haematological disease. The introduction of high-dose melphalan followed by autologous haematopoietic cell transplant (HDT/ASCT) for young patients and the availability of novel agents for young and elderly patients with multiple myeloma have dramatically changed the perspective of treatment. However, further research is necessary if we want to definitively cure the disease. Treatment goals for transplant-eligible and non-transplant-eligible patients should be to prolong survival by achieving the best possible response, while ensuring quality of life. The treatment should be individualized on the basis of host and disease features and better monitoring of the response upon use of high-sensitivity techniques for evaluating residual disease. For young patients, HDT/ASCT is a standard of care for treatment and its efficacy has been enhanced and challenged by the new drugs. For elderly patients, treatment options were limited to alkylators, but new upfront treatment combinations based on novel agents (proteasome inhibitors and immunomodulatory drugs) combined or not with alkylators have significantly improved outcomes.Extended treatment for young and elderly patients improves the quality and duration of clinical responses; however,the optimal scheme, appropriate doses and duration of long-term therapy have not yet been fully determined.This review summarises the progress in the treatment of patients with newly diagnosed multiple myeloma, addressing critical questions such as the optimal induction, early versus late ASCT, consolidation and/or maintenance for young patients, and how we can choose the best option for non-transplant-eligible patients.

Topics: Age Factors; Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Clinical Trials as Topic; Dexamethasone; Drug Administration Schedule; Hematopoietic Stem Cell Transplantation; Humans; Lenalidomide; Melphalan; Multiple Myeloma; Precision Medicine; Survival Analysis; Thalidomide; Transplantation Conditioning; Transplantation, Autologous

High-dose chemotherapy with melphalan followed by autologous haematopoietic cell transplantation (AHCT) is a standard of care in young patients (<65 years) with multiple myeloma. Most myeloma patients, however, are older than 65 years at the time of diagnosis, and the findings of numerous single-centre and registry studies provide evidence that AHCT can be a feasible and effective treatment option in these patients. Nevertheless, AHCT is not generally recommended as standard treatment in the elderly, due to the fact that a benefit of AHCT over conventional-dose therapy has not been demonstrated by prospective randomized trials. Yet, the use of AHCT has increased substantially in older patients in recent years, and an increasing number of reports suggest comparable outcomes for older and younger patients after AHCT. In this review we summarize the results of AHCT for elderly patients with multiple myeloma.

Topics: Adult; Age Factors; Age of Onset; Aged; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Comorbidity; Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Middle Aged; Multicenter Studies as Topic; Multiple Myeloma; Patient Selection; Prospective Studies; Randomized Controlled Trials as Topic; Registries; Retrospective Studies; Survival Analysis; Transplantation Conditioning; Transplantation, Autologous; Treatment Outcome

Despite many recent advances in the treatment of multiple myeloma, the course of the disease is characterized by a repeating pattern of periods of remission and relapse as patients cycle through the available treatment options. Evidence is mounting that long-term maintenance therapy may help suppress residual disease after definitive therapy, prolonging remission and delaying relapse. For patients undergoing autologous stem cell transplantation (ASCT), lenalidomide maintenance therapy has been shown to improve progression-free survival (PFS); however, it is still unclear whether this translates into extended overall survival (OS). For patients ineligible for ASCT, continuous therapy with lenalidomide and low-dose dexamethasone was shown to improve PFS and OS (interim analysis) compared with a standard, fixed-duration regimen of melphalan, prednisone, and thalidomide in a large phase 3 trial. Other trials have also investigated thalidomide and bortezomib maintenance for ASCT patients, and both agents have been evaluated as continuous therapy for those who are ASCT ineligible. However, some important questions regarding the optimal regimen and duration of therapy must be answered by prospective clinical trials before maintenance therapy, and continuous therapy should be considered routine practice. This article reviews the available data on the use of maintenance or continuous therapy strategies and highlights ongoing trials that will help to further define the role of these strategies in the management of patients with newly diagnosed multiple myeloma.

Topics: Clinical Trials, Phase III as Topic; Dexamethasone; Disease-Free Survival; Flow Cytometry; Hematology; Humans; Lenalidomide; Medical Oncology; Melphalan; Multiple Myeloma; Neoplasm Recurrence, Local; Prednisone; Remission Induction; Stem Cell Transplantation; Thalidomide; Transplantation, Autologous; Treatment Outcome

Lenalidomide has been linked to second primary malignancies in myeloma. We aimed to pool and analyse available data to compare the incidence of second primary malignancies in patients with and without lenalidomide exposure.. We identified relevant studies through a search of PubMed and abstracts from the American Society of Clinical Oncology, American Society of Hematology, and the International Myeloma Workshop. Randomised, controlled, phase 3 trials that recruited patients with newly diagnosed multiple myeloma between Jan 1, 2000, and Dec 15, 2012, and in which at least one group received lenalidomide were eligible for inclusion. We obtained individual patient data (age, sex, date of diagnosis, allocated treatment and received treatment, duration of treatment and cause of discontinuation, maintenance treatment, date of first relapse, date of second primary malignancy diagnosis, type of second primary malignancy, date of death or last contact, and cause of death) by direct collaboration with the principal investigators of eligible trials. Primary outcomes of interest were cumulative incidence of all second primary malignancies, solid second primary malignancies, and haematological second primary malignancies, and were analysed by a one-step meta-analysis.. We found nine eligible trials, of which seven had available data for 3254 patients. 3218 of these patients received treatment (2620 had received lenalidomide and 598 had not), and were included in our analyses. Cumulative incidences of all second primary malignancies at 5 years were 6·9% (95% CI 5·3-8·5) in patients who received lenalidomide and 4·8% (2·0-7·6) in those who did not (hazard ratio [HR] 1·55 [95% CI 1·03-2·34]; p=0·037). Cumulative 5-year incidences of solid second primary malignancies were 3·8% (95% CI 2·7-4·9) in patients who received lenalidomide and 3·4% (1·6-5·2) in those that did not (HR 1·1 [95% CI 0·62-2·00]; p=0·72), and of haematological second primary malignancies were 3·1% (95% CI 1·9-4·3) and 1·4% (0·0-3·6), respectively (HR 3·8 [95% CI 1·15-12·62]; p=0·029). Exposure to lenalidomide plus oral melphalan significantly increased haematological second primary malignancy risk versus melphalan alone (HR 4·86 [95% CI 2·79-8·46]; p<0·0001). Exposure to lenalidomide plus cyclophosphamide (HR 1·26 [95% CI 0·30-5·38]; p=0·75) or lenalidomide plus dexamethasone (HR 0·86 [95% CI 0·33-2·24]; p=0·76) did not increase haematological second primary malignancy risk versus melphalan alone.. Patients with newly diagnosed myeloma who received lenalidomide had an increased risk of developing haematological second primary malignancies, driven mainly by treatment strategies that included a combination of lenalidomide and oral melphalan. These results suggest that alternatives, such as cyclophosphamide or alkylating-free combinations, should be considered instead of oral melphalan in combination with lenalidomide for myeloma.. Celgene Corporation.

Topics: Angiogenesis Inhibitors; Humans; Lenalidomide; Melphalan; Multiple Myeloma; Neoplasms, Second Primary; Thalidomide

Drug resistance in cancer refers to recurrent or primary refractory disease following drug therapy. At the cellular level, it is a consequence of molecular functions that ultimately enable the cell to resist cell death-one of the classical hallmarks of cancer. Thus, drug resistance is a fundamental aspect of the cancer cell phenotype, in parallel with sustained proliferation, immortality, angiogenesis, invasion, and metastasis. Here we present a preclinical model of human B-cell cancer cell lines used to identify genes involved in specific drug resistance. This process includes a standardized technical setup for specific drug screening, analysis of global gene expression, and the statistical considerations required to develop resistance gene signatures. The state of the art is illustrated by the first-step classical drug screen (including the CD20 antibody rituximab, the DNA intercalating topoisomerase II inhibitor doxorubicin, the mitotic inhibitor vincristine, and the alkylating agents cyclophosphamide and melphalan) along with the generation of gene lists predicting the chemotherapeutic outcome as validated retrospectively in clinical trial datasets. This B-cell lineage-specific preclinical model will allow us to initiate a range of laboratory studies, with focus on specific gene functions involved in molecular resistance mechanisms.

Topics: Antibodies, Monoclonal, Murine-Derived; Antineoplastic Agents; B-Lymphocytes; Cell Line, Tumor; Cyclophosphamide; Doxorubicin; Drug Evaluation, Preclinical; Drug Resistance, Neoplasm; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Lymphoma, Large B-Cell, Diffuse; Melphalan; Models, Biological; Multiple Myeloma; Neoplasm Proteins; Rituximab; Vincristine

Of the 13 286 autologous haematopoietic cell transplant procedures reported in the US in 2010-2012 for plasma cell disorders, 10 557 used single agent, high-dose melphalan. Despite 30 years of clinical and pharmacokinetic (PK) experience with high-dose melphalan, and its continuing central role as cytoreductive therapy for large numbers of patients with myeloma, the pharmacodynamics and pharmacogenomics of melphalan are still in their infancy. The addition of protectant agents such as amifostine and palifermin allows dose escalation to 280 mg/m(2), but at these doses it is cardiac, rather than gut, toxicity that is dose-limiting. Although combination with additional alkylating agents is feasible, the additional TRM may not be justified when so many post-consolidation therapies are available for myeloma patients. Current research should optimise the delivery of this single-agent chemotherapy. This includes the use of newer formulations and real-time PKs. These strategies may allow a safe and effective platform for adding synergistic novel therapies and provide a window of lymphodepletion for the addition of immunotherapies.

Topics: Amifostine; Antineoplastic Agents, Alkylating; Fibroblast Growth Factor 7; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Melphalan; Multiple Myeloma; Neoplasms; Obesity; Reproducibility of Results

Considerable progress has been recently made in the treatment of elderly patients with multiple myeloma (MM). In Europe the combination of thalidomide with melphalan and prednisone and of bortezomib with melphalan and prednisone are 2 standards of care for frontline therapy for elderly patients. In United States the combination of lenalidomide and dexamethasone is the preferred option in this setting. This article focuses on more recent therapeutic approaches in older MM patients, not eligible for high-dose therapy and autologous stem cell transplantation.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Boronic Acids; Bortezomib; Dexamethasone; Humans; Lenalidomide; Melphalan; Multiple Myeloma; Prednisone; Pyrazines; Thalidomide

Topics: Antineoplastic Combined Chemotherapy Protocols; Autografts; Bendamustine Hydrochloride; Boronic Acids; Bortezomib; Combined Modality Therapy; Consolidation Chemotherapy; Cyclophosphamide; Dexamethasone; Drug Discovery; Hematopoietic Stem Cell Transplantation; Humans; Induction Chemotherapy; Lenalidomide; Maintenance Chemotherapy; Melphalan; Multiple Myeloma; Neoplasm, Residual; Nitrogen Mustard Compounds; Pyrazines; Remission Induction; Thalidomide; Transplantation Conditioning

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Autografts; Boronic Acids; Bortezomib; Clinical Trials as Topic; Contraindications; Cyclophosphamide; Dexamethasone; Drug Discovery; Hematopoietic Stem Cell Transplantation; Humans; Japan; Lenalidomide; Maintenance Chemotherapy; Melphalan; Multiple Myeloma; Practice Guidelines as Topic; Prednisone; Pyrazines; Risk Factors; Thalidomide

Autologous stem cell transplant (ASCT) remains an integral part of the treatment strategy for many myeloma patients. The role of allogeneic stem cell transplant continues to be defined. There is increasing evidence that posttransplant maintenance therapy can significantly improve outcomes. It is predicted that with more routine use of cytogenetic and gene expression profiling in the future, we will be better able to identify those subgroups of patients who are expected to benefit most from early versus late versus no ASCT and those who will benefit from allogeneic stem cell transplant.

Topics: Antineoplastic Agents, Alkylating; Combined Modality Therapy; Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Multiple Myeloma; Salvage Therapy; Survival Analysis; Transplantation, Autologous; Treatment Outcome

An eighty-one-year-old male with lower leg edema and proteinuria was diagnosed as having nephrotic syndrome and was hospitalized for a detailed examination. Kidney biopsy and immunostaining revealed nodular glomerulosclerosis and deposition of lambda chains, respectively. Because these findings indicate the occurrence of light chain deposition disease (LCDD), the underlying disease was found to be multiple myeloma BJ-lambda. After the administration of melphalan and prednisolone, followed by further addition of zoledronic acid, the patient's nephrosis remitted. However, renal dysfunction gradually deteriorated further and hemodialysis was instituted. He eventually died of gastrointestinal bleeding and biliary infection. The period of time from the initial diagnosis to death was thirty months. Autopsy revealed pervasive infiltration of plasma cells and light chain deposition in multiple organs. The uncontrollable gastrointestinal bleeding appears to have been caused by light chain deposition in the vascular walls of a bile duct. Although medical treatment for elderly LCDD cases depends on chemotherapy alone, it is difficult to obtain a complete remission with melphalan and prednisolone, according to the literature. Reports on the validities of biological agents, such as bortezomib, are beginning to appear, and accumulation of further therapeutic experience is eagerly awaited.

Topics: Aged, 80 and over; Autopsy; Humans; Immunoglobulin Light Chains; Kidney; Male; Melphalan; Microscopy, Electron; Multiple Myeloma; Nephrotic Syndrome; Prednisolone

The role of high-dose chemotherapy (HDC) followed by autologous-progenitor cell transplantation (auto-HPCT) in the treatment of multiple myeloma (MM) continues to evolve in the novel agent era. Administration of high-dose melphalan (HDM) is considered the standard conditioning regimen. Nevertheless, several attempts have recently been made to improve the conditioning phase of the HDC procedure.. We reviewed all the reported experiences and illustrated current knowledge in the field of conditioning regimens.. For fit MM patients, HDC followed by auto-HPCT remains the standard of care. The available data confirm that melphalan (MEL) 200 mg/m(2) should continue to be considered the gold standard conditioning regimen, with dose reduction based on age and renal function. Targeting exposure to MEL by using area under the curve is a particularly appealing approach that could be explored to maximize efficacy and minimize toxicity of this drug. Other strategies are currently being evaluated in different trials, and the most interesting areas of research involve the incorporation of newer agents like bortezomib (BOR) into conditioning regimens. Moreover, intravenous busulfan has become available and this formulation may reduce toxicity and result in greater efficacy in association with MEL-based conditioning.

Topics: Antineoplastic Agents, Alkylating; Hematopoietic Stem Cell Transplantation; Hematopoietic Stem Cells; Humans; Melphalan; Multiple Myeloma; Myeloablative Agonists; Transplantation Conditioning; Transplantation, Autologous

Multiple myeloma is a malignancy of B cells characterized by accumulation of abnormal plasma cells in the bone marrow. In the past 20 years, the use of high-dose therapies and novel agents has resulted in significant and meaningful improvements in survival. Autologous stem cell transplantation (auto-SCT) following a high-dose melphalan-conditioning regimen represents the standard of care for younger patients as well as older patients with a good performance status. A number of strategies have been proposed to improve the outcome of auto-SCTs, including the incorporation of new agents such as thalidomide, lenalidomide, and bortezomib into the induction regimen administered before auto-SCT; the administration of maintenance therapy after auto-SCT; the incorporation of novel agents into chemotherapeutic regimens after transplantation as consolidation therapy; and the use of reduced-intensity allogeneic transplantation after an initial autograft. Although these approaches have demonstrated some success in improving responses after auto-SCT, none of these strategies are curative. An additional strategy to improve outcomes after auto-SCT is to enhance the immediate pretransplant conditioning regimens by either increasing the dose of melphalan or by incorporating novel agents, such as busulfan. This literature review focuses on the efficacy and safety of busulfan-based conditioning regimens for auto-SCT in patients with multiple myeloma.

Topics: Antineoplastic Combined Chemotherapy Protocols; Autografts; Busulfan; Humans; Melphalan; Multiple Myeloma; PubMed; Stem Cell Transplantation; Transplantation Conditioning; Treatment Outcome

There have been major advances in the past decade in the continuum of therapy for transplantation-eligible multiple myeloma patients. For patients requiring therapy, recommended induction treatment consists of triple drug regimens followed by the collection of hematopoietic stem cells. The question of early versus delayed transplantation is under investigation and may identify patients for whom early transplantation is optimal therapy and those for whom it may be delayed. For transplantation-eligible patients, high-dose melphalan remains the standard regimen. After transplantation, consolidation can be considered for patients with less than a complete remission. Maintenance therapy with bortezomib or lenalidomide (or both in very-high-risk patients) is a reasonable option for long-term disease control and improvement in overall survival. Incorporation of new agents into the continuum of multiple myeloma care should result in improved outcomes and long-term disease control.

Topics: Angiogenesis Inhibitors; Autografts; Boronic Acids; Bortezomib; Hematopoietic Stem Cell Transplantation; Humans; Lenalidomide; Melphalan; Multiple Myeloma; Myeloablative Agonists; Pyrazines; Remission Induction; Thalidomide; Time Factors; Transplantation Conditioning

Multiple myeloma (MM) is an ancient disease, but until the alkylating agent melphalan was found to have anti-myeloma properties in the 1950s there was virtually no effective therapy. By the late 1960s, extended dosing with melphalan and prednisone tripled survival from diagnosis and became the standard of care for newly diagnosed MM. "Maintenance therapy" to prolong survival through sustained disease control following induction chemotherapy was sought by 1970, but early strategies were ineffective and toxic. Subsequent applications of high-dose therapy (HDT)/autologous stem cell transplant (ASCT) changed the treatment paradigm for MM from extended dosing to an intensive strategy designed to eradicate the malignant cells in a single course of treatment. Although HDT-ASCT resulted in prolonged duration of remission and improved survival, the vast majority of patients still relapsed. Interferon (IFN) and glucocorticoid maintenance therapies demonstrated marginal improvements in outcomes but significant adverse effects. Novel agents introduced over the last decade have prolonged survival when given for maintenance following HDT-ASCT, but have also challenged the HDT-ASCT paradigm by achieving comparable remission rates when used alone as extended frontline therapy. This article reviews the evolution of therapeutic strategies for MM and discusses future questions facing MM investigators.

Topics: Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Glucocorticoids; Humans; Interferons; Melphalan; Multiple Myeloma; Prednisone; Stem Cell Transplantation; Transplantation, Autologous

Melphalan remains the most widely used agent in preparative regimens for hematopoietic stem cell transplantation (SCT). From its initial discovery more than 50 years ago, it has been gradually incorporated in the conditioning regimens for both autologous and allogeneic transplantations because of its myeloablative properties and broad antitumor effects as a DNA alkylating agent. Melphalan remains the mainstay conditioning for multiple myeloma and lymphomas, and it has been used successfully in preparative regimens of a variety of other hematological and nonhematological malignancies. The addition of newer agents to conditioning, such as bortezomib or lenalidomide for myeloma or clofarabine for myeloid malignancies, may improve antitumor effects for transplantation, whereas melphalan in combination with alemtuzumab may represent a backbone for future cellular therapy because of reliable engraftment and low toxicity profile. This review summarizes the development and the current use of this remarkable drug in hematopoietic SCT.

Topics: Adenine Nucleotides; Alemtuzumab; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Arabinonucleosides; Boronic Acids; Bortezomib; Clofarabine; Graft Survival; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Lenalidomide; Melphalan; Multiple Myeloma; Myeloablative Agonists; Pyrazines; Thalidomide; Transplantation Conditioning; Transplantation, Autologous; Transplantation, Homologous

This is a review regarding the current therapeutic strategies in the management of multiple myeloma. Due to the introduction of several new effective therapeutic agents, multiple myeloma is one of the most active and changing fields in clinical oncology. Multiple myeloma is caused by the expansion of monoclonal plasma cells and secretion of M-protein (immunoglobulins, Bence Jones protein and free light chain). High-dose chemotherapy supported with autologous peripheral blood stem cells is an effective treatment for the disease. However, multiple myelomas are still difficult to cure and require long-term disease control. In recent years, the introduction of novel drugs (bortezomib, lenalidomide and thalidomide) has improved treatment.

Topics: Age Factors; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bone and Bones; Bone Density Conservation Agents; Boronic Acids; Bortezomib; Clinical Trials as Topic; Creatinine; Cyclophosphamide; Denosumab; Dexamethasone; Diphosphonates; Doxorubicin; Hematopoietic Stem Cell Transplantation; Humans; Imidazoles; Immunoglobulins; Kidney; Lenalidomide; Leukemia, Myeloid, Acute; Maintenance Chemotherapy; Melphalan; Molecular Targeted Therapy; Multiple Myeloma; Neoplasms, Second Primary; Precision Medicine; Prednisolone; Pyrazines; Quality of Life; Recurrence; Remission Induction; Survival Rate; Thalidomide; Zoledronic Acid

Treatment options for patients with newly diagnosed myeloma have evolved significantly over the past 10 years. Although response rates after induction for older or younger patients were limited, with few patients achieving complete remission, more recent combinations have cleared the way for major response and even complete remissions after induction therapy. As a consequence of these changes, patients are now achieving more durable and longer remissions, which have ultimately improved overall survival for patients with myeloma. The age-appropriate use of induction therapy, autologous transplant, and maintenance therapy, all keeping in mind the specific genetic risk group of a given patient, requires a long-term treatment plan for each patient defined early in the treatment course.

Topics: Antineoplastic Combined Chemotherapy Protocols; Boronic Acids; Bortezomib; Cyclophosphamide; Dexamethasone; Doxorubicin; Hematopoietic Stem Cell Transplantation; Humans; Induction Chemotherapy; Lenalidomide; Maintenance Chemotherapy; Melphalan; Multiple Myeloma; Prednisone; Pyrazines; Thalidomide; Transplantation, Autologous; Transplantation, Homologous

Many advances were made in the treatment of multiple myeloma since the introduction of the immunomodulatory drugs thalidomide and lenalidomide and the proteasome inhibitor bortezomib. An increasing number of clinical trials have examined consolidation/maintenance therapy as part of a sequential approach after induction therapy and demonstrated benefit in patients eligible and ineligible for transplantation. This outcome improvement reported with consolidation/maintenance therapy should be balanced against the toxicity profile, and prompt management of adverse events is necessary. This article provides an overview of the main trials including consolidation/maintenance therapy after induction for transplant-ineligible patients. Recommendations on how to manage treatment-related toxicities are also provided.

Topics: Antineoplastic Combined Chemotherapy Protocols; Boronic Acids; Bortezomib; Cyclophosphamide; Dexamethasone; Doxorubicin; Humans; Lenalidomide; Maintenance Chemotherapy; Melphalan; Multiple Myeloma; Prednisone; Pyrazines; Thalidomide; Vincristine

High-dose chemotherapy and autologous stem cell transplantation remains a standard procedure in relatively young and selected older patients with multiple myeloma. High-dose melphalan has remained the chemotherapeutic agent of choice based on earlier prospective randomized trials. Despite investigations involving different combinations of chemotherapeutics, radiation and novel agents with and without melphalan, none of these alternative preparative regimens have demonstrated superiority to high-dose melphalan used as a single agent in multiple published studies. In this article, we review the published literature regarding preparative regimens used in patients with multiple myeloma undergoing autologous stem cell transplantation.

Topics: Age Factors; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Multiple Myeloma; Randomized Controlled Trials as Topic; Transplantation, Autologous

Light-chain (AL) amyloidosis may present with features suggesting vasculitis, including giant-cell arteritis (GCA). We describe a case of an 80-year-old man, who initially presented with bilateral jaw claudication, bi-temporal headache and arthralgia, however a temporal-artery biopsy then revealed AL amyloidosis. A diagnosis of AL amyloidosis complicating multiple myelome simulates GCA and polymyalgia rheumatica was established. The patient was successfully treated with melphalan and dexamethasone: the free kappa light chains decreased, the patient's jaw claudication and headache disappeared. Then we discuss similarities between GCA and AL amyloidosis and potential confusion in diagnosis. We suggest that, in patients with clinical features of GCA without any temporal-artery typical findings, specimens are stained with Congo red, which then results in a different diagnosis and treatment.

Topics: Aged, 80 and over; Amyloid; Amyloidosis; Antineoplastic Agents; Biopsy; Comorbidity; Dexamethasone; Diagnosis, Differential; Giant Cell Arteritis; Humans; Male; Melphalan; Multiple Myeloma; Polymyalgia Rheumatica; Temporal Arteries; Treatment Outcome

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Boronic Acids; Bortezomib; Denosumab; Diphosphonates; Humans; Imidazoles; Melphalan; Multiple Myeloma; Peripheral Nervous System Diseases; Prednisolone; Pyrazines; Randomized Controlled Trials as Topic; Thalidomide; Zoledronic Acid

Immune thrombocytopenic purpura associated with multiple myeloma is extremely rare. Here, we present the successful management of an elderly Japanese patient with multiple myeloma complicated by immune thrombocytopenia with low dose cepharanthine - a plant derived alkaloid. A 78-year-old male patient with IgGκ multiple myeloma was repetitively treated with melpharan and prednisolone. In each chemotherapy course, we demonstrated a close relationship between platelet recovery and administration of high dose prednisolone. When further chemotherapy was avoided because of the patient's poor general condition, administration of cepharanthine was effective in halting progressive thrombocytopenia due to abnormal immune mechanisms. We propose the usefulness of cepharanthine in management of this rare disease.

Topics: Aged; Benzylisoquinolines; Humans; Immunoglobulin G; Male; Melphalan; Multiple Myeloma; Platelet Count; Prednisolone; Purpura, Thrombocytopenic, Idiopathic

Drug-induced liver injury (DILI) is a leading cause of liver failure and an important safety issue in drug development. Thalidomide is nowadays used for the treatment of several conditions including multiple myeloma (MM). Several adverse effects have been described but liver toxicity was seldom reported. We describe a case of thalidomide-induced hepatitis in a man treated for MM. The clinical setting and temporal association between the start of the drug and liver injury allowed the assumption of the causative role of thalidomide. As its clinical indications expand we wish to increase awareness of a new potential side effect of thalidomide. A short review on thalidomide-induced liver injury is also presented.

Topics: Acute Disease; Aged; Antineoplastic Combined Chemotherapy Protocols; Biopsy; Chemical and Drug Induced Liver Injury; Darbepoetin alfa; Diazepam; Erythropoietin; Fatal Outcome; Humans; Jaundice, Obstructive; Liver Function Tests; Male; Melphalan; Multiple Myeloma; Omeprazole; Pneumonia; Polypharmacy; Prednisolone; Thalidomide

Despite the curative potential of allogeneic hematopoietic stem cell transplantation (allo HSCT) for patients with multiple myeloma, and reduction of transplant-related mortality with nonmyeloablative transplant approaches, rates of acute and chronic graft-versus-host disease and disease progression remain high. It is unclear if nonmyeloablative transplants are more effective than autologous (auto). Novel promising drugs and maintenance treatment strategies following auto SCT may also delay allo transplantation. In this review, we summarize the emerging data on allo HSCT and provide suggestions for its optimal role in the treatment of myeloma.. Large cooperative group studies comparing allo HSCT with auto SCT as frontline therapy have been performed with reduced intensity conditioning regimens using unmanipulated peripheral blood stem cells from human leukocyte antigen (HLA)-compatible donors and standard calcineurin inhibitor graft-versus-host disease prophylaxis. Two recent reports show conflicting data. Although the Blood and Marrow Transplant Clinical Trials Network 0102 study demonstrated no progression-free or overall survival advantage at 3 years, a European study demonstrated superior 5-year outcome after auto/HLA-matched sibling allo HSCT compared with tandem auto SCT in previously untreated multiple myeloma patients. The advent of maintenance therapy could potentially improve outcomes of both transplant types.. High rates of acute and chronic graft-versus-host disease currently limit the implementation of nonmyeloablative allo HSCT. Novel approaches are required so that patients with myeloma can undergo allo HSCT before resistance develops to standard drug combinations.

Topics: Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunotherapy; Melphalan; Multiple Myeloma; Myeloablative Agonists; Risk; Standard of Care; Transplantation, Homologous; Treatment Outcome

Multiple myeloma (MM) and AL amyloidosis are caused by the expansion of monoclonal plasma cells and secretion of dysproteinemia (Bence Jones protein and free light chain) and some patients require the hemodialysis. Myeloma kidney is mainly caused by the cast nephropathy of the distal tubuli, whereas, AL amyloid-protein is mainly deposited in glomeruli with massive fibrillar involvement. Therefore, almost MM patients presents a symptom of renal insufficiency, whereas, almost patients of AL amyloidosis present a nephrotic syndrome with severe hypoalbuminemia. These two diseases have some similar characteristics such as up-regulation of cyclin D1 gene by 11:14 chromosomal translocation. High-dose chemotherapy supported with autologous peripheral blood stem cells is effective for these two diseases. However, they are still difficult to be cured and require long-term disease control. In recent years, introduction of novel agents has changed their treatment strategies from the palliation therapy to the clinical cure.

Topics: Aged; Amyloidosis; Bence Jones Protein; Boronic Acids; Bortezomib; Cyclophosphamide; Dexamethasone; Humans; Immunoglobulin Light-chain Amyloidosis; Kidney; Lenalidomide; Melphalan; Methylprednisolone; Middle Aged; Multiple Myeloma; Neoplasms, Second Primary; Pyrazines; Renal Insufficiency; Thalidomide

The treatment of newly diagnosed multiple myeloma has evolved rapidly over the recent years. In younger patients, autologous stem cell transplantation (ASCT) is still considered the standard of care, but the availability of new effective drugs with novel mechanisms of action in the last decade has resulted in a new scenario that has caused the role of transplantation itself to be currently undergoing scrutiny.. Maintaining the response of first-line therapy is an important objective in multiple myeloma, where despite intensive therapy followed by ASCT the majority of patients will relapse. In this field, the recent results of different consolidation and maintenance therapies after transplant are very encouraging. These strategies have come to stay and will play an essential role in the next future to improve the prognosis of young patients with newly diagnosed multiple myeloma. Finally, new conditioning regimens will also be tested in the forthcoming years in an attempt to further improve posttransplant responses.. Multiple myeloma ASCT must be integrated within a more global therapeutic approach including new and more effective induction, consolidation, and maintenance approaches. Efforts aimed in the development of more effective and less toxic preparative regimens to further augment disease control are also warranted.

Topics: Antineoplastic Agents; Bone Marrow Transplantation; Clinical Trials as Topic; Consolidation Chemotherapy; Humans; Induction Chemotherapy; Maintenance Chemotherapy; Melphalan; Multiple Myeloma; Salvage Therapy; Transplantation, Autologous

The treatment of multiple myeloma is evolving rapidly. A plethora of doublet, triplet, and quadruplet combinations have been studied for the treatment of newly diagnosed myeloma. Although randomized trials have been conducted comparing older regimens such as melphalan-prednisone with newer regimens containing drugs such as thalidomide, lenalidomide, or bortezomib, there are few if any randomized trials that have compared modern combinations with each other. Even in the few trials that have done so, definitive overall survival or patient-reported quality-of-life differences have not been demonstrated. Therefore, there is marked heterogeneity in how newly diagnosed patients with myeloma are treated around the world. The choice of initial therapy is often dictated by availability of drugs, age and comorbidities of the patient, and assessment of prognosis and disease aggressiveness. This chapter reviews the current data on the most commonly used and tested doublet, triplet, and quadruplet combinations for the treatment of newly diagnosed myeloma and provides guidance on choosing the optimal initial treatment regimen.

Topics: Antineoplastic Combined Chemotherapy Protocols; Boronic Acids; Bortezomib; Clinical Trials as Topic; Drug Therapy; Humans; Lenalidomide; Medical Oncology; Melphalan; Models, Biological; Multiple Myeloma; Oligopeptides; Prednisone; Pyrazines; Risk; Thalidomide; Treatment Outcome

Multiple myeloma (MM) has been the most intractable hematological disease for many years. Recently, basic and clinical research has advanced remarkably and a new therapeutic strategy has been established. The introduction of high-dose melphalan with autologous stem-cell transplantation and the availability of molecular-targeted novel agents such as immunomodulatory drugs and proteasome inhibitors have dramatically changed the treatment strategies for MM. Achievement of a high response rate resulted in the extension of overall survival, but further research and the development of more multimodality therapeutic approaches is warranted to cure this disease.

Topics: Antineoplastic Agents, Alkylating; Disease Management; Drug Administration Schedule; Hematopoietic Stem Cell Transplantation; Humans; Immunologic Factors; Melphalan; Molecular Targeted Therapy; Multiple Myeloma; Proteasome Inhibitors; Survival Analysis; Transplantation, Autologous

Thalidomide (T) or bortezomib (B) in combination with melphalan plus prednisone (MP) is superior to MP as first line therapy for previously untreated myeloma. However, direct head-to-head comparison of Melphalan, Prednisone plus Bortezomib (MPB) versus Melphalan, Prednisone plus Thalidomide (MPT) is lacking. We performed an indirect meta-analysis to assess the treatment effects of MPB versus MPT via common comparator MP using the systematic review and meta-analytical techniques. A comprehensive literature search (MEDLINE and gray literature) was undertaken. Systematic review was performed as per the Cochrane Collaboration recommendations. Initial search yielded 1,013 citations, of which six randomized controlled trials (RCTs) enrolling 2,798 patients met the inclusion criteria. Comparison of MPT versus MP (five RCTs) showed no survival difference [hazard ratio (HR) 0.82, 95% confidence interval (CI) 0.64-1.05] but a statistically significant difference in event-free survival favoring MPT (HR 0.66, 95% CI 0.56-0.77) without excessive treatment-related mortality [risk ratio (RR) 1.11, 95% CI 0.64-1.92]. Comparison of MPB vs. MP (one RCT) showed a statistically significant benefit for survival (HR 0.65, 95% CI 0.51-0.84) and event-free survival (HR 0.48, 95% CI 0.37-0.63) without difference in treatment-related mortality (RR 0.42, 95% CI 0.11-1.63) with MPB. The indirect comparison of MPB versus MPT showed no difference between MPB versus MPT for all outcomes but a significant benefit for complete response (RR 2.34, 95% CI 1.12-4.90), and grade III/IV adverse events (RR 0.53, 95% CI 0.38-0.73) favoring MPB. There is an uncertainty about definitive superiority of one type of regimen over the other. Therefore, direct head-to-head comparison between these competing regimens is warranted.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Boronic Acids; Bortezomib; Disease-Free Survival; Female; Humans; Male; Melphalan; Multiple Myeloma; Prednisone; Pyrazines; Thalidomide

Trials comparing efficacy of melphalan prednisone (MP) with MP plus thalidomide in transplant ineligible, elderly patients with multiple myeloma have provided conflicting evidence. Although there is agreement regarding improved response rates (RRs) and higher toxicity with the addition of thalidomide to MP, the impact on progression free survival (PFS) and overall survival (OS) is less clear. We performed a meta-analysis comparing efficacy of melphalan, prednisone and thalidomide (MPT) and MP by pooling results on RR, PFS and OS reported in all the identified randomized controlled trials (RCTs) under a random effects model. Overall, six prospective RCTs, with data extractable from five published trials (n=1571) [corrected] were identified. The pooled odds ratio of responding to therapy with MPT vs MP was 3.39 (P<0.001, 95% CI: 2.24-5.12). The pooled hazard ratios for PFS and OS were and 0.68 (P<0.001; 95% CI: 0.55-0.82) and 0.80 (P=0.07; 95% CI: 0.63-1.02), respectively, in favor of MPT. The odds ratios for high grade peripheral neuropathy and deep venous thrombosis were 6.6 and 2.4, respectively, in favour of MP. There was significant heterogeneity among the RCTs. Our meta-analysis demonstrates that in previously untreated, transplant ineligible, elderly myeloma patients, the addition of T to MP results in significantly improved RR and PFS with a trend towards improvement in OS compared with MP alone, but at a cost of significantly greater toxicity.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Humans; Melphalan; Middle Aged; Multiple Myeloma; Prednisone; Randomized Controlled Trials as Topic; Survival Rate; Thalidomide; Transplants; Treatment Outcome

Melphalan plus prednisone (MP) has long been considered the gold-standard treatment for elderly patients with newly diagnosed myeloma, and it still forms the backbone for combinations based on novel agents. MP plus thalidomide (MPT), bortezomib (VMP), or lenalidomide (MPR), as induction plus maintenance, have proved to be superior to MP and are currently the treatment of choice for this population. Low-dose dexamethasone in combination with thalidomide and cyclophosphamide (CTDa) or with lenalidomide can be an alternative option for these patients. The benefit of these novel agents in terms of prolonged survival is accompanied by increases in treatment-related adverse events, however, which may be particularly pronounced in older individuals. In managing these patients, efficacy and toxicity should be balanced, and thus prophylactic measures to avoid adverse effects are mandatory. Moreover, reduced-intensity regimens are recommended for fragile or very elderly patients. Finally, the wide array of new treatment options will facilitate individualized treatment approaches, based on characteristics of the disease, patient comorbidities, and personal and social circumstances.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Boronic Acids; Bortezomib; Cyclophosphamide; Dexamethasone; Humans; Lenalidomide; Melphalan; Multiple Myeloma; Prednisone; Pyrazines; Thalidomide; Treatment Outcome

The current standard conditioning regimen before auto-SCT in patients with multiple myeloma is melphalan 200 mg/m(2). Several attempts have recently been made to improve this aspect of the high-dose therapy procedure. The scope of this review article is to summarize current knowledge on conditioning regimens in this setting.

Topics: Antineoplastic Agents, Alkylating; Humans; Melphalan; Multiple Myeloma; Stem Cell Transplantation; Transplantation Conditioning

Topics: Acute Kidney Injury; Antineoplastic Combined Chemotherapy Protocols; Boronic Acids; Bortezomib; Chronic Disease; Combined Modality Therapy; Dexamethasone; Down-Regulation; Doxorubicin; Hematopoietic Stem Cell Transplantation; Humans; Immunoglobulin lambda-Chains; Kidney Diseases; Male; Melphalan; Middle Aged; Multiple Myeloma; Myeloma Proteins; Pyrazines; Remission Induction; Renal Dialysis; Transplantation, Autologous

High dose therapy (HDT) with autologous stem cell transplantation (ASCT) is the standard of care for eligible newly diagnosed MM patients. Several randomized studies demonstrated a survival advantage for patients undergoing transplantation, compared with conventional chemotherapy. Introduction of new drugs in this setting have markedly increased survival rates within the last 10 years. Efforts to further improve response rates and survival in those patients are still needed, mainly by increasing the depth of tumor reduction and the duration of response through more effective induction, consolidation and maintenance therapies. Nevertheless, this approach is currently challenged by the promising results of long-term treatment with novel agents. Recent data suggest that the upfront combination of a proteasome inhibitor plus one immunomodulatory drug (IMiD) is highly effective. The most promising 3-drug association might be Bortezomib, Lenalidomide and dexamethasone (VRD). Adjunction of a 4th drug is not proven to be more efficient. Consolidation and maintenance therapies are emerging in all trials with great results. For elderly patients, or not eligible for ASCT, the introduction of novel agents has also changed the management of the disease. Melphalan-prednisone-thalidomide and bortezomib-melphalan-prednisone are the two standards of care. Current trials are challenging the role of alkylators in the frontline setting. Maintenance therapy is also undergoing evaluation.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Boronic Acids; Bortezomib; Dexamethasone; Dose-Response Relationship, Drug; Humans; Lenalidomide; Melphalan; Middle Aged; Multiple Myeloma; Prednisone; Pyrazines; Standard of Care; Stem Cell Transplantation; Thalidomide; Transplantation, Autologous; Treatment Outcome

Renal failure, mostly related to myeloma cast nephropathy (MCN), is a frequent complication of multiple myeloma (MM), which occurs in up to 50% of patients during the course of the disease. Persistent renal failure in MM is associated with poor survival. Treatment of MCN relies on urgent symptomatic measures (alkalinisation, rehydration, correction of hypercalcemia, and withdrawal of nephrotoxic drugs), with rapid introduction of chemotherapy to efficiently reduce the production of monoclonal light chains (LC). Recent studies suggest that, in patients with MM and severe renal failure due to MCN, rapid removal of circulating LC, through intensive hemodialysis sessions using a new generation high cut-off dialysis membrane, might result in dialysis withdrawal in most patients. If the development of intensive therapy and new efficient chemotherapy agents (thalidomide, bortezomib, lenalidomide) has transformed the care and prognosis of MM, the modalities and safety of these therapeutic regimens in patients with renal failure remain to be defined. The association of bortezomib with dexamethasone should be considered currently as first-line treatment in patients with MM and impaired renal function.

Topics: Angiogenesis Inhibitors; Antineoplastic Combined Chemotherapy Protocols; Boronic Acids; Bortezomib; Clinical Trials as Topic; Contraindications; Cyclophosphamide; Dexamethasone; Fluid Therapy; Humans; Hypercalcemia; Immunoglobulin Light Chains; Kidney Failure, Chronic; Lenalidomide; Melphalan; Multicenter Studies as Topic; Multiple Myeloma; Myeloma Proteins; Prospective Studies; Protease Inhibitors; Pyrazines; Randomized Controlled Trials as Topic; Renal Dialysis; Thalidomide

The role of thalidomide for previously untreated elderly patients with multiple myeloma remains unclear. Six randomized controlled trials, launched in or after 2000, compared melphalan and prednisone alone (MP) and with thalidomide (MPT). The effect on overall survival (OS) varied across trials. We carried out a meta-analysis of the 1685 individual patients in these trials. The primary endpoint was OS, and progression-free survival (PFS) and 1-year response rates were secondary endpoints. There was a highly significant benefit to OS from adding thalidomide to MP (hazard ratio = 0.83; 95% confidence interval 0.73-0.94, P = .004), representing increased median OS time of 6.6 months, from 32.7 months (MP) to 39.3 months (MPT). The thalidomide regimen was also associated with superior PFS (hazard ratio = 0.68, 95% confidence interval 0.61-0.76, P < .0001) and better 1-year response rates (partial response or better was 59% on MPT and 37% on MP). Although the trials differed in terms of patient baseline characteristics and thalidomide regimens, there was no evidence that treatment affected OS differently according to levels of the prognostic factors. We conclude that thalidomide added to MP improves OS and PFS in previously untreated elderly patients with multiple myeloma, extending the median survival time by on average 20%.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Cohort Studies; Female; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Neoadjuvant Therapy; Prednisone; Randomized Controlled Trials as Topic; Survival Analysis; Thalidomide

Multiple myeloma (MM) is the second most common haematological cancer in the UK. MM is not curable but can be treated with a combination of supportive measures and chemotherapy that aim to extend the duration and quality of survival. The majority of patients are not able to withstand intensive treatment, such as high-dose chemotherapy with autologous stem cell transplantation (SCT), and so they are offered single-agent or combination chemotherapy. Combination therapies typically include chemotherapy with an alkylating agent and a corticosteroid. More recently, combination therapies have incorporated drugs such as thalidomide (Thalidomide Celgene®, Celgene) and bortezomib (Velcade®, Janssen-Cilag).. To assess the clinical effectiveness and cost-effectiveness of bortezomib or thalidomide in combination chemotherapy regimens with an alkylating agent and a corticosteroid for the first-line treatment of MM.. Electronic bibliographic databases, including MEDLINE, EMBASE and The Cochrane Library, were searched from 1999 to 2009 for English-language articles. Bibliographies of articles, grey literature sources and manufacturers' submissions were also searched. Experts in the field were asked to identify additional published and unpublished references.. Titles and abstracts were screened for eligibility by two reviewers independently. The inclusion criteria specified in the protocol were applied to the full text of retrieved papers by one reviewer and checked independently by a second reviewer. Data extraction and quality assessment were undertaken by one reviewer and checked by a second reviewer. Differences in opinion were resolved through discussion at each stage. A cost-utility decision-analytic model was used to compare the cost-effectiveness estimates of bortezomib in combination with melphalan and prednisolone/prednisone (VMP), thalidomide in combination with cyclophosphamide and attenuated dexamethasone (CTDa), and thalidomide in combination with melphalan and prednisolone/prednisone (MPT) versus melphalan and prednisolone/prednisone (MP).. A total of 1436 records were screened and 40 references were retrieved for the systematic review of clinical effectiveness. Five randomised controlled trials (RCTs) met the inclusion criteria for the review: one RCT evaluated VMP, three evaluated MPT and one evaluated CTDa. The comparator in all of the included trials was MP. The review found that VMP and MPT can both be considered more clinically effective than MP for the first-line treatment of MM in people for whom high-dose therapy and SCT would not be appropriate. CTDa was more effective than MP in terms of complete response but data on survival outcomes did not meet the inclusion criteria. Cost-effectiveness analysis indicated that MPT has a greater probability of being cost-effective than either VMP or CTDa.. For most RCTs, details needed to judge study quality were incompletely reported. All studies stated that the analyses followed intention-to-treat principles but none adequately reported data censoring. Only one RCT contributed data on VMP and the published peer-reviewed follow-up data were immature. For MPT, overall survival data from two trials were eligible for inclusion but the doses of thalidomide differed between the trials and the treatment period was not reflective of current UK practice so the generalisability of the findings was uncertain. Two RCTs had a maintenance phase with thalidomide that did not meet the inclusion criteria so some of these results were not eligible for the review. Limited evidence on health-related quality of life (HRQoL) was provided by the single trial of VMP versus MP.. Service provision is unlikely to change greatly. As uncertainties remain, further research is needed regarding the use of bortezomib- and thalidomide-containing combination regimens. Head-to-head trials of bortezomib- and thalidomide-containing combination regimes are required, including assessments of patient HRQoL in response to treatment.. The National Institute for Health Research Health Technology Assessment programme.

Topics: Adrenal Cortex Hormones; Alkylating Agents; Antineoplastic Combined Chemotherapy Protocols; Boronic Acids; Bortezomib; Cost-Benefit Analysis; Cyclophosphamide; Humans; Immunosuppressive Agents; Melphalan; Multiple Myeloma; Pyrazines; Quality of Life; Quality-Adjusted Life Years; Randomized Controlled Trials as Topic; Survival Analysis; Thalidomide

The management of multiple myeloma has benefited substantially from the introduction of three new drugs, namely, the proteasome inhibitor bortezomib and the immunomodulators thalidomide and lenalidomide. These drugs were initially shown to improve the outcome of advanced myeloma and were subsequently found to transform the treatment of patients with previously untreated myeloma. Melphalan and prednisone combined with thalidomide or bortezomib is the new treatment of reference for patients who are elderly or ineligible for intensification. The introduction of these new drugs into induction regimens, intensified conditioning regimens, and posttransplantation regimens may improve overall survival among young patients by increasing the rate and quality of the treatment responses. Although myeloma remains incurable, prolonged survival is now a reasonable objective.

Topics: Boronic Acids; Bortezomib; Drug Therapy, Combination; Humans; Immunosuppressive Agents; Lenalidomide; Melphalan; Multiple Myeloma; Myeloablative Agonists; Neoplasm Staging; Prednisone; Protease Inhibitors; Pyrazines; Survival Rate; Thalidomide

Much progress has been made in the treatment of patients with multiple myeloma (MM). The introduction of new drugs such as thalidomide, bortezomib and lenalidomide has created more possibilities for patients than many years before. In addition, autologous peripheral blood stem cell transplantation after high-dose melphalan has become the standard of care for younger patients. Allogeneic stem cell transplantation is an experimental option for those younger patients with a human leucocyte antigen identical donor. Because of these rapid developments and many treatment options we need good quality clinical studies that can guide us in what to do in everyday practice. This review will focus on those studies that have changed the treatment guidelines for patients with MM.

Topics: Antineoplastic Agents; Antineoplastic Agents, Alkylating; Antineoplastic Agents, Hormonal; Boronic Acids; Bortezomib; Dexamethasone; Humans; Lenalidomide; Melphalan; Multiple Myeloma; Peripheral Blood Stem Cell Transplantation; Pyrazines; Recurrence; Thalidomide

A 67-year-old woman with refractory multiple myeloma was admitted to our hospital for salvage therapy. She developed fever several days after chemotherapy was initiated and complained of chest pain. Since abnormal electrocardiogram was demonstrated. Emergency coronary angiography was performed, but the coronary artery did not demonstrate stenosis. Thereafter, the patient was diagnosed as having takotsubo cardiomyopathy. Hydragogue and nitric acid preparation transiently improved chest symptoms, but high fever persisted despite antibiotic and antifungal agents. She died on the 9th day after the initiation of chemotherapy. Physicians need to be aware that cardiomyopathy may develop as a severe side effect of chemotherapy.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Doxorubicin; Fatal Outcome; Female; Humans; Melphalan; Multiple Myeloma; Prednisolone; Salvage Therapy; Takotsubo Cardiomyopathy; Vincristine

Renal impairment is a common complication of multiple myeloma (MM). The estimated glomerular filtration rate (eGFR) using the Modification of Diet in Renal Disease formula is the recommended method for the assessment of renal function in patients with MM with stabilized serum creatinine. In acute renal injury, the RIFLE (risk, injury, failure, loss and end-stage kidney disease) and Acute Renal Injury Network criteria seem to be appropriate to define the severity of renal impairment. Novel criteria based on eGFR measurements are recommended for the definition of the reversibility of renal impairment. Rapid intervention to reverse renal dysfunction is critical for the management of these patients, especially for those with light chain cast nephropathy. Bortezomib with high-dose dexamethasone is considered as the treatment of choice for such patients. There is limited experience with thalidomide in patients with myeloma with renal impairment. Thus, thalidomide can be carefully administered, mainly in the context of well-designed clinical trials, to evaluate if it can improve the rapidity and probability of response that is produced by the combination with bortezomib and high-dose dexamethasone. Lenalidomide is effective in this setting and can reverse renal insufficiency in a significant subset of patients, when it is given at reduced doses, according to renal function. The role of plasma exchange in patients with suspected light chain cast nephropathy and renal impairment is controversial. High-dose melphalan (140 mg/m(2)) and autologous stem-cell transplantation should be limited to younger patients with chemosensitive disease.

Topics: Boronic Acids; Bortezomib; Glomerular Filtration Rate; Hematopoietic Stem Cell Transplantation; Humans; Incidence; Melphalan; Multiple Myeloma; Prognosis; Pyrazines; Renal Insufficiency; Thalidomide; Transplantation, Autologous

Until recently, standard treatment of multiple myeloma (MM) in elderly patients who were not candidates for autologous stem cell transplantation was with the combination of melphalan plus prednisone (MP). Novel agents (thalidomide, lenalidomide, bortezomib) are dramatically changing frontline therapy of MM. Randomized studies have shown the superiority of adding one novel agent to MP, either thalidomide (MPT) or bortezomib (MPV). The combination of lenalidomide with low doses of dexamethasone is another attractive alternative. Recent results show that maintenance therapy with low-dose lenalidomide may prolong progression-free survival. The objective of these improved treatment regimens should be to achieve complete response, as in younger patients. However, toxicity is a significant concern, and doses of thalidomide and of myelotoxic agents should be reduced in patients who are older than 75 years or who have poor performance status. Weekly bortezomib appears to induce severe peripheral neuropathy less frequently than the same agent administered twice weekly. Autologous stem cell transplantation is feasible in selected fit patients over 65 years of age, and its results are improved by the addition of novel agents before and after high-dose therapy. However, considering the progress in non-intensive therapy, autologous transplantation should not currently be offered to elderly patients outside of a clinical trial.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Multiple Myeloma; Prednisone; Thalidomide; Transplantation, Autologous

To review the clinical trials that have impacted treatment standards of multiple myeloma (MM).. A PubMed search (1980-June 2008) restricted to English-language publications was conducted using the key words multiple myeloma, clinical trials, targeted therapy, thalidomide, lenalidomide, bortezomib, dexamethasone, melphalan, autologous stem-cell transplantation, and tumor biology. Abstracts emanating from the meetings of the American Society of Clinical Oncology and American Society of Hematology from June 2002 to June 2008 were also reviewed.. Although hematopoietic stem-cell transplantation has improved the response rate and duration of overall survival, MM remains an incurable disease. However, focused research aimed at the molecular basis of the disease has led to a number of new treatment strategies. Evidence from clinical trials indicates that each of the 3 novel agents, thalidomide, lenalidomide, and bortezomib, is remarkably effective as first-line therapy. The data also suggest that clinicians may need to reevaluate the role of stem-cell transplantation in the disease.. Thalidomide, lenalidomide, or bortezomib in combination with dexamethasone have replaced traditional chemotherapy such as melphalan, doxorubicin, and vincristine as initial therapy of patients with MM who are eligible for stem-cell transplantation. Furthermore, these novel drugs can be incorporated into regimens used to treat transplant-ineligible patients or those with relapsing disease.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Boronic Acids; Bortezomib; Clinical Trials as Topic; Combined Modality Therapy; Dexamethasone; Drug Delivery Systems; Hematopoietic Stem Cell Transplantation; Humans; Lenalidomide; Melphalan; Multiple Myeloma; Prednisolone; Pyrazines; Salvage Therapy; Thalidomide; Transplantation Conditioning

Topics: Antineoplastic Agents; Drug Resistance, Neoplasm; Hematopoietic Stem Cell Transplantation; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Practice Guidelines as Topic; Transplantation Conditioning; Transplantation, Autologous

Multiple myeloma is characterised by clonal proliferation of malignant plasma cells, and mounting evidence indicates that the bone marrow microenvironment of tumour cells has a pivotal role in myeloma pathogenesis. This knowledge has already expanded treatment options for patients with multiple myeloma. Prototypic drugs thalidomide, bortezomib, and lenalidomide have each been approved for the treatment of this disease by targeting both multiple myeloma cells and the bone marrow microenvironment. Although benefit was first shown in relapsed and refractory disease, improved overall response, duration of response, and progression-free and overall survival can be achieved when these drugs are part of first-line regimens. This treatment framework promises to improve outcome not only for patients with multiple myeloma, but also with other haematological malignancies and solid tumours.

Topics: Antineoplastic Agents; Boronic Acids; Bortezomib; Clinical Trials as Topic; Combined Modality Therapy; Genetic Predisposition to Disease; Humans; Lenalidomide; Melphalan; Multiple Myeloma; Neoplasm Staging; Protease Inhibitors; Pyrazines; Remission Induction; Stem Cell Transplantation; Survival Rate; Thalidomide; Treatment Outcome

Multiple myeloma (MM) is a neoplastic disorder affecting elderly people. The treatment for all patients with MM was, for about 40 years, based on the combination of melphalan plus prednisone, with a very low rate of complete remissions and a survival that remained unacceptably low (about 36 months). Diverse factors, including comorbidity, performance status, decreased physiologic reserve, and potential undertreatment, contribute to these poor outcomes. Recently, however, the reduced treatment-related morbidity and mortality associated with autologous stem-cell transplantation and the availability of effective new drugs with acceptable toxicity, such as thalidomide, lenalidomide and bortezomib, have greatly modified the traditional treatment paradigms in older patients with MM, challenging, in some cases, the definition of elderly and rapidly transforming the traditional palliative treatments to a new global therapeutic strategy, with the final objective of significantly improving the quality and the duration of life for elderly people with this disease. In this review, we report updated data for the front-line treatment of MM in the elderly population, examining the role of new drugs combined with melphalan or their incorporation within more complex combinations, including other so-called conventional drugs such as (pegylated)-doxorubicin, cyclophosphamide, and dexamethasone. We also assess the role of autologous and allogeneic stem-cell transplantation with adjusted conditioning regimens in selected elderly patients.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Humans; Melphalan; Multiple Myeloma; Quality of Life; Stem Cell Transplantation; Survival Rate; Transplantation Conditioning; Treatment Outcome

Topics: Antineoplastic Combined Chemotherapy Protocols; Boronic Acids; Bortezomib; Clinical Trials as Topic; Dexamethasone; Doxorubicin; Drug Discovery; Graft vs Tumor Effect; Hematopoietic Stem Cell Transplantation; Humans; Interferons; Melphalan; Multiple Myeloma; Prednisolone; Pyrazines; Thalidomide; Transplantation Conditioning; Transplantation, Autologous; Transplantation, Homologous; Vincristine

Topics: Antineoplastic Combined Chemotherapy Protocols; Boronic Acids; Bortezomib; Clinical Trials, Phase III as Topic; Dexamethasone; Diagnosis, Differential; Doxorubicin; Drug Discovery; Female; Humans; Lenalidomide; Male; Melphalan; Multiple Myeloma; Peripheral Blood Stem Cell Transplantation; Prednisolone; Pyrazines; Remission Induction; Salvage Therapy; Thalidomide; Vincristine

Light chain deposition disease (LCDD) damages most frequently kidneys, and less frequently other organs. The incidence of LCDD is lower than the incidence of AL-amyloidosis. Symmetric swelling of both legs was the first sign of nephrotic syndrome with renal insufficiency in our female patient. Renal biopsy specimen revealed the diagnosis of LCDD. Bone marrow biopsy contained 40% of plasma cells. Bone survey showed no osteolytic changes. These findings confirmed the diagnosis of multiple myeloma (MM) Durie Salmon stage IB with LCDD. The patient was initially treated with 4 cycles of VAD (vinkristine, adriamycine, dexamethasone) chemotherapy with no response. Followed collection of peripheral haematopoietic stem cells and later high dose chemotherapy with reduced dose of melphalan 140 mg/sqm and autologous peripheral haematopoietic stem cells transplantation. Melphalan dose was reduced because of renal insufficiency (serum creatinine 290 micromol/l) before application of conditioning regimen. High dose therapy was complicated by with deterioration of renal function, creatinine increased to 600 micromol/l. Worsening of renal function was most likely caused by nephrotoxicity of melphalan in nephrotic syndrome. This has been previously described in patients with AL-amyloidosis, and nephrotic syndrome who were treated with high dose melphalan. This phenomenon was entitled "post conditioning renal insufficiency". Hypoalbuminemia hypoproteinemia and reduced intravascular volume and renal damage caused by amyloid deposits as well as probably, amorphous non-amyloid deposits of monoclonal immunoglobulin are likely to have contributed to nephrotoxicity of the high dose of melphalan. However, worsening of renal insufficiency was facilitated by the mucositis-associated sepsis. Follow-up examination one month after high dose chemotherapy showed complete remission, that was confirmed by further examinations. In the course of the first year after high dose chemotherapy renal function gradually improved and nephrotic syndrome completely disappeared (complete kidney remission). Proteinuria declined to 2-3 g/24 hours and glomerular filtration slowly improved. Three years after high dose chemotherapy the patient is still in complete remission of multiple myeloma and free of nephrotic syndrome, with slightly increased creatinine (160 micromol/l) that, nevertheless, has had an improving tendency over last 3 years. The present case study illustrates accomplishment of complete ha

Topics: Adult; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Drug Resistance, Neoplasm; Female; Hematopoietic Stem Cell Transplantation; Humans; Immunoglobulin Light Chains; Kidney; Melphalan; Multiple Myeloma; Nephrotic Syndrome; Remission Induction; Transplantation, Autologous

Several intracytoplasmic morphological changes in the plasma cells of multiple myeloma have been described previously. However, Auer rod-like inclusions are rarely found in these types of cells. Here, we report a case of multiple myeloma with Auer rod-like, needle-shaped intracytoplasmic inclusions in plasma cells. A review of all published cases revealed that this phenomenon is exclusively found in myeloma with kappa-type paraprotein. The nature of these intracellular inclusions and the relationship to prognostic implications and concomitant illnesses are discussed.

Topics: Aged; Antineoplastic Agents, Alkylating; Bone Marrow Cells; Glucocorticoids; Hematologic Neoplasms; Humans; Inclusion Bodies; Male; Melphalan; Multiple Myeloma; Plasma Cells; Prednisolone; Prognosis

Until 2007, frontline chemotherapy with melphalan and prednisone (MP) was considered as the standard of care in the treatment of elderly patients with multiple myeloma (MM). Recently, several prospective randomized studies comparing MP with the same combination plus new agents such as thalidomide (MPT) or bortezomib (MPV) clearly showed that MPT and MPV were superior to MP in terms of progression-free and overall survival. Melphalan-prednisone-lenalidomide (MPR) is currently compared to MP in one prospective trial and will also probably be superior to MP. Lenalidomide plus low-dose dexamethasone is a promising combination. Thus, at least four highly active new treatment options are now available to treat elderly patients with MM. The goal of future trials will be to determine the best treatment strategy in this group of patients.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Boronic Acids; Bortezomib; Dexamethasone; Disease-Free Survival; Female; Health Services for the Aged; Humans; Lenalidomide; Male; Melphalan; Multiple Myeloma; Prednisone; Pyrazines; Survival Rate; Thalidomide

Topics: Antineoplastic Combined Chemotherapy Protocols; Bone Density Conservation Agents; Boronic Acids; Bortezomib; Combined Modality Therapy; Diphosphonates; Immunologic Factors; Japan; Melphalan; Multiple Myeloma; Peripheral Blood Stem Cell Transplantation; Pyrazines; Recurrence; Thalidomide; Time Factors; Transplantation, Autologous

To summarize the results of treatment of multiple myeloma in the era of novel agents.. Recent publications comparing autologous stem cell transplantation (ASCT) with conventional chemotherapy in the era of 'old' drugs have shown that the contribution of ASCT in the treatment of multiple myeloma has been modest. Five trials comparing single vs. double ASCT showed an increased progression-free survival in three of them, whereas the overall survival was significantly prolonged in one. The benefit would be only for patients failing to achieve very good partial response with the first transplant. The results of allogeneic transplantation with reduced-intensity conditioning, particularly after debulking with an ASCT, are encouraging. On the contrary, the impact of pretransplant induction regimens with novel agents (thalidomide, bortezomib and lenalidomide) on the posttransplant outcome is being investigated in several large phase III trials. For elderly patients, the combination of 'old' therapies with thalidomide, bortezomib or lenalidomide has resulted in the melphalan-prednisone-thalidomide, melphalan-prednisone-Velcade, melphalan-prednisone-Revlimid and lenalidomide/dexamethasone regimens, which are highly effective.. ASCT has resulted in a modest contribution in the treatment of multiple myeloma. Hopefully, its impact will be increased with the incorporation of novel agents in the pretransplant induction regimens. The combination of thalidomide, bortezomib or lenalidomide with melphalan-prednisone or with dexamethasone has resulted in highly effective regimens for patients not eligible for high-dose therapy/stem cell transplantation.

Topics: Antineoplastic Combined Chemotherapy Protocols; Boronic Acids; Bortezomib; Dexamethasone; Disease-Free Survival; Humans; Lenalidomide; Medical Oncology; Melphalan; Multiple Myeloma; Prednisone; Pyrazines; Stem Cell Transplantation; Thalidomide; Transplantation, Homologous; Treatment Outcome

Thalidomide represents one of the most relevant therapeutic advances for patients with multiple myeloma over the last 10 years. Despite some toxicities, it has demonstrated significant efficacy in elderly patients, as well as in the setting of younger subjects receiving autologous stem cell transplantation. Here, we report and discuss the clinical results achieved with thalidomide alone or in combination with dexamethasone or other drugs, such as melphalan, cyclophosphamide, doxorubicin and bortezomib, in previously untreated myeloma patients.

Topics: Antineoplastic Agents; Clinical Trials as Topic; Dexamethasone; Drug Synergism; Drug Therapy, Combination; Humans; Melphalan; Multiple Myeloma; Thalidomide

Multiple mycloma causes a disproportionate amount of the malignancy-related renal insufficiency. Acute renal insufficiency in myeloma patients can occur due to dehydration, hypercalcemia, side effects of medications (NSAIDs) or tumor lysis syndrome in addition to cast nephropathy, amyloidosis and light chain deposition disease. Patients on hemodialysis have traditionally been excluded from antineoplastic therapy due to fear of side effects and lack of studies addressing benefit. Melphalan is the most effective chemotherapeutic agent in myeloma and its PK (pharmacokinetics) are not adversely affected by impaired renal function. Because of more pronounced toxicity of Melphalan 200 mg/m2 conditioning regimen, Melphalan 140 mg/m2 has become the standard of care. 24% of patients become dialysis-independent at a median of 4 months after autotransplantation. Favorable factors for becoming dialysis independent were duration of dialysis 10 ml/min. While no good data are available on the use of thalidomide in the presence of renal failure, it is our experience that severe neuropathy, constipation, lethargy and bradycardia are more frequent in patients with creatinine >or=3 mg/dl. It has become apparent that bisphosphanates-zoledronic acid more than pamidronate-cause renal dysfunction. If patients remain dialysis-dependent after autotransplantation, we recommend to delay considering a renal transplant until at least 3 years after the first transplant.

Topics: Antineoplastic Agents, Alkylating; Busulfan; Dose-Response Relationship, Drug; Humans; Kidney; Kidney Transplantation; Melphalan; Multiple Myeloma; Paraproteinemias; Renal Dialysis

Topics: Age Factors; Antineoplastic Agents, Alkylating; Boronic Acids; Bortezomib; Diphosphonates; Drug Design; Football; Humans; Immunosuppressive Agents; Melphalan; Multiple Myeloma; Prednisolone; Pyrazines; Randomized Controlled Trials as Topic; Reference Standards; Thalidomide

After decades of minimal progress, two new classes of drugs with novels mechanisms of action: immunomodulatory drugs (thalidomide and lenalidomide) and proteasome inhibitors (bortezomib) have shown great activity for the treatment of multiple myeloma.. Thalidomide acts by a variety of mechanisms; its efficacy is well known in disease relapse especially associated with dexamethasone. Recent results prove that combination of thalidomide with melphalan and prednisone should be considered as the first line standard of care in elderly patient. The main side effects are peripheral neuropathy and deep-vein thrombosis. Bortezomib is the first proteasome inhibitor. It is approved for the treatment in first disease relapse. The combination with glucocorticoids is synergistic. This combination in induction treatment before autologous stem cell transplantation is promising, as well as the combination with melphalan and prednisone in elderly patient. The main toxicities are fatigue and peripheral neuropathy. Lenalidomide is a structural analogue of thalidomide. Its efficacy in combination with dexamethasone has been proved in relapsing patients. The main toxicity is hematologic. Utilisation as first line treatment is also promising.. These three drugs have toxicities predictable and manageable and can be used successively or in combination for greater effectiveness. They have an impact on the multiple myeloma treatment strategies and on the disease course itself.

Topics: Antineoplastic Agents; Antineoplastic Agents, Alkylating; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Boronic Acids; Bortezomib; Humans; Immunosuppressive Agents; Lenalidomide; Melphalan; Multiple Myeloma; Protease Inhibitors; Pyrazines; Thalidomide

Multiple myeloma is a heterogeneous disease with complex genetics, including a variety of primary and secondary genetic events that contribute to disease pathogenesis. Good risk genetics include hyperdiploidy (approximately 40%) and cyclin D translocations (t[11;14] and t[6;14]; approximately 18%). Poor risk genetics include t(4;14), approximately 15%; MAF translocations (t[14;16]) and t[14;20]; approximately 8%); secondary genetic events such as deletion p53, and abnormal cytogenetics (deletion 13 or hypodiploidy). Proliferation is the other poor risk feature, as measured by either plasma cell labeling index, beta(2)-microglobulin, or gene expression profiling; it is identified in all genetic subtypes and not yet captured by any genetic marker. Altogether, approximately 75% of patients are good risk and if eligible, do well with high-dose melphalan and autologous stem cell transplantation. In contrast, about 25% of the patients have poor risk features and receive only transient benefit from this approach. We propose the Mayo Stratified Myeloma and Risk-Adapted Therapy. Stem cell transplantation is deferred in patients with high-risk molecular markers, and in all patients, response is followed closely and determines the individual timing and sequence of therapeutic regimens.

Topics: Biomarkers, Tumor; Cell Proliferation; Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Multiple Myeloma; Neoplasm Staging; Ploidies; Prognosis; Risk Factors; Transplantation, Autologous; Treatment Outcome

Melphalan is an alkylating agent approved for the treatment of multiple myeloma and ovarian cancer. The combination of oral melphalan and prednisone was first introduced in the 1960s and remains the standard therapy for elderly multiple myeloma patients. High-dose melphalan followed by autologous stem cell support became the standard treatment for younger patients since the 1990s. The occurrence of drug resistance is the major limiting factor for the long-term success of this therapy, and relapse always occurs. In recent years, advances in the understanding of the pathogenesis of myeloma and the mechanism of drug resistance have led to the development of novel targeted therapies that are able to overcome resistance and show additive or synergistic effects with melphalan. Thalidomide, its immunomodulatory derivative lenalidomide and the proteasome inhibitor bortezomib, in combination with oral melphalan in the elderly and with intravenous melphalan in younger patients, are changing the traditional treatment paradigm of multiple myeloma.

Topics: Antineoplastic Agents, Alkylating; Humans; Melphalan; Multiple Myeloma

Topics: Antibiotics, Antineoplastic; Antineoplastic Agents, Alkylating; Antineoplastic Agents, Hormonal; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Dexamethasone; Doxorubicin; Drug Therapy, Combination; Hematologic Neoplasms; Humans; Immunosuppressive Agents; Melphalan; Multiple Myeloma; Prednisone; Thalidomide; Treatment Outcome

The treatment of multiple myeloma has seen significant changes from the initial use of melphalan to the introduction of stem cell transplantation and, most recently, to the era of novel targeted agents. Melphalan still remains as a reference drug for combination regimens, including emerging newer therapeutic options, either used at a standard dose for initial or salvage treatments in patients who are not eligible for more intensive therapies, or in conjunction with new molecules within high-dose chemotherapy programs. In this review, the authors analyze old and novel regimens, including melphalan for the treatment of newly diagnosed or relapsed/resistant patients with multiple myeloma in the clinical settings of standard chemotherapy, as well as autologous or allogeneic stem cell transplantation.

Topics: Animals; Humans; Melphalan; Multiple Myeloma; Neoplasm Recurrence, Local

Many changes have been incorporated into the approach to multiple myeloma over the last few years, due to improvements in our understanding of the disease biology. New diagnostic and prognostic criteria from the International Myeloma Working Group have clarified the initial clinical approach to this disease. The prognostic impact of chromosomal abnormalities is now recognized, and the detection of specific abnormal cytogenetics is beginning to influence therapeutic decisions. The introduction of the novel agents thalidomide, bortezomib and lenalidomide has expanded treatment options at different points in the disease course; these agents are being evaluated in conjunction with conventional chemotherapy and stem cell transplantation. This report highlights some of the key recent findings in multiple myeloma, and describes areas for future research.

Topics: Aged; Antineoplastic Agents; Behavior Therapy; Dose-Response Relationship, Drug; Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Middle Aged; Multiple Myeloma; Myeloablative Agonists; Neoplasm Recurrence, Local; Transplantation, Autologous

The multiple myeloma (MM) has an incidence of 3-4/100,000 in the Caucasian population. MM has to be distinguished from smouldering MM and monoclonal gammopathy of uncertain significance (MGUS). In younger patients (<65 years) a good long-term remission is the aim of therapy, while in the elderly patients with comorbidities the aim is a good partial remission with good quality of life. In the elderly this can be achieved with a combination of melphalan and prednisone. High-dose chemotherapy, often as a tandem transplantation, is part of standard therapy of MM patients <65 years. However, allogeneic stem cell transplantation is the only curative approach. New substances approved for treatment of relapsed MM include bortezomib, thalidomide, and lenalidomide.

Topics: Antineoplastic Combined Chemotherapy Protocols; Boronic Acids; Bortezomib; Combined Modality Therapy; Diphosphonates; Dose-Response Relationship, Drug; Hematopoietic Stem Cell Transplantation; Humans; Lenalidomide; Melphalan; Multiple Myeloma; Neoplasm Staging; Prednisone; Pyrazines; Remission Induction; Thalidomide; Tumor Burden

High-dose chemotherapy (HDT) with autologous stem cell transplantation (ASCT) has been used in the treatment of multiple myeloma since the early 1980s. Its present position as the backbone of first-line treatment in patients up to 60 to 65 years of age is the result of several controlled randomized trials, where its superiority over standard chemotherapy has been demonstrated. However, the method is not considered to have curative potential, with the possible exception of a small proportion of about 5% to 10% of patients with very long-standing complete remissions (CRs) of more than 8 years. Over the years, there have been several attempts to improve the technique, where, for example, tandem transplants and post-transplant maintenance treatment have been successful, at least in certain subgroups of patients, while others, such as graft purging, have been of no value. Treatment results need further improvement, particularly in poor-prognosis disease--based on abnormal karyotype and high beta2-microglobulin--and the future will show if the introduction of novel drugs like bortezomib, thalidomide, and lenalidomide will lead to longer survival and prolongation of disease control in multiple myeloma.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Boronic Acids; Bortezomib; Combined Modality Therapy; Dose-Response Relationship, Drug; Feasibility Studies; Forecasting; Hematopoietic Stem Cell Transplantation; Humans; Life Tables; Melphalan; Middle Aged; Multiple Myeloma; Pyrazines; Randomized Controlled Trials as Topic; Registries; Survival Analysis; Transplantation Conditioning; Transplantation, Autologous; Treatment Outcome

Topics: Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Dexamethasone; Doxorubicin; Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Multiple Myeloma; Practice Guidelines as Topic; Prednisolone; Reference Standards; Salvage Therapy; Severity of Illness Index; Vincristine

Multiple myeloma accounts for approximately 1% of all new cancers and is characterized by abnormal plasma cell proliferation in the bone marrow. As a result, many patients develop bone lesions, hypercalcemia, anemia, and renal impairment. Although no cure exists for multiple myeloma, current treatments, such as oral melphalan and prednisone, can slow disease progression and prolong overall survival. Several new therapeutic options show promise: lenalidomide, thalidomide, liposomal doxorubicin, and bortezomib. Clinical research presented at the 2006 meeting of the American Society of Hematology, the 2007 meeting of the American Society of Clinical Oncology, and the 11th International Myeloma Workshop showed that newer therapeutic combinations were well tolerated and effective in patients with multiple myeloma. Oncology nurses, with their specialized knowledge of treatment administration and monitoring and their expertise in patient education, have an important role in the management of patients with multiple myeloma to help improve overall survival and quality of life. As newer regimens become available, oncology nurses must be aware of factors that optimize outcomes to help patients understand the benefits of treatment, how to manage side effects, and the importance of treatment adherence.

Topics: Anti-Inflammatory Agents; Antineoplastic Agents; Boronic Acids; Bortezomib; Diagnosis, Differential; Disease Progression; Doxorubicin; Drug Administration Schedule; Humans; Lenalidomide; Melphalan; Multiple Myeloma; Neoplasm Staging; Nurse's Role; Oncology Nursing; Patient Compliance; Patient Education as Topic; Practice Guidelines as Topic; Prednisone; Pyrazines; Quality of Life; Survival Rate; Thalidomide; Treatment Outcome

Renal involvement is common in multiple myeloma. Although several types of renal disease are observed, most of them are considered to be specifically related to monoclonal immunoglobulin light chains. Myeloma cast nephropathy is the most frequent and sometimes associated with acute renal failure. AL amyloidosis and monoclonal immunoglobulin deposit disease are often presented as a nephrotic syndrome. In this review, we describe the pathogenesis and diagnosis of these three renal diseases. We also focus on the treatment of renal disease in multiple myeloma, in the view points of the chemotherapy to reduce M-protein and the prevention to reduce the risks of promoting renal injury.

Topics: Amyloidosis; Biomarkers; Combined Modality Therapy; Dexamethasone; Hematopoietic Stem Cell Transplantation; Humans; Hypergammaglobulinemia; Immunoglobulin Light Chains; Kidney Diseases; Melphalan; Multiple Myeloma; Myeloma Proteins; Plasma Exchange; Prednisolone

The combination of the melphalan and prednisolone (MP) can induce objective responses in about 50% of patients with multiple myeloma (MM) since its introduction in 1960. Since then many combination chemotherapy regimens have been used, but a large metaanalysis showed that the combination of oral MP is as effective as combination regimens including intravenous drugs. In recent years, many novel agents (including bortezomib, thalidomide, and liposomal doxorubicin) have been developed for the MM treatment. More recently, MP has been used in combination with these novel agents. The combination treatment of MP and thalidomide, overall survival was significantly better than seen in the MP treatment. In the near future, primary induction therapy will be changed.

Topics: Antineoplastic Combined Chemotherapy Protocols; Boronic Acids; Bortezomib; Cyclophosphamide; Dexamethasone; Doxorubicin; Drug Administration Schedule; Humans; Melphalan; Meta-Analysis as Topic; Multiple Myeloma; Prednisolone; Pulse Therapy, Drug; Pyrazines; Thalidomide; Vincristine

The proteasome inhibitor bortezomib is approved for the treatment of patients with relapsed/refractory multiple myeloma. Botezomib represents a new generation of treatments for multiple myeloma that affects both specific intracellular signaling pathways and the tumor microenvironment. There is a growing body of clinical evidence showing its effectiveness alone and in combination not only in relapsed/refractory cases but also in the front line setting. Regimens incorporating bortezomib and other novel agents such as immunomodulatory derivatives of thalidomide together with commonly used conventional drugs show considerable high response rates including complete response that resulting in improving survival, with or without following stem cell transplantation. Thus these approaches represent a promising future direction in myeloma treatment.

Topics: Antineoplastic Combined Chemotherapy Protocols; Boronic Acids; Bortezomib; Clinical Trials as Topic; Doxorubicin; Humans; Liposomes; Melphalan; Multiple Myeloma; NF-kappa B; Protease Inhibitors; Proteasome Inhibitors; Pyrazines; Thalidomide

Melphalan-prednisone-thalidomide (MPT) currently appears to be the treatment of choice for a large proportion of elderly patients ineligible for autologous stem-cell transplantation (ASCT). It seems certain that in the near future melphalan-prednisone-Velcade (MPV) and melphalan-prednisone-lenalidomide (MPR) will also be proved superior to melphalan-prednisone (MP), thus providing three therapeutic options (MPT, MPV and MPR) in this patient group with multiple myeloma (MM). These therapeutic options could lead to more personalized treatment approaches, based on patient comorbidities, as the three novel therapies have somewhat different toxicity profiles. MP would be appropriate for only a minority of patients with poor performance status and/or significant comorbidities, such as severe neuropathy or a contraindication to anticoagulants. Questions regarding the relative efficacy of melphalan-based regimens versus dexamethasone-based regimens (preferably with low-dose dexamethasone) will require randomized phase-III trials. More intensive approaches with new drug combinations or with the incorporation of polyethylene glycolated (PEGylated) liposomal doxorubicin will also require additional studies. Additionally, the important issue of maintenance treatment needs to be further investigated, especially in elderly patients.

Topics: Age Factors; Aged; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials, Phase III as Topic; Humans; Melphalan; Multiple Myeloma; Prednisone; Remission Induction; Thalidomide

Multiple myeloma is a blood disease that is often easy to diagnose, relying on a combination of an excessive medullary plasmacytosis, a serum and/or urinary monoclonal immunoglobulin and one or several signs of organ involvement (anemia, renal failure, bone lesions, hypercalcaemia, infections). The beta2m, serum albumin, and certain chromosomal anomalies of the malignant clone are the essential prognostic factors. Intensive treatment with auto-transplantation of stem cells of peripheral blood is a significant development from which patients less than or equal to 65 years of age have benefited. The diphosphonates are combined with chemotherapy in order to limit the effect on bones, and recombinant erythropoietin is used in certain patients. Above all, therapeutic progress has been made thanks to thalidomide, bortezomib and lenalidomide, even if the optimal utilisation of these molecules is still to be determined.

Topics: Adrenal Cortex Hormones; Antineoplastic Combined Chemotherapy Protocols; Boronic Acids; Bortezomib; Cyclophosphamide; Humans; Lenalidomide; Melphalan; Multiple Myeloma; Prognosis; Pyrazines; Stem Cell Transplantation; Thalidomide; Transplantation, Autologous

Not all patients who fulfill the minimal criteria for diagnosis of multiple myeloma should be treated. If doubt exists about beginning therapy, one should wait and re-evaluate the patient in 2 or 3 months. There is no evidence that early treatment of multiple myeloma is advantageous. All patients should be considered possible candidates for an autologous stem cell transplantation. If they are deemed to be eligible, they should be treated for 3 to 4 months with therapy that does not damage the hematopoietic stem cells. Currently, most physicians use thalidomide plus dexamethasone or dexamethasone alone for induction. Vincristine, doxorubicin (Adriamycin), and dexamethasone (VAD) have been used in the past. Autologous stem cell transplantation prolongs disease-free survival and overall survival. The treatment-related mortality rate is 1% to 2%. Melphalan, 200 mg/m2, is the most widely used preparative regimen. Although allogeneic transplantation is attractive, the mortality rate (about 20%) is too high to recommend conventional allogeneic transplantation. Non-myeloablative transplantation is currently under investigation. If the patient is not a candidate for autologous stem cell transplantation, therapy with melphalan and prednisone is a good choice. Patients with relapsed or refractory disease may be treated with dexamethasone, thalidomide and dexamethasone, bortezomib (Velcade, PS-341), or lenalidomide (Revlimid, not yet approved by the Food and Drug Administration).

Topics: Angiogenesis Inhibitors; Antineoplastic Agents, Alkylating; Antineoplastic Agents, Hormonal; Boronic Acids; Bortezomib; Dexamethasone; Humans; Immunosuppressive Agents; Lenalidomide; Melphalan; Multiple Myeloma; Prednisone; Protease Inhibitors; Pyrazines; Stem Cell Transplantation; Thalidomide; Transplantation, Autologous

Topics: Antineoplastic Agents; Boronic Acids; Bortezomib; Drug Therapy, Combination; Hematopoietic Stem Cell Transplantation; Humans; Lenalidomide; Melphalan; Multiple Myeloma; Prednisolone; Pyrazines; Thalidomide

Cure for multiple myeloma is rare; the success of treatment is measured by response, and length of remissions and survival. Initial treatment for patients young and fit enough is high-dose chemotherapy with autologous stem cell transplantation. Various chemotherapy regimens are employed as initial therapy in patients who cannot withstand the autologous stem cell transplantation regimen, and for treatment of refractory or relapsed disease. Commonly used agents either alone or in combination have included dexamethasone, vincristine, doxorubicin, melphalan, cyclophosphamide, etoposide, cisplatin and, more recently, thalidomide. Within the past few years, the first-in-class proteasome inhibitor bortezomib has been introduced for the treatment of relapsed multiple myeloma with data demonstrating efficacy and safety. Throughout Europe, a faculty of experts conducted a series of debates with over 450 clinicians to discuss the efficacy of bortezomib vis-à-vis other available therapies. Of primary concern was the place of bortezomib in maximizing efficacy throughout the course of the disease and treatment by increasing response rates and improving duration of response, while maintaining an acceptable level of toxicity. The experts concluded that bortezomib, with its unique mechanism of action and demonstrated clinical efficacy and safety, should be considered as standard, early treatment in patients with relapsed multiple myeloma, especially after first relapse.

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Boronic Acids; Bortezomib; Dexamethasone; Doxorubicin; Drug Administration Schedule; Hemoglobins; Humans; Melphalan; Multiple Myeloma; Neoplasm Recurrence, Local; Pyrazines; Quality of Life; Thalidomide

Multiple myeloma (MM) remains an incurable disease for most patients, with a median survival of 4 to 5 years. High-dose chemotherapy followed by transplantation has resulted in improvement in response rates and survival compared with conventional therapy, but relapse is nearly universal and not all patients are candidates for this option of aggressive treatment. Standard therapeutic strategies for newly diagnosed patients not eligible for transplantation include pulsed high-dose dexamethasone, melphalan with prednisone, and vincristine in combination with doxorubicin and dexamethasone, as well as other combinations of alkylating agents. Emerging therapies under clinical investigation for first-line therapy include thalidomide, the thalidomide analog lenalidomide, and the proteasome inhibitor bortezomib alone and in combination with other agents, particularly dexamethasone. At an interim analysis, thalidomide combined with melphalan and prednisone was shown to induce a complete or near complete remission (CR) rate of 28% and overall (complete+partial) response rate of 77% in elderly patients generally not eligible for transplantation. These results are comparable to those obtained with high-dose therapy and may obviate transplantation in these patients. Induction therapy with bortezomib-based combinations induces complete and near complete remissions in a similar proportion of patients. These regimens include bortezomib and dexamethasone alone and in combination with doxorubicin, thalidomide, or melphalan. Use of thalidomide or bortezomib does not preclude stem cell harvest. Survival benefits need to be firmly established before these novel regimens emerge as the new standard of care for newly diagnosed disease. However, front-line treatment with combinations involving these agents is a promising strategy that may improve the standard of care for patients both eligible and ineligible for stem cell transplantation.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Boronic Acids; Bortezomib; Humans; Melphalan; Multiple Myeloma; Pyrazines; Salvage Therapy; Thalidomide

In most cases multiple myeloma is an incurable plasma cell malignancy. Despite the use of conventional therapy or high-dose chemotherapy with autologous stem cell transplantation (ASCT), patients continue to relapse at a constant rate. A small minority of patients are cured by allogeneic transplantation. Novel drugs targeting not only the myeloma cell but also its interactions with the malignant microenvironment have recently been used in patients with relapsed/refractory disease. So far, ASCT has been the treatment of choice for eligible myeloma patients. However, many questions regarding the management of myeloma patients remain unanswered. How safe is ASCT in elderly patients? Is there a role for non-myeloablative allogeneic transplantation in multiple myeloma? What is the role of novel agents, such as thalidomide, its analogues and bortezomib, in the treatment of newly diagnosed patients or as maintenance post-ASCT? This review summarises all available data for the current treatment options for myeloma providing a useful algorithm for its management.

Topics: Age Factors; Algorithms; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bone Density Conservation Agents; Boronic Acids; Bortezomib; Combined Modality Therapy; Diphosphonates; Doxorubicin; Humans; Melphalan; Multiple Myeloma; Osteolysis; Prednisolone; Pyrazines; Randomized Controlled Trials as Topic; Recurrence; Stem Cell Transplantation; Survival Analysis; Thalidomide; Transplantation, Autologous; Vincristine

Focal and segmental glomerulosclerosis (FSGS) is a common histological finding in patients with proteinuria. The natural history of the condition varies, and although it may be responsive to therapy, FSGS is an important cause of end-stage renal disease. FSGS can be caused by a variety of conditions, but it has been reported rarely in association with a plasma cell disorder.. Mayo Clinic databases were queried and cross-referenced for FSGS and plasma cell disorders. The diagnoses were confirmed, and relevant clinical and laboratory data were abstracted.. A cohort of 13 patients with "idiopathic" FSGS and a monoclonal plasma cell disorder were identified. Four patients had myeloma, and 9 patients had monoclonal gammopathy of undetermined significance. Patients treated for myeloma experienced improvement in their renal lesion, and the latter relapsed when the myeloma relapsed.. We show that FSGS and plasma cell disorders are temporally and epidemiologically linked. Therapy for the underlying plasma cell disorder can lead to resolution of FSGS. The emerging molecular pathogenesis of both FSGS and myeloma also provides potential mechanisms that link the 2 conditions together. Thus, physicians must rule out a plasma cell proliferative disorder in patients with FSGS before concluding that the renal lesion is idiopathic. Moreover, FSGS may respond favorably after the underlying plasma cell disorder is controlled.

Topics: Aged; Amyloidosis; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Biopsy; Cohort Studies; Combined Modality Therapy; Comorbidity; Cytokines; Databases, Factual; Dexamethasone; Female; Glomerulosclerosis, Focal Segmental; Humans; Immunoglobulin Light Chains; Kidney; Male; Melphalan; Metabolic Clearance Rate; Middle Aged; Multiple Myeloma; Myeloma Proteins; Paraneoplastic Syndromes; Paraproteinemias; Peripheral Blood Stem Cell Transplantation; Prednisone; Prevalence; Proteinuria; Recurrence; Remission Induction; Retrospective Studies; Time Factors; Vasculitis

Topics: Antineoplastic Agents, Alkylating; Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Multiple Myeloma; Transplantation Conditioning; Transplantation, Autologous; Transplants

Major advances have occurred in our understanding of the biology of multiple myeloma (MM) and in its treatment in the past decade. New diagnostic criteria have been developed, and an international Staging System has replaced the Durle-Salmon Staging System. It is now possible to classify MM as standard risk or high risk on the basis of specific Independent prognostic factors. The role of single and double autologous stem cell transplantation has been clarified by randomized trials. Most importantly, thalidomide, bortezomib, and lenalidomide have emerged as new active agents and are being incorporated rapidly into the treatment of both newly diagnosed and relapsed MM. The current approach to the diagnosis, prognosis, and management of MM is reviewed.

Topics: Algorithms; Anti-Inflammatory Agents; Antineoplastic Agents, Alkylating; Cyclophosphamide; Dexamethasone; Drug Therapy, Combination; Glucocorticoids; Humans; Melphalan; Multiple Myeloma; Prednisone; Prognosis; Retreatment; Stem Cell Transplantation; Thalidomide; Translocation, Genetic

In 2004, multiple myeloma was diagnosed in more than 15,000 people in the United States and will account for approximately 20% of deaths due to hematologic malignancies. Although traditional therapies such as melphalan (Alkeran)/prednisone, combination chemotherapy with VAD (vincristine, doxorubicin [Adriamycin], and dexamethasone), and high-dose chemotherapy with stem cell transplantation have shown some success, median survival remains between 3 to 5 years. Treatment options for patients with multiple myeloma have increased in recent years, with the promise of improvement in survival. New agents, such as the proteasome inhibitor bortezomib (Velcade), the antiangiogenic and immunomodulator thalidomide (Thalomid) and its analogs, such as lenalidomide (Revlimid), together with other small molecules, including arsenic trioxide (Trisenox), and other targeted therapies, have been studied alone and in combination with other antineoplastic therapies, either as induction therapy prior to stem cell transplantation or in patients with relapsed disease. Bortezomib recently was approved in the United States for the treatment of multiple myeloma in patients who have received at least one prior therapy. The use of bortezomib-based regimens as front-line therapy as well as the use of other agents in multiple myeloma remain under investigation, and approvals for both thalidomide and lenalidomide are hoped for soon, with the overall prospect of patient outcome continuing to be increasingly positive.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Arsenicals; Boronic Acids; Bortezomib; Clinical Trials as Topic; Dexamethasone; Humans; Lenalidomide; Melphalan; Multiple Myeloma; Oxides; Pyrazines; Thalidomide

Autologous peripheral blood stem cell (PBSC)-supported high-dose melphalan is now considered standard therapy for myeloma, at least for younger patients. The markedly reduced toxicity of allotransplants using nonmyeloablative regimens (mini-allotransplantations) may hold promise for more widely exploiting the well-documented graft-versus-myeloma (GVM) effect. New active drugs include immunomodulatory agents, such as thalidomide and CC-5013 (Revimid; Celgene, Warren, NJ), and the proteasome inhibitor, PS 341 (Velcade; Millenium, Cambridge, MA), all of which not only target myeloma cells directly but also exert an indirect effect by suppressing growth and survival signals elaborated by the bone marrow microenvironment's interaction with myeloma cells. Among the prognostic factors evaluated, cytogenetic abnormalities (CAs), which are present in one third of patients with newly diagnosed disease, identify a particularly poor prognosis subgroup with a median survival not exceeding 2 to 3 years. By contrast, in the absence of CAs, 4-year survival rates of 80% to 90% can be obtained with tandem autotransplantations. Fundamental and clinical research should, therefore, focus on the molecular and biologic mechanisms of treatment failure in the high-risk subgroup.

Topics: Amyloidosis; Antineoplastic Agents, Alkylating; Gene Expression Profiling; History, 20th Century; History, 21st Century; Humans; Immunotherapy; Melphalan; Multiple Myeloma; Peripheral Blood Stem Cell Transplantation; Prognosis; Renal Insufficiency; Salvage Therapy; Thalidomide; Transplantation, Autologous; Transplantation, Homologous

Multiple myeloma is a malignant disease of plasma cells that manifests as one or more of lytic bone lesions, monoclonal protein in the blood or urine, and disease in the bone marrow. Treatment for myeloma has changed beyond recognition in the past decade, and now includes state of the art supportive treatment and infusional chemotherapy courses, followed for younger patients by high-dose melphalan and an autologous transplant. Patients younger than 70 years can now expect a doubling of median survival to 5 years, a 20% chance of surviving longer than 10 years, and a 50% chance of attaining complete morphological and biochemical remission. Bisphosphonate control of bone disease is essential. Exploitation of the understanding of the biology of myeloma has led to the development of biological treatments, such as thalidomide, CC-5013, and bortezomib, which target the myeloma cell and the bone-marrow microenvironment, which plays a crucial part in the disease's pathogenesis. These treatments will hold the key to future success.

Topics: Aged; Antineoplastic Agents, Alkylating; Antineoplastic Agents, Hormonal; Dexamethasone; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Male; Melphalan; Multiple Myeloma; Self-Help Groups; Stem Cell Transplantation; Survival Analysis; Transplantation, Autologous

A 68-year-old man was diagnosed as having bronchial asthma in November 1996. He presented with leukocytosis in June 2002. The WBC count was 29,900/microliter with 82% mature neutrophils showing toxic granules. The neutrophil alkaline phosphatase score and serum level of vitamin B12 were elevated. Bone marrow demonstrated myeloid hyperplasia and plasmacytosis. Cytogenetic and molecular analyses were negative for Philadelphia chromosome and BCR/ABL fusion gene. Lambda-type Bence-Jones protein was detected on the serum and urinary immunoelectrophoresis. The coexistence of chronic neutrophilic leukemia and myeloma was suspected based on the clinical features. The serum level of granulocyte-colony stimulating factor (G-CSF) was elevated. Immunohistochemically, atypical plasma cells were positive for anti G-CSF antibody. Finally, we diagnosed this patient as having a G-CSF-producing myeloma. Treatment with melphalan and prednisolone was initiated without beneficial response. He was then admitted to our hospital for ROAD therapy (ranimustine, vincristine, melphalan, and dexamethasone). The neutrophil count decreased in parallel with the serum G-CSF level. These observations indicated that the neutrophilia in this case was probably caused by a reactive response to G-CSF secreted from the myeloma cells.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Diagnosis, Differential; Granulocyte Colony-Stimulating Factor; Humans; Leukemia, Neutrophilic, Chronic; Leukocytosis; Male; Melphalan; Multiple Myeloma; Neutrophils; Nitrosourea Compounds; Treatment Outcome; Vincristine

Topics: Antineoplastic Combined Chemotherapy Protocols; Boronic Acids; Bortezomib; Clinical Trials as Topic; Combined Modality Therapy; Dexamethasone; Hematopoietic Stem Cell Transplantation; Humans; Lenalidomide; Melphalan; Multiple Myeloma; Prednisone; Pyrazines; Remission Induction; Reoperation; Survival Rate; Thalidomide; Transplantation Conditioning; Transplantation, Autologous; Treatment Outcome

The treatment of Multiple Myeloma (MM), a malignant plasma cell disorder has changed considerably over the past decade. It has been convincingly shown that intensive treatment supported by autologous stem cell reinfusion is superior to conventional chemotherapy with alkylating agents or vincristine, doxorubicin and dexamethasone (VAD) alone in terms of a more rapid response and a longer disease-free survival. However, cure is not achieved in the majority of patients. Several trials have therefore focussed on repeated intensive treatments in order to improve the survival of these patients. Other approaches are aimed at identifying patients on the basis of prognostic factors, who may benefit from high-dose therapy. This review discusses the recent developments in intensive therapy for multiple myeloma.

Topics: Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials, Phase II as Topic; Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Multiple Myeloma; Randomized Controlled Trials as Topic; Recurrence

Since new treatments have recently been proposed for patients with multiple myeloma, the aim of this article is to review the main innovations in this therapeutic area and to examine the cost-effectiveness ratio. Innovative approaches include autologous transplantation and thalidomide, which are both utilised as induction or salvage treatments. According to a randomised trial conducted in 1996, the survival after autologous transplantation seems to be better than that following standard therapy; however, this result has not been confirmed by a recent study. Thalidomide has been found to be effective for relapsed or refractory myeloma and, more recently, also as induction therapy. Preliminary cost-effectiveness assessments about autologous transplantation and thalidomide have given promising results; yet one regulatory problem with thalidomide is that, both in Europe and in the US, the drug has not yet been approved for this indication.

Topics: Aged; Cost-Benefit Analysis; Drug Therapy; Economics, Pharmaceutical; Humans; Melphalan; Middle Aged; Multiple Myeloma; Prednisone; Salvage Therapy; Stem Cell Transplantation; Survival Rate; Thalidomide

We have done a systematic review of all randomised studies in myeloma, identified through a comprehensive search. Our aim was to investigate and critically examine the effects of various treatment modalities on outcome in patients with multiple myeloma and address 22 specific clinical questions in the management of this disease. As a result of our analysis we identified two therapeutic advances in the management of myeloma that, according to the evidence, are most important for improving outcome. These advances were: introduction of high dose chemotherapy, which appears to be superior to conventional chemotherapy, and the use of bisphosphonates, which decrease the probability of pathological vertebral fractures. However, the overall quality of the body of evidence for myeloma management was poor. Many trials were done with small sample sizes, and did not include reporting power analysis. The majority of studies had inadequate allocation concealment, and few were analysed according to intention to treat principle. We conclude that the quality of total evidence supporting treatment recommendations in myeloma is modest at best and has an ample scope for improvement.

Topics: Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Purging; Bone Marrow Transplantation; Boronic Acids; Bortezomib; Diphosphonates; Drug Administration Schedule; Epoetin Alfa; Erythropoietin; Hematinics; Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Multiple Myeloma; Neoplasm Staging; Pyrazines; Randomized Controlled Trials as Topic; Recombinant Proteins; Salvage Therapy; Survival Analysis; Time Factors; Transplantation Conditioning; Transplantation, Autologous; Transplantation, Homologous; Treatment Outcome

Topics: Amyloidosis; Antineoplastic Agents, Alkylating; Humans; Immunoglobulin Light Chains; Kidney Diseases; Melphalan; Multiple Myeloma; Paraproteinemias; Stem Cell Transplantation

Although multiple myeloma remains a terminal illness, the past four decades have seen a dramatic change in the outlook for a newly diagnosed patient in terms of therapies available, supportive care and insight into the pathogenesis of this disease. Among the newer agents available for treatment, thalidomide has been resurrected and discovered to be a valuable therapy for myeloma. Thalidomide appears to work, at least in part, through its anti-angiogenic properties, but much remains to be learned about its mechanism of action as well as optimal administration regimens. With the development of increasingly more potent bisphosphonates it has become possible to diminish the painful skeletal complications of myeloma, one of the most devastating problems of this disease. The most recent generation of bisphosphonates, pamidronic acid and zoledronic acid, have provided a statistically significant decrease in the skeletal complications of myeloma when used in a prophylactic manner. These agents appear to work by inhibiting osteoclast function. Progressive improvement in cytogenetic techniques has now demonstrated that almost all patients with myeloma have chromosomal abnormalities, some of which appear to confer varying degrees of prognostic significance. In particular, the changes in chromosome 13 are associated with an unusually poor outcome. These findings are serving as a guide toward learning more about the pathogenesis of myeloma as well as in identifying potential targets for therapy. Stem cell transplantation has emerged as the standard treatment for the large majority of patients with myeloma following the demonstration of superior complete remission and survival, both disease-free and overall, in a French randomised trial. Unfortunately, virtually all patients will eventually relapse following autologous stem cell transplantation, prompting continuing efforts such as tandem transplants, CD34+ selection, as well as modifications in the conditioning regimen to improve outcomes. Allogeneic bone marrow transplants appear to offer a better chance for a possible cure of myeloma but have been associated with an unusually high mortality. However, this approach is being revived with the advent of the less toxic non-myeloablative transplant that has provided an 81% short-term survival in a trial combining this approach with an initial conventional autologous bone marrow transplant. Immunotherapy with dendritic cells appears now to be a feasible way to enhance inna

Topics: Bone Marrow Transplantation; Combined Modality Therapy; Cytogenetic Analysis; Drugs, Investigational; Humans; Immunotherapy; Melphalan; Middle Aged; Multiple Myeloma; Time Factors

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Clostridium Infections; Clostridium perfringens; Embolization, Therapeutic; Fatal Outcome; Hemolysis; Humans; Liver Neoplasms; Lung Neoplasms; Male; Melphalan; Middle Aged; Multiple Myeloma; Neoplasms, Multiple Primary; Prednisone; Sepsis

The treatment of multiple myeloma still remains under investigation. Conventional chemotherapy with currently used agents (i.e., Melphalan) effects complete remission in no more than 5% of patients. High dose chemotherapy followed by hematopoietic stem cells transplantation results in complete remission rates between 25% and 75% and a 3-year probability of event-free survival between 40% and 60% but is not curative since most patients relapse after 1.5 to 3 years. Therefore, it becomes the treatment of choice for multiple myeloma. The drugs used in high dose therapy include: high dose melphalan (200 mg/m2) as single agent., melphalan (140 mg/m2) and total body irradiation (TBI), Busulfan and melphalan... etc. The use of the peripheral blood stem cell transplantation has allowed a reduction in the toxicity of high-dose regimens, but has not led to an increase in the overall response rate or survival. Hematopoietic stem cells from peripheral blood are preferred for transplantation because they restore hematopoiesis more rapidly than do bone marrow cells and the numbers of tumor cells are lower in peripheral blood than bone marrow cells. Peripheral blood stem cell transplantation was associated with significant reduction in the duration of aplasia and transfusion requirements. Several regimens have been proposed for stem cells mobilization including: High-dose cyclophosphamide and G or GM-CSF, G-CSF alone, and cyclophosphamide and etoposide with G-CSF... ect.. Further attempts to improve the results of autotransplantation have included intensification with tandem transplantations (double transplants) and reduction of tumor cells in stem cell infusion. The aim of this review is to summarize the current knowledge about the treatment of multiple myeloma with high dose chemotherapy with autologous hematopoietic stem cell transplantation.

Topics: Antigens, CD; Antigens, CD34; Antineoplastic Agents; Bone Marrow Transplantation; Clinical Trials as Topic; Cyclophosphamide; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cells; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Melphalan; Multiple Myeloma; Recombinant Proteins; Stem Cell Transplantation; Transplantation, Autologous; Whole-Body Irradiation

The principle of alkylating agent dose intensity, especially with melphalan-based tandem autotransplants, has been effective in increasing the rate of complete remission beyond 40% and effecting 10-year survivorship in about 40% of the three fourths of patients presenting without cytogenetic abnormalities (Total Therapy I). Further dose escalation and post-transplant consolidation therapy, as practiced with Total Therapy II, seems to further improve results in these patients, but not in those with chromosome 13 abnormalities or lactate dehydrogenase elevation. Phase III trials for post-transplant relapse indicate higher complete remission and near-complete remission rates among patients randomized to thalidomide added to dexamethasone versus dexamethasone alone. In a phase I/II study, thalidomide derivative CC-5013, with less sedative and neurotoxic effects, promoted responses in eight of 15 patients with post-transplant relapse, refractory to other salvage therapies, at dose levels of > or = 25 mg daily. Based on a profound graft-vs-myeloma effect with allografts, mini-allotransplants were evaluated in 31 high-risk patients with cytogenetic abnormalities and prior autotransplants; all nine with responsive disease and only one prior autotransplant remain disease-free and alive. Such mini-allotransplants are now offered as consolidation after one standard autotransplant to patients with cytogenetic abnormalities. The systematic application of gene expression profiling attempts to classify multiple myeloma (MM) patients according to molecular features and to dissect the genetic basis for drug sensitivity or resistance. Given the availability of an expanding treatment armamentarium (eg, thalidomide, CC-5013, the proteasome inhibitor PS-341, farnesyltransferase inhibitors, IL-6 receptor antibody, endothelial receptor inhibitor), gene expression profiling is anticipated to help in the selection of agents with the greatest probability of activity toward individualized treatment. Careful scrutiny of gene expression will also help in the identification of unrecognized targets for therapeutic intervention.

Topics: Antineoplastic Combined Chemotherapy Protocols; Boronic Acids; Bortezomib; Clinical Trials as Topic; Gene Expression Profiling; Humans; Interferons; Lenalidomide; Melphalan; Multiple Myeloma; Protease Inhibitors; Pyrazines; Stem Cell Transplantation; Thalidomide

The association of sarcoidosis with Hodgkin disease and non-Hodgkin lymphoma is well known. However, multiple myeloma also can occur rarely in association with sarcoidosis. We describe a patient with sarcoidosis who subsequently developed multiple myeloma. The patient was a 49-year-old woman with a 4-year history of severe, chronic, active sarcoidosis involving her lungs, lymph nodes, eyes, and bone marrow. During the initial clinical workup, a serum monoclonal paraprotein was detected and bone marrow examination revealed a slight increase in plasma cells (4%), in addition to noncaseating granulomas. Thus, the diagnoses of monoclonal gammopathy of undetermined significance and sarcoidosis were established simultaneously. She sought medical attention for her current illness when she developed low back pain and weakness of her lower extremities. Serum protein electrophoresis and immunofixation revealed a monoclonal paraprotein, immunoglobulin (Ig) G kappa type, and quantification revealed an IgG level of 46.67 g/L (normal, 5.88--15.73 g/L). Bone marrow aspiration and biopsy revealed multiple myeloma and sarcoidosis. Including this patient, 11 cases of sarcoidosis and multiple myeloma have been reported to date, including 3 patients with monoclonal gammopathy of undetermined significance preceding the onset of multiple myeloma. In this case, as in most of the cases reported previously, sarcoidosis preceded the development of multiple myeloma.

Topics: Antineoplastic Agents, Alkylating; Bone Marrow Cells; Drug Therapy, Combination; Female; Granuloma; Humans; Immunoenzyme Techniques; Immunoglobulin kappa-Chains; Melphalan; Middle Aged; Multiple Myeloma; Prednisone; Sarcoidosis; Treatment Outcome

Melphalan was the first described treatment for patients with multiple myeloma in the 1960s and is still being used in clinical practice. However, the use of melphalan in combination with prednisone resulted in a median survival of only 2-3 years. Therefore, the dose of melphalan has been intensified since then (140-200 mg/m(2)). In order to diminish treatment-related morbidity and mortality due to severe myelosuppression induced by these regimens, high-dose melphalan is currently supported with autologous stem cells. Indications for high-dose therapy and the role of further intensification by performing second or allogeneic transplantations are discussed. Furthermore, new therapeutic modalities, such as inhibitors of angiogenesis, also showing direct antiproliferative, cytokine-related and immunomodulatory effects on plasma cells (thalidomide and its newer derivatives), inhibitors of the transcription factor NF-kappa B (proteasome inhibitors) and immunotherapy are described.

Topics: Aged; Antineoplastic Agents, Alkylating; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Chromosome Aberrations; Combined Modality Therapy; Humans; Interferons; Melphalan; Multiple Myeloma; Neoplasm Staging; Netherlands; Prednisone; Stem Cell Transplantation; Thalidomide

Progressive multiple myeloma may manifest features of 'de-differentiation', including a plasmablastic appearance, failure to secrete paraprotein, extramedullary involvement, and resistance to treatment. A 44-year-old woman with kappa-light chain myeloma underwent allogeneic stem cell transplantation (SCT). Twenty months later she developed paraspinal plasmablastic myeloma in the absence of paraprotein in urine or myeloma in the marrow. The paraspinal masses responded to chemotherapy. At 30 months she developed myelomatous meningitis, which proved resistant to intrathecal chemotherapy, irradiation, and donor lymphocyte infusion (DLI). The leptomeningeal disease led to death at 38 months. This is the first report of leptomeningeal relapse of myeloma after allografting.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Cell Differentiation; Combined Modality Therapy; Dexamethasone; Diphosphonates; Doxorubicin; Fatal Outcome; Female; Hematopoietic Stem Cell Transplantation; Humans; Immunologic Factors; Immunosuppressive Agents; Interleukin-2; Melphalan; Meninges; Methotrexate; Multiple Myeloma; Neoplastic Stem Cells; Osteolysis; Pamidronate; Paraparesis; Recurrence; Salvage Therapy; Seizures; Transplantation Conditioning; Transplantation, Homologous; Vincristine

Topics: Humans; Melphalan; Multiple Myeloma; Radiotherapy, Adjuvant; Stem Cell Transplantation; Thalidomide

Few studies have been performed regarding multiple myeloma (MM) in elderly patients. We report a retrospective series of 130 unselected patients with MM aged 75 yr or more at diagnosis. Presenting features were identical to those reported in younger patients, except for a higher rate of infection. Heavy comorbidity was characteristic of unselected geriatric patients. Ninety-four patients received conventional chemotherapy. The response rate was 62%. Treatment toxicity was mild. Median survival was 22 months. Durie-Salmon (DS) clinical stages II and III MM were severe and often led to death, while significantly more patients with DS stage I MM died from unrelated causes (p<0.0001). Univariate analysis showed that age > or = 85 yr, performance status > or = 2, creatinine level > or = 120 micromol/l, beta 2 microglobulin level > 4 mg/l, C-reactive protein level > 6 mg/l, platelet count < 100 x 10(9)/l, presence of infection and lack of response to chemotherapy were adverse prognostic factors for survival. In Cox multivariate regression analysis, age > or = 85 yr (p<0.0001), performance status > or = 2 (p<0.0001) and creatinine level > or = 120 micromol/l (p<0.0001) were independent factors in predicting short survival. This study provides evidence that in patients with symptomatic MM age should not be considered as a major obstacle to active treatment. Prospective clinical trials are needed in this population of patients and should include an assessment of quality of life.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Cause of Death; Comorbidity; Cyclophosphamide; Dexamethasone; Doxorubicin; Etoposide; Female; France; Humans; Interferon-alpha; Life Tables; Lomustine; Male; Melphalan; Multiple Myeloma; Myeloma Proteins; Neoplasm Staging; Paraneoplastic Syndromes; Prednimustine; Prednisone; Prognosis; Proportional Hazards Models; Retrospective Studies; Survival Analysis; Treatment Outcome; Vincristine

CY and L-PAM potentiated specific anti-tumor response in addition to their killing effect. The immunomodulating effect of a low dose of either CY or L-PAM was expressed in mice bearing large s.c. MOPC-315 plasmacytoma tumors. Cured mice were resistant to a challenge dose of the syngeneic tumor and their spleens contained specific cytotoxic T cells. Induction of specific anti-tumor response by a low dose of alkylating drugs was due to expression of "latent anti-tumor" capability. This fitted with the conception that "suppressed concomitant immunity" occurring in tumor-bearing animals can be activated. The immunomodulating activity of alkylating drugs was related to enhancement of T-cell functions:impairment of suppressor T-cell activity,enhancement of effector T-cell activity and increase in production of cytokines at the tumor site. The target tumor killing activity of a low dose alkylating drug was dissociated from its immunomodulating activity by treating mice bearing a tumor resistant to an alkylating drug. A low dose of CY had an immunomodulating effect in human cancer such as reduction of ConA-induced suppressor cell activity in melanoma, some improvement in addition to use of melanoma vaccine, and potentiation of DTH in cancer patients. The immunomodulating effect of alkylating drugs suggest that their use might be beneficial not only for killing tumor cells but also for promoting specific anti-tumor immune response.

Topics: Adjuvants, Immunologic; Animals; Antineoplastic Agents, Alkylating; Cyclophosphamide; Disease Models, Animal; Humans; Immunity; Macrophages; Melphalan; Mice; Multiple Myeloma; T-Lymphocytes

We summarize the Southwest Oncology Group (SWOG) experience with standard therapy for multiple myeloma by reviewing and updating data from seven consecutive SWOG trials. Some modest progress has been made since the introduction of melphalan and prednisone (MP) for induction therapy, using regimens that involve vincristine and doxorubicin, and which save alkylating agents for possible later high-dose therapy. For maintenance, it appears that prednisone plays a useful role. We demonstrate the use of the data collected in these trials with a proposed new staging system.

Topics: Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Doxorubicin; Humans; Melphalan; Multiple Myeloma; Prednisone; Retrospective Studies; Survival Analysis; Vincristine

This article summarizes clinical results of the Intergroupe Francophone du Myélome (IFM) trials: high-dose therapy (HDT) supported with autologous stem cells improves survival, melphalan 200 mg/m(2) is the best preparative regimen, unpurged peripheral blood stem cells (PBSC) are the recommended source of stem cells to support HDT, and tandem transplants significantly improve survival. Although these results are encouraging, the current IFM 99 protocol will evaluate innovative strategies with the goal to improve long-term survival.

Topics: Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Multiple Myeloma; Randomized Controlled Trials as Topic; Survival Analysis; Transplantation, Autologous

Treatment of Multiple Myeloma in the Elderly: Consensus of the Cooperative Group of Geriatric Oncology of the DGHO and DGG Multiple myeloma is an illness of old age. Often, in elderly people the diagnosis is delayed by the fact that bone pain, which is the most frequently presenting symptom, is not correctly interpreted because this is a common complaint in the elderly. In contrast to younger patients with multiple myeloma, elderly patients often present with infections at diagnosis. After the diagnosis is established, careful observation is very important. This applies both to patients who require still no therapy and to patients under treatment. In order to optimize the care of older patients, apart from tumor-specific investigations multidimensional geriatric assessment is helpful. This specifically applies for multiple myeloma which predisposes the patient to 'instability' and 'immobility', both belonging to the typical geriatric symptoms. Geriatric assessment may also be helpful in the selection of those elderly patients who are candidates for a possible prognosis-improving experimental intense chemotherapy. For the majority of the elderly patients in need of treatment the standard is melphalan/prednisone accompanied by one of the biphosphonates. Nevertheless, in order to improve prospects also for this group of patients, as many elderly patients as possible should be included into studies. This is the only way to compile valid recommendations for the treatment of elderly patients with multiple myeloma.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Diphosphonates; Geriatric Assessment; Humans; Melphalan; Multiple Myeloma; Prednisone; Prognosis

Treatment for multiple myeloma should not be given until the patient is symptomatic or at risk for the occurrence of complications of the disease. If the patient is younger than 70 years, the physician should seriously consider an autologous peripheral blood stem cell transplant. Most physicians initially administer vincristine/doxorubicin/dexamethasone (VAD) for 3 to 4 months and then collect the stem cells before exposure to alkylating agents. Following stem cell collection, one may proceed with high-dose chemotherapy and then infusion of the stem cells, or one can administer alkylating agents until a plateau is reached and delay transplantation until progressive disease occurs. There is no difference in overall survival between early and late transplantation, but the former avoids the cost and inconvenience of alkylating agent therapy. Double or tandem autologous stem cell transplants may produce better results, but the evidence is not strong. Almost all patients have a relapse after an autologous stem cell transplant, so efforts are being made to prolong the response with a2-interferon or dendritic cell therapy. Allogeneic bone marrow transplantation is feasible for only 5%-10% of patients, but the mortality is high and it is curative in only a small fraction of patients. Treatment with melphalan and prednisone results in an objective response in 50%-60% of patients. Combinations of alkylating agents produce a higher response rate, but there is no survival benefit. Thalidomide produces an objective response in about one third of patients with refractory disease. It currently is being studied in conjunction with dexamethasone for conventional initial therapy.

Topics: Adult; Age Factors; Aged; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Dexamethasone; Disease Progression; Doxorubicin; Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Middle Aged; Multiple Myeloma; Prednisone; Recurrence; Risk Factors; Transplantation, Autologous; Transplantation, Homologous; Vincristine

We report a series of 37 consecutive patients with multiple myeloma (MM) who received an allograft between 1990 and 2000 at our institution. Median age was 47 years, and nearly 70% of patients were Durie-Salmon stage III. A median of five cycles of chemotherapy were given before transplant, with a median interval between diagnosis and transplant of 9.3 months. We report a nonrelapse mortality rate of 22% with a median follow-up period of 40 months, whereas complete remission (CR) rate at 12 months is estimated at 57%. Treatment failure rate and overall survival at 40 months are estimated at 52% and 32%, respectively. The number of chemotherapy cycles prior to allotransplantation achieved borderline statistical significance as a poor prognosis factor for overall survival (P = 0.05), while the presence of chronic graft-versus-host disease (cGVHD) was significantly correlated with CR achievement (P = 0.036). Our study confirms that early allografting in MM can yield toxicity rates significantly lower than those associated with historical cohorts, and supports the hypothesis that cumulative chemotoxicity has a negative influence on mortality and survival rates. More importantly, our study clearly demonstrates an association between cGVHD and CR and brings further evidence in favor of a graft-versus-myeloma effect.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Combined Modality Therapy; Cyclophosphamide; Dexamethasone; Doxorubicin; Graft vs Host Disease; Graft vs Tumor Effect; Humans; Life Tables; Melphalan; Middle Aged; Multiple Myeloma; Prednisone; Remission Induction; Retrospective Studies; Survival Analysis; Survival Rate; Transplantation, Homologous; Treatment Outcome; Vincristine

Mucocutaneous involvement occurs predominantly in primary systemic amyloidosis as well as in myeloma-associated systemic amyloidosis. It is rarely observed in other types of amyloidoses. Signs of such involvement may aid in the early diagnosis of the disease process. Herein, we describe a 64-year-old white male patient with myeloma-associated systemic amyloidosis in whom the disease presented with unique cutaneous lesions consisting of chronic paronychia and palmodigital erythematous swelling and induration of the hands. Following weekly regimens with prednisone (20 mg/day) and melphalan (2 mg/day) administered every 16 weeks, almost complete resolution of the cutaneous lesions was observed after 1 year of therapy. Also, in response to chemotherapy, modest regression of the myelomatous bone lesions and complete resolution of the underlying gammopathy occurred.

Topics: Amyloidosis; Antineoplastic Agents, Alkylating; Chronic Disease; Drug Therapy, Combination; Erythema; Glucocorticoids; Hand Dermatoses; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Paronychia; Prednisone; Recurrence; Time Factors

Multiple myeloma is still an incurable disease. The standard conventional chemotherapy comprises melphalan and prednisone (MP). Combination chemotherapy regimens could not improve the median survival of 36 months observed with MP. In the French IFM90 study, HD therapy with TBI plus melphalan 140 mg/m2 was shown to prolong overall survival and progression-free survival compared to conventional treatment. Nonetheless, most patients eventually succumb due to disease progression. Allogeneic transplantation may induce long-term remissions and even cure, but is hampered by a high transplantation-related mortality (TRM). Currently, efforts are made to reduce this TRM and to evaluate the graft-versus-myeloma effect.

Topics: Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Graft vs Tumor Effect; Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Multiple Myeloma; Prednisone; Transplantation, Autologous; Transplantation, Homologous; Whole-Body Irradiation

Topics: Diagnosis, Differential; Drug Therapy, Combination; Hematopoietic Stem Cell Transplantation; Humans; Immune System Diseases; Interferons; Melphalan; Multiple Myeloma; Prednisolone; Prognosis

Multiple myeloma (MM) accounts for about 10% of all hematologic malignancies. The standard treatment with intermittent courses of melphalan and prednisone (MP) was introduced more than 30 years ago and, since then there has been little improvement in event-free and overall survival (EFS & OS). The aim of this article is to review: 1) the role of initial chemotherapy (ChT), maintenance treatment with alpha-interferon and salvage ChT, 2) the results of high-dose therapy (HDT) followed by allogeneic or autologous stem cell transplantation (allo-SCT and auto-SCT), and 3) the most important supportive measures.. The authors of this review have been actively working and contributing with original investigations on the treatment of MM during the last 15 years. In addition, the most relevant articles and recent abstracts published in journals covered by the Science Citation Index and Medline are also reviewed.. The importance of avoiding ChT in asymptomatic patients (smoldering MM) is emphasized. The criteria and patterns of response are reviewed. MP is still the standard initial ChT with a response rate of 50-60% and an OS of 2-3 years. Combination ChT usually increases the response rate but does not significantly influence survival when compared with MP. Exposure to melphalan should be avoided in patients in whom HDT followed by auto-SCT is planned, in order to not preclude the stem cell collection. The median response duration to initial ChT is 18 months. Interferon maintenance usually prolongs response duration but in most studies does not significantly influence survival (a large meta-analysis by the Myeloma Trialists' Collaborative Group in Oxford is being finished). In alkylating-resistant patients, the best rescue regimens are VBAD or VAD. In patients already resistant to VBAD or VAD and in those in whom these treatments are not feasible we recommend a conservative approach with alternate day prednisone and pulse cyclophosphamide. While HDT followed by autotransplantation is not recommended for patients with resistant relapse, patients with primary refractory disease seem to benefit from early myeloablative therapy. Although results from large randomized trials are still pending in order to establish whether early HDT intensification followed by auto-SCT is superior to continuing standard ChT in responding patients, the favorable experience with autotransplantation of the French Myeloma Intergroup supports this approach. However, although the complete response rate is higher with intensive therapy, the median duration of response is relatively short (median, 16 to 36 months), with no survival plateau. There are several ongoing trials comparing conventional ChT with HDT/autoSCT in order to identify the patients who are likely to benefit from one or another approach. With allo-SCT there is a transplant-related mortality ranging from 30 to 50% and also a high relapse rate in patients achieving CR. However, 10 to 20% of patients undergoing allo-SCT are long-term survivors (> 5 years) with no evidence of disease and, consequently, probably cured. The use of allogeneic peripheral blood stem cells (PBSC) in order to speed the engraftment and also the use of partially T-cell depleted PBSC which can decrease the incidence of graft-versus-host disease are promising approaches. In the setting of allo-SCT, donor lymphocyte infusion is an encouraging strategy in orde

Topics: Anemia; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Purging; Bone Marrow Transplantation; Contraindications; Diphosphonates; Disease-Free Survival; Drug Resistance, Neoplasm; Female; Hematopoietic Stem Cell Transplantation; Humans; Immunologic Factors; Infection Control; Interferon-alpha; Kidney Failure, Chronic; Male; Melphalan; Multiple Myeloma; Myeloma Proteins; Osteolysis; Prednisone; Prognosis; Remission Induction; Salvage Therapy; Transplantation Conditioning; Transplantation, Autologous; Transplantation, Homologous

This is a general overview on the treatment of multiple myeloma (MM) with particular emphasis on controversial aspects. The importance of avoiding treatment for asymptomatic patients is emphasized. The selection of initial treatment (melphalan/prednisone vs. combination chemotherapy) is summarized. The duration of initial treatment, the role of interferon maintenance, as well as the treatment of resistant myeloma patients are critically reviewed. Finally, the treatment of particular subsets of myeloma patients (i.e., young patients, elderly people, patients presenting with renal failure) is discussed.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Child; Combined Modality Therapy; Drug Administration Schedule; Drug Resistance, Neoplasm; Humans; Interferons; Melphalan; Middle Aged; Multiple Myeloma; Prednisone

Since 1983 an increasing number of clinical trials have used high-dose melphalan with or without autologous stem cell support in patients with multiple myeloma. It has been shown that high-dose therapy including high-dose melphalan may be considered as the treatment of choice in newly diagnosed patients. The purpose of this report is to review and summarize the clinical information on IV high-dose melphalan in patients with multiple myeloma and to examine potential areas of future investigation.

Topics: Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Drug Resistance, Neoplasm; Hematopoietic Stem Cell Transplantation; Humans; Injections, Intravenous; Melphalan; Multiple Myeloma; Transplantation Conditioning

Multiple myeloma with IgG-lambda monoclonal gammopathy and severe renal impairment with light-chain deposit disease was diagnosed in a 51-year-old man. Following conventional therapy with VAD (vincristine, adriamycin, dexamethasone) a partial remission was achieved. Peripheral blood stem cells (PBSC) were then collected following mobilization with cyclophosphamide and recombinant human granulocyte colony-stimulating factor and enriched for CD34-positive cells by immunoaffinity column. Fourteen months after diagnosis high-dose melphalan was given, followed by infusion of CD34-positive PBSC. Aside from mild oral mucositis and trigonitis, high-dose therapy was tolerated well. After he underwent PBSC transplantation his renal function improved, and the patient has been in in continuous complete remission for 1 year. Thus, high-dose chemotherapy can be safely administered to patients with multiple myeloma and severe renal impairment. Our findings confirm previous reports summarized in the current presentation.

Topics: Antineoplastic Agents, Alkylating; Dose-Response Relationship, Drug; Hematopoietic Stem Cell Transplantation; Humans; Kidney; Male; Melphalan; Middle Aged; Multiple Myeloma; Renal Insufficiency

Topics: Adult; Aged; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Child; Diagnosis, Differential; Heavy Chain Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Melphalan; Multiple Myeloma; Paraproteinemias; Prednisone; Prognosis; Time Factors; Vidarabine; Waldenstrom Macroglobulinemia

Respiratory syncytial virus (RSV) has been reported as a cause of death among autologous peripheral blood stem cell (ASCT) and marrow recipients and recommendations for therapy with aerosolized ribavirin plus intravenous immunoglobulin (IVIG) made. This therapy is expensive, may be toxic, and causes a significant disruption of patient care. The purpose of this study was to evaluate the morbidity and mortality of RSV infections in patients with multiple myeloma undergoing ASCT without ribavirin therapy. During the months of February-April 1997, 10 consecutive patients (median age 57 years, seven males) with advanced and heavily pretreated myeloma underwent ASCT while having active RSV upper respiratory tract infection. After melphalan (200 mg/m2), all patients became neutropenic (<1000 cells/mm3) for a median of 7 days. Ribavirin was not given to any patient. No patient developed lower respiratory tract infection, required transfer to intensive care or died at a median follow-up of 8 months. One patient developed tracheobronchitis requiring oxygenation by nasal cannula. No delay in the treatment of the underlying myeloma was incurred. RSV infection may not necessarily be a contraindication for ASCT or an indication for therapy with aerosolized ribavirin. Additional studies are needed to confirm our preliminary findings.

Topics: Aged; Combined Modality Therapy; Female; Hematopoietic Stem Cell Transplantation; Humans; Immunocompromised Host; Immunoglobulins, Intravenous; Incidence; Male; Melphalan; Middle Aged; Multiple Myeloma; Neutropenia; Pilot Projects; Respiratory Syncytial Virus Infections; Ribavirin; Transplantation Conditioning

Following recent data on multiple myeloma (MM) in the literature, a possible model of myeloma development, involving different cytokine signals, is advanced, and the prognostic significance of two principle staging systems is evaluated. Different therapeutic approaches to MM have been employed, consisting of either treatment with only melphalan and prednisone, or combination chemotherapy, especially in patients with a poor prognosis. However, for the initial therapy, melphalan plus prednisone in doses that compensate for individual variation in drug absorption still appears the best choice in the vast majority of MM patients. The main clinical and hematological features which distinguish Waldenström's macroglobulinemia from MM are described, as are the criteria which should be used in choosing the most appropriate treatment based, when necessary, on chemotherapy with standard alkylating agents, as well as on the new nucleoside analogues, and repeated courses of plasmapheresis.

Topics: Aging; Antineoplastic Agents, Alkylating; Antineoplastic Agents, Hormonal; Diagnosis, Differential; Drug Therapy, Combination; Hematologic Diseases; Humans; Melphalan; Multiple Myeloma; Prednisone; Waldenstrom Macroglobulinemia

Topics: Adult; Age Factors; Aged; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Combined Modality Therapy; Female; Humans; Interferon-alpha; Male; Melphalan; Middle Aged; Multiple Myeloma; Prednisolone; Prognosis; Survival Rate; Transplantation, Homologous

To compare combination chemotherapy (CCT) versus melphalan plus prednisone (MP) as treatment for multiple myeloma.. In a collaborative worldwide overview of randomized trials of CCT versus MP, individual patient data on 4,930 patients from 20 trials were analyzed, with the addition of published data on a further 1,703 patients from seven trials. The main outcome measure was mortality, with response and recurrence rates being subsidiary end points.. Taking all of the trials together, response rates were significantly higher with CCT than with MP (60.0% v 53.2%; P < .00001, two-tailed). There was no evidence of any difference in mortality between CCT and MP, with a nonsignificant 1.5% reduction in death rate in favor of CCT (P = .6, two-tailed). There is heterogeneity of design between the trials, but subgroup analyses by type of CCT or by dose-intensities of CCT, of melphalan, or of prednisone did not identify any particular forms of therapy that were either clearly beneficial or clearly adverse. Similarly, analysis of the presentation features of the patients did not find any categories in which CCT differed significantly from MP in its effects on mortality; in particular, there was no evidence that poor-risk patients benefited more from CCT.. This overview found no difference, either overall or within any subgroup, in mortality between CCT and MP. In terms of survival, these therapeutic options, as tested in the trials considered, are approximately equivalent.

Topics: Adult; Aged; Antineoplastic Agents, Alkylating; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Female; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Prednisone; Randomized Controlled Trials as Topic; Recurrence; Survival Analysis; Treatment Outcome

Topics: Antineoplastic Agents, Alkylating; Hematopoietic Stem Cell Transplantation; Humans; Immunoglobulin D; Melphalan; Multiple Myeloma

Topics: Amyloidosis; Anti-Inflammatory Agents; Antineoplastic Agents, Alkylating; Humans; Melphalan; Multiple Myeloma; Prednisolone

An uncommon case of breast metastasis from multiple myeloma that regressed significantly after treatment by radiation is described.

Topics: Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Fatal Outcome; Female; Humans; Melphalan; Middle Aged; Multiple Myeloma; Palliative Care; Prednisone; Radiotherapy, Adjuvant; Radiotherapy, High-Energy; Tomography, X-Ray Computed; Treatment Outcome

Topics: Antineoplastic Agents; Biomarkers; Bone Marrow Transplantation; Clinical Trials as Topic; Glucocorticoids; Humans; Interferons; Melphalan; Multiple Myeloma; Prognosis

The diagnosis of multiple myeloma (MM) is often difficult; most patients present with asymptomatic gammopathy. The only findings that confirm a diagnosis of MM are an elevation in the M-component or extension of the lytic bone lesions that are the hallmark of the disease. Tests that delineate plasma cell biology, such as plasma cell proliferation rate, are helpful; magnetic resonance imaging can disclose bone marrow lesions leading to subsequent osteolytic disease. After the diagnosis of MM has been established and prognostic factors identified, the appropriate therapy can be determined. Melphalan and prednisone are no longer considered to be the "gold standard" of therapy. In fact, this approach is suitable for less than half of patients with myeloma. This article presents guidelines for standard treatment options and examines the efficacy of new high-dose chemotherapy approaches.

Topics: Adult; Age Factors; Aged; Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Humans; Melphalan; Middle Aged; Multiple Myeloma; Prednisone; Prognosis

Since the introduction of melphalan, little progress has be obtained in the treatment of multiple myeloma. Complete remission is rarely achieved with classical single-drug or combined chemotherapy protocols: median survival remains low at 2 to 3 years. A NEW APPROACH: High-dose melphalan therapy with hemopoietic stem cell support it a new approach providing promising results. There is a dose effect and 70 to 80% of naive patients, at the cost of severe prolonged aplasia, respond to high-dose melphalan. HEMATOPOIETIC SUPPORT: Allogeneic or autologous bone marrow or blood stem cell grafts are used. Peripheral blood autographs can be used in most patients; contamination with tumoural cells is generally lower. The period of aplasia after chemotherapy and hematopoietic autograft is relatively short. MAIN INDICATIONS: For most authors, high-dose melphalan should be reserved for younger patients with active myeloma: complete remission is achieved in 20 to 30% of cases although relapse still occurs. Other techniques under study (several sequences of high-dose sessions, reduction of graft contamination) should help improve results.

Topics: Antineoplastic Agents, Alkylating; Bone Marrow Transplantation; Combined Modality Therapy; Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Multiple Myeloma

We report a case of 77-year-old woman who presented with lumbago and hypercalcemia. Multiple myeloma (MM) was first diagnosed by serum protein electrophoresis and bone marrow aspiration, but intact parathyroid hormone (intactPTH) was also found to be high in the presence of persistent hypercalcemia with anorexia and nausea. After lowering serum calcium with bisphosphonate administration, parathyroidectomy was performed. Upon histologic examination, the tumor was determined to be parathyroidal chief-cell hyperplasia and the patient was treated with melphalan and prednisolone. The relationship between MM and primary hyperparathyroidism (I degree HPT) remains unknown. Although the co-existence of MM and I degree HPT was reported in 12 reports from various parts of the world, there was only 1 report in Japan. The present case is an example of successful treatment for a complicated disorder, and suggests that patients suffering from bone pain or hypercalcemia need to be examined both endocrinologically and hematologically.

Topics: Aged; Antineoplastic Agents; Female; Humans; Hypercalcemia; Hyperparathyroidism; Hyperplasia; Low Back Pain; Melphalan; Multiple Myeloma; Osteoporosis; Parathyroid Glands; Prednisolone

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Arthritis, Rheumatoid; Cyclophosphamide; Dexamethasone; Doxorubicin; Humans; Male; Melphalan; Multiple Myeloma; Paraproteins; Prednisolone; Prednisone; Risk Factors; Vincristine

The association of melphalan and prednisone, introduced in the sixties, allowed a dramatic improvement in the prognosis of multiple myeloma. The subsequent evaluation of different polychemotherapeutic schedules did not ameliorate the results with respect to the melphalan-prednisone association, which remains the treatment of choice in patients older than 60-65 years. In younger patients high dose therapy allowed, in the recent years, significant improvement in terms of reduction of tumor mass and survival. The use of interferon as maintenance treatment allowed a prolongation of the response phase obtained after induction treatment. In this paper we discuss current trends in the management of multiple myeloma and related complication.

Topics: Adult; Age Factors; Aged; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Humans; Melphalan; Middle Aged; Multiple Myeloma; Prednisone; Prognosis; Time Factors

The association of systemic lupus erythematosus (SLE) and multiple myeloma (MM) is an uncommon event. We report the relapse of SLE in a patient with a previous history of MM, treated with chemotherapy and, subsequently, with alpha-2b interferon (alpha-2b IFN) as a maintenance therapy. The case is discussed in light of past relevant literature.. The history and clinical, laboratory and radiographic findings of the patient, as well as the subsequent therapeutic approach are discussed. In our review of the literature, journal articles are identified by Medline search.. We describe the case of a woman who developed a multiple myeloma 14 years after a diagnosis of SLE. A careful literature review confirms that the association of these two diseases has been reported only in a few cases. When the plasma cell neoplasia occurred, SLE had been quiescent for several years; the patient was treated with prednisone-melphalan and, subsequently, with alpha-2b IFN as a maintenance therapy. On admission to our department, SLE was in a relapse phase, probably because of IFN treatment. The disease was poorly responsive to steroid therapy and required the use of cytotoxic drugs.. The coexistence of SLE and MM is very rare and the possible pathogenetic mechanisms underlying this association remain unclear. The use of interferon in a patient with an autoimmune disease always invites caution.

Topics: Antineoplastic Agents; Cyclophosphamide; Female; Humans; Interferon alpha-2; Interferon-alpha; Lupus Erythematosus, Systemic; Melphalan; Methylprednisolone; Middle Aged; Multiple Myeloma; Recombinant Proteins; Recurrence

Melphalan and prednisolone (MP) have been the standard therapy for multiple myeloma for more than 25 years. Although they produce an objective response in 50-60% of patients, complete remission (CR) is rare and the median survival period is generally 24 to 30 months. Many combination chemotherapeutic agents have been used and resulted in approximately 70% objective response, but the median duration of survival has not significantly been improved. VAD regimen is effective for many patients with myeloma resistant to MP therapy. Furthermore, VAD-cyclosporin combination induces responses in approximately 40% of patients with VAD-resistant myeloma, with increased expression of the multi-drug resistant gene (MDR). Intravenous administration of high dose-melphalan also produces responses in approximately 30% of patients with myeloma resistant to VAD. Interferon-alpha therapy with an alkylating agent-glucocorticoid regimen, shows a higher response rate but similar survival time, compared with those obtained with the MP therapy alone. High-dose therapy with transplantation is promising. High-dose therapy combined with autologous bone marrow transplantation improves the response rate, event-free survival (EFS), and overall survival (OS) in patients with myeloma, demonstrated in the prospective, randomized trial by Attal et al. Total therapy by Barlogie et al. consisted of non-cross-resistant induction regimens, followed by a double autotransplantation (AT) procedure. Compared with the outcome of patients receiving standard therapy, dose intensification with double AT produces not only higher CR rates but also significantly extends EFS and OS in previously untreated patients with myeloma. The reduced mortality rate associated with transplantation, and development of new chemotherapeutic agents will lead to future improvements of the therapy for multiple myeloma.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Cisplatin; Cytarabine; Dexamethasone; Doxorubicin; Etoposide; Humans; Interferon-alpha; Melphalan; Multiple Myeloma; Prednisone; Remission Induction; Vincristine

With conventional therapy, multiple myeloma (MM) has a poor prognosis. During the last few years, it has become clear that high-dose chemotherapy with autologous stem cell support can increase overall survival of MM patients, but further improvement in outcome is desperately needed. The monoclonal immunoglobulin (Ig) produced by the MM cells called idiotypes (Id) is a tumor-specific antigen due to unique antigenic determinants that are localized in the variable regions of the Ig molecule. Conceivably, Id immunization of MM patients in complete remission could further increase survival. Here we review the scientific basis for such Id immunization.

Topics: Adjuvants, Immunologic; Antibodies, Monoclonal; Antineoplastic Agents, Alkylating; Combined Modality Therapy; Dose-Response Relationship, Drug; Hematopoietic Stem Cell Transplantation; Humans; Immunoglobulin Idiotypes; Melphalan; Multiple Myeloma; Transplantation, Autologous; Vaccination

The median survival of conventionally treated patients with multiple myeloma is 3 years. Modifications of conventional chemotherapy have failed to show an improved survival rate in most randomized trials. Therapy regimens with dose-escalated alkylating agents (ie melphalan) have induced higher remission rates in comparison to conventional treatment modalities. With the support of autologous or allogeneic hematopoietic progenitor cells, it has been possible to reduce the hematoxicity of these dose-escalated treatments. The transplantation of autologous peripheral blood progenitor cells results in faster hematopoietic reconstitution with decreased high-dose therapy-related morbidity compared to autologous bone marrow. The randomized French myeloma trial and the pair-mate analysis of the results of the 'total therapy' including double autografting of the Barlogie group with data from the South Western Oncology Group (SWOG) showed a significant survival advantage for patients following autologous transplantation. Although a graft-versus-myeloma effect was described, the benefit of high-dose treatment with allogeneic transplantation is less clear, mainly due to the high transplantation-related mortality rate. In this paper, results of transplantation trials are summarized. Prognostic factors and future treatment modalities for myeloma are discussed.

Topics: Antineoplastic Agents; Bone Marrow Transplantation; Combined Modality Therapy; Cyclophosphamide; Disease-Free Survival; Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Multiple Myeloma; Survival Rate; Whole-Body Irradiation

Topics: Antineoplastic Agents, Alkylating; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Multiple Myeloma; Prednisone; Remission Induction; Survival Rate

Previous reports have stressed the association between autoimmune disease and lympho-proliferative neoplasm. Here we report a patient in whom multiple myeloma developed about 30 years after the onset of rheumatoid arthritis. A 79 year-old woman with an about 30-year history of rheumatoid arthritis was admitted because of lumbago in December, 1993. Laboratory findings revealed M-proteinemia (IgA 2,380 mg/dl, IgG 728 mg/dl, IgM 51 mg/dl) and serum immunoelectrophoresis showed monoclonal IgA with lambda type light chain. Bone marrow aspirate contained 66.0% plasma cells. Serological tests of rheumatoid factor were positive. X-ray findings revealed radiolucent myelomatous foci in the skull and typical destructive changes of rheumatoid arthritis in multiple joint. From these findings, IgA lambda-type multiple myeloma with rheumatoid arthritis was diagnosed. Although the pathogenesis of the association between rheumatoid arthritis and multiple myeloma is unknown, prolonged antigenic stimulation manifested by rheumatoid arthritis is considered to be a possible pathogenetic factor in the development of multiple myeloma.

Topics: Aged; Anti-Inflammatory Agents; Antineoplastic Agents, Alkylating; Arthritis, Rheumatoid; Female; Humans; Melphalan; Multiple Myeloma; Prednisolone

Melphalan has brought the first improvement in the therapy of multiple myeloma at the beginning of the sixties. The median of survival was prolonged from several months to three years. In the following three decades new drugs were tested, but no other drug brought better results than melphalan. The comparative studies have proved, that therapy response has been reached more rapidly after polychemotherapy than monotherapy, but none of the treatment modalities differed in the survival parameters. The significance of interferon alpha for the treatment of multiple myeloma has been tested since the beginning of the eighties. Many clinical trials have brought contraverse results. The latest metaanalysis and data published by Ludwig support the indication of interferon alpha for the multiple myeloma maintenance treatment. Important progress in the therapy of multiple myeloma has been done in the nineties. High doses of alkylating cytostatics with the support of autologous peripheral blood stem cells transplantation or bone marrow transplantation enhanced the number of therapy-responses and prolonged the survival. The results of autologous transplantations are so favourable, that this procedure can be recommended as the first line treatment in suitable patients. Allogenic bone marrow transplantation is linked with many complications and therefore this method will be performed only in a limited number of patients. Trials dealing with this new therapy-trend are reviewed in this paper.

Topics: Antineoplastic Agents, Alkylating; Bone Marrow Transplantation; Combined Modality Therapy; Humans; Melphalan; Multiple Myeloma

Standard chemotherapy with melphalan-prednisone or a combination of alkylating agents has not extended the overall survival of patients with multiple myeloma during the last 30 years and strictly defined complete remissions (CR) are exceedingly rare. The early mortality with conventional therapy varies between 2 and 10 percent. A substantial increase in the dose of melphalan (100-140 mg/m2) has resulted in a 30-45% CR rate in newly diagnosed patients and an overall survival advantage of approximately 1 year. However, treatment related morbidity and mortality, due to prolonged cytopenia was unacceptably high. Based on these findings the dose intensity was further increased by either escalating melphalan to 200 mg/m2 or by adding total body irradiation, while at the same time providing stem cell support to shorten the duration of cytopenia. Autologous transplants, especially with peripheral blood stem cells and hematopoietic growth factors, can now be performed safely up to the age of 70 with a low transplant-related mortality (2-10%). A CR is attained in approximately 50% of previously untreated patients and 10-20% of refractory cases. Overall survival of newly diagnosed and refractory patients treated with autotransplants appears superior to that of patients receiving conventional chemotherapy. Therefore, autotransplantation should be considered as a treatment option in all patients with multiple myeloma at least up to the age of 65. Despite these encouraging findings, most myeloma patients ultimately relapse and the survival curves do not suggest that autotransplantation as currently performed is a curative approach in a substantial proportion of patients. Further improvement with autotransplants should be achieved by providing tumor-free grafts and by introducing post-transplantation manipulations, aimed at eradicating minimal residual disease.

Topics: Adult; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Clinical Trials as Topic; Combined Modality Therapy; Disease-Free Survival; Hematopoietic Cell Growth Factors; Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Middle Aged; Multiple Myeloma; Neoplasm Recurrence, Local; Neoplasm, Residual; Pancytopenia; Plasma Cells; Prednisone; Prognosis; Remission Induction; Salvage Therapy; Survival Analysis; Survival Rate; Transplantation Conditioning; Whole-Body Irradiation

Melphalan has brought the first improvement in the therapy of multiple myeloma at the beginning of the sixties. The median of survival was prolonged from several months to 3 years. In the following 3 decades new drugs were tested, but no other drug brought better results than melphalan. The comparative studies have proved, that therapy response has been reached more rapidly after polychemotherapy than after monotherapy, but none of the treatment modalities differed in the survival parameters. The significance of interferon alpha for the treatment of multiple myeloma has been tested since the beginning of the eighties. Many clinical trials have brought controversial results. The latest metaanalysis and data published support the indication of interferon alpha for the multiple myeloma maintenance treatment. Important progress in the therapy of multiple myeloma has been done in the nineties. High doses of alkylating cytostatics with the support of autologous peripheral blood stem cells transplantation or bone marrow transplantation enhanced the number of therapy-responses and prolonged the survival. The results of autologous transplantations are so favourable, that this procedure can be recommended as the first line treatment in suitable patients. Allogenic bone marrow transplantation is linked with many complications and therefore this method will be performed only in a limited number of patients. Trials dealing with this new therapy-trends are viewed in this paper.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Clinical Trials as Topic; Humans; Interferon-alpha; Melphalan; Multiple Myeloma; Survival Rate; Treatment Outcome

Transfusion of autologous peripheral blood stem cells (PBSCs) of good quality ensures fast hematopoietic engraftment after myeloablative therapy with a decrease in procedure-related morbidity and mortality. We have analyzed variables influencing the kinetics of engraftment, and therefore reflecting the quality of PBSC collections, in 225 patients with newly diagnosed or refractory multiple myeloma (MM) who received an autotransplant in support of high dose melphalan (200 mg/m2); 132 of these patients also completed a second transplant. All PBSCs were collected before the first transplant after high-dose cyclophosphamide (6 g/m2) and hematopoietic growth factors, mainly granulocyte-macrophage colony-stimulating factor. PBSCs were administered either alone (91 patients) or with bone marrow (134 patients). A highly significant correlation was observed between the number of CD34+ cells per kilogram infused and prompt recovery of both granulocytes (P = .0001) and platelets (P = .0001). After correction for the proportion of patients with > or = 2 x 10(6)/kg CD34 PBSCs infused and with < or = 12 months of prior therapy, no difference in engraftment kinetics was seen between patients receiving PBSCs only and those also receiving bone marrow. Exposure to chemotherapy, even to < or = 6 months of alkylating agents, significantly delayed hematopoietic recovery posttransplantation. The threshold dose of CD34 cells necessary for prompt engraftment was > or = 2.0 x 10(6)/kg for patients with < or = 24 months of chemotherapy before the first transplant, whereas greater than 5 x 10(6)/kg CD34 cells were required to assure rapid recovery also in those with longer exposure. Such quantities, easily collected in the large majority of patients with shorter exposure (91%), were obtained in only 28% of patients with more than 24 months of prior chemotherapy. Rapid platelet recovery within a narrow range of time (before day 14) was almost invariably seen (94%) when greater than 5 x 10(6)/kg CD34 cells were infused, irrespective of the duration of prior therapy, whereas the range widened progressively when less CD34 cells were infused. In the absence of CD34 measurements, fast recovery of platelets to greater than 50 x 10(9)/L within 14 days after high-dose cyclophosphamide and < or = 12 months of prior chemotherapy were the best predictors of early engraftment. Prudent use of stem cell-damaging agents, such as melphalan and nitrosoureas, is recommended in MM patients who might b

Topics: Adult; Antigens, CD; Antigens, CD34; Antineoplastic Agents; Bone Marrow Transplantation; Combined Modality Therapy; Cyclophosphamide; Graft Survival; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Hematopoiesis; Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Middle Aged; Multiple Myeloma; Multivariate Analysis; Retrospective Studies; Salvage Therapy; Treatment Outcome

Topics: Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Drug Therapy, Combination; Humans; Interferon-alpha; Melphalan; Multiple Myeloma; Prednisone; Vincristine

To review the clinical pharmacology and clinical trials that have used intravenous (IV) high-dose melphalan (HDM).. We reviewed the mechanism of action, clinical pharmacology, and clinical studies of HDM with and without autologous bone marrow support (ABMT) or peripheral-blood progenitor cells (PBPCs) in the following disease areas: myeloma, ovarian cancer, malignant lymphoma, breast cancer, neuroblastoma, Ewing's sarcoma, and acute leukemia.. HDM has a distribution half-life (t1/2 alpha) of 5 to 15 minutes and an elimination half-life (t1/2 beta) of 17 to 75 minutes at doses of 140 to 180 mg/m2, with significant intrapatient variability. At these doses, a wide range of areas under the concentration/time curve (AUC) have been reported, ie, 146 to 1,515 mg/min/mL. HDM has significant clinical activity in patients with multiple myeloma in relapse or when used as consolidative therapy in relapsed ovarian cancer, relapsed Hodgkin's disease, breast cancer, and relapsed neuroblastoma. Additional studies are required to determine the activity of HDM in Ewing's sarcoma or acute leukemia. Toxicities of HDM include myelosuppression, moderate nausea and vomiting, moderate to severe mucositis and diarrhea, and, infrequently, hepatic venoocclusive disease.. HDM has become an established and effective salvage regimen for children with relapsed neuroblastoma, as well as an effective consolidative treatment for children with high-risk disease (stage IV). HDM is emerging as an active and effective mode of treatment in patients with stage II and III myeloma. The favorable toxicity profile of HDM and the availability of PBPCs allows for repetitive therapy.

Topics: Acute Disease; Administration, Oral; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Female; Forecasting; Half-Life; Humans; Infusions, Intravenous; Leukemia; Lymphoma; Melphalan; Multiple Myeloma; Neuroblastoma; Ovarian Neoplasms; Sarcoma, Ewing

The crucial first step in management of multiple myeloma is to be certain regarding the diagnosis. Multiple myeloma must be distinguished from monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma. Therapy should be administered to patients with advanced and active myeloma involving anemia, osteolysis or renal failure. Chemotherapy with a single agent (melphalan) is the preferred initial treatment for overt, symptomatic multiple myeloma. Cytostatic drug combinations produce a higher response rate, but survival and remission during are the same compared with melphalan/prednisone therapy. However, in patients with renal failure and/or poor prognostic factors (advanced stage, elevated beta 2-microglobulin, high bone marrow plasma cell labeling index, high levels of C-reactive protein and lactate dehydrogenase and/or nodular pattern of bone marrow infiltration), combined treatment with adriamycin, vincristine and prednisone should be administered to prevent nephrotoxicity and attain a rapid paraprotein decrease. Alpha interferon treatment as maintenance seems to prolong the duration of the plateau state after response to chemotherapy, but apparently does not prolong survival. Allogeneic bone marrow transplantation involves significant early mortality (50%); the risk of graft versus host disease, infections and renal failure is a problem, and relapse is common. High dose chemotherapy followed by autologous bone marrow transplantation or peripheral blood stem cell reinfusion may prolong survival and free time to progression, but, to date, there are no indications of cure. This therapeutic procedure, therefore, should be considered for randomized trials for young patients with poor prognostic factors.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Diagnosis, Differential; Drug Therapy, Combination; Erythropoietin; Humans; Interferon-alpha; Melphalan; Middle Aged; Monoclonal Gammopathy of Undetermined Significance; Multiple Myeloma; Prednisone; Prognosis

Topics: Bone Marrow Transplantation; Cyclophosphamide; Drug Administration Schedule; Drug Therapy, Combination; Humans; Interferons; Melphalan; Multiple Myeloma; Prednisolone; Prognosis

Topics: Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Bone Marrow Transplantation; Chromosome Aberrations; Clinical Trials as Topic; Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Multiple Myeloma; Neutropenia; Plasma Cells; Prognosis

Topics: Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Dexamethasone; Doxorubicin; Humans; Melphalan; Multiple Myeloma; Prednisone; Vincristine

The interrelation between plasma cell dyscrasia and myelofibrosis or agnogenic myeloid metaplasia (AMM) is unclear. The existence of two distinct syndromes has been proposed: (1) plasma cell dyscrasia associated with simple marrow fibrosis caused by the secretion of lymphokines and (2) myeloma coexisting with AMM representing two distinct clonal diseases.. The authors report the case of a 68 year-old man seen initially with severe anemia, massive splenomegaly, a leuko-erythroblastic blood morphology, and myelofibrosis coexisting with massive bone marrow infiltration with IgA lambda-producing plasmacytoid cells.. Cyclic therapy with vincristine, carmustine, cyclophosphamide, melphalan, and prednisone resulted in clinical remission of the myeloma lasting for 2 years and complete resolution of all the clinical features resembling AMM.. The authors' observations and the report of two other patients in whom remission of AMM has been observed after myeloma treatment underline the broad spectrum of secondary abnormalities ranging from moderate bone marrow fibrosis to the full clinical expression of a syndrome closely mimicking AMM. These secondary abnormalities are potentially reversible even in the presence of advanced bone marrow fibrosis and massive splenomegaly.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Cyclophosphamide; Diagnosis, Differential; Female; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Paraproteinemias; Prednisone; Primary Myelofibrosis; Splenomegaly; Vincristine

Topics: Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Dexamethasone; Doxorubicin; Drug Resistance; Humans; Interferon-alpha; Interferons; Melphalan; Multiple Myeloma; Vincristine

Topics: Adenocarcinoma; Aged; Colonoscopy; Gastroscopy; Humans; Male; Melphalan; Multiple Myeloma; Neoplasms, Second Primary; Prednisolone; Sigmoid Neoplasms; Stomach Neoplasms

The author presents part II of his review on the treatment of refractory myeloma. Treatment with large doses of melphalane, 140 mg/m2, was associated with a high death rate and therefore it is used nowadays only in combination with autologous transplantation or treatment with leucocytic growth factors (GM-CSF and G-CSF). Medium doses of melphalane (25 mg/m2 to 70 mg/m2) are tolerated better and are one of the possible approaches. Another possible therapeutic procedure is whole-body irradiation. The advantage of extensive irradiation is rapid regression of pain. Interferon-alpha achieves a therapeutic response in some 20% of refractory patients. Finally the author presents some data on transplantation of bone marrow in patients with multiple myeloma.

Topics: Bone Marrow Transplantation; Combined Modality Therapy; Humans; Interferon-alpha; Melphalan; Multiple Myeloma

Topics: Melphalan; Meta-Analysis as Topic; Multiple Myeloma; Prednisolone; Randomized Controlled Trials as Topic; Survival Rate

Topics: Blood Transfusion; Bone Marrow Purging; Bone Marrow Transplantation; Combined Modality Therapy; Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Multiple Myeloma; Transplantation, Autologous; Whole-Body Irradiation

Before proceeding to treatment selection for multiple myeloma, it is important to exclude monoclonal gammopathy of unknown significance or any similar smouldering or indolent type of myeloma not requiring immediate chemotherapy. In patients with active myeloma, pretreatment prognostic classification is important for appropriate balancing of the risks and benefits of particular treatment options. For example, conventional chemotherapy such as melphalan/prednisone may be appropriate for an elderly patient with active stage III myeloma, whereas high dose chemotherapy with or without bone marrow transplantation or cytokine support may be considered for the patient under age 45 with even earlier stage disease. A variety of options are now available for patients with relapsing or resistant disease, particularly using agents with potential for reversal of multi-drug resistance. The use of interferon-alpha as maintenance following initial response to chemotherapy is important for prolongation of remission, duration and potentially survival. A variety of supportive measures are also helpful including the use of epoetin (erythropoietin) to improve refractory anaemia and bisphosphonates for the inhibition of ongoing bone resorption. With the availability of various treatment options, it has become important for patients to be evaluated by a specialist in the field.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Combined Modality Therapy; Diphosphonates; Drug Resistance; Erythropoietin; Humans; Interferon-alpha; Interleukins; Melphalan; Multiple Myeloma; Prednisolone; Prednisone

Topics: Antineoplastic Combined Chemotherapy Protocols; Humans; Melphalan; Meta-Analysis as Topic; Multiple Myeloma; Prednisone; Survival Analysis; Treatment Outcome

Multiple myeloma still remains a fatal disease. However, in the last months new biological and clinical informations have been provided about this disease. In particular, the immunophenotype of myeloma cells seems indicate, in some patients, a clonal involvement of a stem cell in the pathogenesis of mieloma. Moreover, new biological insights concerning the cytokine network, have revealed a probable effect of some cytokines, such as IL6, IL3, IL4. Finally, new insights in the biology of multiple myeloma have been provided by studies of molecular biology and flow cytometry. As for therapy, the best conventional induction treatment still remains to be defined. In the last years, the increased use of alpha Interferon and new therapeutic modalities, such as transplantation procedures in multiple myeloma, open new hopes toward a cure of this disease. Therefore, in the future a better knowledge of the multiple myeloma biology, associated with a wider use of new effective therapeutic approaches will certainly improve the natural course of this disease.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Humans; Interferon-alpha; Karyotyping; Melphalan; Multiple Myeloma; Phenotype; Prednisone; Prospective Studies; Randomized Controlled Trials as Topic

A 59-year-old female was admitted to Tsukuba University Hospital and diagnosed as IgA-lambda multiple myeloma (stage IIIA). No cardiovascular disorder with the exception of minor ischemic changes in ECG was revealed before treatment. Recombinant human alpha-interferon (IFN) at a dose of 3 million units combined with melphalan and prednisolone was administrated. Sixteen hours after the first administration of IFN, IFN was suspended by the symptoms of congestive heart failure (CHF). Treatment with diuretics and catecholamine products showed almost complete recovery from CHF in 3 weeks. An adverse reaction to IFN was strongly suspected as the cause of CHF.

Topics: Antineoplastic Combined Chemotherapy Protocols; Cardiotonic Agents; Combined Modality Therapy; Cyclophosphamide; Diuretics; Female; Heart Failure; Humans; Immunologic Factors; Interferon Type I; Melphalan; Middle Aged; Multiple Myeloma; Plasmapheresis; Prednisolone; Recombinant Proteins; Vindesine

Topics: Antineoplastic Combined Chemotherapy Protocols; Follow-Up Studies; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Prednisone; Survival Rate

Topics: Antineoplastic Combined Chemotherapy Protocols; Humans; Melphalan; Meta-Analysis as Topic; Multiple Myeloma; Prednisone; Survival Rate

A meta-analysis was performed to compare survival after treatment with melphalan and prednisolone (M + P) with that after combination chemotherapy (CCT) in patients with multiple myeloma.. Meta-analysis was performed on 18 published trials comprising 3,814 patients comparing M + P with CCT. Two-year survival percentages with observed and expected deaths at 2 years were calculated for each trial, and the overview methodology was applied to these figures.. Overall results from the 18 trials suggest that there is no difference in efficacy between the two treatments. This finding, however, masks a highly significant correlation between 2-year survival rates for M + P-treated patients in individual studies and the difference between the M + P and CCT 2-year survival rates for that study (r = .69; P = .0008). In separate overviews, those studies with a high M + P 2-year survival rate showed a survival difference in favor of M + P (P = .02), whereas those with a low rate suggested a difference in favor of CCT (P V .07). Comparison of the 2-year survival rates in the M + P treatment arms of each of the studies with available data showed an inverse correlation between survival and the proportion of patients with either poor performance status (P less than .001) or immunoglobulin A (IgA) M band (P = .02).. These results imply that M + P is superior for patients with an intrinsically good prognosis and inferior for those patients with a poor prognosis. If reliable prognostic factors can be established for this disease, they could be used to select therapy for individual patients.

Topics: Actuarial Analysis; Antineoplastic Combined Chemotherapy Protocols; Humans; Melphalan; Meta-Analysis as Topic; Multiple Myeloma; Prednisolone; Prognosis; Randomized Controlled Trials as Topic; Survival Rate

Topics: Algorithms; Antineoplastic Combined Chemotherapy Protocols; Bone Transplantation; Combined Modality Therapy; Humans; Interferon-alpha; Melphalan; Multiple Myeloma; Radiotherapy Dosage; Remission Induction

L-PAM and prednisone (MP) has been challenged, almost from the start, by combination chemotherapy (CT) with its strong theoretic backing, as the standard chemotherapy for multiple myeloma. In effect, the two contestants were really evenly matched. Unfortunately, neither of them has been able to provide a satisfactory weapon against this remarkably resistant disease. This lack of an effective therapy has stimulated both the search for new strategies and an ongoing controversy. MP remains the standard induction chemotherapy for MM. Nevertheless, in several clinical conditions CT is preferable. The 18% of MM patients who show at presentation acute or chronic renal failure may be safely treated with regimens including cytotoxic drugs with a nonrenal excretion, such as doxorubin. Moreover, low-dose oral melphalan is not recommended for young patients in the event of their enrollment in high-dose programs. The standard chemotherapy for MM will continue to be an area of great controversy until a new treatment strategy proves to be clearly superior in large randomized studies.

Topics: Antineoplastic Combined Chemotherapy Protocols; Humans; Melphalan; Multiple Myeloma; Prednisone; Prognosis

Chemotherapy remains the mainstay in the treatment of multiple myeloma today. Despite improvements in survival and quality of life that can be attributed to advances in chemotherapeutic treatment, multiple myeloma remains an incurable disease. The development of drug resistance accounts for most treatment failures. Mechanisms of resistance for chemotherapeutic agents occur at the cellular level. Some of these mechanisms are unique for a given individual drug, whereas other mechanisms may confer resistance to a wide variety of agents. Important steps for improving treatment include investigating the resistance mechanisms, developing methods to identify drug-resistant cells, and preventing or circumventing drug resistance once it occurs.

Topics: Drug Resistance; Humans; Melphalan; Multiple Myeloma; Nitrosourea Compounds

Topics: Antineoplastic Combined Chemotherapy Protocols; Carmustine; Cyclophosphamide; Doxorubicin; Drug Evaluation; Humans; Melphalan; Multiple Myeloma; Prednisone; Remission Induction; Vincristine

Topics: Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Bone Marrow Transplantation; Combined Modality Therapy; Humans; Melphalan; Multiple Myeloma; Myeloma Proteins; Pain; Palliative Care; Plasmacytoma; Prednisone; Prognosis

Topics: Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Combined Modality Therapy; Humans; Melphalan; Multiple Myeloma; Prognosis; Survival Analysis; Transplantation, Homologous; Whole-Body Irradiation

During the past 5 years, several new treatments and strategies have been developed for patients with multiple myeloma. For patients with disease resistant to standard therapies, these include the VAD regimen, dexamethasone alone, high-dose melphalan, and intensive chemoradiotherapy with bone marrow transplantation. Alpha interferon appears to have its greatest potential as part of early induction therapy or during remission maintenance. The role of hemopoietic growth factors or blood stem cells in support of high-dose therapy and drugs that may overcome multiple drug resistance continues under study. A sequence of non-cross resistant therapies early in the disease course seems worthy of investigation, especially in patients at high risk for early relapse.

Topics: Antineoplastic Combined Chemotherapy Protocols; Blood Transfusion; Bone Marrow Transplantation; Dexamethasone; Doxorubicin; Drug Resistance; Humans; Melphalan; Multiple Myeloma; Vincristine

A dramatic improvement in the prognosis of multiple myeloma has been obtained since treatment with alkylating agents was introduced in the sixties. In recent years much effort has been made to ameliorate the obtained results by employing polychemotherapy schedules of treatment. However, no significant improvements with respect to the conventional melphalan-prednisone treatment, in terms of survival duration, have been observed. New therapeutic approaches, such as the use of biological response modifiers and the autologous or allogeneic bone marrow transplantation offer new perspectives for multiple myeloma patients. In this paper we discuss current trends in the therapy of multiple myeloma and of related complications.

Topics: Acute Kidney Injury; Alkylating Agents; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Humans; Hypercalcemia; Interferon Type I; Kidney Failure, Chronic; Melphalan; Multiple Myeloma; Prednisone; Recurrence

Topics: Antineoplastic Combined Chemotherapy Protocols; Humans; Melphalan; Multiple Myeloma; Prednisone; Prognosis

Topics: Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Combined Modality Therapy; Dexamethasone; Doxorubicin; Humans; Interferon Type I; Melphalan; Multiple Myeloma; Prednisone; Remission Induction; Vincristine

Reports of 13 prospective, randomized clinical trials comparing standard treatment with melphalan and prednisone (MP) versus various drug combinations in the treatment of myeloma patients are presented. These studies reveal that patients with Durie-Salmon Stage III disease respond significantly more frequently to MP and drug combinations than those with Stage I and II. Drug combinations may be more effective in inducing objective responses. The response rates were significantly better for the drug combinations in 3 of the 13 comparisons. There was little evidence that either form of treatment was superior in prolonging survival, for in one study the patients treated with a drug combination lived significantly longer than those treated with MP, while in another the reverse was true, and there was no difference in the survival of the two groups in the remaining 11 studies. In the Vth MRC myelomatosis trial, patients treated with a combination of adriamycin, carmustine, cyclophosphamide and melphalan are living significantly longer than those treated with melphalan alone, and this survival advantage persists after correction for the most important prognostic factor, beta 2 microglobulin. Attempts to increase the intensity of treatment by using syngeneic, allogeneic or autologous marrow transplantation to rescue patients following otherwise lethal chemoradiotherapeutic treatments, have not yet demonstrated conclusively that the myeloma clone can be eliminated by this form of treatment.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Combined Modality Therapy; Humans; Melphalan; Multiple Myeloma; Prednisone; Prospective Studies; Randomized Controlled Trials as Topic

In three studies we have attempted to increase the complete remission rate in a series of patients with multiple myeloma under the age of 69. A CR rate of 27% was seen in 63 patients treated with intravenous high-dose melphalan 140 m/m2 with or without the addition of high-dose methyl prednisolone 1 g/m2 for 5 days (in 22 patients). In a third study a CR rate of 50% was seen in 50 patients treated in a programme in which vincristine, adriamycin and methyl prednisolone was first given and patients then received high-dose melphalan 140-200 mg/m2 with an autologous bone marrow transplant where possible. Median remission duration in the first two studies was 19 months with a median survival of 5 years. A definition of complete remission in myeloma is proposed.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Combined Modality Therapy; Doxorubicin; Evaluation Studies as Topic; Humans; Melphalan; Methylprednisolone; Multiple Myeloma; Remission Induction; Transplantation, Autologous; Vincristine

Topics: Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Cyclophosphamide; Humans; Interferon Type I; Melphalan; Multiple Myeloma; Prednisone; Recombinant Proteins; Vincristine

A 37-year-old male patient with advanced refractory plasma cell myeloma underwent T-cell depleted bone marrow transplantation (BMT) after 7 years of active disease previously treated with combination chemotherapy and irradiation. After the BMT there was marked clinical improvement and the patient is currently in good clinical condition two years after the BMT was performed. However, residual myeloma cells are still seen in the marrow and stable levels of paraprotein are still present in the serum. No GVHD was encountered after BMT. The problems of BMT in myeloma are discussed with a review of the current pertinent literature.

Topics: Adult; Bone Marrow Cells; Bone Marrow Transplantation; Combined Modality Therapy; Cyclophosphamide; Humans; Lymphocyte Depletion; Male; Melphalan; Multiple Myeloma; T-Lymphocytes; Whole-Body Irradiation

We had the opportunity to treat a patient with progressive heavily pretreated multiple myeloma with high-dose chemoradiotherapy with hematopoietic rescue by syngeneic bone marrow transplantation. The patient was a 53-year-old male who had previously received melphalan, prednisone, 1,3-bis (2-chloroethyl)-l-nitrosourea (BCNU), vincristine, and standard radiation therapy. At the time of bone marrow transplantation, he had increasing bone pain, increasing M-protein (IgG kappa), and a bone marrow diagnostic of myeloma. The transplant regimen consisted of cyclophosphamide, 60 mg/kg intravenously for 2 days, and total body irradiation--1,200 rads given as 200-rad fractions, twice daily for three days. The transplant course was complicated by confusion, herpes simplex mucositis, fever, and two episodes of idiopathic diffuse interstitial pneumonia. Over the next 2 years the patient did well and was in immunologic and bone marrow complete remission. Unfortunately, 3 years after treatment, the myeloma relapsed with detectable M-protein. Three and one-half years after transplant, clinical relapse occurred with bone pain and lytic lesions necessitating additional radiation and chemotherapy. Salvage therapy has produced clinical improvement and the patient is alive almost 4 years from transplant and almost 7 years from diagnosis. Although intense chemoradiotherapy did not cure this patient, substantial control of a refractory tumor was observed. This case, together with other cases of intense therapy for myeloma which are reviewed in this paper, support the concept of high-dose therapy and should foster further investigation of high-dose therapy.

Topics: Bone Marrow Transplantation; Combined Modality Therapy; Cyclophosphamide; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Radiotherapy Dosage; Whole-Body Irradiation

Topics: Antineoplastic Combined Chemotherapy Protocols; Drug Administration Schedule; Humans; Melphalan; Multiple Myeloma; Neoplasm Staging; Prednisone; Prospective Studies; Random Allocation

Topics: Adrenal Cortex Hormones; Animals; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Breast Neoplasms; Cyclophosphamide; Dacarbazine; Doxorubicin; Drug Therapy, Combination; Dyspnea; Fluorouracil; Hodgkin Disease; Humans; Hypercalcemia; Leukemia; Leukemia, Lymphoid; Lymphoma; Mechlorethamine; Melphalan; Methotrexate; Multiple Myeloma; Palliative Care; Prednisone; Procarbazine; Receptors, Glucocorticoid; Vinblastine; Vincristine; Vomiting

Topics: Alkylating Agents; Amyloidosis; Anemia; Anemia, Refractory; Animals; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Bacterial Infections; Blood Transfusion; Bone and Bones; Bone Marrow Examination; Bone Marrow Transplantation; Bone Neoplasms; Calcium; Combined Modality Therapy; Diagnosis, Differential; Heavy Chain Disease; Humans; Immunoglobulin D; Immunotherapy; Interferons; Kidney Failure, Chronic; Leukemia; Melphalan; Mice; Monoclonal Gammopathy of Undetermined Significance; Multiple Myeloma; Myeloma Proteins; Osteolysis; Osteosclerosis; Paraproteinemias; Plasma Cells; Plasmacytoma; Prednisone; Radionuclide Imaging; Waldenstrom Macroglobulinemia

Topics: Antineoplastic Combined Chemotherapy Protocols; Bone and Bones; Clinical Trials as Topic; Cyclophosphamide; Drug Administration Schedule; Drug Resistance; Humans; Interferon Type I; Interferons; Melphalan; Multiple Myeloma; Prednisone; Radiography; Recombinant Proteins

Topics: Alkylating Agents; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Doxorubicin; Drug Administration Schedule; Drug Resistance; Humans; Melphalan; Multiple Myeloma; Time Factors

Patients with benign monoclonal gammopathy or smouldering multiple myeloma should not be treated. The plasma cell labelling index utilizing tritiated thymidine or a monoclonal antibody to 5-bromo-2-deoxyuridine is helpful in differentiating patients with benign monoclonal gammopathy or smouldering myeloma from those with overt myeloma. Although combinations of chemotherapeutic agents seem to produce a greater number of objective responses than does melphalan-prednisone, a significant difference in survival has not been proved. Possibilities for future treatment include chemotherapy with large intravenous doses of melphalan, very small doses of cyclophosphamide or melphalan, the administration of hydroxyurea before chemotherapy, combination of interferon with alkylating agents, autologous bone marrow transplantation, and improvement of the soft-agar colony-forming assay for myeloma cells. The therapeutic use of monoclonal antibodies to plasma cell antigens may be possible in the future. Much more needs to be learned about the biologic basis of myeloma before real progress can be made.

Topics: Acute Kidney Injury; Anemia; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Blood Viscosity; Bone Diseases; Bone Marrow Transplantation; Drug Resistance; Humans; Hypercalcemia; Kidney Failure, Chronic; Melphalan; Multiple Myeloma; Prednisone; Spinal Cord Compression; Time Factors

Topics: Acute Kidney Injury; Altretamine; Anemia; Bacterial Infections; Bone Neoplasms; Cyclophosphamide; Doxorubicin; Drug Therapy, Combination; Humans; Hypercalcemia; Interferons; Kidney Failure, Chronic; Melphalan; Meningeal Neoplasms; Multiple Myeloma; Spinal Cord Compression; Vinblastine; Vincristine; Vindesine

Topics: Antineoplastic Agents; Drug Therapy, Combination; Humans; Hypercalcemia; Kidney Diseases; Melphalan; Multiple Myeloma; Myeloma Proteins; Pain; Prognosis

A case of immunoglobulin E (IgE) myeloma with clinical features of "classic" myeloma is presented. Skeletal roentgenograms showed osteoporosis and compression fractures of the vertebrae but no osteosclerosis. Protein analyses revealed an M component of the IgE kappa type with a concentration of 3.1 g/dl. Although morphologic examination revealed that the plasma cells were not so differentiated, well-developed Golgi apparatus and abundant rough-surfaced endoplasmic reticulum were observed. An indirect immunofluorescence technique showed characteristic apple green fluorescence. The E myeloma protein of our patient had no antibody activity. Treatment with melphalan or cyclophosphamide resulted in a decrease in the serum IgE level and in the level of Bence Jones protein in the urine. The clinical and laboratory features of IgE myeloma were summarized and compared with those of other classes of myeloma.

Topics: Aged; Bence Jones Protein; Cyclophosphamide; Female; Humans; Immunoglobulin E; Male; Melphalan; Middle Aged; Multiple Myeloma; Myeloma Proteins; Plasma Cells; Radiography

Topics: Antineoplastic Agents; Azathioprine; Carmustine; Chlorambucil; Cyclophosphamide; Drug Therapy, Combination; Humans; Melphalan; Multiple Myeloma; Prednisone; Procarbazine; Vincristine

Topics: Adrenal Cortex Hormones; Antineoplastic Agents; Blood Viscosity; Cyclophosphamide; Drug Therapy, Combination; Humans; Leukemia; Melphalan; Multiple Myeloma; Neoplasm Staging; Prognosis

Topics: Adult; Aged; Arsenic; Benzene; Bone Marrow; Breast Neoplasms; Female; Hodgkin Disease; Humans; Leukemia; Leukemia, Lymphoid; Lymphoma; Male; Melphalan; Middle Aged; Multiple Myeloma; Mycosis Fungoides; Ovarian Neoplasms; Paraproteinemias; Waldenstrom Macroglobulinemia

The basic pathologic process in multiple myeloma is the neoplastic proliferation of a single clone of plasma cells. Although the events which trigger autonomous cell growth are not well understood, the secretion of an M component, a serum or urinary immunoglobulin molecule or a light chain fragment by the vast majority of myeloma cells has provided a biologic marker which has greatly facilitated the study of this disease Some of the more recent clinical concepts which have evolved from studies on the plasma cell and the immunoglobulin molecule are discussed.

Topics: Alkylating Agents; Amyloidosis; Bacterial Infections; Blood Viscosity; Bone Diseases; Clone Cells; Hemostasis; Humans; Hypercalcemia; Kidney Failure, Chronic; Melphalan; Multiple Myeloma; Paraproteins

Topics: Antineoplastic Agents; Carmustine; Cyclophosphamide; Drug Therapy, Combination; Humans; Immunoglobulins; Lomustine; Melphalan; Multiple Myeloma; Neoplasm Staging; Plasmapheresis; Prednisone; Risk; Sodium Fluoride; Uremia

Topics: Age Factors; Blood Viscosity; Cyclophosphamide; Drug Therapy, Combination; Humans; Kidney; Melphalan; Multiple Myeloma; Neoplasm Recurrence, Local; Neoplasm Staging; Prognosis

The results of a follow-up study of 112 patients with multiple myeloma are presented. Three of these patients developed acute leukaemia during the respective period of clinical observation (maximum: 11 years)--one case of acute myeloblastic leukaemia, myelomonocytic leukaemia and erythroleukaemia, respectively. For estimating the incidence of acute leukaemia in the presence of multiple myeloma an extended life table method was applied. On the basis of our data this method gave a probability of 5.9% for a patient to develop acute leukaemia at any time after the diagnosis of multiple myeloma. In a statistical discussion this result is considered to confirm the assumption of a highly increased AL-risk in patients with multiple myeloma. In a survey of the literature some important data of 100 cases with the association acute leukaemia--multiple myeloma are reported.

Topics: Acute Disease; Aged; Female; Humans; Leukemia; Leukemia, Erythroblastic, Acute; Leukemia, Monocytic, Acute; Leukemia, Myeloid, Acute; Male; Melphalan; Middle Aged; Multiple Myeloma; Probability; Time Factors

A case of fatal pulmonary fibrosis and atypical epithelial proliferation (AEP) in a patient with multiple myeloma treated with melphalan is presented. Review of 10 other autopsied patients with myeloma treated with melphalan but no thoracic radiation, other cytotoxic agents, or highdose oxygen therapy revealed one other patient who died with extensive pulmonary fibrosis and AEP. Four other patients with AEP not associated with pneumonitis or fibrosis were also found, while no such changes were found in 11 autopsy controls or 11 patients with myeloma who did not receive cytotoxic agents. Melphalan should be added to the growing list of agents capable of causing severe fibrotic pulmonary reactions.

Topics: Aged; Drug Therapy, Combination; Epithelium; Humans; Lung; Male; Melphalan; Middle Aged; Multiple Myeloma; Prednisone; Pulmonary Fibrosis

Topics: Adult; Aged; Antineoplastic Agents; Carmustine; Cyclophosphamide; Drug Therapy, Combination; Female; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Prednisone; Procarbazine

Although cytotoxic immunosuppressive agents play an unquestionably useful role in treating many neoplastic and non-neoplastic disorders, there is accumulating evidence that the toxicity associated with their use is considerable. The therapeutic successes obtained with antitumor agents have led to increases in the life span of cancer patients, but have also provided the opportunity for this toxicity to become manifest. A search of the available literature was carried out, with emphasis on cases in which a malignancy developed in patients following chemotherapy for either neoplastic or non-neoplastic (e.g., renal transplantation, psoriasis) conditions; particular focus was given to the incidence of acute myelogenous leukemia in various groups of Hodgkin's disease and multiple myeloma patients. That patients with nonmalignant conditions treated with cytotoxic immunosuppressive agents are also at increased risk of developing a malignancy raises the possibility that these agents may have oncogenic potential. Therefore, one may be faced with the paradox that the patients benefiting most from chemotherapy may be at highest risk of suffering its consequences.

Topics: Alkylating Agents; Animals; Antineoplastic Agents; Azathioprine; Burkitt Lymphoma; Choriocarcinoma; Cyclophosphamide; Dactinomycin; Female; Hodgkin Disease; Humans; Immunosuppressive Agents; Kidney Neoplasms; Leukemia, Myeloid, Acute; Lymphoma; Mechlorethamine; Melphalan; Mercaptopurine; Methotrexate; Mice; Multiple Myeloma; Neoplasms; Prednisone; Pregnancy; Procarbazine; Time Factors; Vincristine

Topics: Blood Coagulation; Blood Coagulation Disorders; Blood Coagulation Factors; Fibrinolysis; Humans; Leukemia, Plasma Cell; Melphalan; Multiple Myeloma; Paraproteinemias; Plasminogen; Plasminogen Activators

Topics: Bone Neoplasms; Carmustine; Cyclophosphamide; Drug Therapy, Combination; Humans; Melphalan; Multiple Myeloma; Prednisone; Procarbazine; Urethane; Vincristine

Topics: Animals; Carmustine; Cytarabine; Doxorubicin; Drug Evaluation, Preclinical; Fluorouracil; Humans; Melphalan; Methotrexate; Mice; Mice, Inbred BALB C; Multiple Myeloma; Myeloma Proteins; Prednisone; Procarbazine; Remission, Spontaneous

Topics: Antibody Formation; Cell Count; Cell Movement; Diagnosis, Computer-Assisted; DNA, Neoplasm; Evaluation Studies as Topic; Humans; Immunity, Cellular; Immunoglobulins; In Vitro Techniques; Melphalan; Models, Theoretical; Multiple Myeloma; Regression Analysis; Thymidine; Tritium

Topics: Anemia; Blood Protein Electrophoresis; Blood Transfusion; Blood Viscosity; Chlorambucil; Drug Therapy, Combination; Humans; Melphalan; Multiple Myeloma; Plasmacytoma; Prednisolone; Waldenstrom Macroglobulinemia

Topics: Antineoplastic Agents; Cyclophosphamide; Drug Therapy, Combination; Humans; Melphalan; Multiple Myeloma; Nitrosourea Compounds; Plasmacytoma; Procarbazine; Waldenstrom Macroglobulinemia

Topics: Adult; Aged; Antineoplastic Agents; Bone Marrow; Bone Marrow Cells; Drug Therapy, Combination; Female; Hematocrit; Hemoglobins; Humans; Immunoglobulins; Leukemia; Leukemia, Myeloid, Acute; Leukocyte Count; Male; Melphalan; Middle Aged; Multiple Myeloma; Prednisone; Remission, Spontaneous; Syndrome

Topics: Adrenal Cortex Hormones; Adrenocorticotropic Hormone; Anemia; Anemia, Hemolytic, Autoimmune; Blood Urea Nitrogen; Glucocorticoids; Humans; Hypercalcemia; Immunoglobulins; Leukemia; Lymphoma; Melphalan; Multiple Myeloma; Myeloma Proteins; Prednisone; Waldenstrom Macroglobulinemia

Topics: Adenocarcinoma; Alkylating Agents; Antineoplastic Agents; Breast Neoplasms; Carcinoma; Carcinoma, Bronchogenic; Carmustine; Cyclohexanes; Cyclophosphamide; Cytarabine; Drug Therapy, Combination; Hodgkin Disease; Humans; Hydroxyurea; Leukemia, Lymphoid; Leukemia, Myeloid; Lymphoma; Melanoma; Melphalan; Multiple Myeloma; Nitrosourea Compounds; Prednisone; Vincristine

Topics: Amino Acid Sequence; Amyloid; Amyloidosis; Antigen-Antibody Complex; Aspartic Acid; Bence Jones Protein; Bone Neoplasms; Cyclophosphamide; Fluorescent Antibody Technique; Humans; Immunoglobulins; Melphalan; Molecular Weight; Multiple Myeloma; Myeloma Proteins; Peptides; Plasma Cells; Polysaccharides; Ultracentrifugation

Topics: Animals; Antibody-Producing Cells; Blood Protein Disorders; Clone Cells; Cyclophosphamide; Humans; Immunoglobulins; Melphalan; Mice; Multiple Myeloma; Plasma Cells

Topics: Adrenal Cortex Hormones; Antineoplastic Agents; Carmustine; Cell Division; Cyclophosphamide; Drug Resistance; Humans; Melphalan; Multiple Myeloma; Nitrosourea Compounds; Prednisone; Procarbazine; Prognosis; Remission, Spontaneous

Topics: Bence Jones Protein; Blood Protein Electrophoresis; Bone Marrow Cells; Cell Count; Clone Cells; Cyclophosphamide; DNA; gamma-Globulins; Humans; Immunoglobulin G; Immunoglobulins; Leukemia, Myeloid; Melphalan; Middle Aged; Multiple Myeloma; Mutation; Plasmacytoma; Ribosomes

Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Bone Marrow; Bone Marrow Cells; Cell Division; Cyclophosphamide; Cytarabine; Female; Fluorouracil; Humans; Leukemia L1210; Leukemia, Lymphoid; Lymphoma; Melphalan; Mercaptopurine; Methotrexate; Mice; Multiple Myeloma; Neoplasms; Nitrogen Mustard Compounds; Prednisone; Pregnancy; Time Factors; Trophoblastic Neoplasms; Vinblastine

Topics: Amyloid; Amyloidosis; Anemia; Antineoplastic Agents; Clinical Trials as Topic; Cyclophosphamide; Hodgkin Disease; Humans; Immunodiffusion; Immunoelectrophoresis; Immunoglobulin G; Immunoglobulin M; Immunoglobulins; Infections; Leukemia, Lymphoid; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Non-Hodgkin; Melphalan; Multiple Myeloma; Prognosis; Pyelonephritis

A second intensification is an option at first relapse in multiple myeloma (MM) after more than 36 months of initial remission. Many conditioning regimens have been tested, with or without total body irradiation (TBI). Recently, it was found that TBI could be replaced by total marrow irradiation (TMI) using helical tomotherapy, with promising results.. This study was a prospective multicenter phase 1 trial that aimed to determine the maximum tolerated dose (MTD) of TMI administered in association with melphalan 140 mg/m², followed by autologous stem cell transplantation as consolidation at first relapse in MM. Four dose levels were explored: 8 Gy, 10 Gy, 12 Gy, and 14 Gy. The dose-limiting toxicity (DLT) was defined as grade 4 neutropenia >15 days, grade 4 thrombopenia >28 days, and all other grade 4 nonhematologic toxic effects except nausea, vomiting, alopecia, mucositis, and reaction to autologous stem cell infusion.. Thirteen patients were included; only 1 DLT at the third escalated dose level (12 Gy) was observed, whereas 1 patient was treated at 14 Gy with no adverse events. The MTD was not reached. The rate of acute toxicity was low: 38% of grade 3-4 diarrhea, mucositis, or unexplained fever. Regarding the lungs, the mean dose administered was systematically less than 8 Gy. After a median follow-up of 55 months, 70% of participants were alive. Of these 13 patients, 38.5% were in very good partial response and 30.8% were in complete response. Three of them were progression-free. Six patients were long survivors, still alive after 55 months of follow-up.. Total marrow irradiation provides good results with a good tolerance profile at first relapse in MM and makes it possible to increase the dose delivered to the planning target volume while sparing organs at risk. This technique could be discussed for all regimens before auto- or allo-stem cell rescue when TBI is required.

Topics: Bone Marrow; Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Mucositis; Multiple Myeloma; Prospective Studies; Radiotherapy, Intensity-Modulated; Recurrence; Transplantation, Autologous; Whole-Body Irradiation

Topics: Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Disease-Free Survival; Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Multiple Myeloma; Transplantation Conditioning; Transplantation, Autologous; Treatment Outcome

Relapsed/refractory multiple myeloma (RRMM) is known to have a high burden of disease and complications associated with refractoriness to prior lines of therapy. Severe pain and fatigue symptoms and impairments in physical and emotional functioning have been strongly linked to reduced health-related quality of life (HRQoL) in patients with RRMM. Assessment of patient reported-outcome measures from the pivotal, Phase II HORIZON study (OP-106; NCT02963493) in patients with RRMM (n = 64) demonstrated that melphalan flufenamide (melflufen) plus dexamethasone treatment preserved HRQoL. Patients had clinically meaningful improvements, even after eight treatment cycles, in relevant scales such as global health status/QoL, physical functioning, emotional functioning, pain, and fatigue. Patients with triple-class-refractory disease (n = 50) displayed similar improvements. Patient-reported outcome deterioration was delayed for a substantial amount of time in patients who experienced a response to melflufen plus dexamethasone treatment relative to patients who did not experience a response. These findings support the notion that treatment with melflufen plus dexamethasone may sustain or improve HRQoL over time in patients with RRMM, including in patients with triple-class-refractory disease for whom outcomes are generally worse. The clinical benefits observed in patients from the HORIZON trial are encouraging and supportive of translation into real-world practice.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Dexamethasone; Female; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Neoplasm Grading; Neoplasm Staging; Patient Reported Outcome Measures; Treatment Outcome

Melphalan flufenamide (melflufen), an alkylating peptide-drug conjugate, plus dexamethasone showed clinical activity and manageable safety in the phase 2 HORIZON study. We aimed to determine whether melflufen plus dexamethasone would provide a progression-free survival benefit compared with pomalidomide plus dexamethasone in patients with previously treated multiple myeloma.. In this randomised, open-label, head-to-head, phase 3 study (OCEAN), adult patients (aged ≥18 years) were recruited from 108 university hospitals, specialist hospitals, and community-based centres in 21 countries across Europe, North America, and Asia. Eligible patients had an ECOG performance status of 0-2; must have had relapsed or refractory multiple myeloma, refractory to lenalidomide (within 18 months of randomisation) and to the last line of therapy; and have received two to four previous lines of therapy (including lenalidomide and a proteasome inhibitor). Patients were randomly assigned (1:1), stratified by age, number of previous lines of therapy, and International Staging System score, to either 28-day cycles of melflufen and dexamethasone (melflufen group) or pomalidomide and dexamethasone (pomalidomide group). All patients received dexamethasone 40 mg orally on days 1, 8, 15, and 22 of each cycle. In the melflufen group, patients received melflufen 40 mg intravenously over 30 min on day 1 of each cycle and in the pomalidomide group, patients received pomalidomide 4 mg orally daily on days 1 to 21 of each cycle. The primary endpoint was progression-free survival assessed by an independent review committee in the intention-to-treat (ITT) population. Safety was assessed in patients who received at least one dose of study medication. This study is registered with ClinicalTrials.gov, NCT03151811, and is ongoing.. Between June 12, 2017, and Sept 3, 2020, 246 patients were randomly assigned to the melflufen group (median age 68 years [IQR 60-72]; 107 [43%] were female) and 249 to the pomalidomide group (median age 68 years [IQR 61-72]; 109 [44%] were female). 474 patients received at least one dose of study drug (melflufen group n=228; pomalidomide group n=246; safety population). Data cutoff was Feb 3, 2021. Median progression-free survival was 6·8 months (95% CI 5·0-8·5; 165 [67%] of 246 patients had an event) in the melflufen group and 4·9 months (4·2-5·7; 190 [76%] of 249 patients had an event) in the pomalidomide group (hazard ratio [HR] 0·79, [95% CI 0·64-0·98]; p=0·032), at a median follow-up of 15·5 months (IQR 9·4-22·8) in the melflufen group and 16·3 months (10·1-23·2) in the pomalidomide group. Median overall survival was 19·8 months (95% CI 15·1-25·6) at a median follow-up of 19·8 months (IQR 12·0-25·0) in the melflufen group and 25·0 months (95% CI 18·1-31·9) in the pomalidomide group at a median follow-up of 18·6 months (IQR 11·8-23·7; HR 1·10 [95% CI 0·85-1·44]; p=0·47). The most common grade 3 or 4 treatment-emergent adverse events were thrombocytopenia (143 [63%] of 228 in the melflufen group vs 26 [11%] of 246 in the pomalidomide group), neutropenia (123 [54%] vs 102 [41%]), and anaemia (97 [43%] vs 44 [18%]). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]). 27 [12%] patients in the melflufen group and 32 [13%] in the pomalidomide group had fatal treatment-emergent adverse events. Fatal treatment-emergent adverse events were considered possibly treatment related in two patients in the melflufen group (one with acute myeloid leukaemia, one with pancytopenia and acute cardiac failure) and four patients in the pomalidomide group (two patients with pneumonia, one with myelodysplastic syndromes, one with COVID-19 pneumonia).. Melflufen plus dexamethasone showed superior progression-free survival than pomalidomide plus dexamethasone in patients with relapsed or refractory multiple myeloma.. Oncopeptides AB.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; COVID-19 Drug Treatment; Dexamethasone; Female; Humans; Lenalidomide; Male; Melphalan; Middle Aged; Multiple Myeloma; Phenylalanine; SARS-CoV-2; Thalidomide

High-dose melphalan (HDM) and transplantation are recommended for eligible patients with multiple myeloma. No other conditioning regimen has proven to be more effective and/or safer. We previously reported in a phase 2 study that bortezomib can safely and effectively be combined with HDM (Bor-HDM), with a 32% complete response (CR) rate after transplantation. These data supported a randomized phase 3 trial. Randomization was stratified according to risk and response to induction: 300 patients were enrolled, and 154 were allocated to the experimental arm (ie, arm A) with bortezomib (1 mg/m2 intravenously [IV]) on days -6, -3, +1, and +4 and melphalan (200 mg/m2 IV) on day -2. The control arm (ie, arm B) consisted of HDM alone (200 mg/m2 IV). There were no differences in stringent CR + CR rates at day 60 posttransplant (primary end point): 22.1% in arm A vs 20.5% in arm B (P = .844). There were also no differences in undetectable minimum residual disease rates: 41.3% vs 39.4% (P = .864). Median progression-free survival was 34.0 months for arm A vs 29.6 months for arm B (adjusted HR, 0.82; 95% CI, 0.61-1.13; P = .244). The estimated 3-year overall survival was 89.5% in both arms (hazard ratio, 1.28; 95% CI, 0.62-2.64; P = .374). Sixty-nine serious adverse events occurred in 18.7% of Bor-HDM-treated patients (vs 13.1% in HDM-treated patients). The proportion of grade 3/4 AEs was similar within the 2 groups (72.0% vs 73.1%), mainly (as expected) blood and gastrointestinal disorders; 4% of patients reported grade 3/4 or painful peripheral neuropathy in arm A (vs 1.5% in arm B). In this randomized phase 3 study, a conditioning regimen with Bor-HDM did not improve efficacy end points or outcomes compared with HDM alone. The original trial was registered at www.clinicaltrials.gov as #NCT02197221.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Humans; Melphalan; Multiple Myeloma; Transplantation, Autologous

Total body irradiation in combination with melphalan for multiple myeloma (MM) has been shown to be prohibitively toxic. To ameliorate toxicity, total marrow irradiation (TMI) has been administered as the sole ablative modality during the second cycle of tandem autologous stem cell transplantation (TASCT) for MM patients on a phase I-II trial. Patients with MM in response or with stable disease and ≤18 months from diagnosis received melphalan 200 mg/m

Topics: Bone Marrow; Follow-Up Studies; Hematopoietic Stem Cell Transplantation; Humans; Male; Melphalan; Multiple Myeloma; Transplantation, Autologous

High-dose chemotherapy causes intestinal inflammation and subsequent breakdown of the mucosal barrier, permitting translocation of enteric pathogens, clinically manifesting as fever. Antibiotics are mainstay for controlling these complications, however, they are increasingly recognized for their detrimental effects, including antimicrobial resistance and dysbiosis. Here, we show that mucosal barrier injury induced by the mucotoxic chemotherapeutic agent, high-dose melphalan (HDM), is characterized by hyper-active IL-1b/CXCL1/neutrophil signaling. Inhibition of this pathway with IL-1RA, anakinra, minimized the duration and intensity of mucosal barrier injury and accompanying clinical symptoms, including diarrhea, weight loss and fever in rats. 16S analysis of fecal microbiome demonstrated a more stable composition in rats receiving anakinra, with reduced pathogen expansion. In parallel, we report through Phase IIA investigation that anakinra is safe in stem cell transplant patients with multiple myeloma after HDM. Ramping-up anakinra (100-300 mg administered intravenously for 15 days) did not cause any adverse events or dose limiting toxicities, nor did it change time to neutrophil recovery. Our results reinforce that strengthening the mucosal barrier may be an effective supportive care strategy to mitigate local and systemic clinical consequences of HDM. We are now conducting a Phase IIB multicenter, placebo-controlled, double-blinded trial to assess clinical efficacy of anakinra (AFFECT-2).Trial registration: ClinicalTrials.gov identifier: NCT03233776.

Topics: Animals; Fever; Hematopoietic Stem Cell Transplantation; Humans; Interleukin 1 Receptor Antagonist Protein; Interleukin-1; Melphalan; Multiple Myeloma; Rats; Tumor Microenvironment

Single-agent high-dose melphalan (Mel) followed by autologous stem cell transplantation (ASCT) remains a standard of care in eligible patients with multiple myeloma (MM), and efforts to improve transplant outcomes by intensifying transplant conditioning have mostly failed. Bendamustine combines both alkylating and antimetabolite properties, can induce responses in MM resistant to other alkylators and represents a promising agent to combine with Mel prior to ASCT. We performed a phase II study to test the safety and efficacy of the high-dose chemotherapy combination of bendamustine, etoposide, cytarabine, and melphalan (BeEAM) in newly diagnosed MM patients up to 70 years of age. The primary study endpoint was the day 100 complete response rate. Sixty-five patients with a median (range) age of 59 (40-69) years underwent transplantation from 2015 to 2020. Other characteristics included Karnofsky performance status <80%, hematopoietic cell transplantation-comorbidity index ≥3, International Staging System III, and high-risk fluorescein in situ hybridization (FISH) in 35%, 46%, 26%, and 44%, respectively. ASCT after BeEAM was well tolerated, and there were no non-relapse deaths through 1 year after transplantation. Although at least 1 nonhematologic grade 3 toxicity was reported in 58 (89%) patients (including grade 3 febrile neutropenia in 48% and stomatitis/esophagitis in 28%), there were no grade ≥3 renal or hepatic toxicity and no grade ≥4 non-hematologic toxicity. The day 100 response rate was ≥CR1 and ≥ very good partial response (VGPR1) in 40% and 89%, respectively. With a median follow-up of 44 (13-70) months, the 3-year overall survival was 92%, 96%, and 90% for all patients and those with standard- and high-risk FISH, respectively. The corresponding values for 3-year progression-free survival was 57%, 72%, and 40%, respectively. When BeEAM-conditioned patients were compared to historical Mel-conditioned cohort, no significant differences were noted in relapse or survival outcomes in univariate or multivariable analysis. In summary, BeEAM was shown to be a safe and effective conditioning regimen before up-front autologous transplant for MM. Although the BeEAM regimen does not appear to offer a significant advantage over single-agent Mel, further studies combining bendamustine and melphalan in the front-line setting may be warranted.

Topics: Bendamustine Hydrochloride; Cytarabine; Drug Therapy, Combination; Etoposide; Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Multiple Myeloma; Neoplasm Recurrence, Local; Transplantation, Autologous

In patients with newly diagnosed multiple myeloma, the effect of adding autologous stem-cell transplantation (ASCT) to triplet therapy (lenalidomide, bortezomib, and dexamethasone [RVD]), followed by lenalidomide maintenance therapy until disease progression, is unknown.. In this phase 3 trial, adults (18 to 65 years of age) with symptomatic myeloma received one cycle of RVD. We randomly assigned these patients, in a 1:1 ratio, to receive two additional RVD cycles plus stem-cell mobilization, followed by either five additional RVD cycles (the RVD-alone group) or high-dose melphalan plus ASCT followed by two additional RVD cycles (the transplantation group). Both groups received lenalidomide until disease progression, unacceptable side effects, or both. The primary end point was progression-free survival.. Among 357 patients in the RVD-alone group and 365 in the transplantation group, at a median follow-up of 76.0 months, 328 events of disease progression or death occurred; the risk was 53% higher in the RVD-alone group than in the transplantation group (hazard ratio, 1.53; 95% confidence interval [CI], 1.23 to 1.91; P<0.001); median progression-free survival was 46.2 months and 67.5 months. The percentage of patients with a partial response or better was 95.0% in the RVD-alone group and 97.5% in the transplantation group (P = 0.55); 42.0% and 46.8%, respectively, had a complete response or better (P = 0.99). Treatment-related adverse events of grade 3 or higher occurred in 78.2% and 94.2%, respectively; 5-year survival was 79.2% and 80.7% (hazard ratio for death, 1.10; 95% CI, 0.73 to 1.65).. Among adults with multiple myeloma, RVD plus ASCT was associated with longer progression-free survival than RVD alone. No overall survival benefit was observed. (Funded by the National Heart, Lung, and Blood Institute and others; DETERMINATION ClinicalTrials.gov number, NCT01208662.).

Topics: Adult; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Dexamethasone; Disease Progression; Disease-Free Survival; Humans; Lenalidomide; Maintenance Chemotherapy; Melphalan; Multiple Myeloma; Stem Cell Transplantation; Transplantation, Autologous

This study estimated the comparative efficacy of ciltacabtagene autoleucel (cilta-cel; CARTITUDE-1), a chimeric antigen receptor (CAR)-T-cell therapy, versus 3 non-CAR-T therapies (belantamab mafodotin [DREAMM-2], selinexor plus dexamethasone [STORM Part 2], and melphalan flufenamide plus dexamethasone [HORIZON]), each with distinct mechanisms of action, for the treatment of patients with relapsed or refractory multiple myeloma (RRMM) who were triple-class exposed to an immunomodulatory drug, proteasome inhibitor, and an anti-CD38 monoclonal antibody.. Pairwise matching-adjusted indirect treatment comparisons (MAICs) were conducted using patient-level data for cilta-cel from CARTITUDE-1 and summary level data for each comparator (2.5 mg/kg cohort in DREAMM-2, modified intention-to-treat population in STORM Part 2, and triple-class refractory patients in HORIZON). Treated patients from CARTITUDE-1 who satisfied the eligibility of the comparator trial were included. MAICs adjusted for imbalances in important prognostic factors between CARTITUDE-1 and the comparator populations. Comparative efficacy of cilta-cel versus each therapy was estimated for overall response rate, complete response or better rate, progression-free survival, and overall survival.. After adjustment, patients treated with cilta-cel demonstrated at least a 3.1-fold and at least a 10.3-fold increase in the likelihood of achieving an overall response or complete response or better, respectively, at least a 74% reduction in the risk of disease progression or death, and at least a 47% reduction in the risk of death. These results were statistically significant.. Cilta-cel showed improved efficacy over each comparator for all outcomes, demonstrating its potential as an efficacious treatment for patients with triple-class exposed RRMM.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Humans; Hydrazines; Melphalan; Multiple Myeloma; Triazoles

Bortezomib (Btz) shows robust efficacy in patients with multiple myeloma (MM); however, some patients experience suboptimal responses and show specific toxicities. Therefore, we attempted to identify specific HLA alleles associated with Btz-related toxicities and response to treatment. Eighty-two transplant-ineligible patients with newly diagnosed MM enrolled in a phase II study (JCOG1105) comparing two less intensive melphalan, prednisolone, plus Btz (MPB) regimens were subjected to HLA typing. The frequency of each allele was compared between the groups, categorized based on toxicity grades and responses to MPB therapy. Among 82 patients, the numbers of patients with severe peripheral neuropathy (PN; grade 2 or higher), skin disorders (SD; grade 2 or higher), and pneumonitis were 16 (19.5%), 15 (18.3%), and 6 (7.3%), respectively. Complete response was achieved in 10 (12.2%) patients. Although no significant HLA allele was identified by multiple comparisons, several candidates were identified. HLA-B*40:06 was more prevalent in patients with severe PN than in those with less severe PN (odds ratio [OR] = 6.76). HLA-B*40:06 and HLA-DRB1*12:01 were more prevalent in patients with SD than in those with less severe SD (OR = 7.47 and OR = 5.55, respectively). HLA-DRB1*08:02 clustered in the group of patients with pneumonitis (OR = 11.34). Complete response was achieved in patients carrying HLA-DQB1*03:02, HLA-DQB1*05:01, and HLA-DRB1*01:01 class II alleles. HLA genotyping could help predict Btz-induced toxicity and treatment efficacy in patients with MM, although this needs further validation.

Topics: Aged; Antineoplastic Agents; Bortezomib; Female; Gene Frequency; Genotyping Techniques; HLA Antigens; Humans; Japan; Male; Melphalan; Multiple Myeloma; Peripheral Nervous System Diseases; Pneumonia; Prednisolone; Skin Diseases; Treatment Outcome

Predicting patient outcome in multiple myeloma remains challenging despite the availability of standard prognostic biomarkers. We investigated outcome for patients relapsing early from intensive therapy on NCRI Myeloma XI. Relapse within 12 months of autologous stem cell transplant was associated with markedly worse median progression-free survival 2 (PFS2) of 18 months and overall survival (OS) of 26 months, compared to median PFS2 of 85 months and OS of 91 months for later relapsing patients despite equal access to and use of subsequent therapies, highlighting the urgent need for improved outcome prediction and early intervention strategies for myeloma patients.

Topics: Adult; Aged; Autografts; Cost of Illness; Disease-Free Survival; Female; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Risk Factors; Stem Cell Transplantation; Survival Rate

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Female; Humans; Male; Melphalan; Multiple Myeloma; Prednisolone; Survival Analysis; Treatment Outcome

Melphalan flufenamide (melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and rapidly and selectively releases alkylating agents into tumor cells. The phase II HORIZON trial evaluated the efficacy of melflufen plus dexamethasone in relapsed and refractory multiple myeloma (RRMM), a population with an important unmet medical need.. Patients with RRMM refractory to pomalidomide and/or an anti-CD38 monoclonal antibody received melflufen 40 mg intravenously on day 1 of each 28-day cycle plus once weekly oral dexamethasone at a dose of 40 mg (20 mg in patients older than 75 years). The primary end point was overall response rate (partial response or better) assessed by the investigator and confirmed by independent review. Secondary end points included duration of response, progression-free survival, overall survival, and safety. The primary analysis is complete with long-term follow-up ongoing.. Of 157 patients (median age 65 years; median five prior lines of therapy) enrolled and treated, 119 patients (76%) had triple-class-refractory disease, 55 (35%) had extramedullary disease, and 92 (59%) were refractory to previous alkylator therapy. The overall response rate was 29% in the all-treated population, with 26% in the triple-class-refractory population. In the all-treated population, median duration of response was 5.5 months, median progression-free survival was 4.2 months, and median overall survival was 11.6 months at a median follow-up of 14 months. Grade ≥ 3 treatment-emergent adverse events occurred in 96% of patients, most commonly neutropenia (79%), thrombocytopenia (76%), and anemia (43%). Pneumonia (10%) was the most common grade 3/4 nonhematologic event. Thrombocytopenia and bleeding (both grade 3/4 but fully reversible) occurred concomitantly in four patients. GI events, reported in 97 patients (62%), were predominantly grade 1/2 (93%); none were grade 4.. Melflufen plus dexamethasone showed clinically meaningful efficacy and a manageable safety profile in patients with heavily pretreated RRMM, including those with triple-class-refractory and extramedullary disease.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Disease Progression; Drug Resistance, Neoplasm; Europe; Female; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Phenylalanine; Progression-Free Survival; Recurrence; Time Factors; United States

The goal of this phase II trial was to evaluate safety and efficacy of a tandem autologous hematopoietic cell transplantation (auto-HCT) using sequentially total marrow irradiation (TMI) at the dose of 12 Gy (4 Gy on days -3, -2, and -1) and melphalan 200 mg/m

Topics: Adult; Bone Marrow; Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Middle Aged; Multiple Myeloma; Transplantation Conditioning; Transplantation, Autologous; Treatment Outcome

An updated survival analysis was conducted for the Phase II study O-12-M1 of melphalan flufenamide (melflufen) plus dexamethasone in patients with relapsed/refractory multiple myeloma (RRMM) with two or more prior lines of therapy (including bortezomib and lenalidomide). Partial response or better was seen in 31%. After a 46-month median overall survival (OS) follow-up, melflufen plus dexamethasone had a median OS of 20·7 months (75th percentile OS, 47·5 months). The median time-to-next treatment for melflufen plus dexamethasone was 7·9 months. In summary, melflufen plus dexamethasone resulted in sustained long-term clinical benefit in patients with RRMM.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Disease-Free Survival; Female; Follow-Up Studies; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Phenylalanine; Survival Rate

The International Myeloma Working Group response criteria require two consecutive assessments of paraprotein levels. We conducted an exploratory analysis to evaluate whether a single response assessment could be a substitute for the International Myeloma Working Group criteria using data from JCOG1105, a randomized phase II study on melphalan, prednisolone and bortezomib.. Of 91 patients with transplant-ineligible newly diagnosed multiple myeloma, 79 patients were included. We calculated the kappa coefficient to evaluate the degree of agreement between the International Myeloma Working Group criteria and the single response assessment.. Based on the International Myeloma Working Group criteria, 11 (13.9%), 20 (25.3%), 36 (45.6%) and 12 (15.2%) patients had stringent complete response/complete response, very good partial response, partial response and stable disease, respectively. Based on the single response assessment, 17 (21.5%), 19 (24.1%), 35 (44.3%) and 8 (10.1%) patients had stringent complete response/complete response, very good partial response, partial response and stable disease, respectively. The kappa coefficient was 0.76 (95% confidence interval, 0.65-0.88), demonstrating good agreement. The single response assessment was not inferior to the International Myeloma Working Group criteria in the median progression-free survival (3.8 and 2.9 years) in stringent complete response/complete response patients, suggesting that the single response assessment was not an overestimation.. The single response assessment could be a substitute for the current International Myeloma Working Group criteria for transplant-ineligible newly diagnosed multiple myeloma.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Female; Humans; Male; Melphalan; Multiple Myeloma; Prednisolone; Progression-Free Survival

In the phase III ALCYONE trial, daratumumab plus bortezomib/melphalan/prednisone (D-VMP) significantly improved overall response rate and progression-free status compared with VMP alone in transplant-ineligible patients with newly diagnosed multiple myeloma (NDMM). Here, we present patient-reported outcomes (PROs) from ALCYONE.. The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30-item (EORTC QLQ-C30) and EuroQol 5-dimensional descriptive system (EQ-5D-5L) questionnaire were administered at baseline, every 3 months (year 1) and every 6 months (until progression). Treatment effects were assessed using a repeated-measures, mixed-effects model.. Compliance with PRO assessments was comparable at baseline (> 90%) and throughout study (> 76%) for both treatment groups. Improvements from baseline were observed in both groups for EORTC QLQ-C30 Global Health Status (GHS), most functional scales, symptom scales and EQ-5D-5L visual analog scale (VAS). Between-group differences were significant for GHS (p = 0.0240) and VAS (p = 0.0160) at month 3. Improvements in pain were clinically meaningful in both groups at all assessment time points. Cognitive function declined in both groups, but the magnitude of the decline was not clinically meaningful.. Patients with transplant-ineligible NDMM demonstrated early and continuous improvements in health-related quality of life, including improvements in functioning and symptoms, following treatment with D-VMP or VMP.. ClinicalTrials.gov identifier NCT02195479 , registered September 21, 2014.

Topics: Aged; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Disease Progression; Drug Administration Schedule; Female; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Patient Reported Outcome Measures; Prednisone; Quality of Life; Treatment Outcome

Topics: Antineoplastic Combined Chemotherapy Protocols; Autografts; Bone Marrow Cells; Bortezomib; Dexamethasone; Disease-Free Survival; Female; Flow Cytometry; Hematopoietic Stem Cell Transplantation; Humans; Lenalidomide; Male; Melphalan; Middle Aged; Multiple Myeloma; Neoplasm, Residual; Survival Rate

Patients with multiple myeloma are generally older and vary in fitness levels, which may influence the clinical benefit of treatment. Patients from the large, phase 3 FIRST trial in newly diagnosed multiple myeloma (NDMM) were retrospectively investigated to determine outcomes based on frailty using scores for age, Charlson Comorbidity Index (CCI), and Eastern Cooperative Oncology Group performance status (ECOG PS), instead of the EQ-5D quality-of-life questionnaire, as previously reported. ECOG PS (n = 1618) was investigated in frailty groups: frail (49%) and nonfrail (51%). Frail patients experienced worse progression-free and overall survival vs nonfrail patients. Prognostic assessment was improved when combining frailty and International Staging System stage (I/II vs III). Frail patients had a higher risk of developing grade 3/4 treatment-emergent adverse events. Treatment effects observed in the FIRST trial were confirmed per frailty group and per frailty and ISS group. The use of this ECOG PS-containing frailty scale as a predictive measure of clinical outcomes in patients with transplant-ineligible NDMM is supported by data from the FIRST trial. This score, based on age, CCI, and ECOG PS, can be easily replicated and may help design future myeloma studies in frail or nonfrail elderly patients.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Female; Frail Elderly; Frailty; Humans; Lenalidomide; Male; Melphalan; Middle Aged; Multiple Myeloma; Prednisone; Thalidomide; Treatment Outcome

Data on the impact of long term treatment with immunomodulatory drugs (IMiD) on health-related quality of life (HRQoL) is limited. The HOVON-87/NMSG18 study was a randomized, phase 3 study in newly diagnosed transplant ineligible patients with multiple myeloma, comparing melphalan-prednisolone in combination with thalidomide or lenalidomide, followed by maintenance therapy until progression (MPT-T or MPR-R). The EORTC QLQ-C30 and MY20 questionnaires were completed at baseline, after three and nine induction cycles and six and 12 months of maintenance therapy. Linear mixed models and minimal important differences were used for evaluation. 596 patients participated in HRQoL reporting. Patients reported clinically relevant improvement in global quality of life (QoL), future perspective and role and emotional functioning, and less fatigue and pain in both arms. The latter being of large effect size. In general, improvement occurred after 6-12 months of maintenance only and was independent of the World Health Organisation performance at baseline. Patients treated with MPR-R reported clinically relevant worsening of diarrhea, and patients treated with MPT-T reported a higher incidence of neuropathy. Patients who remained on lenalidomide maintenance therapy for at least three months reported clinically meaningful improvement in global QoL and role functioning at six months, remaining stable thereafter. There were no clinically meaningful deteriorations, but patients on thalidomide reported clinically relevant worsening in neuropathy. In general, HRQoL improves both during induction and maintenance therapy with immunomodulatory drugs. The side effect profile of treatment did not negatively affect global QoL, but it was, however, clinically relevant for the patients. (

Topics: Antineoplastic Combined Chemotherapy Protocols; Humans; Lenalidomide; Melphalan; Multiple Myeloma; Prednisone; Prospective Studies; Quality of Life; Thalidomide

n the EMN01 trial, the addition of an alkylator (melphalan or cyclophosphamide) to lenalidomide-steroid induction therapy was prospectively evaluated in transplant-ineligible patients with multiple myeloma. After induction, patients were randomly assigned to maintenance treatment with lenalidomide alone or with prednisone continuously. The analysis presented here (median follow-up of 71 months) is focused on maintenance treatment and on subgroup analyses defined according to the International Myeloma Working Group Frailty Score. Of the 654 evaluable patients, 217 were in the lenalidomide-dexamethasone arm, 217 in the melphalan-prednisone-lenalidomide arm and 220 in the cyclophosphamide-prednisone-lenalidomide arm. With regards to the Frailty Score, 284 (43%) patients were fit, 205 (31%) were intermediate-fit and 165 (25%) were frail. After induction, 402 patients were eligible for maintenance therapy (lenalidomide arm, n=204; lenalidomide-prednisone arm, n=198). After a median duration of maintenance of 22.0 months, progression-free survival from the start of maintenance was 22.2 months with lenalidomide-prednisone

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Disease-Free Survival; Humans; Lenalidomide; Maintenance Chemotherapy; Melphalan; Multiple Myeloma; Prednisone; Progression-Free Survival; Treatment Outcome

The German Maintenance Study (GERMAIN) was designed to evaluate the impact of lenalidomide maintenance after induction therapy with bortezomib, melphalan and prednisolone (VMP) in transplant-ineligible newly diagnosed multiple myeloma (MM) patients.. Due to poor accrual and high dropout rate, only 85 patients (planned 286) entered the trial and 40 (planned 200) were randomized to lenalidomide maintenance (n = 19) vs. observation (n = 21).. The primary endpoint, improved progression-free survival, was not met (p = 0.3572). After a median follow-up of 12.9 months, median progression-free survival in the lenalidomide arm was 14.4 months and 11.4 months with placebo. The hazard ratio 0.621 (95% confidence interval: [0.224, 1.725]) was about the same as expected (0.625). However, with only 40 patients randomized, the actual power to detect a difference was 11%. Of patients receiving at least one dose of induction, 54% were frail according to a modified International Myeloma Working Group frailty score. Discontinuations were high during induction (47%), and affected mainly frail patients (54%). Despite a higher rate of adverse events in the lenalidomide arm (p = 0.0061), only 2 patients discontinued lenalidomide due to toxicity.. A frailty assessment with appropriate dose modification for induction therapy should be mandatory for all elderly non-transplant-eligible myeloma patients.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Double-Blind Method; Female; Frail Elderly; Frailty; Humans; Induction Chemotherapy; Lenalidomide; Maintenance Chemotherapy; Male; Melphalan; Multiple Myeloma; Prednisolone; Progression-Free Survival

G-CSF administration after high-dose chemotherapy and autologous stem cell transplantation (ASCT) has been shown to expedite neutrophil recovery. Several studies comparing filgrastim and pegfilgrastim in the post-ASCT setting concluded that the two are at least equally effective. Lipegfilgrastim (LIP) is a new long-acting, once-per-cycle G-CSF. This multicentric, prospective study aimed to describe the use of LIP in multiple myeloma patients receiving high-dose melphalan and autologous stem cell transplantation (ASCT) and compare LIP with historic controls of patients who received short-acting agent (filgrastim [FIL]). Overall, 125 patients with a median age of 60 years received G-CSF after ASCT (80 patients LIP on day 1 post-ASCT and 45 patients FIL on day 5 post-ASCT). The median duration of grade 4 neutropenia (absolute neutrophil count [ANC] < 0.5 × 10 [9]/L) was 5 days in both LIP and FIL groups, whereas the median number of days to reach ANC ≥ 0.5 × 10 [9]/L was 10% lower in the LIP than in the FIL group (10 vs 11 days), respectively. Male sex was significantly associated with a faster ANC ≥ 0.5 × 10 [9] L response (p = 0.015). The incidence of FN was significantly lower in the LIP than in the FIL group (29% vs 49%, respectively, p = 0.024). The days to discharge after ASCT infusion were greater in patients with FN (p < 0.001). The study indicates that LIP had a shorter time to ANC recovery and is more effective than FIL for the prevention of FN in the ASCT setting.

Topics: Aged; Autografts; Female; Filgrastim; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Polyethylene Glycols; Prospective Studies; Sex Factors; Stem Cell Transplantation

Patients with transplant-ineligible relapsed and refractory multiple myeloma (RRMM) have a short life expectancy, especially when they have failed both the proteasome inhibitor and immunomodulator therapies. This study aimed to assess the efficacy and safety of pomalidomide, cyclophosphamide, and dexamethasone (PCd) in elderly patients with RRMM. This phase 2 clinical trial recruited 55 elderly patients with RRMM. The patients underwent a 28-day treatment cycle: pomalidomide (4 mg/day on days 1-21, administered orally) and cyclophosphamide (400 mg/day on days 1, 8, and 15; administered orally) plus dexamethasone. The median (range) age of the patients was 73.3 (64-86) years, and 8 (14.5%) patients who were ≥ 80 years old. Eight (14.5%) and 31 (56.4%) patients exhibited stage III (revised international staging system) and frail status (simplified frailty scale), respectively. The overall response rate (ORR) and clinical benefit rate (CBR) of PCd therapy were 58.2% and 72.7%, respectively. The median PFS and median overall survival (OS) were 6.90 months (95% CI, 4.7-9.0) and 18.48 months (95% CI, 9.4-27.6), respectively. The incidence rate of grade ≥ 3 non-hematological toxicities was 70.8%. In particular, the incidence rate of primary infection was 45.4%, including 21.8% for pneumonia, 9.0% for sepsis, and 14.6% for febrile neutropenia. In conclusion, PCd is an effective regimen for elderly patients with RRMM who had failed both bortezomib and lenalidomide treatments, but in whom the treatment-associated infection is the main cause of morbidity and mortality.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Cyclophosphamide; Dexamethasone; Drug Resistance, Neoplasm; Febrile Neutropenia; Female; Frail Elderly; Frailty; Hematologic Diseases; Humans; Incidence; Infections; Kaplan-Meier Estimate; Lenalidomide; Male; Melphalan; Middle Aged; Multiple Myeloma; Myeloma Proteins; Prednisone; Progression-Free Survival; Recurrence; Republic of Korea; Thalidomide

The MM5 trial aimed at demonstrating a progression-free survival (PFS) difference in continued vs. response-adapted (in case of complete response, CR) lenalidomide (LEN) maintenance therapy (MT) in newly diagnosed, transplant-eligible multiple myeloma (MM). Patients were equally randomized to receive induction therapy with PAd (bortezomib/doxorubicin/dexamethasone) or VCD (bortezomib/cyclophosphamide/dexamethasone), high-dose melphalan and autologous blood stem cell transplantation, and LEN consolidation, followed by either LEN MT for a fixed duration of 2 years (LEN-2Y) or until achievement of CR (LEN-CR, intention-to-treat population n = 502): arms A1:PAd + LEN-2Y (n = 125), B1:PAd + LEN-CR (n = 126), A2:VCD + LEN-2Y (n = 126), B2:VCD + LEN-CR (n = 125). In the LEN-CR group (B1 + B2), n = 88/17.5% patients did not start or discontinued LEN MT due to CR. There was no PFS (p = 0.60, primary endpoint) nor overall survival (OS) (p = 0.15) difference between the four study arms. On pooled LEN MT strategies, OS (hazard ratio, hazard ratio [HR] = 1.42, p = 0.03) but not PFS (HR = 1.15, p = 0.20) was shorter in LEN-CR (B1 + B2) vs. LEN-2Y (A1 + A2) groups. PFS was shortened on landmark analyses from the start of LEN MT in patients being in CR in the LEN-CR group (LEN-CR vs. LEN-2Y, HR = 1.84, p = 0.02). OS from first progression was shortened in the LEN-CR vs. LEN-2Y group (HR = 1.60, p = 0.01). LEN MT should be applied beyond CR for at least 2 years.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Combined Modality Therapy; Consolidation Chemotherapy; Cyclophosphamide; Dexamethasone; Female; Follow-Up Studies; Hematopoietic Stem Cell Transplantation; Humans; Lenalidomide; Maintenance Chemotherapy; Male; Melphalan; Multiple Myeloma; Prognosis; Prospective Studies; Remission Induction; Survival Rate; Thalidomide; Transplantation, Autologous

Melflufen is a novel peptide-drug conjugate that rapidly delivers a cytotoxic payload into tumor cells. It has emerged as a potential new multiple myeloma treatment, particularly for late-stage forms of the disease. Here we describe the rationale and design of OCEAN (NCT03151811), a randomized, head-to-head, superiority, open-label, global, Phase III study evaluating the efficacy and safety of melflufen + dexamethasone versus pomalidomide + dexamethasone. Eligible patients with relapsed refractory multiple myeloma have received 2-4 previous treatments and are refractory to both lenalidomide and their last treatment. Patients are excluded if they have previously received pomalidomide. The primary endpoint is progression-free survival, and key secondary endpoints include overall response rate, duration of response and overall survival.

Topics: Antineoplastic Combined Chemotherapy Protocols; Clinical Trials, Phase III as Topic; Dexamethasone; Drug Resistance, Neoplasm; Humans; Lenalidomide; Melphalan; Multiple Myeloma; Phenylalanine; Progression-Free Survival; Randomized Controlled Trials as Topic; Recurrence; Thalidomide

Most studies addressing the impact of hematopoietic stem cell transplantation (SCT) on pulmonary function test (PFT), and the various factors affecting that impact have been performed on the allogenic type. Few have addressed PFT changes in autologous SCT. This study describes PFT changes seen in autologous SCT recipients and addresses the various factors impacting these changes.. We reviewed the medical records of 223 consecutive adult autologous SCT recipients. We collected pre-transplant and post-transplant data, as well as PFT data and long-term mortality.. A total of 123 patients with lymphoma receiving the BEAM (carmustine, etoposide, aracytin, and melphalan) conditioning regimen had a significant 5% drop in mean forced vital capacity and total lung capacity but no significant change in forced expiratory volume in one second/forced vital capacity ratio nor in diffusion lung capacity of carbon monoxide adjusted to volume. Fifteen percent of the patients with lymphoma had a clinically significant drop of 15% in their lung volume parameters. The patients with multiple myeloma receiving the melphalan conditioning regimen had no significant change in any of the PFT parameters. Smoking, baseline PFT parameters, and radiation did not affect lung function or mortality.. Autologous SCT impact on lung function depends on the disease and conditioning regimen. It leads to a drop in lung volumes but no obstruction or decrease in diffusion in patients with lymphoma receiving the BEAM regimen. Autologous SCT did not affect lung functions in patients with multiple myeloma, and these patients may not need screening PFTs.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Autografts; Carmustine; Cytarabine; Disease-Free Survival; Female; Hematopoietic Stem Cell Transplantation; Humans; Lung; Lymphoma; Male; Melphalan; Middle Aged; Multiple Myeloma; Podophyllotoxin; Respiratory Function Tests; Retrospective Studies; Survival Rate; Transplantation Conditioning

Multiple myeloma is an incurable haematological malignancy, representing over 10% of haematological cancers in the USA. We did a phase 1-2 study of melflufen and dexamethasone in patients with relapsed and refractory multiple myeloma to determine the maximum tolerated dose of melflufen and to investigate its safety and efficacy.. We did a multicentre, international, dose-confirmation and dose-expansion, open-label, phase 1-2 study in seven centres in the USA and Europe. Eligible patients were aged 18 years or older, had relapsed and refractory multiple myeloma, had received two or more previous lines of therapy (including lenalidomide and bortezomib), were refractory to their last line of therapy, and had an Eastern Cooperative Oncology Group performance status of 2 or less. In phase 1, patients received an intravenous infusion of melflufen at 15 mg, 25 mg, 40 mg, or 55 mg for 30 min on day 1 in 21-day cycles plus oral dexamethasone 40 mg weekly and did not receive melflufen as a single agent. Melflufen was also tested in a single-agent cohort late in phase 2 in a small number of patients at the maximum tolerated dose identified in phase 1. In phase 2, patients were enrolled at the maximum tolerated dose in the melflufen plus dexamethasone in the combination cohort.. The phase 1 primary objective was to determine the maximum tolerated dose. The phase 2 primary objective was to evaluate overall response rate and clinical benefit rate. This primary analysis was done per protocol, in the all-treated and efficacy-evaluable population (defined as patients who received at least two doses of melflufen and who had a response assessment after baseline). The single-agent melflufen cohort was closed on October 6, 2016, as per the recommendation by the data safety monitoring committee on the basis of interim data suggesting greater activity in the melflufen plus dexamethasone cohort. The study is completed but survival follow-up is ongoing. This study is registered with ClinicalTrials.gov, NCT01897714.. Patients were enrolled between July 4, 2013, and Dec 31, 2016: 23 patients in phase 1 and 58 in phase 2, including six patients from phase 1 treated at the maximum tolerated dose of melflufen 40 mg plus weekly dexamethasone. In phase 2, 45 patients were given a combination of melflufen plus dexamethasone and 13 patients were given single-agent melflufen. In phase 1, the established maximum tolerated dose was 40 mg of melflufen in combination with dexamethasone. No dose-limiting toxicities were observed in the first three dose cohorts (15 mg, 25 mg, and 40 mg). The highest dose cohort tested (55 mg) exceeded the maximum tolerated dose because four of six patients experienced grade 4 neutropenia with grade 4 thrombocytopenia also occurring in three of these patients; therefore, the planned highest dose of 70 mg was not tested. In phase 2, patients treated with combination therapy achieved an overall response rate of 31% (14 of 45 patients; 95% CI 18-47) and clinical benefit rate of 49% (22 of 45; 34-64) in the all-treated population, and 41% (14 of 34; 25-59) and 65% (22 of 34; 47-80) in the efficacy-evaluable population. In the phase 2 single-agent cohort, the overall response rate was 8% (one of 13 patients; 0·2-36·0) and the clinical benefit rate was 23% (three of 13; 5-54). Among the 45 patients given melflufen plus dexamethasone during phase 2, the most common grade 3-4 adverse events were clinically manageable thrombocytopenia (28 [62%] patients) and neutropenia (26 [58%]), and non-haematological toxicity was infrequent. 24 serious adverse events were reported in 17 (38%) of 45 patients, most commonly pneumonia (five [11%]). The most common grade 3-4 adverse events that occurred in the phase 2 single-agent cohort of 13 patients were neutropenia (nine [69%]) and thrombocytopenia (eight [62%]). Nine patients experienced serious adverse events in the single-agent cohort, most commonly thrombocytopenia (two [15%]). There were three deaths from adverse events within 30 days of treatment that were possibly related to treatment: one in the 25 mg cohort in phase 1 (due to bacteraemia) and two in the phase 2 combination cohort (one due to neutropenic sepsis and one due to Escherichia coli sepsis), each in the setting of progressive disease.. These data show that melflufen is active in patients with relapsed and refractory multiple myeloma and tolerable in most patients. These results show the feasibility of this regimen and support the initiation of additional clinical studies of melflufen in multiple myeloma, both in combination with dexamethasone as well as in triplet regimens with additional classes of drugs.. Oncopeptides AB.

Topics: Aged; Antineoplastic Agents, Alkylating; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Disease-Free Survival; Female; Humans; Kaplan-Meier Estimate; Male; Maximum Tolerated Dose; Melphalan; Middle Aged; Multiple Myeloma; Neoplasm Recurrence, Local; Phenylalanine

These are the results of phase II study of bortezomib-melphalan-prednisolone (VMP) induction therapy followed by lenalidomide-dexamethasone (Rd) consolidation and lenalidomide maintenance in transplant-ineligible patients with newly diagnosed multiple myeloma (NDMM). The primary end point was progression-free survival (PFS). Secondary end points included overall survival (OS), overall response rates (ORRs), and safety. Eighty-three eligible patients were enrolled between October 2012 and August 2014. The median PFS was 28.0 months (95% CI 19.6-36.7) and the median OS was 55.3 months (95% CI 51.6-NA). Among the patients who received lenalidomide maintenance therapy, median PFS was significantly improved in patients who had achieved a very good partial response (VGPR) or better (41.8 vs 20.7 months, p = 0.0070). As the best response, the rates of partial response or better were 85.5% comprising stringent complete response (sCR, 21.7%), complete response (CR, 10.8%), VGPR (18.1%), and partial response (PR, 34.9%). The most frequently observed grade 3 or higher adverse events during the VMP therapy were anemia (28.9%), neutropenia (15.6%), thrombocytopenia (6.0%), and peripheral neuropathy (2.4%). The most frequently observed grade 3 or higher adverse events during the Rd therapy were anemia (3.5%), neutropenia (1.8%), and skin rush (5.3%). The most frequently observed grade 3 or higher adverse events during lenalidomide maintenance therapy were anemia (7.4%) and neutropenia (24.1%). Thus, VMP induction therapy followed by Rd consolidation and lenalidomide maintenance is considered a well-tolerated and effective regimen in transplant-ineligible NDMM. This trial is registered with UMIN-CTR with the identification number UMIN000009042.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Disease-Free Survival; Female; Humans; Lenalidomide; Male; Melphalan; Middle Aged; Multiple Myeloma; Prednisolone; Survival Rate

Bortezomib, melphalan, and prednisone (VMP) is the standard of care for transplant-ineligible newly diagnosed multiple myeloma. The phase III VISTA trial established the bortezomib dosing schedule for VMP. To mitigate bortezomib-associated toxicity, the phase III ALCYONE study of daratumumab plus VMP (D-VMP) versus VMP used modified bortezomib dosing. D-VMP demonstrated improved progression-free survival and overall response rate. Propensity score matching enables indirect comparisons by controlling for differences in baseline covariates.. The efficacy and safety of both arms of ALCYONE were compared with VISTA VMP using propensity score matching. ALCYONE D-VMP and VMP patients were matched on selected baseline characteristics to VISTA VMP patients, reducing or eliminating systematic differences between treatment groups.. After matching, median progression-free survival and overall response rate were comparable for ALCYONE VMP and VISTA VMP, and were significantly improved with ALCYONE D-VMP versus VISTA VMP. Rates of grade 3/4 peripheral sensory neuropathy were significantly lower for both arms of ALCYONE versus VISTA VMP, with or without matching.. This propensity score matching analysis demonstrates significant improvements in efficacy with ALCYONE D-VMP versus VISTA VMP and a significantly lower incidence of peripheral sensory neuropathy in both arms of ALCYONE versus VISTA VMP, although safety improvements may be due to different bortezomib administration routes (ALCYONE, subcutaneous; VISTA, intravenous).

Topics: Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Female; Humans; Male; Melphalan; Multiple Myeloma; Prednisone; Propensity Score; Treatment Outcome

Newly diagnosed multiple myeloma (NDMM) patients treated with immunomodulatory drugs are at high risk of venous thromboembolism (VTE), but data are lacking from large prospective cohorts. We present thrombosis outcome data from Myeloma IX (n = 1936) and Myeloma XI (n = 4358) phase 3 randomized controlled trials for NDMM that treated transplant-eligible and transplant-ineligible patients before and after publication of thrombosis prevention guidelines. In Myeloma IX, transplant-eligible patients randomly assigned to cyclophosphamide, vincristine, doxorubicin, and dexamethasone (CVAD) induction had higher risk of VTE compared with patients treated with cyclophosphamide, thalidomide, and dexamethasone (CTD) (22.5% [n = 121 of 538] vs 16.1% [n = 89 of 554]; adjusted hazard ratio [aHR],1.46; 95% confidence interval [95% CI], 1.11-1.93). For transplant-ineligible patients, those randomly assigned to attenuated CTD (CTDa) induction had a higher risk of VTE compared with those treated with melphalan and prednisolone (MP) (16.0% [n = 68 of 425] vs 4.1% [n = 17 of 419]; aHR, 4.25; 95% CI, 2.50-7.20). In Myeloma XI, there was no difference in risk of VTE (12.2% [n = 124 of 1014] vs 13.2% [n = 133 of 1008]; aHR, 0.92; 95% CI, 0.72-1.18) or arterial thrombosis (1.2% [n = 12 of 1014] vs 1.5% [n = 15 of 1008]; aHR, 0.80; 95% CI, 0.37-1.70) between transplant-eligible pathways for patients treated with cyclophosphamide, lenalidomide, and dexamethasone (CRD) or CTD. For transplant-ineligible patients, there was no difference in VTEs between attenuated CRD (CRDa) and CTDa (10.4% [n = 95 of 916] vs 10.7% [n = 97 of 910]; aHR, 0.97; 95% CI, 0.73-1.29). However, arterial risk was higher with CRDa than with CTDa (3.1% [n = 28 of 916] vs 1.6% [n = 15 of 910]; aHR, 1.91; 95% CI, 1.02-3.57). Thrombotic events occurred almost entirely within 6 months of treatment initiation. Thrombosis was not associated with inferior progression-free survival (PFS) or overall survival (OS), apart from inferior OS for patients with arterial events (aHR, 1.53; 95% CI, 1.12-2.08) in Myeloma XI. The Myeloma XI trial protocol incorporated International Myeloma Working Group (IMWG) thrombosis prevention recommendations and compared with Myeloma IX, more patients received thromboprophylaxis (80.5% vs 22.3%) with lower rates of VTE for identical regimens (CTD, 13.2% vs 16.1%; CTDa, 10.7% vs 16.0%). However, thrombosis remained frequent in spite of IMWG-guided thromboprophylaxis, suggesting that new appro

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Dexamethasone; Doxorubicin; Female; Hematopoietic Stem Cell Transplantation; Humans; Immunologic Factors; Incidence; Kaplan-Meier Estimate; Lenalidomide; Male; Melphalan; Middle Aged; Multiple Myeloma; Prednisolone; Progression-Free Survival; Risk Assessment; Thalidomide; Thrombophilia; Thrombosis; Transplantation, Autologous; Venous Thromboembolism; Vincristine

Lenalidomide (Len) and dexamethasone (dex) therapy is a standard therapy in patients with multiple myeloma. Elderly or unfit patients may reduce Len or dex doses to prevent toxicities that lead to treatment discontinuation. However, there have been few studies evaluating the efficacy and safety of lower doses of Len and dex. We conducted a phase II study of 1.5-year low-dose Len and dex therapy following melphalan and prednisolone (MP), the number of which cycles was determined by a response within 9 cycles. The Len dose was 10 mg daily and the dex dose was 20 mg weekly, which were continued for 1.5 years. Twenty-one patients were enrolled. The median number of cycles of MP was 3 (range, 2-9). The overall response rate was 81% and a very good partial response or better was achieved in 33.3% of patients. The median follow-up time for survivors was 70.5 months (range, 42-83 months), the median progression-free survival (PFS) was 27 months (95% CI, 21-33 months), and the median overall survival was not reached. Grade 3 or 4 adverse events were observed in 28.6% of patients. In conclusion, the low-dose Len and dex therapy safely achieved comparable efficacies to the standard-dose regimen in elderly patients with newly diagnosed multiple myeloma. UMIN000007889.

Topics: Adult; Age Factors; Aged; Aged, 80 and over; Anemia; Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Dose-Response Relationship, Drug; Drug Administration Schedule; Febrile Neutropenia; Female; Follow-Up Studies; Humans; Kaplan-Meier Estimate; Lenalidomide; Male; Melphalan; Middle Aged; Multiple Myeloma; Prednisolone; Progression-Free Survival; Remission Induction; Treatment Outcome; Young Adult

High-dose melphalan (Mel) conditioning before autologous hematopoietic cell transplantation (autoHCT) is standard of care for patients with transplantation-eligible multiple myeloma. The traditional lyophilized Mel formulation has inadequate solubility and stability after reconstitution, leading to the use of propylene glycol (PG) as a solubilizing agent. A newer PG-free Mel preparation (Evomela) uses beta cyclodextrin captisol as a solubilizing agent and was approved by the United States Food and Drug Administration as a conditioning agent based on a single-phase IIb study showing bioequivalence. We compared the outcomes of consecutive patients with myeloma undergoing autoHCT using the 2 formulations of Mel for conditioning as our center switched from using the older formulation (PG-Mel) to the newer one (PGF-Mel). Of 294 autoHCT recipients, 162 received PG-Mel conditioning and 132 received PGF-Mel conditioning. The PGF-Mel group was older and had a lower average Karnofsky Performance Status score. PGF-Mel was associated with faster neutrophil recovery (median, 12 days versus 13 days; P < .001), fewer grade 3-4 infections within 30 days of autoHCT (1.5% versus 8.0%; P = .048), and a lower 30-day rehospitalization rate (6.8% versus 17.9%; P = .04), as confirmed by propensity-weighted analysis. No significant between-group differences were detected in mucositis, organ toxicity, myeloma response, or 100-day mortality.

Topics: Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Multiple Myeloma; Myeloablative Agonists; Transplantation Conditioning; Transplantation, Autologous

The phase 3 FIRST trial demonstrated significant improvement in progression-free survival (PFS) and overall survival (OS) with an immune-stimulatory agent, lenalidomide, in combination with low-dose dexamethasone until disease progression (Rd continuous) vs melphalan +prednisone + thalidomide (MPT) in transplant-ineligible patients with newly diagnosed multiple myeloma (NDMM). Rd continuous similarly extended PFS vs fixed-duration Rd for 18 cycles (Rd18). Outcomes in the Canadian/US subgroup (104 patients per arm) are reported in this analysis. Rd continuous demonstrated a significant improvement in PFS vs MPT (median, 29.3 vs 20.2 months; HR, 0.69 [95% CI, 0.49-0.97]; p = 0.03326) and an improvement vs Rd18 (median, 21.9 months). Median OS was 56.9 vs 46.8 months with Rd continuous vs MPT (p = 0.15346) and 59.5 months with Rd18. The overall response rate was higher with Rd continuous and Rd18 (78.8% and 79.8%) vs MPT (65.4%). In the 49.0%, 52.9%, and 29.8% of patients with at least very good partial response in the Rd continuous, Rd18, and MPT arms, respectively, the median PFS was 56.0, 30.9, and 40.2 months, respectively. The most common grade 3/4 treatment-emergent adverse events were neutropenia (28.4%, 30.1%, and 52.0%), anemia (23.5%, 21.4%, and 23.5%), and infections (37.3%, 30.1%, and 24.5%) with Rd continuous, Rd18, and MPT, respectively. These results were consistent with those in the intent-to-treat population, confirming the benefit of Rd continuous vs MPT in the Canadian/US subgroup and supporting the role of Rd continuous as a standard of care for transplant-ineligible patients with NDMM.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Canada; Dexamethasone; Disease Progression; Drug Administration Schedule; Eligibility Determination; Female; Hematopoietic Stem Cell Transplantation; Humans; Lenalidomide; Male; Melphalan; Middle Aged; Multiple Myeloma; Prednisone; Progression-Free Survival; Thalidomide; Time Factors; United States

The phase 3 ALCYONE study demonstrated significantly longer progression-free and overall survival (PFS/OS) and higher overall response rates (ORR) with daratumumab plus bortezomib, melphalan, and prednisone (D-VMP) versus VMP alone in transplant-ineligible patients with newly diagnosed multiple myeloma (NDMM). In Latin America, bortezomib- or thalidomide-based regimens remain standard of care (SoC) for this population. No head-to-head trials have compared D-VMP with SoC regimens used in Latin America.. Propensity score matching (PSM) was used to control for baseline differences between patient populations and compare outcomes for D-VMP versus SoC regimens used in Latin America. Data for the D-VMP cohort were from the D-VMP arm of the ALCYONE trial (n = 350). Data for the SoC cohort were from the retrospective, observational Hemato-Oncology Latin America (HOLA) study, which included patients with NDMM who did not receive a transplant (n = 729). Propensity scores were estimated using logistic regression. Exact, optimal, and nearest-neighbor PSM were applied to pick the best-performing method. Doubly robust estimation was the base case, since some baseline imbalances persisted.. All 350 patients from the D-VMP arm of ALCYONE were included in OS/PFS analyses and 338 in ORR analysis; 478 and 324 patients, respectively, from HOLA were included in these analyses. Naïve comparison revealed important differences in baseline characteristics (age, chronic kidney disease, hypercalcemia, and International Staging System [ISS] stage). After nearest-neighbor matching, baseline characteristics, except ISS stage, were well balanced; comparisons favored D-VMP over SoC for OS (hazard ratio = 0.41; 95% confidence interval [CI] 0.25-0.66; P = 0.002) and PFS (hazard ratio = 0.48; 95% CI 0.35-0.67; P < 0.001). After exact matching, imbalances remained in age and ISS stage; comparisons favored D-VMP over SoC for ORR (odds ratio = 5.44; 95% CI 2.65-11.82; P < 0.001).. In transplant-ineligible patients with NDMM, D-VMP showed superior effectiveness versus bortezomib- and thalidomide-based regimens, supporting adoption of daratumumab-containing regimens in Latin America.

Topics: Aged; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Female; Humans; Latin America; Male; Melphalan; Middle Aged; Multiple Myeloma; Prednisone; Progression-Free Survival; Propensity Score; Retrospective Studies; Standard of Care

Bortezomib-melphalan-prednisone (VMP) and continuous lenalidomide-dexamethasone (Rd) represent the standard treatment of transplant-ineligible patients with newly diagnosed multiple myeloma (MM). To date, no randomized trial has compared VMP to Rd, and there is no evidence of the optimal treatment for newly diagnosed MM, particularly in patients with high-risk cytogenetics [del(17p), t(4;14) or t(14;16)]. We pooled together data from patients with newly diagnosed MM treated with VMP or Rd induction followed by lenalidomide maintenance 10 mg (Rd-R) enrolled in the GIMEMA-MM-03-05 and EMN01 trials, to evaluate the efficacy of these treatments in different subgroups of patients, focusing on those with standard- and high-risk cytogenetics. Overall, 474 patients were analyzed (VMP: 257 patients; Rd-R: 217 patients). No differences in progression-free survival (hazard ratio=0.96) and overall survival (hazard ratio=1.08) were observed between standard-risk patients treated with VMP or Rd-R, whereas among the high-risk patients, the probabilities of progression (hazard ratio=0.54) and death (hazard ratio=0.73) were lower in the patients treated with VMP than in those treated with Rd-R. In particular, standard-risk patients >75 years benefited less from VMP than from Rd-R (hazard ratio for progression-free survival=0.96; hazard ratio for overall survival=1.81). In this non-randomized analysis, VMP and Rd-R were equally effective in younger (≤75 years), standard-risk patients, while older ones (>75 years) benefited more from Rd-R. In high-risk patients, VMP improved progression-free survival and overall survival irrespective of age. The source trials are registered at ClinicalTrials.gov (NCT01063179 and NCT01093196).

Topics: Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Dexamethasone; Humans; Lenalidomide; Melphalan; Multiple Myeloma; Prednisone; Treatment Outcome

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Asia, Eastern; Bortezomib; Disease-Free Survival; Female; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Prednisolone; Survival Rate

Topics: Autografts; Cryopreservation; Disease-Free Survival; Female; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Peripheral Blood Stem Cell Transplantation; Peripheral Blood Stem Cells; Retrospective Studies; Survival Rate

The efficacy and safety of lenalidomide (LEN) consolidation therapy and subsequent LEN maintenance therapy after high-dose therapy with autologous peripheral blood stem cell transplantation (auto-PBSCT) were evaluated in patients with newly diagnosed symptomatic multiple myeloma (MM). Forty-one patients were enrolled and received high-dose dexamethasone (DEX) therapy as an initial induction. The patients who did not respond to the DEX therapy were further treated with four cycles of bortezomib plus DEX (BD) induction therapy. For patients who responded to BD, PBSC harvesting was scheduled following high-dose cyclophosphamide and filgrastim administration. After PBSC harvesting, high-dose chemotherapy of melphalan with auto-PBSCT was performed. One hundred days after auto-PBSCT, patients received consolidation therapy consisting two cycles of LEN plus low-dose DEX (Ld) and LEN maintenance therapy. Only one death occurred during mobilization therapy, but the protocol developed in this study was considered generally safe to provide. Overall response rates after consolidation and maintenance therapies were 73.7% and 81.6%, respectively. Two-year progression-free survival and overall survival were 76.3% and 92.1%, respectively. These observations suggest that LEN consolidation and maintenance therapy are effective and safe, and provide favorable response rates in patients with MM.

Topics: Bortezomib; Consolidation Chemotherapy; Dexamethasone; Lenalidomide; Maintenance Chemotherapy; Melphalan; Multiple Myeloma; Peripheral Blood Stem Cell Transplantation; Survival Analysis; Transplantation, Autologous; Treatment Outcome

Patients with symptomatic MM within 12 months from starting therapy and without progression who were age 70 years or younger were randomly assigned to AHCT/AHCT + len (n = 247), AHCT + RVD + len (n = 254), or AHCT + len (n = 257). The primary end point was 38-month PFS.. The study population had a median age of 56 years (range, 20 to 70 years); 24% of patients had high-risk MM, 73% had a triple-drug regimen as initial therapy, and 18% were in complete response at enrollment. The 38-month PFS rate was 58.5% (95% CI, 51.7% to 64.6%) for AHCT/AHCT + len, 57.8% (95% CI, 51.4% to 63.7%) for AHCT + RVD + len, and 53.9% (95% CI, 47.4% to 60%) for AHCT + len. For AHCT/AHCT + len, AHCT + RVD + len, and AHCT + len, the OS rates were 81.8% (95% CI, 76.2% to 86.2%), 85.4% (95% CI, 80.4% to 89.3%), and 83.7% (95% CI, 78.4% to 87.8%), respectively, and the complete response rates at 1 year were 50.5% (n = 192), 58.4% (n = 209), and 47.1% (n = 208), respectively. Toxicity profiles and development of second primary malignancies were similar across treatment arms.. Second AHCT or RVD consolidation as post-AHCT interventions for the up-front treatment of transplantation-eligible patients with MM did not improve PFS or OS. Single AHCT and len should remain as the standard approach for this population.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Consolidation Chemotherapy; Dexamethasone; Disease Progression; Female; Hematopoietic Stem Cell Transplantation; Humans; Lenalidomide; Maintenance Chemotherapy; Male; Melphalan; Middle Aged; Multiple Myeloma; Myeloablative Agonists; Progression-Free Survival; Prospective Studies; Remission Induction; Reoperation; Time Factors; Transplantation, Autologous; United States; Young Adult

The conditioning therapy used in connection with haematopoietic stem cell transplantation (HSCT) can induce painful oral mucositis, which has negative impacts on patient quality of life and survival, as well as on health-care costs. While cooling of the oral mucosa (cryotherapy) is regarded as standard prophylaxis against oral mucositis, the long duration of the treatment affects compliance owing to side effects. In this prospective, randomised trial, 94 patients (62 males/32 females; median age 59 years, range 34-69) with a diagnosis of myeloma who were undergoing autologous HSCT were randomised 1:1 to receive cryotherapy for 7 h (N = 46) or 2 h (N = 48). Oral mucositis was evaluated prospectively. No significant difference was observed with respect to the proportion of patients who showed grades 3 and 4 toxicity according to the WHO scale (2.1 and 4.3% for 2 and 7 h, respectively; 95% CI -0.09 to 0.049; p = 0.98) as between the groups. Two hours of cryotherapy was as effective as 7 h in terms of protecting against severe oral mucositis in connection with autologous HSCT for myeloma. This trial is registered with ClinicalTrials.gov (NCT03704597).

Topics: Adolescent; Adult; Aged; Autografts; Cryotherapy; Female; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Prospective Studies; Stem Cell Transplantation; Stomatitis

The risk of venous thromboembolism (VTE) is higher in myeloma patients receiving immunomodulatory compounds. A VTE prophylaxis using low-molecular-weight heparin or aspirin is therefore proposed. Apixaban is an oral direct anti-Xa. Several studies have shown the efficacy and safety of apixaban in VTE prophylaxis compared to enoxaparin. The objective of this prospective phase 2 pilot study was to assess the risk of VTE and bleeding in patients with myeloma treated with immunomodulatory compounds lenalidomide (len) or thalidomide (thal), using apixaban in a preventive scheme. Myeloma patients requiring Melphalan-Prednisone-Thalidomide in the first line, or Lenalidomide-Dexamethasone in the relapse setting received apixaban, 2.5 mg x 2/day for 6 months. Venous (pulmonary embolism-PE, or symptomatic proximal or distal deep vein thrombosis-DVT, or all proximal asymptomatic events detected by systematic proximal bilateral compression ultrasound) or arterial thrombotic events, and bleeding events (ISTH 2005) were registered. One hundred and four patients were enrolled (mean age 69.8 ± 7.8 years), 11 in first line and 93 in relapse. Two venous thrombotic events were observed, for example, an asymptomatic proximal DVT and a symptomatic distal DVT, in the context of apixaban stopped 14 days before, due to lenalidomide-induced thrombocytopenia. No PE or arterial cardiovascular events were reported. Only one major and 11 CRNM hemorrhages were reported. These data must now be confirmed on a randomized large study.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Female; Humans; Lenalidomide; Male; Melphalan; Middle Aged; Multiple Myeloma; Prednisolone; Pyrazoles; Pyridones; Thalidomide; Venous Thromboembolism

The Japan Study Group for Cell Therapy and Transplantation (JSCT) organized a phase II study to evaluate the efficacy and safety of a treatment protocol (JSCT-MM12) for multiple myeloma (MM) patients who were previously untreated and transplantation-eligible. Since bortezomib-based therapy is known to be effective for MM, the protocol is intensified more than the previous protocol (JSCT-MM10) and comprised the subsequent treatments: bortezomib + cyclophosphamide + dexamethasone (VCD) induction; bortezomib + high-dose-melphalan (B-HDM) conditioning with autologous stem cell transplantation (ASCT); bortezomib + thalidomide + dexamethasone (VTD) consolidation; and lenalidomide (LEN) maintenance.. Sixty-four symptomatic patients aged between 20 and 65 years were enrolled for treatment and received three cycles of VCD, followed by cyclophosphamide administration for autologous stem cell harvest and B-HDM/ASCT, and subsequently two cycles of VTD, after that LEN for 1 year.. Complete response (CR)/stringent CR (sCR) rates for induction, ASCT, consolidation, and maintenance therapies were 20, 39, 52, and 56%, respectively. The grade 3/4 toxicities (≥ 10%) with VCD treatment included neutropenia (27%), anemia (19%), and thrombocytopenia (11%). There was no treatment-related mortality. After median follow-up of 41 months, estimated 3-year progression-free survival (PFS) and overall survival (OS) rates were 64% and 88%, respectively. The high-risk group revealed lower CR/sCR, PFS, and OS than the standard-risk group.. The study revealed that the treatment protocol consisting of VCD induction, B-HDM/ASCT followed by VTD consolidation, and LEN maintenance could produce highly beneficial responses and favorable tolerability in newly diagnosed MM. However, future study is required for improving treatment in the high-risk group.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Combined Modality Therapy; Cyclophosphamide; Dexamethasone; Female; Humans; Japan; Lenalidomide; Male; Melphalan; Middle Aged; Multiple Myeloma; Neoadjuvant Therapy; Prognosis; Stem Cell Transplantation; Survival Rate; Thalidomide; Transplantation, Autologous

Microbiome dysbiosis has been associated with adverse outcomes of hematopoietic cell transplantation (HCT). We hypothesized that exposure to high-dose melphalan and antimicrobials in patients undergoing autologous HCT for plasma cell disorders results in oral and gastrointestinal microbial dysbiosis, which in turn is associated with regimen-related toxicities. We conducted a prospective study describing the longitudinal changes in oral and gastrointestinal bacteriome and mycobiome in this patient population. Our findings show that microbiome composition present at baseline is associated with the incidence and severity of post-transplantation nausea, vomiting, and culture-negative neutropenic fever, as well as with the rate of neutrophil engraftment. We also have evidence of an association between the microbial communities at count nadir and the development of regimen-related gastrointestinal toxicities commonly observed after exposure to high-dose melphalan. Although bacteriome diversity largely recovers within 1 month after transplantation, we observed a continuous decrease in oral and gastrointestinal mycobiome diversity, suggesting that the mycobiome requires a longer time to recover compared with the bacteriome.

Topics: Adult; Aged; Anti-Infective Agents; Autografts; Dysbiosis; Female; Gastrointestinal Microbiome; Hematopoietic Stem Cell Transplantation; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Pilot Projects; Prospective Studies; Time Factors

GMMG-HD6 is a randomized, open, multicenter phase III trial. The planned recruitment number is 564 NDMM patients. All patients will receive 4 VRD cycles as induction and undergo peripheral blood stem cell mobilization and harvesting. Thereafter they will be treated with high dose melphalan therapy plus autologous stem cell transplantation followed by 2 cycles of VRD consolidation and lenalidomide maintenance. Patients in arm B1 + B2 will additionally receive elotuzumab in the induction phase, whereas patients in A2 + B2 will be treated with elotuzumab added to consolidation and maintenance. The primary endpoint of the trial is PFS. Secondary objectives and endpoints are OS, CR rates after induction therapy comparing the two arms VRD (A1 + A2) vs VRD + elotuzumab (B1 + B2), CR rates after consolidation treatment, best response to treatment during the study, time to progression (TTP), duration of response (DOR), toxicity and quality of life.. Since this is the publication of a study protocol of an ongoing study, no results can be presented.. This phase III trial is designed to evaluate whether the addition of elotuzumab to an intensified treatment concept with high dose melphalan chemotherapy plus autologous stem cell transplantation and induction, consolidation and maintenance treatment with bortezomib and lenalidomide is able to improve PFS compared to the same concept without elotuzumab.. NCT02495922 on June 24th, 2015.

Topics: Adult; Aged; Antibodies, Monoclonal, Humanized; Bortezomib; Consolidation Chemotherapy; Dexamethasone; Female; Hematopoietic Stem Cell Transplantation; Humans; Induction Chemotherapy; Lenalidomide; Maintenance Chemotherapy; Male; Melphalan; Middle Aged; Multiple Myeloma; Prospective Studies; Quality of Life; Research Design; Survival Analysis; Treatment Outcome; Young Adult

Multiple myeloma (MM) is a disease characterized by antitumoral immune dysfunction. The objective of the present study was to determine lymphocyte subsets (B, T, NK, NKT, iNKT, dendritic cells, and regulatory T cells) in 68 newly diagnosed patients and 113 healthy donors. Lymphocyte subsets were studied in the same patients 6 months after treatment. Pre-treatment values of CD4+ T cells, NK cells, type 2 dendritic cells, and B cells in MM patients were lower than in healthy donors. Forty patients (59%) received MPT treatment and 28 (41%) thal-dex. Patients with no response to treatment, exhibited a decrease in CD4+ T cells and NK cells, as well as an increase in Treg cell numbers. Median DFS and OS was lower in patients not achieving response, in patients having low numbers of NK cells, and higher values of LDH. The number of CD4 T cells, NK, DC2, and B cells at diagnosis is lower in patients with MM. Non-responder patients had lower CD4 and NK, but higher Treg cell values. Patients in which response is not achieved, and those holding lower values of NK cells and higher levels of LDH, have poor DFS and OS.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Disease-Free Survival; Female; Humans; Killer Cells, Natural; Lymphocyte Count; Male; Melphalan; Middle Aged; Multiple Myeloma; Prednisolone; Survival Rate; Thalidomide

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bendamustine Hydrochloride; Female; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Transplantation, Autologous; Young Adult

We conducted a phase I study to determine the recommended dose of thalidomide combined with melphalan plus prednisolone (MPT) and a phase II study evaluating the efficacy and safety of this MPT regimen in transplant-ineligible Japanese patients with untreated multiple myeloma. The recommended dose was determined to be 100 mg/day in the phase I study. In the phase II, randomized, double-blind, parallel-group study, patients were allocated to either MPT (n = 52) or MP (n = 51), with 21 and 29 patients completing the study, respectively. Overall response rate, the primary endpoint, was significantly higher in the MPT [40.4% (21/52 patients), 95% confidence interval (CI) 27.0-54.9%] than in the MP [19.6% (10/51 patients), 95% CI 9.8-33.1%] group (P = 0.022). Time to response was also significantly shorter in the MPT group. Incidences of hematological toxicities were similar in the two groups, suggesting that addition of thalidomide did not increase hematological toxicity. Although incidences of some non-hematological toxicities tended to be higher in the MPT group, the low incidence of ≥ Grade 3 toxicities suggests that MPT therapy was well tolerated. These results support the safety and efficacy of MPT therapy in untreated Japanese multiple myeloma patients.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Asian People; Autografts; Double-Blind Method; Female; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Prednisolone; Stem Cell Transplantation; Thalidomide; Treatment Outcome

Topics: Adolescent; Adult; Aged; Bortezomib; Chromosome Aberrations; Female; Follow-Up Studies; Hematopoietic Stem Cell Transplantation; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Prognosis; Progression-Free Survival; Thalidomide; Transplantation, Autologous; Young Adult

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Female; Follow-Up Studies; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Neoplasm Recurrence, Local; Panobinostat; Prednisone; Prognosis; Survival Rate; Thalidomide

High-dose melphalan is an important component of conditioning regimens for patients undergoing hematopoietic stem cell transplantation. The current dosing strategy based on body surface area results in a high incidence of oral mucositis and gastrointestinal and liver toxicity. Pharmacokinetically guided dosing will individualize exposure and help minimize overexposure-related toxicity.. The purpose of this study was to develop a population pharmacokinetic model and optimal sampling strategy.. A population pharmacokinetic model was developed with NONMEM using 98 observations collected from 15 adult patients given the standard dose of 140 or 200 mg/m. A two-compartment model best described the data. The final model included body weight and creatinine clearance as predictors of clearance. The determinant-optimal sampling strategies (and windows) were identified at 0.08 (0.08-0.19), 0.61 (0.33-0.90), 2.0 (1.3-2.7), and 4.0 (3.6-4.0) h post-infusion. An excellent correlation was observed between area under the curve estimates obtained with the full and the proposed four-sample strategy (R. The developed pharmacokinetic model-based sparse sampling strategy promises to achieve the target area under the curve as part of precision dosing.

Topics: Aged; Area Under Curve; Bayes Theorem; Blood Specimen Collection; Female; Hematopoietic Stem Cell Transplantation; Humans; Male; Melphalan; Middle Aged; Models, Biological; Multiple Myeloma; Myeloablative Agonists

In this phase 1 study, we tested increasing doses of total marrow irradiation (TMI) in addition to standard intravenous melphalan at 200 mg/m

Topics: Adult; Aged; Combined Modality Therapy; Drug Resistance, Neoplasm; Female; Hematopoietic Stem Cell Transplantation; Humans; Male; Maximum Tolerated Dose; Melphalan; Middle Aged; Multiple Myeloma; Recurrence; Retreatment; Survival Analysis; Transplantation Conditioning; Transplantation, Autologous; Treatment Outcome; Whole-Body Irradiation

The combination of bortezomib, melphalan, and prednisone is a standard treatment for patients with newly diagnosed multiple myeloma who are ineligible for autologous stem-cell transplantation. Daratumumab has shown efficacy in combination with standard-of-care regimens in patients with relapsed or refractory multiple myeloma.. In this phase 3 trial, we randomly assigned 706 patients with newly diagnosed multiple myeloma who were ineligible for stem-cell transplantation to receive nine cycles of bortezomib, melphalan, and prednisone either alone (control group) or with daratumumab (daratumumab group) until disease progression. The primary end point was progression-free survival.. At a median follow-up of 16.5 months in a prespecified interim analysis, the 18-month progression-free survival rate was 71.6% (95% confidence interval [CI], 65.5 to 76.8) in the daratumumab group and 50.2% (95% CI, 43.2 to 56.7) in the control group (hazard ratio for disease progression or death, 0.50; 95% CI, 0.38 to 0.65; P<0.001). The overall response rate was 90.9% in the daratumumab group, as compared with 73.9% in the control group (P<0.001), and the rate of complete response or better (including stringent complete response) was 42.6%, versus 24.4% (P<0.001). In the daratumumab group, 22.3% of the patients were negative for minimal residual disease (at a threshold of 1 tumor cell per 10. Among patients with newly diagnosed multiple myeloma who were ineligible for stem-cell transplantation, daratumumab combined with bortezomib, melphalan, and prednisone resulted in a lower risk of disease progression or death than the same regimen without daratumumab. The daratumumab-containing regimen was associated with more grade 3 or 4 infections. (Funded by Janssen Research and Development; ALCYONE ClinicalTrials.gov number, NCT02195479 .).

Topics: Adult; Aged; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Disease-Free Survival; Female; Follow-Up Studies; Humans; Infections; Intention to Treat Analysis; Kaplan-Meier Estimate; Male; Melphalan; Middle Aged; Multiple Myeloma; Prednisone; Survival Rate

Topics: Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Confidence Intervals; Disease-Free Survival; Female; Hospitals, University; Humans; Male; Melphalan; Multiple Myeloma; Prednisone; Prognosis; Proportional Hazards Models; Spain; Survival Analysis

Topics: Administration, Intravenous; Adult; Aged; Busulfan; Female; Humans; Infections; Male; Melphalan; Middle Aged; Multiple Myeloma; Stem Cell Transplantation; Stomatitis; Transplantation Conditioning; Transplantation, Autologous; Venous Insufficiency; Young Adult

Multiple myeloma is usually fatal due to serial relapses that become progressively refractory to therapy. CD19 is typically absent on the dominant multiple myeloma cell population but may be present on minor subsets with unique myeloma-propagating properties. To target myeloma-propagating cells, we clinically evaluated autologous T cells transduced with a chimeric antigen receptor (CAR) against CD19 (CTL019).. Subjects received CTL019 following salvage high-dose melphalan and autologous stem cell transplantation (ASCT). All subjects had relapsed/refractory multiple myeloma and had previously undergone ASCT with less than 1 year progression-free survival (PFS).. ASCT + CTL019 was safe and feasible, with most toxicity attributable to ASCT and no severe cytokine release syndrome. Two of 10 subjects exhibited significantly longer PFS after ASCT + CTL019 compared with prior ASCT (479 vs. 181 days; 249 vs. 127 days). Correlates of favorable clinical outcome included peak CTL019 frequency in bone marrow and emergence of humoral and cellular immune responses against the stem-cell antigen Sox2. Ex vivo treatment of primary myeloma samples with a combination of CTL019 and CAR T cells against the plasma cell antigen BCMA reliably inhibited myeloma colony formation in vitro, whereas treatment with either CAR alone inhibited colony formation inconsistently.. CTL019 may improve duration of response to standard multiple myeloma therapies by targeting and precipitating secondary immune responses against myeloma-propagating cells.. Clinicaltrials.gov identifier NCT02135406.. Novartis, NIH, Conquer Cancer Foundation.

Topics: Aged; Antigens, CD19; B-Cell Maturation Antigen; Combined Modality Therapy; Female; Hematopoietic Stem Cell Transplantation; Humans; Immunity, Cellular; Immunotherapy, Adoptive; Male; Melphalan; Middle Aged; Multiple Myeloma; Myeloablative Agonists; Receptors, Antigen, T-Cell; SOXB1 Transcription Factors; T-Lymphocytes; Transplantation, Autologous; Treatment Outcome

High-dose melphalan followed by autologous hematopoietic stem cell transplantation (ASCT) is a standard treatment for younger myeloma patients. However, the correlation between its toxicity and renal impairment is not clear. We analyzed this relationship, focusing on estimated glomerular filtration rate (eGFR) as an index of renal function. We evaluated 78 multiple myeloma patients who underwent ASCT following high-dose melphalan at our center. Patients were divided into a higher eGFR group (eGFR ≥ 60) and a lower eGFR group (eGFR < 60). Multivariate analyses revealed that lower eGFR was independently associated with alkaline phosphatase elevation (OR 10.2, P = 0.038), mucositis (OR 10.5, P = 0.032), grade 2-4 co-elevation of both aspartate aminotransferase and alanine aminotransferase (OR 21.3, P = 0.016), delay of reticulocyte engraftment (HR 0.524, P = 0.034), and delay of platelet engraftment (HR 0.535, P = 0.0016). However, lower eGFR was not correlated with overall survival or time-to-next treatment. In summary, renal dysfunction secondary to administration of high-dose melphalan was associated with increased hepatic and mucosal toxicity and delay of hematological recovery, but did not affect survival outcomes.

Topics: Adolescent; Adult; Aged; Female; Follow-Up Studies; Glomerular Filtration Rate; Humans; Liver; Male; Melphalan; Middle Aged; Mucous Membrane; Multiple Myeloma; Retrospective Studies

The phase 3, randomized Frontline Investigation of Revlimid and Dexamethasone Versus Standard Thalidomide (FIRST) trial investigating lenalidomide plus low-dose dexamethasone until disease progression (Rd continuous) vs melphalan, prednisone and thalidomide for 12 cycles (MPT) and Rd for 18 cycles (Rd18) in transplant-ineligible patients with newly diagnosed multiple myeloma (NDMM) showed that Rd continuous prolonged progression-free survival and overall survival compared with MPT. A subanalysis of the FIRST trial was conducted to determine the benefits of Rd continuous in patients with NDMM based on depth of response. Patients randomized 1:1:1 to Rd continuous, Rd18 or MPT were divided into subgroups based on best response: complete response (CR; n=290), ⩾very good partial response (VGPR; n=679), ⩾partial response (PR; n=1 225) or ⩽stable disease (n=299). Over 13% of patients receiving Rd continuous who achieved ⩾VGPR as best response did so beyond 18 months of treatment. Rd continuous reduced the risk of progression or death by 67%, 51% and 35% vs MPT in patients with CR, ⩾VGPR and ⩾PR, respectively. Similarly, Rd continuous reduced the risk of progression or death by 61%, 54% and 38% vs Rd18 in patients with CR, ⩾VGPR and ⩾PR, respectively. In patients with CR, ⩾VGPR or ⩾PR, 4-year survival rates in the Rd continuous arm (81.1%, 73.1% or 64.6%, respectively) were higher vs MPT (70.8%, 59.8% or 57.2%, respectively) and similar vs Rd18 (76.5%, 67.7% and 62.5%, respectively). Rd continuous improved efficacy outcomes in all responding patients, including those with CR, compared with fixed duration treatment.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Female; Humans; Lenalidomide; Male; Melphalan; Middle Aged; Multiple Myeloma; Prednisone; Thalidomide

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Disease Progression; Drug Resistance, Neoplasm; Female; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Prednisone; Recurrence; Survival Analysis; Treatment Outcome

The usefulness of pharmacokinetics of bortezomib for multiple myeloma (MM) with respect to the maximum response to bortezomib and bortezomib-induced peripheral neuropathy (BIPN) development was studied. Maximum response to subcutaneous bortezomib therapy and BIPN occurrence for the first 12 weeks of treatment in 35 MM patients treated by bortezomib-dexamethasone (VD) and bortezomib-melphalan-prednisone (VMP) were evaluated. On day 1 of cycle 1, seven whole-blood samples were collected for 3 h after dosing completion to obtain the maximum plasma concentration and area under the time-concentration curve during 3 h postdose (AUC0-3) in each patient. A total of 35 patients with complete data were analyzed and the overall response rate was 91.4%. Complete response (CR) was observed in 42.9% patients. The maximum plasma concentration (Cmax) was significant for the CR rate in two different models [full model: odds ratio (OR)=1.092; P=0.038, final model: OR=1.081; P=0.038]. In addition, Cmax was associated with a progression-free survival advantage. Overall, 48.6% of patients developed BIPN including peripheral sensory neuropathy and neuralgia. The VMP-treated patients had a higher risk compared with the VD-treated patients (OR=21.662; P=0.029). Cmax had a tendency to affect the occurrence of BIPN (≥grade 2) (OR=1.064; P=0.092). In real-world clinical practice using bortezomib for MM patients, Cmax among pharmacokinetic factors significantly affected the achievement of CR. The VMP-treated patients showed vulnerability to BIPN, suggesting the necessity for more careful monitoring.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Dexamethasone; Female; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Peripheral Nervous System Diseases; Prednisone

Topics: Adult; Aged; Cryotherapy; Female; Hematopoietic Stem Cell Transplantation; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Prospective Studies; Stomatitis; Transplantation, Autologous

Chemotherapy-induced nausea and vomiting (CINV) is a significant side effect in multiple myeloma (MM) patients receiving high-dose melphalan treatment followed by autologous stem cell transplantation (ASCT). We evaluated the efficacy and safety of a triple antiemetic combination of palonosetron, aprepitant, and low-dose dexamethasone in 24 MM patients who received melphalan conditioning (100 mg/m

Topics: Adult; Aged; Antiemetics; Aprepitant; Dexamethasone; Drug Therapy, Combination; Humans; Isoquinolines; Melphalan; Middle Aged; Morpholines; Multiple Myeloma; Myeloablative Agonists; Palonosetron; Postoperative Nausea and Vomiting; Quinuclidines; Transplantation, Autologous; Treatment Outcome

There are currently no direct head-to-head clinical trials evaluating bortezomib-melphalan-prednisone (VMP) versus lenalidomide and low-dose dexamethasone (Rd). VMP (257 cases) and Rd (222 cases) arms of two randomized phase III trials were employed to assess the treatment influence on outcome in untreated elderly MM patients. Progression free survival (PFS) and overall survival (OS) were the primary and secondary end-points, respectively, and were investigated according to treatments administered over a 60-months follow-up period. While VMP significantly reduced the disease progression rate between enrolment and 12 months of follow-up, no difference between the two schedules was found between 12 and 32 months. After 32 months, Rd-treated patients had a lower incidence of disease progression. A statistically significant higher OS rate was seen in the VMP arm, which was maintained after data adjustment for potential confounders. Both approaches showed acceptable toxicity profiles. The profound tumor reduction by VMP over Rd justifies the initial higher PFS rate in favor of the bortezomib schedule, while the Rd regimen overcomes this evident initial drawback in reducing the tumor burden by long-term drug administration, gaining a subsequent improved disease control. VMP is associated with a significant reduced risk of death. This study may help physicians make a more informed therapy choice.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Dexamethasone; Disease-Free Survival; Female; Humans; Lenalidomide; Male; Melphalan; Multiple Myeloma; Prednisone; Prospective Studies; Survival Rate; Thalidomide; Treatment Outcome; Tumor Burden

The phase 3 FIRST (Frontline Investigation of REVLIMID + Dexamethasone Versus Standard Thalidomide) trial demonstrated that lenalidomide plus low-dose dexamethasone (Rd) until disease progression (Rd continuous) is an effective treatment option for transplant-ineligible patients with newly diagnosed multiple myeloma (NDMM). Given genetic differences between Asian and Western populations, this subanalysis of the FIRST trial examined the safety and efficacy of Rd (given continuously or for 18 cycles [Rd18]) and MPT (melphalan, prednisone, thalidomide) in 114 Asian patients from Mainland China, South Korea and Taiwan. Efficacy and safety with Rd continuous in Asian patients were consistent with those in the overall study population. The overall response rates were 77·8% for Rd continuous, 57·5% for MPT and 65·8% for Rd18. The risk of progression or death was reduced by 39% with Rd continuous versus MPT and by 35% with Rd continuous versus Rd18. Rd continuous improved the 3-year survival rate compared with MPT (70·2% vs. 56·4%) and Rd18 (58·1%). Common grade 3/4 adverse events in the Rd continuous and MPT arms were neutropenia (25·0% vs. 43·6%), infection (19·4% vs. 28·2%) and anaemia (19·4% vs. 15·4%), respectively. Thromboembolic event rates were low, and no second primary malignancies were observed. Rd continuous is safe and effective in transplant-ineligible Asian patients with NDMM.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Angiogenesis Inhibitors; Antineoplastic Combined Chemotherapy Protocols; Asia; Asian People; Dexamethasone; Disease Progression; Disease-Free Survival; Female; Humans; Infections; Lenalidomide; Male; Melphalan; Middle Aged; Multiple Myeloma; Neutropenia; Prednisone; Remission Induction; Thalidomide; Treatment Outcome

High-dose melphalan followed by autologous stem cell transplantation remains the standard of care for eligible patients with multiple myeloma, but disease response and toxicity, including severe mucositis, varies among patients. Our randomized trial investigated duration of cryotherapy (2 and 6 h) for reduction of mucositis prevalence and severity and explored factors associated with variability in pharmacokinetics and outcomes from melphalan therapy. The results demonstrate that 2-h is at least as effective as 6-h cryotherapy in decreasing severe mucositis. From a population pharmacokinetic model, we identified that fat-free mass, hematocrit, and creatinine clearance were significant covariates, as reported previously. Furthermore, we observed the rs4240803 SLC7A5 polymorphism was significantly associated with pharmacokinetic variability, and pharmacokinetics was associated with both mucositis and neutropenia. However, melphalan exposure was not associated with progression-free or overall survival in our dataset. These findings contribute to ongoing efforts to personalize melphalan dosing in transplant patients.

Topics: Adult; Aged; Antineoplastic Agents, Alkylating; Combined Modality Therapy; Creatinine; Cryotherapy; Disease-Free Survival; Dose-Response Relationship, Drug; Female; Hematopoietic Stem Cell Transplantation; Humans; Large Neutral Amino Acid-Transporter 1; Male; Melphalan; Middle Aged; Multiple Myeloma; Polymorphism, Genetic; Stomatitis; Survival Rate; Time Factors

Autologous stem cell transplantation (ASCT) conditioned with high-dose chemotherapy has long been established as the standard of care for eligible patients with newly diagnosed multiple myeloma. Despite recent therapeutic advances, high-dose melphalan (HDM) remains the chemotherapy regimen of choice in this setting. Lenalidomide (LEN) in combination with low-dose dexamethasone is recognized as a standard of care for patients with relapsed or refractory multiple myeloma (RRMM), and there is growing support for the administration of LEN as maintenance therapy post-ASCT. In view of the above, the present phase I clinical trial was designed to evaluate the safety and tolerability of high-dose LEN (HDLEN) in patients with RRMM, and to determine the maximum tolerated dose of HDLEN when added to HDM before ASCT. Despite administering HDLEN at doses of up to 350 mg/day, the maximum tolerated dose could not be determined, owing to an insufficient number of dose-limiting toxicities in the 21 patients enrolled in the trial. Conditioning with HDLEN plus HDM was associated with a favorable tolerability profile. Adverse events following ASCT were as expected with HDM. Median progression-free and overall survival were 10 months and 22 months, respectively, in this population of heavily pretreated patients. Our findings suggest that HDLEN in combination with HDM may offer significant potential as a conditioning regimen before ASCT in patients with RRMM. These preliminary findings are now being evaluated further in an ongoing phase II clinical trial.

Topics: Adult; Aged; Female; Hematopoietic Stem Cell Transplantation; Humans; Lenalidomide; Male; Maximum Tolerated Dose; Melphalan; Middle Aged; Multiple Myeloma; Salvage Therapy; Survival Analysis; Thalidomide; Transplantation Conditioning; Transplantation, Autologous

We aimed to examine whether doses of melphalan higher than 200 mg/m(2) improve response rates when used as conditioning before autologous transplant (ASCT) in multiple myeloma (MM) patients. Patients with MM, n=131, were randomized to 200 mg/m(2) (mel200) vs 280 mg/m(2) (mel280) using amifostine pretreatment. The primary end point was the proportion of patients achieving near complete response (⩾nCR). No treatment-related deaths occurred in this study. Responses following ASCT were for mel200 vs mel280, respectively, ⩾nCR 22 vs 39%, P=0.03, ⩾PR 57 vs 74%, P=0.04. The hazard of mortality was not statistically significantly different between groups (mel200 vs mel280; hazard ratio (HR)=1.15 (95% confidence interval (CI), 0.62-2.13, P=0.66)) nor was the rate of progression/mortality (HR=0.81 (0.52-1.27, P=0.36)). The estimated PFS at 1 and 3 years were 83 and 46%, respectively, for mel200 and 78 and 54%, respectively, for mel280. Amifostine and mel280 were well tolerated, with no grade 4 regimen-related toxicities and only one grade 3 mucositis (none with mel200) and three grade 3 gastrointestinal (GI) toxicities (two in mel200). Hospitalization rates were more frequent in the mel280 group (59 vs 43%, P=0.08). Mel280 resulted in a higher major response rate (CR+nCR) and should be evaluated in larger studies.

Topics: Adult; Aged; Autografts; Disease-Free Survival; Female; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Stem Cell Transplantation; Survival Rate; Transplantation Conditioning

Bortezomib plus melphalan and prednisone (VMP) and lenalidomide plus low-dose dexamethasone (Rd) are 2 standards of care for elderly untreated multiple myeloma (MM) patients. We planned to use VMP and Rd for 18 cycles in a sequential or alternating scheme. Patients (233) with untreated MM, >65 years, were randomized to receive 9 cycles of VMP followed by 9 cycles of Rd (sequential scheme; n = 118) vs 1 cycle of VMP followed by 1 cycle of Rd, and so on, up to 18 cycles (alternating scheme; n = 115). VMP consisted of one 6-week cycle of bortezomib using a biweekly schedule, followed by eight 5-week cycles of once-weekly VMP. Rd included nine 4-week cycles of Rd. The primary end points were 18-month progression free survival (PFS) and safety profile of both schemes. The 18-month PFS was 74% and 80% in the sequential and alternating arms, respectively (P = .21). The sequential and alternating groups exhibited similar hematologic and nonhematologic toxicity. Both arms yielded similar complete response rate (42% and 40%), median PFS (32 months vs 34 months, P = .65), and 3-year overall survival (72% vs 74%, P = .63). The benefit of both schemes was remarkable in patients aged 65 to 75 years. In addition, achieving complete and immunophenotypic response was associated with better outcome. The present approach, based on VMP and Rd, is associated with high efficacy and acceptable toxicity profile with no differences between the sequential and alternating regimens. This trial was registered at www.clinicaltrials.gov as #NCT00443235.

Topics: Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Dexamethasone; Female; Humans; Lenalidomide; Male; Melphalan; Multiple Myeloma; Prednisone; Thalidomide; Treatment Outcome

Response criteria for multiple myeloma are based upon changes in monoclonal protein levels quantified using serum and/or urine protein electrophoresis. The latter lacks sensitivity at low monoclonal protein levels and since 2001, the serum free light chain test has been available and its clinical utility proven, yet guidelines have not recommended it as a replacement for urine assessment. Herein we evaluated responses using serum free light chain measurements and serum and urine electrophoresis after 2 and 4 cycles of therapy and after stem cell transplantation in 25 light chain and 157 intact immunoglobulin myeloma patients enrolled in the IFM 2007-02 MM trial. All 25 light chain patients had measurable disease by serum free light chain and urine methods at presentation. By contrast 98 out of 157 intact immunoglobulin patients had measurable disease by serum free light chain compared to 55 out of 157 by urine electrophoresis. In all patients there was substantial agreement between predicate (serum/urine protein electrophoresis) and test (serum protein electrophoresis and serum free light chain) methods for response assessment (Weighted Kappa=0.83). Urine immunofixation became negative in 47% light chain and 43% intact immunoglobulin patients after 2 cycles of therapy. At this time the serum free light chain ratio normalised in only 11% and 27% patients, respectively. In summary we found good agreement between methods for response assessment, but the serum free light chain test provided greater sensitivity than urine electrophoresis for monitoring. To our knowledge this is the first report comparing both methods for response assignment based on the International Myeloma Working Group guidelines. (Clinical Trials Register.eu identifier: 2007-005204-40).

Topics: Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Pharmacological; Bortezomib; Dexamethasone; Electrophoresis; Hematopoietic Stem Cell Transplantation; Humans; Immunoglobulin kappa-Chains; Immunoglobulin lambda-Chains; Melphalan; Multiple Myeloma; Nephelometry and Turbidimetry; Practice Guidelines as Topic; Retrospective Studies; Thalidomide; Transplantation, Homologous

Renal impairment is associated with poor prognosis in myeloma. This analysis of the pivotal phase 3 FIRST trial examined the impact of renally adapted dosing of lenalidomide and dexamethasone on outcomes of patients with different degrees of renal impairment. Transplant-ineligible patients not requiring dialysis were randomized 1:1:1 to receive continuous lenalidomide and dexamethasone until disease progression (n=535) or for 18 cycles (72 weeks; n=541), or melphalan, prednisone, and thalidomide for 12 cycles (72 weeks; n=547). Follow-up is ongoing. Patients were grouped by baseline creatinine clearance into no (≥ 80 mL/min [n=389]), mild (≥ 50 to < 80 mL/min [n=715]), moderate (≥ 30 to < 50 mL/min [n=372]), and severe impairment (< 30 mL/min [n=147]) subgroups. Continuous lenalidomide and dexamethasone therapy reduced the risk of progression or death in no, mild, and moderate renal impairment subgroups vs. melphalan, prednisone, and thalidomide therapy (HR = 0.67, 0.70, and 0.65, respectively). Overall survival benefits were observed with continuous lenalidomide and dexamethasone treatment vs. melphalan, prednisone, and thalidomide treatment in no or mild renal impairment subgroups. Renal function improved from baseline in 52.6% of lenalidomide and dexamethasone-treated patients. The safety profile of continuous lenalidomide and dexamethasone was consistent across renal subgroups, except for grade 3/4 anemia and rash, which increased with increasing severity of renal impairment. Continuous lenalidomide and dexamethasone treatment, with renally adapted lenalidomide dosing, was effective for most transplant-ineligible patients with myeloma and renal impairment. Trial registration: ClinicalTrials.gov (NCT00689936); EudraCT (2007-004823-39). Funding: Intergroupe Francophone du Myélome and the Celgene Corporation.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Creatinine; Dexamethasone; Disease Progression; Drug Administration Schedule; Female; Humans; Lenalidomide; Male; Melphalan; Middle Aged; Multiple Myeloma; Prednisone; Prognosis; Prospective Studies; Renal Insufficiency; Severity of Illness Index; Survival Analysis; Thalidomide; Treatment Outcome

Persistence of chemoresistant minimal residual disease (MRD) plasma cells (PCs) is associated with inferior survival in multiple myeloma (MM). Thus, characterization of the minor MRD subclone may represent a unique model to understand chemoresistance, but to our knowledge, the phenotypic and genetic features of the MRD subclone have never been investigated. Here, we compared the antigenic profile of MRD vs diagnostic clonal PCs in 40 elderly MM patients enrolled in the GEM2010MAS65 study and showed that the MRD subclone is enriched in cells overexpressing integrins (CD11a/CD11c/CD29/CD49d/CD49e), chemokine receptors (CXCR4), and adhesion molecules (CD44/CD54). Genetic profiling of MRD vs diagnostic PCs was performed in 12 patients; 3 of them showed identical copy number alterations (CNAs), in another 3 cases, MRD clonal PCs displayed all genetic alterations detected at diagnosis plus additional CNAs that emerged at the MRD stage, whereas in the remaining 6 patients, there were CNAs present at diagnosis that were undetectable in MRD clonal PCs, but also a selected number of genetic alterations that became apparent only at the MRD stage. The MRD subclone showed significant downregulation of genes related to protein processing in endoplasmic reticulum, as well as novel deregulated genes such as ALCAM that is prognostically relevant in MM and may identify chemoresistant PCs in vitro. Altogether, our results suggest that therapy-induced clonal selection could be already present at the MRD stage, where chemoresistant PCs show a singular phenotypic signature that may result from the persistence of clones with different genetic and gene expression profiles. This trial was registered atwww.clinicaltrials.gov as #NCT01237249.

Topics: Aged; Bortezomib; Cell Adhesion Molecules; Dexamethasone; Disease Progression; Down-Regulation; Drug Resistance, Neoplasm; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Genomics; Humans; Immunophenotyping; Integrins; Lenalidomide; Male; Melphalan; Models, Genetic; Multiple Myeloma; Neoplasm, Residual; Phenotype; Plasma Cells; Prednisone; Prognosis; Thalidomide

We conducted a phase II trial investigating the impact of fractionated hematopoietic cell infusions on engraftment kinetics and symptom burden in patients with plasma cell myeloma (PCM) undergoing autologous hematopoietic cell transplant (AHCT). We hypothesized that multiple hematopoietic cell infusions would reduce duration of neutropenia and enhance immune recovery resulting in a better tolerated procedure. Twenty-six patients received high-dose melphalan followed by multiple cell infusions (Days 0, +2, +4, +6) and were compared to PCM patients (N = 77) who received high-dose melphalan and a single infusion (Day 0) (concurrent control group). The primary endpoint was number of days with ANC <500K/mcL. Symptom burden was assessed using the MSK-modified MD Anderson Symptom Inventory. Median duration of neutropenia was similar in study (4 days, range 3-5) and control patients (4 days, range 3-9) (p = 0.654). There was no significant difference in the number of red cell or platelet transfusions, days of fever, diarrhea, antibiotics, number of documented infections, or length of admission. Symptom burden surveys showed that AHCT was well-tolerated in both study and control patients. We conclude that fractionated stem cell infusions following high-dose melphalan do not enhance engraftment kinetics or significantly alter patients' clinical course following AHCT in PCM.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Blood Component Transfusion; Female; Hematopoietic Stem Cell Transplantation; Humans; Leukocyte Count; Male; Melphalan; Middle Aged; Multiple Myeloma; Myeloablative Agonists; Neutropenia; Neutrophils; Pilot Projects; Time Factors; Transplantation Conditioning; Transplantation, Autologous; Treatment Outcome

The combination of melphalan, prednisone, and thalidomide (MPT) is considered standard therapy for newly diagnosed patients with multiple myeloma who are ineligible for stem cell transplantation. Long-term treatment with thalidomide is hampered by neurotoxicity. Melphalan, prednisone, and lenalidomide, followed by lenalidomide maintenance therapy, showed promising results without severe neuropathy emerging. We randomly assigned 668 patients between nine 4-week cycles of MPT followed by thalidomide maintenance until disease progression or unacceptable toxicity (MPT-T) and the same MP regimen with thalidomide being replaced by lenalidomide (MPR-R). This multicenter, open-label, randomized phase 3 trial was undertaken by Dutch-Belgium Cooperative Trial Group for Hematology Oncology and the Nordic Myeloma Study Group (the HOVON87/NMSG18 trial). The primary end point was progression-free survival (PFS). A total of 318 patients were randomly assigned to receive MPT-T, and 319 received MPR-R. After a median follow-up of 36 months, PFS with MPT-T was 20 months (95% confidence interval [CI], 18-23 months) vs 23 months (95% CI, 19-27 months) with MPR-R (hazard ratio, 0.87; 95% CI, 0.72-1.04; P = .12). Response rates were similar, with at least a very good partial response of 47% and 45%, respectively. Hematologic toxicity was more pronounced with MPR-R, especially grades 3 and 4 neutropenia: 64% vs 27%. Neuropathy of at least grade 3 was significantly higher in the MPT-T arm: 16% vs 2% in MPR-R, resulting in a significant shorter duration of maintenance therapy (5 vs 17 months in MPR-R), irrespective of age. MPR-R has no advantage over MPT-T concerning efficacy. The toxicity profile differed with clinically significant neuropathy during thalidomide maintenance vs myelosuppression with MPR.

Topics: Aged; Aged, 80 and over; Disease-Free Survival; Female; Humans; Lenalidomide; Maintenance Chemotherapy; Male; Melphalan; Middle Aged; Multiple Myeloma; Prednisone; Thalidomide; Treatment Outcome; Withholding Treatment

This phase 2 trial evaluated three low-dose intensity subcutaneous bortezomib-based treatments in patients ⩾75 years with newly diagnosed multiple myeloma (MM). Patients received subcutaneous bortezomib plus oral prednisone (VP, N=51) or VP plus cyclophosphamide (VCP, N=51) or VP plus melphalan (VMP, N=50), followed by bortezomib maintenance, and half of the patients were frail. Response rate was 64% with VP, 67% with VCP and 86% with VMP, and very good partial response rate or better was 26%, 28.5% and 49%, respectively. Median progression-free survival was 14.0, 15.2 and 17.1 months, and 2-year OS was 60%, 70% and 76% in VP, VCP, VMP, respectively. At least one drug-related grade ⩾3 non-hematologic adverse event (AE) occurred in 22% of VP, 37% of VCP and 33% of VMP patients; the discontinuation rate for AEs was 12%, 14% and 20%, and the 6-month rate of toxicity-related deaths was 4%, 4% and 8%, respectively. The most common grade ⩾3 AEs included infections (8-20%), and constitutional (10-14%) and cardiovascular events (4-12%); peripheral neuropathy was limited (4-6%). Bortezomib maintenance was effective and feasible. VP, VCP and VMP regimens demonstrated no substantial difference. Yet, toxicity was higher with VMP, suggesting that a two-drug combination followed by maintenance should be preferred in frail patients.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Cyclophosphamide; Disease-Free Survival; Female; Humans; Male; Melphalan; Multiple Myeloma; Prednisone; Survival Rate

The prospective, randomized phase III trial GMMG-HD2 aimed at demonstrating non-inferiority of single (Arm A) versus tandem (Arm B) high-dose melphalan followed by autologous transplantation (HDM/ASCT) with regard to 2-year event-free survival (EFS) in newly-diagnosed multiple myeloma (MM) and included 358 evaluable patients [Intention-to-treat population, (ITT), single/tandem HDM/ASCT: n = 177/181]. After a median follow-up of more than 11 years, non-inferiority of single versus tandem HDM/ASCT was demonstrated using the planned non-inferiority threshold of 15% of the 2-year EFS rate. Neither EFS (P = 0·53) nor overall survival (OS) (P = 0·33) differences were observed in the ITT population. In the tandem arm, 26% (n = 47/181) of patients refused a second HDM/ASCT due to non-medical reasons. A per-protocol (PP) analysis, including patients who received the intervention (single/tandem HDM/ASCT: n = 156/93) and patients who did not receive a second HDM/ASCT due to medical reasons (12%, n = 22/181), did not yield differences in EFS (P = 0·61) or OS (P = 0·16). In the ITT and PP set of the tandem arm, the rates of complete responses increased from first to second HDM/ASCT (both P = 0·04). Ten-year OS for the entire ITT was 34% (95% confidence interval: 29-40%). OS after first relapse was significantly shortened in the tandem arm (P = 0·04). In this study single HDM/ASCT was non-inferior to tandem HDM/ASCT in MM.

Topics: Adult; Aged; Combined Modality Therapy; Female; Follow-Up Studies; Hematopoietic Stem Cell Transplantation; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Myeloablative Agonists; Prospective Studies; Remission Induction; Survival Analysis; Transplantation, Autologous

This phase II trial evaluates, for the first time, the safety and efficacy of bendamustine plus high-dose melphalan (HDM) as a conditioning regimen before the second autologous stem cell transplantation (ASCT) in previously untreated multiple myeloma (MM) patients. In total, 32 ASCT patients received HDM (200 mg/m(2)) as conditioning for the first ASCT. After 3-6 months from the first ASCT, responding patients underwent a second ASCT following bendamustine (200 mg/m(2)) and HDM (140 mg/m(2)). High-dose chemotherapy and ASCT were performed with complete neutrophil and platelet recovery in all patients. The median number of days to neutrophil and platelet engraftment was 11 (range 9-15) and 12 (range 10-19), respectively. Only one subject experienced grade 3 diarrhea; the rate of mucositis and vomiting was significantly lower with the bendamustine plus HDM regimen compared with the HDM-only regimen (81.2 vs 96.9%, P=0.025 and 78.1 vs 100%, P=0.008). Overall response rate (ORR) was 81.2% after the first transplant, and 90.6% after the second, while complete response rates were 46.8 and 62.5%, respectively (P=0.016). Actuarial 2-year PFS and OS were 79% (95% confidence interval (CI), 60-98) and 97% (95% CI, 91-100), respectively. Bendamustine+HDM is feasible as the conditioning regimen for second ASCT in MM patients. The present study may pave the way for phase III studies specifically aimed at further investigating this combination strategy. The role of this combination in MM for conditioning regimen in a first or single ASCT setting should be also investigated.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bendamustine Hydrochloride; Diarrhea; Female; Graft Survival; Hematopoietic Stem Cell Transplantation; Humans; Male; Melphalan; Middle Aged; Mucositis; Multiple Myeloma; Transplantation Conditioning; Treatment Outcome; Vomiting

The value of minimal residual disease (MRD) in multiple myeloma (MM) has been more frequently investigated in transplant-eligible patients than in elderly patients. Because an optimal balance between treatment efficacy and toxicity is of utmost importance in patients with elderly MM, sensitive MRD monitoring might be particularly valuable in this patient population. Here, we used second-generation 8-color multiparameter-flow cytometry (MFC) to monitor MRD in 162 transplant-ineligible MM patients enrolled in the PETHEMA/GEM2010MAS65 study. The transition from first- to second-generation MFC resulted in increased sensitivity and allowed us to identify 3 patient groups according to MRD levels: MRD negative (<10(-5); n = 54, 34%), MRD positive (between <10(-4) and ≥10(-5); n = 20, 12%), and MRD positive (≥10(-4); n = 88, 54%). MRD status was an independent prognostic factor for time to progression (TTP) (hazard ratio [HR], 2.7; P = .007) and overall survival (OS) (HR, 3.1; P = .04), with significant benefit for MRD-negative patients (median TTP not reached, 70% OS at 3 years), and similar poorer outcomes for cases with MRD levels between <10(-4) and ≥10(-5) vs ≥10(-4) (both with a median TTP of 15 months; 63% and 55% OS at 3 years, respectively). Furthermore, MRD negativity significantly improved TTP of patients >75 years (HR, 4.8; P < .001), as well as those with high-risk cytogenetics (HR, 12.6; P = .01). Using second-generation MFC, immune profiling concomitant to MRD monitoring also contributed to identify patients with poor, intermediate, and favorable outcomes (25%, 61%, and 100% OS at 3 years, respectively; P = .01), the later patients being characterized by an increased compartment of mature B cells. Our results show that similarly to transplant candidates, MRD monitoring is one of the most relevant prognostic factors in elderly MM patients, irrespectively of age or cytogenetic risk. This trial was registered at www.clinicaltrials.gov as #NCT01237249.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Pharmacological; Biomarkers, Tumor; Dexamethasone; Drug Monitoring; Female; Humans; Immunity; Lenalidomide; Male; Melphalan; Monitoring, Physiologic; Multiple Myeloma; Neoplasm, Residual; Prednisone; Prognosis; Survival Analysis; Thalidomide; Vincristine

High-dose melphalan 200 mg/m(2) (MEL 200) is the standard of care as a conditioning regimen for autologous hematopoietic stem cell transplantation (AHSCT) for multiple myeloma (MM). We compared a novel conditioning combination incorporating busulfan, melphalan, and bortezomib (BUMELVEL) versus standard MEL 200 in newly diagnosed patients undergoing AHSCT for MM. Between July 2009 and May 2012, 43 eligible patients received BUMELVEL conditioning followed by AHSCT. BU was administered i.v. daily for 4 days to achieve a target area under the concentration-time curve total of 20,000 mM·min based on pharmacokinetic analysis after the first dose. MEL 140 mg/m(2) (MEL 140) and VEL 1.6 mg/m(2) were administered i.v. on days -2 and -1, respectively. Outcomes were compared with a contemporaneous North American cohort (n = 162) receiving MEL 200 matched for age, sex, performance status, stage, interval from diagnosis to AHSCT, and disease status before AHSCT. Multivariate analysis of relapse, progression-free survival (PFS), and overall survival (OS) was performed. The median follow-up was 25 months. No transplant-related mortality was observed in the study cohort at 1 year. PFS at 1 year was superior in the BUMELVEL cohort (90%) in comparison with 77% in MEL 200 historical control subjects (P = .02). Cumulative incidence of relapse was lower in the BUMELVEL group versus the MEL 200 group (10% at 1 year versus 21%; P = .047). OS at 1 year was similar between cohorts (93% versus 93%; P = .89). BU can be safely combined with MEL 140 and VEL without an increase in toxicities or transplant-related mortality. We observed a superior PFS in the BUMELVEL cohort without maintenance therapy, warranting further trials.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Busulfan; Case-Control Studies; Female; Hematopoietic Stem Cell Transplantation; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Myeloablative Agonists; Transplantation Conditioning; Transplantation, Autologous; Treatment Outcome

Purpose This analysis of the FIRST trial in patients with newly diagnosed multiple myeloma (MM) ineligible for stem-cell transplantation examined updated outcomes and impact of patient age. Patients and Methods Patients with untreated symptomatic MM were randomly assigned at a one-to-one-to-one ratio to lenalidomide plus low-dose dexamethasone until disease progression (Rd continuous), Rd for 72 weeks (18 cycles; Rd18), or melphalan, prednisone, and thalidomide (MPT; 72 weeks), stratified by age (≤ 75 v > 75 years), disease stage (International Staging System stage I/II v III), and country. The primary end point was progression-free survival. Rd continuous and MPT were primary comparators. Results Between August 21, 2008, and March 7, 2011, 1,623 patients were enrolled (Rd continuous, n = 535; Rd18, n = 541; MPT, n = 547), including 567 (35%) age older than 75 years. Higher rates of advanced-stage disease and renal impairment were observed in patients older than 75 versus 75 years of age or younger. Rd continuous reduced the risk of progression or death compared with MPT by 31% (hazard ratio [HR], 0.69; 95% CI, 0.59 to 0.80; P < .001) overall, 36% (HR, 0.64; 95% CI, 0.53 to 0.77; P < .001) in patients age 75 years or younger, and 20% (HR, 0.80; 95% CI, 0.62 to 1.03; P = .084) in those age older than 75 years. Median overall survival was longer with Rd continuous than with MPT, including a 14-month difference in patients age older than 75 years. Progression-free survival with Rd18 was similar to that with MPT, and overall survival with Rd18 was marginally inferior to that with Rd continuous. Rates of grade 3 to 4 treatment-emergent adverse events were similar for Rd continuous-treated patients age 75 years or older and those age older than 75 years; however, older patients had more frequent lenalidomide dose reductions. Conclusion Results support Rd continuous treatment as a new standard of care for stem-cell transplantation-ineligible patients with newly diagnosed MM of all ages.

Topics: Adult; Age Factors; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Disease Progression; Disease-Free Survival; Female; Humans; Lenalidomide; Male; Melphalan; Middle Aged; Multiple Myeloma; Neoplasm Staging; Prednisone; Survival Rate; Thalidomide

Multiple myeloma (MM) is a heterogeneous disease with high-risk patients progressing rapidly despite treatment. Various definitions of high-risk MM are used and we reported that gene expression profile (GEP)-defined high risk was a major predictor of relapse. In spite of our best efforts, the majority of GEP70 high-risk patients relapse and we have noted higher relapse rates during drug-free intervals. This prompted us to explore the concept of less intense drug dosing with shorter intervals between courses with the aim of preventing inter-course relapse. Here we report the outcome of the Total Therapy 5 trial, where this concept was tested. This regimen effectively reduced early mortality and relapse but failed to improve progression-free survival and overall survival due to relapse early during maintenance.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Disease-Free Survival; Dose-Response Relationship, Drug; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Lenalidomide; Male; Melphalan; Middle Aged; Multiple Myeloma; Neoplasm Proteins; Thalidomide

Autologous transplantation is controversial for older patients with multiple myeloma. The role of age-adjusted high-dose melphalan and the impact of induction chemotherapy cycles is still unclear. A total of 434 patients aged 60-70 years were randomly assigned to 4 cycles of standard anthracycline-based induction chemotherapy or no induction. For all patients, double autologous transplantation after melphalan 140 mg/m

Topics: Aged; Cytogenetics; Disease-Free Survival; Female; Hematopoietic Stem Cell Mobilization; Humans; Induction Chemotherapy; Male; Melphalan; Middle Aged; Mucositis; Multiple Myeloma; Stem Cell Transplantation; Transplantation, Autologous; Treatment Outcome

Melphalan followed by hematopoietic stem-cell transplantation (HSCT) is the standard treatment for multiple myeloma and other hematopoietic neoplasms. However, high doses of melphalan cause severe oral mucositis (OM). The objective was to verify the efficacy of cryotherapy plus laser therapy on reduction of OM severity. HSCT patients undergoing melphalan chemotherapy (n = 71) were randomly divided into two groups according to OM treatment: oral cryotherapy performed with ice chips for 1 h 35 min followed by low-level laser therapy (InGaAIP, 660 nm, 40 mW, 6 J/cm(2) ) (n = 54) and laser therapy alone with the same protocol (n = 17). A control group (n = 33) was composed of HSCT patients treated with melphalan who received no specific treatment for OM. OM scores and clinical information were collected from D0 to D + 11. The cryotherapy/laser therapy group showed the lowest OM scores (maximum Grade I) and the lowest mean number of days (8 days) with OM in comparison with the other groups (p < 0.001). OM Grades III and IV were present with high frequency only in the control group. The association of cryotherapy with laser therapy was effective in reducing OM severity in HSCT patients who underwent melphalan conditioning.

Topics: Adolescent; Adult; Aged; Child; Cryotherapy; Female; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Laser Therapy; Male; Melphalan; Middle Aged; Multiple Myeloma; Prospective Studies; Retrospective Studies; Stomatitis; Time Factors; Treatment Outcome; Young Adult

Therapeutic options for patients with multiple myeloma (MM) whose disease has relapsed after a prior autologous stem cell transplant (ASCT) include an expanding armamentarium of novel agents, often combined with traditional chemotherapy, or a second ASCT, with no clear standard of care. We retrospectively analyzed the outcomes of 75 patients who underwent salvage melphalan-based ASCT for relapsed MM at Memorial Sloan-Kettering Cancer Center between 1995 and 2012. Conditioning was performed with melphalan 200 mg/m(2) (n = 43), 180 mg/m(2) (n = 1), 140 mg/m(2) (n = 22), and 100 mg/m(2) (n = 9). The median age at second ASCT was 59 years (range, 36 to 75), and 58% (n = 35) were men. Of those with available data, 19% had high-risk cytogenetics (including t (4;14), p53 loss, or del 13q by karyotype) at the time of second ASCT. Median interval between first and salvage ASCT was 37.5 months (range, 6.9 to 111.4). Of 72 assessable patients, 57% had chemotherapy-sensitive disease before to salvage ASCT and 43% were chemoresistant. Four patients died within 100 days of ASCT. Response was assessed at 2 to 3 months post-ASCT, and of 71 assessable patients, 82% achieved at least a partial response, 15% had stable disease, and 3% progressed despite salvage ASCT. After salvage ASCT, 38 patients received maintenance therapy and 14 went on to allogeneic ASCT. The median progression-free survival (PFS) after second autograft was 10.1 months (95% confidence interval [CI], 7.6 to 13.4) and median overall survival (OS) 22.7 months (95% CI, 19.2 to 41.2). Patients with chemosensitive relapse had a trend toward better PFS (hazard ratio [HR], .60 [95% CI, .36 to 1.02]; P = .058) and significantly longer OS (HR, .49 [95% CI, .27 to .88]; P = .017) than patients with resistant relapse. Those with high-risk cytogenetics at the time of second ASCT had higher risk of death (HR, 2.98 [95% CI, 1.28 to 6.97]; P = .012) compared with patients with standard-risk cytogenetics. Salvage ASCT is an effective strategy for relapsed MM with chemosensitive disease and results in comparable PFS and OS to other salvage strategies.

Topics: Adult; Aged; Autografts; Disease-Free Survival; Female; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Myeloablative Agonists; Retrospective Studies; Stem Cell Transplantation; Survival Rate; Transplantation Conditioning

This analysis, using data from the bortezomib-melphalan-prednisone (VMP) arm of the Phase III VISTA study, investigated whether increased cumulative bortezomib dose could improve overall survival (OS) in transplant-ineligible patients with previously untreated multiple myeloma. Median cumulative bortezomib dose received by the 340 patients was 39 mg/m(2); this was selected as the cut-off for defining the dose groups to be compared for OS. Patient characteristics were well balanced between dose groups except for age. OS was significantly longer in the higher (≥39 mg/m(2)) versus lower (<39 mg/m(2)) cumulative bortezomib dose group (median 66.3 vs. 46.2 months; hazard ratio (HR) 0.533, P < 0.0001; age-adjusted HR 0.561, P = 0.0002). To overcome confounding effects of early discontinuations/deaths, which were more common in the lower cumulative dose group (27 vs. 4% of patients discontinued due to adverse events (AEs) in the lower and higher cumulative dose groups, respectively), a landmark analysis was conducted at 180 days, eliminating patients who died or discontinued before this time from the analysis. OS from this landmark remained significantly longer in the higher dose group (median 60.4 vs. 50.3 months; HR 0.709, P = 0.0372). Thus, higher cumulative bortezomib dose, reflecting prolonged treatment duration and/or dose intensity, appears associated with improved OS. Approaches to achieve higher cumulative doses could include subcutaneous bortezomib administration, dose/schedule modifications, continuing therapy in responding patients, and proactive AE management.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Boronic Acids; Bortezomib; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Male; Melphalan; Multiple Myeloma; Prednisone; Pyrazines; Survival Analysis

Topics: Antineoplastic Combined Chemotherapy Protocols; Hematopoietic Stem Cell Transplantation; Humans; Lenalidomide; Melphalan; Multiple Myeloma; Thalidomide; Transplantation, Autologous; Treatment Outcome

We compared the health-related quality-of-life of patients with newly diagnosed multiple myeloma aged over 65 years or transplant-ineligible in the pivotal, phase III FIRST trial. Patients received: i) continuous lenalidomide and low-dose dexamethasone until disease progression; ii) fixed cycles of lenalidomide and low-dose dexamethasone for 18 months; or iii) fixed cycles of melphalan, prednisone, thalidomide for 18 months. Data were collected using the validated questionnaires (QLQ-MY20, QLQ-C30, and EQ-5D). The analysis focused on the EQ-5D utility value and six domains pre-selected for their perceived clinical relevance. Lenalidomide and low-dose dexamethasone, and melphalan, prednisone, thalidomide improved patients' health-related quality-of-life from baseline over the duration of the study across all pre-selected domains of the QLQ-C30 and EQ-5D. In the QLQ-MY20, lenalidomide and low-dose dexamethasone demonstrated a significantly greater reduction in the Disease Symptoms domain compared with melphalan, prednisone, thalidomide at Month 3, and significantly lower scores for QLQ-MY20 Side Effects of Treatment at all post-baseline assessments except Month 18. Linear mixed-model repeated-measures analyses confirmed the results observed in the cross-sectional analysis. Continuous lenalidomide and low-dose dexamethasone delays disease progression versus melphalan, prednisone, thalidomide and has been associated with a clinically meaningful improvement in health-related quality-of-life. These results further establish continuous lenalidomide and low-dose dexamethasone as a new standard of care for initial therapy of myeloma by demonstrating superior health-related quality-of-life during treatment, compared with melphalan, prednisone, thalidomide.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Cross-Sectional Studies; Dexamethasone; Female; Health Status; Humans; Lenalidomide; Male; Melphalan; Multiple Myeloma; Prednisone; Quality of Life; Thalidomide

This phase 1/2 dose-escalation study investigated the combination of carfilzomib with melphalan and prednisone (CMP) in patients aged >65 years with newly diagnosed multiple myeloma (MM). Melphalan and prednisone were administered orally on days 1 to 4; carfilzomib was IV administered on days 1, 2, 8, 9, 22, 23, 29, and 30 of a 42-day cycle. Patients received up to 9 cycles of CMP. In the phase 1 dose-escalation portion, the primary objectives were to determine the incidence of dose-limiting toxicities during the first cycle of CMP treatment to define the maximal tolerated dose (MTD) of carfilzomib. In the phase 2 portion, the primary objective was to evaluate the overall response rate (ORR) of CMP. In the phase 1 portion of the study, 24 patients received CMP at carfilzomib dosing levels of 20 mg/m(2), 27 mg/m(2), 36 mg/m(2), and 45 mg/m(2). The MTD was established as 36 mg/m(2). In the phase 2 portion of the study, 44 patients were enrolled at the MTD. Among 50 efficacy-evaluable patients treated at the MTD, the ORR was 90%. The projected 3-year overall survival rate was 80%. The combination of CMP was observed to be effective in elderly patients with newly diagnosed MM. This trial was registered at www.clinicaltrials.gov as #NCT01279694 (Eudract identifier 2010-019462-92).

Topics: Age Factors; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Drug Monitoring; Female; Humans; Male; Melphalan; Multiple Myeloma; Neoplasm Staging; Oligopeptides; Prednisone; Treatment Outcome

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Female; Humans; Lenalidomide; Male; Melphalan; Middle Aged; Multiple Myeloma; Prednisone; Stem Cell Transplantation; Thalidomide

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Dexamethasone; Female; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma

High-dose melphalan (MEL) is the standard therapy for autologous stem cell transplantation (ASCT) in multiple myeloma (MM), although the optimal conditioning regimen remains yet to be identified. Thiotepa (THIO) appears to be a potentially effective option, with broad-spectrum antitumor efficacy that can be added to myeloablative multiagent regimens for ASCT in hematopoietic tumors. We conducted a phase II trial, adding THIO (275 mg/m(2)) to high-dose MEL (140 mg/m(2)) before a second ASCT, in a tandem ASCT strategy, in 64 patients with "de novo" MM. Overall, there was no transplant-related mortality. The incidence of neutropenic fever and mucositis (grades 3 to 4) was 39% and 9%, respectively. Median number of days to neutrophil and platelet engraftment were 11 and 12, respectively. After the second transplantation, the complete response improved to 43.8%. Overall response rate was 86%. After a median follow-up of 18.1 months, 13 patients had progressed and 3 died from MM. Median progression-free survival was not reached, and actuarial 2-year rates of progression-free and overall survival were 71% and 88.9%, respectively. Our results suggest that THIO/MEL is a feasible and safe conditioning regimen for ASCT in MM and should be explored for efficacy in a phase III study.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Blood Platelets; Female; Fever; Graft Survival; Hematopoietic Stem Cell Transplantation; Humans; Male; Melphalan; Middle Aged; Mucositis; Multiple Myeloma; Neutrophils; Prospective Studies; Survival Analysis; Thiotepa; Transplantation Conditioning; Transplantation, Autologous

This phase 3 trial (Eastern Cooperative Oncology Group [ECOG] E1A06) compared melphalan, prednisone, and thalidomide (MPT-T) with melphalan, prednisone, and lenalidomide (mPR-R) in patients with untreated multiple myeloma (MM). A noninferiority design was used, and inferiority was defined as a progression-free survival (PFS) hazard ratio (HR) of MPT-T/mPR-R ≤0.82. A total of 306 patients enrolled, with a median age of 75.7 years. Median follow-up was 40.7 months. Median time on therapy was 12.1 months and 23.1 months for the 46.6% of treated patients who received maintenance, with no differences by arm. Median PFS was 21 months on MPT-T and 18.7 months on mPR-R (HR, 0.84; 95% confidence interval, 0.64-1.09). Overall survival was 52.6 months (MPT-T) vs 47.7 months (mPR-R) (P = .476). Per-protocol response rates were 63.6% (MPT-T) and 59.9% (mPR-R) (P = .557). Grade ≥3 nonhematologic toxicity was 59.5% for MPT-T vs 40.0% for mPR-R (P = .001). Second malignancies were observed in 18 MPT-T patients vs 14 mPR-R patients. Quality-of-life analysis favored mPR-R by induction end (P = .007). Use of MPT-T or mPR-R in elderly patients with untreated MM demonstrates no statistical or clinically relevant differences in response rates, PFS, and OS; however, quality of life at end of induction was improved and lower toxicity reported with mPR-R. This trial was registered at www.clinicaltrials.gov as #NCT00602641.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Female; Humans; Kaplan-Meier Estimate; Lenalidomide; Male; Melphalan; Middle Aged; Multiple Myeloma; Neoplasms, Second Primary; Prednisone; Quality of Life; Thalidomide

Continuous therapy (CT) prolongs progression-free survival 1 (PFS1; time from random assignment until the first progression or death), but chemotherapy-resistant relapse may negatively impact overall survival (OS). Progression-free survival 2 (PFS2; time from random assignment until the second progression or death) may represent an additional tool to estimate outcome. This study evaluates the benefit of novel agent-based CT versus fixed duration of therapy (FDT) in patients with newly diagnosed myeloma.. We included patients enrolled onto three phase III trials that randomly assigned patients to novel agent-based CT versus FDT. Primary analyses were restricted to the intent-to-treat population eligible for CT (patients progression free and alive at 1 year after random assignment). Primary end points were PFS1, PFS2, and OS. All hazard ratios (HRs) and 95% CIs were adjusted for several potential confounders using Cox models.. In the pooled analysis of the three trials, 604 patients were randomly assigned to CT and 614 were assigned to FDT. Median follow-up was 52 months. In the intent-to-treat CT population, CT (n = 417), compared with FDT (n = 410), significantly improved PFS1 (median, 32 v 16 months, respectively; HR, 0.47; 95% CI, 0.40 to 0.56; P < .001), PFS2 (median, 55 v 40 months, respectively; HR, 0.61; 95% CI, 0.50 to 0.75; P < .001), and OS (4-year OS, 69% v 60%, respectively; HR, 0.69; 95% CI, 0.54 to 0.88; P = .003).. In this pooled analysis, CT significantly improved PFS1, PFS2, and OS. The improvement in PFS2 suggests that the benefit reported during first remission is not cancelled by a shorter second remission. PFS2 is a valuable end point to estimate long-term clinical benefit and should be included in future trials.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Dexamethasone; Disease-Free Survival; Drug Administration Schedule; Female; Humans; Lenalidomide; Male; Melphalan; Middle Aged; Multiple Myeloma; Prednisone; Thalidomide

Autologous stem cell transplantation (ASCT) after high-dose melphalan conditioning is considered a standard of care procedure for patients with multiple myeloma (MM). Current formulations of melphalan (eg, Alkeran for Injection [melphalan hydrochloride]; GlaxoSmithKline, Research Triangle Park, NC, USA) have marginal solubility and limited chemical stability upon reconstitution. Alkeran requires the use of propylene glycol as a co-solvent, which itself has been reported to cause such complications as metabolic/renal dysfunction and arrhythmias. EVOMELA (propylene glycol-free melphalan HCl; Spectrum Pharmaceuticals, Inc., Irvine, CA, USA) is a new i.v. melphalan formulation that incorporates Captisol (Ligand Pharmaceuticals, Inc., La Jolla, CA, USA), a specially modified cyclodextrin that improves the solubility and stability of melphalan and eliminates the need for propylene glycol. This new formulation has been shown to be bioequivalent to Alkeran. EVOMELA (200 mg/m(2)) was administered as 2 doses of 100 mg/m(2) each in a phase IIb, open-label, multicenter study to confirm its safety and efficacy as a high-dose conditioning regimen for patients with MM undergoing ASCT. At 5 centers, 61 patients (26 women) with a median age of 62 years (range, 32-73) were enrolled. All patients achieved myeloablation with a median time of 5 days post-ASCT, and all successfully achieved neutrophil and platelet engraftment with median times of 12 days post-ASCT and 13 days post-ASCT, respectively; treatment-related mortality on day 100 was 0%. Overall response rate (according to independent, blinded review) was high (100%), with an overall complete response rate of 21% (13% stringent complete response; 8% complete response) and overall partial response rate of 79% (61% very good partial response; 18% partial response). The incidence of grade 3 mucositis and stomatitis was low (10% and 5%, respectively) with no grade 4 mucositis or stomatitis reported (graded according to National Cancer Institute Common Terminology Criteria for Adverse Events). Based on investigators' assessment of mucositis using the World Health Organization (WHO) oral toxicity scale, 75% of patients had a shift in mucositis score from WHO grade 0 at baseline to a higher grade on study, of which 13% of patients reported WHO grade 3 as the worst post-treatment mucositis over the course of the study; there were no reports of WHO grade 4 mucositis during the study. This study confirms the efficacy and accept

Topics: Adult; Aged; Cyclodextrins; Drug Administration Schedule; Female; Graft Survival; Hematopoietic Stem Cell Transplantation; Humans; Male; Melphalan; Middle Aged; Mucositis; Multiple Myeloma; Myeloablative Agonists; Propylene Glycol; Severity of Illness Index; Solubility; Stomatitis; Transplantation Conditioning; Transplantation, Autologous; Treatment Outcome

High-dose melphalan plus autologous stem-cell transplantation (ASCT) is the standard approach in transplant-eligible patients with newly diagnosed myeloma. Our aims were to compare consolidation with high-dose melphalan plus ASCT versus chemotherapy (cyclophosphamide and dexamethasone) plus lenalidomide, and maintenance with lenalidomide plus prednisone versus lenalidomide alone.. We did an open-label, randomised, multicentre, phase 3 study at 59 centres in Australia, Czech Republic, and Italy. We enrolled transplant-eligible patients with newly diagnosed myeloma aged 65 years or younger. Patients received a common induction with four 28-day cycles of lenalidomide (25 mg, days 1-21) and dexamethasone (40 mg, days 1, 8, 15, and 22) and subsequent chemotherapy with cyclophosphamide (3 g/m(2)) followed by granulocyte colony-stimulating factor for stem-cell mobilisation and collection. Using a 2 × 2 partial factorial design, we randomised patients to consolidation with either chemotherapy plus lenalidomide (six cycles of cyclophosphamide [300 mg/m(2), days 1, 8, and 15], dexamethasone [40 mg, days 1, 8, 15, and 22], and lenalidomide [25 mg, days 1-21]) or two courses of high-dose melphalan (200 mg/m(2)) and ASCT. We also randomised patients to maintenance with lenalidomide (10 mg, days 1-21) plus prednisone (50 mg, every other day) or lenalidomide alone. A simple randomisation sequence was used to assign patients at enrolment into one of the four groups (1:1:1:1 ratio), but the treatment allocation was disclosed only when the patient reached the end of the induction and confirmed their eligibility for consolidation. Both the patient and the treating clinician did not know the consolidation and maintenance arm until that time. The primary endpoint was progression-free survival assessed by intention-to-treat. The trial is ongoing and some patients are still receiving maintenance. This study is registered at ClinicalTrials.gov, number NCT01091831.. 389 patients were enrolled between July 6, 2009, and May 6, 2011, with 256 eligible for consolidation (127 high-dose melphalan and ASCT and 129 chemotherapy plus lenalidomide) and 223 eligible for maintenance (117 lenalidomide plus prednisone and 106 lenalidomide alone). Median follow-up was 52·0 months (IQR 30·4-57·6). Progression-free survival during consolidation was significantly shorter with chemotherapy plus lenalidomide compared with high-dose melphalan and ASCT (median 28·6 months [95% CI 20·6-36·7] vs 43·3 months [33·2-52·2]; hazard ratio [HR] for the first 24 months 2·51, 95% CI 1·60-3·94; p<0·0001). Progression-free survival did not differ between maintenance treatments (median 37·5 months [95% CI 27·8-not evaluable] with lenalidomide plus prednisone vs 28·5 months [22·5-46·5] with lenalidomide alone; HR 0·84, 95% CI 0·59-1·20; p=0·34). Fewer grade 3 or 4 adverse events were recorded with chemotherapy plus lenalidomide than with high-dose melphalan and ASCT; the most frequent were haematological (34 [26%] of 129 patients vs 107 [84%] of 127 patients), gastrointestinal (six [5%] vs 25 [20%]), and infection (seven [5%] vs 24 [19%]). Haematological serious adverse events were reported in two (2%) patients assigned chemotherapy plus lenalidomide and no patients allocated high-dose melphalan and ASCT. Non-haematological serious adverse events were reported in 13 (10%) patients assigned chemotherapy plus lenalidomide and nine (7%) allocated high-dose melphalan and ASCT. During maintenance, adverse events did not differ between groups. The most frequent grade 3 or 4 adverse events were neutropenia (nine [8%] of 117 patients assigned lenalidomide plus prednisone vs 14 [13%] of 106 allocated lenalidomide alone), infection (eight [8%] vs five [5%]), and systemic toxicities (seven [6%] vs two [2%]). Non-haematological serious adverse events were reported in 13 (11%) patients assigned lenalidomide plus prednisone versus ten (9%) allocated lenalidomide alone. Four patients died because of adverse events, three from infections (two during induction and one during consolidation) and one because of cardiac toxic effects.. Consolidation with high-dose melphalan and ASCT remains the preferred option in transplant-eligible patients with multiple myeloma, despite a better toxicity profile with chemotherapy plus lenalidomide.. Celgene.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Australia; Chemotherapy, Adjuvant; Cyclophosphamide; Czech Republic; Dexamethasone; Disease Progression; Disease-Free Survival; Female; Hematopoietic Stem Cell Transplantation; Humans; Italy; Kaplan-Meier Estimate; Lenalidomide; Maintenance Chemotherapy; Male; Melphalan; Middle Aged; Multiple Myeloma; Prednisone; Proportional Hazards Models; Risk Factors; Thalidomide; Time Factors; Transplantation, Autologous; Treatment Outcome

Panobinostat is a histone deacetylase inhibitor that has shown synergistic preclinical anti-myeloma activity when combined with other agents, recently exhibiting synergy with the alkylating agent melphalan (Sanchez et al., Leuk Res 35(3):373-379, 2011). This phase 1/2 trial investigated the safety and efficacy of panobinostat in combination with melphalan for relapsed/refractory multiple myeloma patients. There were four different trial treatment schedules due to tolerability issues, with the final treatment schedule (treatment schedule D) consisting of panobinostat (15 or 20 mg) and melphalan (0.05 or 0.10 mg/kg), both administered on days 1, 3, and 5 of a 28-day cycle. A total of 40 patients were enrolled; 3 in treatment schedule A, 9 in schedule B, 7 in schedule C, and finally 21 schedule D. Patients had been treated with a median of four regimens (range, 1-16) and two prior bortezomib-containing regimens (range, 0-9). Maximum-tolerated dose was established at 20 mg panobinostat and 0.05 mg/kg melphalan in treatment schedule D. Overall, 3 patients (7.5 %) achieved ≥partial response (two very good PRs and one PR) while 23 exhibited stable disease and 14 showed progressive disease. All three responders were enrolled in cohort 2 of treatment schedule B (panobinostat 20 mg thrice weekly continuously with melphalan 0.05 mg/kg on days 1, 3, and 5). Neutropenia and thrombocytopenia were common, with 30.8 and 23.1 % of patients exhibiting ≥grade 3, respectively. Panobinostat + melphalan appears to have tolerability issues in a dosing regimen capable of producing a response. Care must be taken to balance tolerability and efficacy with this combination.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Disease Progression; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Gastrointestinal Diseases; Hematologic Diseases; Humans; Hydroxamic Acids; Indoles; Infections; Kaplan-Meier Estimate; Male; Maximum Tolerated Dose; Melphalan; Middle Aged; Multiple Myeloma; Panobinostat; Recurrence; Salvage Therapy

In the MM-015 trial, melphalan-prednisone-lenalidomide followed by lenalidomide maintenance (MPR-R) significantly prolonged progression-free survival versus melphalan-prednisone (MP) in newly diagnosed patients with multiple myeloma aged ≥ 65 years. Health-related quality of life (HRQoL), a secondary endpoint of MM-015, was also improved with MPR-R. This sub-analysis evaluated the impact of individual predictive factors on HRQoL. Patients completed HRQoL questionnaires at baseline, every third cycle and at progressive disease (PD)/treatment discontinuation. In a mixed-effects model female gender, advanced age and PD negatively affected HRQoL while better treatment responses showed positive effects. Compared to PD, HRQoL during MPR-R treatment was statistically significantly better in two of six preselected domains both of which were also clinically meaningful. HRQoL scores at end of treatment were all either improved or not statistically significantly different versus baseline. In conclusion, continuous treatment with MPR-R, which delays PD, appears to be associated with clinically meaningful improvements in HRQoL.

Topics: Age Factors; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Female; Humans; Induction Chemotherapy; Lenalidomide; Maintenance Chemotherapy; Male; Melphalan; Multiple Myeloma; Neoplasm Staging; Prednisone; Quality of Life; Thalidomide; Treatment Outcome

Bortezomib-melphalan-prednisone (VMP) has improved overall survival in multiple myeloma. This randomized trial compared VMP plus thalidomide (VMPT) induction followed by bortezomib-thalidomide maintenance (VMPT-VT) with VMP in patients with newly diagnosed multiple myeloma.. We randomly assigned 511 patients who were not eligible for transplantation to receive VMPT-VT (nine 5-week cycles of VMPT followed by 2 years of VT maintenance) or VMP (nine 5-week cycles without maintenance).. In the initial analysis with a median follow-up of 23 months, VMPT-VT improved complete response rate from 24% to 38% and 3-year progression-free-survival (PFS) from 41% to 56% compared with VMP. In this analysis, median follow-up was 54 months. The median PFS was significantly longer with VMPT-VT (35.3 months) than with VMP (24.8 months; hazard ratio [HR], 0.58; P < .001). The time to next therapy was 46.6 months in the VMPT-VT group and 27.8 months in the VMP group (HR, 0.52; P < .001). The 5-year overall survival (OS) was greater with VMPT-VT (61%) than with VMP (51%; HR, 0.70; P = .01). Survival from relapse was identical in both groups (HR, 0.92; P = .63). In the VMPT-VT group, the most frequent grade 3 to 4 adverse events included neutropenia (38%), thrombocytopenia (22%), peripheral neuropathy (11%), and cardiologic events (11%). All of these, except for thrombocytopenia, were significantly more frequent in the VMPT-VT patients.. Bortezomib and thalidomide significantly improved OS in multiple myeloma patients not eligible for transplantation.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Boronic Acids; Bortezomib; Disease-Free Survival; Female; Follow-Up Studies; Humans; Induction Chemotherapy; Kaplan-Meier Estimate; Maintenance Chemotherapy; Male; Melphalan; Middle Aged; Multiple Myeloma; Neutropenia; Peripheral Nervous System Diseases; Prednisone; Pyrazines; Thalidomide; Thrombocytopenia; Treatment Outcome

Observational data from clinical studies indicate that the goal of first-line therapy in newly diagnosed patients with symptomatic multiple myeloma (MM) should be very good partial response (VGPR) or better, preferably before high-dose treatment. We evaluated the value of early measurements of involved free light chains (iFLC) in prediction of high-quality responses. Measuring iFLC has a potential advantage due to a short half-life compared to the half-life of the M-protein.. In 36 multiple myeloma (MM) patients, we measured serial changes in iFLC and M-protein after start of treatment. iFLC and M-protein were measured before treatment, the following 5 wk days, 2, 3 and 6 wks after start of treatment.. Median iFLC and M-protein half-life was 2.75 and 11.9 d, respectively. All patients with an iFLC >75 mg/L had an initial significant reduction (>20%) in iFLC, even patients with no response to treatment. The mean per cent reduction in iFLC 3 d after start of treatment was 52.3% and 23.6% (P = 0.021) in patients achieving ≥VGPR and PR, respectively. The mean per cent reduction in M-protein in patients achieving ≥VGPR and PR was not significantly different in the 6-wk study period. As a predictor of VGPR, an 80% reduction in iFLC at day 21 resulted in a sensitivity of 87.5% and a specificity of 100%.. Changes in iFLC could be a tool for early identification of responders to anti-myeloma therapy. Early, sequential measurements of iFLC within the first week after start of treatment are not meaningful.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Boronic Acids; Bortezomib; Cyclophosphamide; Dexamethasone; Drug Monitoring; Female; Half-Life; Humans; Immunoglobulin Light Chains; Lenalidomide; Male; Melphalan; Middle Aged; Multiple Myeloma; Myeloma Proteins; Prednisone; Prospective Studies; Pyrazines; Sensitivity and Specificity; Thalidomide; Treatment Outcome

Because interleukin-6 (IL-6) is considered important in the proliferation of early multiple myeloma (MM), we hypothesized that the addition of the anti-IL-6 monoclonal antibody siltuximab to the bortezomib-melphalan-prednisone (VMP) regimen would improve outcomes in transplant-ineligible patients with newly diagnosed MM. One hundred and six patients were randomized to receive 9 cycles of VMP or VMP plus siltuximab (11 mg/kg every 3 weeks) followed by siltuximab maintenance. Baseline characteristics were well balanced except for immunoglobulin A subtype and 17p deletions. With a complete response (CR) rate of 27% on siltuximab plus VMP (S+VMP) and 22% on VMP, the study did not confirm its hypothesis that the addition of siltuximab would increase the CR rate by at least 10%. Overall response rate was 88% on S+VMP and 80% on VMP, and at least very good partial response rates were 71% and 51% (P = .0382), respectively. Median progression-free survival (17 months) and 1-year overall survival (88%) were identical in the 2 arms. Grade ≥3 adverse-event incidence was 92% on S+VMP and 81% on VMP (P = .09), with trends toward more hematologic events and infections on S+VMP. Maintenance therapy with siltuximab was well tolerated. In conclusion, the addition of siltuximab to VMP did not improve the CR rate or long-term outcomes. This study was registered at http://clinicaltrials.gov as #NCT00911859.

Topics: Aged; Aged, 80 and over; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Boronic Acids; Bortezomib; Chromosome Deletion; Chromosomes, Human, Pair 17; Disease-Free Survival; Female; Follow-Up Studies; Humans; Immunoglobulin A; Interleukin-6; Male; Melphalan; Middle Aged; Multiple Myeloma; Prednisone; Pyrazines; Survival Rate

The aim of this study is to evaluate the efficacy of aprepitant as part of the antiemetic regimen for high-dose melphalan conditioning in multiple myeloma patients.. This is a prospective, single-arm study.. The study was conducted at an Academic Medical Facility.. Twenty-six patients receiving high-dose melphalan with autologous stem cell support were included in this study.. Eligible patients were >18 years with a diagnosis of MM undergoing high-dose melphalan followed by autologous peripheral blood stem cell transplantation (PBSCT). All patients had serum aminotransferases and total bilirubin less than 2× upper limit of normal. Treatment consisted of aprepitant 125 mg orally on day 1, followed by 80 mg orally 24 and 48 h after the initial dose; ondansetron 16 mg orally day 1; dexamethasone 12 mg orally day 1, and 8 mg orally days 2-4 with breakthrough medications as needed.. Patients were evaluated for the frequency of emetic episodes, the need for breakthrough antiemetic medication, and the mean nausea score in 24-h increments beginning 24 h after chemotherapy and continuing until 120 h. Nausea score was determined using a linear analog scale (0-10). Complete response (CR) was defined as no more than one (1) emetic episode during the evaluation period. A total of 26 patients (17 male, 9 female) were enrolled in the study. Of these, 25 (96 %) were complete responders and 24 (92 %) had no documented emetic episodes during the study period. One patient (4 %) had 1 emetic episode and one patient (4 %) had 2 emetic episodes. Some degree of nausea was reported by 23/26 patients, and the mean nausea score for the entire group over the study period was 0.7 (range 0-10).. Addition of aprepitant to standard antiemetics resulted in low rates of delayed nausea/vomiting associated with high-dose melphalan and PBSCT, and has now become standard practice in this patient population at our institution.

Topics: Antiemetics; Aprepitant; Female; Humans; Male; Melphalan; Middle Aged; Morpholines; Multiple Myeloma; Nausea; Peripheral Blood Stem Cell Transplantation; Prospective Studies; Transplantation Conditioning; Vomiting

Propylene Glycol-Free melphalan HCL for Injection (PGF-Mel) is a new formulation that incorporates Captisol, a specially modified cyclodextrin, to improve melphalan stability. In this phase IIa, open-label, randomized, cross-over design bioequivalence study, the pharmacokinetics of PGF-Mel were compared with the marketed formulation of melphalan, or Alkeran. Patients received half of the total dose of melphalan in the form of Alkeran and the other half in the form of PGF-Mel in an alternating manner. The pharmacokinetic measures were determined using WinNonlin 6.2 and bioequivalence was assessed using log-transformed systemic exposure parameters. Twenty-four patients, 11 females and 13 males, were enrolled between 4 February 2010 and 16 May 2011 at The University of Kansas Medical Center and The University of Kansas Cancer Center. The median age of enrolled subjects was 58 years (range: 48-65). All patients achieved myeloablation 3 days post autologous graft followed by successful neutrophil engraftment with a median of 11 days after transplant. Pharmacokinetic analysis showed that PGF-Mel was bioequivalent with Alkeran and also revealed that maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) were higher (~10%) after PGF-Mel administration. In conclusion, PGF-Mel is considered bioequivalent to Alkeran while also demonstrating a marginally higher systemic drug exposure.

Topics: Aged; Autografts; Cross-Sectional Studies; Female; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Myeloablative Agonists; Stem Cell Transplantation; Transplantation Conditioning

Relapsed multiple myeloma has no standard treatment, and the role of autologous stem-cell transplantation (ASCT) has not been fully defined. We aimed to compare high-dose melphalan plus salvage ASCT with cyclophosphamide in patients with relapsed multiple myeloma who had previously undergone ASCT.. This multicentre, randomised, open-label, phase 3 study recruited patients aged at least 18 years with multiple myeloma who needed treatment for first progressive or relapsed disease at least 18 months after a previous ASCT from 51 centres across the UK. Before randomisation, eligible patients received bortezomib, doxorubicin, and dexamethasone (PAD) induction therapy and then underwent peripheral blood stem-cell mobilisation and harvesting if applicable. Eligible patients (with adequate stem-cell harvest) were randomly assigned (1:1), using an automated telephone randomisation line, to either high-dose melphalan 200 mg/m(2) plus salvage ASCT or oral cyclophosphamide (400mg/m(2) per week for 12 weeks). Randomisation was stratified by length of first remission or plateau and response to PAD re-induction therapy. The primary endpoint was time to disease progression, analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00747877, and EudraCT, number 2006-005890-24.. Between April 16, 2008, and Nov 19, 2012, 297 patients were registered, of whom 293 received PAD re-induction therapy. Between Aug 26, 2008, and Nov 16, 2012, 174 patients with sufficient PBSCs were randomised to salvage ASCT (n=89) or cyclophosphamide (n=85). After a median follow-up of 31 months (IQR 19-42), median time to progression was significantly longer in the salvage ASCT than in the cyclophosphamide group (19 months [95% CI 16-25] vs 11 months [9-12]; hazard ratio 0·36 [95% CI 0·25-0·53]; p<0·0001). Frequently reported (in >10% of patients) grade 3-4 adverse events with PAD induction, salvage ASCT, and cyclophosphamide were: neutropenia (125 [43%] of 293 patients after PAD, and 63 [76%] of 83 patients in the salvage ASCT group vs 11 [13%] of 84 patients in the cyclophosphamide group), thrombocytopenia (150 [51%] after PAD, and 60 [72%] vs four [5%], respectively), and peripheral neuropathy (35 [12%] after PAD, and none vs none, respectively).. This study provides evidence for the improved efficacy of high-dose melphalan plus salvage ASCT when compared with cyclophosphamide in patients with relapsed multiple myeloma eligible for intensive therapy, which might help to guide clinical decisions regarding the management of such patients.. Cancer Research UK.

Topics: Adult; Aged; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Boronic Acids; Bortezomib; Consolidation Chemotherapy; Cyclophosphamide; Dexamethasone; Disease Progression; Doxorubicin; Female; Humans; Induction Chemotherapy; Intention to Treat Analysis; Male; Melphalan; Middle Aged; Multiple Myeloma; Neutropenia; Peripheral Nervous System Diseases; Proportional Hazards Models; Pyrazines; Recurrence; Retreatment; Salvage Therapy; Stem Cell Transplantation; Thrombocytopenia; Time Factors; Transplantation, Autologous

We compared the three arms of the MM-015 randomized phase III clinical trial [melphalan and prednisone (MP), MP plus lenalidomide (MPR), and MPR plus lenalidomide maintenance (MPR-R)] to determine whether the addition of lenalidomide maintenance therapy for primary treatment of multiple myeloma is cost-effective. We used progression-free survival and adverse event data from the MM-015 study for the analysis. Two novel measures of cost-effectiveness termed the Average Cumulative Cost per Patient (ACCP) and the Average Cumulative Cost per Progression-Free Survivor (ACCPFS) were developed for the purpose of this analysis. The ACCP of MP was USD 18,218, compared to USD 167,862 for MPR and USD 309,173 for MPR-R. The ACCPFS was highest with MPR at USD 1,555,443, while MP was USD 313,592 and MPR-R was USD 690,111. MPR-R is superior to MPR in terms of preventing the first progression after initial therapy. However, the addition of lenalidomide to MP in the induction and also in the maintenance setting leads to significant costs.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cost-Benefit Analysis; Disease-Free Survival; Economics, Pharmaceutical; Humans; Induction Chemotherapy; Lenalidomide; Maintenance Chemotherapy; Melphalan; Multiple Myeloma; Prednisone; Thalidomide

High-dose melphalan has been the standard conditioning regimen for auto-SCT in multiple myeloma (MM) for decades. A more effective conditioning regimen may induce deeper responses and longer remission duration. It is especially needed in the setting of second auto-SCT, which rarely achieves comparable results with the first auto-SCT using the same conditioning regimen. Here we conducted a phase II study to investigate the efficacy and safety of a conditioning regimen V-BEAM (bortezomib-BEAM) before second auto-SCT for multiple myeloma. Ten patients were enrolled from September 2012 to May 2013. The CR rate at day +100 after auto-SCT was 75%; all except for one patient remained in remission after a median follow-up of 6 months. Three patients developed Clostridium difficile infection. Two patients died within the first 30 days of auto-SCT from neutropenic colitis and overwhelming sepsis, respectively. Due to the high rate of morbidity and mortality, the study was terminated after 10 patients. In summary, although the conditioning regimen V-BEAM before second auto-SCT for MM provided promising responses, it was associated with unexpected treatment-related toxicity and should not be investigated further without modifications.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Autografts; Boronic Acids; Bortezomib; Carmustine; Cytarabine; Female; Follow-Up Studies; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Podophyllotoxin; Pyrazines; Stem Cell Transplantation; Transplantation Conditioning

Melphalan (M), in combination with prednisone (MP), has been the backbone of new combinations, including bortezomib plus MP (VMP). However, new alkylator-free schemes, such as lenalidomide plus low-dose dexamethasone, are challenging the role of alkylators in myeloma treatment of elderly patients. Here we have updated, after a long follow-up (median 6 years), the results of the GEM2005 study that addressed this question by comparing VMP with bortezomib plus thalidomide and prednisone (VTP) as induction. Between April 2005 and October 2008, 260 patients were randomized to receive 6 cycles of VMP or VTP as induction. The median progression-free survival was 32 months for the VMP and 23 months for the VTP arms (P 5 .09). VMP significantly prolonged the overall survival (OS) compared with VTP (median of 63 and 43 months, respectively; hazard ratio [HR]: 0.67, P 5 .01). Achieving immunophenotypic complete response was associated with a significantly longer OS, especially in the VMP arm (66%remain alive after 8 years). Melphalan, plus bortezomib, should be maintained as standard care for the treatment of elderly multiple myeloma patients. This trial was registered at www.clinicaltrials.gov as #NCT00443235.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Boronic Acids; Bortezomib; Disease-Free Survival; Female; Follow-Up Studies; Humans; Induction Chemotherapy; Kaplan-Meier Estimate; Maintenance Chemotherapy; Male; Melphalan; Multiple Myeloma; Prednisone; Pyrazines; Thalidomide

This open-label, randomized, phase 3 study compared melphalan at a dose of 200 mg per square meter of body-surface area plus autologous stem-cell transplantation with melphalan-prednisone-lenalidomide (MPR) and compared lenalidomide maintenance therapy with no maintenance therapy in patients with newly diagnosed multiple myeloma.. We randomly assigned 273 patients 65 years of age or younger to high-dose melphalan plus stem-cell transplantation or MPR consolidation therapy after induction, and 251 patients to lenalidomide maintenance therapy or no maintenance therapy. The primary end point was progression-free survival.. The median follow-up period was 51.2 months. Both progression-free and overall survival were significantly longer with high-dose melphalan plus stem-cell transplantation than with MPR (median progression-free survival, 43.0 months vs. 22.4 months; hazard ratio for progression or death, 0.44; 95% confidence interval [CI], 0.32 to 0.61; P<0.001; and 4-year overall survival, 81.6% vs. 65.3%; hazard ratio for death, 0.55; 95% CI, 0.32 to 0.93; P=0.02). Median progression-free survival was significantly longer with lenalidomide maintenance than with no maintenance (41.9 months vs. 21.6 months; hazard ratio for progression or death, 0.47; 95% CI, 0.33 to 0.65; P<0.001), but 3-year overall survival was not significantly prolonged (88.0% vs. 79.2%; hazard ratio for death, 0.64; 95% CI, 0.36 to 1.15; P=0.14). Grade 3 or 4 neutropenia was significantly more frequent with high-dose melphalan than with MPR (94.3% vs. 51.5%), as were gastrointestinal adverse events (18.4% vs. 0%) and infections (16.3% vs. 0.8%); neutropenia and dermatologic toxic effects were more frequent with lenalidomide maintenance than with no maintenance (23.3% vs. 0% and 4.3% vs. 0%, respectively).. Consolidation therapy with high-dose melphalan plus stem-cell transplantation, as compared with MPR, significantly prolonged progression-free and overall survival among patients with multiple myeloma who were 65 years of age or younger. Lenalidomide maintenance, as compared with no maintenance, significantly prolonged progression-free survival. (Funded by Celgene; ClinicalTrials.gov number, NCT00551928.).

Topics: Adult; Aged; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Consolidation Chemotherapy; Disease-Free Survival; Humans; Kaplan-Meier Estimate; Lenalidomide; Maintenance Chemotherapy; Melphalan; Middle Aged; Multiple Myeloma; Neutropenia; Prednisone; Stem Cell Transplantation; Thalidomide; Transplantation, Autologous

The combination melphalan-prednisone-thalidomide (MPT) is considered a standard therapy for patients with myeloma who are ineligible for stem-cell transplantation. However, emerging data on the use of lenalidomide and low-dose dexamethasone warrant a prospective comparison of the two approaches.. We randomly assigned 1623 patients to lenalidomide and dexamethasone in 28-day cycles until disease progression (535 patients), to the same combination for 72 weeks (18 cycles; 541 patients), or to MPT for 72 weeks (547 patients). The primary end point was progression-free survival with continuous lenalidomide-dexamethasone versus MPT.. The median progression-free survival was 25.5 months with continuous lenalidomide-dexamethasone, 20.7 months with 18 cycles of lenalidomide-dexamethasone, and 21.2 months with MPT (hazard ratio for the risk of progression or death, 0.72 for continuous lenalidomide-dexamethasone vs. MPT and 0.70 for continuous lenalidomide-dexamethasone vs. 18 cycles of lenalidomide-dexamethasone; P<0.001 for both comparisons). Continuous lenalidomide-dexamethasone was superior to MPT for all secondary efficacy end points, including overall survival (at the interim analysis). Overall survival at 4 years was 59% with continuous lenalidomide-dexamethasone, 56% with 18 cycles of lenalidomide-dexamethasone, and 51% with MPT. Grade 3 or 4 adverse events were somewhat less frequent with continuous lenalidomide-dexamethasone than with MPT (70% vs. 78%). As compared with MPT, continuous lenalidomide-dexamethasone was associated with fewer hematologic and neurologic toxic events, a moderate increase in infections, and fewer second primary hematologic cancers.. As compared with MPT, continuous lenalidomide-dexamethasone given until disease progression was associated with a significant improvement in progression-free survival, with an overall survival benefit at the interim analysis, among patients with newly diagnosed multiple myeloma who were ineligible for stem-cell transplantation. (Funded by Intergroupe, Francophone du Myélome and Celgene; FIRST ClinicalTrials.gov number, NCT00689936; European Union Drug Regulating Authorities Clinical Trials number, 2007-004823-39.).

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Disease-Free Survival; Female; Humans; Kaplan-Meier Estimate; Lenalidomide; Male; Melphalan; Middle Aged; Multiple Myeloma; Prednisone; Thalidomide

The optimal regimen to prevent chemotherapy-induced nausea and vomiting (CINV) for patients undergoing high-dose chemotherapy and autologous stem-cell transplantation (ASCT) is unclear. To evaluate the effect of aprepitant in addition to a standard regimen, we conducted this randomized, placebo-controlled phase III trial.. Patients with multiple myeloma were randomly assigned at a one-to-one ratio to receive either aprepitant (125 mg orally on day 1 and 80 mg orally on days 2 to 4), granisetron (2 mg orally on days 1 to 4), and dexamethasone (4 mg orally on day 1 and 2 mg orally on days 2 to 3) or matching placebo, granisetron (2 mg orally on days 1 to 4), and dexamethasone (8 mg orally on day 1 and 4 mg orally on days 2 to 3). Melphalan 100 mg/m(2) was administered intravenously on days 1 to 2. ASCT was performed on day 4. The primary end point (complete response) was defined as no emesis and no rescue therapy within 120 hours of melphalan administration. Quality of life was assessed by modified Functional Living Index-Emesis (FLIE) questionnaire on days -1 and 6.. Overall, 362 patients were available for the efficacy analysis (181 in each treatment arm). Significantly more patients receiving aprepitant reached the primary end point (58% v 41%; odds ratio [OR], 1.92; 95% CI, 1.23 to 3.00; P = .0042). Absence of major nausea (94% v 88%; OR, 2.37; 95% CI, 1.09 to 5.15; P = .026) and emesis (78% v 65%; OR, 1.99; 95% CI, 1.25 to 3.18; P = .0036) within 120 hours was increased by aprepitant. Mean total FLIE score (± standard deviation) was 114 ± 18 for aprepitant and 106 ± 26 for placebo (P < .001).. The addition of aprepitant resulted in significantly less CINV and had a positive effect on quality of life.

Topics: Aprepitant; Dexamethasone; Double-Blind Method; Granisetron; Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Morpholines; Multiple Myeloma; Nausea; Prospective Studies; Quality of Life; Transplantation, Autologous; Vomiting

Bendamustine has efficacy in multiple myeloma with a toxicity profile limited to myelosuppression. We hypothesized that adding bendamustine to autologous stem cell transplant conditioning in myeloma would enhance response without significant additional toxicity. We conducted a phase 1 trial adding escalating doses of bendamustine to the current standard conditioning of melphalan 200 mg/m(2). Twenty-five subjects were enrolled into 6 cohorts. A maximum tolerated dose was not encountered and the highest dose level cohort of bendamustine 225 mg/m(2) + melphalan 200 mg/m(2) was expanded to further evaluate safety. Overall, there was no transplant related mortality and only one grade 4 dose-limiting toxicity was observed. Median number of days to neutrophil and platelet engraftment were 11 (range, 9 to 14) and 13 (range, 10 to 21), respectively. Disease responses at day +100 posttransplantation were progression in 5 (21%), partial response in 1 (4%), very good partial response in 7 (33%), complete response in 1 (4%), and stringent complete response in 9 (38%). Six patients (24%) with pre-existing high-risk disease died from progressive myeloma during study follow-up, all at or beyond 100 days after autologous stem cell transplant. Bendamustine up to a dose of 225 mg/m(2) added to autologous stem cell transplantation conditioning with high-dose melphalan in patients with multiple myeloma did not exacerbate expected toxicities.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bendamustine Hydrochloride; Combined Modality Therapy; Dose-Response Relationship, Drug; Female; Hematopoietic Stem Cell Transplantation; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Nitrogen Mustard Compounds; Transplantation Conditioning; Transplantation, Autologous

This phase I/II study was conducted to evaluate the safety and efficacy of bortezomib-melphalan-prednisolone in Japanese patients with previously untreated multiple myeloma who are ineligible for hematopoietic stem cell transplantation. One hundred and one patients were enrolled, and 99 patients received up to nine 6-week cycles of bortezomib (0.7/1.0/1.3 mg/m²) on days 1, 4, 8, 11, 22, 25, 29, and 32 in cycles 1-4 and on days 1, 8, 22, and 29 in cycles 5-9, with melphalan (9 mg/m²) and prednisolone (60 mg/m²) on days 1-4 of each cycle. The recommended dose was determined in the phase I portion, and the overall response rate and safety of bortezomib-melphalan-prednisolone at the recommended dose were assessed in the phase II portion. The recommended dose of bortezomib was determined to be 1.3 mg/m². Grade 3 or higher non-hematological adverse events included diarrhea (12%) and peripheral neuropathy (10%); grade 4 hematological adverse events included lymphopenia (41%), neutropenia (30%), and thrombocytopenia (22%). Eleven patients had lung injury associated with bortezomib; two had grade 3 disease, and the other nine had grade 1 or 2 disease. Of the 86 patients treated with 1.3-mg/m² bortezomib in phases I and II, the median number of treatment cycles was 4.5, and the overall response rate was 70% (95% confidence interval: 59-79%). Bortezomib-melphalan-prednisolone with 1.3-mg/m² bortezomib was considered to be tolerable and effective in Japanese patients with previously untreated multiple myeloma. However, further investigation is needed to refine the administration schedule.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Boronic Acids; Bortezomib; Combined Modality Therapy; Female; Hematopoietic Stem Cell Transplantation; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Prednisolone; Pyrazines; Treatment Outcome

The current study was designed to assess the safety and efficacy of bortezomib in combination with fludarabine and melphalan as reduced intensity conditioning before allogeneic stem cell transplantation in patients with high risk multiple myeloma. Sixteen patients were evaluable. The median number of previous line of treatment was 3; all patients had relapsed following a prior autograft and 13 had previously received bortezomib. Fifteen of them either remained stable or improved disease status at day +100 post-transplant, including 11 patients with active disease. More specifically, nine patients (56%) and five patients (31%) reached complete remission and partial response, respectively. 25% developed grade III acute graft-versus-host disease. The cumulative incidence of non-relapse mortality, relapse and overall survival were 25%, 54% and 41%, respectively, at 3 years. Regarding the non-haematological toxicity (grade>2), two patients developed peripheral neuropathy, two patients liver toxicity and 1 pulmonary toxicity early post-transplant. The haematological toxicity was only observed during the first three cycles mostly related to low haemoglobin and platelet levels. The current trial is the first one evaluating the safety and efficacy of bortezomib as part of a reduced intensity conditioning regimen among patients with high risk multiple myeloma.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Boronic Acids; Bortezomib; Chemical and Drug Induced Liver Injury; Combined Modality Therapy; Cyclosporine; Drug Synergism; Female; Graft vs Host Disease; Hematologic Diseases; Humans; Immunosuppressive Agents; Maintenance Chemotherapy; Male; Melphalan; Middle Aged; Multiple Myeloma; Peripheral Blood Stem Cell Transplantation; Peripheral Nervous System Diseases; Protease Inhibitors; Pyrazines; Remission Induction; Reoperation; Salvage Therapy; T-Lymphocyte Subsets; Transplantation Conditioning; Transplantation, Autologous; Transplantation, Homologous; Vidarabine

A sequential approach including bortezomib induction, intermediate-dose melphalan, and autologous stem cell transplantation (ASCT), followed by lenalidomide consolidation-maintenance, has been evaluated. Efficacy and safety data have been analyzed on intention-to-treat and results updated. Newly diagnosed myeloma patients 65 to 75 years of age (n = 102) received 4 cycles of bortezomib-pegylated liposomal doxorubicin-dexamethasone, tandem melphalan (100 mg/m(2)) followed by ASCT (MEL100-ASCT), 4 cycles of lenalidomide-prednisone consolidation (LP), and lenalidomide maintenance (L) until disease progression. The complete response (CR) rate was 33% after MEL100-ASCT, 48% after LP and 53% after L maintenance. After a median follow-up of 66 months, median time-to-progression (TTP) was 55 months and median progression-free survival 48 months. Median overall survival (OS) was not reached, 5-year OS was 63%. In CR patients, median TTP was 70 months and 5-year OS was 83%. Median survival from relapse was 28 months. Death related to adverse events (AEs) occurred in 8/102 patients during induction or transplantation. Rate of death related to AEs was higher in patients ≥70 years compared with younger (5/26 vs 3/76, P = .024). Bortezomib-induction followed by ASCT and lenalidomide consolidation-maintenance is a valuable option for elderly myeloma patients, with the greatest benefit in those younger than 70 years of age.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Boronic Acids; Bortezomib; Dexamethasone; Disease Progression; Disease-Free Survival; Doxorubicin; Drug Administration Schedule; Female; Humans; Lenalidomide; Male; Melphalan; Middle Aged; Multiple Myeloma; Polyethylene Glycols; Pyrazines; Recurrence; Stem Cell Transplantation; Thalidomide; Transplantation, Autologous; Treatment Outcome

There have been few Bayesian analyses of phase III sequential clinical trials that model divergent expert opinions in a single distribution.. We used modeling of experts' opinions to perform additional Bayesian analyses of a randomized clinical trial (designed as a sequential trial), particularly when a bimodal shape is observed. We provide an illustrative example based on a randomized trial conducted in patients aged between 65 and 75 years with multiple myeloma as the case study.. The main endpoint of the trial was overall survival (OS). Prior distribution of the log hazard ratio of death in the experimental versus the control arm ( $$\\theta $$ ) was constructed based on elicitation of experts using a mixture of normal distributions estimated by the Expectation-Maximisation (EM) algorithm. At each interim and terminal analysis, the posterior probability of $$\\theta $$ and the resulting increases in median OS in the experimental arm compared to the control were computed. The results were compared to results obtained using either skeptical, enthusiastic, or a mixture of those priors. Finally, we discuss our results in light of the frequentist approach originally designed for the trial.. A total of 39 experts reported their opinion on the median OS in the experimental arm compared to the median control survival of 30 months. The resulting pooled distribution of the log hazard ratios exhibited a bimodal profile. When the prior mixture of the normal distribution was fitted to the data sets from the experts, 44% of the experts' opinions were optimistic and 56% were doubtful. At the final analysis, the percentage of doubting experts dropped to 18%. This corresponded to a posterior probability of an improved OS in the experimental arm compared to the control arm of at least 0.98, regardless of the prior. These findings are in agreement with the original conclusion of the trial regarding the beneficial effect of the experimental treatment in this population.. Only 39 experts among the 120 questioned physicians responded to the inquiry. Our approach was hybrid because the prior mixture was estimated using the EM algorithm, and a full Bayesian approach may have been used.. Bayesian inference allows the quantification of increased survival in terms of probability distributions and provides investigators with an additional tool in the analysis of a randomized phase III clinical trial. Using a mixture of densities appears to be a promising strategy for incorporating the bimodal profile of prior opinion, with actualization of the two components along the trial as an illustration of the evolution of opinions as data are accumulated.

Topics: Aged; Angiogenesis Inhibitors; Antineoplastic Agents, Hormonal; Bayes Theorem; Drug Therapy, Combination; Expert Testimony; Humans; Melphalan; Models, Statistical; Multiple Myeloma; Myeloablative Agonists; Prednisone; Stem Cell Transplantation; Surveys and Questionnaires; Survival Analysis; Thalidomide

We designed a trial using two sequential cycles of modified high-dose melphalan at 100 mg/m(2) and autologous SCT (mHDM/SCT) in AL amyloidosis (light-chain amyloidosis, AL), AL with myeloma (ALM) and host-based high-risk myeloma (hM) patients through SWOG-0115. The primary objective was to evaluate OS. From 2004 to 2010, 93 eligible patients were enrolled at 17 centers in the United States (59 with AL, 9 with ALM and 25 with hM). The median OS for patients with AL and ALM was 68 months and 47 months, respectively, and has not been reached for patients with hM. The median PFS for patients with AL and ALM was 38 months and 16 months, respectively, and has not been reached for patients with hM. The treatment-related mortality (TRM) was 12% (11/93) and was observed only in patients with AL after SCT. Grade 3 and higher non-hematologic adverse events were experienced by 81%, 67% and 57% of patients with AL, ALM and hM, respectively, during the first and second HDM/SCT. This experience demonstrates that with careful selection of patients and use of mHDM for SCT in patients with AL, ALM and hM, even in the setting of a multicenter study, OS can be improved with acceptable TRM and morbidity.

Topics: Adult; Aged; Aged, 80 and over; Amyloidosis; Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Female; Hematopoietic Stem Cell Transplantation; Humans; Immunoglobulin Light-chain Amyloidosis; Male; Melphalan; Middle Aged; Multiple Myeloma; Prognosis; Thalidomide; Transplantation Conditioning; Transplantation, Autologous

Allogeneic hematopoietic stem cell transplantation (allo-HCT) is a potentially curative treatment for multiple myeloma (MM); however, because of high treatment-related mortality (TRM), its role is not well defined. Patients with newly diagnosed, relapsed, or primary refractory myeloma were enrolled in a randomized phase II trial of 2 reduced-intensity conditioning regimens: fludarabine 120 mg/m(2) + melphalan 100 mg/m(2) (FM100) versus fludarabine 120 mg/m(2) + melphalan 140 mg/m(2) (FM140) before allo-HCT from related or unrelated donors. Fifty patients underwent allo-HCT using FM100 (n = 23) or FM140 (n = 27) conditioning between April 2002 and 2011. There were no significant differences between FM100 and FM140 in time to neutrophil engraftment (P = .21), acute grade II to IV graft-versus-host disease (GVHD) (P = 1.0), chronic GVHD (P = .24), response rate (P = 1.0), TRM (13% versus 15%, P = 1.0), median progression-free survival (PFS), 11.7 versus 8.4 months, P = .12, and median overall survival (OS), 35.1 versus 19.7 months, P = .38. Cumulative incidence of disease progression in FM100 and FM140 was 43% and 70%, respectively (P = .08). Recurrent disease was the most common cause of death for both FM100 (26%) and FM140 (44%), P = .24. On multivariate analysis, disease status at allo-HCT, complete response or very good partial response (VGPR) was significantly associated with longer PFS (15.6 versus 9.6 months in patients with

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Dose-Response Relationship, Drug; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Transplantation Conditioning; Transplantation, Homologous; Vidarabine

Bortezomib and melphalan have synergistic effects against multiple myeloma (MM) cells. We conducted a pilot study on the combination of bortezomib and high-dose melphalan (Bor-HDM) as a conditioning regimen followed by autologous stem cell transplant (ASCT) in 17 Japanese patients with newly diagnosed MM, in comparison with a historical control of patients who received high-dose melphalan (HDM) only followed by ASCT. Nine patients received a single dose of bortezomib 1.3 mg/m(2) on day -1 in combination with melphalan 100 mg/m(2) on days -3 and -2 (Bor1-HDM), and eight received two doses of bortezomib 1.3 mg/m(2) on days -4 and -1 (Bor2-HDM) in combination with HDM. Engraftment of autologous peripheral blood stem cells and regimen-related toxicities (RRT) were comparable among the HDM and Bor-HDM groups. Probability of upgrading from a less than very good partial response (VGPR) to VGPR after ASCT was approximately two times higher in the Bor-HDM group than in the HDM group. However, we observed no significant differences in engraftment, RRT, and response rates between the Bor1-HDM and Bor2-HDM groups. The present study showed that concurrent administration of at least two doses of bortezomib in combination with HDM can be safe in Japanese patients. Additional large prospective randomized trials are required to address the optimal dosages and schedules of bortezomib administration, as well as the efficacy of the Bor-HDM conditioning regimen for ASCT.

Topics: Adult; Aged; Antineoplastic Agents; Asian People; Boronic Acids; Bortezomib; Drug Synergism; Drug Therapy, Combination; Female; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Peripheral Blood Stem Cell Transplantation; Pyrazines; Transplantation Conditioning; Transplantation, Autologous

Melphalan 200 mg/m(2) is the standard conditioning regimen for patients with multiple myeloma (MM) with normal renal function (NRF) undergoing autologous stem cell transplant (ASCT). In an effort to escalate the dose of melphalan and to improve the efficacy, we designed a dose-escalation study of melphalan in conjunction with palifermin in patients with NRF, with the hope that a higher dose of melphalan can be administered with an acceptable degree of oral mucositis (OM). We enrolled 19 patients (18 evaluable) with NRF. Dose-escalation of melphalan administered on day -2 began at 200 mg/m(2) with palifermin administered at a fixed dose of 60 mcg/kg/day. Palifermin was given as an i.v. bolus on day -5, -4, and -3, and then on day +1, +2, and +3. Subsequent dose escalations of melphalan were done at 20 mg/m(2) increments up to a maximum dose of 280 mg/m(2). Of 18 evaluable patients, there were no treatment-related deaths by day 100. The median age was 48.5 years (range, 33-65 years). The most common adverse events related to palifermin included rash (18 events, no ≥ grade 3 events), elevation of amylase (10 events, 4 were grade 3 but asymptomatic), and lipase (5 events, 2 were grade 3 but asymptomatic), edema (11 events, no ≥ grade 3). The overall incidence of OM grade 3 was 44% (8/18) with a median duration of severe mucositis of 5 days (range, 3-6 days). Eleven patients (61%) required opioid analgesics. None of the patients received total parenteral nutrition (TPN)/nasogastric feeding. Two of 6 patients who were given melphalan 280 mg/m(2) did not develop OM. Cardiac dose-limiting toxicity (DLT) in the form of atrial fibrillation did occur in 1 of 6 patients treated with melphalan 280 mg/m(2). Palifermin has permitted safe dose escalation of melphalan up to 280 mg/m(2), thus reaching the cumulative dosage of melphalan administered in tandem ASCT. This higher dose of melphalan has the potential to improve the efficacy and, hopefully, outcomes of patients with MM with a single ASCT. A phase 2 trial is necessary to better delineate the antimyeloma efficacy of this regimen.

Topics: Adult; Aged; Cytoprotection; Female; Fibroblast Growth Factor 7; Humans; Kidney; Male; Melphalan; Middle Aged; Multiple Myeloma; Myeloablative Agonists; Stem Cell Transplantation; Stomatitis; Transplantation, Autologous

Melphalan 200 mg/m(2) (MEL200) is the standard conditioning regimen administered to newly diagnosed patients with multiple myeloma (MM) undergoing autologous stem cell transplantation (ASCT). Few alternatives have been explored in order to improve the antimyeloma activity of this conditioning. We compare i.v. busulfan (BU) 9.6 mg/kg and MEL 140 mg/m(2) (MEL140) versus MEL200 mg/m(2) as a conditioning regimen before ASCT for newly diagnosed patients with MM. For this purpose, 51 patients receiving i.v. BU plus MEL were compared to 102 patients receiving MEL200 mg/m(2) in a 1:2 matched control analysis. Matching criteria included age, clinical stage at diagnosis, and response to induction therapy. No differences in the overall and complete response (CR) rates were observed after ASCT between both groups. After a median follow-up of 63 and 50 months in control and BU plus MEL groups, progression-free survival (PFS) was 24 and 33 months, respectively (P = .10). Most frequent toxicities included mucositis and febrile neutropenia in both groups. No case of sinusoidal obstruction syndrome was observed. Transplant-related mortality was 4% and 2% in BU plus MEL and control groups, respectively. ASCT conditioned with i.v. BU plus MEL may be considered an effective and well-tolerated alternative to a MEL-only approach as a conditioning regimen for patients with MM who are candidates for ASCT.

Topics: Administration, Intravenous; Adult; Aged; Busulfan; Disease-Free Survival; Female; Follow-Up Studies; Hematopoietic Stem Cell Transplantation; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Myeloablative Agonists; Survival Rate; Transplantation Conditioning; Transplantation, Autologous

This multicenter phase II trial evaluated the safety and efficacy of lenalidomide-prednisone (RP) induction, followed by lenalidomide-melphalan-prednisone (MPR) consolidation and RP maintenance in elderly unfit newly diagnosed myeloma patients. Patients received four 28-day RP induction courses (lenalidomide 25 mg/day on days 1-21 and prednisone 50 mg three times/week), followed by six 28-day MPR consolidation cycles (melphalan 2 mg, prednisone 50 mg three times/week and lenalidomide 10-15 mg/day on days 1-21), and maintenance with lenalidomide (10 mg/day on days 1-21 every 28 days) plus prednisone (25 mg three times/week). Forty-six patients were enrolled. Median age was 75 years, 59% of patients had at least one comorbidity and 35% at least two. Partial response rate was 80%, including 29% very good partial response. Median time to progression was 19.6 months, median progression-free survival was 18.4 months and 2-year overall survival was 80%. At the tolerated consolidation dose (melphalan 25 mg/month and lenalidomide 10 mg/day), the most frequent grade 3 adverse events were neutropenia (36.4%), anemia (12.1%), cutaneous reactions (18.2%) and infections (12.1%). Grade 4 neutropenia occurred in 12.1% of patients. In conclusion, RP induction followed by MPR consolidation and RP maintenance showed a manageable safety profile, and reduced the risk of severe hematological toxicity in unfit elderly myeloma patients.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Female; Humans; Lenalidomide; Male; Melphalan; Multiple Myeloma; Neoplasm Staging; Prednisone; Prognosis; Survival Rate; Thalidomide

In elderly patients with newly diagnosed multiple myeloma (MM), the addition of bortezomib to standard, combined oral melphalan and prednisone (MP) significantly increases the response rate and event-free survival compared with MP alone.. In this phase 1/2 trial, the authors assessed the dosing, efficacy, and safety of a lower dose-intensity MP schedule plus weekly bortezomib as salvage treatment for elderly patients with MM. To assess the maximum tolerated dose, 19 patients who had relapsed/refractory MM after 1 or 2 lines of treatment entered the first phase of the study. They received melphalan at a dose of 24 mg for 28 days; bortezomib 1.3 mg/m(2) on days 1, 8, 15, and 22; and prednisone at a dose of 50 mg every other day of a 28-day cycle for a total of 9 cycles. At the end of the first phase, based on the good efficacy and acceptable toxicity of this combination, an additional 23 patients were enrolled.. After a median follow-up of 21 months, of 42 patients who relapsed, 24 (57%) obtained at least a partial response, 4 had stable disease, and 11 had progressive disease. The median time to progression was 18 months, and the median overall survival was 30 months. Grade 3 and 4 toxicity was observed in 16 of 42 patients (38%) and was more frequent during the early cycles.. A weekly infusion of bortezomib associated with lower dose-intensity MP induced a high proportion of responses and was well tolerated in elderly patients with relapsed/refractory MM.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Boronic Acids; Bortezomib; Disease-Free Survival; Female; Humans; Male; Maximum Tolerated Dose; Melphalan; Multiple Myeloma; Prednisone; Pyrazines; Recurrence

We conducted a phase II trial that evaluated the tolerability and efficacy of combining lenalidomide with melphalan in previously untreated patients with multiple myeloma who were not candidates for autologous stem cell transplantation.. After a run-in phase of 6 patients, we planned to conduct a randomized phase II selection-design trial that assessed 2 dose levels of lenalidomide, given days 1 to 21, combined with melphalan, given days 1 to 4, and every 28 days. Planned doses of melphalan were 9 mg/m(2)/d and respective doses of lenalidomide were 10 and 20 mg/d (M9L10 and M9L20). Coprimary endpoints were the frequency of dose-limiting Planned doses of melphalan were 9 mg/m(2)/d and respective doses of lenalidomide were 10 and 20 mg/d (M9L10 and M9L20). toxicities (DLT) and complete response (CR).. Four patients received M9L10; all experienced DLTs, which resulted in closure of this cohort. When using the same schedule, we then sequentially tested M6L10 (melphalan 6 mg/m(2) on days 1 to 4 and lenalidomide 10 mg/d on days 1 to 21 every 28 days) (6 patients), M4L15 (melphalan 4 mg/m(2) on days 1 to 4 and lenalidomide 15 mg/d on days 1 to 21 every 28 days) (6 patients), and M5L10 (melphalan 5 mg/m(2) days 1 to 4 and lenalidomide 10 mg/d days 1 to 21 every 28 days) (34 patients). In each cohort, the DLT endpoint was reached because of severe and prolonged hematologic toxicity. At the final dose level, M5L10, 20 of 27 patients experienced DLTs within their first 3 cycles; among 10 patients who received at least 6 cycles, none achieved a CR.. Combining lenalidomide plus melphalan without prednisone is associated with substantial hematologic toxicity that precludes cyclical administration of adequate drug doses.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Female; Humans; Lenalidomide; Male; Melphalan; Multiple Myeloma; Neoplasm Staging; Prednisone; Stem Cell Transplantation; Thalidomide; Transplantation, Autologous

This final analysis of the phase III VISTA trial (Velcade As Initial Standard Therapy in Multiple Myeloma: Assessment With Melphalan and Prednisone) was conducted to determine whether the overall survival (OS) benefit with bortezomib-melphalan-prednisone (VMP) versus melphalan-prednisone (MP) in patients with myeloma who were ineligible for transplantation was maintained after 5 years of follow-up and to explore the risk of second primary malignancies.. In all, 682 patients received up to nine 6-week cycles of VMP or MP and were then observed every 12 weeks or less. Data on second primary malignancies were collected by individual patient inquiries at all sites from 655 patients.. After median follow-up of 60.1 months (range, 0 to 74 months), there was a 31% reduced risk of death with VMP versus MP (hazard ratio [HR], 0.695; P < .001; median OS 56.4 v 43.1 months). OS benefit with VMP was seen across prespecified patient subgroups (age ≥ 75 years, stage III myeloma, creatinine clearance < 60 mL/min). Sixty-three percent of VMP patients and 73% of MP patients had received subsequent therapy. Time to next therapy (median, 30.7 v 20.5 months; HR, 0.557; P < .001) was longer with VMP than with MP. Among patients who received subsequent therapies, survival from start of subsequent therapy was similar following VMP (median, 28.1 months) or MP (median, 26.8 months; HR, 0.914). Following VMP/MP, incidence proportions of hematologic malignancies (1%/1%) and solid tumors (5%/3%) and exposure-adjusted incidence rates (0.017/0.013 per patient-year) were similar and were consistent with background rates.. VMP resulted in a significant reduction in risk of death versus MP that was maintained after 5 years' follow-up and despite substantial use of novel-agent-based salvage therapies. There is no emerging safety signal for second primary malignancies following VMP.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; beta 2-Microglobulin; Biomarkers, Tumor; Boronic Acids; Bortezomib; Drug Administration Schedule; Female; Follow-Up Studies; Humans; Incidence; Kaplan-Meier Estimate; Male; Melphalan; Middle Aged; Multiple Myeloma; Multivariate Analysis; Neoplasm Staging; Neoplasms, Second Primary; Odds Ratio; Prednisone; Proportional Hazards Models; Pyrazines; Risk; Spain; Treatment Outcome

This randomized-controlled trial studied the efficacy of palifermin in a chemotherapy-only, high-dose Melphalan (HDM) transplant setting, to reduce oral mucositis (OM) and its sequelae measured by patient-reported outcomes (PRO) and medical resource use. Palifermin, relative to placebo was given either pre-/post-HDM or pre-HDM in patients with multiple myeloma (MM) undergoing auto-SCT at 39 European centers. Oral cavity assessment (WHO) and PRO questionnaires (oral mucositis daily questionnaire (OMDQ) and EQ 5D) were used in 281 patients (mean age 56, ± s.d.=8 years). 57 patients received placebo. One hundred and fifteen subjects were randomized to pre-/post-HDM receiving palifermin on 3 consecutive days before HDM and after auto-SCT and 109 patients were randomized to pre-HDM, receiving palifermin (60 μg/kg/day) i.v. for 3 consecutive days before HDM. There was no statistically significant difference in maximum OM severity. Severe OM occurred in 37% (placebo), 38% (pre-/post-HDM) and 24% (pre-HDM) of patients. No significant difference was observed with respect to PRO assessments or medical resource use, but more infections and fever during neutropenia were reported in pre-/post-HDM vs placebo (for example, 51 and 26%). To conclude, palifermin was unable to reduce OM or OM-related patient's burden in MM transplant patients.

Topics: Adolescent; Adult; Aged; Autografts; Female; Fibroblast Growth Factor 7; Follow-Up Studies; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Myeloablative Agonists; Stem Cell Transplantation; Stomatitis; Transplantation Conditioning

The MM-015 trial assessed the effect of lenalidomide-based therapy on health-related quality of life. Patients (n=459) with newly diagnosed multiple myeloma aged 65 years or over were randomized 1:1:1 to nine 4-week cycles of lenalidomide, melphalan, and prednisone, followed by lenalidomide maintenance; or lenalidomide, melphalan, and prednisone, or melphalan and prednisone, with no maintenance therapy. Patients completed health-related quality of life questionnaires at baseline, after every third treatment cycle, and at treatment end. Health-related quality of life improved in all treatment groups during induction therapy. Patients receiving lenalidomide maintenance had the most pronounced improvements, Global Health Status/Quality of Life (P<0.05), Physical Functioning (P<0.01), and Side Effects of Treatment (P<0.05) out of 6 pre-selected health-related quality of life domains. More patients receiving lenalidomide maintenance achieved minimal important differences (P<0.05 for Physical Functioning). Therefore, lenalidomide, melphalan, and prednisone, followed by lenalidomide maintenance, improves health-related quality of life in patients with newly diagnosed multiple myeloma. (Clinicaltrials.gov identifier NCT00405756).

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Humans; Induction Chemotherapy; Lenalidomide; Maintenance Chemotherapy; Melphalan; Multiple Myeloma; Prednisone; Quality of Life; Surveys and Questionnaires; Thalidomide

A majority of multiple myeloma (MM) patients fail to achieve complete response (CR) to peripheral blood stem cell transplantation (PBSCT); effective options following autologous transplantation are needed. Bortezomib (B) is active against MM. This study was conducted to determine the feasibility, safety, tolerability, and efficacy of B following high-dose melphalan therapy and PBSCT. Methods Fifty patients enrolled (48 evaluable) and 49 were treated (safety population).. 4 cycles B 1.3 mg/m(2) Days 1, 4, 8, and 11/21-days; 4 additional cycles were permitted for stable or responding patients. Results Median age was 55 years (range, 38-73), 68% male, 64% ECOG PS = 0, 44% Durie-Salmon Stage IIIA prior to induction, 42% had symptomatic IgG MM; 74% had prior single transplant (26% tandem). Responses post-transplant: 70% PRs, 18% MRs. A median of 4 cycles (range, 2-8) of B were administered. Responses: CR 8%, uCR 2%, PR 23%, uPR 19%, MR 10%, and no change 35%; median time-to-treatment failure (TTF) was 6.2 months (range, 1.0-19.4). Three deaths occurred (n = 1 sepsis, n = 2 disease progression). Grade 3-4 treatment-related toxicities included: thrombocytopenia, neuropathy (14%, each); asthenia, neutropenia (10%, each); and nausea (4%). Twelve patients (24%) discontinued treatment due to toxicity and 30 patients (60%) completed the study; 20 patients started new treatment (median 5.8 months [range, 1.5-20.3]).. The study closed early due to widespread availability of B, and the lack of B-naïve patients. Bortezomib monotherapy after melphalan and autologous PBSCT was feasible, safe and well-tolerated (toxicities were manageable), but failed to produce the hypothesized response rates.

Topics: Aged; Antineoplastic Agents; Boronic Acids; Bortezomib; Chemotherapy, Adjuvant; Chi-Square Distribution; Disease Progression; Disease-Free Survival; Feasibility Studies; Female; Humans; Kaplan-Meier Estimate; Male; Melphalan; Middle Aged; Multiple Myeloma; Myeloablative Agonists; Peripheral Blood Stem Cell Transplantation; Pyrazines; Time Factors; Transplantation, Autologous; Treatment Failure; United States

Single autologous hematopoietic cell transplant (AHCT) with high-dose melphalan prolongs survival in patients with multiple myeloma but is not curative. We conducted a study of intensive single AHCT using tandem chemo-mobilization with CY and etoposide followed by high-dose conditioning with melphalan 200 mg/m(2) plus carmustine 15 mg/kg. One hundred and eighteen patients in first consolidation (CON1) and 58 patients in relapse (REL) were transplanted using this intensified approach. Disease response improved from 32% very good PR (VGPR)+CR pre-mobilization to 76% VGPR+CR post transplant in CON1. With a median follow-up of 4.7 years, the median EFS was 2.8 years, and the median OS was 5.1 years in CON1. OS from time of transplant was significantly shorter for REL (3.4 years) compared with CON1 (5.1 years; P=0.02). However, OS from time of diagnosis was similar in REL (6.1 years) and CON1 (6.0 years; P=0.80). The 100-day non-relapse mortality in the CON1 and REL groups was 0% and 7%, respectively. In summary, intensified single AHCT with tandem chemo-mobilization and augmented high-dose therapy is feasible in multiple myeloma and leads to high-quality response rates.

Topics: Adolescent; Adult; Aged; Antineoplastic Agents, Alkylating; Carmustine; Disease-Free Survival; Female; Follow-Up Studies; Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cell Transplantation; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Survival Rate; Time Factors; Transplantation Conditioning; Transplantation, Autologous

Bortezomib is active for newly diagnosed and relapsed multiple myeloma, and it has synergistic activity with melphalan. The authors of this report conducted a randomized trial to determine the safety and efficacy of adding bortezomib to a preparative regimen of arsenic trioxide (ATO), ascorbic acid (AA), and melphalan.. Among 60 patients who enrolled between October 2006 and September 2007, 58 patients underwent autologous transplantation with a preparative regimen of melphalan 200 mg/m(2) intravenously, AA 1000 mg daily intravenously for 7 days, and ATO 0.25 mg/kg intravenously for 7 days. Patients were randomized to receive no bortezomib (Group 1), bortezomib 1 mg/m(2) × 3 doses (Group 2), and bortezomib 1.5 mg/m(2) × 3 doses (Group 3). Primary endpoints were complete response (CR), grade IV toxicity, and 90-day treatment-related mortality (TRM). Secondary endpoints were progression-free survival (PFS) and overall survival (OS).. The median follow-up of all surviving patients was 36 months (range, 20-43 months). The CR rates in Groups 1, 2, and 3 were 20%, 10%, and 10%, respectively. Grade 3 and 4 nonhematologic toxicities and TRM were comparable. The median OS was not reached in the groups, whereas the median PFS in Groups 1, 2, and 3 was 17.8 months, 17.4 months, and 20.7 months, respectively. PFS and OS were significantly shorter in patients who had high-risk cytogenetics (P = .016 and P = .0001, respectively) and relapsed disease (P = .0001 and P = .0001, respectively) regardless of the treatment group.. Adding bortezomib to a preparative regimen of ATO, AA, and high-dose melphalan was safe and well tolerated in patients with multiple myeloma. There was no significant improvement in the CR rate, PFS, or OS in the bortezomib groups.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Arsenicals; Ascorbic Acid; Blood Transfusion, Autologous; Boronic Acids; Bortezomib; Disease-Free Survival; Drug Administration Schedule; Female; Follow-Up Studies; Hematopoietic Stem Cell Transplantation; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Oxides; Prognosis; Pyrazines; Transplantation Conditioning

The combination of melphalan, prednisone and thalidomide (MPT) has demonstrated efficacy and acceptable toxicity in newly diagnosed and relapsed/refractory patients with multiple myeloma (MM). Panobinostat is a potent oral pan-deacetylase inhibitor (pan-DACi). In preclinical and clinical studies, panobinostat showed good anti-myeloma activity in combination with several agents. This phase II study evaluated the combination of a fixed dose of MPT with escalating doses of panobinostat (three times weekly for 3 weeks, followed by a 9-day rest period) in relapsed/refractory MM. We used a two-stage design to determine whether the combination was safe and effective. At least a partial response was observed in 38.5% of patients. The maximum tolerated dose of panobinostat in combination with MPT could not be determined due to the high rate of dose-limiting toxicities experienced with panobinostat at doses of 10 and 15 mg. The most common grade 3/4 adverse events were neutropenia (71%) and thrombocytopenia (35.5%). In conclusion, MPT in combination with panobinostat three times weekly for 3 weeks followed by a 9-day rest period is not well tolerated in patients with relapsed/refractory MM. Future studies should evaluate alternative dose schedules of panobinostat.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Resistance, Neoplasm; Female; Humans; Hydroxamic Acids; Indoles; Male; Melphalan; Middle Aged; Multiple Myeloma; Neoplasm Staging; Neutropenia; Panobinostat; Prednisone; Recurrence; Thalidomide; Thrombocytopenia; Time Factors; Treatment Outcome

Thalidomide and bortezomib have been frequently used for second-line therapy in patients with myeloma relapsing after or refractory to initial melphalan-based treatment, but no randomized trials have been published comparing these two treatment alternatives.. Thalidomide- and bortezomib-naïve patients with melphalan refractory myeloma were randomly assigned to low-dose thalidomide + dexamethasone (Thal-Dex) or bortezomib + dexamethasone (Bort-Dex). At progression on either therapy, the patients were offered crossover to the alternative drug combination. An estimated 300 patients would be needed for the trial to detect a 50% difference in median PFS between the treatment arms.. After inclusion of 131 patients, the trial was prematurely closed because of low accrual. Sixty-seven patients were randomized to Thal-Dex and 64 to Bort-Dex. Progression-free survival was similar (median, 9.0 months for Thal-Dex and 7.2 for Bort-Dex). Response rate was similar (55% for Thal-Dex and 63% for Bort-Dex), but time to response was shorter (P < 0.05) and the VGPR rate higher (P < 0.01) for Bort-Dex. Time-to-other treatment after crossover was similar (median, 13.2 months for Thal-Dex and 11.2 months for Bort-Dex), as was overall survival (22.8 months for Thal-Dex and 19.0 for Bort-Dex). Venous thromboembolism was seen in seven patients and cerebrovascular events in four patients in the Thal-Dex group. Severe neuropathy, reactivation of herpes virus infections, and mental depression were more frequently observed in the Bort-Dex group. In the quality-of-life analysis, no difference was noted for physical function, pain, and global quality of life. Fatigue and sleep disturbances were significantly more prevalent in the Bort-Dex group.. Thalidomide (50-100 mg daily) in combination with dexamethasone seems to have an efficacy comparable with that of bortezomib and dexamethasone in melphalan refractory myeloma. However, the statistical strength of the results in this study is limited by the low number of included patients.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Boronic Acids; Bortezomib; Cross-Over Studies; Dexamethasone; Disease-Free Survival; Drug Resistance, Neoplasm; Female; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Pyrazines; Quality of Life; Recurrence; Thalidomide

We conducted a Phase 1/2 study of bortezomib administered in combination with high-dose melphalan followed by tandem autologous transplants in patients with primary resistant multiple myeloma. Thirty patients received two cycles of salvage bortezomib followed by stem cell mobilization with granulocyte colony-stimulating factor and harvest. Melphalan 100 mg/m(2) per day on two consecutive days was administered, immediately followed by one dose of bortezomib (dose escalation) and stem cell infusion. The median beta 2-microglobulin was 4·35 mg/l (range: 1·8-11·4); albumin was 37 g/l (range: 3·1-4·9); high-risk karyotypes were noted in 45% of patients. The maximum planned dose of bortezomib at 1·3 mg/m(2) was well tolerated and a formal maximum tolerated dose was not determined. The peak of best overall response (≥partial response) and complete response rates after tandem transplants were 84% and 36%, respectively. With a median follow-up of 48 months, the median progression-free survival was 15 [95% confidence interval (CI): 11-21] months and the median overall survival was 35 (95% CI: 22-43) months. Correlative studies demonstrated decreased expression of BRCA2 (P = 0·0072) and FANCF (P = 0·0458) mRNA following bortezomib treatment. Bortezomib combined with high-dose melphalan is a well-tolerated conditioning with some activity in patients with resistant myeloma.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Boronic Acids; Bortezomib; Disease Progression; Fanconi Anemia Complementation Group Proteins; Female; Hematopoietic Stem Cell Transplantation; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Pyrazines; Salvage Therapy; Signal Transduction; Survival Analysis; Transplantation Conditioning; Transplantation, Autologous; Treatment Outcome

High-dose melphalan 140 mg/m2 is the standard of care for patients with multiple myeloma (MM) with renal insufficiency (RI). Palifermin as a cytoprotective agent has demonstrated efficacy in reducing the intensity and duration of oral mucositis (OM) in patients who receive intensive chemotherapy/radiotherapy. There is no prospective data on the use of palifermin in patients with MM with RI.. creatinine clearance ≤60 mL/minute/1.73 m2, age >18 years, no dialysis, no active OM, and a suitable candidate for autologous stem cell transplant (ASCT). Melphalan dose ranged from 140 to 200 mg/m2 and escalated at the increment of 20 mg/m2. Six dosages of palifermin 60 mcg/kg/day were given intravenously between day -5 to day +3. Dose escalations were to stop if dose-limiting toxicities (DLTs) occurred at melphalan dose in ≥2 of 3 patients, with that dose declared as the maximal administered dose and the level below where ≤1 of 6 patients had DLTs was considered the maximally tolerated dose (MTD). Nineteen patients were enrolled from June 2007 to June 2011. Data on 15 evaluable patients is reported as 4 patients were removed. Median age was 59 years (range, 36-67 years). The overall incidence of OM ≥ grade 3 was 53% (8 of 15) and a median duration of ≥grade 3 OM was 6.5 days (range, 3-42 days). One patient in L2 (melphalan 160 mg/m2) developed atrial fibrillation on day +9. Two patients in L4 (melphalan 200 mg/m2) developed grade 4 OM, hence reaching DLT. No DLT was observed in 6 patients enrolled in L3 (melphalan 180 mg/m2). Palifermin has permitted safe dose escalation of melphalan up to 180 mg/m(2) in patients with RI.

Topics: Adult; Aged; Antineoplastic Agents, Alkylating; Creatinine; Cytoprotection; Drug Administration Schedule; Drug Therapy, Combination; Female; Fibroblast Growth Factor 7; Hematopoietic Stem Cell Transplantation; Humans; Injections, Intravenous; Male; Melphalan; Middle Aged; Multiple Myeloma; Renal Insufficiency, Chronic; Stomatitis; Transplantation Conditioning; Transplantation, Autologous

The phase 3 VISTA study (ClinicalTrials.gov NCT00111319) in transplant-ineligible myeloma patients demonstrated superior efficacy with bortezomib-melphalan-prednisone (VMP; nine 6-wk cycles) vs. melphalan-prednisone (MP) but also increased toxicity. Health-related quality of life (HRQoL; exploratory endpoint) was evaluated using the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30). The phase 3 VISTA study (ClinicalTrials.gov NCT00111319) in transplant-ineligible myeloma patients demonstrated superior efficacy with bortezomib-melphalan-prednisone (VMP; nine 6-wk cycles) vs. melphalan-prednisone (MP) but also increased toxicity. Health-related quality of life (HRQoL; exploratory endpoint) was evaluated using the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30).. EORTC QLQ-C30 was administered at screening, on day 1 of each cycle, at the end-of-treatment visit, and every 8 wk until progression. EORTC QLQ-C30 scores were evaluated among patients with a valid baseline and at least one post-baseline HRQoL assessment.. At baseline, domain scores were similar between arms. By cycle 4, mean differences were clinically meaningful for most domains, indicating poorer health status with VMP. From cycle 5 onwards, improvements relative to baseline/MP were observed for all domains with VMP. Mean scores were generally improved by the end-of-treatment assessment vs. baseline in both arms. Among responding patients, mean scores generally improved from time of response to end-of-treatment assessment, substantially driven by patients achieving complete response (CR). Multivariate analysis showed a significant impact of duration of response/CR on improving global health status, pain, and appetite loss scores. Analyses by bortezomib dose intensity indicated better HRQoL in patients receiving lower dose intensity.. These findings demonstrate clinically meaningful, transitory HRQoL decrements with VMP and relatively lower HRQoL vs. MP during early treatment cycles, associated with the expected additional toxicities. However, HRQoL is not compromised in the long term, recovering by the end-of-treatment visit to be comparable vs. MP.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Boronic Acids; Bortezomib; Female; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Prednisone; Pyrazines; Quality of Life; Treatment Outcome

Topics: Antineoplastic Combined Chemotherapy Protocols; Bipolar Disorder; Boronic Acids; Bortezomib; Combined Modality Therapy; Dose-Response Relationship, Drug; Female; Humans; Induction Chemotherapy; Kaplan-Meier Estimate; Male; Melphalan; Middle Aged; Multiple Myeloma; Nausea; Neutropenia; Pyrazines; Remission Induction; Stem Cell Transplantation; Transplantation Conditioning; Transplantation, Autologous; Treatment Outcome

High-dose melphalan (HD-Mel) is considered the current standard of care among the preparative regimens used in autologous peripheral blood stem cell transplantation (SCT) for multiple myeloma (MM), but optimal time and schedule of administration is not defined. We retrospectively analyzed outcomes and toxicities of HD-Mel administered on day -2 vs. day -1 before autologous stem cells infusion. A total of 138 consecutive MM patients treated at Penn State Hershey Cancer Institute between 2007 and 2010 were included in this study. No difference in time to hematopoietic recovery, common SCT-related toxicities, and clinical outcomes was seen between patients who received HD-Mel on day -2 (group A, n = 47), and those who received it on day -1 (group B, n = 91). Prompt and full hematopoietic recovery occurred even when stem cells were infused between 8 and 24 h after completion of chemotherapy. In the absence of prospective and randomized data, we conclude that a single I.V. infusion of HD-Mel on day -1 is a safe and effective practice, and the so-called 'day of rest' before the transplant appears not to be necessary.

Topics: Adult; Aged; Disease-Free Survival; Female; Hematopoietic Stem Cells; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Myeloablative Agonists; Peripheral Blood Stem Cell Transplantation; Retrospective Studies; Survival Rate; Time Factors; Transplantation, Autologous

Lenalidomide has tumoricidal and immunomodulatory activity against multiple myeloma. This double-blind, multicenter, randomized study compared melphalan-prednisone-lenalidomide induction followed by lenalidomide maintenance (MPR-R) with melphalan-prednisone-lenalidomide (MPR) or melphalan-prednisone (MP) followed by placebo in patients 65 years of age or older with newly diagnosed multiple myeloma.. We randomly assigned patients who were ineligible for transplantation to receive MPR-R (nine 4-week cycles of MPR followed by lenalidomide maintenance therapy until a relapse or disease progression occurred [152 patients]) or to receive MPR (153 patients) or MP (154 patients) without maintenance therapy. The primary end point was progression-free survival.. The median follow-up period was 30 months. The median progression-free survival was significantly longer with MPR-R (31 months) than with MPR (14 months; hazard ratio, 0.49; P<0.001) or MP (13 months; hazard ratio, 0.40; P<0.001). Response rates were superior with MPR-R and MPR (77% and 68%, respectively, vs. 50% with MP; P<0.001 and P=0.002, respectively, for the comparison with MP). The progression-free survival benefit associated with MPR-R was noted in patients 65 to 75 years of age but not in those older than 75 years of age (P=0.001 for treatment-by-age interaction). After induction therapy, a landmark analysis showed a 66% reduction in the rate of progression with MPR-R (hazard ratio for the comparison with MPR, 0.34; P<0.001) that was age-independent. During induction therapy, the most frequent adverse events were hematologic; grade 4 neutropenia was reported in 35%, 32%, and 8% of the patients in the MPR-R, MPR, and MP groups, respectively. The 3-year rate of second primary tumors was 7% with MPR-R, 7% with MPR, and 3% with MP.. MPR-R significantly prolonged progression-free survival in patients with newly diagnosed multiple myeloma who were ineligible for transplantation, with the greatest benefit observed in patients 65 to 75 years of age. (Funded by Celgene; MM-015 ClinicalTrials.gov number, NCT00405756.).

Topics: Administration, Oral; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Double-Blind Method; Female; Follow-Up Studies; Humans; Induction Chemotherapy; Kaplan-Meier Estimate; Lenalidomide; Maintenance Chemotherapy; Male; Melphalan; Multiple Myeloma; Neoplasms, Second Primary; Neutropenia; Prednisone; Thalidomide

Despite the good response of stem cell transplant (SCT) in the treatment of multiple myeloma (MM), most patients relapse or do not achieve complete remission, suggesting that additional treatment is needed. We assessed the impact of thalidomide in maintenance after SCT in untreated patients with MM. A hundred and eight patients (<70 years old) were randomized to receive maintenance with dexamethasone (arm A; n = 52) or dexamethasone with thalidomide (arm B; n = 56; 200 mg daily) for 12 months or until disease progression. After a median follow-up of 27 months, an intention to treat analysis showed a 2-year progression-free survival (PFS) of 30% in arm A (95% CI 22-38) and 64% in arm B (95% CI 57-71; P = 0.002), with median PFS of 19 months and 36 months, respectively. In patients who did not achieve at least a very good partial response, the PFS at 2 years was significantly higher when in use of thalidomide (19 vs. 59%; P = 0.002). Overall survival at 2 years was not significantly improved (70 vs. 85% in arm A and arm B, respectively; P = 0.27). The addition of thalidomide to dexamethasone as maintenance improved the PFS mainly in patients who did not respond to treatment after SCT.

Topics: Adult; Aged; Angiogenesis Inhibitors; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Cyclophosphamide; Dexamethasone; Disease-Free Survival; Doxorubicin; Female; Granulocyte Colony-Stimulating Factor; Humans; Kaplan-Meier Estimate; Maintenance Chemotherapy; Male; Melphalan; Middle Aged; Multiple Myeloma; Peripheral Blood Stem Cell Transplantation; Proportional Hazards Models; Remission Induction; Thalidomide; Transplantation, Autologous; Vincristine

We enrolled 15 patients in this phase I dose de-escalation trial. Twelve patients are evaluable. The primary objective was to determine the safest and best tolerated maintenance dosing (MD) of bortezomib (B). The secondary endpoints were to evaluate complete response (CR), overall response (OR) and response duration. All patients receiving autologous stem cell transplant (ASCT) were eligible and registered between D+30 to D+120 after ASCT. A maximum number of 8 cycles of B was planned. Two evaluable patients in level (L) 1 received therapeutic dose of B 1.3 mg/m(2) intravenously on days (D) 1, 4, 8, and 11 in a 21 day cycle. Both these patients experienced dose limiting toxicities (DLTs). Four evaluable patients were then enrolled in dose L2 utilizing B 1.3 mg/m(2) on D 1, 4, 8, and 11 in a 28 day cycle. Two patients in L2 developed DLTs. Six evaluable patients were thereafter enrolled in L3 utilizing B 1 mg/m(2) on D 1, 8, and 15 in a 28 day cycle. Median 8 cycles of B were administered (2-8). No DLTs were observed in L3. The median duration of follow up for the entire cohort is 33 months (12-62). The median duration of response in L3 is 29.1 months (12-33). We conclude that B 1 mg/m(2) administered intravenously and may be subcutaneously on D 1, 8, and 15 in a 28 day cycle is the best tolerated MD and can be safely given beginning around D+100 post-ASCT.

Topics: Adult; Aged; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Boronic Acids; Bortezomib; Female; Humans; Maintenance Chemotherapy; Male; Melphalan; Middle Aged; Multiple Myeloma; Pyrazines; Remission Induction; Stem Cell Transplantation; Transplantation, Autologous

In spite of high-dose chemotherapy followed by autologous hematopoietic SCT multiple myeloma (MM) eventually recurs, highlighting the need for more effective treatment approaches. Patients received topotecan 3.5 mg/m(2) intravenously on days -6 to -2, melphalan 70 mg/m(2) intravenously on days -3 and -2 and CY 1 g/m(2) intravenously on days -6, -5 and -4. Overall response rate (ORR) consisting of complete response and partial response (CR+PR, PFS, OS and toxicity are reported. Between August 2002 to March 2004, 60 patients (34 men and 26 women) with a median age of 61 years (range 45-72) were enrolled. Forty-one patients were treated for consolidation of first remission, while 19 patients had relapsed/refractory disease. ORR was 85% (CR 12%, very good PR 43% and PR 30%). Median time to neutrophil (ANC>0.5 × 10(9)/L) and plt engraftment (>20 × 10(9)/L) was 10 (range 7-12 days) and 9 days (range 6-79 days), respectively. A majority of the common adverse events were grade 1-3 mucositis/stomatitis (65%), grade 1 or 2 nausea (59%) and grade 1 or 2 diarrhea (41%). Median PFS was 18.5 months and median OS has yet not been reached. In conclusion, topotecan, melphalan and CY is a safe and active conditioning regimen for auto hematopoietic SCT in MM. The ORR and PFS were comparable to high-dose melphalan.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Disease-Free Survival; Female; Graft Survival; Hematopoietic Stem Cell Transplantation; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Recurrence; Remission Induction; Topotecan; Transplantation, Autologous; Treatment Outcome

We investigated the administration of intravenous (i.v.) busulfan (Bu) combined with melphalan (Mel) in patients with advanced lymphoid malignancies undergoing autologous stem cell transplantation. Bu 130 mg/m(2) was infused daily for 4 days, either as a fixed dose per body surface area (BSA), or to target an average daily area under the curve of 5000 μmol-min, determined by a test dose of i.v. Bu at 32 mg/m(2) given 48 hours prior to the high-dose regimen, followed by a rest day, followed by 2 daily doses of Mel at 70 mg/m(2). Stem cells were infused the following day. Eighty patients had i.v. Bu delivered per test dose guidance. The median daily systemic Bu exposure was 4867 μmol-min. One hundred two patients (Hodgkin lymphoma n = 49, non-Hodgkin lymphoma n = 12, multiple myeloma = 41) with a median age of 44 years (range: 19-65 years) were treated. The 2-year overall survival and progression-free survival rates were 85% and 57%, respectively, for patients with Hodgkin lymphoma, 67% and 64%, respectively, for patients with non-Hodgkin lymphoma, and 82% and 42%, respectively, for patients with multiple myeloma. The regimen was very well tolerated with treatment-related mortality at 100 days, 1 year, and 2 years of 1%, 3%, and 3%, respectively. Intravenous Bu-Mel was well tolerated. Disease control wa encouraging, and should be explored in larger phase II studies.

Topics: Adult; Aged; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Busulfan; Female; Hematopoietic Stem Cell Transplantation; Hodgkin Disease; Humans; Infusions, Intravenous; Lymphoma, Non-Hodgkin; Lymphoproliferative Disorders; Male; Melphalan; Middle Aged; Multiple Myeloma; Severity of Illness Index; Survival Analysis; Transplantation Conditioning; Transplantation, Autologous; Young Adult

This subanalysis of the phase 3 VISTA trial aimed to assess the frequency, characteristics and reversibility of, and prognostic factors for, bortezomib-associated peripheral neuropathy (PN) in newly diagnosed patients with multiple myeloma ineligible for high-dose therapy who received bortezomib plus melphalan-prednisone.. Patients received nine 6-wk cycles of VMP (bortezomib 1.3 mg/m(2), days 1, 4, 8, 11, 22, 25, 29, 32, cycles 1-4, and days 1, 8, 22, 29, cycles 5-9; melphalan 9 mg/m(2), days 1-4, cycles 1-9; and prednisone 60 mg/m(2), days 1-4, cycles 1-9).. Overall, 47% of patients receiving VMP developed PN, including 19% grade 2 and 13% grade ≥ 3 (<1% grade 4). The PN incidence was dose-related and reached a plateau at a cumulative bortezomib dose of approximately 45 mg/m(2). Median time to PN onset was 2.3 months. Bortezomib-associated PN was reversible; 79% of events improved by at least one NCI CTCAE grade within a median of 1.9 months and 60% completely resolved within a median of 5.7 months, with reversibility similar in responding and non-responding patients. By multivariate analysis, baseline neuropathy was the only consistent risk factor for any PN [hazard ratio (HR) 1.785, P=0.0065], grade ≥ 2 PN (HR 2.205, P=0.0032), and grade ≥ 3 PN (HR 2.438, P=0.023); age, pre-existing diabetes, International Staging System stage, obesity, and creatinine clearance did not affect the overall rate of PN.. Rates of bortezomib-induced PN in the frontline setting were similar to those in relapsed patients and resolved in most cases.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Boronic Acids; Bortezomib; Female; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Multivariate Analysis; Peripheral Nervous System Diseases; Prednisone; Pyrazines; Risk Factors

Plerixafor in combination with granulocyte-colony-stimulating factor (G-CSF) has been shown to enhance stem cell mobilization in patients with multiple myeloma, non-Hodgkin's lymphoma, and Hodgkin's disease who demonstrated with previous mobilization failure. In this named patient program we report the Austrian experience in insufficiently mobilizing patients.. Twenty-seven patients from eight Austrian centers with a median (range) age of 58 (19-70) years (18 female, nine male) were included in the study. Plerixafor was limited to patients with previous stem cell mobilization failure and was given in the evening of Day 4 of G-CSF application.. A median increase of circulating CD34+ cells within 10 to 11 hours from administration of plerixafor by a factor of 4.7 over baseline was noted. Overall, 20 (74%) patients reached more than 10 × 10(6) CD34+ cells/L in the peripheral blood, resulting in 17 (63%) patients collecting at least 2 × 10(6) CD34+ cells/kg body weight (b.w.; median, 2.6 × 10(6) CD34+ cells/kg b.w.; range, 0.08 × 10(6) -8.07 × 10(6) ). Adverse events of plerixafor were mild to moderate and consisted of gastrointestinal side effects and local reactions at the injection site. Thirteen (48%) patients underwent autologous transplantation receiving a median of 2.93 × 10(6) CD34+ cells/kg (range, 1.46 × 10(6) -5.6 × 10(6) ) and showed a trilinear engraftment with a median neutrophil recovery on Day 12 and a platelet recovery on Day 14.. Our study confirms previous investigations showing that plerixafor in combination with G-CSF is an effective and well-tolerated mobilization regimen with the potential of successful stem cell collection in patients with previous mobilization failure.

Topics: Adolescent; Adult; Aged; Antigens, CD34; Austria; Benzylamines; Combined Modality Therapy; Cyclams; Drug Therapy, Combination; Female; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cell Transplantation; Hematopoietic Stem Cells; Heterocyclic Compounds; Humans; Immunoglobulin G; Leukapheresis; Lymphoma; Male; Melphalan; Middle Aged; Multiple Myeloma; Receptors, CXCR4; Transplantation, Autologous; Young Adult

Explore safety and efficacy of three palonosetron-containing regimens for emesis prevention over 7 days in multiple myeloma (MM) patients receiving melphalan (100 mg/m(2)) and hematopoietic stem cell transplantation (HSCT).. Randomized, double-blind pilot study in MM patients (n=73) receiving 1, 2, or 3 days of 0.25 mg palonosetron (30-s i.v. bolus) 30 min before melphalan (days -2 and -1) and HSCT (day 0). Patients received dexamethasone (20 mg i.v., days -2 and -1) immediately before or after study drug/placebo. Daily diaries recorded emesis, rescue medication, nausea duration, and adverse events (AEs).. Seven-day complete protection (no emesis) occurred in 41.7% [95% confidence interval (CI) 22.1% to 63.4%], 41.7% (95% CI 22.1% to 63.4%), and 44.0% (95% CI 24.2% to 65.1%) of patients receiving 1, 2, or 3 days of palonosetron, respectively (P=0.43). Complete response (emesis free without rescue medication) occurred in 8.3%, 20.8%, and 20.0% (P=0.14). Common AEs (≥10%) were mild-to-moderate diarrhea, constipation, headache, insomnia, and flatulence. No serious AEs occurred.. Palonosetron with dexamethasone was safe and effective in preventing emesis in MM patients receiving melphalan and HSCT. This pilot study with a limited number of patients suggests that multiple doses of palonosetron could be more effective than a single dose in making patients emesis free without need for rescue medication. However, even multiple doses of palonosetron resulted in only 20% of patients being emesis free without rescue medication, suggesting that further improvement will require development of more effective combination antiemetic therapy.

Topics: Adult; Aged; Antineoplastic Agents, Alkylating; Dexamethasone; Double-Blind Method; Female; Hematopoietic Stem Cell Transplantation; Humans; Isoquinolines; Male; Melphalan; Middle Aged; Multiple Myeloma; Nausea; Palonosetron; Quinuclidines; Vomiting

The combination of melphalan-prednisone-thalidomide (MPT) has been investigated in several clinical studies that differed significantly with regard to patient characteristics and treatment schedules. This prospective trial differs from previous melphalan-prednisone (MP) vs. MPT trials by treatment dosing, duration, routine anticoagulation, and permission for a crossover. Newly diagnosed patients with multiple myeloma (MM) (n=122) aged greater than 55 yr, not eligible for transplantation were randomized to receive 8 cycles of M (9 mg/m(2) /d) and P (60 mg/m(2) /d) for 4d every 6 wk (n=62) or MP and thalidomide (100 mg/d) continuously (n=60). Primary endpoint was treatment response and toxicities following 4 and 8 cycles of therapy. Secondary endpoints were disease-free (DFS) and overall survival (OS). Overall, MPT-treated patients were younger (median 69 yr vs. 72 yr; P=0.016) and had a higher incidence of renal impairment (RI, 19% vs. 7%, respectively; P=0.057). After 4 cycles of treatment (n=115), there were more partial responses or better in the MPT arm than in the MP arm (57.9% vs. 37.5%; P=0.030). However, DFS and OS were not significantly different between the arms after a median of 23 months follow-up (median OS 26.0 vs. 28.0 months, P=0.655; DFS 21.0 vs. 14.0 months, P=0.342, respectively). Crossover to MPT was required in 11 patients, 57% of whom responded to treatment. A higher rate of grade 3-4 infections was observed in the MPT arm compared with the MP arm (22.4% vs. 7.0%; P=0.033). However, none of these infections were associated with febrile neutropenia. Death within the first 3 months was observed more frequently in the MP arm (n=8, 14.0%) than in the MPT arm (n=2, 3.4%; P=0.053). Long-term discontinuation and dose reduction rates were also analyzed (MPT: 15.5% vs. MP: 5.3%; P=0.072). Although patients treated with MPT were relatively younger and had more frequent RI, better responses and less early mortality were observed in all age groups despite more frequent discontinuation.

Topics: Age Factors; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Cross-Over Studies; Female; Humans; Kidney Diseases; Male; Melphalan; Middle Aged; Multiple Myeloma; Opportunistic Infections; Prednisone; Survival Analysis; Thalidomide; Treatment Outcome

We used genome-wide methylation microarrays to analyze differences in CpG methylation patterns in cells relevant to the pathogenesis of myeloma plasma cells (B cells, normal plasma cells, monoclonal gammopathy of undetermined significance [MGUS], presentation myeloma, and plasma cell leukemia). We show that methylation patterns in these cell types are capable of distinguishing nonmalignant from malignant cells and the main reason for this difference is hypomethylation of the genome at the transition from MGUS to presentation myeloma. In addition, gene-specific hypermethylation was evident at the myeloma stage. Differential methylation was also evident at the transition from myeloma to plasma cell leukemia with remethylation of the genome, particularly of genes involved in cell-cell signaling and cell adhesion, which may contribute to independence from the bone marrow microenvironment. There was a high degree of methylation variability within presentation myeloma samples, which was associated with cytogenetic differences between samples. More specifically, we found methylation subgroups were defined by translocations and hyperdiploidy, with t(4;14) myeloma having the greatest impact on DNA methylation. Two groups of hyperdiploid samples were identified, on the basis of unsupervised clustering, which had an impact on overall survival. Overall, DNA methylation changes significantly during disease progression and between cytogenetic subgroups.

Topics: Antineoplastic Combined Chemotherapy Protocols; Cluster Analysis; Cyclophosphamide; Dexamethasone; Disease Progression; DNA Methylation; Doxorubicin; Humans; In Situ Hybridization, Fluorescence; Melphalan; Monoclonal Gammopathy of Undetermined Significance; Multiple Myeloma; Precancerous Conditions; Prednisolone; Prognosis; Stem Cell Transplantation; Thalidomide; Vincristine

The individual risk of infection and requirements for medical treatment after high-dose chemotherapy have been unpredictable. In this prospective, multicenter, open-label study we investigated the potential of granulocyte colony-stimulating factor (G-CSF) responsiveness as a predictor. A total of 168 patients with multiple myeloma or lymphoma received a single dose of subcutaneous G-CSF (lenograstim, 263 μg) after high-dose chemotherapy. Highly variable leukocyte peaks were measured and grouped as low (quartile 1; leukocytes 100-10 100/μL), medium (quartile 2; leukocytes > 10 100-18 300/μL), and high (quartiles 3/4; leukocytes > 18 300-44 800/μL). G-CSF responsiveness (low vs medium vs high) was inversely correlated with febrile neutropenia (77% vs 60% vs 48%; P = .0037); the rate of infection, including fever of unknown origin (91% vs 67% vs 54%; P < .0001); days with intravenous antibiotics (9 vs 6 vs 5; P < .0001); and antifungal therapy (P = .042). In multivariate analysis, G-CSF responsiveness remained the only factor significantly associated with infection (P = .016). In addition, G-CSF responsiveness was inversely correlated with grade 3/4 oral mucositis (67% vs 33% vs 23%; P < .0001). G-CSF responsiveness appears as a signature of the myeloid marrow reserve predicting defense against neutropenic infection after intensive chemotherapy. This study is registered at http://www.clinicaltrials.gov as NCT01085058.

Topics: Adolescent; Adult; Aged; Antineoplastic Agents; Female; Granulocyte Colony-Stimulating Factor; Humans; Infections; Lenograstim; Lymphoma; Male; Melphalan; Middle Aged; Multiple Myeloma; Multivariate Analysis; Neutropenia; Peripheral Blood Stem Cell Transplantation; Predictive Value of Tests; Prognosis; Prospective Studies; Recombinant Proteins; Risk Factors; Young Adult

The current definition of complete remission (CR) in multiple myeloma (MM) requires a negative serum and urine immunofixation (IFE) and <5% bone marrow plasma cells (BMPCs). The aim of this study was to determine the value of BMPCs count by standard microscopic evaluation in patients with MM in serologic CR after autologous stem cell transplantation (ASCT). Thirty-five patients with a median follow-up after ASCT of 7.3 years were studied. The percentage of BMPCs was an independent predictor of progression in multivariate model (hazard ratio 2.02, P = .009). Patients with >1.5% BMPCs (median: 0.8%) after ASCT had an increased risk of progression (P = .016) and a trend toward a shorter survival (P = .195). In conclusion, conventional morphology of bone marrow is a useful and rapid tool as a first step to assess the residual tumor mass in patients with MM in CR after ASCT, and it constitutes a strong predictor for disease progression.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Bone Marrow Examination; Busulfan; Cell Count; Combined Modality Therapy; Disease Progression; Female; Humans; Kaplan-Meier Estimate; Male; Melphalan; Middle Aged; Multiple Myeloma; Neoplasm, Residual; Peripheral Blood Stem Cell Transplantation; Plasma Cells; Prognosis; Proportional Hazards Models; Remission Induction; Risk Factors; Sensitivity and Specificity; Transplantation Conditioning; Transplantation, Autologous; Whole-Body Irradiation

A multicenter phase III study for untreated multiple myeloma was conducted to investigate a switch-induction chemotherapy with melphalan-prednisolone and vincristine-doxorubicin-dexamethasone followed by randomization on maintenance therapy for patients achieving plateau. Between November 2002 and November 2005, 34 patients were registered. The study was closed early because of poor accrual. Thirty-three eligible patients, with a median age of 65 years (range: 47-77 years) were analyzed for the secondary purpose. For induction therapy, 16 patients were treated with vincristine-doxorubicin-dexamethasone and 17 with melphalan-prednisolone initially. In eight cases, induction therapy was switched because of a poor response. Both regimens were well tolerated, but neutropenia, anorexia, constipation and infection with neutropenia were more frequent for vincristine-doxorubicin-dexamethasone. Best response rates were 44% (95% confidence interval, 20-70) and 47% (95% confidence interval, 23-72), respectively, for vincristine-doxorubicin-dexamethasone and melphalan-prednisolone. Vincristine-doxorubicin-dexamethasone/melphalan-prednisolone switch-induction therapy might be feasible and effective for Japanese patients with multiple myeloma.

Topics: Aged; Anorexia; Antineoplastic Combined Chemotherapy Protocols; Constipation; Dexamethasone; Doxorubicin; Feasibility Studies; Female; Humans; Interferons; Japan; Male; Melphalan; Middle Aged; Multiple Myeloma; Neutropenia; Prednisone; Remission Induction; Vincristine

This study combined infusional mitoxantrone with bolus melphalan as a transplant preparative regimen for multiple myeloma. Mitoxantrone was infused over 6 hr on days 6 and 5. Melphalan was given as a 15 min bolus on day 1 followed by autologous transplant on day 0. Thirty-five patients were enrolled; 57% of enrollees had received ≥ 2 prior treatments. The median overall survival was 5 years and 8 months, with 37% of the subjects alive >7 years posttransplantation. Myelosuppression and mucositis were the most frequent adverse events. This regimen is well tolerated and the survival compares well to other transplant trials.

Topics: Adult; Aged; Female; Hematopoietic Stem Cell Transplantation; Humans; Kaplan-Meier Estimate; Male; Melphalan; Middle Aged; Mitoxantrone; Multiple Myeloma; Myeloablative Agonists; Transplantation Conditioning; Transplantation, Autologous

  Bone disease is a key presenting feature of myeloma. This post hoc analysis of the phase III VISTA trial of bortezomib plus melphalan-prednisone (VMP) vs. MP in previously untreated myeloma patients assessed clinical bone disease events and changes in alkaline phosphatase (ALP), a marker for osteoblast activation, and serum Dickkopf-1 (DKK-1), an inhibitor of osteoblast differentiation, during treatment..   Patients received nine 6-wk cycles of VMP (bortezomib 1.3 mg/m(2) , days 1, 4, 8, 11, 22, 25, 29, 32, cycles 1-4, days 1, 8, 22, 29, cycles 5-9, plus melphalan 9mg/m(2) and prednisone 60mg/m(2) , days 1-4, cycles 1-9; N=344) or MP alone (N=338)..   Rates of bisphosphonates use during treatment (73% vs. 82%), progression because of worsening bone disease (3% vs. 11%), and requirement for subsequent radiotherapy (3% vs. 8%) were lower with VMP vs. MP. Median maximum ALP increase was significantly higher with VMP vs. MP overall (49.7% vs. 30.3%, P=0.029), and higher by response group (complete response [CR]: 68.7% vs. 43.9%; partial response [PR]: 41.5% vs. 31.2%). Greater maximum ALP increase was strongly associated with achievement of CR (P≤0.0001) and CR/PR (P≤0.01). Median DKK-1 decreased with VMP by 694.4pg/mL and increased with MP by 1273.3pg/mL from baseline to day 4 (P=0.0069). Available radiologic data revealed evidence of bone healing in 6/11 VMP-treated patients, who achieved best responses of three CR, one PR, and two stable disease..   These results suggest a positive effect of bortezomib on bone metabolism and potentially bone healing in myeloma.

Topics: Aged; Aged, 80 and over; Alkaline Phosphatase; Antineoplastic Combined Chemotherapy Protocols; Biomarkers; Bone Diseases; Bone Remodeling; Boronic Acids; Bortezomib; Cell Differentiation; Female; Humans; Intercellular Signaling Peptides and Proteins; Male; Melphalan; Middle Aged; Multiple Myeloma; Osteoblasts; Prednisone; Pyrazines; Radiotherapy, Adjuvant

Although haematological toxicities, such as anaemia, are common in multiple myeloma (MM), no clear consensus exists on the use and impact of erythropoiesis-stimulating agents (ESA) on outcomes in MM. This analysis characterizes haematological toxicities and associated interventions in the phase III VISTA (Velcade(®) as Initial Standard Therapy in Multiple Myeloma: Assessment with Melphalan and Prednisone) study of bortezomib plus melphalan/prednisone (VMP, n = 344) versus MP (n = 338) in previously untreated MM patients ineligible for high-dose therapy, and evaluates the impact of ESA use or red-blood-cell (RBC) transfusions on outcomes and thromboembolic risk. Incidence of haematological toxicities was similar with VMP and MP; similar rates of interventions and associated complications (e.g. bleeding, febrile neutropenia) were observed. Two hundred thirty three patients received ESA; 204 had RBC transfusions. Frequency of thromboembolic events was low and not affected by ESA use. Median time-to progression (TTP) was similar between ESA/non-ESA [hazard ratio: 1·03 (95% confidence interval 0·76-1·39); P = 0·8478] in both arms (VMP: 19·9/not reached; MP: 15·0/17·5 months). Three-year overall survival (OS) rates were similar between ESA/non-ESA in each arm. Patients receiving RBC transfusions had significantly shorter OS (P < 0·0001) versus non-RBC-transfusion patients. In conclusion, bortezomib did not add to melphalan haematological toxicity. Concomitant ESA use with VMP/MP in previously untreated MM patients did not adversely affect TTP or OS, or increase thromboembolic risk. However, RBC transfusion was associated with significantly shorter survival.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Boronic Acids; Bortezomib; Disease-Free Survival; Erythrocyte Transfusion; Female; Hematinics; Humans; Incidence; Male; Melphalan; Middle Aged; Multiple Myeloma; Prednisolone; Pyrazines; Survival Rate; Thromboembolism

Thalidomide with melphalan/prednisone (MPT) was defined as standard treatment in elderly patients with multiple myeloma (MM) based on five randomized trials. In one of these trials, HOVON49, a prospective health-related quality-of-life (HRQoL) study was initiated in order to assess the impact of thalidomide on QoL. Patients aged >65 years with newly diagnosed MM were randomized to receive melphalan plus prednisone (MP) or MPT, followed by thalidomide maintenance in the MPT arm. Two hundred eighty-four patients were included in this side study (MP, n=149; MPT n=135). HRQoL was assessed with the EORTC Core QoL Questionnaire (QLQ-C30) and the myeloma-specific module (QLQ-MY24) at baseline and at predetermined intervals during treatment. The QLQ-C30 subscales physical function (P=0.044) and constipation (P<0.001) showed an improvement during induction in favour of the MP arm. During thalidomide maintenance, the scores for the QLQ-MY24 paraesthesia became significantly higher in the MPT arm (P<0.001). The QLQ-C30 subscales pain (P=0.12), insomnia (P=0.068), appetite loss (P=0.074) and the QLQ-MY24 item sick (P=0.086) scored marginally better during thalidomide maintenance. The overall QoL-scale QLQ-C30-HRQoL showed a significant time trend towards more favourable mean values during protocol treatment without differences between MP and MPT. For the QLQ-C30 subscales emotional function and future perspectives, difference in favour of the MPT arm from the start of treatment was observed (P=0.018 and P=0.045, respectively) with no significant 'time × arm' interaction, indicating a persistent better patient perspective with MPT treatment. This study shows that the higher frequency of toxicity associated with MPT does not translate into a negative effect on HRQoL and that MPT holds a better patient perspective.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents, Alkylating; Female; Glucocorticoids; Humans; Immunosuppressive Agents; Male; Melphalan; Middle Aged; Models, Statistical; Multiple Myeloma; Prednisone; Prospective Studies; Quality of Life; Surveys and Questionnaires; Thalidomide; Treatment Outcome

For patients with relapsed or refractory multiple myeloma (MM) treated with a prior high-dose therapy (HDT) followed by autologous peripheral blood stem cell transplantation (PBSCT), the reapplication of HDT is a widely used salvage strategy. In this retrospective study, we report on 55 patients who were treated with salvage HDT at our institution. The conditioning regimen consisted of melphalan 200 mg/m(2) (27%), melphalan 140 mg/m(2) and busulfan 12 mg/kg body weight (40%), or melphalan 200 mg/m(2) and bortezomib 1.3 mg/m(2) (33%). Treatment-related mortality was 5% and response rates were as follows: 9% complete remission, 9% very good partial remission, 56% partial remission, 11% minimal response + stable disease, and 4% progressive disease (5% not assessable). Toxicity was moderate and the median event-free (EFS) and overall survival (OS) were 14 months and 52 months, respectively. The different conditioning regimens did not result in differences in terms of remission rates, EFS and OS, or toxicity. In multivariate analysis a duration of remission of more than 12 months after the first transplant was the only predictive factor for both EFS (p < 0.0001) and OS (p = 0.0001). In conclusion, salvage HDT followed by autologous PBSCT is an effective treatment option for patients with relapsed or refractory MM, while patients with an early relapse after their first transplant do not benefit from this treatment modality.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Boronic Acids; Bortezomib; Busulfan; Combined Modality Therapy; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Kaplan-Meier Estimate; Male; Melphalan; Middle Aged; Multiple Myeloma; Multivariate Analysis; Neutropenia; Peripheral Blood Stem Cell Transplantation; Prognosis; Pyrazines; Recurrence; Retrospective Studies; Salvage Therapy; Transplantation Conditioning; Transplantation, Autologous; Treatment Outcome

Several trials comparing the efficacy of standard melphalan and prednisone (MP) therapy with MP plus thalidomide (MPT) in elderly patients with multiple myeloma (MM) have been reported, with inconsistent results. The primary goal of our study was to evaluate the efficacy and toxicity of MP versus MPT in newly diagnosed patients with MM who were transplant-ineligible or over age 65. A total of 135 patients were enrolled. Either minimal response or better or partial response or better were more frequent with MPT treatment (p = 0.001). After a median follow-up of 30 months, median progression-free survival (PFS) and overall survival (OS) were 33 and 52 months for MPT versus 22 and 32 months for MP, respectively. The comparison showed a significant advantage for MPT versus MP in PFS (p = 0.02) and only a trend for OS (p = 0.07). Severe adverse events were observed more frequently with MPT. In conclusion, our results show an improved activity of MPT at a cost of increased toxicity. We believe that MPT can be considered one of the new standard of care for elderly or transplant-ineligible patients with MM.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Drug-Related Side Effects and Adverse Reactions; Humans; Melphalan; Multiple Myeloma; Prednisone; Survival Analysis; Thalidomide; Treatment Outcome

To improve the outcome of allogeneic stem cell transplantation (allo-SCT) in multiple myeloma as part of first-line treatment, we prospectively investigated the feasibility and efficacy of lenalidomide maintenance. Patients started maintenance 1 to 6 months after nonmyeloablative allo-SCT. Lenalidomide was dosed 10 mg on days 1 to 21 of a 28-day schedule for a total of 24 cycles. Peripheral blood samples were taken to evaluate immune modulating effects. Thirty-five eligible patients were enrolled, and 30 started with lenalidomide. After 2 cycles, 14 patients (47%) had to stop treatment, mainly because of the development of acute graft versus host disease (GVHD). In total, 13 patients (43%) stopped treatment because of development of GVHD, 5 patients (17%) because of other adverse events, and 5 patients (17%) because of progression. Responses improved in 37% of patients, and the estimated 1-year progression-free survival from start of maintenance was 69% (90% confidence interval, 53%-81%). Lenalidomide increased the frequency of human leukocyte antigen-DR(+) T cells and regulatory T cells, without correlation with clinical parameters. In conclusion, lenalidomide maintenance 10 mg daily after nonmyeloablative allo-SCT with unmanipulated graft in multiple myeloma patients is not feasible, mainly because of the induction of acute GVHD. This trial was registered at www.trialregister.nl as #NTR1645.

Topics: Acute Disease; Adult; Aged; Antineoplastic Agents; Combined Modality Therapy; Cyclophosphamide; Cyclosporine; Disease-Free Survival; Drug Eruptions; Feasibility Studies; Female; Graft vs Host Disease; Hematologic Diseases; Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cell Transplantation; Humans; Immunologic Factors; Immunosuppressive Agents; Lenalidomide; Lymphocyte Count; Male; Melphalan; Middle Aged; Multiple Myeloma; Mycophenolic Acid; Prospective Studies; Remission Induction; Thalidomide; Transplantation Conditioning; Transplantation, Autologous; Transplantation, Homologous; Whole-Body Irradiation

Using population-based data from Sweden, we identified all multiple myeloma (MM) patients (n = 8740) and 5652 monoclonal gammopathy of undetermined significance (MGUS) patients diagnosed between 1986 and 2005. We calculated standardized incidence rates (SIRs) for all subsequent hematologic and nonhematologic malignancies for MM patients diagnosed before/after 1995 (introduction of high-dose melphalan/autologous stem cell transplantation [HDM-ASCT]) and 2000 (introduction of immunomodulatory drugs [IMiDs]), respectively. MM patients had an 11.51-fold (95% confidence interval: 8.19-15.74) increased risk of acute myeloid leukemia (AML)/myelodysplastic syndromes (MDS); risk was very similar before/after 1995 and 2000, respectively. MGUS patients had an 8.01-fold (5.40-11.43) increased risk of AML/MDS. Risk was confined to IgG/IgA, while no IgM MGUS patients developed AML/MDS; patients with monoclonal-protein (M-protein) concentrations > 1.5 g/dL (SIR = 11.12; 3.61-25.96) had higher risk than those < 1.5 g/dL (SIR = 4.67; 1.71-10.16). An excess risk of nonmelanoma skin cancer was observed subsequent to both MM (SIR = 2.22; 1.74-2.80) and MGUS (SIR = 3.30; 2.76-3.90). Our novel observations of an excess risk for AML/MDS following IgG/IgA (but not IgM) MGUS, and the highest risk associated with M-protein concentrations > 1.5 g/dL, support a role for nontreatment-related factors in plasma cell dyscrasias. AML/MDS risk following MM was the same before/after the introduction of HDM-ASCT. Longer follow-up is needed to characterize second tumor risks in the IMiD era.

Topics: Aged; Antineoplastic Agents, Alkylating; Female; Humans; Immunologic Factors; Incidence; Leukemia, Myeloid, Acute; Male; Melphalan; Middle Aged; Multiple Myeloma; Myelodysplastic Syndromes; Neoplasms, Second Primary; Retrospective Studies; Risk Factors; Stem Cell Transplantation; Sweden; Transplantation, Autologous

We assessed efficacy, safety, and reversal of renal impairment (RI) in untreated patients with multiple myeloma given bortezomib-melphalan-prednisone-thalidomide followed by bortezomib-thalidomide (VMPT-VT) maintenance or bortezomib-melphalan-prednisone (VMP). Exclusion criteria included serum creatinine ≥ 2.5 mg/dL. In the VMPT-VT/VMP arms, severe RI (estimated glomerular filtration rate [eGFR] ≤ 30 mL/min), moderate RI (eGFR 31-50 mL/min), and normal renal function (eGFR > 50 mL/min), were 6%/7.9%, 24.1%/24.9%, and 69.8%/67.2%, respectively. Statistically significant improvements in overall response rates and progression-free survival were observed in VMPT-VT versus VMP arms across renal cohorts, except in severe RI patients. In the VMPT group, severe RI reduced overall survival (OS). RI was reversed in 16/63 (25.4%) patients receiving VMPT-VT versus 31/77 (40.3%) receiving VMP. Multivariate analysis showed male sex (P = .022) and moderate RI (P = .003) significantly predicted RI recovery. VMP patients achieving renal response showed longer OS. In both arms, greater rates of severe hematologic adverse events were associated with RI (eGFR < 50 mL/min), however, therapy discontinuation rates were unaffected. VMPT-VT was superior to VMP for cases with normal renal function and moderate RI, whereas VMPT-VT failed to outperform VMP in patients with severe RI, although the relatively low number of cases analyzed preclude drawing definitive conclusions. VMPT-VT had no advantage in terms of RI reversal over VMP.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Boronic Acids; Bortezomib; Female; Glomerular Filtration Rate; Humans; Induction Chemotherapy; Kidney Diseases; Maintenance Chemotherapy; Male; Melphalan; Multiple Myeloma; Neoadjuvant Therapy; Prednisone; Pyrazines; Survival Analysis; Thalidomide; Treatment Outcome

Oral mucositis (OM) is an unresolved problem among patients treated with a high-dose therapy supported by hematopoietic stem cell transplantation (HSCT). We tested the ability of supersaturated calcium phosphate mouth rinse (Caphosol) to ameliorate oral mucosal injury induced by a conditioning regimen.. Thirty-two patients with hematologic malignancies were treated with Caphosol to prevent OM during HSCT procedures. The conditioning regimens for 16 patients were BGNU 300 mg/m2, day 6; ARA-C 200 mg/m2 daily, days 5, 4, 3, 2; VP-16 200 mg/m2 daily, days 5, 4, 3, 2; L-PAM 140 mg/m2, day 1 (BEAM) and for 16 patients, MEL 200 (non-Hodgkin's lymphoma). A control group was composed of 24 consecutive patients, who had been treated with HSCT before Caphosol was available. The source of the graft was autologous peripheral blood.. Among patients treated with Caphosol no one had to receive total parenteral nutrition. Among the BEAM group no one experienced III to IV degree OM compared with 40% of the control group. The median OM duration was 2.25 days versus controls of 8.6, (P<.001); only one patient received opioids versus 100% of controls. In the MEL 200 group, 93.7% of patients developed 0 to II degree OM vs 94% of the control group (P=.74) with median duration of 1, 73 days versus 2.42 for the controls (P=.73). In both control and Caphosol cohorts one patient received opioids.. Caphosol may reduce the incidence, severity, and duration of oral mucositis and decrease the number of days with painkillers among patients treated with a BEAM but not a Mel 200 regimen.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Calcium Phosphates; Carmustine; Cytarabine; Etoposide; Female; Hematopoietic Stem Cell Transplantation; Hodgkin Disease; Humans; Lymphoma, Non-Hodgkin; Male; Melphalan; Middle Aged; Mouthwashes; Multiple Myeloma; Stomatitis; Transplantation Conditioning; Treatment Outcome; Young Adult

The COBE Spectra AutoPBSC collection set (AUTO-kit; CaridianBCT) is a popular dual-stage collection set for peripheral blood progenitor (PBPC) collection. Although the AUTO-kit is purportedly equivalent to the white blood cell (WBC) collection set (WBC-kit) for PBPC collection, improved CD34 yields after switching from the AUTO-kit to the WBC-kit were anecdotally observed, particularly in patients with higher WBC counts. A prospective, randomized trial of the AUTO- and WBC-kits for PBPC collection in multiple myeloma (MM) patients was therefore designed.. Sixty-eight MM patients were prospectively randomly assigned to either the WBC-kit or the AUTO-kit for PBPC collection. Primary study variables included the number of leukapheresis procedures per transplant, CD34/kg yield per procedure, and cumulative CD34/kg yield per mobilization cycle. Results were compared relative to collection kit and mobilization regimen. Statistics and graphics were performed with commercial software.. CD34/kg yields were higher with the WBC-kit, with 94% of chemotherapy-mobilized MM patients collecting 6 million CD34/kg in a single mobilization (p = 0.06). The WBC-kit also had a faster CD34 collection rate relative to peripheral CD34 counts. The AUTO-kit was significantly sensitive to high WBC counts, with a 50% decrease in CD34 collection efficiency and CD34 collection rate. This effect was specific to MM and not observed in lymphoma patients. Granulocyte-colony-stimulating factor mobilization and the AUTO-kit were associated with an increased incidence and severity of infusion reactions.. The WBC-kit performed consistently better than the AUTO-kit for PBPC collection in chemotherapy-mobilized MM patients, with fewer procedures per mobilization, superior collection rates, and a decreased incidence of infusion reactions.

Topics: Antigens, CD34; Combined Modality Therapy; Female; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cell Transplantation; Hematopoietic Stem Cells; Humans; Immunoglobulin G; Leukapheresis; Leukocyte Count; Male; Melphalan; Middle Aged; Multiple Myeloma; Platelet Count; Prospective Studies; Transplantation, Autologous; Treatment Outcome

The purpose of this study was to evaluate the efficacy and safety of short-course bortezomib, melphalan, prednisone (VMP) in previously untreated multiple myeloma as frontline therapy for transplant-ineligible patients and induction prior to autologous stem cell transplantation (ASCT). Patients received up to 6 28-day cycles of bortezomib 1.3 mg/m(2), days 1, 4, 8, and 11, plus melphalan 6 mg/m(2) and prednisone 60 mg/m(2), days 1-7. After 2-6 cycles, eligible and consenting patients could proceed to ASCT. Responses were assessed by International Uniform Response Criteria. The primary endpoint was complete response (CR) rate with VMP. Forty-five patients were enrolled. Among 44 evaluable patients, response rate was 95%, including 18% >or=CR (9% stringent CR), 27% very good partial responses (VGPR), and 50% partial responses (PR). Twenty patients proceeded to ASCT. Stem cell collection was successful in all; median yield was 5.6 x 10(6) CD34(+) cells/kg. Posttransplant response rates were 30% >or=CR (10% stringent CR), 65% VGPR, and 5% PR. After median follow-up of 14.0/14.6 months, median time to progression and progression-free survival were both 19.8/27.9 months in non-ASCT/ASCT patients. Seven patients have died; 1-year survival rates were 82%/95% in non-ASCT/ASCT patients. The most common grade 3/4 toxicities were thrombocytopenia (20%), neutropenia (28%), and infection (9%). Peripheral neuropathy grade 2-4 was the most common nonhematopoietic side effect occurring 17 patients (38%), although it was typically reversible, and only 5 patients (11%) discontinued therapy as a result of it. Short-course VMP is highly effective and generally well tolerated, both as initial treatment in non-ASCT patients and induction prior to ASCT. VMP did not negatively affect stem cell collection. Longer follow-up and prospective phase III trials are required to validate these initial observations.

Topics: Adult; Aged; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Boronic Acids; Bortezomib; Chemotherapy, Adjuvant; Disease Progression; Drug Administration Schedule; Drug Monitoring; Drug Therapy, Combination; Female; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Peripheral Blood Stem Cell Transplantation; Prednisone; Pyrazines; Statistics as Topic; Transplantation, Autologous; Treatment Outcome

The phase 3 trial HOVON-50 was designed to evaluate the effect of thalidomide during induction treatment and as maintenance in patients with multiple myeloma who were transplant candidates. A total of 556 patients was randomly assigned to arm A: 3 cycles of vincristine, adriamycin, and dexamethasone, or to arm B: thalidomide 200 mg orally, days 1 to 28 plus adriamycin and dexamethasone. After induction therapy and stem cell mobilization, patients were to receive high-dose melphalan, 200 mg/m(2), followed by maintenance with alpha-interferon (arm A) or thalidomide 50 mg daily (arm B). Thalidomide significantly improved overall response rate as well as quality of the response before and after high dose melphalan. Best overall response rate on protocol was 88% and 79% (P = .005), at least very good partial remission 66% and 54% (P = .005), and complete remission 31% and 23% (P = .04), respectively, in favor of the thalidomide arm. Thalidomide also significantly improved event-free survival from median 22 months to 34 months (P < .001), and prolonged progression free from median 25 months to 34 months (P < .001). Median survival was longer in the thalidomide arm, 73 versus 60 months; however, this difference was not significant (P = .77). Patients randomized to thalidomide had strongly reduced survival after relapse. This trial was registered on www.controlled-trials.com as ISRCTN06413384.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Doxorubicin; Female; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Neoplasm Staging; Prognosis; Remission Induction; Survival Rate; Thalidomide; Treatment Outcome; Young Adult

Autologous stem cell transplantation (ASCT) is recommended for younger patients with newly diagnosed multiple myeloma. Achieving complete response (CR) or at least very good partial response (VGPR) is a major prognostic factor for survival with 20% to 30% of patients achieving CR after ASCT. Bortezomib has shown synergistic effects with melphalan and no prolonged hematologic toxicity. In this Intergroupe Francophone du Myélome (IFM) phase 2 study, 54 untreated patients were enrolled between July and December 2007 to receive bortezomib (1 mg/m(2) x 4) and melphalan (200 mg/m(2)) as conditioning regimen (Bor-HDM). Overall, 70% of patients achieved at least VGPR, including 17 patients with CR (32%) after ASCT. No toxic deaths were observed. Bortezomib did not increase hematologic toxicity. Only 1 grade 3 to 4 peripheral neuropathy was reported. A matched control analysis was conducted comparing our cohort with patients from the IFM 2005-01 trial (HDM alone). Patients were matched for response to induction therapy and type of induction: CR was higher in the Bor-HDM group (35% vs 11%; P = .001), regardless of induction therapy. These results suggest that Bor-HDM is a safe and promising conditioning regimen. Randomized studies are needed to assess whether this conditioning regimen is superior to HDM alone. This trial was registered at www.clinicaltrials.gov as NCT00642395.

Topics: Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Boronic Acids; Bortezomib; Case-Control Studies; Demography; Disease Progression; Dose-Response Relationship, Drug; Female; France; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Pyrazines; Stem Cell Transplantation; Survival Analysis; Transplantation Conditioning; Transplantation, Autologous

High-dose (200 mg/m(2), MEL200) and intermediate-dose melphalan (100 mg/m(2), MEL100) showed significant activity in myeloma. In a phase 3 study, 298 patients were randomly assigned to receive 2 autologous transplantations after conditioning with MEL200 or MEL100. Ninety-six of 149 (64%) completed MEL200 and 103 of 149 (69%) MEL100. Best response to MEL200 was: complete remission 22 of 149 (15%); partial remission 95 of 149 (64%), for an overall response rate of 79%. Best response to MEL100 was: complete remission 12 of 149 (8%); partial remission 95 of 149 (64%), for an overall response rate of 72%. Overall survival did not differ (P = .13); median progression-free survival (31.4 vs 26.2 months, P = .01), median time to progression (34.4 vs 27.0 months, P = .014) were longer in the MEL200. Treatment-related mortality was 3.1% in the MEL200 and 2.9% in the MEL100 group. Severe neutropenia and infections were marginally superior, whereas severe thrombocytopenia, mucositis, gastrointestinal adverse events, and the overall occurrence of at least 1 nonhematologic grade 3 or 4 adverse event were significantly higher in the MEL200 cohort. We conclude that MEL200 leads to longer remission duration and should be considered the standard conditioning regimen for autologous transplantation. This study was registered at www.clinicaltrials.gov as #NCT00950768.

Topics: Adult; Aged; Algorithms; Antigens, CD34; Antineoplastic Agents, Alkylating; Bone Marrow Transplantation; Combined Modality Therapy; Dose-Response Relationship, Drug; Female; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Myeloablative Agonists; Neoadjuvant Therapy; Transplantation Conditioning; Transplantation, Autologous

Bortezomib (VELCADE), thalidomide and dexamethasone (VTD), as well as melphalan, prednisolone, and thalidomide (MPT) therapy, are highly effective in patients with multiple myeloma. We evaluated the responses and survival times of 35 patients treated with VTD followed by MPT. All patients were newly diagnosed and non-transplantation candidates. Patients received six cycles of VTD, which were followed by eight cycles of MPT. Approximately 97% of patients exhibited early responses to therapy, as early as the second cycle of VTD. Thirty percent of the responses were high quality, which was defined as a complete response (CR), a near-CR or a very good partial response. High-risk patients were defined as patients with any of the following aberrations: del(13), t(4;14), or del(17p). The remaining patients were defined as standard risk. Eleven high-risk patients showed 100% response rates, including 91% high-quality responses. In contrast, 13 standard-risk patients exhibited 92% response rates, including 61% high-quality responses. The overall 2-year survival rates were 60% in high-risk patients and 85% in standard-risk patients, which was not significantly different. As a first-line therapy, VTD followed by MPT has the potential to provide high-quality responses with durable remission among elderly and high-risk patients (clinicaltrials.gov identifier: NCT00320476).

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Boronic Acids; Bortezomib; Dexamethasone; Female; Hematopoietic Stem Cell Transplantation; Humans; Korea; Male; Melphalan; Middle Aged; Multiple Myeloma; Neoadjuvant Therapy; Prednisolone; Pyrazines; Thalidomide; Treatment Outcome

PURPOSE To evaluate the effect of bortezomib as induction therapy before autologous transplantation, followed by lenalidomide as consolidation-maintenance in myeloma patients. PATIENTS AND METHODS Newly diagnosed patients age 65 to 75 years were eligible. Induction (bortezomib, doxorubicin, and dexamethasone [PAD]) included four 21-day cycles of bortezomib (1.3 mg/m(2) on days 1, 4, 8, and 11), pegylated liposomal doxorubicin (30 mg/m(2) on day 4), and dexamethasone (40 mg/d; cycle 1: days 1 to 4, 8 to 11, and 15 to 18; cycles 2 to 4: days 1 to 4). Autologous transplantation was tandem melphalan 100 mg/m(2) (MEL100) and stem-cell support. Consolidation included four 28-day cycles of lenalidomide (25 mg/d on days 1 to 21 every 28 days) plus prednisone (50 mg every other day), followed by maintenance with lenalidomide (LP-L; 10 mg/d on days 1 to 21) until relapse. Primary end points were safety (incidence of grade 3 to 4 adverse events [AEs]) and efficacy (response rate). Results A total of 102 patients were enrolled. In a per-protocol analysis, after PAD, 58% of patients had very good partial response (VGPR) or better, including 13% with complete response (CR); after MEL100, 82% of patients had at least VGPR and 38% had CR; and after LP-L, 86% of patients had at least VGPR and 66% had CR. After median follow-up time of 21 months, the 2-year progression-free survival rate was 69%, and the 2-year overall survival rate was 86%. During induction, treatment-related mortality was 3%; grade 3 to 4 AEs included thrombocytopenia (17%), neutropenia (10%), peripheral neuropathy (16%), and pneumonia (10%). During consolidation-maintenance, grade 3 to 4 AEs were neutropenia (16%), thrombocytopenia (6%), pneumonia (5%), and cutaneous rash (4%). CONCLUSION Bortezomib as induction before autologous transplantation, followed by lenalidomide as consolidation-maintenance, is an effective regimen.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Boronic Acids; Bortezomib; Chemotherapy, Adjuvant; Dexamethasone; Disease-Free Survival; Doxorubicin; Female; Humans; Italy; Kaplan-Meier Estimate; Lenalidomide; Male; Melphalan; Middle Aged; Multiple Myeloma; Neoadjuvant Therapy; Polyethylene Glycols; Prednisone; Protease Inhibitors; Pyrazines; Stem Cell Transplantation; Thalidomide; Time Factors; Transplantation, Autologous; Treatment Outcome

Defibrotide is a novel orally bioavailable polydisperse oligonucleotide with anti-thrombotic and anti-adhesive effects. In SCID/NOD mice, defibrotide showed activity in human myeloma xenografts. This phase I/II study was conducted to identify the most appropriate dose of defibrotide in combination with melphalan, prednisone and thalidomide in patients with relapsed and relapsed/refractory multiple myeloma, and to determine its safety and tolerability as part of this regimen.. This was a phase I/II, multicenter, dose-escalating, non-comparative, open label study. Oral melphalan was administered at a dose of 0.25 mg/kg on days 1-4, prednisone at a dose of 1.5 mg/kg also on days 1-4 and thalidomide at a dose of 50-100 mg/day continuously. Defibrotide was administered orally at three dose-levels: 2.4, 4.8 or 7.2 g on days 1-4 and 1.6, 3.2, or 4.8 g on days 5-35.. Twenty-four patients with relapsed/refractory multiple myeloma were enrolled. No dose-limiting toxicity was observed. In all patients, the complete response plus very good partial response rate was 9%, and the partial response rate was 43%. The 1-year progression-free survival and 1-year overall survival rates were 34% and 90%, respectively. The most frequent grade 3-4 adverse events included neutropenia, thrombocytopenia, anemia and fatigue. Deep vein thrombosis was reported in only one patient.. This combination of melphalan, prednisone and thalidomide together with defibrotide showed anti-tumor activity with a favorable tolerability. The maximum tolerated dose of defibrotide was identified as 7.2 g p.o. on days 1-4 followed by 4.8 g p.o. on days 5-35. Further trials are needed to confirm the role of this regimen and to evaluate the combination of defibrotide with new drugs.

Topics: Antineoplastic Combined Chemotherapy Protocols; Dose-Response Relationship, Drug; Humans; Melphalan; Multiple Myeloma; Polydeoxyribonucleotides; Prednisone; Salvage Therapy; Thalidomide; Treatment Outcome

With the aim to address the issue whether high-dose therapy (HDT) is required after new drugs combinations to improve outcome of elderly newly diagnosed multiple myeloma (MM) patients, we compared the toxicity and the outcome of ThaDD plus maintenance to those of ThaDD plus HDT-autologous stem cell transplantation (ASCT).. Sixty-two patients not eligible for HDT receiving six courses of ThaDD regimen plus maintenance with thalidomide were compared to 26 patients eligible for HDT treated with four courses of ThaDD followed by melphalan 100-200 mg/m(2) and ASCT. The two groups were matched for the main characteristics except for age favouring the HDT group.. Complete remission (CR) obtained with ThaDD plus maintenance was 24% whereas it was 57% after ThaDD plus HDT-ASCT (P = 0.0232). However, after a median follow-up of 36 months, median time to progression (TTP) and progression free survival (PFS) of the group of patients undergone HDT were not significantly different to those of patients receiving ThaDD plus maintenance (32 vs. 31 months: P = 0.962; 32 vs. 29 months: P = 0.726, respectively). Five-year overall survival (OS) was 49% in the first group and 46% in the latter one (P = 0.404). As expected, a significantly higher incidence of grade 3-4 neutropenia, thrombocytopenia, infections, mucositis and alopecia were observed in the ThaDD plus HDT group. Our results suggest that in elderly MM patients ThaDD plus HDT, albeit significantly increases CR rate, seems to be equivalent to ThaDD plus maintenance in terms of TTP, PFS and OS. These results challenge the requirement for HDT consolidation in this subset of patients.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Dexamethasone; Disease-Free Survival; Doxorubicin; Female; Humans; Male; Melphalan; Multiple Myeloma; Polyethylene Glycols; Prospective Studies; Stem Cell Transplantation; Survival Analysis; Thalidomide; Transplantation, Autologous; Treatment Outcome

The purpose of this study was to confirm overall survival (OS) and other clinical benefits with bortezomib, melphalan, and prednisone (VMP) versus melphalan and prednisone (MP) in the phase III VISTA (Velcade as Initial Standard Therapy in Multiple Myeloma) trial after prolonged follow-up, and evaluate the impact of subsequent therapies.. Previously untreated symptomatic patients with myeloma ineligible for high-dose therapy received up to nine 6-week cycles of VMP (n = 344) or MP (n = 338).. With a median follow-up of 36.7 months, there was a 35% reduced risk of death with VMP versus MP (hazard ratio, 0.653; P < .001); median OS was not reached with VMP versus 43 months with MP; 3-year OS rates were 68.5% versus 54.0%. Response rates to subsequent thalidomide- (41% v 53%) and lenalidomide-based therapies (59% v 52%) appeared similar after VMP or MP; response rates to subsequent bortezomib-based therapy were 47% versus 59%. Among patients treated with VMP (n = 178) and MP (n = 233), median survival from start of subsequent therapy was 30.2 and 21.9 months, respectively, and there was no difference in survival from salvage among patients who received subsequent bortezomib, thalidomide, or lenalidomide. Rates of adverse events were higher with VMP versus MP during cycles 1 to 4, but similar during cycles 5 to 9. With VMP, 79% of peripheral neuropathy events improved within a median of 1.9 months; 60% completely resolved within a median of 5.7 months.. VMP significantly prolongs OS versus MP after lengthy follow-up and extensive subsequent antimyeloma therapy. First-line bortezomib use does not induce more resistant relapse. VMP used upfront appears more beneficial than first treating with conventional agents and saving bortezomib- and other novel agent-based treatment until relapse.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Boronic Acids; Bortezomib; China; Europe; Female; Humans; Israel; Kaplan-Meier Estimate; Male; Melphalan; Multiple Myeloma; Prednisone; Pyrazines; Recurrence; Risk Assessment; Risk Factors; Time Factors; Treatment Outcome; United States

This multicenter, open-label, non-comparative phase II trial evaluated the safety and efficacy of salvage therapy with lenalidomide, melphalan, prednisone and thalidomide (RMPT) in patients with relapsed/refractory multiple myeloma (MM). Oral lenalidomide (10 mg/day) was administered on days 1-21, and oral melphalan (0.18 mg/kg) and oral prednisone (2 mg/kg) on days 1-4 of each 28-day cycle. Thalidomide was administered at 50 mg/day or 100 mg/day on days 1-28; six cycles were administered in total. Maintenance included lenalidomide 10 mg/day on days 1-21, until unacceptable adverse events or disease progression. Aspirin (100 mg/day) was given as thromboprophylaxis. A total of 44 patients with relapsed/refractory MM were enrolled and 75% achieved at least a partial response (PR), including 32% very good PR (VGPR) and 2% complete response (CR). The 1-year progression-free survival (PFS) was 51% and the 1-year overall survival (OS) from study entry was 72%. Grade 4 hematologic adverse events included neutropenia (18%), thrombocytopenia (7%) and anemia (2%). Grade 3 non-hematologic adverse events were infections (14%), neurological toxicity (4.5%) and fatigue (7%). No grade 3/4 thromboembolic events or peripheral neuropathy were reported. In conclusion, RMPT is an active salvage therapy with good efficacy and manageable side effects. This study represents the basis for larger phase III randomized trials.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Disease Progression; Drug Resistance, Neoplasm; Female; Humans; Lenalidomide; Male; Melphalan; Middle Aged; Multiple Myeloma; Neoplasm Recurrence, Local; Prednisone; Remission Induction; Salvage Therapy; Survival Rate; Thalidomide; Treatment Outcome

Immunoglobulin production by myeloma plasma cells depends on the unfolded protein response for protein production and folding. Recent studies have highlighted the importance of IRE1alpha and X box binding protein 1 (XBP1), key members of this pathway, in normal B-plasma cell development. We have determined the gene expression levels of IRE1alpha, XBP1, XBP1UNSPLICED (XBP1u), and XBP1SPLICED (XBP1s) in a series of patients with myeloma and correlated findings with clinical outcome. We show that IRE1alpha and XBP1 are highly expressed and that patients with low XBP1s/u ratios have a significantly better overall survival. XBP1s is an independent prognostic marker and can be used with beta2 microglobulin and t(4;14) to identify a group of patients with a poor outcome. Furthermore, we show the beneficial therapeutic effects of thalidomide in patients with low XBP1s/u ratios. This study highlights the importance of XBP1 in myeloma and its significance as an independent prognostic marker and as a predictor of thalidomide response.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Cyclophosphamide; Dexamethasone; Disease-Free Survival; DNA-Binding Proteins; Doxorubicin; Drug Resistance, Neoplasm; Female; Gene Expression; Gene Expression Profiling; Humans; Kaplan-Meier Estimate; Male; Melphalan; Middle Aged; Multiple Myeloma; Prednisone; Prognosis; Proportional Hazards Models; Regulatory Factor X Transcription Factors; Thalidomide; Transcription Factors; Vincristine; X-Box Binding Protein 1

In this double-blind, placebo-controlled study, 363 patients with untreated multiple myeloma were randomized to receive either melphalan-prednisone and thalidomide (MPT) or melphalan-prednisone and placebo (MP). The dose of melphalan was 0.25 mg/kg and prednisone was 100 mg given daily for 4 days every 6 weeks until plateau phase. The dose of thalidomide/placebo was escalated to 400 mg daily until plateau phase and thereafter reduced to 200 mg daily until progression. A total of 357 patients were analyzed. Partial response was 34% and 33%, and very good partial response or better was 23% and 7% in the MPT and MP arms, respectively (P < .001). There was no significant difference in progression-free or overall survival, with median survival being 29 months in the MPT arm and 32 months in the MP arm. Most quality of life outcomes improved equally in both arms, apart from constipation, which was markedly increased in the MPT arm. Constipation, neuropathy, nonneuropathy neurologic toxicity, and skin reactions were significantly more frequent in the MPT arm. The number of thromboembolic events was equal in the 2 treatment arms. In conclusion, MPT had a significant antimyeloma effect, but this did not translate into improved survival. This trial was registered at www.clinicaltrials.gov as #NCT00218855.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Double-Blind Method; Female; Humans; Male; Melphalan; Multiple Myeloma; Placebos; Prednisone; Remission Induction; Survival Rate; Thalidomide; Treatment Outcome

Multiple myeloma (MM) remains an incurable illness affecting nearly 20,000 individuals in the United States per year. High-dose melphalan (HDM) with autologous hematopoietic stem cell support (ASCT) is one of the mainstays of therapy for younger patients, but little advancement has been made with regards to conditioning regimens. We opted to combine (153)Samarium ethylenediaminetetramethylenephosphonate ((153)Sm-EDTMP), a radiopharmaceutical approved for the palliation of pain caused by metastatic bone lesions, with HDM and ASCT in a Phase II study. Individualized doses of (153)Sm were based on dosimetry and were calculated to deliver 40 Gy to the bone marrow. The therapeutic dose of (153)Sm-EDTMP was followed by HDM and ASCT. Forty-six patients with newly diagnosed or relapsed disease were treated. Study patients were compared to 102 patients contemporaneously treated with HDM and ASCT. Fifty-nine percent of study patients achieved a very good partial response (VGPR) or better. With a median follow-up of 7.1 years, the median overall survival and progression free survival (PFS) from study registration was 6.2 years (95% CI 4.6-7.5 years) and 1.5 years (1.1-2.2 years), respectively, which compared favorably to contemporaneously treated non-study patients. Addition of high-dose (153)Sm-EDTMP to melphalan conditioning appears to be safe, well tolerated, and worthy of further study in the context of novel agents and in the Phase III setting.

Topics: Adult; Aged; Bone Marrow; Disease-Free Survival; Female; Humans; Kaplan-Meier Estimate; Male; Melphalan; Middle Aged; Multiple Myeloma; Myeloablative Agonists; Organometallic Compounds; Organophosphorus Compounds; Pain; Peripheral Blood Stem Cell Transplantation; Radioisotopes; Radiopharmaceuticals; Radiotherapy Dosage; Salvage Therapy; Samarium; Tissue Distribution; Transplantation Conditioning

For several decades, the treatment of elderly patients with multiple myeloma (MM) has consisted of melphalan and prednisone (MP). The Dutch-Belgium Hemato-Oncology Cooperative Group (HOVON) investigated the efficacy of thalidomide added to MP (MP-T) in a randomized phase III trial. The objective of this study was to investigate the efficacy, toxicity, and effects on quality of life of MP-T.. A randomized phase III trial compared standard MP with MP-T (thalidomide 200 mg/d) in newly diagnosed patients with multiple myeloma older than age 65 years. Maintenance therapy with thalidomide 50 mg/d was administered to patients after MP-T until relapse. The primary end point was event-free survival (EFS); response rate, overall survival (OS), and progression-free survival (PFS) were secondary end points.. An intent-to-treat analysis of 333 evaluable patients showed significantly higher response rates in MP-T-treated patients compared with MP-treated patients a response (> or = partial response: 66% v 45%, respectively; P < .001; and > or = very good partial response [VGPR]: 27% v 10%, respectively; P < .001). EFS was 13 months with MP-T versus 9 months with MP (P < .001). OS was 40 months with MP-T versus 31 months with MP (P = .05).. This study demonstrates that thalidomide improves the response rate and VGPR in elderly patients with newly diagnosed MM. MP-T also results in a better EFS, PFS, and OS.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Female; Humans; Kaplan-Meier Estimate; Male; Melphalan; Multiple Myeloma; Multivariate Analysis; Neoplasm Staging; Neutropenia; Pain; Prednisone; Quality of Life; Regression Analysis; Thalidomide; Treatment Outcome

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Boronic Acids; Bortezomib; Dexamethasone; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Male; Melphalan; Multiple Myeloma; Pyrazines; Treatment Outcome

The phase 3 Velcade as Initial Standard Therapy in Multiple Myeloma: Assessment with Melphalan and Prednisone study in newly diagnosed multiple myeloma patients ineligible for high-dose therapy demonstrated that bortezomib-melphalan-prednisone (VMP) was superior to melphalan-prednisone across all efficacy end points. We assessed the prognostic impact of response on time-to-event parameters in the intent-to-treat population. Patients received nine 6-week cycles of treatment. Time to progression, time to next therapy, and treatment-free interval were associated with quality of response. When European Group for Blood and Marrow Transplantation criteria were used, complete response (CR) was associated with significantly longer time to progression (hazard ratio [HR] = 0.45, P = .004), time to next therapy (HR = 0.46, P = .0004), and treatment-free interval (HR = 0.38, P < .0001) versus partial response, but there was no significant difference in overall survival (HR = 0.87, P = .54); similar differences were seen with CR versus very good partial response by uniform criteria. Quality of response improved with prolonged VMP treatment, with 28% of CRs achieved during cycles 5-9. CR duration appeared similar among patients with "early" (cycles 1-4) and "late" CRs (cycles 5-9) and among patients receiving 9 versus < 9 cycles of bortezomib within VMP. These results highlight that CR is an important treatment goal and support prolonged VMP therapy to achieve maximal response. This study is registered at http://www.clinicaltrials.gov as NCT00111319.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Boronic Acids; Bortezomib; Female; Humans; Kaplan-Meier Estimate; Male; Melphalan; Middle Aged; Multiple Myeloma; Multivariate Analysis; Prednisone; Prognosis; Pyrazines; Remission Induction; Time Factors; Treatment Outcome

The aim of this study was to compare the long-term safety and efficacy of oral busulfan 12 mg/kg plus melphalan 140 mg/m(2) and melphalan 200 mg/m(2) as conditioning regimens for autologous stem cell transplantation in newly diagnosed patients with multiple myeloma in the GEM2000 study.. The first 225 patients received oral busulfan 12 mg/kg plus melphalan 140 mg/m(2); because of a high frequency of veno-occlusive disease, the protocol was amended and a further 542 patients received melphalan 200 mg/m(2).. Engraftment and hospitalization times were similar in both groups. Oral busulfan 12 mg/kg plus melphalan 140 mg/m(2) resulted in higher transplant-related mortality (8.4% versus 3.5%; P=0.002) due to the increased frequency of veno-occlusive disease in this group. Response rates were similar in both arms. With respective median follow-ups of 72 and 47 months, the median progression-free survival was significantly longer with busulfan plus melphalan (41 versus 31 months; P=0.009), although survival was similar to that in the melphalan 200 mg/m(2) group. However, access to novel agents as salvage therapy after relapse/progression was significantly lower for patients receiving busulfan plus melphalan (43%) than for those receiving melphalan 200 mg/m(2) (58%; P=0.01).. Conditioning with oral busulfan 12 mg/kg plus melphalan 140 mg/m(2) was associated with longer progression-free survival but equivalent survival to that achieved with melphalan 200 mg/m(2) but this should be counterbalanced against the higher frequency of veno-occlusive disease-related deaths. This latter fact together with the limited access to novel salvage therapies in patients conditioned with oral busulfan 12 mg/kg plus melphalan 140 mg/m(2) may explain the absence of a survival difference. Oral busulfan was used in the present study; use of the intravenous formulation may reduce toxicity and result in greater efficacy, and warrants further investigation in myeloma patients. (Clinicaltrials.gov identifier: NCT00560053).

Topics: Aged; Aged, 80 and over; Busulfan; Female; Follow-Up Studies; Humans; Male; Melphalan; Multiple Myeloma; Myeloablative Agonists; Retrospective Studies; Stem Cell Transplantation; Transplantation Conditioning; Transplantation, Autologous

An unexplained survival difference was observed in the Nordic Myeloma Study Group (NMSG) high-dose therapy trial 5/94 in Denmark compared with Sweden and Norway; however, this difference was eliminated in the subsequent NMSG trial 7/98. It was hypothesized that a detailed analysis of potential explanations would reveal important information for future designs of clinical trials for multiple myeloma (MM) patients in Denmark.. The analysis is based on 3 consecutive clinical trials coordinated by NMSG from 1990 to 2000: NMSG 4/90 including 583 patients, NMSG 5/94 including 274 patients and NMSG 7/98 including 414 patients with newly diagnosed MM. Event-free and total survival rates were calculated according to the Kaplan-Meier method, and survival comparisons were made by the log-rank test. The Cox proportional hazards regression model was used to estimate the prognostic importance of selected variables.. The analysis revealed no differences in disease stages, prognostic variables, or inclusion bias at diagnosis between the 3 consecutive NMSG trials. However, the number of initial treatment failures was low, and post-relapse survival was superior in Swedish patients as compared to Danish patients. These differences were explained by a defensive clinical practice in Denmark during 1994-1997 for patients with poor risk refractory or relapsed disease.. These initially observed differences were subsequently eliminated most likely as a consequence of international collaboration improving diagnosis, research infrastructure, clinical training, and education as planned within the European Myeloma Network (EMN).

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Denmark; Female; Hematopoietic Stem Cell Transplantation; Humans; Interferons; Male; Melphalan; Middle Aged; Multiple Myeloma; Norway; Prednisone; Prognosis; Proportional Hazards Models; Selection Bias; Sweden; Transplantation, Autologous

Bortezomib plus melphalan and prednisone (VMP) is significantly better than melphalan plus prednisone alone for elderly patients with untreated multiple myeloma; however, toxic effects are high. We investigated a novel and less intensive bortezomib-based regimen to maintain efficacy and to reduce toxic effects.. Between March, 2006, and October, 2008, 260 patients with untreated multiple myeloma, 65 years and older, from 63 Spanish centres, were randomly assigned to receive six cycles of VMP (n=130) or bortezomib plus thalidomide and prednisone (VTP; n=130) as induction therapy, consisting of one cycle of bortezomib twice per week for 6 weeks (1·3 mg/m² on days 1, 4, 8, 11, 22, 25, 29, and 32), plus either melphalan (9 mg/m² on days 1-4) or daily thalidomide (100 mg), and prednisone (60 mg/m² on days 1-4). The first cycle was followed by five cycles of bortezomib once per week for 5 weeks (1·3 mg/m² on days 1, 8, 15, and 22) plus the same doses of melphalan plus prednisone and thalidomide plus prednisone. 178 patients completed the six induction cycles and were randomly assigned to maintenance therapy with bortezomib plus prednisone (n=87) or bortezomib plus thalidomide (n=91), consisting of one conventional cycle of bortezomib for 3 weeks (1·3 mg/m² on days 1, 4, 8, and 11) every 3 months, plus either prednisone (50 mg every other day) or thalidomide (50 mg per day), for up to 3 years. Treatment codes were generated with a computerised random number generator, and neither participants nor study personnel were masked to treatment. The primary endpoint was response rate in induction and maintenance phases. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00443235.. In the induction phase, 105 (81%) patients in the VTP group and 104 (80%) in the VMP group achieved partial responses or better (p=0·9), including 36 (28%) and 26 (20%) complete remissions, respectively (p=0·2). Treatment with VTP resulted in more serious adverse events (40 [31%] vs 20 [15%], p=0·01) and discontinuations (22 [17%] vs 15 [12%], p=0·03) than did treatment with VMP. The most common toxicities (grade 3 or worse) were infections (one [1%] in the VTP group vs nine [7%] in the VMP group), cardiac events (11 [8%] vs 0), and peripheral neuropathy (nine [7%] vs 12 [9%]). After maintenance therapy, the complete remission rate was 42% (40 [44%] patients in complete remission in the bortezomib plus thalidomide group, 34 [39%] in the bortezomib plus prednisone group). No grade 3 or worse haematological toxicities were recorded during maintenance therapy; two (2%) patients in the bortezomib plus prednisone group and six (7%) in the bortezomib plus thalidomide group developed peripheral neuropathy.. Reduced-intensity induction with a bortezomib-based regimen, followed by maintenance, is a safe and effective treatment for elderly patients with multiple myeloma.. Pethema (Spanish Program for the Treatment of Hematologic Diseases).

Topics: Age Factors; Aged; Angiogenesis Inhibitors; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Boronic Acids; Bortezomib; Drug Administration Schedule; Female; Humans; Kaplan-Meier Estimate; Male; Melphalan; Multiple Myeloma; Prednisone; Proportional Hazards Models; Protease Inhibitors; Pyrazines; Risk Assessment; Risk Factors; Spain; Thalidomide; Time Factors; Treatment Outcome

We did a randomized phase I/II trial designed to evaluate the safety and efficacy of combining the proteasome inhibitor bortezomib with high-dose melphalan as the conditioning for high-dose therapy and autologous transplant for myeloma.. Enrolled patients were limited to those who did not achieve a very good partial remission (VGPR) following one or more induction regimens, and were randomized to receive a single escalating dose of bortezomib (1.0, 1.3, or 1.6 mg/m(2)) either 24 hours before or 24 hours after high-dose melphalan. Dose escalation was based on the escalation with overdose control (EWOC), a Bayesian statistical model. Bone marrow aspirates were collected before initiation of therapy and at the time of transplant to evaluate which sequence resulted in maximal plasma cell apoptosis, and response to transplant was assessed by the International Myeloma Working Group criteria.. Among 39 randomized patients, 20 received bortezomib after melphalan and 19 received bortezomib before melphalan. Toxicities and posttransplant hematopoietic recovery rates were similar between arms. The overall response rate for all patients was 87%, with 51% achieving a VGPR or better. Pharmacodynamic studies showed greater plasma cell apoptosis among patients who received bortezomib following melphalan.. The use of bortezomib in conjunction with high-dose melphalan is safe, with data suggesting improved efficacy. A single dose of bortezomib administered after high-dose melphalan is the recommended dose and schedule for future clinical investigation.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Boronic Acids; Bortezomib; Combined Modality Therapy; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Hematopoietic Stem Cell Transplantation; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Pyrazines; Transplantation Conditioning

In a recent phase 3 trial, bortezomib-melphalan-prednisone-thalidomide followed by maintenance treatment with bortezomib-thalidomide demonstrated superior efficacy compared with bortezomib-melphalan-prednisone. To decrease neurologic toxicities, the protocol was amended and patients in both arms received once-weekly instead of the initial twice-weekly bortezomib infusions: 372 patients received once-weekly and 139 twice-weekly bortezomib. In this post-hoc analysis we assessed the impact of the schedule change on clinical outcomes and safety. Long-term outcomes appeared similar: 3-year progression-free survival rate was 50% in the once-weekly and 47% in the twice-weekly group (P > .999), and 3-year overall survival rate was 88% and 89%, respectively (P = .54). The complete response rate was 30% in the once-weekly and 35% in the twice-weekly group (P = .27). Nonhematologic grade 3/4 adverse events were reported in 35% of once-weekly patients and 51% of twice-weekly patients (P = .003). The incidence of grade 3/4 peripheral neuropathy was 8% in the once-weekly and 28% in the twice-weekly group (P < .001); 5% of patients in the once-weekly and 15% in the twice-weekly group discontinued therapy because of peripheral neuropathy (P < .001). This improvement in safety did not appear to affect efficacy. This study is registered at http://www.clinicaltrials.gov as NCT01063179.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Boronic Acids; Bortezomib; Disease-Free Survival; Drug Administration Schedule; Female; Humans; Incidence; Kaplan-Meier Estimate; Male; Melphalan; Middle Aged; Multiple Myeloma; Neoplasm Staging; Peripheral Nervous System Diseases; Prednisone; Pyrazines; Thalidomide; Treatment Outcome

The combination of bortezomib-melphalan-prednisone (VMP) is a new standard of care for newly diagnosed multiple myeloma. This phase III study examined the efficacy of the four-drug combination of bortezomib-melphalan-prednisone-thalidomide (VMPT) followed by maintenance with bortezomib-thalidomide (VMPT-VT) compared with VMP treatment alone in untreated multiple myeloma patients who are ineligible for autologous stem-cell transplantation.. A total of 511 patients were randomly assigned to receive nine cycles of VMPT followed by continuous VT as maintenance, or nine cycles of VMP at the same doses with no additional therapy. The primary end point was progression-free survival.. The 3-year estimates of progression-free survival were 56% in patients receiving VMPT-VT and 41% in those receiving VMP (hazard ratio [HR], 0.67; 95% CI, 0.50 to 0.90; P = .008). At 3 years, the cumulative proportions of patients who did not go on to the next therapy were 72% with VMPT-VT and 60% with VMP (HR, 0.58; 95% CI, 0.50 to 0.90; P = .007). Complete response rates were 38% in the VMPT-VT group and 24% in the VMP group (P < .001). The 3-year overall survival was 89% with VMPT-VT and 87% with VMP (HR, 0.92; 95% CI, 0.53 to 1.60; P = .77). Grade 3 to 4 neutropenia (38% v 28%; P = .02), cardiologic events (10% v 5%; P = .04), and thromboembolic events (5% v 2%; P = .08) were more frequent among patients assigned to the VMPT-VT group than among those assigned to the VMP group; treatment-related deaths were 4% with VMPT-VT and 3% with VMP.. VMPT followed by VT as maintenance was superior to VMP alone in patients with multiple myeloma who are ineligible for autologous stem-cell transplantation.

Topics: Antineoplastic Combined Chemotherapy Protocols; Boronic Acids; Bortezomib; Disease-Free Survival; Humans; Kaplan-Meier Estimate; Melphalan; Multiple Myeloma; Prednisone; Proportional Hazards Models; Pyrazines; Thalidomide; Treatment Outcome

The objective of this investigation was to assess the effect of aprepitant on the pharmacokinetics of high-dose melphalan used as conditioning therapy before blood stem cell transplantation in multiple myeloma.. Aprepitant (125 mg) or placebo was administered 1 h before melphalan therapy (1 h infusion of 100 mg m⁻²). Eleven plasma samples were obtained over 8 h and melphalan was quantified using an LC/MS/MS method. Standard pharmacokinetic parameters were calculated and nonparametric testing was applied to assess the differences between aprepitant and placebo treatment.. Twenty patients received placebo and 10 patients aprepitant treatment. There were no differences observed for C(max) at the end of melphalan infusion (placebo 3431 ± 608 ng ml⁻¹ vs. aprepitant 3269 ± 660 ng ml⁻¹). In addition, AUC and terminal elimination half-life were not changed by aprepitant. Total clearance of melphalan was 304 ± 58 ml min⁻¹ m⁻² (placebo) which was not influenced by aprepitant (288 ± 78 ml min⁻¹ m⁻²).. The administration of the NK₁ receptor antagonist aprepitant 1 h before a high-dose chemotherapy does not influence the exposure and the elimination of melphalan. Therefore, oral administration of 125 mg aprepitant 1 h before melphalan infusion does not alter the disposition of intravenously administered melphalan.

Topics: Adult; Aged; Antiemetics; Antineoplastic Agents, Alkylating; Aprepitant; Double-Blind Method; Drug Administration Schedule; Drug Interactions; Female; Hematopoietic Stem Cell Transplantation; Humans; Infusions, Intravenous; Male; Melphalan; Middle Aged; Morpholines; Multiple Myeloma; Neurokinin-1 Receptor Antagonists; Prospective Studies; Transplantation Conditioning

A successful stem cell harvest is a prerequisite for peripheral blood SCT. We investigated the number of CD34(+) cells mobilized, the number of leukaphereses needed and the expenses of treatment for 28 patients with multiple myeloma randomly assigned to receive either G-CSF alone or G-CSF+EPO for stem cell mobilization after chemotherapy with ifosfamide, epirubicin and etoposide. All patients treated with G-CSF+EPO reached the threshold of 6 x 10(6) CD34(+) cells per kg body weight (kgbw), with a mean of 1.3 leukaphereses. On average 15.4 x 10(6) CD34(+) cells/kgbw were collected. In the G-CSF-alone group, the mean number of leukaphereses was 1.8, and 12.6 x 10(6) CD34(+) cells/kgbw were collected, and two patients failed the threshold. Overall costs per patient for mobilization and leukaphereses were 8339 euro (G-CSF+EPO) and 8842 euro (G-CSF). After transplantation, fewer blood transfusions (0.6 versus 1.3, P=0.05), fewer days on antibiotics (2.3 versus 6.1, P=0.02) and a shorter hospital stay (15.2 versus 17.8, P=0.06) were noted in the G-CSF+EPO group resulting in a 19.2% reduction of costs for each transplant (P=0.018). In summary, EPO improves the mobilization efficiency of G-CSF and so reduces costs of mobilization and SCT.

Topics: Aged; Antigens, CD34; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Epirubicin; Erythropoietin; Etoposide; Female; Filgrastim; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cell Transplantation; Humans; Ifosfamide; Leukapheresis; Leukocyte Count; Leukocytes; Male; Melphalan; Middle Aged; Multiple Myeloma; Neoplasm Staging; Prospective Studies; Recombinant Proteins

We compared thalidomide-dexamethasone (TD) with melphalan-prednisolone (MP) in 289 elderly patients with multiple myeloma (MM). Patients received either thalidomide 200 mg plus dexamethasone 40 mg, days 1 to 4 and 15 to 18 on even cycles and days 1 to 4 on odd cycles, during a 28-day cycle or to melphalan 0.25 mg/kg and prednisolone 2 mg/kg orally on days 1 to 4 during a 28- to 42-day cycle. Patients achieving stable disease or better were randomly assigned to maintenance therapy with either thalidomide 100 mg daily and 3 MU interferon alpha-2b thrice weekly or to 3 MU interferon alpha-2b thrice weekly only. TD resulted in a higher proportion of complete and very good remissions (26% vs 13%; P= .006) and overall responses (68% vs 50%; P= .002) compared with MP. Time to progression (21.2 vs 29.1 months; P= .2), and progression-free survival was similar (16.7 vs 20.7 months; P= .1), but overall survival was significantly shorter in the TD group (41.5 vs 49.4 months; P= .024). Toxicity was higher with TD, particularly in patients older than 75 years with poor performance status. The study was registered at ClinicalTrials.gov as NCT00205751.

Topics: Aged; Aged, 80 and over; Anti-Inflammatory Agents; Antineoplastic Agents, Alkylating; Dexamethasone; Disease-Free Survival; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Male; Melphalan; Middle Aged; Multiple Myeloma; Predictive Value of Tests; Prednisolone; Survival Rate; Thalidomide; Treatment Outcome

The underlying mechanism of high-dose therapy (HDT)-related oral mucositis (OM) may be partly mediated by alterations in the normal salivary composition. This study evaluated salivary antioxidant and immunological capacities observed in myeloma patients suffering from HDT-related OM, and assessed potential contribution of these factors to OM development. Twenty-five consecutive myeloma patients treated with melphalan 200 mg/m(2) followed by autologous SCT were enrolled. Patients underwent a daily assessment for OM, and salivary samples were collected on days -3 and +7 of transplantation and analyzed for secretory IgA and antioxidant capacity. The degree of mucosal damage was assessed by measuring the salivary carbonyl and albumin (Alb) levels. OM, reported in 96% of patients, appeared to be most severe on 8 day after transplantation (range: +2 to +14). Clinical mucositis was associated with significant reduction in salivary secretory IgA (54%; P=0.05), and antioxidant activity, measured by total antioxidant status (40%; P=0.0004), antioxidant capacity (ImAnOx) (23%; P=0.002) and uric acid level (51%; P=0.006). The increase found in salivary Alb (119%; P=0.024) and carbonyl (28%; P=0.047) levels, indicates mucosal and oxidative damage, respectively. These salivary changes might enhance mucositis development and symptoms. Therapeutic interventions, enhancing antioxidative and immunological activities need to be investigated.

Topics: Adult; Aged; Albumins; Antineoplastic Agents; Antioxidants; Female; Hematopoietic Stem Cell Transplantation; Humans; Immunoglobulin A; Male; Melphalan; Middle Aged; Mouth; Mucositis; Multiple Myeloma; Oxidative Stress; Saliva; Transplantation, Autologous

The appropriate induction therapy before and the role of maintenance therapy after auto-SCT for patients with multiple myeloma remain areas of active investigation. We conducted a study in 40 patients with bortezomib given sequentially pre-auto-SCT and as maintenance therapy post auto-SCT. Pre-transplant bortezomib was administered for two cycles followed by high-dose melphalan 200 mg/m(2) with auto-SCT of G-CSF-mobilized PBMCs. Post transplant bortezomib was administered weekly for 5 out of 6 weeks for six cycles. No adverse effects were observed on stem cell mobilization or engraftment. An overall response rate of 83% with a CR+very good partial remission (VGPR) of 50% was observed with this approach. Three-year Kaplan-Meier estimates of disease-free survival and overall survival (OS) were 38.2 and 63.1%, respectively. Bortezomib reduced CD8(+) cytotoxic T cell and CD56(+) natural killer cell PBL subsets and was clinically associated with high rates of viral reactivation to varicella zoster.

Topics: Adult; Aged; Boronic Acids; Bortezomib; Female; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Mobilization; Herpesvirus 3, Human; Humans; Killer Cells, Natural; Lymphocyte Subsets; Male; Melphalan; Middle Aged; Multiple Myeloma; Peripheral Blood Stem Cell Transplantation; Pyrazines; Remission Induction; Survival Analysis; T-Lymphocytes, Cytotoxic; Transplantation, Autologous; Treatment Outcome; Virus Activation

Conventional allogeneic hematopoietic stem cell transplantation (HSCT) for multiple myeloma is associated with high transplantation-related mortality (TRM). Nonmyeloablative allogeneic transplantation (NST) uses the well-known graft-versus-myeloma (GVM) effect to eradicate minimal residual disease. The Eastern Cooperative Oncology Group conducted a Phase II trial of autologous HSCT followed by NST to provide maximal tumor cytoreduction to allow for a subsequent GVM effect. Patients received melphalan 200 mg/m(2) with autologous HSCT, followed by fludarabine 30 mg/m(2) in 5 daily doses and cyclophosphamide 1 g/m(2) in 2 daily doses with matched sibling donor NST. Graft-versus-host disease (GVHD) prophylaxis included cyclosporine and corticosteroids. The primary endpoints were TRM, graft failure, acute GVHD, progression-free survival (PFS), and overall survival (OS). Thirty-two patients were enrolled into the study; 23 patients completed both transplantations (72%). Best responses post-NST were 7 (30%) complete remission (CR), 11 (48%) partial remission (PR), 2 (9%) no response, and 3 (13%) not evaluable. Acute grade III-IV GVHD was observed in 4 patients (17%), and chronic GVHD was seen in 13 patients (57%; 7 limited, 6 extensive). Chronic GVHD resulted in the following responses: 3 (23%) CR, 1 continuing CR, and 6 (46%) PR. Two patients (8.7%) had early TRM. With a median follow up of 4.6 years, the median PFS was 3.6 years, and the 2-year OS was 78%. Our findings indicate that autologous HSCT followed by NST is feasible, with a low early TRM in a cooperative group setting. The overall response rate was 78%, including 30% CR, similar to other reports for autologous HSCT-NST. Because a plateau in PFS or OS was not observed with this treatment approach even in patients achieving CR, we suggest that future studies use posttransplantation maintenance therapy.

Topics: Adult; Aged; Cyclophosphamide; Female; Graft vs Host Disease; Graft vs Tumor Effect; Hematopoietic Stem Cell Transplantation; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Premedication; Reoperation; Survival Analysis; Transplantation, Autologous; Transplantation, Homologous; Treatment Outcome; Vidarabine

This multicenter phase I/II study investigated the maximum tolerated dose (MTD), safety, and efficacy of low dose intravenous (IV) melphalan in combination with bortezomib for patients with relapsed multiple myeloma (MM). Patients received bortezomib 1.3 mg/m(2) on days 1, 4, 8, and 11 and escalating doses of IV melphalan (2.5-10.0 mg/m(2)) on day 2 of a 28-day cycle for a maximum of eight cycles. Dexamethasone 20 mg was added for progressive or stable disease. Fifty-three patients were enrolled. The MTD was defined at melphalan 7.5 mg/m(2) and bortezomib 1.3 mg/m(2). The overall response rate (ORR) was 68% (23% complete or near-complete responses [CR/nCR]) whilst at the MTD (n = 33) the ORR was 76% (34% CR/nCR). After median follow-up of 17 months, the median progression free survival was 10 months, rising to 12 months at the MTD (P < 0.05 vs. non-MTD regimens). The median overall survival was 28 months, but was not yet reached at the MTD. Grade 3/4 adverse events included thrombocytopenia (62%), neutropenia (57%), infection (21%), and neuropathy (15%). Bortezomib and low-dose IV melphalan combination therapy is a safe and highly effective regimen for patients with relapsed MM. These data suggest further investigation of this combination is warranted.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Boronic Acids; Bortezomib; Dexamethasone; Disease-Free Survival; Drug Administration Schedule; Female; Follow-Up Studies; Humans; Infusions, Intravenous; Kaplan-Meier Estimate; Male; Maximum Tolerated Dose; Melphalan; Middle Aged; Multiple Myeloma; Pyrazines; Recurrence; Statistics, Nonparametric; Thrombocytopenia

We evaluated the toxicity and outcome of a conditioning regimen comprising intravenous (iv) busulfan (BU) and melphalan (MEL) in 55 patients (median age, 61 years; range, 34-71) with multiple myeloma (MM) undergoing autologous stem-cell transplantation (ASCT). In 49 patients, this was the first ASCT. At transplant, 3 patients were in complete response (CR), 8 in near CR (nCR) and 30 in partial response (PR). The conditioning regimen comprised ivBU (3.2 mg/kg in a single daily dose, days -5 to -3) and MEL (140 mg/m(2), day -2). Mucositis was the most frequent non-hematopoietic toxicity (47 patients). No patient developed sinusoidal occlusive syndrome. Febrile events were observed in 46 patients and were the cause of death in two (3.6%) transplant-related deaths. With a median follow-up of 15 months, 27 patients achieved CR/nCR (11 CR) and 21 a PR. The one-year actuarial overall and progression-free survival rates are 96% and 87%, respectively. This ivBU-containing regimen is associated with an acceptable toxicity and a high-response rate.

Topics: Adult; Aged; Busulfan; Cell Movement; Cell Separation; Disease Progression; Female; Hematopoietic Stem Cells; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Neoplasm Staging; Stem Cell Transplantation; Survival Rate; Transplantation Conditioning; Transplantation, Homologous

We conducted a single-arm, multicentre phase 2 study to evaluate bortezomib, ascorbic acid and melphalan (BAM) for patients with newly diagnosed multiple myeloma (MM).. Induction consisted of up to eight 28-d cycles of bortezomib 1.0 mg/m(2) on days 1, 4, 8 and 11, plus oral ascorbic acid 1 g and oral melphalan 0.1 mg/kg on days 1-4, followed by maintenance bortezomib 1.3 mg/m(2) every 2 wk until progression.. Among 35 patients enrolled (median age 70 yr), responses occurred in 23/31 evaluable patients (74%) including five (16%) complete, three (10%) very good partial, six (19%) partial and nine (29%) minimal responses. Six patients (19%) had stable disease. Thus, disease control was achieved in 29 (94%) patients. Median times to first and best responses were 2 and 3 months (ranges 1-5 and 1-7), respectively. Median time to progression was 19 months and median overall survival has not been reached (range 2-23+ months). Grade 3 and 4 adverse events occurred in 17 and 5 patients, respectively; the most common were neutropenia, neuropathy and thrombocytopenia.. BAM is an efficacious, well-tolerated and steroid- and immunomodulatory drug (IMiD)-free frontline treatment regimen for MM patients.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Ascorbic Acid; Boronic Acids; Bortezomib; Humans; Melphalan; Middle Aged; Multiple Myeloma; Pyrazines; Survival Analysis; Treatment Outcome

A randomized controlled trial tested the hypothesis that aggressive initial therapy using high-dose cyclophosphamide (HiCy) and alpha(2)beta interferon (IFN) may be superior to standard combination alkylating agent regimens in the treatment of newly diagnosed myeloma.. This Eastern Cooperative Oncology Group trial evaluated 268 previously untreated patients with active multiple myeloma randomized to vincristine, carmustine, melphalan, cyclophosphamide, and prednisone (VBMCP) or VBMCP plus HiCy and recombinant IFN.. The overall objective response was 62% in the VBMCP regimen and 68% in the VBMCP + HiCy + IFN group. The near complete response and complete response rates were 8.1% and 8.9%, respectively. Progression-free survival was 22.1 and 25.3 months, respectively. The median overall survival was 37.1 months for patients treated with VBMCP and 41.3 months for those treated with VBMCP + HiCy + IFN (P = .38). The 5-year overall survival rates were not significantly different between the 2 arms: 26.4% and 33%, respectively. Lethal toxicities occurred in 15 patients, including 10 from infection, but there was no significant difference in lethal toxicities between the 2 regimens.. The study showed no significant benefit with the addition of HiCy and IFN to VBMCP.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carmustine; Cyclophosphamide; Disease-Free Survival; Female; Humans; Interferon Type I; Male; Melphalan; Middle Aged; Multiple Myeloma; Prednisone; Recombinant Proteins; Survival Rate; Vincristine

Thalidomide is effective in the treatment of newly diagnosed and relapsed/refractory multiple myeloma (MM). However, the role of thalidomide in the post-autologous stem cell transplantation (ASCT) context remains unclear. This study assessed whether the addition of thalidomide consolidation following ASCT would improve the durability of responses achieved and overall survival.. Between January 2002 and March 2005, 269 patients with newly diagnosed MM who achieved disease stabilization or better with conventional induction chemotherapy received a single high-dose melphalan conditioned ASCT. Post-ASCT, 129 patients were randomly assigned to receive indefinite prednisolone maintenance therapy (control group) and 114 to receive the same in addition to 12 months of thalidomide consolidation (thalidomide group). The primary study end points were progression-free survival (PFS) and overall survival (OS). The secondary end point was tolerability.. After a median follow-up of 3 years, the postrandomization 3-year PFS rates were 42% and 23% (P < .001; hazard ratio [HR], 0.5; 95% CI, 0.35 to 0.71) and the OS rates were 86% and 75% (P = .004; HR, 0.41; 95% CI, 0.22 to 0.76) in the thalidomide and control groups, respectively. There was no difference in survival between groups 12 months after disease progression (79% v 77%; P = .237). Neurological toxicities were more common in the thalidomide arm but there were no differences between arms for thromboembolic events.. Consolidation therapy with 12 months of thalidomide combined with prednisolone prolongs survival when used after a single high-dose therapy supported ASCT in patients with newly diagnosed MM. Furthermore, thalidomide consolidation therapy did not adversely impact on survival in the subsequent salvage setting.

Topics: Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Female; Glucocorticoids; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Prednisolone; Stem Cell Transplantation; Survival Analysis; Thalidomide; Transplantation, Autologous

Initial analysis of the combination melphalan, prednisone, plus lenalidomide (MPR) showed significant antimyeloma activity in patients with untreated multiple myeloma, with neutropenia and thrombocytopenia as the most frequent side effects. This updated analysis reassessed the kinetics of neutropenia and thrombocytopenia as well as the safety and efficacy of MPR.. A total of 21 patients with newly diagnosed myeloma received melphalan 0.18 mg/kg on days 1-4, prednisone 2 mg/kg on days 1-4, and lenalidomide 10 mg daily on days 1-21 for nine 28-day cycles, followed by maintenance therapy with lenalidomide 10 mg daily on days 1-21.. Grade 3/4 neutropenia occurred in 52% of the patients, and granulocyte colonystimulating factor was administered in 43%. The mean neutrophil counts at the start of each MPR cycle, during nadir, and after 6 months of maintenance were 2.69 x 109/L, 1.43 x 109/L, and 2.11 x 109/L, respectively. Grade 3/4 thrombocytopenia occurred in 24% of the patients. Platelet transfusions were required by 1 patient (5%) with a platelet count of 16 x 109/L; however, no thrombocytopenia-associated bleeding was reported. The mean platelet counts at the start of each cycle, during nadir, and after 6 months of maintenance were 174 x 109/L, 121 x 109/L, and 158 x 109/L, respectively. Median follow-up was 29.6 months, median progression-free survival was 28.5 months, and 2-year overall survival was 91%.. MPR is a promising regimen with manageable hematologic toxicity.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Dose-Response Relationship, Drug; Granulocyte Colony-Stimulating Factor; Humans; Lenalidomide; Melphalan; Middle Aged; Multiple Myeloma; Neutropenia; Prednisone; Thalidomide; Thrombocytopenia

Until recently, melphalan and prednisone were the standards of care in elderly patients with multiple myeloma. The addition of thalidomide to this combination demonstrated a survival benefit for patients age 65 to 75 years. This randomized, placebo-controlled, phase III trial investigated the efficacy of melphalan and prednisone plus thalidomide in patients older than 75 years with newly diagnosed myeloma.. Between April 2002 and December 2006, 232 previously untreated patients with myeloma, age 75 years or older, were enrolled and 229 were randomly assigned to treatment. All patients received melphalan (0.2 mg/kg/d) plus prednisone (2 mg/kg/d) for 12 courses (day 1 to 4) every 6 weeks. Patients were randomly assigned to receive 100 mg/d of oral thalidomide (n = 113) or placebo (n = 116), continuously for 72 weeks. The primary end point was overall survival.. After a median follow-up of 47.5 months, overall survival was significantly longer in patients who received melphalan and prednisone plus thalidomide compared with those who received melphalan and prednisone plus placebo (median, 44.0 v 29.1 months; P = .028). Progression-free survival was significantly prolonged in the melphalan and prednisone plus thalidomide group (median, 24.1 v 18.5 months; P = .001). Two adverse events were significantly increased in the melphalan and prednisone plus thalidomide group: grade 2 to 4 peripheral neuropathy (20% v 5% in the melphalan and prednisone plus placebo group; P < .001) and grade 3 to 4 neutropenia (23% v 9%; P = .003).. This trial confirms the superiority of the combination melphalan and prednisone plus thalidomide over melphalan and prednisone alone for prolonging survival in very elderly patients with newly diagnosed myeloma. Toxicity was acceptable.

Topics: Age Factors; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Cause of Death; Disease-Free Survival; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Follow-Up Studies; Geriatric Assessment; Humans; Kaplan-Meier Estimate; Male; Maximum Tolerated Dose; Melphalan; Multiple Myeloma; Neoplasm Staging; Prednisone; Probability; Proportional Hazards Models; Risk Assessment; Statistics, Nonparametric; Survival Analysis; Thalidomide; Treatment Outcome

Previously, we showed that adoptive transfer of in vivo vaccine-primed and ex vivo (anti-CD3/anti-CD28) costimulated autologous T cells (ex-T) at day +12 after transplant increased CD4 and CD8 T-cell counts at day +42 and augmented vaccine-specific immune responses in patients with myeloma. Here, we investigated the safety and kinetics of T-cell recovery after infusing ex-T at day +2 after transplant.. In this phase I/II two-arm clinical trial, 50 patients with myeloma received autografts after high-dose melphalan followed by infusions of ex-T at day +2 after transplant. Patients also received pretransplant and posttransplant immunizations using a pneumococcal conjugate vaccine only (arm B; n = 24) or the pneumococcal conjugate vaccine plus an HLA-A2-restricted microltipeptide vaccine for HLA-A2(+) patients (arm A; n = 26).. The mean number of T cells infused was 4.26 x 10(10) (range, 1.59-5.0). At day 14 after transplant, the median CD3, CD4, and CD8 counts were 4,198, 1,545, and 2,858 cells/microL, respectively. Interleukin (IL)-6 and IL-15 levels increased early after transplant and IL-15 levels correlated significantly to day 14 T-cell counts. Robust vaccine-specific B- and T-cell responses were generated. T-cell infusions were well tolerated with no effect on hematopoietic recovery. Eight patients (16%) developed a T-cell "engraftment syndrome" characterized by diarrhea and fever that was clinically and histopathologically indistinguishable from grade 1 to 3 acute graft-versus-host disease (GVHD) of the gastrointestinal tract (seven patients) and/or grade 1 to 2 cutaneous GVHD (four patients).. Adoptive T-cell transfers achieve robust T-cell recovery early after transplant and induce moderate-to-severe autologous GVHD in a subset of patients.

Topics: Adult; Aged; Algorithms; Cells, Cultured; Female; Graft vs Host Disease; HLA-A2 Antigen; Humans; Immunotherapy, Adoptive; Lymphocyte Activation; Male; Melphalan; Middle Aged; Multiple Myeloma; Myeloablative Agonists; Recovery of Function; Syndrome; T-Lymphocytes; Transplantation, Autologous

PURPOSE Thalidomide-dexamethasone (THAL-DEX) is standard induction therapy for multiple myeloma (MM). Tandem melphalan-based transplantations have yielded superior results to single transplantations. Phase II trial S0204 was designed to improve survival results reported for the predecessor, phase III trial S9321 by 50%. PATIENTS AND METHODS Newly diagnosed patients with MM were eligible for S0204 with THAL-DEX induction, tandem melphalan-based tandem transplantation, and THAL-prednisone maintenance. Results Of 143 eligible patients, 142 started induction, 73% completed first transplantation, 58% completed second transplantation, and 56% started maintenance. The quantity of stem cells required for two transplantations was reached in 88% of 111 patients undergoing collection, 74% of whom completed both transplantations. Partial response, very good partial remission, and complete response were documented after 12 months of maintenance therapy in 87%, 72%, and 22% of patients, respectively. During a median follow-up time of 37 months, 4-year estimates of event-free and overall survival were 50% and 64%, respectively. Survival outcomes were superior for International Staging System (ISS) stage 1 disease, when lactate dehydrogenase (LDH) levels were normal and a second transplantation was applied in a timely fashion. CONCLUSION Both overall survival (P = .0002) and event-free survival (P < .0001) were significantly improved with S0204 compared with S9321 when 121 and 363 patients, respectively, were matched on ISS stage and LDH.

Topics: Dexamethasone; Disease-Free Survival; Drug Administration Schedule; Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Multiple Myeloma; Prednisone; Quality of Life; Thalidomide; Time Factors; Transplantation, Autologous

PURPOSE To assess bortezomib plus melphalan and prednisone (VMP) and melphalan and prednisone (MP) in previously untreated patients with multiple myeloma (MM) with renal impairment enrolled on the phase III VISTA study, and to evaluate renal impairment reversibility. PATIENTS AND METHODS Patients received nine 6-week cycles of VMP (bortezomib 1.3 mg/m(2), melphalan 9 mg/m(2), prednisone 60 mg/m(2)) or MP. Patients with serum creatinine higher than 2 mg/dL were excluded. Results In the VMP/MP arms, 6%/4%, 27%/30%, and 67%/66% of patients had baseline glomerular filtration rate (GFR) of < or = 30, 31 to 50, and higher than 50 mL/min, respectively. Response rates were higher and time to progression (TTP) and overall survival (OS) longer with VMP versus MP across renal cohorts. Response rates with VMP and TTP in both arms did not appear significantly different between patients with GFR < or = 50 or higher than 50 mL/min; OS appeared somewhat longer in patients with normal renal function in both arms. Renal impairment reversal (baseline GFR < 50 improving to > 60 mL/min) was seen in 49 (44%) of 111 patients receiving VMP versus 40 (34%) of 116 patients receiving MP. By multivariate analysis, younger age (< 75 years; P = .006) and less severe impairment (GFR > or = 30 mL/min; P = .027) were associated with higher reversal rates. In addition, treatment with VMP approached significance (P = .07). In both arms, rates of grade 4 and 5 adverse events (AEs) and serious AEs appeared higher in patients with renal impairment; with VMP, rates of discontinuations/bortezomib dose reductions due to AEs did not appear affected. CONCLUSION VMP is a feasible, active, and well-tolerated treatment option for previously untreated patients with MM with moderate renal impairment, resulting in 44% renal impairment reversal.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Boronic Acids; Bortezomib; Cohort Studies; Disease Progression; Female; Humans; Kaplan-Meier Estimate; Kidney Diseases; Male; Melphalan; Multiple Myeloma; Multivariate Analysis; Prednisone; Prognosis; Pyrazines; Treatment Outcome

Recent experience with thalidomide maintenance after high-dose chemotherapy with autologous stem cell support has demonstrated improvement in progression-free survival (PFS) and overall survival (OS). We further explored the tolerability and efficacy of lower doses of maintenance thalidomide in this single-institution study.. Thirty-eight patients with myeloma were enrolled and treated with melphalan 200 mg/m(2) followed by autologous stem cell transplantation. Thalidomide 50 mg per day was started on day > or = 60 after recovery of blood counts and was escalated to a maximum dose of 200 mg per day. Responses were assessed at 2 months, 1 year, and 2 years after transplantation.. Of the 38 enrolled patients, 7 patients never received thalidomide. Among 31 patients receiving thalidomide, complete or very good partial responses were observed in 65% and 42% of patients at 1 and 2 years, respectively. Tolerability was a major issue, with only 17 patients completing 1 year of thalidomide. The goal of dosing 200 mg per day was achieved in just 17 of 31 patients, and the median tolerated thalidomide dose was 100 mg per day. Sensory neuropathy was the primary reason for dose modification and discontinuation. No thromboembolic events were observed. The median PFS was 20.8 months, and the median OS was > 60 months.. Thalidomide maintenance at a goal dose of 200 mg per day was not feasible in this population, with our data suggesting that 100 mg per day is a more reasonable maintenance dose.

Topics: Adolescent; Adult; Aged; Disease-Free Survival; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Male; Melphalan; Middle Aged; Multiple Myeloma; Myeloablative Agonists; Stem Cell Transplantation; Survival Rate; Thalidomide; Transplantation, Autologous

Quality and quantity of mobilized peripheral blood stem cells determine the safety of tandem autologous transplants in myeloma. Using the same mobilization chemotherapy with DT-PACE in two consecutive protocols, robustness of stem cell collection and rapidity of engraftment after transplantation were assessed. We employed either twice a day filgrastim versus two doses of pegfilgrastim. Advantages of pegfilgrastim were: (i) a higher percentage of patients collected 15x10(6)/kg in the first three days (p<0.001); (ii) the median number of CD34 cells/kg collected on day 1 was higher (p=0.004); (iii) the median number of growth factor injections was 2 versus 26 (p<0.0001); (iv) post-transplantation neutrophil recovery was faster after first and second transplant (p<0.001) and (v) platelet recovery was faster after first transplant (when less stem cells were infused) (p=0.01). Pegfilgrastim may be considered the standard of care for stem cell mobilization.

Topics: Adult; Aged; Antineoplastic Agents, Alkylating; Combined Modality Therapy; Dose-Response Relationship, Drug; Filgrastim; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cell Transplantation; Hemoglobins; Humans; Melphalan; Middle Aged; Multiple Myeloma; Platelet Count; Polyethylene Glycols; Recombinant Proteins

The standard treatment for patients with multiple myeloma who are not candidates for high-dose therapy is melphalan and prednisone. This phase 3 study compared the use of melphalan and prednisone with or without bortezomib in previously untreated patients with multiple myeloma who were ineligible for high-dose therapy.. We randomly assigned 682 patients to receive nine 6-week cycles of melphalan (at a dose of 9 mg per square meter of body-surface area) and prednisone (at a dose of 60 mg per square meter) on days 1 to 4, either alone or with bortezomib (at a dose of 1.3 mg per square meter) on days 1, 4, 8, 11, 22, 25, 29, and 32 during cycles 1 to 4 and on days 1, 8, 22, and 29 during cycles 5 to 9. The primary end point was the time to disease progression.. The time to progression among patients receiving bortezomib plus melphalan-prednisone (bortezomib group) was 24.0 months, as compared with 16.6 months among those receiving melphalan-prednisone alone (control group) (hazard ratio for the bortezomib group, 0.48; P<0.001). The proportions of patients with a partial response or better were 71% in the bortezomib group and 35% in the control group; complete-response rates were 30% and 4%, respectively (P<0.001). The median duration of the response was 19.9 months in the bortezomib group and 13.1 months in the control group. The hazard ratio for overall survival was 0.61 for the bortezomib group (P=0.008). Adverse events were consistent with established profiles of toxic events associated with bortezomib and melphalan-prednisone. Grade 3 events occurred in a higher proportion of patients in the bortezomib group than in the control group (53% vs. 44%, P=0.02), but there were no significant differences in grade 4 events (28% and 27%, respectively) or treatment-related deaths (1% and 2%).. Bortezomib plus melphalan-prednisone was superior to melphalan-prednisone alone in patients with newly diagnosed myeloma who were ineligible for high-dose therapy. (ClinicalTrials.gov number, NCT00111319.)

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Boronic Acids; Bortezomib; Disease Progression; Female; Follow-Up Studies; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Prednisone; Pyrazines; Survival Analysis; Time Factors; Treatment Outcome

This phase 2 study aimed to determine the efficacy and safety of the combination of bortezomib, melphalan, dexamethasone and intermittent thalidomide (VMDT) and its effect on bone remodeling and angiogenesis in relapsed/refractory myeloma. Bortezomib (1.0 mg/m(2)) was given on days 1, 4, 8, 11, oral melphalan (0.15 mg/kg) on days 1-4, whereas thalidomide (100 mg per day) and dexamethasone (12 mg/m(2)) were administered on days 1-4 and 17-20 of a 28-day cycle, for four cycles. Patients without disease progression continued for up to eight cycles. VMDT effect on bone remodeling was evaluated by measuring osteoclast regulators (soluble receptor activator of nuclear factor-kappa B ligand/osteoprotegerin ratio, osteopontin, macrophage inflammatory protein-1alpha), dickkopf-1 protein, bone resorption and formation markers, whereas its effect on angiogenesis was assessed by measuring serum vascular endothelial growth factor, angiogenin, angiopoietin-2 and basic fibroblast growth factor, after four cycles and at the study end. A total of 62 patients were enrolled. The overall response rate was 66%: CR 13%, vgPR 27% and PR 26%. Median time to response was 35 days and median time to progression was 9.3 months. Common adverse events included cytopenias, peripheral neuropathy and infections. No patient experienced deep-vein thrombosis. VMDT reduced angiogenic cytokines, osteoclast regulators, dickkopf-1 and bone resorption. We conclude that VMDT with intermittent thalidomide is an active and well-tolerated regimen for relapsed/refractory myeloma, affecting abnormal bone remodeling and angiogenesis.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Alkylating; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Biomarkers; Bone and Bones; Bone Remodeling; Boronic Acids; Bortezomib; Cytokines; Dexamethasone; Female; Humans; Immunosuppressive Agents; Male; Melphalan; Middle Aged; Multiple Myeloma; Neovascularization, Physiologic; Pyrazines; Recurrence; Survival Rate; Thalidomide

Recent studies have demonstrated that novel therapeutic combinations are challenging melphalan and prednisone (MP) as the standard of care in elderly patients with multiple myeloma. Combination regimens containing bortezomib or thalidomide can achieve response rates, especially complete response rates, which are superior to those seen with standard MP alone, and offer new possibilities for this patient population.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Boronic Acids; Bortezomib; Humans; Melphalan; Multiple Myeloma; Prednisone; Pyrazines; Thalidomide; Treatment Outcome

Arsenic trioxide (ATO) is synergistic with ascorbic acid (AA) and melphalan against myeloma both in vitro and in vivo. The aim of this randomized phase II trial was to determine the safety and efficacy of a combination of ATO, melphalan, and AA as preparative regimen in 48 patients undergoing autologous hematopoietic stem cell transplantation (ASCT) for multiple myeloma (MM). Forty-eight patients received melphalan 200 mg/m2 i.v. over 2 days and AA 1000 mg i.v. over 7 days in 3 treatment arms: no ATO (arm 1), ATO 0.15 mg/kg i.v. x 7 days (arm 2), and ATO 0.25 mg/kg i.v. x 7 days (arm 3). No dose-limiting toxicity, engraftment failure, or nonrelapse mortality (NRM) was seen in the first 100 days post-ASCT. Complete responses (CR) were seen in 12 of 48 patients (25%), with an overall response rate (ORR = CR + PR) of 85%. Median progression-free survival (PFS) was 25 months; median overall survival (OS) has not yet been reached. There was no significant difference in CR, PFS, or OS among the 3 treatment arms, and no adverse effect of ATO on melphalan pharmacokinetics. Addition of ATO + AA to high-dose melphalan is safe and well tolerated as a preparative regimen for MM.

Topics: Adult; Aged; Antineoplastic Agents; Antioxidants; Arsenic Trioxide; Arsenicals; Ascorbic Acid; Disease-Free Survival; Female; Hematopoietic Stem Cell Transplantation; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Myeloablative Agonists; Oxides; Survival Rate; Time Factors; Transplantation Conditioning; Transplantation, Autologous

This study examines the response to dexamethasone-doxorubicin-vincristine (DAV) therapy, followed by conditioning regimen and autologous stem cells transplantation (ASCT) in patients with multiple myeloma in relation with the presence of polymorphisms in genes involved in drug metabolism (GSTP1) and DNA synthesis (TYMS). GSTP1 G313G genotype (OR=5.49; 95% CI, 1.3-22.5, p=0.02) and TYMS A227A genotype (OR=3.41; 95% CI, 1.3-8.9, p=0.01) resulted significantly associated with a poor response following chemotherapy and the risk increased for the combined genotype (OR=13.54; 95% CI, 2.0-91.3, p=0.01). TYMS T157T genotype was significantly associated with a poor response after ASCT (OR=4.60; 95% CI, 1.2-16.9, p=0.02). Pre-therapeutic individual determination of the GSTP1 and TYMS polymorphisms could help in choosing the most appropriate protocol.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Dacarbazine; Female; Glutathione S-Transferase pi; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Nimustine; Polymorphism, Single Nucleotide; Stem Cell Transplantation; Survival Analysis; Thymidylate Synthase; Transplantation Conditioning; Transplantation, Autologous; Treatment Outcome; Vincristine

Today, intensive therapy that includes high-dose melphalan with autologous stem cell transplantation (ASCT) is considered standard therapy in younger patients with newly diagnosed myeloma. When the current trial was initiated, combined vincristine, doxorubicin, and dexamethasone (VAD) was the most commonly used induction therapy before ASCT and yielded rapid major responses without interfering with stem cell harvest. However, the administration of VAD demands a central venous access, and well-described toxicities are associated with the therapy. This randomized trial, which was initiated in 2001 by the Nordic Myeloma Study Group, was an attempt to bring a larger portion of patients to ASCT more quickly.. Patients were randomized to receive either 3 cycles of VAD or 2 courses of cyclophosphamide plus dexamethasone (Cy-Dex) (cyclophosphamide at a dose of 1000 mg/m(2) on Day 1 and dexamethasone at a dose of 40 mg per day on Days 1-4 and 9-12, repeated on Day 22) as initial therapy followed by stem cell mobilization, harvest, and finally ASCT.. No significant difference was observed in the proportion of patients undergoing ASCT (VAD [86%] vs Cy-Dex [87%]). During the first 4 months after the initiation of therapy, the mortality rates were 5.8% for VAD and 1.9% for Cy-Dex (P = .08). The response rates after ASCT were comparable (partial response or better: VAD: 80% vs Cy-Dex: 81%). In both groups, the median event-free survival was 29 months, and the overall survival rate at 3 years was 75%.. The current results indicated that Cy-Dex before ASCT has efficacy comparable to that of VAD. It also demonstrated that a short course of alkylator therapy using cyclophosphamide does not affect stem cell harvest or transplantation.

Topics: Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Cyclophosphamide; Dexamethasone; Doxorubicin; Drug Administration Schedule; Female; Hematopoietic Stem Cell Transplantation; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Survival Rate; Vincristine

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Busulfan; Combined Modality Therapy; Cyclophosphamide; Dexamethasone; Disease-Free Survival; Doxorubicin; Humans; Melphalan; Middle Aged; Multiple Myeloma; Stem Cell Transplantation; Transplantation, Autologous; Treatment Outcome; Vincristine

New treatment options offering enhanced activity in elderly, newly diagnosed patients with multiple myeloma are required. One strategy is to combine melphalan and prednisone with novel agents. We previously reported an 89% response rate, including 32% complete responses and 11% near complete responses, in our phase 1/2 study of bortezomib plus melphalan and prednisone (VMP) in 60 newly diagnosed multiple myeloma patients with a median age of 75 years. Here, we report updated time-to-events data and the impact of poor prognosis factors on outcome.. Updated analyses of time to biochemical progression and overall survival with VMP were conducted, and compared with those of historical controls treated with melphalan and prednisone. A univariate analysis was performed to evaluate the influence of known prognostic factors on the time to progression.. After a median follow-up of 26 months, the median time to progression with VMP was 27.2 months, compared with 20.0 months with melphalan plus prednisone. The median overall survival with VMP was not reached versus 26 months with melphalan and prednisone; the survival rate at 38 months was 85% versus 38%, respectively. Time to progression was not significantly affected by elevated beta(2)-microglobulin or lactate dehydrogenase levels, advanced age, or cytogenetic abnormalities, but was shorter in patients with albumin < 3 g/dL, Karnofsky performance status < or =70%, bone marrow plasma cell infiltration > or =40%, and, particularly, high plasma cell proliferative activity (> or = 2.5% S-phase cells).. VMP is highly active and well tolerated in elderly patients with newly diagnosed multiple myeloma, with 85% of patients alive at 3 years. Moreover, VMP may overcome the poor prognostic impact of various factors, particularly cytogenetic abnormalities.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Boronic Acids; Bortezomib; Disease Progression; Disease-Free Survival; Female; Follow-Up Studies; Gastrointestinal Diseases; Hematologic Diseases; Humans; Karnofsky Performance Status; Male; Melphalan; Multiple Myeloma; Prednisone; Prognosis; Pyrazines; Survival Analysis

Bortezomib synergizes with melphalan in preclinical and early clinical studies. Updated data from our phase 1/2 study assessing the safety and efficacy of bortezomib plus melphalan in relapsed/refractory multiple myeloma (MM) are presented. Bortezomib (0.7, 1.0, or 1.3 mg/m(2)) on days 1, 4, 8, and 11 and oral melphalan (0.025-0.25 mg/kg) on days 1-4 of a 28-day cycle were administered. Hematologic toxicities defined the maximum tolerated dose as bortezomib 1.0 mg/m(2) and melphalan 0.10 mg/kg. Because dose-limiting toxicities were attributed to the more myelosuppressive melphalan, cohorts 9 and 10 with higher bortezomib (1.3 mg/m(2)) and lower melphalan (0.025 and 0.10 mg/kg) doses were added. Responses occurred in 32/46 (70%) evaluable patients: two complete (4%), five near-complete (11%), 16 partial (35%), and nine minimal (20%). Complete and near-complete responses were observed only with higher bortezomib doses. Response rates were similar in patients with prior melphalan or bortezomib. Median progression-free survival was 9 months (range, 1-24), and overall survival was 32 months (range, 1-54). The most common grade 3/4 hematologic adverse events (AEs) were neutropenia (31%/0%), thrombocytopenia (25%/2%), and anemia (13%/0%). Grade 4 tumor lysis syndrome was reported in one patient. Fewer grade 3/4 hematologic AEs were reported in cohorts 9 and 10 than in cohorts receiving lower bortezomib and higher melphalan doses. In conclusion, bortezomib plus melphalan is a steroid- and immunomodulatory drug-free regimen that may provide a treatment alternative for elderly patients and patients with significant comorbidity.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Antineoplastic Combined Chemotherapy Protocols; Boronic Acids; Bortezomib; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Neoplasm Recurrence, Local; Neutropenia; Pyrazines; Thrombocytopenia

The initial analysis of the oral combination melphalan, prednisone, and thalidomide (MPT) in newly diagnosed patients with myeloma showed significantly higher response rate and longer progression-free survival (PFS) than did the standard melphalan and prednisone (MP) combination and suggested a survival advantage. In this updated analysis, efficacy and safety end points were updated. Patients were randomly assigned to receive oral MPT or MP alone. Updated analysis was by intention to treat and included PFS, overall survival (OS), and survival after progression. After a median follow-up of 38.1 months, the median PFS was 21.8 months for MPT and 14.5 months for MP (P = .004). The median OS was 45.0 months for MPT and 47.6 months for MP (P = .79). In different patient subgroups, MPT improved PFS irrespective of age, serum concentrations of beta(2)-microglobulin, or high International Staging System. Thalidomide or bortezomib administration as salvage regimens significantly improved survival after progression in the MP group (P = .002) but not in the MPT group (P = .34). These data confirm activity of MPT for PFS but failed to show any survival advantage. New agents in the management of relapsed disease could explain this finding. The study is registered at www.clinicaltrials.gov as #NCT00232934.

Topics: Administration, Oral; Age Factors; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Disease-Free Survival; Follow-Up Studies; Humans; Melphalan; Methotrexate; Middle Aged; Multiple Myeloma; Prednisone; Thalidomide; Treatment Outcome

In multiple myeloma (MM), the addition of thalidomide or bortezomib to the standard oral melphalan/prednisone combination significantly increased response rate and event-free survival. In this multicenter phase 1/2 trial, dosing, safety, and efficacy of the 4-drug combination, bortezomib, melphalan, prednisone, and thalidomide (VMPT) was determined. Bortezomib was administered at 3 dose levels (1.0 mg/m2, 1.3 mg/m2, or 1.6 mg/m2) on days 1, 4, 15, and 22; melphalan was given at a dose of 6 mg/m2 on days 1 through 5 and prednisone at 60 mg/m2 on days 1 through 5. Thalidomide was delivered at 50 mg on days 1 through 35. Each course was repeated every 35 days. The maximum tolerated dose of bortezomib was 1.3 mg/m2. Thirty patients with relapsed or refractory MM were enrolled; 20 patients (67%) achieved a partial response (PR) including 13 patients (43%) who achieved at least a very good PR. Among 14 patients who received VMPT as second-line treatment, the PR rate was 79% and the immunofixation-negative complete response rate 36%. The 1-year progression-free survival was 61%, and the 1-year survival from study entry was 84%. Grade 3 nonhematologic adverse events included infections (5 patients), fatigue (1), vasculitis (1), and peripheral neuropathy (2); no grade 4 toxicities were recorded. Initial results showed that VMPT is an effective salvage therapy with a very high proportion of responses. The incidence of neurotoxicities was unexpectedly low.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Boronic Acids; Bortezomib; Drug Tolerance; Female; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Prednisone; Pyrazines; Recurrence; Safety; Salvage Therapy; Thalidomide

The prognostic value of chromosomal abnormalities was studied in untreated multiple myeloma patients who were registered into a prospective randomised multicentre phase 3 study for intensified treatment (HOVON24). A total of 453 patients aged less than 66 years with stage II and III A/B disease were registered in the clinical study. Cytogenetic analysis was introduced as a standard diagnostic assay in 1998. It was performed at diagnosis in 160 patients and was successful in 137/160 patients (86%). An abnormal karyotype was observed in 53/137 (39%) of the patients. Abnormalities of chromosome 1p and 1q were found in 19 (36% of patients with an abnormal karyotype) and 21 patients (40%). There was a strong association between chromosome 1p and/or 1q abnormalities and deletion of chromosome 13 or 13q (n = 27, P < 0.001). Patients with karyotypic abnormalities had a significantly shorter overall survival (OS) than patients with normal karyotypes. Complex abnormalities, hypodiploidy, chromosome 1p abnormalities, chromosome 1q abnormalities, and chromosome 13 abnormalities were associated with inferior OS on univariate analysis, as well as after adjustment for other prognostic factors. In conclusion, chromosome 13 abnormalities and chromosome 1p and/or 1q abnormalities were highly associated, and are risk factors for poor outcome after intensive therapy in multiple myeloma.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Chromosome Aberrations; Chromosome Deletion; Chromosomes, Human, Pair 1; Chromosomes, Human, Pair 13; Cyclophosphamide; Dexamethasone; Doxorubicin; Epidemiologic Methods; Female; Humans; Karyotyping; Male; Melphalan; Middle Aged; Multiple Myeloma; Neoplasm Staging; Prognosis; Treatment Outcome; Vincristine

The effectiveness of melphalan plus dexamethasone (M-Dex) with melphalan plus prednisone (MP) as induction therapy and dexamethasone with observation as maintenance therapy was compared in 585 older patients with multiple myeloma. Randomization to the M-Dex arm was stopped as a result of an analysis performed which met a predetermined event-related criterion. Of 466 patients randomised to MP or M-Dex, no differences were detected in the respective median progression-free survivals (PFS) [1.8 vs. 1.9 years; Hazard Ratio (HR) = 0.88, 95% CI 0.72-1.07; P = 0.2] or overall survivals (OS) (2.5 vs. 2.7 years; HR = 0.91, 95% CI 0.74-1.11; P = 0.3). Of the initial 585 patients, 292 remained evaluable for maintenance therapy. Patients randomised to maintenance dexamethasone had a superior median PFS (2.8 years vs. 2.1 years; HR = 0.61, 95% CI 0.47-0.79; P = 0.0002). No difference in median OS was detected (4.1 years vs. 3.8 years; HR = 0.88, 95% CI 0.65-1.18; P = 0.4). The maintenance therapy results were robust when analysed by using two additional methodologies. Dexamethasone did not improve clinical outcome when combined with melphalan during induction; maintenance dexamethasone improved PFS, but this did not translate into a detectable survival advantage.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Drug Administration Schedule; Female; Glucocorticoids; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Prednisone; Proportional Hazards Models; Remission Induction; Survival Rate; Treatment Outcome

Several clinical trials have shown the superiority of autologous stem cell transplantation over conventional dose therapy for patients with multiple myeloma. This treatment, however, is limited to younger patients (<65 years) owing to concerns about toxicity and treatment-related mortality (TRM) in older patients. We treated 26 elderly myeloma patients (>70 years), who received a preparative regimen of melphalan 200 mg/m2 (19 patients), melphalan 180 mg/m2 (six patients) or melphalan 140 mg/m2 (one patient). Twenty-two of the 26 patients were alive after a median follow-up of 25 months (range=8-74). Responses (complete+partial response) were seen in 20 patients (77%), five (19%) of which were complete responses. Median PFS was 24 months, whereas median OS has not been reached. Cumulative incidence of 100-day TRM was 0%. Three-year PFS and OS were 39% (range=16-61) and 65% (range=35-83), respectively. A low serum albumin (<3.5 g/dl) was associated with a shorter PFS (P=0.02). Patients with relapsed disease at transplant, and an interval of >12 months between diagnosis and autotransplant, had a shorter OS (P=0.0004 and 0.04). HDT and autologous transplant is safe and feasible in elderly myeloma patients.

Topics: Aged; Aged, 80 and over; Disease-Free Survival; Female; Follow-Up Studies; Humans; Male; Melphalan; Multiple Myeloma; Myeloablative Agonists; Peripheral Blood Stem Cell Transplantation; Retrospective Studies; Survival Rate; Transplantation, Autologous

We performed a prospective, randomized study of single (arm A) versus double (arm B) autologous stem-cell transplantation (ASCT) for younger patients with newly diagnosed multiple myeloma (MM).. A total of 321 patients were enrolled onto the study and were randomly assigned to receive either a single course of high-dose melphalan at 200 mg/m2 (arm A) or melphalan at 200 mg/m2 followed, after 3 to 6 months, by melphalan at 120 mg/m2 and busulfan at 12 mg/kilogram (arm B).. As compared with assignment to the single-transplantation group (n = 163 patients), random assignment to receive double ASCT (n = 158 patients) significantly increased the probability to attain at least a near complete response (nCR; 33% v 47%, respectively; P = .008), prolonged relapse-free survival (RFS) duration of 18 months (median, 24 v 42 months, respectively; P < .001), and significantly extended event-free survival (EFS; median, 23 v 35 months, respectively; P = .001). Administration of a second transplantation and of novel agents for treating sequential relapses in up to 50% of patients randomly assigned to receive a single ASCT likely contributed to prolong the survival duration of the whole group, whose 7-year rate (46%) was similar to that of the double-transplantation group (43%; P = .90). Transplantation-related mortality was 3% in arm A and 4% in arm B (P = .70).. In comparison with a single ASCT as up-front therapy for newly diagnosed MM, double ASCT effected superior CR or nCR rate, RFS, and EFS, but failed to significantly prolong overall survival. Benefits offered by double ASCT were particularly evident among patients who failed at least nCR after one autotransplantation.

Topics: Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Dexamethasone; Disease-Free Survival; Doxorubicin; Female; Humans; Kaplan-Meier Estimate; Male; Melphalan; Middle Aged; Multiple Myeloma; Stem Cell Transplantation; Transplantation, Autologous; Vincristine

The impact of high dose dexamethasone containing regimens with or without the novel agents thalidomide and bortezomib on the reversal of renal failure (RF) was evaluated in 41 consecutive newly diagnosed patients with multiple myeloma (MM) treated in a single institution. RF was reversed in 73% of all patients within a median of 1.9 months. In patients treated with dexamethasone and novel agents (thalidomide and/or bortezomib) the reversibility rate was 80% within a median of 0.8 months. Severe RF and significant Bence Jones proteinuria were associated with a lower probability of RF reversal. Patients who responded to treatment achieved RF reversal more often than in those who did not (85% versus 56%, p=0.046). In conclusion, RF is reversible in the majority of newly diagnosed MM patients treated with high-dose dexamethasone containing regimens. The addition of novel agents induces a more rapid RF reversal.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bence Jones Protein; Boronic Acids; Bortezomib; Dexamethasone; Doxorubicin; Female; Humans; Hypercalcemia; Kidney Failure, Chronic; Male; Melphalan; Middle Aged; Multiple Myeloma; Myeloma Proteins; Proteinuria; Pyrazines; Thalidomide; Treatment Outcome; Vincristine

In a previous trial among 137 previously untreated patients with multiple myeloma, the combination of thalidomide-dexamethasone induced remission in 66% of patients, including complete remission in 13%. In an attempt to induce more frequent remissions, we added bortezomib to this program. Between 7/03 and 3/06, 38 newly diagnosed patients with multiple myeloma received at least one, but no more than 3, courses of bortezomib in a dose of 1.3 mg/m(2) IV x 4; dexamethasone 20 mg/m(2) PO for 4 days beginning on days 1, 9, 17; thalidomide 100 mg PO daily increasing to a maximum of 200 mg. There was rapid onset of remission in 33 patients (87%) including 6 patients with complete remission (16%). Most side effects were preventable, but otherwise were usually mild and reversible. After a median of 4 months, 25 eligible patients received intensive therapy with high-dose melphalan supported by autologous blood stem cells, so that the myeloma was in complete remission in 14 patients (37% of all patients). The combination of bortezomib-thalidomide-dexamethasone was a highly effective primary treatment for newly diagnosed patients with multiple myeloma.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Boronic Acids; Bortezomib; Dexamethasone; Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Middle Aged; Multiple Myeloma; Pyrazines; Remission Induction; Thalidomide; Transplantation, Autologous; Treatment Outcome

Total therapy 3 incorporated bortezomib into a melphalan-based tandem transplant regimen for 303 newly diagnosed patients with myeloma. Induction chemotherapy prior to and consolidation chemotherapy after transplants each consisted of two cycles of VTD-PACE (bortezomib, thalidomide, dexamethasone and 4-d continuous infusions of cis-platin, doxorubicin, cyclophosphamide, etoposide); 3-year maintenance comprised monthly cycles of VTD in the first and TD in the remaining years. The median age was 59 years (age >64 years, 28%). A minimum of 20 x 10(6) CD34 cells/kg was collected in 87% of patients; 83% completed both transplants, and only 5% suffered a treatment-related death. At 24 months, 83% had achieved near-complete remission, which was sustained in 88% at 2 years from its onset. With a median follow-up of 20 months, 2-year estimates of event-free and overall survival were 84% and 86% respectively. The 44 patients who experienced an event more often had a high-risk gene array profile, cytogenetic abnormalities and indicators of high lactate dehydrogenase, beta-2-microglobulin, creatinine and International Staging System stage. Toxicities of grade > 2 included thrombo-embolic events in 27% and peripheral neuropathy in 12%. Results of this phase-2 study demonstrated that bortezomib could be safely combined with multi-agent chemotherapy, effecting near-complete remission status and 2-year survival rates in more than 80% of patients.

Topics: Aged; Angiogenesis Inhibitors; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Boronic Acids; Bortezomib; Combined Modality Therapy; Dexamethasone; Female; Humans; Kaplan-Meier Estimate; Male; Melphalan; Middle Aged; Multiple Myeloma; Pyrazines; Stem Cell Transplantation; Thalidomide; Treatment Outcome

The Dutch-Belgian HOVON group performed a randomized phase 3 trial to compare single non-myeloablative intensive treatment with double, intensive treatment in previously untreated patients with multiple myeloma (MM).. Three hundred and three patients with stage II/III MM were randomized after VAD induction chemotherapy to receive two cycles of non-myeloablative intermediate-dose melphalan (70 mg/m2) (single treatment) or the same regimen followed by cyclophosphamide 120 mg/kg iv plus total body irradiation (TBI) 9 Gy and autologous stem cell transplantation (double, intensive treatment). In both treatment arms interferon .IIa was given as maintenance until relapse/progression.. A significantly higher proportion of patients achieved a complete remission (CR) on protocol treatment with double, intensive therapy (32 % vs 13 %, p<0.001). Double treatment produced better outcome in terms of event-free survival (median 22 vs 21 months, 28% vs 14% at 4 years and 15% vs 7% at 6 years after randomization; logrank p=0.013; univariate HR 0.74, 95% CI, 0.58-0.94), progression-free survival (median 27 vs 24 months, 33% vs 16% at 4 years, and 17% vs 9% at 6 years after randomization; logrank p=0.006; HR=0.71, 95% CI 0.56-0.91), but not overall survival (median 50 vs 55 months, 52% vs 56% at 4 years and 39% vs 36% at 6 years after randomization; logrank p=0.51; HR=1.10, 95% CI 0.83-1.46). The achievement of a CR had a favorable prognostic impact on event-free survival (HR=0.60 , 95% CI=0.44 -0.82 , p=0.001) and progression-free survival (HR=0.62 , 95% CI=0.45 -0.84, p=0.002).. Double, intensive treatment resulted in a better CR rate, event-free survival and progression-free survival but not overall survival compared to single non-myeloablative treatment in previously untreated patients with multiple myeloma.

Topics: Adolescent; Adult; Aged; Follow-Up Studies; Humans; Melphalan; Middle Aged; Multiple Myeloma; Myeloablative Agonists; Netherlands; Remission Induction; Survival Analysis

Lenalidomide has shown significant antimyeloma activity in clinical studies. Oral melphalan, prednisone, and thalidomide have been regarded as the standard of care in elderly multiple myeloma patients. We assessed dosing, efficacy, and safety of melphalan, prednisone, and lenalidomide (MPR) in newly diagnosed elderly myeloma patients.. Oral melphalan was administered in doses ranging from 0.18 to 0.25 mg/kg on days 1 to 4, prednisone at a 2-mg/kg dose on days 1 to 4, and lenalidomide at doses ranging from 5 to 10 mg on days 1 to 21, every 28 days for nine cycles, followed by maintenance therapy with lenalidomide alone. Aspirin was given as a prophylaxis for thrombosis.. Fifty-four patients were enrolled and evaluated after completing the assigned treatment schedule. The maximum tolerated dose was defined as 0.18 mg/kg melphalan and 10 mg lenalidomide. With these doses, 81% of patients achieved at least a partial response, 47.6% achieved a very good partial response, and 23.8% achieved a complete immunofixation-negative response. In all patients, 1-year event-free and overall survival rates were 92% and 100%, respectively. At the maximum tolerated dose, grade 3 adverse events included neutropenia (38.1%), thrombocytopenia (14.2%), febrile neutropenia (9.5%), vasculitis (9.5%), and thromboembolism (4.8%); grade 4 adverse events were neutropenia (14.2%) and thrombocytopenia (9.5%).. Oral MPR therapy is a promising first-line treatment for elderly myeloma patients. Hematologic adverse events were frequent but manageable. A low incidence of nonhematologic adverse events was noted. Aspirin appears to provide adequate antithrombosis prophylaxis.

Topics: Administration, Oral; Aged; Antineoplastic Combined Chemotherapy Protocols; Dose-Response Relationship, Drug; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Lenalidomide; Male; Maximum Tolerated Dose; Melphalan; Middle Aged; Multiple Myeloma; Prednisone; Survival Analysis; Thalidomide

Topics: Aged; Aged, 80 and over; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Delivery of Health Care; Humans; Immunosuppressive Agents; Melphalan; Multiple Myeloma; Prednisone; Stem Cell Transplantation; Survival Rate; Thalidomide

In multiple myeloma, combination chemotherapy with melphalan plus prednisone is still regarded as the standard of care in elderly patients. We assessed whether the addition of thalidomide to this combination, or reduced-intensity stem cell transplantation, would improve survival.. Between May 22, 2000, and Aug 8, 2005, 447 previously untreated patients with multiple myeloma, who were aged between 65 and 75 years, were randomly assigned to receive either melphalan and prednisone (MP; n=196), melphalan and prednisone plus thalidomide (MPT; n=125), or reduced-intensity stem cell transplantation using melphalan 100 mg/m2 (MEL100; n=126). The primary endpoint was overall survival. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00367185.. After a median follow-up of 51.5 months (IQR 34.4-63.2), median overall survival times were 33.2 months (13.8-54.8) for MP, 51.6 months (26.6-not reached) for MPT, and 38.3 months (13.0-61.6) for MEL100. The MPT regimen was associated with a significantly better overall survival than was the MP regimen (hazard ratio 0.59, 95% CI 0.46-0.81, p=0.0006) or MEL100 regimen (0.69, 0.49-0.96, p=0.027). No difference was seen for MEL100 versus MP (0.86, 0.65-1.15, p=0.32).. The results of our trial provide strong evidence to indicate that the use of thalidomide in combination with melphalan and prednisone should, at present, be the reference treatment for previously untreated elderly patients with multiple myeloma.

Topics: Aged; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Female; Humans; Immunosuppressive Agents; Male; Melphalan; Multiple Myeloma; Prednisone; Stem Cell Transplantation; Survival Rate; Thalidomide

Veno-occlusive disease of the liver (VOD) is a potentially severe complication of high-dose cytoreductive therapy (HDT) used for stem cell transplantation (SCT). This complication is uncommon after HDT for autologous SCT (ASCT) in patients with multiple myeloma (MM). The Spanish Myeloma Group/PETHEMA conducted a study (MM2000) for patients with newly diagnosed MM consisting of induction with alternating VBMCP/VBAD chemotherapy followed by intensification with busulfan/melphalan (Bu/MEL) with a second high-dose therapy procedure in patients not achieving at least near-complete remission with the first procedure. After 2 years of the trial, a number of episodes resembling classical VOD but with a late onset were recognized. Consequently, the protocol was modified, and Bu/MEL was replaced by melphalan 200 mg/m(2) (MEL-200). Three years later, after a total of 734 patients had undergone first autologous SCT, the incidence and characteristics of VOD episodes were analyzed in the whole series. Nineteen cases of VOD (8%) were observed among the first 240 patients receiving Bu/MEL, whereas only 2 (0.4%) were observed among the 494 patients treated with MEL-200 (P < .0001). VOD manifestations in the Bu/MEL group appeared at a median of 29 days (range, 3-57 days) after ASCT. Mortality directly attributable to VOD was 2% in the Bu/MEL group and 0.2% in the MEL-200 group (P = .026). This high incidence of severe VOD probably had a multifactorial origin (busulfan followed by melphalan and previous use of BCNU). This observation should be kept in mind when designing future trials for the treatment of MM.

Topics: Adult; Aged; Busulfan; Dose-Response Relationship, Drug; Female; Hematopoietic Stem Cell Transplantation; Hepatic Veno-Occlusive Disease; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Myeloablative Agonists; Peripheral Blood Stem Cell Transplantation; Spain; Transplantation Conditioning; Transplantation, Autologous

As new therapeutic options for multiple myeloma (MM) emerge, identification of biological markers which could predict clinical response to standard treatment with high-dose melphalan (HDM) supported by autologous stem cell transplantation (ASCT) becomes more important.. Melphalan-induced damage formation and repair of monoadducts and interstrand cross-links in the p53 gene were studied in peripheral blood mononuclear cells obtained from 32 patients prior to therapy. The same studies were performed in the peripheral blood cells of these patients immediately after subsequent HDM administration. Clinical response and time to progression were correlated with molecular endpoints obtained in vitro.. Values for all molecular end-points examined in vitro were highly correlated with the respective in vivo results within individual patients. All in vitro end-points indicative of increased DNA damage and slower repair capacity were predictive of a favorable response to HDM; the area under the curve of total adducts (AUC-TA) had the highest predictive ability. Using the cut-off value of 736 adducts/10(6) nucleotides x h for the AUC-TA, the positive predictive value for clinical response to HDM was 100%. Moreover, patients with an AUC-TA equal to or higher than this cut-off value had significantly longer times to progression than had patients with an AUC-TA lower than the cut-off value (hazard ratio 0.19; 95% confidence intervals 0.06 to 0.60).. An in vitro assay to quantify melphalan-induced p53-specific damage formation/repair can be used to select those patients with MM who are more likely to benefit from HDM supported by ASCT.

Topics: Adult; Aged; DNA Damage; Female; Hematopoietic Stem Cell Transplantation; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Patient Selection; Predictive Value of Tests; Treatment Outcome

Clonotypic B lymphocytes may underlie relapse of patients with multiple myeloma. Rituximab, a CD20 monoclonal antibody, may result in eradication of the monoclonal B cells. We conducted a phase II study of rituximab in combination with melphalan and prednisone therapy (MP) followed by rituximab maintenance in newly diagnosed multiple myeloma patients. Sixteen patients (35%) had CD20 positive bone marrow plasma cells, while 9 patients (20%) had unknown CD20 status. No patient had a complete remission, 26 patients (58%) had a partial response, 6 patients (13%) had a minimal response, and 8 patients (18%) had stable disease. The median event-free survival was 14 months, and the 7-year overall survival was 30%. The toxicity of the combination was overall manageable and consistent with what is generally noted with MP chemotherapy. The combination of rituximab to MP therapy did not result in improved response rate or event-free survival.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Antigens, CD20; Antineoplastic Combined Chemotherapy Protocols; Female; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Prednisone; Prospective Studies; Rituximab

The antimyeloma agent bortezomib functions as an inhibitor of nuclear factor (NF)-kappaB. Although NF-kappaB inhibition is predicted to affect osteoclast function, preclinical and clinical studies have primarily reported an effect on osteoblasts.. We examined parameters of bone turnover prospectively in patients with multiple myeloma treated with bortezomib before and after autologous transplantation. Thirty-nine patients received 2 cycles of bortezomib on days 1, 4, 8, and 11 of a 21-day cycle. After high-dose melphalan with autologous stem cell transplantation, bortezomib 1.3 mg/m2 on days 1, 8, 15, and 22 of a 5-week cycle was administered as maintenance therapy.. During posttransplantation bortezomib, decreases in the urinary excretion of collagen N-telopeptide indicated that bortezomib suppresses osteoclast function.. The effects on osteoclasts occurred in the absence of bisphosphonate treatment and independently of changes in monoclonal protein levels. Further studies exploring the role of bortezomib as a bone protective agent could be warranted.

Topics: Adult; Antineoplastic Agents; Blood Component Removal; Boronic Acids; Bortezomib; Combined Modality Therapy; Drug Administration Schedule; Granulocyte Colony-Stimulating Factor; Humans; Melphalan; Multiple Myeloma; Osteoclasts; Patient Selection; Pyrazines; Stem Cell Transplantation; Transplantation, Autologous

The combination of high levels of beta2-microglobulin (beta2-m) and chromosome 13 deletion allows identification of a high-risk subgroup of patients with de novo multiple myeloma (MM). In this population of patients, we have evaluated the impact of a murine anti-interleukin 6 (anti-IL-6) monoclonal antibody (BE-8) as part of the second conditioning regimen in a multicenter prospective randomized trial of tandem autologous stem cell transplantation (ASCT). Conditioning for the first ASCT was accomplished with melphalan 200 mg/m2 and for the second one with melphalan 220 mg/m2 plus dexamethasone with or without BE-8 infusion. This trial included 219 patients, of whom 166 were randomized, 85 without BE-8 (arm A) and 81 with BE-8 (arm B). The median overall survival (OS) and event-free survival (EFS) times of the whole group of patients were 41 and 30 months, respectively. Response rates, OS, and EFS were not different between the 2 arms of the trial. OS at 54 months was 46% in arm A and 51% in arm B (P = .90); median EFS was 35 months in arm A and 31 in arm B (P = .39). In high-risk patients the dose intensity of melphalan at 420 mg/m2 led to encouraging results, but the addition of anti-IL-6 monoclonal antibody to the second conditioning regimen did not improve either OS nor EFS.

Topics: Adult; Aged; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; beta 2-Microglobulin; Chromosome Deletion; Chromosomes, Human, Pair 13; Dexamethasone; Female; Hematopoietic Stem Cell Transplantation; Humans; Interleukin-6; Male; Melphalan; Middle Aged; Multiple Myeloma; Risk Factors; Survival Analysis; Transplantation Conditioning; Transplantation, Autologous

Dexamethasone alone increases life expectancy in patients with relapsed multiple myeloma (MM); however, no large randomized study has compared dexamethasone and dexamethasone-based regimens with standard melphalan-prednisone in newly diagnosed MM patients ineligible for high-dose therapy. In the Intergroupe Francophone du Myélome (IFM) 95-01 trial, 488 patients aged 65 to 75 years were randomized between 4 regimens of treatment: melphalan-prednisone, dexamethasone alone, melphalan-dexamethasone, and dexamethasone-interferon alpha. Response rates at 6 months (except for complete response) were significantly higher among patients receiving melphalan-dexamethasone, and progression-free survival was significantly better among patients receiving melphalan (P < .001, for both comparisons), but there was no difference in overall survival between the 4 treatment groups. Moreover, the morbidity associated with dexamethasone-based regimens was significantly higher than with melphalan-prednisone, especially for severe pyogenic infections in the melphalan-dexamethasone arm and hemorrhage, severe diabetes, and gastrointestinal and psychiatric complications in the dexamethasone arms. Overall, these results indicated that dexamethasone should not be routinely recommended as first-line treatment in elderly patients with MM. In the context of the IFM 95-01 trial, the standard melphalan-prednisone remained the best treatment choice when efficacy and patient comfort were both considered. These results might be useful in the context of future combinations with innovative drugs.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Disease-Free Survival; Female; Humans; Infections; Interferon-alpha; Male; Melphalan; Multiple Myeloma; Neoplasm Staging; Patient Selection; Prednisone; Survival Analysis; Treatment Outcome

High-dose chemotherapy with autologous stem cell transplantation in patients with newly diagnosed multiple myeloma can prolong survival but is not curative. Maintenance therapy post transplant may prolong the disease-free interval and impact overall survival. We have conducted a phase II pilot study of 28 post transplant myeloma patients treated with a sequential, cycling maintenance regimen. The regimen was designed to include a variety of active myeloma agents chosen for ease of administration to enhance patient compliance and scheduled sequentially to minimize toxicity. The 12-month cycling schedule included dexamethasone (months 1-3); melphalan and prednisone (months 4, 5); cyclophosphamide and prednisone (months 6, 7); alpha-interferon (months 8-10); followed by a drug holiday (months 11, 12). The regimen was generally well tolerated with five patients developing reversible grade III-IV toxicity (diabetes-induced hyperglycemia in four, neutropenia in one). There was one toxic death on study due to non-neutropenic pneumonia and sepsis. Median event-free survival from transplant was 36.9 months (95% CI 23.6 - upper limit not yet reached) with median overall survival not yet reached at a median follow-up of 44 months. This concept of cycling, sequential maintenance with various agents, perhaps including newer biological, targeted agents, warrants further investigation in multiple myeloma.

Topics: Anti-Inflammatory Agents; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Cyclophosphamide; Dexamethasone; Disease-Free Survival; Female; Follow-Up Studies; Humans; Interferon-alpha; Male; Melphalan; Multiple Myeloma; Pilot Projects; Prednisone; Recurrence; Stem Cell Transplantation; Transplantation, Autologous

Topics: Adolescent; Adult; Amifostine; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Child; Cytarabine; Female; Graft Survival; Hodgkin Disease; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Podophyllotoxin; Radiation-Protective Agents; Stem Cell Transplantation; Transplantation, Homologous

Autologous stem cell transplantation (SCT) with high-dose melphalan (HDM, 200 mg/m2) is the most effective therapy for multiple myeloma. To determine the feasibility of combining carmustine (300 mg/m2) with HDM, we enrolled 49 patients with previously treated Durie-Salmon stage II/III myeloma (32M/17W, median age 53) on a phase I/II trial involving escalating doses of melphalan (160, 180, 200 mg/m2). The median beta2-microglobulin was 2.5 (0-9.3); marrow karyotypes were normal in 88%. The phase I dose-limiting toxicity was > or =grade 2 pulmonary toxicity 2 months post-SCT. Other endpoints were response rate and progression-free survival (PFS). HDM was safely escalated to 200 mg/m2; treatment-related mortality was 2% and > or =grade 2 pulmonary toxicity 10%. The complete (CR) and near complete (nCR) response rate was 49%. With a median post-SCT follow-up of 2.9 years, the PFS and overall survival (OS) post-SCT were 2.3 and 4.7 years. PFS for those with CR or nCR was 3.1 years while for those with stable disease (SD) it was 1.3 years (P=0.06). We conclude that carmustine can be combined with HDM for myeloma with minimal pulmonary toxicity and a high response rate.

Topics: Adult; Aged; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Combined Modality Therapy; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Humans; Lung Diseases; Male; Melphalan; Middle Aged; Multiple Myeloma; Peripheral Blood Stem Cell Transplantation; Recurrence; Survival Analysis; Transplantation, Autologous

This randomized phase III study compared bendamustine and prednisone (BP) to standard melphalan and prednisone (MP) treatment in previously untreated patients with multiple Myeloma (MM).. To be included, patients had to have histologically and cytologically proven stage II with progressive diseases or stage III MM. They were randomly assigned to receive BP (n=68) or MP (n=63). The primary endpoint was the time to treatment failure (TTF). Secondary endpoints included survival, remission rate, toxicity and quality of life.. The overall response rate was 75% in the BP and 70% in the MP group. A significantly higher number of patients treated with BP achieved a complete remission than did patients receiving MP (32 vs. 13%; P=0.007), and the maximum response was achieved more rapidly in patients treated with BP compared to those receiving MP (6.8 vs. 8.7 cycles; P<0.02). TTF and remission duration were significantly longer in the BP group. Patients receiving BP had higher QoL scores and reported pain less frequently than patients receiving MP.. BP is superior to MP with respect to complete remission rate, TTF, cycles needed to achieve maximum remission and quality of life and should be considered the new standard in first-line treatment of MM patients not eligible for transplantation.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bendamustine Hydrochloride; Disease-Free Survival; Female; Germany, East; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Nitrogen Mustard Compounds; Prednisone; Quality of Life; Remission Induction; Survival Analysis; Time Factors; Treatment Failure

Bortezomib has shown synergy with melphalan in preclinical models. We assessed the safety, tolerability, and response rate in a dose-escalation study of this combination for relapsed or refractory multiple myeloma patients.. Bortezomib was administered from 0.7 to 1.0 mg/m(2) on days 1, 4, 8, and 11 of a 28-day cycle for up to eight cycles. Oral melphalan was administered in escalating doses from 0.025 to 0.25 mg/kg on days 1 to 4.. Thirty-five patients with relapsed or refractory myeloma were enrolled, 34 of whom were assessable for response. Dose-limiting toxicity of grade 4 neutropenia in two of six patients in the highest dose cohort led to the assignment of bortezomib 1.0 mg/m2 and melphalan 0.10 mg/kg as the maximum-tolerated dose (MTD). Responses (minimal [MR], partial [PR], or complete [CR]) occurred in 23 of 34 patients (68%), including two CRs (6%), three immunofixation-positive CRs (9%), 11 PRs (32%), and seven MRs (21%). Responses were observed in five of six assessable patients (83%) at the MTD. Median progression-free survival for all patients was 8 months (range, 2 to 18 months). Grade > or = 3 toxicities were related mostly to myelosuppression. Among the 15 patients with grade 1/2 neuropathy at baseline, it resolved during treatment in one, worsened in four, and remained stable in 10 patients. Eight other patients developed grade 1/2 neuropathy during the study.. Bortezomib plus melphalan given on a 28-day schedule showed encouraging activity with manageable toxicity and represents a promising treatment for myeloma patients.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Boronic Acids; Bortezomib; Disease-Free Survival; Drug Administration Schedule; Drug Synergism; Female; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Neoplasm Recurrence, Local; Neutropenia; Pyrazines; Severity of Illness Index; Survival Analysis; Treatment Outcome

Results of a prospective randomized trial conducted by the Intergroupe Francais du Myélome (IFM 90) indicated that autologous hematopoietic cell-supported high-dose therapy (HDT) effected higher complete response rates and extended progression-free survival (PFS) and overall survival (OS) compared with standard-dose therapies (SDT) for patients with multiple myeloma (MM).. In 1993, three North American cooperative groups launched a prospective randomized trial (S9321) comparing HDT (melphalan [MEL] 140 mg/m2 plus total-body irradiation 12 Gy) with SDT using the vincristine, carmustine, MEL, cyclophosphamide, and prednisone regimen. Responders on both arms (> or = 75%) were randomly assigned to interferon (IFN) or no maintenance treatment.. With a median follow-up time of 76 months, no differences were observed in response rates between the two study arms (HDT, n = 261 patients; SDT, n = 255 patients). Similarly, PFS and OS durations did not differ between the HDT and SDT arms, with 7-year estimates of PFS of 17% and 16%, respectively, and OS of 37% and 42%, respectively. Of 242 patients achieving at least 75% tumor reduction, no difference was observed in PFS or OS among the 121 patients randomly assigned to IFN and the 121 patients randomly assigned to no maintenance therapy. Among 157 patients relapsing on SDT, 87 received a salvage autotransplantation; their median survival time of 30 months was only slightly better than the survival time of the remaining patients who were managed with further SDT (23 months; P = .13).. The HDT and SDT regimens used in S9321 yielded comparable response rates and PFS and OS durations. IFN maintenance therapy did not benefit patients who achieved > or = 75% tumor reduction on either arm.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Carmustine; Chemotherapy, Adjuvant; Clinical Protocols; Cyclophosphamide; Disease-Free Survival; Drug Administration Schedule; Female; Hematopoietic Stem Cell Transplantation; Humans; Interferons; Male; Melphalan; Middle Aged; Multiple Myeloma; Prednisone; Prospective Studies; Radiotherapy, Adjuvant; Salvage Therapy; Survival Analysis; Transplantation, Autologous; Transplantation, Homologous; Treatment Failure; Treatment Outcome; United States; Vincristine; Whole-Body Irradiation

Fifty patients with multiple myeloma >or=75 years of age received primary treatment with melphalan (M) 8 mg/m(2) on days 1-4, dexamethasone (D) 12 mg/m2 on days 1-4 and 17-20 and thalidomide (T) 300 mg at bedtime on days 1-4 and 17-20. This regimen was repeated every 5 weeks for three courses. Patients without evidence of disease progression received nine additional courses of MDT, but without DT on days 17-20, every 5 weeks. Sixty-two percent of patients achieved a partial response and 10% a complete response. The median time to response was 2 months. The median time to progression for all patients was 21.2 months. Deep venous thrombosis and peripheral neuropathy each occurred in 9% of patients.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Disease-Free Survival; Female; Humans; Male; Melphalan; Multiple Myeloma; Peripheral Nervous System Diseases; Remission Induction; Thalidomide; Venous Thrombosis

Thalidomide combined with conventional chemotherapies including oral melphalan shows significant anti-myeloma activity. To address this issue, feasibility and efficacy of a three drug combination consisting of intravenous (i.v.) melphalan, thalidomide and prednisone [M(i.v.)PT] was evaluated in advanced myeloma patients.. Twenty-four advanced myeloma patients were treated with multiple cycles of a regimen consisting of low dose i.v. melphalan (20 mg/m2) at d 1, thalidomide at the dose of 50-100 mg/d given continuously and oral prednisone at the planned dose of 50 mg/d every other day. Intravenous melphalan was administered every fourth month. Median time from diagnosis was 40 months (range: 8-144 months). Fifteen patients (66%) had previously been treated with a combination of thalidomide and dexamethasone or with thalidomide alone.. Overall, on an intent-to treat basis, 14 patients responded: three achieved near complete remission (nCR), seven achieved partial response (PR), four minimal response (MR). Six patients showed stable disease (SD) and four-disease progression. Interestingly, of five patients who had previously progressed while on thalidomide and prednisone, one reached nCR, two PR and one MR. After a median follow up of 14 months, median progression free survival was 9 months. Response duration was longer than that induced by the previous line of treatment in eight patients (33%). Thalidomide-associated toxicity mainly consisted of constipation, tingling and sedation.. M(i.v.)PT is an effective regimen, which can overcome resistance to thalidomide plus prednisone in advanced myeloma with acceptable toxicity.

Topics: Anti-Inflammatory Agents; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Disease-Free Survival; Drug Resistance, Neoplasm; Female; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Male; Melphalan; Middle Aged; Multiple Myeloma; Recurrence; Thalidomide; Transplantation, Autologous; Treatment Outcome

High-dose therapy with melphalan can prolong survival among patients with multiple myeloma. We assessed whether the addition of thalidomide, which has activity against advanced and refractory myeloma, would further improve survival.. Between October 1998 and February 2004, 668 patients with newly diagnosed multiple myeloma received two cycles of intensive melphalan-based chemotherapy, each supported by autologous hematopoietic stem-cell transplantation. A total of 323 were randomly assigned to receive thalidomide from the outset until disease progression or undue adverse effects, and 345 did not receive thalidomide. The primary end point was the five-year event-free survival rate. Secondary end points were complete response and overall survival.. After a median follow-up of 42 months among survivors, the thalidomide and control groups had rates of complete response of 62 percent and 43 percent, respectively (P<0.001), and five-year event-free survival rates of 56 percent and 44 percent (P=0.01). The five-year rate of overall survival was approximately 65 percent in both groups (P=0.90). Median survival after relapse was 1.1 years in the thalidomide group and 2.7 years in the control group (P=0.001). Severe peripheral neuropathy and deep-vein thrombosis occurred more frequently in the thalidomide group than in the control group.. When incorporated into high-dose therapy for myeloma, thalidomide increased the frequency of complete responses and extended event-free survival at the expense of added adverse effects without improving overall survival. (ClinicalTrials.gov number, NCT00083551.).

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Disease-Free Survival; Female; Hematopoietic Stem Cell Transplantation; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Recurrence; Salvage Therapy; Survival Rate; Thalidomide

Since 1960, oral melphalan and prednisone (MP) has been regarded as the standard of care in elderly multiple myeloma patients. This multicentre randomised trial compared oral MP plus thalidomide (MPT) with MP alone in patients aged 60-85 years.. Patients with newly diagnosed multiple myeloma were randomly assigned to receive oral MP for six 4-week cycles plus thalidomide (n=129; 100 mg per day continuously until any sign of relapse or progressive disease) or MP alone (n=126). Analysis was intention-to-treat. This study is registered at , number NCT00232934.. Patients treated with thalidomide had higher response rates and longer event-free survival (primary endpoints) than patients who were not. Combined complete or partial response rates were 76.0% for MPT and 47.6% for MP alone (absolute difference 28.3%, 95% CI 16.5-39.1), and the near-complete or complete response rates were 27.9% and 7.2%, respectively. 2-year event-free survival rates were 54% for MPT and 27% for MP (hazard ratio [HR] for MPT 0.51, 95% CI 0.35-0.75, p=0.0006). 3-year survival rates were 80% for MPT and 64% for MP (HR for MPT 0.68, 95% CI 0.38-1.22, p=0.19). Rates of grade 3 or 4 adverse events were 48% in MPT patients and 25% in MP patients (p=0.0002). Introduction of enoxaparin prophylaxis reduced rate of thromboembolism from 20% to 3% (p=0.005).. Oral MPT is an effective first-line treatment for elderly patients with multiple myeloma. Anticoagulant prophylaxis reduces frequency of thrombosis. Longer follow-up is needed to assess effect on overall survival.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents, Alkylating; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Female; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Prednisone; Thalidomide

The importance of obtaining a complete response (CR) in multiple myeloma (MM) treated with chemotherapy is unclear.. The Eastern Cooperative Oncology Group evaluated 653 previously untreated patients with active MM randomized to vincristine, carmustine (BCNU), melphalan, cyclophosphamide, and prednisone (VBMCP), to VBMCP and recombinant interferon alfa-2 (INFalpha-2), or to VBMCP and high-dose cyclophosphamide.. Objective response was achieved in 420 (67%) of the 628 eligible patients, and 85 (14%) achieved a CR. Patients receiving VBMCP and recombinant INFalpha-2 had a significantly higher CR (18%) than those receiving VBMCP alone (10%) (P = .02). The CR rate for VBMCP and high-dose cyclophosphamide was 12%. Median duration of survival was 3.5 years for all eligible patients, and the estimated 5-year survival rate was 31%. The median duration of survival from the date of objective response was 5.1 years for those who achieved a CR and 3.3 years for those with a partial response (P < .0001). The median postresponse survival was 6.6 years in the 21 patients in CR with nonclonal disease and 4.4 years in the 11 patients in CR who had persistent clonal disease. All patients with negative immunofixation results and nonclonal plasma cells in whom polymerase chain reaction was performed had a positive result (presence of tumor DNA).. Patients in whom a CR was achieved had a longer survival than those who had a partial response.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Cyclophosphamide; Female; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Prednisone; Vincristine

Circulating soluble CD86 (sCD86) levels are elevated in a number of leukaemias and are an independent prognostic factor in acute myeloid leukaemia. We investigated the clinical significance of circulating sCD86 in 299 patients from the UK Medical Research Council myeloma VIth trial, where patients received ABCM [adriamycin, carmustine (BCNU), cyclophosphamide, melphalan] either alone or with prednisolone (ABCM + P). Serum levels of sCD86 were significantly elevated (P = 0.0001) in myeloma patients and using the median normal donor level (0.621 ng/ml) as a cut-off point, 70% of patients had elevated levels (range = 0.015-15.87 ng/ml, median = 1.1 ng/ml). In univariate analysis elevated sCD86 levels were associated with significantly shorter (P < 0.001) survival (median = 22 vs. 51 months) and event-free survival (median = 14 vs. 31 months) in ABCM + P but not ABCM patients. Multivariate analysis demonstrated that sCD86 was a significant, independent prognostic marker of both overall [risk ratio (RR) = 2.04, P = 0.0006] and event-free (RR = 1.95, P = 0.0004) survival in ABCM + P patients. In conclusion, this study demonstrated that sCD86 levels are a significant independent prognostic marker in at least some myeloma treatment groups and its biological role and prognostic value should be further investigated.

Topics: Adult; Aged; Antigens, Neoplasm; Antineoplastic Combined Chemotherapy Protocols; B7-2 Antigen; Biomarkers, Tumor; Carmustine; Cyclophosphamide; Doxorubicin; Enzyme-Linked Immunosorbent Assay; Epidemiologic Methods; Female; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Prednisolone; Prognosis; Treatment Outcome

Although alkylating agents are clearly beneficial in multiple myeloma (MM), their deleterious effect on bone marrow hematopoietic progenitor cells usually precludes their use as front-line therapy in patients scheduled to undergo autologous stem cell transplantation (ASCT). We analyzed the impact of first-line chemotherapy with alkylating agents on stem cell collection in MM patients.. Seven hundred and eighty-nine patients included in the Spanish multicenter protocol GEM-2000 underwent mobilization therapy after four courses of alternating VBMCP/VBAD chemotherapy.. The mobilization regimens consisted of standard or high-dose granulocyte colony-stimulating factor (G-CSF) in 551 (70%) patients, and chemotherapy and G-CSF in 206 (26%) patients. The CD34+ cell yield was lower than 4x10(6)/kg in 388 patients (49%), and equal or greater than 4x10(6)/kg in 401 patients (51%). Multivariate analysis indicated that advanced age (p<0.0001) and longer interval between diagnosis and mobilization (p=0.012) were the two variables associated with a lower CD34+ cell yield. Significant differences in CD34+ cell yield were not observed between the mobilization regimens. Of the 789 patients included in the protocol, 726 (92%) underwent the planned ASCT, whereas 25 (3%) patients did not because of the low number of CD34+ cells collected. Following ASCT, 0.5x10(9) neutrophils/L could be recovered after 11 days (median time; range, 5-71 days) and 20x10(9) platelets/L could be recovered after 12 days (median time; range, 6-69 days).. A short-course of therapy with alkylating agents according to the GEM-2000 protocol was associated with an appropriate CD34+ cell collection, and allowed the planned ASCT to be performed in the majority of MM patients.

Topics: Adult; Age Factors; Aged; Antigens, CD34; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Blood Cell Count; Carmustine; Combined Modality Therapy; Cyclophosphamide; Dexamethasone; Doxorubicin; Drug Administration Schedule; Female; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Mobilization; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Peripheral Blood Stem Cell Transplantation; Prednisone; Transplantation Conditioning; Transplantation, Autologous; Treatment Outcome; Vincristine

Forty patients with multiple myeloma scheduled to receive melphalan 200 mg/m(2) followed by autologous stem cell transplantation were randomly assigned to receive oral cryotherapy or room temperature normal saline rinses 30 min before and for 6 h after high-dose therapy. Patients were evaluated for the development of mucositis using the National Cancer Institute grading system as well as evaluation of secondary measures such as days of total parenteral nutrition (TPN), narcotic use, hospitalization, weight loss and resumption of oral caloric intake for 28 days after transplant. Patients self-scored their pain, swallowing, drinking, eating, sleeping and taste alterations for 28 days. The primary end point of this trial was the incidence of grades 3-4 mucositis. Compared to the normal saline group, patients using cryotherapy experienced less grade 3-4 mucositis, 14 vs 74%, P=0.0005. Patients receiving cryotherapy also had statistically lower uses of narcotics and TPN, although there were no differences in length of hospitalization or weight loss. Patient-reported pain was significantly lower and activities were significantly better in the cryotherapy group.

Topics: Adult; Aged; Antineoplastic Agents, Alkylating; Cryotherapy; Female; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Pain; Peripheral Blood Stem Cell Transplantation; Prospective Studies; Stomatitis; Transplantation, Autologous

The value of intensive therapy, including autologous stem cell transplantation, in newly diagnosed myeloma patients >60 years is not clear. We evaluated the impact of age (<60 years vs. 60-64 years) on survival in a prospective, population-based setting and compared survival with conventionally treated historic controls. The prospective population comprised 452 patients registered between 1998 and 2000. Of these, 414 received intensive therapy. The historic population, derived from our most recent population-based study on conventional therapy, comprised 281 patients. Of these, 243 fulfilled our eligibility criteria for intensive therapy. For patients undergoing intensive therapy it was found that two factors, beta-2-microglobulin and age <60 years vs. 60-64 years, had independent prognostic impact on survival. However, compared with the historic controls a survival advantage was found both for patients <60 (median 66 months vs. 43 months, P < 0.001) and 60-64 years (median 50 months vs. 27 months; P = 0.001). We conclude that in a population-based setting higher age adversely influences outcome after intensive therapy. Our results indicate that intensive therapy prolongs survival also at age 60-64 years but with less superiority than in younger patients.

Topics: Age Factors; Antineoplastic Combined Chemotherapy Protocols; beta 2-Microglobulin; Biomarkers, Tumor; Dexamethasone; Doxorubicin; Epidemiologic Methods; Female; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Peripheral Blood Stem Cell Transplantation; Prognosis; Treatment Outcome; Vincristine

Limited information is available on the feasibility and efficacy of autologous stem cell transplantation (ASCT) in multiple myeloma (MM) patients >65 years of age. In 1995-2005, 22 myeloma patients >or=65 years (median 68, eight >or=70) and 79 patients <65 years (median 57) were included in an identical treatment protocol. The first progenitor cell mobilization with cyclophosphamide plus granulocyte-colony stimulating factor (G-CSF) was successful in 95 and 96% of the patients, respectively. To date, 92 patients have received MEL (melphalan) 200 mg/m2 supported by ASCT. No early treatment-related deaths were observed among 22 elderly patients, whereas one younger patient died early. Engraftment and the need for supportive care were comparable between groups. The elderly patients tended to have more WHO grade 3-4 oral or gastrointestinal toxicity when compared to the younger patients (45 vs 23%, P=0.06). After ASCT, a complete response was observed in 44% of the elderly patients and 36% of the younger patients, respectively. No difference was observed between these age groups in progression-free survival (23 vs 21 months) or overall survival (57 vs 66 months) after ASCT. We conclude that MEL200 is a safe and efficacious treatment in selected elderly myeloma patients.

Topics: Adult; Age Factors; Aged; Disease-Free Survival; Female; Granulocyte Colony-Stimulating Factor; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Myeloablative Agonists; Stem Cell Transplantation; Stem Cells

Between August 1993 and March 2003, 130 consecutive multiple myeloma (MM) patients eligible for high-dose treatment were offered a program including up-front autologous stem cell transplantation (ASCT) after conditioning with 200 mg/m(2) melphalan followed by a second ASCT in case of relapse or progression. A total of 107 (82%) patients completed the first ASCT. The best response obtained after ASCT was complete response (CR) 23%, very good partial response (VGPR) 28%, partial response (PR) 42%, and minimal response (MR) 7%. Median overall survival (OS) and event-free survival (EFS) were 65.4 and 27.7 months, respectively. Relapse or progression occurred in 70 patients; 26 received a second ASCT (with a median time of 20.4 months from first ASCT). A major response (> or =PR) was obtained in 69% of these patients. Median OS and EFS after the second ASCT were 38.1 and 14.8 months. Treatment-related mortality was 1.9% after the first ASCT but no deaths occurred after the second. Our experience suggests that elective up-front single ASCT followed by second ASCT after relapse or progression is a safe and effective global strategy to treat MM patients.

Topics: Adult; Aged; Disease Progression; Disease-Free Survival; Female; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Myeloablative Agonists; Recurrence; Remission Induction; Retrospective Studies; Stem Cell Transplantation; Survival Rate; Transplantation Conditioning; Transplantation, Autologous

Standard first-line treatment for elderly multiple myeloma (MM) patients ineligible for stem cell transplantation is melphalan plus prednisone (MP). However, complete responses (CRs) are rare. Bortezomib is active in patients with relapsed MM, including elderly patients. This phase 1/2 trial in 60 untreated MM patients aged at least 65 years (half older than 75 years) was designed to determine dosing, safety, and efficacy of bortezomib plus MP (VMP). VMP response rate was 89%, including 32% immunofixation-negative CRs, of whom half of the IF- CR patients analyzed achieved immunophenotypic remission (no detectable plasma cells at 10(-4) to 10(-5) sensitivity). VMP appeared to overcome the poor prognosis conferred by retinoblastoma gene deletion and IgH translocations. Results compare favorably with our historical control data for MP--notably, response rate (89% versus 42%), event-free survival at 16 months (83% versus 51%), and survival at 16 months (90% versus 62%). Side effects were predictable and manageable; principal toxicities were hematologic, gastrointestinal, and peripheral neuropathy and were more evident during early cycles and in patients aged 75 years or more. In conclusion, in elderly patients ineligible for transplantation, the combination of bortezomib plus MP appears significantly superior to MP, producing very high CR rates, including immunophenotypic CRs, even in patients with poor prognostic features.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Boronic Acids; Bortezomib; Cohort Studies; Disease-Free Survival; Humans; Immunophenotyping; Maximum Tolerated Dose; Melphalan; Multiple Myeloma; Prednisone; Pyrazines

Bortezomib and thalidomide have shown synergy with melphalan and dexamethasone. We used this 4-drug combination as conditioning before autologous hematopoietic cell infusions.. Twenty-six patients with advanced-stage myeloma were treated with melphalan 50 mg/m(2) and bortezomib 1.3 mg/m(2) on days -6 and -3 in association with thalidomide 200 mg and dexamethasone 20 mg on days -6 through -3, followed by hematopoietic cell support on day 0.. Nonhematologic toxicities included pneumonia, febrile neutropenia, and peripheral neuropathy. All patients had undergone autologous transplantation at diagnosis, and 13 patients (50%) underwent an additional transplantation at relapse. Responses occurred in 17 of 26 patients (65%), including 1 complete remission, 3 near complete remissions (12%), and 2 very good partial remissions (8%). Response rate was higher than that induced by the previous line of treatment in 12 patients (46%).. Melphalan/bortezomib/thalidomide/dexamethasone showed encouraging antimyeloma activity in patients with advanced-stage myeloma.

Topics: Antineoplastic Combined Chemotherapy Protocols; Boronic Acids; Bortezomib; Combined Modality Therapy; Dexamethasone; Drug Administration Schedule; Female; Hematopoietic Stem Cell Transplantation; Humans; Male; Melphalan; Multiple Myeloma; Neoplasm Staging; Pyrazines; Recurrence; Salvage Therapy; Survival Analysis; Thalidomide

The recent development of reduced intensity conditioning and allotransplantation (RICT) has opened a new way to assure engraftment of donor cells while reducing early transplant-related mortality. We evaluated the combination of high-dose therapy and autologous peripheral blood stem cells transplantation (APBSCT) followed by RICT to extend the benefit of allografting procedures in de novo multiple myeloma (MM) patients. Fifteen subjects with stage III MM (median age 51 years, range 40-57) received high dose melphalan (200 mg/m(2)) followed by APBSCT previously collected after cyclophosphamide (4 g/m(2)) and granulocyte colony-stimulating factor (G-CSF). After 3-4 months from APBSCT, the patients underwent RICT, consisting of fludarabine 30 mg/m(2) + cyclophosphamide 300 mg/m(2) on days -4, -3, and -2. Acute graft-versus-host disease (GVHD) occurred in 2 patients; 6 patients developed chronic GVHD; 4 patients developed CMV antigenemia and were treated pre-emptively with ganciclovir. No transplant related mortality was shown. Response was simultaneously measured by both electrophoresis (EP) and immunofixation (IF); when IF was negative, patients were classified in complete remission (CR) and when it remained positive, near CR (nCR). After a median follow up of 44 months post APBSCT, 100 and 43% of patients are still alive and progression-free, respectively. Overall, the CR + nCR rate after dose-reduced allograft was enhanced from 26.7 to 73.3%. A correlation not statistically significant between GVHD and remission was found. In conclusion, an up-front tandem strategy with a very low reduced intensity-conditioning regimen for allografting following autografting is feasible and induces high CR/nCR rate in MM.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Disease-Free Survival; Female; Follow-Up Studies; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Myeloablative Agonists; Peripheral Blood Stem Cell Transplantation; Remission Induction; Retrospective Studies; Survival Rate; Transplantation Conditioning; Transplantation, Autologous; Vidarabine

We undertook a comparative study of Pegfilgrastim vs. Filgrastim after high-dose melphalan and autologous peripheral blood stem cell transplantation (APBSCT) in multiple myeloma (MM) patients. Thirty-seven consecutive patients were randomly assigned to receive a single 6 mg dose of Pegfilgrastim on day 1 post-transplant (n = 18 patients) vs. daily subcutaneous injections of Filgrastim 5 microg/kg (n = 19 patients) starting on day 5 post-transplant. The median duration of grade 4 neutropenia in the Pegfilgrastim and Filgrastim groups was 5 and 6 d, respectively (P = ns). The results for the two groups were also not significantly different for time to neutrophil and platelet recovery, but incidence of febrile neutropenia (61.1% vs. 100%, P = 0.003) and duration of febrile neutropenia (1.5 d vs. 4 d, P = 0.005), were lower in the Pegfilgrastim arm. After initial haematopoietic reconstitution, we observed significantly higher value of leukocytes x 10(9) L on day 15 (6.0 vs. 2.7, P = 0.004), in the Pegfilgrastim group compared with the Filgrastim group. This study shows that a single injection Pegfilgrastim can be used with safety and efficacy similar to those provided by daily injections of Filgrastim and it is associated with a decrease incidence of infectious events after APBSCT in MM patients.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Dacarbazine; Female; Filgrastim; Granulocyte Colony-Stimulating Factor; Hematopoiesis; Humans; Infection Control; Infections; Male; Melphalan; Middle Aged; Multiple Myeloma; Myeloablative Agonists; Neutropenia; Nimustine; Peripheral Blood Stem Cell Transplantation; Polyethylene Glycols; Recombinant Proteins; Recovery of Function; Time Factors; Transplantation, Autologous; Vincristine

A single injection of pegfilgrastim has been shown to be equivalent to daily filgrastim in enhancing neutrophil recovery after chemotherapy, whereas the experiences with pegfilgrastim in mobilization of peripheral blood progenitor cells (PBPCs) are limited.. Forty unselected patients with lymphoma or multiple myeloma were treated with different chemotherapy regimens followed by 6 mg of pegfilgrastim for mobilization of autologous PBPCs. Patients with an inadequate mobilization (blood CD34+ cells

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Cytarabine; Dexamethasone; Etoposide; Female; Filgrastim; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Mobilization; Humans; Lymphoma; Male; Melphalan; Middle Aged; Multiple Myeloma; Peripheral Blood Stem Cell Transplantation; Polyethylene Glycols; Recombinant Proteins; Remission Induction; Transplantation, Autologous; Treatment Outcome

Total Therapy 1, the first tandem autotransplant trial for newly diagnosed patients with multiple myeloma, was designed to increase the frequency of complete response (CR) and thereby extend survival. With a median follow-up of 12 years, 62 of 231 initially enrolled patients are alive (17% at 15 years); 31 remain event free (7% at 15 years) including 16 of 94 (41%) that initially achieved CR. Currently alive patients less frequently had cytogenetic abnormalities (CAs) at baseline (P = 0.002), postenrolment (P < 0.001) and at relapse (P = 0.004); elevations of serum C-reactive protein (CRP) (P = 0.003) and lactate dehydrogenase (P = 0.029), anaemia (P = 0.029) and they more often completed two transplants within 12 months (P = 0.019). Postenrolment overall survival (OS) and event-free survival (EFS) were superior in the absence of CA of the hypodiploidy or deletion 13 variety (P < 0.001 and 0.037 respectively) and in the presence of low CRP at baseline (P = 0.001 and 0.017 respectively). Postrelapse survival was longer in the absence of CA at relapse (P < 0.001), IgA isotype (P = 0.002), International Staging System stage 3 (P = 0.014), and when patients had two protocol transplants prior to relapse (P = 0.038). Ten-year EFS and OS could be accomplished in 15% and 33% of patients, respectively, when all agents available in 1989, especially high-dose melphalan, were applied together upfront for the management of myeloma.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Disease Progression; Drug Administration Schedule; Epidemiologic Methods; Female; Hematopoietic Stem Cell Transplantation; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Prognosis; Recurrence; Treatment Outcome

Melphalan & Prednisone (MP) is considered as the standard therapy for Multiple Myeloma (MM) patients not eligible for high-dose therapy. Here, we report the results of a phase I-II study to evaluate the feasibility and efficacy of the association of PLD to the conventional MP regimen during the first six cycles of the front-line therapy for untreated MM patients older than 70. Thirty patients were included in the study with a median age of 77 years (71-84) and a M/F ratio of 17/13. The phase I of the study demonstrated that the maximum tolerable dose of PLD in this setting was 30 mg/m(2), so it was the final dose evaluated in the study. Twenty-nine patients were valuable for response, which was: complete in 4 (14%) partial in 15 (52%) minor/no changes in 7 (24%) and progressive in 3 (10%). The median progression free survival (PFS) was 24 months. The median overall survival (OS) has not been reached yet, with a 3-year probability for OS and PFS of 52 and 37%, respectively. Haematological toxicity was frequent but usually weak/moderate (grades 1 & 2 of the WHO scale) and it was resolved only with dose delays. Infection was a relatively frequent event (30% of patients), but only in 4 cases it was of grade 3. No cases of palmar-plantar erythrodysesthesia were observed. In conclusion, pegylated liposomal doxorubicin can be safely added to the other chemotherapeutic drugs in the treatment of elderly MM patients, which can be very useful for patients in whom novel agents are not tolerated or inefficient.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Doxorubicin; Female; Humans; Infections; Male; Maximum Tolerated Dose; Melphalan; Multiple Myeloma; Polyethylene Glycols; Prednisone; Survival Rate; Treatment Outcome

We assessed the safety and efficacy of melphalan, arsenic trioxide (ATO) and ascorbic acid (AA) (MAC) combination therapy for patients with multiple myeloma (MM) who failed more than two different prior regimens. Patients received melphalan (0.1 mg/kg p.o.), ATO (0.25 mg/kg i.v.) and AA (1 g i.v) on days 1-4 of week 1, ATO and AA twice weekly during weeks 2-5 and no treatment during week 6 of cycle 1; during cycles 2-6, the schedule remained the same except ATO and AA were given twice weekly in week 1. Objective responses occurred in 31 of 65 (48%) patients, including two complete, 15 partial and 14 minor responses. Median progression-free survival and overall survival were 7 and 19 months respectively. Twenty-two patients had elevated serum creatinine levels (SCr) at baseline, and 18 of 22 (82%) showed decreased SCr levels during treatment. Specific grade 3/4 haematological (3%) or cardiac adverse events occurred infrequently. Frequent grade 3/4 non-haematological adverse events included fever/chills (15%), pain (8%) and fatigue (6%). This steroid-free regimen was effective and well tolerated in this heavily pretreated group. These results indicate that the MAC regimen is a new therapeutic option for patients with relapsed or refractory MM.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Arsenicals; Ascorbic Acid; Creatinine; Female; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Oxides; Prospective Studies; Recurrence; Survival Analysis; Treatment Outcome

Despite response rates of 30% after high-dose chemotherapy with autologous hematopoietic stem cell transplant, patients with multiple myeloma are not cured. 153Samarium ethylenediaminetetramethylenephosphonate (153Sm-EDTMP; Quadramet) is a short-range, beta-emitting therapeutic radiopharmaceutical with avid skeletal uptake. In total, 12 patients were treated with escalating doses of 153Sm-EDTMP (N=3/group; 6, 12, 19.8, and 30 mCi/kg) and a fixed dose of melphalan (200 mg/m(2)). No dose limiting toxicity was seen. To better standardize the marrow compartment radiation dose, the study was modified such that an additional six patients were treated at a targeted absorbed radiation dose to the red marrow of 40 Gy based on a trace labeled infusion 1 week prior to the therapy. Despite rapid elimination of unbound radiopharmaceutical via kidneys and bladder, no episodes of nephrotoxicity, hemorrhagic cystitis, or delayed radiation nephritis were observed with a median follow-up of 31 months (range 8.5-44). Median times to ANC>0.5 and platelet >20 x 10(6)/l were 12 and 11 days, respectively, with no graft failures. Overall response rate was 94% including seven very good partial responses and five complete responses. Addition of 153Sm EDTMP to melphalan conditioning appears to be safe, well-tolerated and worthy of further study.

Topics: Adult; Aged; Antineoplastic Agents, Alkylating; Combined Modality Therapy; Dose-Response Relationship, Drug; Female; Humans; Male; Maximum Tolerated Dose; Melphalan; Middle Aged; Multiple Myeloma; Organometallic Compounds; Organophosphorus Compounds; Radioisotopes; Samarium; Stem Cell Transplantation; Tissue Distribution; Transplantation Conditioning

Following induction therapy and 4 g/m(2) cyclophosphamide, a single dose of 12 mg polyethyleneglycol-conjugated G-CSF (pegfilgrastim; n=12) or daily doses of unconjugated G-CSF (8.5 mug/kg/day) (n=12) were administered to myeloma patients. Pegfilgrastim was associated with an earlier leukocyte recovery (12 vs 14 days) and peripheral blood CD34+ cell peak (12 vs 15 days). The peripheral blood CD34+ cell peak was lower in the pegfilgrastim group (78 vs 111/mul). Following high-dose melphalan (200 mg/m(2)) and autografting, leukocyte and platelet reconstitution was similar in both groups and stable blood counts were observed 100 days post transplant. In summary, a single dose of pegfilgrastim after chemotherapy is capable of mobilizing a sufficient number of CD34+ cells for successful autografting with early engraftment and sustained hematological reconstitution in patients with myeloma. These data provide the basis for randomized studies evaluating the optimal dose and time of pegfilgrastim as well as long-term outcome in larger cohorts of patients.

Topics: Adult; Antigens, CD34; Blood Platelets; Cyclophosphamide; Female; Filgrastim; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Mobilization; Humans; Kinetics; Leukapheresis; Leukocytes; Male; Melphalan; Middle Aged; Multiple Myeloma; Peripheral Blood Stem Cell Transplantation; Polyethylene Glycols; Protein Synthesis Inhibitors; Recombinant Proteins; Stem Cell Transplantation; Stem Cells; Time Factors

Multiple myeloma (MM) is an incurable hematologic malignancy for which autologous hematopoietic stem cell transplantation (HCT) is a standard therapy. The optimal method of stem cell mobilization is not defined. We evaluated intravenous melphalan (60 mg/m2), the most effective agent for MM, and G-CSF (10 microg/kg/day) for mobilization. End points were safety, adequacy of CD34+ collections, MM response, and contamination of stem cell components (SCC). In total, 32 patients were mobilized. There were no deaths or significant bleeding episodes; 14 patients (44%) required hospitalization for neutropenic fever. Median days of grade 3 or 4 neutropenia or thrombocytopenia were 7 (2-20) and 8 (3-17). Median mobilization days, CD34+ cells/kg and total leukaphereses were 16 (12-30), 12.1 million (2.6-52.8), and 2 (1-5) respectively. Four patients (12.5 %) failed to achieve the target of 4 million CD34+ cells/kg in five leukaphereses. Reduction in myeloma was seen in 11 patients (34%) with 3 (9%) achieving complete response; 15 (47%) maintained prior responses. Estimated MM contamination per SCC (N=48) was 0.0009% (range 0-0.1) and 0.21 x 10(4) cells per kg (range 0-41.2). Increased contamination was associated with increased patient age. This strategy for mobilization is feasible, frequently requires hospitalization and transfusion, and controls disease in most patients.

Topics: Adult; Age Factors; Aged; Female; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cell Transplantation; Humans; Leukapheresis; Male; Melphalan; Middle Aged; Multiple Myeloma; Neoplastic Cells, Circulating; Neutropenia; Transplantation, Autologous; Treatment Outcome

High dose chemotherapy with supporting autologous stem cell transplantation is now considered the treatment of choice in patients with multiple myeloma <65 years old. The best regimen appears to be VAD (vincristine, doxorubicin and dexamethasone), but acute and late toxicity can limit the use of this combination. The use of biological modifiers has not been considered in this situation. We developed a new cytoreductive regimen, in an attempt to retain clinical efficacy but reduce toxicity.. Thirty-six patients, previously untreated with diagnosis of multiple myeloma were enrolled to received the DAI regimen (dexamethasone 30 mg/m(2), i.v., days 1-4, all-trans-retinoic acid 45 mg/m(2), p.o., days 5-14 and interferon alpha 2a, 4.5 MU s.c., days 5-14) administered every 28 days for six cycles before high-dose chemotherapy (melphalan 200 g/m(2)) and autologous stem cell transplantation.. Overall response was observed in 29 cases (80%), complete response in 19 and partial response in 10 patients. Five patients were >65 years old and were treated with dexamethasone/thalidomide. Twenty-four patients underwent transplants. At a median follow-up of 31.6 months, no relapse or disease progression was observed, thus actuarial curves at 3-years showed that event-free survival was 86% and overall survival was 94%. Toxicity was mild.. This regimen appears to be an excellent alternative as cytoreductive treatment before high-dose chemotherapy and autologous stem cell transplantation with excellent overall response and minimal toxicity. Controlled clinical trials are warranted to define the role of this new therapeutic approach.

Topics: Administration, Oral; Adult; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Disease Progression; Disease-Free Survival; Female; Humans; Immunologic Factors; Infusions, Intravenous; Interferon alpha-2; Interferon-alpha; Male; Melphalan; Middle Aged; Multiple Myeloma; Peripheral Blood Stem Cell Transplantation; Recombinant Proteins; Transplantation, Autologous; Treatment Outcome; Tretinoin

Haematological and infectious toxicity was correlated to renal function in 272 newly diagnosed myeloma patients given standard dose melphalan-prednisone (MP) as initial treatment without dose adjustment for renal impairment. The glomerular filtration rate (GFR) was estimated by calculated creatinine clearance. Haematological toxicity was found to be significantly related to renal dysfunction. Haematological toxicity World Health Organization (WHO) grades 3-4 after the first MP course was seen in 18%, 28% and 36% of patients with a creatinine clearance of >50, 30-50 and <30 ml/min respectively. WHO grades 3-4 infections occurred in 6% and were not significantly related to renal function. We conclude that MP therapy can be used for initial therapy in myeloma patients with renal impairment but suggest that reduction of the melphalan dose should be considered in patients with a GFR of <30 ml/min. As only 2% of our patients had a clearance of < or =10 ml/min no conclusions can be drawn for this subgroup.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Drug Administration Schedule; Female; Glomerular Filtration Rate; Humans; Kidney Failure, Chronic; Male; Melphalan; Middle Aged; Multiple Myeloma; Prednisone; Retrospective Studies; Survival Rate

In this prospective multicentre trial, 90 patients undergoing autologous stem cell transplantation (ASCT) were randomised to receive (n=43) or not receive (n=47) amifostine 910 mg/m(2) prior to melphalan 200 mg/m(2). Patients were monitored for regimen-related toxicity, engraftment, supportive care, response and survival. Both groups underwent ASCT at a median of 8 months from diagnosis and were matched for disease characteristics, prior therapy and pre-ASCT disease responsiveness. Amifostine infusional side-effects were frequent, occurring in 65% of patients, but of mild severity. Amifostine use was associated with a reduction in the median grade of oral mucositis (1 vs 2, P=0.01) and the frequency of severe (WHO grades 3 or 4) mucositis (12 vs 33%, P=0.02), but no reduction in the requirement for parenteral nutrition or analgesic use. Conversion to complete remission post-ASCT occurred in 30 and 14% of the amifostine and control groups, respectively (P=0.09). With a median follow-up of 35 months, there was no statistically significant difference between the median progression-free or overall survival times for the two groups. We conclude that amifostine can be safely administered prior to high-dose melphalan and significantly reduces the frequency and severity of therapy-induced oral mucositis.

Topics: Adult; Aged; Amifostine; Cytoprotection; Female; Hematopoietic Stem Cell Transplantation; Humans; Male; Melphalan; Middle Aged; Mouth Mucosa; Multiple Myeloma; Prospective Studies; Stomatitis; Transplantation Conditioning; Transplantation, Autologous

We analyzed both morphologic and phenotypic findings of myeloma cells before and after chemotherapy in 21 patients with multiple myeloma. The morphologic analysis was based on the Greipp classification, and phenotypic analysis was performed by 3-color flow cytometry using the CD38 plasma gating method (Marrow plasma 38). Results with flow cytometry using a combination of MPC1, CD49e, and CD45 supported the morphologic findings for the myeloma cells. Treatment with 3 or 4 cycles of VAD (vincristine, doxorubicin, and dexamethasone) therapy was effective in reducing the total numbers of myeloma cells, but the proportion of immature myeloma cells increased after this treatment. However, the immature myeloma cells were reduced by high-dose melphalan (HD-Mel) therapy followed by autologous stem cell transplantation (ASCT). High-dose cyclophosphamide treatment for stem cell harvesting did not show an effect on the residual immature myeloma cells after VAD treatment. In addition, thalidomide was not effective in reducing the numbers of immature myeloma cells. These results suggest that VAD (3 or 4 cycles) therapy plus HD-Mel followed by ASCT is a reasonable treatment for multiple myeloma and that Marrow plasma 38 analysis is a useful method for monitoring the response of multiple myeloma to chemotherapy.

Topics: ADP-ribosyl Cyclase; ADP-ribosyl Cyclase 1; Aged; Antigens, CD; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cell Differentiation; Cyclophosphamide; Dexamethasone; Doxorubicin; Drug Resistance, Neoplasm; Female; Flow Cytometry; Humans; Male; Melphalan; Membrane Glycoproteins; Middle Aged; Multiple Myeloma; Phenotype; Prednisone; Prognosis; Stem Cell Transplantation; Treatment Outcome; Vincristine

We conducted a randomised trial comparing an intensified versus a standard conditioning regimen for high-dose chemotherapy followed by autologous stem-cell transplantation in patients with multiple myeloma. In this study, 56 patients were randomly assigned for high-dose therapy with melphalan 200 mg/m2 or with idarubicin 42 mg/m2, melphalan 200 mg/m2 and cyclophosphamide 120 mg/kg. The primary objective was response rate. Acute toxicity, mainly because of infections, was higher in the intensified treatment arm with a treatment-related mortality of 20% versus 0% in the standard arm. This lead to the early discontinuation of the study. Response rates did not differ significantly between both treatment arms {intensified versus standard: complete response+near complete remission 50% [95% confidence interval (CI) 26-74%] vs. 33% (95% CI 17-55%), partial remission 35% (95% CI 16-61%) vs. 50% (95% CI 30-70%)}. After a follow-up of 5 years, the median time-to-progression and overall survival were not significantly different between both patient groups. Analysis restricted to patients surviving the first 100 d after transplant showed a better outcome for patients with >or=2 bad prognostic risk factors in the intensified treatment arm, however all treatment-related deaths occurred within this group of patients. In conclusion, intensified conditioning for high-dose therapy had intolerably high toxicity without improving outcome in patients with multiple myeloma.

Topics: Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Disease-Free Survival; Drug Administration Schedule; Female; Humans; Idarubicin; Male; Melphalan; Middle Aged; Multiple Myeloma; Prognosis; Remission Induction; Risk Factors; Stem Cell Transplantation; Survival Rate; Transplantation Conditioning

The aim of the present randomized trial was to compare high-dose therapy (HDT) with continued conventional chemotherapy in patients with multiple myeloma (MM) who responded to the initial treatment. From May 1994 to October 1999, 216 patients (122 men/94 women; stage II or III; Eastern Cooperative Oncology Group [ECOG] score less than 3) entered the study. Initial chemotherapy consisted of 4 cycles of alternating vincristine, BCNU, melphalan, cyclophosphamide, prednisone/vincristine, BCNU, Adriamycin, dexamethasone (VBMCP/VBAD). Responding patients were randomly assigned to receive 8 additional cycles of VBMCP/VBAD, intensification with melphalan 200 mg/m2, or melphalan 140 mg/m2 plus 12 Gy fractionated total body irradiation (TBI). One-hundred sixty-four patients were randomly assigned, 83 to continued chemotherapy and 81 to HDT. The complete remission (CR) rate was significantly higher with HDT (30% vs 11%; P = .002). However, progression-free survival (PFS) was not significantly different between HDT and conventional therapy (median, 42 vs 33 months; P = not significant [NS]), and overall survival (OS) was similar in both groups (median, 61 vs 66 months). Finally, survival after relapse was identical in the 2 arms (15.9 vs 16.4 months). In conclusion, these results show that HDT intensification, when given to myeloma patients who have responded to the initial chemotherapy, significantly increases the CR rate but has no significant impact on PFS or OS.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carmustine; Cyclophosphamide; Dexamethasone; Dose-Response Relationship, Drug; Doxorubicin; Female; Humans; Male; Melphalan; Multiple Myeloma; Prednisone; Remission Induction; Spain; Survival Analysis; Treatment Outcome; Vincristine

Interleukin-6 (IL-6) is a major survival factor for multiple myeloma (MM) cells preventing apoptosis induced by dexamethasone (DEX) or chemotherapy. In all, 24 consecutive patients with MM in first-line therapy received DEX for 4 days, followed by melphalan (HDM: 140 mg/m2) and autologous stem cell transplantation (ASCT). The anti-IL-6 monoclonal antibody (mAb) (B-E8) was given till haematological recovery, starting 1 day before DEX. Results were historically compared to MM patients treated with HDM 140 and 200 mg/m2. Our results show (1) that B-E8 was able to fully neutralize IL-6 activity in vivo before and after HDM as shown by inhibition of C reactive protein (CRP) production; (2) no haematological toxicity; (3) a significant reduction of mucositis and fever; (4) a median event-free survival of 35 months and an overall survival of 68.2% at 5 years with a median follow-up of 72 months; and (5) the overall daily IL-6 production progressively increased on and after 7 days post-HDM, with the increased serum CRP levels. In the 5/24 patients with uncontrolled CRP production, a large IL-6 production was detected (320 microg/day) that could not possibly be neutralized by B-E8. These data show the feasibility to neutralize IL-6 in vivo with anti-IL-6 mAb in the context of HDM.

Topics: Adult; Aged; Anti-Inflammatory Agents; Antibodies, Monoclonal; C-Reactive Protein; Dexamethasone; Disease-Free Survival; Drug Evaluation; Female; Humans; Interleukin-6; Male; Melphalan; Middle Aged; Mucositis; Multiple Myeloma; Myeloablative Agonists; Pilot Projects; Stem Cell Transplantation; Transplantation, Autologous

We report on a randomised trial that aimed to compare the efficacy of continued daily prednisolone treatment during the entire induction phase, with prednisolone given for 2 weeks of each cycle in combination with VMCP (vincristine, melphalan, cyclophosphamide, prednisolone)-interferon-alpha 2b (IFN-alpha 2b) treatment in 299 previously untreated elderly patients (median age: 67 years) with multiple myeloma. After completion of induction treatment patients were randomised to IFN-alpha 2b with or without prednisolone, thrice weekly. Response rate was 62% in the continuous and 60% in the control arm (intent to treat analysis, P=0.81). Progression-free survival [median: 20 months vs. 19 months; hazard ratio (HR): 0.99, 95% confidence interval (CI): 0.74-1.33, P=0.97] and overall survival (median: 34 months vs. 37 months; HR: 1.16, 95% CI: 0.85-1.59, P=0.35) were similar in both groups. Reduced performance status (Eastern Cooperative Oncology Group, grades 2-4) was the predominant risk factor for poor survival followed by age >65 years, high beta2-microglobulin, and impaired renal function. There was more grades 3-4 dyspnoea and cardiac impairment and grades 1-2 hyperglycaemia, but less nausea, emesis and anaemia in patients on continuous prednisolone therapy. In conclusion, continuing prednisolone treatment during the entire duration of the induction phase with VMCP-IFN-alpha 2b did not improve outcome.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Drug Administration Schedule; Female; Glucocorticoids; Humans; Interferon alpha-2; Interferon-alpha; Male; Melphalan; Middle Aged; Multiple Myeloma; Neoplasm Staging; Prednisolone; Prednisone; Recombinant Proteins; Survival Analysis; Treatment Outcome; Vincristine

To study the impact of high-dose therapy (HDT) with autologous stem-cell support in patients with symptomatic multiple myeloma (MM) between the ages of 55 and 65 years.. One hundred ninety patients between 55 and 65 years old who had newly diagnosed stage II or III MM were randomly assigned to receive either conventional chemotherapy (CCT; ie, monthly courses of a regimen of vincristine, melphalan, cyclophosphamide, and prednisone) or HDT and autologous blood stem-cell transplantation (using either melphalan alone 200 mg/m(2) intravenous [IV] or melphalan 140 mg/m(2) IV plus busulfan 16 mg/kg orally as pretransplantation cytoreduction).. Within a median follow-up of 120 months, median event-free survival (EFS) times were 25 and 19 months in the HDT and CCT groups, respectively. Median overall survival (OS) time was 47.8 months in the HDT group compared with 47.6 months in the CCT group. A trend to better EFS (P = .07) was observed in favor of HDT, whereas OS curves were not statistically different (P = .91). The period of time without symptoms, treatment, and treatment toxicity (TwiSTT) was significantly longer for the HDT patients than for the CCT patients (P = .03).. With a median follow-up time of approximately 10 years, this randomized trial confirmed a benefit of HDT in terms of EFS and TwiSTT but did not provide evidence for superiority of HDT over CCT in OS of patients aged 55 to 65 years with symptomatic newly diagnosed MM.

Topics: Age Factors; Aged; Antineoplastic Combined Chemotherapy Protocols; Busulfan; Cyclophosphamide; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Peripheral Blood Stem Cell Transplantation; Prednisone; Transplantation, Autologous; Treatment Outcome; Vincristine

Several trials have shown the superior impact of high-dose melphalan (usually 200 mg/m(2), MEL200) vs standard therapy in myeloma patients. Intermediate-dose melphalan (100 mg/m(2), MEL100) is also superior to the standard dose, but has not been clinically compared with MEL200. A total of 90 patients at diagnosis were treated with two MEL100 courses. Their clinical outcome was compared with that of a control group of 90 pair mates matched for serum beta2-microglobulin levels and Durie and Salmon clinical stage. These patients were treated at diagnosis with two MEL200 courses. Patient characteristics were similar in both groups except that the median age of the MEL100 group was significantly higher (P<0.0001). Complete remission was 35% after MEL100 and 48% after MEL200 (P=0.08). Median event-free survival (EFS) was 32 months in the MEL100 group and 42 months in the MEL200 group (P<0.005), but overall survival (OS) was not different. Transplant-related mortality was not significantly different. Haematological and extra-haematological toxicity was significantly reduced after MEL100. Despite the significant age difference, tandem MEL100 was less toxic than tandem MEL200, and MEL100 was inferior to MEL200 in terms of EFS but not in terms of OS. The intensified nonmyeloablative MEL100 regimen is an effective first-line treatment.

Topics: Adult; Aged; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Neoplasm Staging; Survival Rate

High-dose therapy (HDT) followed by autologous stem cell support is widely used as intensification treatment in patients with multiple myeloma (MM) responsive to the initial chemotherapy. However, there is growing evidence that only the subset of patients who achieve complete remission (CR) actually benefit from this approach. The aim of this study was to identify pretransplant predictors of CR in responding myeloma patients intensified with HDT. A total of 59 patients with chemosensitive disease received myeloablative therapy. The intensification regimen consisted of MEL-200 (23), MEL-140/TBI 12 Gy (21) or busulfan-based regimens (15). Serum and urine negative immunofixation were required for CR. After HDT, the CR rate increased from 8 to 37%. For the overall series, the median event-free survival (EFS) and overall survival (OS) from the initiation of therapy were 41 and 68 months, respectively. Patients who achieved CR had an EFS (median 47 vs 36 months; P=0.023) as well as an OS (median not reached vs 60 months; P=0.006) significantly longer than those attaining a lower degree of response. Finally, the pretransplant features significantly associated to CR were a low M-protein size (serum

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Busulfan; Female; Hematopoietic Stem Cell Transplantation; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Myeloma Proteins; Prognosis; Remission Induction; Risk Factors; Survival Analysis; Transplantation, Autologous

To investigate whether combination chemotherapy with vincristine, cyclophosphamide, prednisolone, and melphalan (COP/ MP) with the addition of ranimustine (MCNU) (MCNU-COP/MP) is superior to the slightly modified COP/MP (mCOP/MP) regimen in multiple myeloma (MM), a multicenter randomized study was performed. Two hundred ten patients with newly diagnosed, overt MM not treated with chemotherapy were enrolled from 32 institutions of the Lymphoma Study Group of the Japan Clinical Oncology Group and were randomized to receive either MCNU-COP/MP or mCOP/MP. The response rate (RR) to mCOP/MP was 43.7% (95% confidence interval [CI], 33.9%-53.8%] and to MCNU-COP/MP was 56.1% (95% CI, 46.1%-65.7%) (P = .097). The progression-free survival (PFS) was significantly longer for patients treated with MCNU-COP/MP than for patients treated with mCOP/MP (median, 23.0 months [95% CI, 18.9-25.8] versus 15.8 months [95% CI, 14.1-19.4]) (P = .014). However, no significant difference in overall survival rate (OS) was observed between the groups (median, 49.9 months [95% CI, 40.4-59.1] versus 44.0 months [95%, CI, 32.8-59.8]) (P = .75). Grades 3 and 4 hematological toxicities were more frequently observed with MCNU-COP/MP than with mCOP/MP, but the incidence of grades 3 and 4 nonhematological toxicities was low in both groups. In conclusion, MCNU-COP/MP in comparison with mCOP/MP improved RR and PFS in overt MM; however, this outcome did not contribute to prolonging OS, indicating that addition of MCNU to mCOP/MP has no benefit on survival.

Topics: Adult; Aged; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Disease-Free Survival; Female; Humans; Japan; Male; Melphalan; Middle Aged; Multiple Myeloma; Nitrosourea Compounds; Prednisone; Treatment Outcome; Vincristine

Whether the response to chemotherapy is a prognosticator in multiple myeloma (MM) is still not known. Therefore, the relationship between survival and the rate of monoclonal protein (M-protein) decrement during the first cycles of therapy was prospectively assessed in 262 patients with newly diagnosed MM that were included in a phase III trial (HOVON-16). M-proteins were collected monthly during melphalan-prednisone therapy (MP: melphalan 0.25 mg/kg, prednisone 1.0 mg/kg orally for 5 d every 4 weeks). Patients with light chain disease (n = 18), immunoglobulin M (IgM)-MM (n = 1) and no immunotyping (n = 1) were excluded. Of the 242 patients studied, 75% had IgG M-protein and 25% IgA; MM stages: I: 1%, II: 35% and III: 64%. The median M-protein decrease after the first cycle of MP was 21% for IgG and 27% for IgA, and declined to < 5% after four cycles. An obvious survival advantage was seen for patients who had an M-protein decrease of at least 30% after the first MP cycle, which became significant when an M-protein decrease of 40% or more was reached. As established prognostic parameters (Salmon & Durie stage, serum creatinine, and haemoglobin) also remained prognostically significant, we concluded that early response to MP predicts for survival in MM.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Female; Humans; Immunoglobulin A; Immunoglobulin G; Male; Melphalan; Middle Aged; Multiple Myeloma; Myeloma Proteins; Prednisone; Prospective Studies; Survival Analysis; Treatment Outcome

A prospective randomised phase III study in patients < or =65 years old with previously untreated multiple myeloma (MM), intensive chemotherapy followed by myeloablative chemotherapy and autologous stem-cell rescue was compared with intensive chemotherapy alone. This economic evaluation was based on detailed data from patient charts and hospital information systems. In the intention-to-treat analysis, mean total treatment and follow-up costs of the myeloablative treatment arm were 81,643 euros compared to 68,802 euros for the chemotherapy arm (P=0.09). Costs per quality-adjusted life year were 51,357 euros versus 37,328 euros. In the clinical study, no significant differences were found in overall survival after a median follow-up of 33 months from randomisation. Intensive chemotherapy is regarded as standard therapy for younger patients with previously untreated MM. Cost-effectiveness of myeloma therapy after 3 years of follow up seems not to be favoured by myeloablative treatment with autologous stem-cell rescue.

Topics: Adult; Aged; Antineoplastic Agents, Alkylating; Cost-Benefit Analysis; Costs and Cost Analysis; Cyclophosphamide; Female; Follow-Up Studies; Hematopoietic Stem Cell Transplantation; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Prospective Studies; Transplantation, Autologous

Thalidomide has demonstrated a remarkable efficacy in the treatment of multiple myeloma but its use may cause several toxicities. We have investigated the common and rare side-effects, especially analysing peripheral neuropathy, in order to optimise the thalidomide dose for minimizing this harmful side-effect.. Fifty-nine patients were treated with thalidomide alone or combined with oral melphalan. The median age was 69 yr. The initial dose of thalidomide was 100 mg/day increasing weekly by 100 mg increments until a maximum dose of 400 mg was attained. Melphalan was administered at a dose of 0.20 mg/kg/d for 4 d every 28 d.. Nearly one-fourth of patients discontinued thalidomide because of toxicity. Constipation (71%), somnolence (36%) and fatigue (20%) were the most common side-effects and they were not dose dependent. Peripheral neuropathy occurred in 39% of patients and a thalidomide median daily dose of more than 150 mg was significantly associated with higher frequency and actuarial risk of peripheral neuropathy without improving the response rate. Deep venous thrombosis was observed in 7% of patients and other side-effects were rare. In patients with advanced multiple myeloma we found that a thalidomide daily dose of 150 mg minimizes peripheral neuropathy without jeopardizing response and survival.

Topics: Aged; Aged, 80 and over; Constipation; Disorders of Excessive Somnolence; Dose-Response Relationship, Drug; Fatigue; Female; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Peripheral Nervous System Diseases; Probability; Thalidomide; Venous Thrombosis

The goal of this trial was to assess the toxicity and potential efficacy of high-dose topotecan, melphalan and cyclophosphamide as a preparative regimen for patients with multiple myeloma undergoing autologous stem cell transplantation. Eighteen patients were treated, 8 for first remission consolidation, 4 with relapse sensitive disease, 3 primary refractory and 3 relapsed refractory. The median age was 56 (38 - 65) and the median number of prior regimens was 3 (1 - 8). Patients received cyclophosphamide 1 g/m2/d on days -6, -5, -4; melphalan 70 mg/m2 on days -3, -2 and topotecan 3.0 to 3.5 mg/m2/d on days -6 to -2. Peripheral blood stem cells were infused on day 0. Toxicity (Bearman Toxicity Criteria) was mostly limited to grade 1 - 2 mucositis and grade 1 diarrhea. There were no transplant-related deaths. The overall response rate at 3 months post transplantation was 89% with 17% CR, 2 of those in refractory patients. The overall response rate in refractory patients was 67%. With a median follow up of 12.3 months, 89% of patients are alive. The TMC regimen is well tolerated and produces high response rates. Further evaluation of TMC to fully assess response and survival is ongoing.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Female; Hematopoietic Stem Cell Transplantation; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Pilot Projects; Remission Induction; Survival Rate; Topotecan; Transplantation, Autologous; Treatment Outcome

High-dose therapy is an effective standard treatment for multiple myeloma patients. Evidence that intermediate-dose therapy improves survival is limited. At diagnosis, about 70% of patients are older than 65. Intermediate-dose regimen is very well tolerated in older patients. In a multicenter study, 194 patients were randomized to receive at diagnosis either conventional chemotherapy (6 courses of oral melphalan and prednisone [MP]) or intermediate-dose therapy (2 courses of melphalan at 100 mg/m(2) [MEL100]) with stem cell support. Response rate was higher after MEL100. Near-complete remission (nCR) was 6% after MP and 25% after MEL100 (P = .0002). At 3 years, MEL100 increased event-free survival (EFS) from 16% to 37% and overall survival (OS) from 62% to 77% (P < .001). Similar results were observed in patients aged 65 to 70: nCR was 8% after MP and 25% after MEL100 (P = .05); at 3 years, MEL100 improved EFS from 18% to 31% (P = .01) and OS from 58% to 73% (P = .01). Patients aged 65 to 70 had a median OS of 37.2 months (MP) versus 58 months (MEL100). Intermediate-dose melphalan improves response rate, EFS, and OS in myeloma patients, specifically in those aged 65 to 70. It constitutes a more effective first-line regimen than standard treatment for elderly patients.

Topics: Aged; Antineoplastic Agents, Alkylating; Disease-Free Survival; Female; Follow-Up Studies; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Salvage Therapy; Survival Analysis; Treatment Outcome

Thalidomide, the prototype of a new class of agents active against multiple myeloma (MM), exerts synergistic/additive effects when combined with other drugs. The aim of this study was to compare the toxicity and efficacy of thalidomide alone and in combination with oral melphalan. Patients with advanced MM received 100 mg/day oral thalidomide escalated weekly up to 600 mg/day (n=23; T group), alone or with 0.20 oral mg/kg/die melphalan administered monthly for four consecutive days (n=27; TM group). A>/=50% paraprotein reduction was observed in 59% of TM compared with 26% of T patients (P=0.009); three TM patients were found to have an absence of paraprotein by immunofixation. After a median follow-up of 13 months (range 6-32), progression-free survival (PFS) at 2 years was significantly longer in the TM group (61 versus 45%; P=0.0376), whereas overall survival did not differ significantly. Toxicity was not significantly greater with the combination therapy; although DVT was more frequent (11 versus 4%), as was grade 3 leukopenia (30 versus 13%; P=0.073), there were no cases of severe infection. Thalidomide administered with oral melphalan improved response rates and PFS in patients with advanced MM without significantly increasing severe toxicity.

Topics: Administration, Oral; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Female; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Survival Analysis; Thalidomide

Standard treatment for patients with multiple myeloma is debulking chemotherapy with non-alkylating agents followed by a regimen to mobilize peripheral blood stem cells (PBSC) and the transplantation of the mobilized, autologous PBSC. The aim of this study was to evaluate the efficacy of a new regimen and compare it with that of a previous regimen.. In a large cohort of 106 patients (group I) we administered a new pre-transplant program which includes 2 courses of pulsed-VAD (vincristine, adriamycin, dexamethasone) followed by 2 courses of DCEP (dexamethasone, cyclophosphamide, etoposide and cis-platinum). We compared the efficacy of this new VAD-DCEP sequence, in terms of mobilizing capacity, toxicity and anti-myeloma activity in comparison with that of the previous VAD-high-dose cyclophosphamide program (group II, 40 patients).. In group I 81/106 (76.4%) patients yielded >or= 4x10(6)/kg CD34+ cells, as did 30/40 (75%) in group II but with a significantly higher toxicity in this latter group. In detail, 9 patients in group I (8.5%) had WHO grade III neutropenia versus 35 in group II (87.5%), 5 patients of group I (4.7%) had grade III thrombocytopenia versus 12 patients in group II (30%), and 8 patients in group I (7.5%) experienced an infections fever versus 9 patients in group II (22.5%). Therefore, nearly all patients in group II had to be admitted to hospital (39/40, 97.5%). There was a higher percentage of responses (CR+VGPR+PR) in group I than in group II: 73% versus 50% (p=0.02).. the VAD-DCEP sequence has an adequate mobilizing capacity, without significant toxicity, and a good anti-myeloma activity, and therefore represents a safe and effective therapeutic approach for multiple myeloma patients at the onset of their disease.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Cohort Studies; Combined Modality Therapy; Cyclophosphamide; Dexamethasone; Doxorubicin; Drug Administration Schedule; Etoposide; Female; Hematopoietic Stem Cell Mobilization; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Neoadjuvant Therapy; Neutropenia; Thrombocytopenia; Transplantation Conditioning; Transplantation, Autologous; Treatment Outcome; Vincristine

We evaluated prognostic factors of melphalan/fludarabine-based dose-reduced allografts in patients with multiple myeloma. From 1998 to 2002, 120 patients with multiple myeloma were treated with melphalan/fludarabine followed by allogeneic stem cell transplantation. The cumulative risk at 1 year for treatment-related mortality (TRM) was 18% (95% confidence interval [CI], 12%-28%). In a multivariate analysis, relapse after prior high-dose chemotherapy was the most significant risk factor for TRM (hazard ratio [HR], 2.80; 95% CI, 1.16-6.74; P =.02), relapse (HR, 4.14; 95% CI, 2.04-8.38; P <.001), event-free survival (HR, 3.11; 95% CI, 1.77-5.46; P <.001), and overall survival (HR, 2.69; 95% CI, 1.35-5.35; P =.005). In addition, relapse was also significantly diminished by chronic graft-versus-host disease (GVHD) in a time-dependent Cox model (HR, 0.37; 95% CI, 0.16-0.87; P =.02). At transplantation, 8% of the patients were in complete remission, whereas 27% had progressive disease. After allografting, 49% achieved complete remission, and 38% achieved partial remission. In a subgroup of patients with chemosensitivity at transplantation and no relapse after prior high-dose chemotherapy who underwent transplantation with peripheral blood stem cells (n = 46), the cumulative risk of TRM at 1 year was only 8% (95% CI, 1%-54%). The 2-year estimated event-free and overall survival was 60% (95% CI, 42%-78%) and 75% (95% CI, 59%-91%), respectively, for related donors (n = 34) and was 81% (95% CI, 59%-100%) and 92% (95% CI, 76%-100%), respectively, for unrelated donors (n = 12).

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Chronic Disease; Female; Graft Survival; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Prognosis; Recurrence; Remission Induction; Salvage Therapy; Survival Analysis; Transplantation, Autologous; Transplantation, Homologous; Treatment Outcome; Vidarabine

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Arsenic Trioxide; Arsenicals; Ascorbic Acid; Disease Progression; Drug Resistance, Neoplasm; Humans; Melphalan; Middle Aged; Multiple Myeloma; Oxides; Prospective Studies; Recurrence; Time Factors; Treatment Outcome

Melphalan-prednisone (MP) has been the gold standard treatment for more than 30 years in elderly multiple myeloma (MM) patients. In order to assess whether the combination of dexamethasone with melphalan (MD) could improve on the efficacy of MP, we have carried out a randomized trial comparing both treatment approaches. A total of 201 patients >/=70 years old were included in the study. The overall response rate was similar after six cycles (MP: 67.9%versus MD: 64.5%) and after 12 cycles (MP: 49.4%versus MD: 46.1%). However, the proportion of complete responses (CR) was higher in the MD arm, particularly after 12 cycles (MD: 22.4%versus MP: 9.1%; P < 0.05). There was no significant difference in event-free survival (MP: 15.9 months versus MD: 23.3 months). The median overall survival in both arms was almost identical (MP: 29.4 months versus MD: 27.2 months; P = 0.63). No significant differences in haematological toxicity were observed, but non-haematological toxicity was significantly higher in the MD arm. According to these results MP remains as the gold standard for treatment of MM and should be the reference for comparison of new therapeutic approaches involving novel agents.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Female; Follow-Up Studies; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Prednisone; Regression Analysis; Survival Rate

Tandem stem cell transplantation is an important treatment option for patients with myeloma and some additional tumors. In an attempt to reduce the contamination of the stem cell graft with tumor cells, patients with myeloma who entered complete remission after the first transplant underwent a second episode of mobilization to obtain progenitor cells for the second transplant.. Twenty-two patients with myeloma participated in the study. The first mobilization utilized CY, etoposide and filgrastim. The second mobilization used the same regimen, but seven patients received only filgrastim. The interval between the two collection periods was 6 months (median; range 4-9 months). The preparative regimen for the first transplant consisted of melphalan 200 mg/m(2).. The number of total white cells collected during the two collection episodes was similar: 10.8+/-1.6 x 10(8)/kg white cells vs. 11.8+/-1.7 x 10(8)/kg white cells (P=0.63). The collected CD34(+) cell dose was much larger during the first collection: 45.2+/-8.4 x 10(6)/kg vs. 6.9+/-2.7 x 10(6)/kg (P<0.001). Similarly, the collected colony-forming unit (CFU)-GM dose was much larger during the first collection: 295.4+/-59.3 x 10(4)/kg vs. 67.3+/-21.6x10(4)/kg (P<0.001). While the CD34(+) cells collected during the two collection episodes correlated significantly (r=0.55, P<0.01); the first dose was a median of 14.9-fold larger.. No laboratory parameter was able reliably to predict the results of the second collection. A second mobilization/collection episode as part of a tandem transplant approach carries a considerable risk of failing to obtain sufficient progenitor cells.

Topics: Adult; Aged; Antineoplastic Agents, Alkylating; Female; Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cells; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Transplantation, Autologous

Sixteen patients with stage III multiple myeloma (MM) and a median age of 51 years were treated with autografting followed by reduced intensity conditioning allotransplantation (RICT). Nine patients are alive in remission at a median of 30 months after their transplants, one patient is alive in relapse and 6 patients died of progressive disease (5) or extensive chronic graft-versus-host disease, infections and progressive disease (1). We suggest that this two-step approach is feasible and it has strong anti-myeloma activity.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Cyclophosphamide; Disease Progression; Disease-Free Survival; Feasibility Studies; Female; Graft vs Host Disease; Granulocyte Colony-Stimulating Factor; Humans; Immunosuppressive Agents; Infections; Male; Melphalan; Middle Aged; Multiple Myeloma; Peripheral Blood Stem Cell Transplantation; Postoperative Complications; Remission Induction; Salvage Therapy; Survival Analysis; Transplantation Conditioning; Transplantation, Autologous; Transplantation, Homologous; Treatment Outcome; Vidarabine; Whole-Body Irradiation

We compared the efficacy of intensified chemotherapy followed by myeloablative therapy and autologous stem cell rescue with intensified chemotherapy alone in patients newly diagnosed with multiple myeloma. There were 261 eligible patients younger than 66 years with stage II/III multiple myeloma who were randomized after remission induction therapy with vincristine, adriamycin, dexamethasone (VAD) to receive intensified chemotherapy, that is, melphalan 140 mg/m(2) administered intravenously in 2 doses of 70 mg/m(2) (intermediate-dose melphalan [IDM]) without stem cell rescue (n = 129) or the same regimen followed by myeloablative therapy consisting of cyclophosphamide, total body irradiation, and autologous stem cell reinfusion (n = 132). Interferon-alpha-2a was given as maintenance. Of the eligible patients, 79% received both cycles of IDM and 79% of allocated patients actually received myeloablative treatment. The response rate (complete remission [CR] plus partial remission [PR]) was 88% in the intensified chemotherapy group versus 95% in the myeloablative treatment group. CR was significantly higher after myeloablative therapy (13% versus 29%; P =.002). With a median follow-up of 33 months (range, 8-65 months), the event-free survival (EFS) was not different between the treatments (median 21 months versus 22 months; P =.28). Time to progression (TTP) was significantly longer after myeloablative treatment (25 months versus 31 months; P =.04). The overall survival (OS) was not different (50 months versus 47 months; P =.41). Intensified chemotherapy followed by myeloablative therapy as first-line treatment for multiple myeloma resulted in a higher CR and a longer TTP when compared with intensified chemotherapy alone. However, it did not result in a better EFS and OS.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cause of Death; Chromosome Aberrations; Combined Modality Therapy; Cyclophosphamide; Dexamethasone; Disease-Free Survival; Doxorubicin; Female; Granulocyte Colony-Stimulating Factor; Humans; Leukocyte Count; Male; Melphalan; Middle Aged; Multiple Myeloma; Myeloablative Agonists; Prognosis; Prospective Studies; Quality of Life; Remission Induction; Stem Cell Transplantation; Survival Rate; Transplantation, Autologous; Vincristine; Whole-Body Irradiation

In this study we evaluated whether a good response to conventional chemotherapy, i.e. a significant tumour reduction, is a prerequisite for improved survival in multiple myeloma (MM). Between January 1987 and March 1990, 341 consecutive previously untreated patients with MM received chemotherapy within the prospective, multicentre, randomised Protocol MM87. Of these, 258 patients were evaluable for both response and long-term survival and 244 (94.6%) have died. The median survival of all patients was 40 months (6-162 months). The median survival did not differ between patients who had complete response (CR) (50 months (9-162 months)), partial response (PR) (46 months (8-147 months)) or stable disease (SD) (41 months (7-135 months)). The median survival was shorter (13.6 months (6-135 months)) (P<0.0001) in patients whose disease progressed while they were receiving first induction chemotherapy. Causes of death were more frequently (P=0.04) related to MM in patients who had progressive disease (PD) than in patients who had a CR or PR or SD. The main clinical and laboratory characteristics were similar in the four groups. These data indicate that patients who maintain SD during first-line chemotherapy have a prognosis similar to that of patients who attain a response. Only patients whose disease progresses have a distinctly worse outcome.

Topics: Analysis of Variance; Antineoplastic Combined Chemotherapy Protocols; Cause of Death; Drug Evaluation; Female; Humans; Male; Melphalan; Multiple Myeloma; Peptichemio; Prednisone; Prospective Studies; Software Design; Survival Analysis; Vincristine

Optimal methods of stem cell mobilization in multiple myeloma are undefined, and contaminating clonotypic cells could contribute to disease recurrence. A phase 2 trial of intravenous melphalan (60 mg/m2) and granulocyte colony-stimulating factor (G-CSF) (10 microg/kg/d) for mobilization was performed. To enhance reliability, contamination was assessed with 2 sensitive methods, immunoglobulin light and heavy chain variable region patient-specific limiting-dilution polymerase chain reaction (PCR). We evaluated 29 stem cell components (SCCs) from 15 patients; for 9 SCCs, only VL PCR was used because of light chain disease or technical problems with VH primers. For 20 SCCs, VL and VH PCR results were highly correlated (r2 = 0.93, P <.01), with 35% (7 of 20) having identical estimates. VH PCR gave significantly higher estimates for 8-and VL PCR for 5-SCCs, supporting the utility of using 2 methods. Estimated clonotypic contamination per SCC was 0.0009% (range, 0%-0.1%) or 0.5 x 10(4) clonotypic cells per kilogram (range, 0-41.2 x 10(4)/kg), and contamination correlated with CD34+ cells collected (r2 = 0.42, P <.01). Melphalan-mobilized SCCs contain minimal clonotypic contamination.

Topics: Adult; Aged; Clone Cells; Female; Gene Rearrangement, B-Lymphocyte, Heavy Chain; Gene Rearrangement, B-Lymphocyte, Light Chain; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Mobilization; Humans; Leukapheresis; Male; Melphalan; Middle Aged; Multiple Myeloma; Myeloma Proteins; Neoplastic Cells, Circulating; Polymerase Chain Reaction; Sensitivity and Specificity; Somatic Hypermutation, Immunoglobulin

High dose chemotherapy with autologous stem cell transplantation (ASCT) improves outcomes in patients 65 years of age or less with multiple myeloma. Survival and costs in a cohort of 16 patients who received melphalan and prednisone as part of a clinical trial were compared with those of 36 patients referred to our centre for consideration of ASCT. In the transplant group, survival and costs were extrapolated to match the period of observation in the melphalan and prednisone group. Patient-specific and average costs were calculated from the perspective of the Ontario Ministry of Health. Costs and survival were varied by 50% in the sensitivity analysis. Transplantation improved life expectancy by 19.3 months with a cost difference of 30,517 Canadian dollars. The incremental cost-effectiveness of transplantation compared with melphalan and prednisone was 25,710 Canadian dollars per life-year gained when additional pamidronate and follow-up costs were considered. Discounting costs and survival at 3 and 5% did not result in important differences. The sensitivity analysis resulted in best and worse case scenarios for transplantation compared with melphalan and prednisone of 13,049 dollars and 63,954 dollars per life-year gained respectively. In comparison with melphalan and prednisone, ASCT appears to be cost-effective in patients 65 years old or younger with myeloma.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cohort Studies; Cost-Benefit Analysis; Female; Financing, Organized; Health Expenditures; Hematopoietic Stem Cell Transplantation; Humans; Male; Melphalan; Middle Aged; Models, Statistical; Multiple Myeloma; Prednisone; Survival Analysis

The pharmacokinetics of two etoposide (E) formulations were evaluated in patients with refractory hematologic malignancies receiving high-dose conditioning with autologous stem cell transplantation. Patients were randomized to either E at 800 mg/m(2) (containing polysorbate 80 and polyethylene glycol) or etoposide phosphate (EP) at 910 mg/m(2) on days -7 and -5, prior to melphalan, 80 mg/m(2) on day -5. On day -3, EP was repeated. Plasma E was analyzed after each formulation on days -7 and -5 to compare intrapatient pharmacokinetics. In total, 10 patients were treated: four each with multiple myeloma or Hodgkin's disease and two with non-Hodgkin's lymphoma. Mucositis was the major toxicity with seven patients. EP first produced grade 3 mucositis. There was no procedure-related mortality and eight patients remained alive 1 year post-transplant. Cumulative etoposide exposure (AUC) was slightly greater with EP (P=0.056). Conversely, the volume of distribution was slightly, 33%, larger (P=0.052) and clearance was increased with the E infusion (P=0.14). As none of the differences reached statistical significance, both E formulations appear to be pharmacokinetically equivalent in the high-dose transplant setting. The combination of high-dose EP with melphalan is an active preparative regimen prior to ABMT for hematologic malignancies.

Topics: Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Area Under Curve; Chromatography, High Pressure Liquid; Etoposide; Hodgkin Disease; Humans; Life Expectancy; Lymphoma; Lymphoma, Non-Hodgkin; Melphalan; Middle Aged; Multiple Myeloma; Organophosphorus Compounds; Stem Cell Transplantation; Time Factors; Transplantation, Autologous

We used a sensitive real-time reverse transcription-polymerase chain reaction assay to quantify cyclin D1 mRNA levels in bone marrow samples collected at diagnosis from 74 newly diagnosed multiple myeloma (MM) patients who were randomized to undergo either single or double autologous peripheral blood stem cell transplantation as part of first-line therapy for their malignancy. In 46 cases, fluorescence in situ hybridization (FISH) analysis and/or conventional cytogenetics were performed to detect chromosome 11 abnormalities. Patients with the t(11;14) or trisomy 11 significantly overexpressed cyclin D1 (P <.0001) in comparison with patients without 11q abnormalities, who had cyclin D1 mRNA levels similar to healthy donors. Overall, 32 (43%) of 74 patients showed cyclin D1 overexpression. No difference was found between cyclin D1-positive (group A) and cyclin D1-negative (group B) patients with respect to presenting clinical and laboratory characteristics, including chromosome 13 abnormalities, as well as to response to therapy and overall survival, both of which were calculated on an intent-to-treat basis. Patients who overexpressed cyclin D1 had significantly longer duration of remission in comparison with patients who did not (41 vs 26 months, respectively; P =.02). As a result, median event-free survival (EFS) was longer in group A than in group B (33 vs 24 months, respectively; P =.055). We concluded that cyclin D1 overexpression is closely associated with 11q abnormalities and identifies a subset of MM patients who are more likely to have prolonged duration of remission and EFS following autologous transplantation.

Topics: Adult; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Chromosome Aberrations; Chromosomes, Human, Pair 11; Chromosomes, Human, Pair 13; Combined Modality Therapy; Cyclin D1; Cyclophosphamide; Dexamethasone; Disease-Free Survival; Doxorubicin; Female; Gene Expression; Hematopoietic Stem Cell Transplantation; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Predictive Value of Tests; Prognosis; Reproducibility of Results; Reverse Transcriptase Polymerase Chain Reaction; Sensitivity and Specificity; Vincristine

High-dose therapy with supporting autologous stem-cell transplantation remains a controversial treatment for cancer. In multiple myeloma, first-line regimens incorporating high-dose therapy yield higher remission rates than do conventional-dose treatments, but evidence that this translates into improved survival is limited.. In this multicenter study, the Medical Research Council Myeloma VII Trial, we randomly assigned 407 patients with previously untreated multiple myeloma who were younger than 65 years of age to receive either standard conventional-dose combination chemotherapy or high-dose therapy and an autologous stem-cell transplant.. Among the 401 patients who could be evaluated, the rates of complete response were higher in the intensive-therapy group than in the standard-therapy group (44 percent vs. 8 percent, P<0.001). The rates of partial response were similar (42 percent and 40 percent, respectively; P=0.72), and the rates of minimal response were lower in the intensive-therapy group than in the standard-therapy group (3 percent vs. 18 percent, P<0.001). Intention-to-treat analysis showed a higher rate of overall survival (P=0.04 by the log-rank test) and progression-free survival (P<0.001) in the intensive-therapy group than in the standard-therapy group. As compared with standard therapy, intensive treatment increased median survival by almost 1 year (54.1 months [95 percent confidence interval, 44.9 to 65.2] vs. 42.3 months [95 percent confidence interval, 33.1 to 51.6]). There was a trend toward a greater survival benefit in the group of patients with a poor prognosis, as defined by a high beta2-microglobulin level (more than 8 mg per liter).. High-dose therapy with autologous stem-cell rescue is an effective first-line treatment for patients with multiple myeloma who are younger than 65 years of age.

Topics: Adult; Aged; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Cause of Death; Combined Modality Therapy; Cyclophosphamide; Doxorubicin; Female; Hematopoietic Stem Cell Transplantation; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Prognosis; Survival Analysis

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Doxorubicin; Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Multiple Myeloma; Salvage Therapy; Thalidomide; Vincristine

Glutathione S-transferase P1 (GSTP1) is a phase 2 drug metabolism enzyme involved in the metabolism and detoxification of a range of chemotherapeutic agents. A single nucleotide polymorphism (Ile105Val) results in a variant enzyme with lower thermal stability and altered catalytic activity. We hypothesized that patients with the less stable variant have a decreased ability to detoxify chemotherapeutic substrates, including melphalan, and have an altered outcome following treatment for multiple myeloma. We have assessed the impact of GSTP1 codon 105 polymorphisms in 222 patients entered into the Medical Research Council (MRC) myeloma VII trial (comparing standard-dose chemotherapy with high-dose therapy). In the standard-dose arm, patients with the variant allele (105Val) had an improved progression-free survival (PFS) (adjusted hazard ratios for PFS were 0.55 for heterozygotes and 0.52 for 105Val homozygotes, compared with 105Ile homozygotes; P for trend =.04); this was supported by a trend to improved overall survival, greater likelihood of entering plateau and shorter time to reach plateau in patients with the 105Val allele. No difference in outcome by genotype was found for patients treated with high-dose therapy. However, the progression-free survival advantage of the high-dose arm was seen only in patients homozygous for 105Ile (P =.008).

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Case-Control Studies; Cyclophosphamide; Disease-Free Survival; Doxorubicin; Female; Genetic Variation; Genotype; Glutathione S-Transferase pi; Glutathione Transferase; Humans; Incidence; Isoenzymes; Male; Melphalan; Middle Aged; Multiple Myeloma; Polymorphism, Genetic; Prednisolone; Survival Rate; Treatment Outcome; Vincristine

A study was undertaken to determine the maximum tolerated dose of (166)Ho-DOTMP that could be administered safely, without negatively impacting marrow re-engraftment, in patients with multiple myeloma treated with melphalan prior to transplant. Ho-166 DOTMP is a tetraphosphonate that localizes rapidly to bone surface. The Ho-166 physical half-life is 26.8 hr and the maximum beta energy is 1.8 MeV. Standard dosimetry models were adapted for radiation absorbed dose estimates using data obtained from whole body counting of the low abundance photons emitted by (166)Ho. Eighty-three patients received high dose (166)Ho-DOTMP followed by melphalan and transplant of peripheral blood stem cells. Twenty-five patients also received 8 Gy total body radiation (TBI). Dosages administered ranged from 460 to 4476 mCi (166)Ho-DOTMP. Marrow dose was derived using the assumption that all radioactivity not excreted by 20 hours was localized to the bone surfaces, and applying the Eckerman bone and marrow dose model to the calculated bone residence times. The dosimetry of the urinary bladder and kidneys was important because of the rapid excretion of the non-targeted radioactivity via the urinary pathway. The dynamic bladder model was used for bladder wall surface dose, and the ICRP 53 kinetic model was used to model kidney kinetics with an additional blood component included. Marrow doses ranged from 13 to 59 Gy and successful hematapoietic recovery occurred. Bladder doses ranged from 4.7 to 157 Gy. Hemorrhagic cystitis occurred in some patients who received more than 40 Gy to the bladder wall surface. Bladder irrigation was successful in protecting patients from bladder toxicity. Kidney doses ranged from 0.5-7.9 Gy. Kidney toxicity in the form of thrombotic microangiopathy with renal dysfunction was observed, with the severity being related to Ho-166-DOTMP radiation dose and probably the dose rate as well. In a future trial, kidney dosimetry will be assessed using early serial gamma camera imaging and modifications will be implemented to reduce renal toxicity.

Topics: Antineoplastic Agents, Alkylating; Cohort Studies; Combined Modality Therapy; Holmium; Humans; Maximum Tolerated Dose; Melphalan; Multiple Myeloma; Muscle, Skeletal; Organophosphorus Compounds; Radioisotopes; Radiometry; Radiotherapy Dosage; Tissue Distribution

Current treatment in multiple myeloma consists of three courses of chemotherapy in low doses with subsequent hematopoietic stem cell mobilization to the peripheral blood using high-dose cyclophosphamide, collection and conditioning with high-dose chemotherapy (melphalan) followed by retransplantation of autologous peripheral blood stem cells (PBSCT). Only a few studies compare the effects of different phases of therapy on parameters, such as monoclonal immunoglobulin level and the presence of malignant CD38(+) and CD56(+) cells in blood and marrow. The aim of this study was to compare the effects of these two major phases of treatment (conventional and high dose) in the same patients, and furthermore, to compare the effects of the second course of high-dose therapy followed by PBSCT with the effects of the first one. Fifteen patients were included in the study. On average, conventional chemotherapy only slightly reduced the values of all disease markers. In contrast, high-dose therapy resulted in a dramatic effect, rapidly normalizing the values of all parameters. The effects of second PBSCT were only modest compared to the first. These data suggest that high-dose therapy is an efficient method to reduce tumor load in multiple myeloma. Conventional-dose chemotherapy may be simply a waste of time for some patients and may be either omitted or administered after high-dose therapy to consolidate remission.

Topics: ADP-ribosyl Cyclase; ADP-ribosyl Cyclase 1; Adult; Aged; Antibodies, Monoclonal; Antigens, CD; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; beta 2-Microglobulin; Bone Marrow Cells; Combined Modality Therapy; Doxorubicin; Etoposide; Female; Flow Cytometry; Humans; Immunoglobulin G; Male; Melphalan; Membrane Glycoproteins; Middle Aged; Multiple Myeloma; Stem Cell Transplantation

Approximately one third of multiple myeloma patients (below 60 years) are diagnosed either in advanced disease or with significant comorbidities. Many other patients referred to transplant centers have already been heavily pretreated with multiple courses of various conventional chemotherapies. These patients are frequently in bad or even grave clinical condition; they are unlikely to survive standard high-dose melphalan (200 mg/m(3)) chemotherapy and autologous hematopoietic stem cell transplantation. Palumbo et al reported a protocol for elderly patients that utilized reduced conditioning (melphalan 100 mg/m(2) three times at 2-month intervals, each time supported by autologous hematopoietic rescue). We have used this protocol as a start to develop a method to induce a remission in the aforementioned subgroup of myeloma patients. Patients with stage III disease and WHO performance status 2 or higher are treated with one or two cycles of cyclophosphamide (2 to 4 g/m(2)) and undergo peripheral blood stem cells collection. Subsequently, they are treated with three to four doses of melphalan (100 mg/m(2)) at 8- to 12-weeks intervals each time supported by infusion of peripheral blood stem cells. To date 13 patients have been entered into the protocol. With one exception of transiently stable disease, the remaining patients obtained at least partial remission and three, complete remission. The compliance was good and better with each subsequent course. For half of the patients the problem was a short duration of response. This method when developed may offer a new treatment alternative for a subgroup of high-risk multiple myeloma patients.

Topics: Adult; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Dexamethasone; Disease Progression; Disease-Free Survival; Doxorubicin; Humans; Immunoglobulins; Melphalan; Middle Aged; Multiple Myeloma; Stem Cell Transplantation; Transplantation, Autologous; Treatment Outcome; Vincristine

We conducted a phase II multicenter trial to estimate the response and survival of patients with newly diagnosed multiple myeloma to high dose melphalan therapy followed by autologous peripheral blood stem cell transplantation. Eligible patients who had undergone induction with vincristine, adriamycin and dexamethasone (VAD) should have adequate cardiac, pulmonary and renal function (creatinine <2 mg/dL). Melphalan at 200 mg/m2 was used as a conditioning regimen. Eighty patients were enrolled from 13 centers. The median age of the patients was 53 yr (range; 20 to 68 yr). The initial stage was IA/IIA/IIB/IIIA/IIIB in 3/8/1/54/14 patients, respectively. Beta2-microglobulin, CRP and LDH were increased in 74, 42 and 34% of the patients examined. Cytogenetic data were available in 30 patients, and 6 patients showed numeric or structural abnormalities. Two therapy-related mortalities occurred from infection. Among the 78 evaluable patients, CR/PR/MR/NC/PD were achieved in 48/26/2/1/1 patients, respectively. After a median follow-up of 30 months, the median overall and event-free survivals were 66 months (95% CI: 20-112) and 24 months (95% CI: 18-29), respectively. This study verifies the efficacy and feasibility of high dose melphalan therapy with autologous stem cell transplantation in newly diagnosed multiple myeloma.

Topics: Adult; Aged; Antigens, CD34; Antineoplastic Agents, Alkylating; beta 2-Microglobulin; C-Reactive Protein; Cell Survival; Combined Modality Therapy; Cytogenetics; Disease-Free Survival; Female; Humans; Korea; L-Lactate Dehydrogenase; Male; Melphalan; Middle Aged; Multiple Myeloma; Peripheral Blood Stem Cell Transplantation; Time Factors; Transplantation, Autologous

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Boronic Acids; Bortezomib; Humans; Melphalan; Multiple Myeloma; Neoplasm Recurrence, Local; Prognosis; Prospective Studies; Pyrazines; Safety; Treatment Outcome

Although high-dose therapy (HDT) with autologous hematopoietic stem cell transplantation (ASCT) is widely accepted as an effective and safe consolidation therapy for multiple myeloma (MM), few reports on its efficacy are available in Korea. We present the results of a prospective phase II study, involving 33 patients with MM treated with HDT with ASCT. The treatment consisted of 4 courses of VAD (vincristine, adriamycin, dexamethasone) induction, peripheral blood stem cell collection, and high-dose melphalan with stem cell infusion. The overall response rate was 93%, with 45% of patients having complete responses. The toxicity was predictable and tolerable. With a median follow-up of 27.6 months, the 2-year event free survival rate was 43%. At the time of writing, the median overall survival duration had not been reached with 2-year survival and projected 3-year survival rates of 81% and 74%, respectively. The overall survival was significantly better than that of the historical control patients (N=82) treated with conventional chemotherapy at our institution. The results suggest that HDT with ASCT is a valuable first or second-line treatment for patients with MM.

Topics: Adult; Aged; Female; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Neoplasm Staging; Peripheral Blood Stem Cell Transplantation; Prognosis; Prospective Studies; Survival Rate; Transplantation, Autologous

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Female; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Salvage Therapy; Survival Analysis; Thalidomide; Treatment Outcome; Venous Thrombosis

We evaluated toxicity, engraftment, chimerism, graft-versus-host disease (GVHD), and response to a dose-reduced allograft after cytoreductive autografting in 17 patients with advanced stage II/III multiple myeloma (MM). After autografting with melphalan (200 mg/m2) the patients received after a median interval of 119 days (range 60-210) a dose-reduced regimen consisting of fludarabine (180 mg/m2), melphalan (100 mg/m2), and antithymocyte globulin (3 x 10 mg/kg) followed by allografting from related (n = 7), mismatched related (n = 2), or unrelated (n = 8) donors to induce a graft-versus-myeloma effect. After dose-reduced allografting all patients became neutropenic (< 0.2 x 10(9)/L) for at least 8 days. All patients engrafted with a median time for leukocyte (> 1 x 10(9)/L) and platelet (> 20 x 10(9)/L) counts of 16 (range, 11-24) and 23 days (range, 12-43), respectively. Complete donor chimerism was detected after a median of 30 days (range, 19-38). Acute GVHD stage II occurred in 4 patients (25%) and grade III GVHD in 2 patients (13%). Chronic GVHD developed in 40% of the patients, but only 1 patient experienced extensive chronic GVHD requiring further immunosuppressive therapy. Two patients died of alveolar hemorrhage and pneumonia, resulting in a day 100 mortality rate of 11%. The rate of complete remission with negative immunofixation increased from 18% after autografting to 73% after allografting. After a median follow-up of 17 months after autologous and 13 months after allogeneic transplantation 13 patients are alive and 12 of them free of relapse or progression. The tandem auto-allotransplant protocol is highly active and provides rapid engraftment with complete donor chimerism and tolerable toxicity.

Topics: Adult; Antineoplastic Agents, Alkylating; Female; Graft Survival; Graft vs Host Disease; Graft vs Leukemia Effect; Hematopoietic Stem Cell Transplantation; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Remission Induction; Survival Rate; Transplantation Chimera; Transplantation, Autologous; Transplantation, Homologous; Treatment Outcome

Multiple myeloma (MM) is a malignancy of terminally differentiated plasma cells typically occurring in elderly patients. The clinical manifestations of this disease result primarily from the accumulation of monoclonal protein (paraprotein) in the serum and/or urine, anemia, lytic bone lesions, hypercalcemia, renal insufficiency, and immune deficiency. Multiple myeloma is incurable with standard chemotherapy. Melphalan and prednisone has been the mainstay of treatment for MM for about three decades. This regimen results in a clinical response in approximately 60% of patients and a median survival of approximately 36 months. A variety of combination therapies have also been used in MM, but have not been considered to offer a significant benefit compared with standard therapy. In early trials, bendamustine monotherapy was as effective as cyclophosphamide and various combination therapies in achieving remission in MM. This article describes a prospective, randomized, phase III study designed to compare the efficacy of bendamustine/prednisolone with a standard melphalan/prednisolone regimen.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Bendamustine Hydrochloride; Cyclophosphamide; Female; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Nitrogen Mustard Compounds; Prednisolone; Prednisone; Prospective Studies; Remission Induction; Survival Rate

In patients with multiple myeloma, a good complete response rate and disease-free survival may be achieved with sequential chemotherapy using VAD and VMCP, which is an alternative effective and less expensive treatment regimen. This regimen thus assumes particular significance in developing nations like India, where the majority of patients with myeloma cannot afford the cost of high-dose chemotherapy with stem cell rescue.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Dexamethasone; Disease-Free Survival; Doxorubicin; Drug Administration Schedule; Female; Humans; India; Male; Melphalan; Middle Aged; Multiple Myeloma; Prednisolone; Vincristine

In the absence of a cure for multiple myeloma (MM) with standard-dose therapy, any strategy that can be expected to increase tumor reduction and to extend survival duration is likely to be of clinical relevance. The primary end-point of the present study was to investigate whether the alternating combination of vincristine-doxorubicin-dexamethasone (VAD) and melphalan-prednisone (MP) or vincristine-mitoxantrone-dexamethasone (VND) and MP could improve the clinical outcome of MM patients thus treated in comparison with those receiving MP alone.. Between November 1990 and April 1994, 527 previously untreated, stage I-III, MM patients from 29 Italian institutions were randomized to receive one of three remission induction chemotherapy regimens consisting of 8-monthly courses of either MP alone or alternating VAD/MP or VND/MP.. On an intent-to-treat basis, the objective response rates were 53% with MP (objective + minor: 67%), 47% with VAD/MP (objective + minor: 61%) and 49% with VND/MP (objective + minor: 61%). Median survival duration was 36.5 months with MP, 29 months with VAD/MP and 32.5 months with VND/MP. The difference among these groups was not statistically significant, even after stratifying patients into high-risk and low-risk subgroups, as assessed by a multifactor proportional hazard analysis. In both younger and elderly patients, severe granulocytopenia and related infections were significantly more frequent with VND/MP compared to the remaining arms of treatment (p < 0.001 and p = 0.009, respectively). Similarly, the frequency of WHO grade III-IV cardiovascular events was significantly higher for patients receiving anthracycline-containing regimens (VND/MP and VAD/MP) than for those treated with MP alone (p = 0.04).. Alternating VAD/MP and VND/MP failed to improve the clinical outcome for MM patients, at the cost of increased toxicity and morbidity. Resistance to standard-dose chemotherapy remains a significant obstacle to the treatment of MM.

Topics: Adult; Age Factors; Aged; Antineoplastic Combined Chemotherapy Protocols; Doxorubicin; Etoposide; Female; Humans; Male; Melphalan; Middle Aged; Mitoxantrone; Multiple Myeloma; Prednisone; Randomized Controlled Trials as Topic; Salvage Therapy; Survival Rate; Time Factors; Treatment Outcome

The purpose of the study was to determine the feasibility and efficacy of a reduced intensity conditioning regimen of fludarabine and melphalan for allogeneic transplantation in patients with multiple myeloma. From August 1996 to December 2000, 22 patients received a reduced intensity conditioning regimen with fludarabine and melphalan. Median age was 51 years (range, 45-64), median time from initial therapy to transplant was 36 months (range, 3-135 months). Disease phase prior to transplant was primary refractory in two patients, refractory relapse in 11 patients, sensitive relapse in eight patients and initial remission consolidation in one patient. The median number of prior therapies was five (range, 1-7), and median beta 2 microglobulin prior to transplant was 3.0 mg/l (range, 1.0-7.3). All patients received unmanipulated grafts from either HLA matched sibling donors (n = 13) or matched unrelated donors (n = 9). Eighteen patients received fludarabine 30 mg/m(2) for 4 days with melphalan 140 mg/m(2) as a single dose and four patients received fludarabine 25 mg/m(2) for 5 days with melphalan 90 mg/m(2) daily for 2 days. All 21 patients evaluable for engraftment achieved a neutrophil count of >0.5 x 10(9)/l after a median of 12 days (range, 9-24), 18 patients achieved platelet transfusion independence after a median of 14 days (range, 8-47). All engrafting patients had 100% donor cell engraftment. Seven patients achieved a complete remission. Six patients are currently alive with a median follow-up of 15 months (range, 10-47 months). The actuarial survival and progression-free survival is 30 +/- 11% and 19 +/- 9% at 2 years. Non-relapse mortality at 100 days was 19 +/- 10% and 40 +/- 10% at 1 year. Fludarabine/melphalan combinations are feasible and allow consistent engraftment of allogeneic progenitor cells from both related and unrelated donors in patients with multiple myeloma and should be explored in patients with less advanced disease.

Topics: Antineoplastic Agents; Bone Marrow Transplantation; Disease-Free Survival; Female; Graft Survival; Graft vs Host Disease; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Peripheral Blood Stem Cell Transplantation; Transplantation Conditioning; Transplantation, Homologous; Treatment Outcome; Vidarabine

Thirty-two patients with multiple myeloma were treated with high doses of 166Ho-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetramethylene-phosphonic acid (DOTMP) and were a subset of patients enrolled in a multicenter phase I/II dose escalation myeloablative trial. 166Ho with beta-emission (half-life, 26.8 h; beta-particle energies, 1.85 MeV [51%] and 1.77 MeV [48%]; gamma-photons, 80.6 keV [6.6%] and 1.38 MeV [0.9%]) was complexed to DOTMP, a macrocyclic tetraphosphonate. Pharmacokinetics, dosimetry, and biodistribution were studied.. Patients were treated at escalating dose levels of 20, 30, and 40 Gy to the bone marrow in combination with high-dose melphalan, with or without total-body irradiation, to evaluate toxicity and efficacy. After infusion with 1,110 MBq (30 mCi) of 166Ho-DOTMP for evaluation of biodistribution and dosimetry calculation, patients received the calculated amount of radioactivity for therapy in a single administration based on estimated dose calculations.. Thirty-two patients participated in the study and were then treated. The average amount of administered radioactivity was 74.3 GBq (2,007 mCi) (range, 21.5-147.5 GBq [581-3,987 mCi]) of 166Ho-DOTMP.. 166Ho-DOTMP has physical and pharmacokinetic characteristics compatible with high-dose myeloablative treatment of multiple myeloma.

Topics: Antineoplastic Agents, Alkylating; Bone Marrow Purging; Female; Holmium; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Organophosphorus Compounds; Radioisotopes; Radiometry; Radiotherapy Dosage; Tissue Distribution

We have shown that primary therapy with non-myeloablative (140 mg/m(2)) high-dose melphalan (HDM) without hematopoietic support results in high response rates in untreated myeloma and very long-term survival of some patients. This study was designed to see if sufficient CD34 (+) cells can be harvested at presentation in newly diagnosed patients to administer myeloablative HDM (200 mg/m(2); HDM200) with autograft as primary therapy. This may improve outcome by rapid achievement of complete remission (CR) and possible avoidance of late myelodysplasia as a consequence of non-transplant induction chemotherapy. Thirty untreated patients received 1 g/m(2) methylprednisolone daily (days 1-6) and 12-16 micro g/kg G-CSF daily (days 3-6), and underwent leukapheresis on days 6 and 7. The median CD34(+) cell yield was 1.31 x10(6)/kg (range, 0.23-5.63), and was > or =1 x10(6)/kg in 73%. Cell yields were significantly lower than in 82 historical controls apheresed after completion of induction chemotherapy (median 2.16 x 10(6)/kg), and improved in patients who were apheresed again after induction chemotherapy. Three patients received primary therapy with HDM200 and autograft using these cells and attained CR. We conclude that it is possible to harvest stem cells in three-quarters of untreated myeloma patients. Increasing the number of apheresis procedures is needed to improve the number of CD34(+) cells collected.

Topics: Adult; Aged; Antigens, CD34; Antineoplastic Combined Chemotherapy Protocols; Cell Count; Cyclophosphamide; Doxorubicin; Female; Hematopoietic Stem Cell Mobilization; Humans; Leukapheresis; Male; Melphalan; Methylprednisolone; Middle Aged; Multiple Myeloma; Peripheral Blood Stem Cell Transplantation; Transplantation, Autologous; Treatment Outcome; Vincristine

We investigated the feasibility of unrelated stem cell transplantation in 21 patients with advanced stage II/III multiple myeloma after a reduced-intensity conditioning regimen consisting of fludarabine (150 mg/m(2)), melphalan (100-140 mg/m(2)), and antithymocyte globulin (ATG; 10 mg/kg on 3 days). The median patient age was 50 years (range, 32-61 years). All patients had received at least one prior autologous transplantation, in 9 cases as part of an autologous-allogeneic tandem protocol. No graft failure was observed. At day 40 complete donor chimerism was detected in all patients. Grade II to IV acute graft-versus-host disease (GVHD) was seen in 8 patients (38%), and severe grade III/IV GVHD was observed in 4 patients (19%). Six patients (37%) developed chronic GVHD, but only 2 patients (12%) experienced extensive chronic GVHD. The estimated probability of nonrelapse mortality at day 100 was 10% and at 1 year was 26%. After allografting, 40% of the patients achieved a complete remission, and 50% achieved a partial remission, resulting in an overall response rate of 90%. After a median follow-up of 13 months, the 2-year estimated overall and progression-free survival rates are 74% (95% CI, 54%-94%) and 53% (95% CI, 29%-87%), respectively. A shorter progression-free survival was seen in patients who already experienced relapse to prior autograft (26% versus 86%, P =.04). Dose-reduced conditioning with pretransplantation ATG followed by unrelated stem cell transplantation provides durable engraftment and donor chimerism, reduces substantially the risk of transplant-related organ toxicity, and induces high remission rates.

Topics: Adult; Antilymphocyte Serum; Antineoplastic Combined Chemotherapy Protocols; Feasibility Studies; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Survival Analysis; Transplantation Conditioning; Transplantation, Homologous; Treatment Outcome; Vidarabine

Two hundred and twenty-two myeloma patients autografted after 200 mg/m(2)melphalan were studied to examine the relationship between response to induction chemotherapy and outcome. Induction comprised cyclophosphamide, vincristine, doxorubicin and methylprednisolone (C-VAMP) every 3 weeks for one cycle beyond maximum response. 81% responded to C-VAMP (chemosensitive) with 40 complete (CR) and 139 partial (PR) remissions, and 43 did not respond (NR; <50% reduction in paraprotein; primary refractory). Overall, 130 patients (59%) attained or remained in CR post-transplant; including 40% of NR, 53% of PR, and 97% of CR after C-VAMP (P < 0.0001). Amongst these 130 patients, the 5-year OS was independent of response to C-VAMP (NR 79%, PR 74%, CR 60%; P = 0.69). Similarly, among the 69 patients in PR post-transplant, the 5-year OS was independent of response to C-VAMP. In Cox analysis, lack of response to C-VAMP did not affect outcome significantly. These data show that lack of response to induction therapy does not automatically predict poor long-term outcome in myeloma, since a substantial proportion of these patients attain CR after autograft and enjoy extended survival. Myeloma patients should not be disqualified from an autograft based upon lack of response to induction chemotherapy.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Female; Humans; Longitudinal Studies; Male; Melphalan; Middle Aged; Multiple Myeloma; Multivariate Analysis; Peripheral Blood Stem Cell Transplantation; Recurrence; Remission Induction; Survival Rate; Transplantation, Autologous; Treatment Outcome

Hepatocyte growth factor (HGF) is a cytokine produced by myeloma cells. We examined serum HGF levels in a population of young myeloma patients (median age 52 years) treated with high-dose chemotherapy. Sera from 128 myeloma patients at diagnosis and serial samples from 16 patients were analysed. Compared with 62 healthy controls, HGF was elevated at diagnosis in 25% of patients (median 0.48 and 1.08 ng/ml respectively; P < 0.0001). The 95 patients who completed therapy were analysed for the impact of HGF on survival. Median survival was not reached after 77 months in the patient group with normal HGF values (< 1.7 ng/ml, n = 69). In the group with elevated HGF (>/= 1.7 ng/ml, n = 26), median survival was 63 months (P = 0.08). In 16 patients, serum was drawn at diagnosis and at the time of expected disease remission (6 weeks to 3 months after chemotherapy). HGF values declined after treatment in 14 of these patients, from a median of 0.9 ng/ml (0.49-1.65) to 0.42 ng/ml (0.32-0.73) (P = 0.005). Our results show that in young myeloma patients HGF is elevated, and that patients with higher levels had a trend towards poorer prognosis. Treatment with high-dose chemotherapy reduced HGF in the serum of the majority of patients.

Topics: Adult; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Doxorubicin; Enzyme-Linked Immunosorbent Assay; Female; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Transplantation; Hepatocyte Growth Factor; Humans; Infusions, Intravenous; Interferon alpha-2; Interferon-alpha; Male; Melphalan; Middle Aged; Multiple Myeloma; Recombinant Proteins; Survival Analysis; Treatment Outcome; Vincristine

High-dose melphalan (HDM) has been adopted as standard therapy in the treatment of multiple myeloma. This treatment is associated with non-selective cytotoxicity, causing oral mucositis as the major non-hematological side-effect. Amifostine is a cytoprotector which prevents toxicity induced by anticancer therapy. We prospectively compared two groups of patients who either received (group A, n = 21) or did not receive (group B, n = 20) amifostine (740 mg/m(2)) before HDM (200 mg/m(2)) followed by autologous peripheral blood progenitor cell transplantation. The occurrence of severe oral mucositis was significantly decreased in group A in comparison to group B (33% vs 65%, P < 0.05). Six patients in group A required opioid analgesic therapy during a mean period of 4.8 days as compared to eight patients for 6.5 days in group B (P = NS). Delayed vomiting was less frequent in group A (43% vs 70%, P = 0.07) and significantly less severe in group A (grade 2-4) vomiting: two patients vs nine patients, P < 0.02). No difference was observed between the two groups in either hematological toxicity after HDM or in response rate. Grade I emesis was the only immediate side-effect observed after amifostine administration. We conclude that amifostine can reduce mucositis induced by HDM.

Topics: Adult; Aged; Amifostine; Antineoplastic Combined Chemotherapy Protocols; Female; Graft Survival; Humans; Kinetics; Male; Melphalan; Middle Aged; Mouth Mucosa; Multiple Myeloma; Peripheral Blood Stem Cell Transplantation; Stomatitis; Transplantation Conditioning; Transplantation, Autologous; Treatment Outcome

To evaluate feasibility and potential efficacy of amifostine (AMI) in the prevention of toxicities associated with high-dose melphalan (MEL), ten myeloma patients received AMI 910 mg/m2 in 15 min infusion preceding MEL 200 mg/m2 followed by stem cell infusion (AMI group). Hematologic and extra-hematologic toxicities as well as the need for supportive care observed in the AMI group were compared with ten myeloma patients treated in an identical protocol but without AMI. Hypotension was the most important adverse event of AMI infusion. No differences were observed in the time of engraftment between the AMI group and the control group neither was there any difference in the need for supportive care. Oral mucositis grade >2 was observed in 30% of the patients in both groups. Diarrhea grade >2 occurred only in two AMI patients but in five control patients. AMI preceding high-dose MEL is feasible, although adverse events are observed in some patients. Whether AMI could reduce the gastrointestinal toxicity associated with high-dose MEL can be reliably assessed only in prospective randomized trials.

Topics: Adult; Amifostine; Antineoplastic Combined Chemotherapy Protocols; Diarrhea; Feasibility Studies; Female; Graft Survival; Humans; Hypotension; Male; Melphalan; Middle Aged; Mouth Mucosa; Multiple Myeloma; Peripheral Blood Stem Cell Transplantation; Pilot Projects; Stomatitis; Transplantation, Autologous

High-dose therapy has become a common treatment for myeloma. The objective of this study (Intergroupe Francophone du Myélome [IFM] 9502 trial) was to compare in a prospective and randomized trial the 2 most widely used conditioning regimens before autologous stem cell transplantation in newly diagnosed symptomatic patients younger than 65 years old: 8 Gy total body irradiation plus 140 mg/m(2) melphalan (arm A) versus 200 mg/m(2) melphalan (arm B). A total of 282 evaluable patients were compared--140 in arm A and 142 in arm B. Baseline characteristics and disease response to 4 cycles of the VAD regimen performed before randomization and autologous stem cell transplantation were identical in the 2 treatment arms. In arm B, hematologic recovery was significantly faster for both the duration of neutropenia and thrombocytopenia, transfusion requirements were also significantly lower, and the median duration of hospitalization was significantly shorter. In arm A, the incidence of severe mucositis was significantly increased. The median duration of event-free survival was similar in both arms (21 vs 20.5 months, P =.6), but the 45-month survival was 65.8% in arm B versus 45.5% in arm A (P =.05). This difference might be attributed in part to better salvage regimens after relapse in arm B compared with arm A. We conclude that 200 mg/m(2) melphalan is a less toxic and at least as effective conditioning regimen when compared with 8 Gy total body irradiation with 140 mg/m(2) melphalan. This regimen should be considered as the standard of care before autologous stem cell transplantation in multiple myeloma.

Topics: Adult; Aged; Antineoplastic Agents, Alkylating; Combined Modality Therapy; Female; Graft Survival; Hematopoietic Stem Cell Transplantation; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Prospective Studies; Remission Induction; Survival Analysis; Transplantation Conditioning; Transplantation, Autologous; Treatment Outcome; Whole-Body Irradiation

A phase I-II study of high-dose (HD) alkylating agents in newly diagnosed patients with multiple myeloma after maximum response to Z-Dex (idarubicin, dexamethasone) therapy and DHAP (cisplatin, HD cytosine arabinoside, dexamethasone), stem cell mobilization is reported. Twenty-six patients, median age 56 years (range 42-66), completed Z-Dex chemotherapy and peripheral blood stem cells (PBSC) were mobilized with DHAP. Patients then preceded to cyclophosphamide (HD Cy: 6 g/m(2)) with granulocyte colony-stimulating factor followed by busulphan-melphalan-conditioned PBSC autograft. Interferon alpha was introduced at 3 months post transplant as maintenance therapy. Six patients failed to complete the full protocol. Median time from diagnosis to transplantation was 8 months (range 6-12). Mean CD34+ cell dose collected was 15.8 x 10(6)/kg (CI 11.8, 19.8). Median time from DHAP to HD-Cy was 6 weeks (range 4-12) and from HD-Cy to transplant was 8 weeks (range 6-12). The median follow-up was 36 months (range 6-63). On an intent-to-treat basis, the response rates were three complete response (CR, 12%), 21 partial response (PR, 80%) and two stable disease (SD, 8%) post Z-Dex, five CR (19%) and 21 PR (81%) post HD-Cy, and 14 CR (54%) and 12 PR (46%) post transplant. The treatment-related mortality (TRM) was 4% (1 patient). Median overall survival (OS) and progression-free survival (PFS) have not been reached; estimated values were 60 and 48 months respectively. The 3-year OS and PFS were 72% and 62%. Actuarial 5-year OS and event-free survival were 49% and 32%. DHAP produces effective PBSC mobilization and sequential HD therapy, including autologous PBSCT, in patients who received Z-Dex; this offers significant durable disease response rates with acceptable TRM.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Busulfan; Cisplatin; Cyclophosphamide; Cytarabine; Dexamethasone; Disease-Free Survival; Drug Administration Schedule; Female; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cell Transplantation; Humans; Idarubicin; Interferon alpha-2; Interferon-alpha; Male; Melphalan; Middle Aged; Multiple Myeloma; Recombinant Proteins; Survival Rate; Treatment Outcome

High-dose chemotherapy (HDT) with autologous peripheral blood progenitor cell (PBPC) transplant has been increasingly used for newly diagnosed multiple myeloma (MM) in recent years. Presently available results suggest an improvement in the complete remission rate and survival as compared to conventional chemotherapy. However, there is no plateau in the survival curves, and experiments with new treatment schedules and conditioning regimens are warranted.. In a non-randomised controlled trial, 20 patients underwent three-step HDT following conventional vincristine/doxorubicin/dexamethasone (VAD)-based induction. In the intensification phase patients received high-dose cyclophosphamide (HD-CY), high-dose etoposide (HD-VP), and mitoxantrone (NOV) plus melphalan (L-PAM) with haemopoietic rescue. Maintenance treatment with interferon was given until relapse. Actuarial overall survival (OS) and event-free survival (EFS) curves were plotted according to the method of Kaplan and Meier. In five of the eight patients achieving complete remission (CR), the molecular disease was monitored by polymerase chain reaction technique (PCR).. Overall 18/20 (90%) patients responded, with a CR rate of 40%. After an average follow-up of 40 months, median EFS and OS are 25.5 and 44.6 months, respectively. Monoclonal cells were detectable in the post-treatment bone marrow and in the aphereses of the five CR patients monitored by PCR.. The present three-step HDT regimen, including conditioning with mitoxantrone and melphalan, proved to be feasible and safe. Our results are in agreement with the hypothesis that HDT results in an increased remission rate and in prolonged survival in newly diagnosed MM, but a cure is unlikely.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Clone Cells; Combined Modality Therapy; Cyclophosphamide; Dexamethasone; DNA, Neoplasm; Doxorubicin; Drug Administration Schedule; Etoposide; Female; Follow-Up Studies; Hematopoietic Stem Cell Transplantation; Humans; Male; Melphalan; Middle Aged; Mitoxantrone; Multiple Myeloma; Remission Induction; Survival Analysis; Transplantation Conditioning; Transplantation, Autologous; Treatment Outcome; Vincristine

The purpose of the study was to evaluate, in a selected group of myeloma patients with favorable prognosis, the effect, on response and survival, of polychymotherapy compared with melphalan prednisone, plus interferon in both arms.. Eighty-nine previously untreated patients with multiple myeloma and prognostic factors indicating a good prognosis were randomized to either oral melphalan plus prednisone (MP) in combination with recombinant interferon-alpha (rIFN-alpha) or combination chemotherapy with vincristine, carmustine, melphalan, cyclophosphamide, and prednisone (VBMCP) alternating with rIFN-alpha. The two treatment groups were comparable in terms of pretreatment characteristics.. The overall response rate was 67.4% (2.3% complete remission, 65.1% partial response) in the MP/IFN-alpha group and 69.1% (14.3% complete remission, 54.8% partial response) in the VBMCP/IFN-alpha group (p=0.59). There were no differences also in response duration and overall survival between the two treatment groups. The median response duration was 39.1 months in the MP/IFN-alpha group and was not reached in the VBMCP/IFN-alpha group (p = 0.6). Overall survival was long in both treatment groups. The estimated 5-yr survival was 66% and 62% in the MP/IFN-alpha and VBMCP/IFN-alpha group, respectively (p=0.8). Toxicity was modest and treatments were well tolerated. Neutropenia (WHO grade 3 or 4) was higher, but not statistically significant, in the VBMCP/IFN-alpha group.. The results of the study show that in myeloma patients with good prognosis, combination chemotherapy alternating with interferon-alpha has no advantage over conventional MP plus interferon-alpha, in regard to response rate, response duration, and overall survival of patients.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Cyclophosphamide; Disease-Free Survival; Female; Follow-Up Studies; Greece; Humans; Interferon alpha-2; Interferon-alpha; Life Tables; Male; Melphalan; Middle Aged; Multiple Myeloma; Prednisone; Prognosis; Prospective Studies; Recombinant Proteins; Remission Induction; Survival Analysis; Treatment Outcome; Vincristine

We evaluated the costs and the cost utility of high-dose melphalan and autologous stem cell support followed by interferon maintenance relative to conventional treatment with melphalan and prednisone, in patients less than 60 yr of age with multiple myeloma. From March 1994 to July 1997, 274 patients with newly diagnosed, symptomatic multiple myeloma were enrolled in a prospective, non-randomized, population-based, multicenter study to evaluate the treatment with high-dose melphalan and autologous blood stem cell support. Health-related quality-of-life was measured prior to treatment and during follow-up, using the EORTC QLQ-C30 questionnaire. Resource consumption was also recorded prospectively. The intensive treatment yielded a significant increase in median survival time from 44 to 62 months compared to conventionally treated patients. The corresponding gain in quality-adjusted life years (QALY) was found to be 1.2. Cost per QALY gained by the treatment with high-dose melphalan and autologous blood stem cell support was estimated at NOK 249,000 (USD 27,000).

Topics: Cost-Benefit Analysis; Female; Health Care Costs; Hematopoietic Stem Cell Transplantation; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Prednisone; Prospective Studies; Quality of Life; Surveys and Questionnaires; Survival Rate; Transplantation, Autologous

In 90 consecutive patients with multiple myeloma, we investigated the feasibility of administering a tandem high-dose therapy regimen, using whole blood for rescue after the first and leucapheresis harvested between the two high doses, for rescue after the second high dose. After 5 days of G-CSF 1 litre of whole blood (WB) was obtained, left undisturbed at 4 degrees C and reinfused 24 h after HDM (140 mg/m(2)). Patients not in progression after 3-6 months were again mobilised, leucapheresed and treated with busulphan 16 mg/kg and cyclophosphamide 120 mg/kg (Bu/Cy) and reinfusion. In 90 patients, WB contained a mean (range) of 0.57 (0.02-3.22) x 10(6)/kg CD34(+) cells. Recovery after HDM was in 13 days for granulocytes and in 18 days for platelets, with 11 patients not recovering within 3 months. There were three toxic deaths. Sixty-six patients qualified for harvesting after HDM. In the first 11, marrow was harvested. The subsequent 55 patients were mobilised and in 45 the preset minimum of 1.5 x 10(6) CD34(+) cells was obtained. Forty-nine patients actually received Bu/Cy. Recovery after Bu/Cy and marrow reinfusion was in 35 days for granulocytes and 20 days for platelets, with two of five patients not recovering after 3 months. After Bu/Cy and leucapheresis reinfusion, recovery was in 17 days for granulocytes and in 34 days for platelets. Nine patients did not recover within 3 months. There were four toxic deaths. The median overall survival from diagnosis for patients receiving HDM was 49 months and for patients also receiving Bu/Cy, 84 months. We conclude that WB rescue after HDM followed by leucapheresis and a second transplant is feasible in the majority of patients. Better mobilisation techniques are required to increase the number of patients who can receive the second transplant.

Topics: Adult; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Blood Transfusion, Autologous; Busulfan; Cohort Studies; Cyclophosphamide; Female; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Transplantation; Humans; Leukapheresis; Male; Melphalan; Middle Aged; Multiple Myeloma; Transplantation, Autologous; Treatment Outcome

The object of this study was to determine the efficacy and safety of glycosylated recombinant human granulocyte colony-stimulating factor (rHuG-CSF; lenograstim) after combination chemotherapy consisting of ranimustine, vindesine, melphalan and prednisolone (MCNU-VMP). One hundred thirty-nine consecutive patients with newly diagnosed multiple myeloma (MM) were allocated at random to a lenograstim group (n = 70) or a placebo group (n = 69). Patients were treated with two cycles of MCNU-VMP, and either lenograstim (2 microg/kg daily, s.c.) or placebo was administered from the day neutrophils decreased to less than 1.000/microl and was discontinued when neutrophils exceeded 5,000/microl. The median duration of neutropenia (neutrophils under 1,000/microl) was significantly shorter for the lenograstim group than the placebo group (2 days vs 9 days in the first cycle; 1 day vs 13 days in the second cycle). The incidence of febrile neutropenia in the first cycle was significantly lower in the lenograstim group than in the placebo group (9.2% vs 30.4%). No life-threatening infections were observed in either group. The two cycles of MCNU-VMP therapy were completed in 90.8% of the patients, and a higher average relative dose intensity (ARDI; 0.94) was achieved in the lenograstim group. The tumor response rate of the lenograstim group (57.8%) was higher than that of the placebo group (43.1%), but the difference was not statistically significant (chi2 = 2.634, df = 1, P = 0.105). Lenograstim was well tolerated, and no unexpected adverse events occurred. Lenograstim proved effective in controlling chemotherapy-induced neutropenia in MM patients under MCNU-VMP therapy.

Topics: Adjuvants, Immunologic; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Chi-Square Distribution; Double-Blind Method; Female; Granulocyte Colony-Stimulating Factor; Humans; Japan; Lenograstim; Male; Melphalan; Middle Aged; Multiple Myeloma; Neutropenia; Nitrosourea Compounds; Prednisolone; Recombinant Proteins; Statistics, Nonparametric; Treatment Outcome; Vindesine

In a population-based study, the Nordic Myeloma Study Group found a survival advantage for high-dose melphalan with autologous blood stem-cell support compared to conventional chemotherapy in myeloma patients under 60 yr of age (risk ratio: 1.62; confidence interval [CI] 1.22-2.15; p = 0.001). A study of health-related quality of life (HRQoL) was integrated in the trial, using the EORTC QLQ-C30 questionnaire. Of the 274 patients receiving intensive therapy 221 (81%) were compared to 113 (94%) of 120 patients receiving conventional melphalan-prednisone treatment. Prior to treatment, there were no statistically significant differences in any HRQoL score between the two groups. One month after the start of induction chemotherapy, the patients on intensive treatment had more sleep disturbance than the control patients. At 6 mo, corresponding to a mean of 52 d after high-dose melphalan, the patients on intensive treatment had moderately lower scores for global QoL and role and social functioning and there was also a significantly higher score for appetite loss. At 12 and 24 mo, the HRQoL was similar to that of the control patients. At 36 mo, there was a trend toward less fatigue, pain, nausea, and appetite loss in the intensive-treatment group. Thus, the 18 mo of prolonged survival seem to be associated with a good health-related quality of life. Despite the moderate HRQoL reduction associated with the early intensive chemotherapy phase, this treatment modality must be regarded as an important step forward in the care of multiple myeloma.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Appetite; Female; Health Status; Hematopoietic Stem Cell Transplantation; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Prospective Studies; Quality of Life; Sleep Wake Disorders; Social Behavior; Social Support; Survival Analysis

Melphalan and prednisone (MP) has been the standard treatment for multiple myeloma (MM) for the last 30 years. Combination chemotherapy at conventional doses has not shown a significant prolongation of survival when compared to MP. There are few data comparing conventional chemotherapy at standard doses with conventional treatment at higher doses. We present the long-term outcome of 914 patients from two randomized trials comparing three different dose intensity regimens.. From 1 January, 1985 to 31 December, 1989, 487 patients were randomized between MP (melphalan 9 mg/m(2) p.o. and prednisone 60 mg/m(2) days 1-4) and alternating VCMP (vincristine 1 mg i.v. on day 1, cyclophosphamide 500 mg/m(2) i.v. on day 1, melphalan 6 mg/m(2) p.o. on days 1-4, and prednisone 60 mg/m(2) on days 1-4) and VBAP (vincristine 1 mg i.v. on day 1, BCNU and doxorubicin 30 mg/m(2) i.v. each on day 1, and prednisone 60 mg/m(2) on days 1-4). From 1 January, 1990 to 31 May, 1994, 427 patients were randomized between VCMP/VBAP at the above detailed doses (VCMP/VBAP 'SD') and the same regimen increasing the doses of cyclophosphamide and doxorubicin from 500 to 1200 mg/m(2) and from 30 to 50 mg/m(2), respectively (VCMP/VBAP 'HD').. Increasing dose intensity produced a significantly higher partial response rate (31% vs 45% vs 51% for MP, VCMP/VBAP 'SD', and VCMP/VBAP 'HD', respectively; P < 0.01). However, a significantly early death rate was observed in the HD arm (7.7, 7.5 and 12.1% for MP, VCMP/VBAP 'SD', and VCMP/VBAP 'HD', respectively; P = 0.05). Median duration of response (20 vs 18 vs 19 months for MP, VCMP/VBAP 'SD', and VCMP/VBAP 'HD', respectively; P = NS) and median survival (25 vs 31 vs 29 months for MP, VCMP/VBAP 'SD', and VCMP/VBAP 'HD', respectively; P = NS) were similar in the three groups. MP produced a higher degree of thrombocytopenia than combination chemotherapy at standard (P = 0.002) or high dose (P = 0.01), this leading to a significantly higher dose reduction in the MP arm (P < 0.001 and P = 0.003 for VCMP/VBAP 'SD' and VCMP/VBAP 'HD', respectively).. In these trials the response rate significantly correlated with the regimen intensity. However, no significant differences in response duration and survival were found. This highlights the limited role of conventional chemotherapy in MM and the need for further trials, aimed at determining the impact of new treatment approaches such as high-dose therapy/autotransplantation.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carmustine; Cause of Death; Cyclophosphamide; Dose-Response Relationship, Drug; Doxorubicin; Female; Follow-Up Studies; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Prednisone; Remission Induction; Survival Analysis; Survival Rate; Vincristine

Serum samples drawn at diagnosis from 174 myeloma patients were analyzed for the presence of the heparan [corrected] sulfate proteoglycan, syndecan-1. Syndecan-1 was elevated in 79% of patients (median, 643 units/mL) compared with 40 healthy controls (median, 128 units/mL), P <.0001. Serum syndecan-1 correlated with the following: serum creatinine, secretion of urine M-component over the course of 24 hours, soluble interleukin-6 (IL-6) receptor, C-terminal telopeptide of type I collagen, beta(2)-microglobulin, percentage of plasma cells in the bone marrow, disease stage, and serum M-component concentration. In order to evaluate syndecan-1 as a prognostic marker in multiple myeloma, it was entered into a multivariate Cox regression model. Data from 138 patients were available for this analysis. As a continuous variable, syndecan-1 was an independent prognostic parameter in addition to serum beta(2)-microglobulin and World Health Organization performance status. When syndecan-1 was dichotomized by the best cutoff (66th percentile, 1170 units/mL), the survival difference between the groups was highly significant: "high" syndecan-1 group had a median survival of 20 months, and the "low" syndecan-1 group had a median of 44 months (P <.0001). We conclude that syndecan-1 is a new independent prognostic parameter in multiple myeloma, and its role in prognostic classification systems should be further investigated. (Blood. 2000;95:388-392)

Topics: Biomarkers; Disease-Free Survival; Humans; Interferon-alpha; Melphalan; Membrane Glycoproteins; Multiple Myeloma; Prednisone; Prognosis; Proteoglycans; Reference Values; Regression Analysis; Survival Analysis; Syndecan-1; Syndecans; Time Factors

The role of more intense conditioning for second transplant was evaluated in myeloma patients achieving at least partial remission (PR) after first transplant with melphalan at 200 mg/m2. Forty-three patients received more intensive conditioning for the second transplant. Nineteen patients received cyclophosphamide 120 mg/kg along with melphalan 200 g/m2 (MEL-CY; group 1) while 24 patients received total body irradiation (1125 cGy) in conjunction with melphalan 140 mg/m2 (MEL-TBI; group 2). Forty-three matched control patients were identified from 450 patients receiving melphalan alone for second transplant (MEL200; group 3). Engraftment and toxicities were comparable among the groups with the exception of increased treatment-related mortality of 8% in group 2 compared to none in groups 1 and 3 (P = 0.07). Despite identical CR rates of 74, 71 and 70%, respectively, in groups 1, 2 and 3 (P = 1.0), event-free survival (median: 27, 15 and 61; P < 0.0001) and overall survival (median: 39, 25 and 76 months; P = 0.003) were significantly decreased in patients receiving more intensive conditioning (groups 1 and 2). Lymphocyte recovery, evaluated as a surrogate for immune recovery, was inferior in more intensively treated patients (groups 1 and 2 compared to group 3). Our findings suggest that more intense conditioning appears to have no benefit in patients responding to their first cycle of high-dose therapy and may even be detrimental in this setting. Bone Marrow Transplantation (2000) 25, 483-487.

Topics: Antigens, CD34; Antineoplastic Agents, Alkylating; beta 2-Microglobulin; Cohort Studies; Combined Modality Therapy; Cyclophosphamide; Disease-Free Survival; Evaluation Studies as Topic; Fever; Graft Survival; Humans; Lymphocyte Count; Melphalan; Multiple Myeloma; Pneumonia; Prognosis; Sepsis; Stomatitis; Survival Rate; Transplantation Conditioning; Transplantation, Autologous; Whole-Body Irradiation

Autologous stem cell transplantation after high-dose melphalan for the treatment with multiple myeloma has resulted in prolonged progression-free survival and overall survival in patients under 65 years. We have examined the role of autologous transplantation in 17 patients with multiple myeloma over 65 years at our centre using a matched pair analysis with younger patients. The median age of this cohort of patients over 65 years was 67 years (65-74) and their outcome and transplant-related morbidity was compared with 17 younger pair mates with a median age of 55 years (31-64). Sixteen patients received high-dose melphalan, and one received busulphan with autologous stem cell rescue. The high-dose therapy was well tolerated in both elderly patients and the matched pairs, with comparable time to recover neutrophils and platelets. Treatment-related mortality also did not differ significantly in both the groups. Median overall survival of the elderly patients was 3.59 years similar to 3.01 years of the pair mates (P = 0.92). Autologous stem cell transplantation after high-dose melphalan conditioning was equally well tolerated in groups of patients above and below 65 years. There was no difference in relapse rate, OS and myelotoxicity in both the groups. These findings suggest that advanced age should not be an exclusion criterion from autologous transplant programmes. Bone Marrow Transplantation (2000) 25, 533-539.

Topics: Adult; Age Factors; Aged; Antineoplastic Combined Chemotherapy Protocols; Busulfan; Carmustine; Chemical and Drug Induced Liver Injury; Cohort Studies; Cyclophosphamide; Disease-Free Survival; Doxorubicin; Female; Graft Survival; Heart Diseases; Hematopoietic Stem Cell Mobilization; Hospitalization; Humans; Interferons; Kidney Diseases; Male; Matched-Pair Analysis; Melphalan; Methylprednisolone; Middle Aged; Multiple Myeloma; Neutropenia; Neutrophils; Platelet Count; Recurrence; Sepsis; Survival Rate; Thrombocytopenia; Transplantation, Autologous; Vincristine

A randomized controlled study of patients with multiple myeloma was performed to evaluate the efficacy and safety of recombinant human granulocyte colony-stimulating factor (rhG-CSF:KW-2228) in treating neutropenia induced by chemotherapy, and its influence on the dose intensity of, and response rate to, chemotherapy. As a rule, 3 courses of chemotherapy at intervals of 4 weeks were administered both to the untreated and KW-2228-treated groups. Among 98 eligible patients evaluated for neutrophil recovery, a markedly reduced duration of neutropenia was observed during each course in the KW-2228 treated group. No significant difference distinguished the two groups in terms of incidence or duration of infection. However, febrile neutropenia appeared only in the untreated group. There was no significant difference in terms of response rate or dose intensity. However, only patients in the untreated group withdrew from the study due to protracted neutropenia. These results demonstrated that KW-2228 is effective and safe, and has a significant effect on the acceleration of neutrophil recovery in patients with neutropenia induced by chemotherapy for multiple myeloma, and is useful for the completion of chemotherapy regimens.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Female; Granulocyte Colony-Stimulating Factor; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Neutropenia; Nitrosourea Compounds; Prednisolone; Treatment Outcome; Vindesine

We conducted a randomized trial to evaluate whether melphalan-prednisone (MPH-P) treatment administered just after diagnosis improves survival of stage I multiple myeloma (MM). Between January 1987 and March 1993, 145 consecutive previously untreated patients with stage I MM were randomized between treatment with MPH-P (administered for 4 days every 6 weeks) just after diagnosis and treatment only at disease progression. Survival was not influenced by MPH-P treatment either administered just after diagnosis or at disease progression (64 vs 71 months respectively). Comparing the first with the second group the odds ratio of death is 1.17 (95% confidence interval 0.57-2.42; P = 0.64). Disease progression occurred within a year in about 50% of patients who were initially untreated. Response rate was similar in both groups, but duration of response was shorter in patients who were treated at disease progression (48 vs 79 months, P = 0.044). Patients actually treated at disease progression (34/70) survived shorter than those who had neither disease progression nor treatment (56 vs > 92 months; P = 0.005). Starting MPH-P just after diagnosis does not improve survival and response rate in stage I MM, with respect to deferring therapy until disease progression. However, patients with stage I MM randomized to have treatment delayed and who actually progressed and were treated had shorter survival than those with stable disease and no treatment. Biologic or other disease features could identify these subgroups of patients.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Disease Progression; Female; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Prednisone; Prognosis; Survival Analysis; Time Factors; Treatment Outcome

Aiming to target the minimal residual disease in patients with multiple myeloma, a phase I/II single centre study was undertaken for feasibility and tolerance of intensive acute lymphoblastic leukaemia consolidation chemotherapy (ALL-IC) as part of a strategy for post-transplant consolidation targeted at pre-B cells. Seventeen newly diagnosed patients with myeloma (median age 55 years; 30-65) were initially treated with courses of infused cyclophosphamide, vincristine, adriamycin and methylprednisolone (C-VAMP) followed by melphalan 200 mg/m2(HDM) and peripheral blood stem cell rescue (PBSC). Forty-seven percent were in CR and the rest in PR after HDM. ALL-IC consisted of vincristine, daunorubicin, etoposide, cytarabine, 6-thioguanine and prednisolone given over 5 days. All patients became neutropenic (<0.5 x 109/l) at a median of 10 days (4-18) and one of the 17 patients (5.8%) died 15 days post ALL-IC of sepsis. A further four have died of relapse with an overall survival (OS) of 67% at 4 years. Two of nine patients in PR at the time of ALL-IC achieved CR. Matched-pair analysis of 34 control patients shows no difference for OS and event-free survival between ALL-IC and controls. We conclude that ALL-IC given to myeloma patients after HDM/PBSC is as safe as when used in ALL and warrants further assessment in randomised trials for myeloma.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Female; Hematopoietic Stem Cell Transplantation; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Neoplasm, Residual; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Transplantation, Autologous; Treatment Outcome

High-dose therapy (HDT) has increased complete remission (CR) rates and survival in multiple myeloma (MM). We now report on continuous CR (CCR) and associated prognostic factors in 1000 consecutive patients receiving melphalan-based tandem HDT. Five-year CCR was 52% among 112 CR patients without chromosome 13 (triangle up13) abnormalities and with beta-2-microglobulin

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Chromosome Deletion; Chromosome Mapping; Chromosomes, Human, Pair 13; Disease-Free Survival; Humans; Melphalan; Middle Aged; Multiple Myeloma; Survival Rate; Time Factors

To improve the complete response (CR) rate in advanced multiple myeloma (MM) without increasing the toxicity of high-dose therapy, we have used a new conditioning regimen. A combination of BE-8 [an anti-interleukin 6 (IL-6) murine monoclonal antibody] and dexamethasone followed by high-dose melphalan (220 mg/m2) and autologous stem cell transplantation was used to treat a series of 16 patients with advanced multiple myeloma. A strong inhibition of IL-6 activity evaluated by quantification of C-reactive protein was observed in all patients and was correlated with the high CR rate achieved with this combination therapy.

Topics: Adult; Animals; Antibodies, Monoclonal; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Drug Administration Schedule; Female; Glucocorticoids; Humans; Interleukin-6; Male; Melphalan; Mice; Middle Aged; Multiple Myeloma; Recurrence; Treatment Outcome

This pilot study evaluated the efficacy of a new combination chemotherapy with a newly developed nitrosourea derivative ranimustine and evaluated the efficacy of interferon alpha (IFN-alpha) maintenance in previously untreated patients with multiple myeloma (MM). The induction therapy (ROAD-IN) was a 6-week regimen consisting of chemotherapy with ranimustine, vincristine (Oncovin), melphalan (Alkeran) and dexamethasone starting on day 1 and IFN-alpha, which was administered three times weekly for 3 weeks starting on day 22. This was repeated for three cycles. The responders were subsequently randomized into two groups that received or did not receive IFN-alpha as maintenance therapy. Of the 164 patients registered, 161 were evaluated. An objective response to induction therapy was seen in 75% of patients; complete remission (CR) in 38 (24%) and partial remission (PR) in 82 (51%). The median survival for all patients was 3.6 years from registration. The survival of responders (CR + PR) was significantly better than that of non-responders (median survival 4.3 years vs. 1.4 years; 7-year survival rate 32% vs. 9%; P < 0.0001). The IFN-alpha maintenance did not show any advantage for either response duration or survival. This pilot study demonstrated that a comparatively short period of induction therapy with the ROAD-IN regimen produced a rather high response rate and a similar survival rate to those achieved with other longer induction regimens, and that good responders to the initial therapy survived significantly longer than non-responders.

Topics: Antineoplastic Combined Chemotherapy Protocols; Chi-Square Distribution; Connectin; Dexamethasone; Humans; Interferon-alpha; Logistic Models; Melphalan; Multiple Myeloma; Muscle Proteins; Myeloma Proteins; Nitrosourea Compounds; Pilot Projects; Prospective Studies; Remission Induction; Vincristine

Fourteen patients, aged 65-85 years, with refractory (11) or relapsing (3) multiple myeloma were treated with a "protracted-sequential" protocol comprising vincristine 1-2 mg or vindesine 3 mg/M(2) (max. 5 mg) IVI over 4 hr on D1, prednisolone 40-50 mg PO D1-14, and melphalan 2-4 mg PO or cyclophosphamide 50-100 mg PO D15-28; cycles were repeated at 4-6 weekly intervals. Treatment was continued for 12 months if the response was optimal or indefinitely if the response was suboptimal. Five patients responded optimally; their survival from the commencement of this protocol ranged from 30 to 120 months. The other nine patients achieved a partial response, their survival ranging from 4+ to 79 months. The treatment is simple, nontoxic, and as convenient as the "classic combination" of melphalan and prednisolone.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Female; Humans; Male; Melphalan; Multiple Myeloma; Prednisolone; Recurrence; Treatment Outcome; Vincristine; Vindesine

Although thalidomide (Thal) was initially used to treat multiple myeloma (MM) because of its known antiangiogenic effects, the mechanism of its anti-MM activity is unclear. These studies demonstrate clinical activity of Thal against MM that is refractory to conventional therapy and delineate mechanisms of anti-tumor activity of Thal and its potent analogs (immunomodulatory drugs [IMiDs]). Importantly, these agents act directly, by inducing apoptosis or G1 growth arrest, in MM cell lines and in patient MM cells that are resistant to melphalan, doxorubicin, and dexamethasone (Dex). Moreover, Thal and the IMiDs enhance the anti-MM activity of Dex and, conversely, are inhibited by interleukin 6. As for Dex, apoptotic signaling triggered by Thal and the IMiDs is associated with activation of related adhesion focal tyrosine kinase. These studies establish the framework for the development and testing of Thal and the IMiDs in a new treatment paradigm to target both the tumor cell and the microenvironment, overcome classical drug resistance, and achieve improved outcome in this presently incurable disease.

Topics: Antineoplastic Agents; Apoptosis; Cell Cycle; Dexamethasone; DNA Replication; Doxorubicin; Drug Resistance, Multiple; Female; G1 Phase; Humans; Immunosuppressive Agents; Male; Melphalan; Multiple Myeloma; Thalidomide; Tumor Cells, Cultured

Melphalan and prednisone have been the backbone in myeloma therapy for more than 40 years. New developments in chemotherapy and supportive therapy, achieved during the two decades which preceded the use of high-dose chemotherapy with stem cell rescue, have not changed the overall prognosis. A study of high-dose melphalan with autologous stem cell support on 274 patients < 60 years, performed by the Nordic Myeloma Study Group, has shown a prolongation of the median survival by 1.5 years. The results confirm that this therapy is a major step forward in myeloma therapy. Cost-utility and quality-of-life studies show that high-dose therapy has acceptable costs and leads to a favorable long-term quality-of-life.

Topics: Adult; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Dose-Response Relationship, Drug; Hematopoietic Stem Cell Transplantation; Humans; Interferons; Melphalan; Multiple Myeloma; Practice Guidelines as Topic; Quality of Life; Radiography; Scandinavian and Nordic Countries; Survival Rate; Transplantation, Autologous

Extensive studies have tested the clinical impact of double and triple sequential transplants as front-line therapy in MM, following the suggestion that dose escalation can overcome the marked drug resistance characteristic of this disease, but the superiority of such approaches vs one single transplant has still to be demonstrated. The aim of our study was to evaluate the feasibility and efficacy of high-dose idarubicine intensification of a standard busulphan-melphalan conditioning regimen in MM. Twenty-eight patients (median age 55 years) with sensitive disease received PBSCT after high-dose idarubicine combined with busulphan and melphalan and followed by s.c. rhG-CSF until PMN recovery. The most severe toxicity was represented by oral mucositis which resolved with hemopoietic reconstitution. Overall response and CR rate were 52% and 40%, respectively. Currently, 36 patients are alive and 19 are progression-free a median of 20 months (12-36) from transplant. The 3-year projected probability of progression-free survival for patients transplanted after first-line treatment is 60%. The combination of Ida/Bu/Melph appears a promising alternative regimen for PBSCT in myeloma, with low transplant-related toxicity and fast hematological recovery. Long-term follow-up and a prospective randomized study, now ongoing, will probably clarify whether an idarubicine-intensified regimen will result in superior outcomes to conventional conditioning and even be comparable to a double consecutive transplant program.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Busulfan; Female; Hematopoietic Stem Cell Transplantation; Humans; Idarubicin; Male; Melphalan; Middle Aged; Multiple Myeloma; Transplantation Conditioning; Transplantation, Autologous

The effect of interferon on the health-related quality of life in multiple myeloma was assessed in two trials carried out by the Nordic Myeloma Study (Group (NMSG). In both trials, the EORTC QLQ-C30 questionnaire, supplemented with 11 items relating to interferon toxicity, was used. The first was a randomized controlled trial (NMSG 4/90) evaluating the addition of interferon alpha-2b to melphalan and prednisone during induction, maintenance and relapse. During the first 12 months, patients on interferon reported more chills, fever, fatigue, pain, nausea/vomiting, appetite loss and dry skin than the control patients, and a slight reduction of global health and quality of life. From 12 months onward there were no significant differences in any score between the two groups. In a later trial (NMSG 5/94) evaluating the effect of high-dose chemotherapy with stem cell support in patients under 60 years of age with newly diagnosed myeloma, interferon was used as maintenance. During the maintenance phase, symptom and toxicity scores were not significantly different from those in control patients under 60 years of age in the previous trial. Thus, interferon appeared to be well tolerated after high-dose chemotherapy with stem cell support.

Topics: Adult; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Female; Health Status; Humans; Interferon-alpha; Male; Melphalan; Middle Aged; Multiple Myeloma; Patient Satisfaction; Prednisone; Quality of Life

We have evaluated the outcome of allogeneic haemopoietic stem cell transplantation for multiple myeloma using a conditioning regimen comprising fractionated total body irradiation and high-dose melphalan (110 mg/m2). The study comprised 25 patients (median age 49 years) who had been transplanted by either bone marrow (n = 13) or G-CSF mobilized peripheral blood stem cells (n = 12). Overall transplant-related mortality was 30% but was lower for patients < 50 years of age at transplant (21%). The main cause of treatment-related mortality was viral infection. Of the 19 patients evaluable post-transplant, 17 have so far achieved complete remissions. Currently, with a median follow-up of 3.4 years, 18 out of 25 patients are alive, of whom 15 are in continuing complete remission (CR) and 2 in second remission after suffering localized relapses, which were treated with radiotherapy and donor leucocyte infusions. Patients transplanted after 1 line of previous therapy, < 50 years of age and receiving peripheral blood stem cells (PBSC) rather than bone marrow (BM) had a superior outcome, although there was no statistically significant factor. We conclude that allogeneic transplantation should be considered as a potentially curative option for younger patients with myeloma and that the regimen using fractionated total body irradiation and melphalan has a high CR rate and a relatively low risk of treatment-related mortality, particularly in younger patients.

Topics: Adult; Age Factors; Age of Onset; Antineoplastic Agents; Disease-Free Survival; Female; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cell Transplantation; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Transplantation Conditioning; Transplantation, Homologous; Treatment Outcome; Whole-Body Irradiation

With the aim of developing an effective therapy for heavily pretreated refractory MM outpatients, we evaluated the OPPEBVCAD regimen, a Hodgkin's disease-derived protocol that includes many drugs effective in MM administered in a sequential schedule. Twenty-two pts aged 42-72 years, with symptomatic highly-pretreated refractory (18 cases), or primary resistant MM (four cases. including two pts with plasma cell leukemia-PCL) received this therapy every 28 days (2-4 cycles, followed by a maintenance program). Therapeutic response (Chronic Leukemia-Myeloma Task Force criteria) and performance status (PS) and pain (W.H.O.) were evaluated. All of the pts were evaluable for response. There were 9 (40%) objective responses (OR: stabilization of blood counts and bone lesions, serum calcium normalization, 50% or more reduction in the concentration of serum monoclonal component (MC), 90% reduction in Bence-Jones proteinuria), 8 (36%) partial responses (PR: 25-50% reduction in serum MC), 1 no response or stable disease (NR), and 4 (18%) cases of progressive disease (PD). OR plus PR were 77%. Of the 4 primary resistant tumors (2 PCL and 2 MM), 2 achieved PR, 1 OR (a PCL case) and 1 progressed. Median survival was 15 months for responding pts (OR plus PR) and 4.5 months for non-responders (NR plus PD). PS and pain improved in 15 pts and did not change in 9. The most frequent side effects were cytopenias, with one drug related infective death. The OPPEBVCAD regimen proved to be an effective therapy for refractory relapsing or primary resistant MM: in responders (two-thirds of the pts), survival was prolonged by about 10 months. Its efficacy in anthracycline-treated pts, as well as the feasibility of using it on an outpatient basis without any continuous drug infusions, make this regimen a promising third line salvage therapy.

Topics: Adult; Aged; Agranulocytosis; Anemia; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Cause of Death; Drug Administration Schedule; Drug Resistance, Neoplasm; Epirubicin; Humans; Lomustine; Melphalan; Middle Aged; Multiple Myeloma; Prednisone; Procarbazine; Salvage Therapy; Survival Rate; Thrombocytopenia; Treatment Outcome; Vinblastine; Vincristine; Vindesine

Between August 1990 and August 1995, 231 patients (median age 51, 53% Durie-Salmon stage III, median serum beta-2-microglobulin 3.1 g/L, median C-reactive protein 4 g/L) with symptomatic multiple myeloma were enrolled in a program that used a series of induction regimens and two cycles of high-dose therapy ("Total Therapy"). Remission induction utilized non-cross-resistant regimens (vincristine-doxorubicin-dexamethasone [VAD], high-dose cyclophosphamide and granulocyte-macrophage colony-stimulating factor with peripheral blood stem cell collection, and etoposide-dexamethasone-cytarabine-cisplatin). The first high-dose treatment comprised melphalan 200 mg/m2 and was repeated if complete (CR) or partial (PR) remission was maintained after the first transplant; in case of less than PR, total body irradiation or cyclophosphamide was added. Interferon--2b maintenance was used after the second autotransplant. Fourteen patients with HLA-compatible donors underwent an allograft as their second high-dose therapy cycle. Eighty-eight percent completed induction therapy whereas first and second transplants were performed in 84% and 71% (the majority within 8 and 15 months, respectively). Eight patients (3%) died of toxicity during induction, and 2 (1%) and 6 (4%) during the two transplants. True CR and at least a PR (PR plus CR) were obtained in 5% (34%) after VAD, 15% (65%) at the end of induction, and 26% (75%) after the first and 41% (83%) after the second transplants (intent-to-treat). Median overall (OS) and event-free (EFS) survival durations were 68 and 43 months, respectively. Actuarial 5-year OS and EFS rates were 58% and 42%, respectively. The median time to disease progression or relapse was 52 months. Among the 94 patients achieving CR, the median CR duration was 50 months. On multivariate analysis, superior EFS and OS were observed in the absence of unfavorable karyotypes (11q breakpoint abnormalities, -13 or 13-q) and with low beta-2-microglobulin at diagnosis. CR duration was significantly longer with early onset of CR and favorable karyotypes. Time-dependent covariate analysis suggested that timely application of a second transplant extended both EFS and OS significantly, independent of cytogenetics and beta-2-microglobulin. Total Therapy represents a comprehensive treatment approach for newly diagnosed myeloma patients, using multi-regimen induction and tandem transplantation followed by interferon maintenance. As a result, the proportion of patients

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Combined Modality Therapy; Cyclophosphamide; Cytarabine; Dexamethasone; Disease-Free Survival; Doxorubicin; Etoposide; Granulocyte-Macrophage Colony-Stimulating Factor; Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Middle Aged; Multiple Myeloma; Prognosis; Remission Induction; Treatment Outcome; Vincristine

The idiotype (Id) determinant on the multiple myeloma (MM) protein can be regarded as a tumor-specific marker. Immunotherapy directed at the MM Id may stem the progression of this disease. We report here on the first 12 MM patients treated at our institution with high-dose therapy and peripheral blood stem cell transplantation (PBSCT) followed by Id immunizations. MM patients received PBSCT to eradicate the majority of the disease. PBSCT produced a complete response in 2 patients, a partial response in 9 patients and stable disease in 1 patient. Three to 7 months after high-dose therapy, patients received a series of monthly immunizations that consisted of two intravenous infusions of Id-pulsed autologous dendritic cells (DC) followed by five subcutaneous boosts of Id/keyhole limpet hemocyanin (KLH) administered with adjuvant. Between 1 and 11 x 10(6) DC were obtained by leukapheresis in all patients even after PBSCT. The administration of Id-pulsed DC and Id/KLH vaccines were well tolerated with patients experiencing only minor and transient side effects. Two of 12 patients developed an Id-specific, cellular proliferative immune response and one of three patients studied developed a transient but Id-specific cytotoxic T-cell (CTL) response. Eleven of the 12 patients generated strong KLH-specific cellular proliferative immune responses showing the patients' immunocompetence at the time of vaccination. The two patients who developed a cellular Id-specific immune response remain in complete remission. Of the 12 treated patients, 9 are currently alive after autologous transplantation with a minimum follow-up of 16 months, 2 patients died because of recurrent MM and 1 patient succumbed to acute leukemia. These studies show that patients make strong anti-KLH responses despite recent high-dose therapy and that DC-based Id vaccination is feasible after PBSCT and can induce Id-specific T-cell responses. Further vaccine development is necessary to increase the proportion of patients that make Id-specific immune responses. The clinical benefits of Id vaccination in MM remain to be determined.

Topics: Adjuvants, Immunologic; Adult; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Cancer Vaccines; Combined Modality Therapy; Cyclophosphamide; Dendritic Cells; Dexamethasone; Doxorubicin; Feasibility Studies; Female; Follow-Up Studies; Hematopoietic Stem Cell Transplantation; Hemocyanins; Humans; Immunocompetence; Immunoglobulin Idiotypes; Immunotherapy, Active; Lymphocyte Activation; Male; Melphalan; Middle Aged; Multiple Myeloma; Prednisone; Recurrence; Remission Induction; T-Lymphocytes, Cytotoxic; Transplantation, Autologous; Treatment Outcome; Vaccination; Vincristine

We performed a phase II study to test the efficacy and feasibility of induction therapy with vincristine, adriamycin and dexamethasone (VAD) and intermediate-dose melphalan, 70 mg/m2 (IDM), to autologous or allogeneic stem cell transplantation in newly diagnosed multiple myeloma (MM). A total of 77 patients received two cycles of VAD (n = 62) and/or two cycles of i.v. IDM 70 mg/m2 (n = 15) combined with G-CSF. PBSC were harvested after the first IDM, successfully in 87% of patients. Patients with a response to induction received myeloablative therapy with PBSCT (n = 50) followed by IFN maintenance or allo-BMT (n = 11). Seventy-two per cent of patients achieved a response after VAD which increased to 85% after IDM. Of patients who received PBSCT and allo-BMT, 24% and 45% achieved CR, respectively. Toxicity of induction consisted mainly of bone marrow suppression after IDM (median 8 days) with prolonged aplasia in 11% of patients after the second IDM. Only six infections WHO grade 3 occurred during induction. Treatment-related mortality of PBSCT and allo-BMT was 6% and 18%, respectively. Median time of follow-up is 44 months, and 50% of patients after PBSCT and 60% of patients after allo-BMT are still in remission. Survival rates of all patients were 82%, 75% and 63%, and for transplanted patients 86%, 79% and 68% after 12, 24 and 36 months. Well known prognostic factors, including alpha-IFN maintenance after PBSCT, were not significant for response or survival although patients in CR after allo-BMT had a strong tendency for better outcome. VAD/IDM is an effective and safe induction therapy for autologous and allogeneic stem cell transplantation. Based on these observations a phase III trial was started in October 1995 comparing IFN maintenance with PBSCT and allo-BMT after response to induction with VAD and IDM.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Dexamethasone; Doxorubicin; Female; Hematopoietic Stem Cell Transplantation; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Survival Analysis; Transplantation, Autologous; Vincristine

The patient registers of five prospective population based Nordic studies were reviewed for patients <60 yr. A total of 313 patients with symptomatic multiple myeloma were identified. Thirty-nine of them were judged retrospectively to have been ineligible for intensive chemotherapy regimens. The remaining 274 patients were considered appropriate as a historical control group for comparison with patients treated with high-dose chemotherapy and autologous stem cell support. Of these, 32 had been diagnosed during the period 1970-83, 101 during the period 1984-89 and 141 during the period 1990-92. The median age was 54 yr. Six percent were Durie/Salmon stage I, 38% stage II and 56% stage III. Melphalan-prednisone was used for initial therapy in 87%. Median survival for all patients with symptomatic myeloma was found to be 41 months, and for those selected for the control group 44 months, with no noted differences between the aforementioned diagnostic periods. We conclude that the expected median survival is 44 months for myeloma patients <60 yr who may be considered for high-dose therapy protocols. New developments in chemotherapy and supportive therapy, achieved during the two decades which preceded the use of high-dose chemotherapy with stem cell rescue, have not changed the overall prognosis in multiple myeloma.

Topics: Age Factors; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Female; Humans; Interferons; Male; Melphalan; Middle Aged; Multiple Myeloma; Norway; Prednisone; Probability; Retrospective Studies; Survival Analysis; Sweden; Time Factors

A clinical relationship between dose-intensity of melphalan and response rate has been demonstrated in multiple myeloma. Promising results have been reported after 200 mg/m(2) melphalan, especially in younger patients. It is uncertain whether 100 mg/m(2) melphalan (MEL100) can offer similar results in older patients. To address this issue, patients were treated with 2 or 3 MEL100 courses followed by stem cell support. Seventy-one patients (median age, 64 years) entered the protocol at diagnosis. Their clinical outcome was compared with that of 71 pair mates (median age, 64 years) selected from patients treated at diagnosis with oral melphalan and prednisone (MP) and matched for age and beta2-microglobulin. Complete remission was 47% after MEL100 and 5% after MP. Median event-free survival was 34 months in the MEL100 group and 17.7 months in the MP group (P <.001). Median overall survival was 56+ months for MEL100 and 48 months for MP (P <.01). In a multivariate analysis, beta2-microglobulin levels and MEL100 were independent risk factors associated with outcome: superior event-free and overall survival were observed in patients presenting low beta2-microglobulin levels at diagnosis and receiving MEL100 as induction regimen. In conclusion, MEL100 was superior to MP in terms of complete remission rate, event-free survival, and overall survival.

Topics: Aged; Antineoplastic Agents, Alkylating; Combined Modality Therapy; Disease-Free Survival; Female; Hematopoietic Stem Cell Transplantation; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Remission Induction; Transplantation, Autologous

Interferon (IFN) has demonstrated activity in the treatment of patients with multiple myeloma. A previous Eastern Cooperative Oncology Group (ECOG) study suggested that the rates of complete response (CR) and survival were increased with a regimen that alternated IFN with chemotherapy. The current study was designed to evaluate the effect of adding alternating cycles of IFN or early intensification with high dose cyclophosphamide (HiCy) to the VBMCP regimen for the treatment of multiple myeloma patients.. From February 1988 to May 1992, the ECOG entered previously untreated patients with active multiple myeloma on a study in which they were randomized to VBMCP (vincristine 1.2 mg/m(2) administered intravenously [i.v.] on Day 1, BCNU 20 mg/m(2) i.v. on Day 1, melphalan 8 mg/m(2) administered orally [p.o.] on Days 1-4, cyclophosphamide 400 mg/m(2) i.v. on Day 1, and prednisone 40 mg/m(2) p.o. on Days 1-7; 5-week cycles) or VBMCP + rIFN(alpha2), the latter given at 5 Mu/m(2) 3 times a week starting on Day 22 of each 6-week cycle after 2 initial cycles of VBMCP. Patients younger than 70 years were also randomized to a third treatment that substituted cyclophosphamide 600 mg/m(2) i.v. on Days 1-4 and prednisone 100 mg/m(2) p.o. on Days 1-4 for cycles 3 and 5 of VBMCP (VBMCP + HiCy). Treatment was continued for 2 years.. Of the 653 patients entered, 628 were eligible for the study. All were evaluated for response. With median follow-up for surviving patients of 54 months, the median survival duration was 42 months-1 year longer than usually reported for melphalan combined with prednisone. A comparison of the three regimens revealed no significant difference in the rates of survival or objective response (OR). However, CRs were increased among patients treated with VBMCP + rIFN(alpha2) compared with VBMCP alone (18% vs. 10%, P = 0.03). Patients treated with VBMCP + rIFN(alpha2) had a longer response duration than patients treated with VBMCP alone (30 vs. 25 months, P = 0.035). There was a greater response rate with the IFN regimen among elderly patients (OR and CR = 67% and 31%, respectively) and patients with immunoglobulin A (IgA) myeloma (OR and CR = 83% and 29%, respectively). Severe infections were seen as often with VBMCP as with VBMCP + rIFN(alpha2) (13% vs. 15%), but they were more frequent with VBMCP + HiCy (25%).. VBMCP + rIFN(alpha2) yields a higher rate of CR and a longer response duration than VBMCP alone but appears to make no difference in the rates of overall response or survival compared with VBMCP or VBMCP + HiCy. The superior ability of VBMCP + rIFN(alpha2) induction therapy to produce CR and more durable responses, as well as its activity in older patients and in those with IgA myeloma, suggest that this therapy has important biologic activity in myeloma and merits further clinical investigation.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Cardiovascular Diseases; Carmustine; Cyclophosphamide; Hematologic Diseases; Humans; Infections; Interferon Type I; Melphalan; Middle Aged; Multiple Myeloma; Prednisone; Recombinant Proteins; Survival Analysis; Vincristine

To evaluate high-dose melphalan followed by autologous stem-cell transplantation in patients with refractory multiple myeloma.. Multiple myeloma patients with alkylating agent or vincristine/doxorubicin/dexamethasone-refractory disease were eligible for the phase II multi-institutional Southwest Oncology Group trial S8993. Patients up to age 70 years were enrolled between April 15, 1991, and May 1, 1996. Patients without prior stem-cell collection were primed with high-dose cyclophosphamide (HD-CTX; 6 g/m(2)) and granulocyte-macrophage colony-stimulating factor. After stem-cell procurement, patients received melphalan 200 mg/m(2) with autologous transplantation. Upon recovery from melphalan, patients were to receive interferon alfa-2b until relapse.. Seventy-two patients were enrolled onto S8993; five were ineligible and one received no therapy. Of the 66 assessable patients, 56 patients underwent the transplant procedure; 54 were assessable for response and 56 for toxicity. The response to HD-CTX (n = 37) included three complete remissions (CRs; 8%) and five partial remissions (PR; 14%); response to melphalan (n = 54) included 16 CRs (30%) and 19 PRs (35%), for an overall CR and >/= PR (n = 66; intent-to-treat) of 27% and 58%, respectively. Toxicities included six treatment-related deaths: two during HD-CTX and four during transplantation. The median progression-free survival (PFS) and overall survival (OS) durations on an intent-to-treat basis from transplant registration was 11 months and 19 months (95% confidence interval, 14 to 29 months), respectively. The 3-year actuarial PFS and OS rates were 25% and 31%, respectively.. High-dose therapy with melphalan 200 mg/m(2) is feasible with high response rates (58% overall) and an OS of 19 months in patients with refractory multiple myeloma.

Topics: Adult; Aged; Analysis of Variance; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Combined Modality Therapy; Disease-Free Survival; Hematopoietic Stem Cell Transplantation; Humans; Interferon alpha-2; Interferon-alpha; Melphalan; Middle Aged; Multiple Myeloma; Prognosis; Recombinant Proteins; Salvage Therapy; Survival Rate; United States

The relationship between plasmablastic cells and outcome in multiple myeloma (MM) has been established for nearly 15 years. But the assessment of these cells is not easy to perform and it allows the identification of only a small proportion of patients. We investigated the plasma cell morphology using a progressive evaluation of consecutive criteria: nucleolus, chromatin and nuclear-cellular ratio (N/C). The combination of these three items produces a subclassification where four cellular subtypes identify 93% of the plasma cells, and these subtypes are related to the outcome. The interest of this methodology is to be based on the mature plasma cells that are easier to identify than the plasmablastic cells. These new cell subtypes introduce a new classification for patients: Group 1 includes patients with at least 66% mature plasma cells (P000). Both Group 2 and 3 have less than 66% P000 and are separated by their degree of maturation (Proplasma I > or = Proplasma II + plasmablastic). The distinction of these three groups of patients is highly related to the prognosis (P < 10(-4)). These results have been confirmed on a second group of patients coming from a different institution. In conclusion, we propose a new methodology for the plasma cell evaluation in MM, that is based on the morphological criteria and that has the advantage of identifying an intermediate (30%) subgroup of patients with a prognostic significance.

Topics: Algorithms; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Cell Differentiation; Combined Modality Therapy; Humans; Melphalan; Multiple Myeloma; Neoplastic Stem Cells; Plasma Cells; Prognosis; Survival Analysis

Thrombocytopoiesis of 21 multiple myeloma patients undergoing single or double transplant regimen was characterized by measuring the level of reticulated platelets and plasma glycocalicin. Since reticulated platelets are an index of thrombopoietic activity and glycocalicin plasma values are related to platelet damage and turnover, it may be possible to perform a novel type of analysis of the thrombopoietic compartment during the mobilizing regimen and during transplant-related chemotherapy. Patients underwent mobilizing therapy and first transplant. Some randomized patients also underwent a second transplant with mobilized peripheral blood stem cells. The results show that the percentage of reticulated platelets decreased after therapy and then gradually increased in the recovery phase either during first or second transplant. By contrast, the percentage of reticulated platelets increased until day +8 and then gradually decreased during the mobilizing regimen. The glycocalicin index (glycocalicin plasma value normalized for the individual platelet count) increased significantly both during the course of mobilization and after transplant-related chemotherapy when the platelet number was at its nadir. However, the glycocalicin index was more elevated after transplant-related chemotherapy than after the mobilizing regimen. Our findings suggest that chemotherapy-related thrombocytopenia may be due to a dual mechanism: thrombocytopenia results from decreased platelet production in addition to increased platelet damage and possible destruction.

Topics: Antigens, CD34; Antineoplastic Combined Chemotherapy Protocols; Behavior Therapy; Biomarkers; Blood Platelets; Busulfan; Cyclophosphamide; Dexamethasone; Doxorubicin; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Mobilization; Humans; Melphalan; Multiple Myeloma; Platelet Aggregation Inhibitors; Platelet Count; Platelet Glycoprotein GPIb-IX Complex; Reticulocytes; RNA; Thrombocytopenia; Transplantation, Autologous; Vincristine

The main form of cytotoxic treatment for multiple myeloma (MM) is conventional dose chemotherapy at present.. Between November 1989 and December 1991, a multicenter phase II study of alternating conventional dose combination chemotherapy (CCT) with COP (cyclophosphamide, vincristine, prednisone) and MP (melphalan and prednisone) to evaluate its clinical usefulness for overt MM patients was conducted by the Lymphoma Study Group of the Japan Clinical Oncology Group (JCOG).. Eighty-one previously untreated patients were enrolled in the study. For 69 eligible patients, the response rate was 50.7% [95% confidence interval (CI) 38.4-63.0%]. The median survival time was 38.5 (95% CI 32.0-44.4) months. The survival rate at 3 and 5 years was 50.7 and 27.3%, respectively. Grade 4 toxicity by the criteria of the World Health Organization consisted of anemia in eight patients, leucocytopenia in three, cardiac in one and hepatic in two, but there was no treatment-related death.. The COP-MP regimen for overt MM is thought to be one of the effective CCTs according to the results of the present phase II study.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Drug Administration Schedule; Drug Evaluation; Female; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Prednisone; Survival Rate; Vincristine

The anti-emetic efficacy of a combination of tropisetron and dexamethasone was studied in 33 patients who underwent bone marrow transplantation. Another 50 patients receiving conventional anti-emetic therapies in bone marrow transplantation served as control. On the first and second days of preconditioning chemotherapy, 51% and 36% respectively of patients in the tropisetron and dexamethasone group did not experience vomiting, compared with only 12% and 10% of control group patients (P < 0.001). The mean number of episodes of vomiting in the tropisetron and dexamethasone group was also significantly lower than in the control group (0.97+/-1.65 vs 3.50+/-2.45 and 1.30+/-1.40 vs 4.44+/-2.91 respectively, both P < 0.001). Control of vomiting in the two groups was not significantly different during days 3-6. Analysis of patients receiving busulfan and cyclophosphamide as the preconditioning regimen still showed better anti-emetic control in the tropisetron and dexamethasone group than in the control group on the first two days of treatment (total control rate 33.3% vs 6.5% and 44.4% vs 12.9% respectively, P < 0.001). Patients given tropisetron and dexamethasone combination more frequently suffered from dizziness and burning sensation of the chest. However, diarrhea and extrapyramidal symptoms were the most frequent adverse effects seen after using conventional anti-emetic combination. The combination of tropisetron and dexamethasone was thus superior to conventional anti-emetic combinations in preventing vomiting during preconditioning period of bone marrow transplantation. The adverse effects of this combination were minimal and well tolerated by patients.

Topics: Adolescent; Adult; Antiemetics; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Busulfan; Carmustine; Child; Cyclophosphamide; Cytarabine; Dexamethasone; Dizziness; Drug Therapy, Combination; Female; Headache; Heartburn; Humans; Indoles; Leukemia; Male; Melphalan; Middle Aged; Multiple Myeloma; Podophyllotoxin; Transplantation Conditioning; Tropisetron; Vomiting; Whole-Body Irradiation

To compare, in the setting of tandem autotransplantations for multiple myeloma (MM), two established methods of peripheral-blood stem-cell (PBSC) procurement with chemotherapy or hematopoietic growth factor alone.. Between June 1994 and July 1995, 44 patients with MM were randomized to PBSC mobilization with either granulocyte colony-stimulating factor (G-CSF) 16 microg/kg (group 1; n = 22) or high-dose cyclophosphamide (HDCTX) 6 g/m2 plus G-CSF 5 microg/kg (group 2; n = 22). All 44 patients received melphalan 200 mg/m2 with their first autograft and 32 patients proceeded to a second transplantation.. Group 2 required a significantly longer time interval for completion of PBSC collection than group 1 (median, 22 v 8 days; P = .0001), greater frequency of hospitalization (100% v 32%; P = .0001), and increased transfusion of platelets (86% v 18%; P = .0001) and packed RBCs (86% v 55%; P = .02). Likewise, the incidence of fever and pneumonia/sepsis were higher in group 2 (P = .02 and P = .04, respectively). Surprisingly, despite greater CD34 cell quantities infused in group 2, median recovery times of granulocytes (both > 500/microL and 2,500/microL) and platelets (both > 50,000/microL and > 100,000/microL) were similar (all P > .7). Posttransplant toxicities were also similar.. Compared with HDCTX plus G-CSF, high-dose G-CSF alone is associated with lower morbidity, shorter duration of PBSC mobilization, and comparable hematopoietic recovery after transplantation, which should result in significant cost reduction. Considering the relatively limited antitumor activity of HDCTX (10% with > or = 50% tumor cytoreduction), PBSC mobilization with HDCTX should be limited to selected patients with persistent MM despite induction chemotherapy.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Cyclophosphamide; Etoposide; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cell Transplantation; Humans; Kinetics; Leukocyte Count; Melphalan; Middle Aged; Multiple Myeloma; Prospective Studies

In order to study whether oral bisphosphonate therapy might prevent or reduce skeletal-related morbidity in patients with newly diagnosed multiple myeloma who required chemotherapy, 300 patients were included in a randomized multi-centre trial. Patients were given oral pamidronate at a dose of 300 mg daily, or placebo, in addition to conventional intermittent melphalan/prednisolone (and in some cases alpha-interferon) treatment. With a median treatment duration of about 550d, no statistically significant reduction in skeletal-related morbidity (defined as bone fracture, related surgery, vertebral collapse, or increase in number and/or size of bone lesions) could be demonstrated. Pamidronate treatment also did not have any influence on patient survival or on the frequency of hypercalcaemia. However, in patients treated with pamidronate there were fewer episodes of severe pain (P=0.02) and a decreased reduction of body height of 1.5 cm (P= 0.02). The overall negative result of the study is attributed to the very low absorption of orally administered bisphosphonates in general.

Topics: Administration, Oral; Aged; Anti-Inflammatory Agents; Antineoplastic Combined Chemotherapy Protocols; Body Height; Bone Diseases; Diphosphonates; Double-Blind Method; Female; Fractures, Bone; Humans; Hypercalcemia; Male; Melphalan; Multiple Myeloma; Pain; Pamidronate; Prednisolone; Treatment Failure

Between 1985 and 1990, 133 patients with advanced multiple myeloma (MM) (74% resistance; 41% resistant relapse, RR) were treated with five high-dose therapy (HDT) regimens including: melphalan < or =100 mg/m2 (MEL 100) (46 patients); MEL 100 plus GM-CSF (24 patients); MEL 140 plus autologous bone marrow transplantation (ABMT) (eight patients); MEL 140 plus TBI 850 cGy plus ABMT (37 patients); and thiotepa 750 mg/m2 (THIO 750) + TBI 850 cGy plus ABMT (18 patients). The median follow-up of alive patients as of December 1997 was 9 years. Overall, 17% experienced treatment-related mortality within 60 days (TRM) and 12% achieved stringently defined complete remission (CR) with a median duration of 16 months; four of 16 patients (25%) remain in CR at 10 years. The median durations of event-free survival (EFS)/overall survival (OS) were 6/15 months. Superior EFS/OS were noted with MEL 100 plus GM-CSF and the two TBI-containing regimens (9/24 months among 79 patients) compared to the remaining 54 patients receiving MEL < or =100 or MEL 140 plus ABMT (3/5 months) (P = 0.0001/0.0001, respectively). Multivariate regression analyses (MVA) were performed so that, despite patient heterogeneity among the five treatment groups, potentially relevant disease, host, treatment, and supportive care variables could be identified that were associated with TRM, CR, EFS and OS. TRM was higher with creatinine >2.0 mg/dl, absence of ABMT/GM-CSF support and age >50 years; CR was superior with TBI-containing regimens and < or =12 months of prior therapy; EFS and OS both were longer with B2M < or =2.5 mg/l, age < or =50 years, absence of RR and with ABMT/GM-CSF support. In the presence of >2 favorable variables (32 % of patients), median EFS/OS durations of 18/48 months were observed which progressively declined with 2 and <2 favorable parameters to 6/11 months (28% of patients) to 3/5 months (40% of patients) (P = 0.0001/0.0001). At 10 years, 10 and 20% of patients with >2 favorable variables were event-free and alive, which was also true for the 37 patients receiving MEL 140 plus TBI. To appreciate possible long-term contributions of supportive care or treatment intensity, landmark analyses performed at 1, 2, 4 and 6 months revealed virtually identical ranking orders of prognostically favorable variables to those seen pre-HDT; once supportive care was accounted for, regimen intensity with added TBI did not emerge as an independent favorable feature.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Combined Modality Therapy; Follow-Up Studies; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Melphalan; Middle Aged; Multiple Myeloma; Multivariate Analysis; Prognosis; Survival Rate; Thiotepa; Transplantation, Autologous; Whole-Body Irradiation

The objectives of the present study were to investigate whether interferon alpha (IFN) maintenance could prolong response duration and survival in patients with multiple myeloma (MM) in objective response and to analyze the characteristics of relapse and subsequent survival. From January 1991 to November 1994, 92 patients from the Spanish Cooperative Group PETHEMA with MM in objective response after 12 courses of VCMP/VBAP chemotherapy were randomized to receive IFN maintenance vs no treatment until relapse. Prognostic factors at diagnosis were similar in both groups. IFN was administered at a starting dose of 3 mU/m2 three times per week. The IFN toxicity was moderate with granulocytopenia and fatigue being the most common adverse effects. Median duration of response from randomization until relapse was 13 months in the IFN group vs 7.7 months in the no treatment arm (P = 0.042). Median survival from randomization was 38.8 months for patients given IFN vs 32.7 months for those allocated to the no treatment arm (P = 0.12). Features at relapse were similar in patients who received IFN maintenance and in those assigned to no treatment. Finally, survival from relapse was identical in both groups. In summary, our results show a significant prolongation of response in patients maintained with IFN with no significant influence on survival. In addition, in our series features at relapse and subsequent outcome were similar in both groups.

Topics: Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Cyclophosphamide; Doxorubicin; Female; Humans; Interferon alpha-2; Interferon-alpha; Male; Melphalan; Middle Aged; Multiple Myeloma; Prednisone; Prognosis; Prospective Studies; Recombinant Proteins; Remission Induction; Therapeutics; Vincristine

36 MM pts in advanced stage, 17 recently diagnozed (group I) and 19 in the progression of the disease (group II) were examined. 10 pts of group I and 12 of group II had renal failure. Levels of II-6, sII-6R and TNF-alpha were measured in pts sera before cytostatic therapy or plasma exchange (PE) and after 4-week therapy. The plasma concentration of II-6, sIl-6R and TNF-alpha before chemotherapy were 47-426 pg/ml, 33-III ng/ml and 19-350 pg/ml respectively and were significantly higher than in healthy control (group III) but no significant changes were observed between group I and group II. Patients with renal failure showed significantly higher II-6 and sIl-6R plasma levels than those with normal renal function. After 4 weeks of chemotherapy plasma concentration of the examined parameters decreased only in those pts of both groups, who later, after 6 mos disclosed a therapeutic response. Median survival time (m-ST) of recently diagnosed MM pts was 38 mos and in those with progression of underlying disease-43 mos. M-ST of 5 pts whose levels of Il-6 > 150 pg/ml, sIl-6R > 55 ng/ml and TNF-alpha-150 pg/ml was only 18 mos, but when only one of them was so much elevated it attained 55 mos. (p = 0.01).

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Cyclophosphamide; Disease Progression; Female; Humans; Interleukin-6; Kidney Failure, Chronic; Male; Melphalan; Methylprednisolone; Middle Aged; Multiple Myeloma; Prednisone; Receptors, Interleukin; Receptors, Interleukin-6; Recombinant Fusion Proteins; Survival Rate; Tumor Necrosis Factor-alpha; Vincristine

We investigated the feasibility of mobilizing peripheral blood stem cells (PBSC) with G-CSF alone in 24 patients with multiple myeloma. The median age was 53 years (range 33-62). All patients had stage II/III disease and responded to standard first-line (n = 6) or salvage chemotherapy (n = 18). The median number of previous chemotherapy cycles was 7 (4-18) and the median number of prior melphalan-cycles was 6 (0-14). Nine (35%) patients had experienced prior radiation therapy. The patients received either 10 microg/kg G-CSF (n = 18) or 24 microg/kg G-CSF (n = 7, including one patient with previous 10 microg/kg G-CSF stimulation) daily s.c. for 5 or more consecutive days until completion of harvesting, starting apheresis on the fifth day. G-CSF treatment was well tolerated, with only slight bone pain in half of the patients (51%). After a median of three (range 1-7) apheresis procedures, medians of 3.8 (0.3-17) x 10(6) CD34+ cells/kg, 8.5 (4.5-24) x 10(8) MNC/kg, 2.9 (0.6-39.4) x 10(4) CFU-GM/kg, and 5.6 (0.9-49) x 10(4) BFU-E/kg were harvested. Three patients (12%) with extensive melphalan pretreatment failed the target collection of at least 2.0 x 10(6) CD34+ cell/kg. Pretreatment with six or more cycles of melphalan yielded a smaller number of CD34+ cells than pretreatment with fewer than six cycles (2.5 vs 5.3 x 10(6)/kg; p = 0.001). Nineteen patients underwent high-dose chemotherapy consisting of either total marrow irradiation (9 Gy)/busulfan (12 mg/kg) and cyclophosphamide (120 mg/kg) (n = 10), or busulfan (14 mg/kg)/cyclophosphamide (120 mg/kg) (n = 5), or tandem melphalan (200 mg/m2). The median time for granulocyte (> 1.0/nl) and platelet (> 50/nl) recovery was 10 and 14 days (ranges 7-12 and 8-40), respectively. G-CSF alone is a safe, alternative approach to mobilizing sufficient PBSC in patients with multiple myeloma and allows an exact prediction of harvest time. G-CSF-mobilized PBSCs ensure rapid engraftment after myeloablative therapy. Melphalan treatment should be avoided in patients who are candidates for high-dose chemotherapy.

Topics: Adult; Antigens, CD34; Antineoplastic Agents, Alkylating; Feasibility Studies; Female; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cells; Humans; Leukapheresis; Leukocyte Count; Male; Melphalan; Middle Aged; Multiple Myeloma

High-dose chemotherapy (melphalan) with autologous marrow stem cell support (AMSCS) results in high response rates in multiple myeloma (MM), with up to 50% of patients achieving complete remission. However, these remissions are generally not durable. As the cytokine interferon alpha has been shown to prolong partial response following conventional chemotherapy, this trial was conducted to evaluate its role following high-dose chemotherapy. 85 patients were randomly assigned to maintenance treatment with interferon alpha, 3 x 10(6) units/m2 subcutaneously three times weekly until relapse or no further treatment following recovery from high-dose chemotherapy (melphalan 140-200 mg/m2 or busulphan 16 mg/kg) combined with AMSCS. At 5.8 years following the accrual of the last patient in this trial, 38 patients had died, 17 in the interferon arm and 21 in the control arm. The median progression-free survival (PFS) in the 42 patients randomized to interferon alpha was 46 months versus 27 months in the controls. Both overall survival and PFS, which were highly significant at median follow-up of 52 months, have now ceased to be significant, because most patients have ultimately succumbed to their disease. Interferon was tolerated by the majority of patients with very good compliance. Toxicity consisted mainly of flu-like symptoms and malaise which were usually self-limiting. The results of such a pilot study should be carefully interpreted and the benefits of interferon should be confirmed in larger multicentre studies in the setting of minimal residual disease following autologous transplantation.

Topics: Adult; Aged; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Busulfan; Disease-Free Survival; Female; Follow-Up Studies; Hematopoietic Stem Cell Transplantation; Humans; Interferon-alpha; Long-Term Care; Male; Melphalan; Middle Aged; Multiple Myeloma; Pilot Projects; Transplantation, Autologous; Treatment Outcome

This study was designed to determine the maximum tolerated dose (MTD) of high-dose melphalan (HDM), with peripheral blood stem cell support, that could be given twice within 90 days to patients with multiple myeloma. Twenty patients received tandem HDM at 160, 180 or 200 mg/m2 and a total of 55 were treated at the estimated MTD of 200 mg/m2. Seventeen of 55 (31%) did not receive cycle 2; six because of low CD34+ cell yields, three because of severe (n = 1) or fatal toxicities (n = 2) and eight for other reasons. The median interval between doses for 38 patients was 70 days (range 41-225). Three of 55 patients (5%) died of treatment-related causes. In patients completing two cycles of HDM, at any dose level, the complete remission rate improved from 15% following cycle 1 to 55% following cycle 2. The probabilities of survival, event-free survival and relapse or progression at 18 months for the 55 patients treated at the MTD were 0.84, 0.76 and 0.20, respectively, with a median follow-up of 19 months (range 9-36) from mobilization chemotherapy. It was concluded that two cycles of HDM, 200 mg/m2, could be administered to approximately 70% of patients under the age of 66 with multiple myeloma in a median interval of 70 days, with improvement in CR rates.

Topics: Adult; Aged; Antineoplastic Agents, Alkylating; Combined Modality Therapy; Drug Administration Schedule; Drug Tolerance; Female; Hematopoietic Stem Cell Transplantation; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Transplantation, Autologous

Results to date indicate that high-dose therapy (HDT) with autologous stem cell support improves survival of patients with symptomatic multiple myeloma (MM). We performed a multicenter, sequential, randomized trial designed to assess the optimal timing of HDT and autotransplantation. Among 202 enrolled patients who were up to 56 years old, 185 were randomly assigned to receive HDT and peripheral blood stem cell (PBSC) autotransplantation (early HDT group, n = 91) or a conventional-dose chemotherapy (CCT) regimen (late HDT group, n = 94). In the late HDT group, HDT and transplantation were performed as rescue treament, in case of primary resistance to CCT or at relapse in responders. PBSC were collected before randomization, after mobilization by chemotherapy, and, in the two groups, HDT was preceded by three or four treatments with vincristine, doxorubicin, and methylprednisolone. Data were analyzed on an intent-to-treat basis using a sequential design. Within a median follow-up of 58 months, estimated median overall survival (OS) was 64.6 months in the early HDT group and 64 months in the late group. Survival curves were not different (P = .92, log-rank test). Median event-free survival (EFS) was 39 months in the early HDT group whereas median time between randomization and CCT failure was 13 months in the late group. Average time without symptoms, treatment, and treatment toxicity (TWiSTT) were 27.8 months (95% confidence interval [CI]; range, 23.8 to 31.8) and 22.3 months (range, 16.0 to 28.6) in the two groups, respectively. HDT with PBSC transplantation obtained a median OS exceeding 5 years in young patients with symptomatic MM, whether performed early, as first-line therapy, or late, as rescue treatment. Early HDT may be preferred because it is associated with a shorter period of chemotherapy.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Cyclophosphamide; Disease-Free Survival; Doxorubicin; Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cell Transplantation; Humans; Life Tables; Melphalan; Methotrexate; Middle Aged; Multiple Myeloma; Prednisone; Procarbazine; Remission Induction; Salvage Therapy; Survival Analysis; Treatment Outcome; Vincristine

263 patients (median age 65+/-10 years) with multiple myeloma were treated with cyclophosphamide-prednisone. Out of this cohort, 103 patients had progressive disease and were randomly assigned to either VAD (vincristine, doxorubicin, dexamethasone; 50 cases) or VMBCP (vincristine, BCNU, cyclophosphamide, melphalan and prednisone; 53 cases). There were no statistical differences between the two groups with the respect to clinical, biological and radiological parameters. There was no difference in survival between the VAD and VMBCP groups. The 4 months response rate was similar in the two groups (50% VAD, 56% VMBCP). With multivariate analysis for survival (Cox model), two factors had a statistically significant impact: Karnofsky index (> 60) and albuminaemia (< 34 g/l). With both Karnofsky index > 60 and albuminaemia > or = 34 g/l, the median survival was 29 months v 2 months with a Karnofsky index < or = 60 and albuminaemia < 34 g/l (P<0.05). In conclusion, VAD or VMBCP had similar activity for salvage treatment in MM refractory or relapsing to first-line treatment with cyclophosphamide-prednisone.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Cyclophosphamide; Dexamethasone; Doxorubicin; Female; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Prednisone; Prognosis; Salvage Therapy; Survival Rate; Treatment Outcome; Vincristine

To compare VMCP, a multidrug combination chemotherapy comprising vincristine (VCR), melphalan (MPH), cyclophosphamide (CPM) and prednisolone (PSL), with MMPP comprising MPH, ranimustine (MCNU), procarbazine, and PSL as induction, to elucidate the value of alternating combination chemotherapy, and to search for an appropriate maintenance therapy in multiple myeloma.. At 16 institutions in the Nagoya City area, we carried out a randomized trial of VMCP versus MMPP as the initial treatment. Patients who were refractory or resistant to the initial therapy were crossed over into the other arm (crossover trial). For patients who achieved a partial response (PR) or a minor response (MR) and in whom the paraprotein level ceased to decrease, the maintenance therapy was randomized either to an MPH/PSL combination (MP) or to alternating combination therapy (AT) with VMCP and MMPP.. In the 94 evaluable patients of the 111 enrolled, the response rate (PR rate) was 27.7% (13/47) in the VMCP arm and 44.7% (21/47) in the MMPP arm (P = 0.0859). The crossover trial resulted in a PR rate of 15.8% (3/19) for the VMCP-->MMPP crossover and 14.3% (2/14) for the MMPP-->VMCP crossover. The median survival time was 23.4 months for those initially begun in the VMCP arm and 24.9 months for those in the MMPP arm, showing a tendency for better survival during a follow-up of 2-6 years with MMPP treatment, but without statistical significance. The survival time of patients with progressive disease was significantly shorter than that of patients with PR, MR or no change (NC). However, there was no significant difference in the survival rate among those who achieved PR, MR, or NC. As to the maintenance therapy, there was no significant difference in survival between MP therapy and AT. Patients who reached a plateau phase survived significantly longer than those who did not. Except for six cases of grade 3 or 4 neurotoxicity in the VMCP arm, there was no significant difference in the hematologic or gastrointestinal toxicity between the two arms.. We conclude that VMCP is less effective for myeloma than MMPP as the induction treatment, that alternating noncrossresistant chemotherapeutic combinations do not offer an advantage in multiple myeloma, and that patients who reach a plateau phase have a significantly longer survival time.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Humans; Melphalan; Middle Aged; Multiple Myeloma; Nitrosourea Compounds; Prednisolone; Prednisone; Procarbazine; Vincristine

To evaluate the impact of granulocyte-macrophage colony-stimulating factor (GM-CSF) or placebo on the durations of intravenous (IV) antibiotic use, hospitalization, neutropenia, and fever, as well as remission rates, after high-dose melphalan (HDM) without stem-cell transplantation (SCT) in patients with multiple myeloma (MM).. One hundred two patients with high-risk MM were randomized 2:1 in a prospective multicenter trial to receive 5 microg/kg/d GM-CSF (69 patients) or placebo (33 patients) starting the day after 140 mg/m2 IV melphalan for up to 21 days.. GM-CSF significantly reduced neutropenia after HDM (median, 23.5 v 29 days; P = .0468), with a trend to reduce the duration of hospitalization (median, 32 v 38 days; P = .0841). Nevertheless, GM-CSF did not significantly reduce infectious toxicity as regards the number of days with fever (median, 5 v 3; P = .359), the number of days with IV antibiotics (median, 22 v 27; P = .14), or early deaths, with an 11.5% treatment-related mortality rate in the GM-CSF group (eight of 69 v two of 32 patients in the placebo group; P = .686). There was no difference in response rates between the two groups of patients.. GM-CSF after HDM without SCT is feasible and significantly shortens neutropenia with a trend toward reduction of hospitalization duration, but does not significantly reduce the morbidity and mortality of such therapy. Thus, when intensive therapy is indicated, given that the mortality of HDM followed by SCT reported in the literature is less than 5% and patients are discharged at approximately day 15, despite the risk of contamination by clonogenic malignant cells, SCT appears to be preferable to GM-CSF after HDM.

Topics: Adult; Antineoplastic Agents, Alkylating; Double-Blind Method; Drug Administration Schedule; Female; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Neutropenia; Prospective Studies; Treatment Outcome

The IFM 90 trial was designed to compare conventional chemotherapy (CC) and high-dose therapy (HDT). This trial demonstrated a significant superiority of HDT over CC regarding response rate, event-free-survival, and overall survival. Further improvements of HDT can be expected both in terms of feasibility (with the combined use of hematopoietic growth factors and peripheral blood stem cells) and in terms of response rate (using tandem transplants). A substantial improvement in long-term survival, however, will require the development of effective maintenance therapy to control the minimal residual disease present after transplant.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Carmustine; Cyclophosphamide; Doxorubicin; Female; Humans; Interferon-alpha; Male; Melphalan; Middle Aged; Multiple Myeloma; Prednisone; Prognosis; Prospective Studies; Vincristine

The Eastern Cooperative Oncology Group (ECOG) performed a Phase III comparison of melphalan and prednisone (MP) with vincristine, carmustine (BCNU), melphalan, cyclophosphamide, and prednisone (VBMCP) in an attempt to determine which of these regimens should be the standard treatment for multiple myeloma.. Four hundred seventy-nine previously untreated patients with multiple myeloma from 23 ECOG institutions were enrolled. Treatment, assigned by randomization, consisted of either 4-week cycles of MP or 5-week cycles of VBCMP. After 1 year of induction therapy, patients received MP or VBMCP maintenance therapy at 6- and 8- week intervals, respectively, until relapse. Patients who experienced treatment failure with MP were eligible for crossover therapy with VBMCP.. Objective responses were obtained for 51% of patients receiving MP, as compared with 72% of patients receiving VBMCP (P < 0.001). Response duration was also longer with VBMCP (median, 18 months with MP vs. 24 months with VBMCP; P = 0.007). Overall survival was not significantly different between MP and VBMCP (P = 0.30). The 5-year survival for VBMCP was 26%, as compared with 19% for MP. VBMCP was associated with more nausea, peripheral nerve toxicity, alopecia, and neutropenia, but the infection rate was equal to that observed with MP. Both regimens were generally well tolerated. The main exception was that elderly patients who were confined to bed had a higher risk of death with VBMCP. The two regimens produced a similar incidence of late secondary myelodysplastic syndrome and acute leukemia. Crossover VBMCP for patients failing with MP was only minimally effective, with an objective response rate of 20% and median survival of 11 months after crossover.. VBMCP is more effective than MP in producing and sustaining remission of multiple myeloma. It is associated with a marginal survival advantage and an apparently greater chance of surviving 5 years for patients who can tolerate moderately intensive combination chemotherapy. Cancer 1997;79:1561-7. 1997 American Cancer Society.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Cross-Over Studies; Cyclophosphamide; Drug Administration Schedule; Female; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Neoplasms, Second Primary; Prednisone; Remission Induction; Survival Analysis; Treatment Outcome; Vincristine

Measurement of health-related quality of life was integrated into a randomized trial (NMSG 4/90) comparing melphalan/prednisone to melphalan/prednisone + interferon alpha-2b in newly diagnosed multiple myeloma. One of the aims of the study was to assess the prognostic significance of quality-of-life scores, using the EORTC QLQ-C30 questionnaire. Univariate analysis showed a highly significant association with survival from the start of therapy for physical functioning as well as role and cognitive functioning, global quality of life, fatigue and pain. In multivariate analysis, physical functioning and W.H.O. performance status were independent prognostic factors (P values = 0.001 for both) when analysed in a Cox regression model with the somatic variables beta-2 microglobulin, skeletal disease and age. The best prediction for survival from the start of therapy was obtained by combining the beta-2 microglobulin and physical functioning scores in a variable consisting of three risk factor levels with an estimated median survival of 17, 29 and 49 months, respectively. At a 12 months landmark analysis, the relative risk for patients with physical functioning score 0-20 v 80-100 was 5.63 (99% CI 2.76-11.49), whereas the relative risk for patients without an objective response to chemotherapy compared to those with at least a minor response was 2.32 (99% CI 1.44-3.74). Quality-of-life assessment may be an independent and valuable addition to the known prognostic factors in multiple myeloma.

Topics: Activities of Daily Living; Aged; Antineoplastic Combined Chemotherapy Protocols; Fatigue; Forecasting; Health Status; Humans; Interferon alpha-2; Interferon-alpha; Melphalan; Multiple Myeloma; Multivariate Analysis; Pain; Prednisone; Prospective Studies; Quality of Life; Recombinant Proteins; Risk Factors; Survival Analysis; Treatment Outcome

The objective of our study was to evaluate the efficacy and toxicity of a high-dose melphalan-based (HD-Mel) therapy with or without total body irradiation (TBI) followed by peripheral blood progenitor (PBPC1 transplantation in patients with multiple myeloma (MM).. Between June 1992 and May 1996, 100 patients (67 males 33 females with a median age of 51 years range 30-65) were transplanted at our centre. PBPC were collected during G-CSF-enhanced leukocyte recovery following high-dose chemotherapy. Fifty patients were treated with TBI + melphalan 140 mg m2, while 50 patients received melphalan 200 mg/m2.. Following PBPC autografting, the median time to reach platelets > or = 20 x 10(9) 1 and neutrophils > or = 0.5 x 10(9)/1 was 11 and 14 days with no difference between the treatment groups. In the TBI group significantly longer periods of total parenteral nutrition were required due to severe mucositis. Two patients from the TBI group died due to transplantation-related complications. Following high-dose treatment, remission state improved in 43 out of 98 patients. No statistically significant advantage in reaching CR or PR was observed with TBI + HD-Mel compared to the treatment with HD-Mel alone.. Dose-escalated treatments, with particular regard to the inclusion or omission of TBI, should be prospectively investigated to find the best high-dose regimen.

Topics: Adult; Aged; Antineoplastic Agents, Alkylating; Combined Modality Therapy; Disease-Free Survival; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Transplantation; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Remission Induction; Transplantation, Autologous; Whole-Body Irradiation

We sought to determine factors that impact on the recovery of platelets after blood cell transplantation in patients with multiple myeloma. We performed retrospective analyses in 51 patients undergoing blood cell transplantation for multiple myeloma. The proportional-hazards model was applied to determine significant risk factors. Of 51 transplants, 14 patients failed to achieve a platelet count of 50 x 10(9)/l. Median time to a neutrophil count of 0.5 x 10(9)/l was 10.5 days. Median time to achieve a platelet count of 50 x 10(9)/l was 32 days. Multivariate analysis revealed that cyclophosphamide and G-CSF priming before collection of hematopoietic precursors (P < 0.001) was a positive predictor of rapid engraftment and prior exposure to melphalan given orally (P = 0.02) was a negative predictor of subsequent platelet engraftment. The number of mononuclear cells collected, the patient's disease status at the time of transplant and the presence of circulating plasma cells in the harvested product did not have a significant impact on time to platelet engraftment. We conclude that cyclophosphamide and G-CSF priming shortened the time to achieve platelet engraftment compared with G-CSF alone. Prior exposure to melphalan delayed platelet engraftment and can lead to complete failure of platelet recovery. Stem cells should be collected before melphalan administration in patients with multiple myeloma who are candidates for possible blood cell transplantation.

Topics: Adult; Aged; Blood Platelets; Colony-Forming Units Assay; Cyclophosphamide; Data Interpretation, Statistical; Dose-Response Relationship, Drug; Female; Graft Rejection; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Transplantation; Humans; In Vitro Techniques; Male; Melphalan; Middle Aged; Multiple Myeloma; Platelet Count; Retrospective Studies; Transplantation Conditioning; Whole-Body Irradiation

We performed a multicenter comparative analysis of autologous peripheral blood stem cell transplantation (PBSCT) and allogeneic bone marrow transplantation (alloBMT) in multiple myeloma. Forty-eight consecutive patients received either PBSCT (24 patients) or alloBMT (24 patients) at one of three institutions in the study group. Preparatory regimens consisted of melphalan and total body irradiation (TBI) or melphalan alone in the PBSCT group. The alloBMT group received one of four regimens: cyclophosphamide and TBI; cyclophosphamide, VP-16 and 1,3-bis(2-chloroethyl)-1-nitrosourea (CVB); busulfan and cyclophosphamide (BU/CY) and total marrow irradiation (TMI); or melphalan and TBI. Procedure-related mortality was 12.5% for the PBSCT group and 25% for the alloBMT group. With a median follow-up for survivors in the PBSCT and alloBMT groups of 11 months (range, 4-46) and 15 months (range, 2-84 months), respectively, there was no significant difference in median overall survival (33.5 versus 38.6 months, p = 0.7637) or event-free survival (16.7 versus 31 months, p = 0.8450). There was, however, a plateau in survival at 40% in the alloBMT group. No plateau in survival was seen in the PBSCT group. Clinical relapses occurred as late as 39 months posttransplant. Patients have survived up to 28 months postrelapse.

Topics: Adult; Antineoplastic Agents, Alkylating; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Purging; Bone Marrow Transplantation; Busulfan; Carmustine; Cause of Death; Cyclophosphamide; Disease-Free Survival; Etoposide; Female; Follow-Up Studies; Hematopoietic Stem Cell Transplantation; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Neoplasm Recurrence, Local; Survival Rate; Transplantation Conditioning; Transplantation, Autologous; Transplantation, Homologous; Whole-Body Irradiation

Following conventional chemotherapy, eight myeloma patients presenting with advanced tumor stages were treated with an intensified high-dose regimen and autologous peripheral blood stem cell transplantation. High-dose chemotherapy consisted of idarubicin 20 mg/m2 on days -13, -12 and -11, melphalan 100 mg/m2 on days -5 and -4 and cyclophosphamide 60 mg/kg (plus mesna 60 mg/kg) on days -3 and -2 (IMC). Seven patients achieved a complete remission or a very good partial remission (reduction of M-component > or =90%). There were no toxic deaths. Severe mucositis and fever of unknown origin were seen in all patients. Reversible supraventricular tachycardias without clinical signs of cardiac failure occurred in five patients. One patient developed a persistent deterioration of cardiac function. We surmise that high-dose chemotherapy with IMC is very effective and well tolerated in myeloma patients.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Disease-Free Survival; Female; Humans; Idarubicin; Male; Melphalan; Middle Aged; Multiple Myeloma; Neoplasm Staging; Tachycardia, Supraventricular

This study evaluated the cost utility of adding interferon-alpha 2b to conventional treatment in patients with multiple myeloma. It also provides a methodology for transforming complex quality-of-life profiles into a single index value on the conventional 0 to 1 quality-adjusted life-year scale (QALY). From 1990 to 1992, 583 patients with newly diagnosed, symptomatic multiple myeloma were enrolled in a randomised, multicentre, phase III study to evaluate the addition of interferon-alpha 2b to treatment with melphalan and prednisone. Addition of interferon-alpha 2b yielded a 12% increase in median survival time, at the expense of a slight reduction in quality of life during the first year of treatment. The gain in survival time was not large enough to reach statistical significance. Patients receiving interferon-alpha 2b also had a 5- to 6-month prolongation of the plateau phase. Cost per QALY gained by adding interferon-alpha 2b was conservatively estimated at $US110,000. Potentially better cost effectiveness may be found in different treatment regimens or in certain patient subgroups.

Topics: Aged; Cost-Benefit Analysis; Drug Combinations; Female; Humans; Interferon-alpha; Male; Melphalan; Middle Aged; Multiple Myeloma; Prednisone; Quality of Life

To evaluate the addition of low-dose interferon-alpha 2b to standard melphalan-prednisone therapy in patients with multiple myeloma.. Randomized, multicenter, phase III study.. 15 university hospitals and 92 county hospitals in Sweden, Norway, Denmark, Finland, and Iceland.. 583 patients with symptomatic multiple myeloma.. All patients received melphalan-prednisone every 6 weeks. Melphalan-prednisone therapy was interrupted after at least 8 courses in responding patients who achieved a plateau phase, and it was reinstituted at time of relapse. Patients randomly assigned to receive melphalan-prednisone and interferon also received interferon, 5 MU three times weekly, from the start of treatment through response, plateau phase, and relapse, until definitive failure of melphalan-prednisone occurred.. Survival was the main outcome measure. Secondary measures were response rate, response and plateau phase duration, and toxicity. All analyses were done according to the principle of intention-to-treat.. 45% of patients receiving melphalan-prednisone and 44% of patients receiving melphalan-prednisone and interferon achieved at least a partial response. Response duration and plateau phase duration were longer for patients receiving melphalan-prednisone and interferon than for patients receiving melphalan-prednisone alone (P < 0.05); the difference in median duration was 5 to 6 months. Toxicity was higher with melphalan-prednisone and interferon, and this led to premature discontinuation of interferon therapy in one third of patients and to a reduced overall dose intensity for melphalan. The median survival time was 29 months for patients receiving melphalan-prednisone and 32 months for patients receiving melphalan-prednisone and interferon. The risk ratio for death for patients receiving melphalan-prednisone compared with patients receiving melphalan-prednisone and interferon was 1.02 (95% CI, 0.89 to 1.40).. Adding continuous low-dose interferon to standard melphalan-prednisone therapy does not improve response rate or survival. However, response duration and plateau phase duration are prolonged by maintenance therapy with interferon.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Dose-Response Relationship, Drug; Female; Humans; Interferon alpha-2; Interferon-alpha; Male; Melphalan; Middle Aged; Multiple Myeloma; Prednisone; Recombinant Proteins; Survival Rate

Twenty-one previously untreated multiple myeloma (MM) patients and 10 previously treated patients with refractory or relapsed disease received two or three cycles of intermediate-dose melphalan (70 mg/m2) (IDM), administered intravenously every 6 weeks. Seven previously untreated patients received three and all other patients received two courses of IDM. The objective of the study was to reduce the toxicity of high-dose melphalan (140 mg/m2) (HDM) while maintaining its cytotoxic efficacy and secondly to ensure the possibility of collecting sufficient numbers of peripheral blood stem cells (PBSC) for transplantation. 18 (85%) previously untreated patients responded, of whom four achieved CR (18%). In addition five out of 10 previously treated patients with refractory or relapsed disease responded although bone marrow toxicity in this category was a major drawback. Toxicity was moderate, consisting of alopecia and moderate bone marrow suppression: the granulocyte count dropped below 0.5 x 10(9)/l and platelets below 25 x 10(9)/l for a median of 8 and 6 d, respectively. No serious infections occurred and the majority of patients attended the out-patient clinic. In 12/14 previously untreated patients sufficient peripheral blood CD34+ cells for harvest were present in the repopulation phase after the first IDM. In nine patients peripheral blood stem cells were collected and eight patients have undergone successful transplantation. Repeated IDM followed by filgrastim is highly effective in untreated MM and may be safely administered to reduce tumour load prior to PBSC collection. Autologous stem cells harvested after repeated IDM have a full long-term repopulating capacity.

Topics: Adult; Aged; Antineoplastic Agents, Alkylating; Disease-Free Survival; Drug Administration Schedule; Female; Filgrastim; Follow-Up Studies; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Transplantation; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Recombinant Proteins

In a multicentre study, 83 patients with advanced and previously uniformly treated multiple myeloma (MM) were randomised between cyclophosphamide (600 mg m-2) and epirubicin (70 mg m-2), administered every 3 weeks for three courses and both associated with prednisone and interferon-alpha2b. Both regimens were administered on an outpatient basis and had low haematological toxicity. Clinical results were similar. Overall response rate (43%) and median response and survival (5.9 and 14.1 months respectively) compare well with those obtained with more aggressive chemotherapy schedules.

Topics: Adult; Aged; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Drug Administration Schedule; Epirubicin; Female; Humans; Interferon alpha-2; Interferon-alpha; Male; Melphalan; Middle Aged; Multiple Myeloma; Myeloproliferative Disorders; Peptichemio; Prednisone; Recombinant Proteins; Vincristine

When a randomized trial (NMSG 4/90) comparing treatment with melphalan/prednisone to melphalan/ prednisone + interferon alpha-2b in newly diagnosed multiple myeloma was initiated in 1990, a quality-of-life assessment was integrated into the study. We used the questionnaire (QLQ-C30) developed by the European Organization of Research and Treatment of Cancer (EORTC) Study Group on Quality of Life. The QLQ-C30 incorporates five functional scales, three symptom scales, a global health and quality-of life scale and some single symptom measures. The questionnaire was completed prior to treatment and after 1, 6, 12, 24, 36 and 48 months. 524 (90.2%) of 581 patients enrolled in the NMSG 4/90 completed the first questionnaire, and 484 (83.3%) completed all questionnaires given to them. All but one of the scales met the minimum criteria of reliability (Cronbach's alpha >/ 0.70). Validity was shown by (1) the ability of the scales to discriminate clearly between patients differing in clinical status as defined by pretreatment W.H.O. performance index and Durie & Salmon stage, and (2) the sensitivity to changes in objective disease status (response and relapse). This is the first report of the measurement of health-related quality of life in a prospective clinical trial in multiple myeloma. The results demonstrate that the QLQ-C30 is a reliable and valid instrument for the measurement of quality of life in these patients. The data will be used for a cost-utility analysis of the results of the NMSG 4/90 trial.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Female; Humans; Interferon alpha-2; Interferon-alpha; Male; Melphalan; Multiple Myeloma; Prednisone; Prospective Studies; Quality of Life; Recombinant Proteins; Sensitivity and Specificity; Surveys and Questionnaires

The objective of this investigation was to assess the impact of race (black v white) on the survival of patients with multiple myeloma treated within the context of a large clinical trial.. A cohort of patients randomized to receive one of two treatment regimens and monitored for at least 10 years was studied to assess the impact of race as a prognostic factor, after adjusting for other known factors such as stage of disease. Patients were recruited from the referral network of the Southwest Oncology Group (SWOG), a national multiinstitutional consortium that includes both academic and community treatment centers. Patients had a diagnosis of multiple myeloma and had not previously been treated for this disease. They were carefully characterized as to demographic and clinical features, and were randomized to receive one of two treatment regimens, which proved to have virtually identical outcomes. The outcome measure was survival, measured from the date of randomization to the date of last contact. Patients still alive at last contact date were treated as censored observation.. Survival for black myeloma patients was similar to that for white patients, both overall and adjusted for prognostic factors such as stage.. Observed differences in mortality between blacks and whites cannot be attributed to differences in survival after diagnosis, given comparable treatment.

Topics: Antineoplastic Combined Chemotherapy Protocols; Black People; Carmustine; Cohort Studies; Cyclophosphamide; Doxorubicin; Female; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Prednisone; Retrospective Studies; Survival Analysis; Vincristine; White People

The current prognostic systems have failed to identify multiple myeloma (MM) patients who require aggressive therapy. These staging systems do not reliably distinguish patients with different prognoses. This paper explores the possibility of improving the prognostic forecast in MM by considering some clinical characteristics at diagnosis together with response to first-line chemotherapy. A total of 231 patients were prospectively randomised in a multicentre trial to no therapy vs melphalan + prednisone (MP) for stage I, MP in stage II, and MP vs peptichemio, vincristine and prednisone for stage III. The clinical features of these groups were evaluated for prognostic variables predictive of overall survival by means of univariate and multivariate analysis. The independently significant variables were incorporated into a model that identified three groups of patients with different risks of death and different overall survival. Three variables retained statistical significance: the staging system proposed by the British Medical Research Council, a composite parameter integrating the percentage of bone marrow plasma cells with cytological features of the infiltrating elements (plasma cell vs plasmablast), and response to 6 months of first-line chemotherapy. These three variables led the proposal of a scoring system able to identify three different risk classes (with median overall survival of 52, 28 and 13 months respectively) and to estimate individual patient prognosis more flexibly. The proposed risk classes, drawn from both diagnostic and therapeutic parameters, are thought to be a clinical and investigational instrument for separating MM patients into comparable groups, for selecting the best available therapy and for evaluating response with respect to the disease of each new patient.

Topics: Aged; Antineoplastic Agents; Bone Marrow; Disease-Free Survival; Female; Follow-Up Studies; Humans; Immunoglobulin Isotypes; Male; Melphalan; Multiple Myeloma; Multivariate Analysis; Neoplasm Staging; Peptichemio; Plasma Cells; Prednisone; Probability; Prognosis; Prospective Studies; Risk Assessment; Survival Rate; Time Factors; Vincristine

The aims of the current study were to evaluate in patients with high-risk multiple myeloma (MM) the feasibility and usefulness of high-dose chemotherapy or chemoradiotherapy followed by hematopoietic stem-cell support with autologous peripheral-blood progenitor cells (PBPC) harvested after high-dose cyclophosphamide (HDCYC).. Seventy-three patients with high-risk MM were entered onto the study. Before the procedure, all patients had received HDCYC to collect PBPC by leukapheresis. One patient died of infection after HDCYC. All other patients subsequently received high-dose melphalan (HDM) (140 mg/m2) either alone (n = 1) or associated with either busulfan (16 mg/kg; n = 4) or total-body irradiation (TBI) (8 to 15 Gy; n= 67). In addition, three of the latter patients received cyclophosphamide (120 mg/kg). Thereafter, PBPC were reinfused either alone in 61 patients or together with back-up bone marrow cells in 11 patients in whom the granulocyte-macrophage colony-forming unit (CFU-GM) cell content of the leukapheresis was low.. One patient died of acute cardiac failure after reinfusion of PBPC; three patients did not respond after autologous blood progenitor cell transplantation (ABPCT), while the other 68 patients achieved either a complete response (CR; n = 32) or partial response (PR; n = 36). Thirty-six patients relapsed or progressed after a median response duration of 14.5 months (range, 3 to 43) and 19 of these subsequently died. Four other patients died while still responsive of lung cancer (n = 1) or infection (n = 3). The remaining 28 patients are currently alive and still responding with a median follow-up duration of 27 months (range, 6 to 66). The 3-year probability of survival was 66% +/- 12% (95% confidence interval [CI] after ABPCT and 77% +/- 51% (95% CI) from diagnosis.. High-dose chemotherapy or chemoradiotherapy followed by autologous PBPC support in MM is feasible and efficient. Further studies are needed to confirm these encouraging, although preliminary, results and to compare this technique with other therapeutic strategies.

Topics: Adult; Aged; Analysis of Variance; Antineoplastic Agents, Alkylating; Busulfan; Chemotherapy, Adjuvant; Cyclophosphamide; Feasibility Studies; Female; Hematopoietic Stem Cell Transplantation; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Prognosis; Proportional Hazards Models; Radiotherapy Dosage; Radiotherapy, Adjuvant; Risk Factors; Survival Analysis; Transplantation, Autologous; Treatment Outcome

The median survival of patients with myeloma after conventional chemotherapy is three years or less. Promising results have been reported with high-dose therapy supported by autologous bone marrow transplantation. We conducted a randomized study comparing conventional chemotherapy and high-dose therapy.. Two hundred previously untreated patients under the age of 65 years who had myeloma were randomly assigned at the time of diagnosis to receive either conventional chemotherapy or high-dose therapy and autologous bone marrow transplantation.. The response rate among the patients who received high-dose therapy was 81 percent (including complete responses in 22 percent and very good partial responses in 16 percent), whereas it was 57 percent (complete responses in 5 percent and very good partial responses in 9 percent) in the group treated with conventional chemotherapy (P < 0.001). The probability of event-free survival for five years was 28 percent in the high-dose group and 10 percent in the conventional-dose group (P = 0.01); the overall estimated rate of survival for five years was 52 percent in the high-dose group and 12 percent in the conventional-dose group (P = 0.03). Treatment-related mortality was similar in the two groups.. High-dose therapy combined with transplantation improves the response rate, eventfree survival, and overall survival in patients with myeloma.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Carmustine; Combined Modality Therapy; Cyclophosphamide; Disease-Free Survival; Doxorubicin; Female; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Multivariate Analysis; Prednisone; Prospective Studies; Salvage Therapy; Survival Analysis; Vincristine

To analyze the outcome of patients with multiple myeloma (MM) who were potential candidates for early high-dose therapy (HDT) intensification followed by autotransplantation from a series treated with conventional chemotherapy.. From January 1985 through December 1989, 487 patients with symptomatic MM were entered onto a randomized study to compare melphalan and prednisone (MP) versus vincristine, cyclophosphamide, melphalan, and prednisone (VCMP) /vincristine, carmustine (BCNU), doxorubicin, and prednisone (VBAP). The sub-group of 77 patients who could have been candidates for early intensification with HDT followed by stem-cell support (ie, < 65 years of age, stage II or III disease, performance status < 3, and objective or partial response to initial chemotherapy) are the subjects of this report.. Seventy-seven of 487 patients could have been candidates for early intensification. The median age was 56 years (range, 27 to 64). At diagnosis, 12% had abnormal renal function, 16% hypercalcemia, and 42% serum beta 2-microglobulin level > or = 6 mg/L; 62% had stage III disease at diagnosis. Thirty-six patients were initially treated with MP and 41 with VCMP/VBAP. The median response duration to initial chemotherapy was 22 months, and the actuarial probability of being in continued first response at 5 years was 14%. After a median follow-up time of 58 months, 59 patients have died, one was lost to follow-up evaluation, and 17 are still alive 69 to 119 months after initial chemotherapy. The median survival time from initiation of treatment was 60 months and from the time when autotransplantation would be considered, 52 months. The only independent prognostic parameter for survival was renal function at diagnosis.. The median survival time of patients with MM who are less than 65 years of age and who respond to initial chemotherapy is 5 years. This survival duration is similar to that reported in selected series of patients given early HDT and stresses the importance of ongoing randomized trials to determine the role of HDT in the treatment of younger myeloma patients.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Combined Modality Therapy; Cyclophosphamide; Female; Hematopoietic Stem Cell Transplantation; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Prednisone; Prospective Studies; Survival Rate; Transplantation, Autologous; Vincristine

In a Nordic multi-centre trial, 583 previously untreated multiple myeloma patients were randomized to receive melphalan-prednisone or melphalan-prednisone+ interferon alpha-2b at a dose of 5 million units subcutaneously, 3 d/week. A quality-of-life study was integrated into the trial, using the EORTC QLQ C-30 questionnaire supplemented with 11 questions concerning interferon toxicity. The questionnaire was completed prior to treatment and after 1, 6, 12, 24, 36 and 48 months. 90% of the patients participated in the quality-of-life study, and 83% completed all questionnaires submitted to them. During the first year of treatment the patients on interferon reported significantly more fever, chills, dry skin, fatigue, pain, nausea/vomiting and appetite loss than the control patients. There was a moderate reduction of the global quality-of-life score and slight, non-significant, reductions of physical, emotional, cognitive, social and role functioning scores. After the first year there were no statistically significant differences in any toxicity, symptom or quality-of-life score, except for an increased frequency of dizziness in the interferon group. As only 60% of the patients remained on interferon after 24 months, our data probably underestimate the potential toxicity of the drug. Although there was no significant survival benefit for the interferon patients, a 5-6 months prolongation of the response and plateau phase duration was observed. However, by intention-to-treat analysis, there was no late quality-of-life benefit for the interferon patients to compensate for the early impairment. Thus, the clinical significance of the plateau-phase prolongation is uncertain.

Topics: Activities of Daily Living; Aged; Antineoplastic Combined Chemotherapy Protocols; Fatigue; Feeding and Eating Disorders; Fever; Humans; Interferon alpha-2; Interferon-alpha; Melphalan; Multiple Myeloma; Nausea; Pain; Prednisone; Quality of Life; Recombinant Proteins; Social Behavior; Vomiting

The purpose of this study was to evaluate a new regimen for the treatment of multiple myeloma based on alternating 3-week cycles of chemotherapy and interferon (rIFN alpha 2). In this prospective phase II clinical trial the Eastern Cooperative Oncology Group evaluated a regimen consisting of 2 cycles of VBMCP (Vincristine 1.2 mg/M(2) IV d1, BCNU 20 mg/M(2) IV d1, Melphalan 8 mg/M(2) PO dl-4, Cyclophosphamide 400 mg/M2 IV d1, Prednisone 40 mg/M(2) PO d1-7) followed by alternating 3-week cycles of VBMCP and rIFN alpha2 5 Mu/M(2) SC 3x/week. Treatment was administered for 2 years. Fifty-eight patients with previously untreated multiple myeloma were entered. Objective response (OR) required 50% decrease in M-protein with correction of severe anemia and no progression of skeletal disease. Complete remission (CR) was defined by disappearance of M-protein and normalization of the bone marrow morphology. Life table analysis was utilized to express survival and response duration. Fifty-four patients were evaluable. Objective response was seen in 80% of patients including CR in 30% (16 patients). The median response duration is 35 months, 46 months for patients with CR. The median survival is 42 months for all patients. Five year survival is 42%. Although 78% of patients had neutrophil nadirs <1000 x 10(9)/L, the incidence of severe infection was only 9%. These data demonstrate that VBMCP + interferon is an effective new regimen combining chemotherapy with a biological response modifier for the treatment of multiple myeloma. The incidence of CR is high, and the response and survival durations appear to be 1 year longer than usually seen with standard chemotherapy. A current ECOG randomized trial compares VBMCP + interferon with VBMCP alone.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Combined Modality Therapy; Cyclophosphamide; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Immunologic Factors; Interferon alpha-2; Interferon-alpha; Life Tables; Male; Melphalan; Middle Aged; Multiple Myeloma; Myocardial Infarction; Neutropenia; Prednisone; Recombinant Proteins; Remission Induction; Survival Analysis; Thrombocytopenia; Treatment Outcome; Vincristine

Mutations of members of the ras family are among the most common oncogene mutations found in multiple myeloma (MM). We have examined the mutational status of the N- and K-ras genes at codons 12, 13, and 61 in 160 newly diagnosed MM patients enrolled on the Eastern Cooperative Oncology Group (ECOG) phase III clinical trial E9486. The total incidence of ras mutations was found to be 39% of the samples analyzed. Five patients showed evidence of more than one mutation. We obtained 22 marrow samples from patients at the time of disease progression or relapse, for whom a ras mutation was identified at diagnosis. In all cases, the ras mutation of the disease progression sample was identical to that found at diagnosis. In contrast, three of 25 patients who did not show any ras mutation at diagnosis acquired a ras mutation at the time of disease progression. No significant association was observed between any ras mutation and stage of disease, beta 2-microglobulin levels, labelling index, or protein type. The mean tumor burden and median survival for patients with mutations of N-ras was indistinguishable from patients with no ras mutations. However, patients with K-ras mutations had a significantly higher mean bone marrow tumor burden at diagnosis than patients with no ras mutations (57% v 36%, P < .02); and the median survival of patients with a K-ras mutation was significantly shorter (2.0 v 3.7 years, P < .02). To determine if the status of ras mutations could affect treatment response, we examined patient survival on the three treatment arms of E9486. Although the presence of a ras mutation in the multidrug treatment, VBMCP alone, showed a marginal significance, neither the VBMCP, nor the addition of interferon-alpha showed statistically significant survival differences between mutant and wildtype ras status. Interestingly, there appeared to be a statistically significant difference in survival of patients treated with VBMCP and alternating high doses of cyclophosphamide + prednisone. Patients with ras mutations had a median survival of 2.1 years; patients with wild-type ras had a median survival of 4.0 years (P < .01).

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Carmustine; Clone Cells; Codon; Combined Modality Therapy; Cyclophosphamide; Disease Progression; DNA Mutational Analysis; DNA, Neoplasm; Female; Genes, ras; Humans; Immunologic Factors; Interferon-alpha; Life Tables; Male; Melphalan; Middle Aged; Multiple Myeloma; Polymorphism, Restriction Fragment Length; Prednisone; Prognosis; Survival Analysis; Vincristine

Results of studies using IFN-alpha treatment for maintaining remission and prolonging survival in multiple myeloma (MM) are in conflict and trials seeking optimum use for this biological response modifier are continuing. Between 1989 and 1993 a prospective randomized multicentre trial was undertaken to evaluate the role of the combination of IFN-alpha with chemotherapy (CT) in maintenance treatment of MM. For remission induction, in patients 65 yr or younger, we used VAD (group A) and for the remaining Melphalan and Prednisone (MP) (group B). For maintenance, patients were randomized to receive IFN-alpha 3 x 10(6) i.u. s.c. t.i.w. (group I) or alternating monthly cycles of IFN-alpha and CT. The CT cycles were also alternated (VAD, MP, CP) in an effort to prevent the development of multidrug resistance. Median survival of the two maintenance groups from randomization (36 months for group I and 31 months for group II, p = 0.3) as well as response duration (13 months in group I and 15 months in group II, p = 0.95) were similar. Toxicities were more pronounced both with VAD induction and in the combination maintenance arm. The addition of chemotherapy to the IFN maintenance regimen in MM did not have an advantage over IFN alone.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Dexamethasone; Disease-Free Survival; Doxorubicin; Drug Administration Schedule; Female; Humans; Immunologic Factors; Interferon-alpha; Life Tables; Male; Melphalan; Middle Aged; Multiple Myeloma; Prednisone; Prognosis; Proportional Hazards Models; Prospective Studies; Remission Induction; Survival Rate; Vincristine

The purposes of the present study have been to analyse the presenting features, response to therapy and survival of myeloma patients aged 70 years or more, in comparison to younger patients. From January 1985 to December 1989, 487 patients with multiple myeloma (MM) were randomized to receive melphalan and prednisone (MP) versus alternating cycles of vincristine, cyclophosphamide, melphalan, and prednisone (VCMP) and vincristine, BCNU, adriamycin, and prednisone (VBAP). The subset of 178 patients who were 70 or more years is the subject of this study, whereas the 309 patients younger than 70 years were used as a control group. The presenting features and response to chemotherapy of older patients were no different to those of the younger population. However, the survival of elderly patients was significantly shorter (median 23.4 vs. 33.5 months, p < 0.001). The overall response rate to MP in older patients was 50% (28% objective plus 22% partial response) compared with 61% (44% objective plus 17% partial response) to combination chemotherapy (p = not significant). Myelosuppression was moderate in both arms, although MP produced a higher degree of thrombocytopenia. There were no significant differences in survival between patients given MP versus VCMP/ VBAP (median, 20 vs. 27 months, p = 0.2). Response to treatment was associated with a significantly longer survival. Older patients with symptomatic myeloma tolerate chemotherapy and should be offered treatment.

Topics: Age Factors; Aged; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Cause of Death; Cyclophosphamide; Doxorubicin; Female; Geriatric Assessment; Humans; Male; Melphalan; Multiple Myeloma; Prednisone; Prognosis; Survival Rate; Vincristine

During the period December 1992 to June 1995, 95 patients were treated with high-dose melphalan (HDM) with peripheral blood stem cell rescue (PBSCR). Sixty-five had received previous treatment and 28 had relapsed. Among patients who had relapsed 21/28 had received HDM previously including one who received HDM twice during the course of the study. Seventy-five patients were given HDM/PBSCR for the first time. Comparisons have been made between engraftment times for platelets and neutrophils among patients who received less than or greater than 2 x 10(6) CD34+ cells at rescue. Analyses have also been done to evaluate the effect of previous HDM on recovery. Mobilization of progenitor cells was done with granulocyte colony-stimulating factor (G-CSF). Patients received only PBSCR. No growth factors were given to the PBSCR recipients during the recovery period. The percentage of patients from whom the number of CD34+ cells mobilized was > 2 x 10(6)/kg was similar in patients who received HDM for the first time (23%) compared with those who had had it previously (19%). The yield of CD34+ cells correlated with the number of granulocyte-macrophage colony forming units (CFU-GM). Although the number of CD34+ cells infused was < 2 x 10(6)/kg in 77% of patients, all engrafted for neutrophils to > 0.5 x 10(9)/l. This was delayed in patients who had had previous HDM (P < 0.02). Platelet recovery to > 25, 50 and 100 x 10(9)/l was delayed in all patients who received < 2 x 10(6) CD34+ cells/kg infused (P < 0.02). In patients who had had previous HDM both neutrophil (P < 0.05) and platelet recovery (P < 0.007) were delayed compared with recovery in patients who had not had HDM. In patients who had had previous HDM and received < 2 x 10(6) CD34+ cells/kg infused only 3/17 regained platelets to > 100 x 10(9)/l compared with 3/4 who had > 2 x 10(6) CD34+ cells/kg infused (P < 0.05 Fisher's exact test). There was no evidence that low numbers of CD34+ cells in the PBSCR were associated with early death. The data show that previous treatment with HDM had adverse effects on the subsequent engraftment of platelets among patients given HDM/PBSCR. The data suggest that additional measures are needed to achieve platelet reconstitution in these heavily pre-treated patients.

Topics: Antigens, CD34; Antineoplastic Agents, Alkylating; Blood Cell Count; Combined Modality Therapy; Graft Survival; Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Multiple Myeloma

In order to shorten the pancytopenic period following high-dose melphalan 140 mg/m2 (HDM) treatment of multiple myeloma patients, we studied the effects of re-infusing granulocyte colony stimulating factor (G-CSF) [Filgrastim, Neupogen]-primed unprocessed whole blood. 30 patients with multiple myeloma were treated with HDM. One litre of blood after 5 or 6 days stimulation with G-CSF (10 micrograms/kg) was drawn, kept unprocessed for 1 day and re-infused 24 h after chemotherapy. Time to granulocyte recovery (> 0.5 x 10(9)/1) and platelet recovery (> 20 x 10(9)/1) were assessed as well as length of hospital stay, number of transfusions and antibiotic use. These 30 patients were compared with 20 historical control patients who were similarly treated but without stem cell support. The response rate was 75% (21/28) including a complete remission (CR) rate of 29% (8/28). Two early deaths due to Aspergillus pneumonia were observed. The median overall survival after HDM has not been reached after a median follow-up of 14 months. 10 patients showed progression at a median of 7 months. Currently, 23 patients are alive with a median follow-up time of 14 months. Haematological recovery was significantly faster in the study group as compared to the historical control group. The neutrophil count reached 0.5 x 10(9)/1 at a median of 14 days after infusion of 1 litre of unprocessed whole blood compared with 38 days in the historical control group. A platelet count of 20 x 10(9)/1 was reached at a median of 26 days compared with 36 days in the historical control group. Length of hospital stay decreased from a median of 43 to 18.5 days. The number of days with antibiotics was reduced from a median of 21 to 6 days. HDM is effective therapy for multiple myeloma. Toxicity of the regimen is considerably reduced by the use of G-CSF-stimulated unprocessed whole blood, an easy to perform and cheap technique to mobilise and collect stem cells.

Topics: Adult; Antineoplastic Agents, Alkylating; Blood Transfusion, Autologous; Disease-Free Survival; Female; Follow-Up Studies; Granulocyte Colony-Stimulating Factor; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Pancytopenia; Recombinant Proteins; Survival Rate

Solitary bone plasmacytoma (SBP) is a rare presentation of plasma cell dyscrasias. Radiotherapy has been considered the treatment of choice, however, most patients will develop multiple myeloma, 3 to 10 years after initial diagnosis and treatment. No innovations have been introduced in the treatment of SBP in the last 30 years. We began a prospective clinical trial to assess the efficacy and toxicity of adjuvant chemotherapy with low doses of melphalan and prednisone administered to patients with SBP after radiation therapy in an attempt to improve the disease-free survival and overall survival. Between 1982 and 1989, 53 patients with SBP were randomly assigned to be treated with either local radiotherapy with doses ranged from 4000 to 5000 cGy to achieve local control of disease (28 patients) or the same radiotherapy schedule followed by melphalan and prednisone given every 6 weeks for 3 years (25 patients). After a median follow-up of 8.9 years, disease-free survival and overall survival were improved in patients who were treated with combined therapy, 22 patients remain alive and free of disease in the combined treatment group compared to only 13 patients in the radiotherapy group (p < 0.01). Treatment was well tolerated; planned doses were administered in all cases; no delays in treatment or acute side-effects were observed during treatment. Long-term secondary toxicities including secondary neoplasms and acute leukaemia, have not been observed. We felt that the use of adjuvant chemotherapy after adequate doses of radiotherapy in patients with SBP improved duration of remission and survival without severe side-effects. However, as with other studies in SBP, the group was too small to draw definitive conclusions and more controlled clinical trials are necessary to define the role of this therapeutic approach in patients with SBP.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Chemotherapy, Adjuvant; Combined Modality Therapy; Disease Progression; Disease-Free Survival; Female; Humans; Life Tables; Male; Melphalan; Middle Aged; Multiple Myeloma; Plasmacytoma; Prednisone; Prospective Studies; Remission Induction; Survival Analysis; Treatment Outcome

Interferon (INF) has been incorporated as part of maintenance therapy after high dose treatment in order to make remissions more durable. In this study we have compared peripheral blood stem cell transplant (PBSCT) versus autologous bone marrow transplant (ABMT) with respect to INF tolerance. Thirty nine PBSCT patients have been compared to 37 ABMT patients for INF tolerance. This is followed by a comparison of 15 PBSCT patients versus 21 ABMT patients for engraftment details, response and survival. INF was started at a median of 61 days in the PBSCT and 58 days in the ABMT patients (P = NS). It was well tolerated in both groups without a significant difference in toxicity in the two arms. Engraftment was more rapid in the PBSCT patients with platelet recovery being significantly faster. Response and survival showed a favourable trend for ABMT patients though statistical significance was not reached and the cost of PBSCT was 12% cheaper. We were thus able to conclude that PBSCT grafts were as durable and could tolerate INF just as well as ABMT. Engraftment was more rapid and the procedure of PBSCT was also cheaper. Further studies with a larger group of patients will be required before comments on the efficacy of treatment can be made.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Combined Modality Therapy; Disease-Free Survival; Fatigue; Female; Fever; Graft Survival; Hematopoietic Stem Cell Transplantation; Humans; Immunologic Factors; Interferon alpha-2; Interferon-alpha; Life Tables; Male; Melphalan; Middle Aged; Multiple Myeloma; Pain; Recombinant Proteins; Remission Induction; Survival Analysis; Thrombocytopenia; Transplantation, Autologous; Treatment Outcome

High serum level of bioactive interleukin-6 (IL-6) is regarded as a predictor of poor prognosis in multiple myeloma (MM). On the other hand, the reported levels of immunoreactive IL-6 have been highly variable, and the prognostic value of immunoreactive IL-6 in MM is not clear. We have analyzed the prognostic significance of serum immunoreactive IL-6, as measured by a sensitive immunosorbent assay, in 210 patients with newly diagnosed MM subsequently treated with intermittent melphalan and prednisone. The serum levels of acute phase proteins C-reactive protein (CRP), alpha 1-antitrypsin (alpha 1AT), and acid alpha 1-glycoprotein (orosomucoid; OM) were evaluated as surrogates for IL-6. Serum IL-6, CRP, alpha 1AT, and OM levels were raised in 42%, 40%, 41%, and 24% of the patients, respectively. There was a significant correlation between the clinical stage of the patients and serum IL-6 (P = .006), alpha 1AT (P = .001), and OM (P = .004) levels at diagnosis. At 3 years, 52% of the patients were alive. Univariate logistic regression analysis showed that high levels of IL-6 (P = .002), CRP (P = .02), alpha 1AT (P < .001), OM (P = .007), beta 2-microglobulin (beta 2M; P < .001), and thymidine kinase (P < .05) were all associated with 3-year mortality. In multivariate regression analysis, beta 2M (P < .0001) and alpha 1AT (P = .01) had independent prognostic significance. The patients with high levels of both beta 2M and alpha 1AT or IL-6 were at very high risk of dying within 3 years from diagnosis (16% and 21% of the patients in these groups were alive, respectively). When the patients were stratified according to the clinical stage, the prognostic significance of serum IL-6 and alpha 1AT was especially evident in stage II patients. When the patients were divided into two groups according to normal or raised serum IL-6 levels, the patients with high IL-6 levels had more frequent osteolytic bone lesions (P = .03) and a more aggressive disease. We conclude that serum immunoreactive IL-6 is a significant prognostic marker in MM.

Topics: Acute-Phase Proteins; Adult; Aged; Aged, 80 and over; Analysis of Variance; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Calcium; Clodronic Acid; Creatinine; Female; Hemoglobins; Humans; Interleukin-6; Male; Melphalan; Middle Aged; Multiple Myeloma; Predictive Value of Tests; Prednisone; Prognosis; Regression Analysis; Risk Factors; Serum Albumin; Survival Rate; Uric Acid

Colony-stimulating activity (CSA) was measured by the production of granulocyte-macrophage colony-forming units (GM-CFU) from normal donor bone marrow in the plasma of 29 patients with multiple myeloma (MM) after intensive treatment with high-dose melphalan (HDM) with or without autologous bone marrow rescue (ABMR). Although patients who received ABMR had an earlier recovery of circulating neutrophils compared with those who received HDM alone, the time at which CSA reached a maximum was similar in both groups (10 to 11 days) after therapy. The decline in CSA correlated with the recovery of the neutrophil count. In plasma from patients who received recombinant human granulocyte colony-stimulating factor (rhG-CSF), in addition to an autograft, CSA reached a maximum earlier (7 days). Furthermore, neutrophil recovery was earlier in these patients. Platelet recovery was not increased by rhG-CSF. The time at which CSA was maximum in four patients who were undergoing intensive therapy for the second time occurred 9 days after treatment with HDM. Although the period without neutrophils was longer in three (of four) patients who survived long term, one patient who received rhG-CSF had a shorter period of neutropenia than the two who had not had the cytokine. G-CSF was detected in plasma from seven of seven patients but not at all times after treatment. In plasma samples that contained G-CSF, colony numbers were increased by recombinant interleukin-4 (rIL-4) in vitro. Neither IL-3 nor GM-CSF was detected in plasma; however, antibody to GM-CSF reduced CSA in all samples after intensive therapy. The data suggest that CSA is a consistent physiologic response to intensive therapy, even in previously treated patients, but that hematologic recovery is dependent on the availability of viable progenitor cells.

Topics: Bone Marrow Transplantation; Colony-Forming Units Assay; Double-Blind Method; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Hematopoiesis; Humans; Interleukin-3; Interleukin-4; Leukocyte Count; Melphalan; Multiple Myeloma; Neutrophils; Platelet Count; Recombinant Proteins

We report here on a preliminary human autologous transplantation study of retroviral gene transfer to bone marrow (BM) and peripheral blood (PB)-derived CD34-enriched cells. Eleven patients with multiple myeloma or breast cancer had cyclophosphamide and filgrastim-mobilized PB cells CD34-enriched and transduced with a retroviral marking vector containing the neomycin resistance gene, and CD34-enriched BM cells transduced with a second marking vector also containing a neomycin resistance gene. After high-dose conditioning therapy, both transduced cell populations were reinfused and patients were followed over time for the presence of the marker gene and any adverse effects related to the gene-transfer procedure. All 10 evaluable patients had the marker gene detected at the time of engraftment, and 3 of 9 patients had persistence of the marker gene for greater than 18 months posttransplantation. The marker gene was detected in multiple lineages, including granulocytes, T cells, and B cells. The source of the marking was both the transduced PB graft and the BM graft, with a suggestion of better long-term marking originating from the PB graft. The steady-state levels of marking were low, with only 1:1000 to 1:10,000 cells positive. There was no toxicity noted, and patients did not develop detectable replication-competent helper virus at any time posttransplantation. These results suggest that mobilized PB cells may be preferable to BM for gene therapy applications and that progeny of mobilized peripheral blood cells can contribute long-term to engraftment of multiple lineages.

Topics: Antigens, CD; Antigens, CD34; Bone Marrow Transplantation; Breast Neoplasms; Cyclophosphamide; Female; Filgrastim; Fluorouracil; Follow-Up Studies; Genes, Reporter; Genetic Markers; Genetic Therapy; Graft Survival; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Transplantation; Hematopoietic Stem Cells; Humans; Kanamycin Kinase; Male; Melphalan; Middle Aged; Multiple Myeloma; Phosphotransferases (Alcohol Group Acceptor); Recombinant Proteins; Treatment Outcome; Whole-Body Irradiation

The participation of minor centres in randomized trials has been questioned because of inferior quality of participation. We have studied this issue in a multicentre trial on myeloma, in which 574 patients were included from 99 participating centres in Sweden, Norway and Denmark from 1 June 1990 until 4 November 1992. Two hundred and eight patients were entered from university hospitals (n = 13), 172 from major county hospitals (n = 25), defined by a population base of > or = 100,000 inhabitants, and 194 from minor county hospitals (n = 61) with a population base of < 100,000 inhabitants. The accrual rate was similar for the three hospital categories, averaging 54% of all reported cases, corresponding to 38% of the expected number of newly diagnosed cases. The adherence to the study protocol from an administrative point of view was judged by the completeness of follow-up forms and the delay in the notification of deaths, and from a clinical point of view by the dose intensity for the principal drugs of the study, melphalan and interferon. For all studied measures of quality, the values were similar for the three hospital categories. We conclude that with due informative and educational support, minor centres can make a considerable contribution to the patient material of a large randomized trial without impairing the quality of the study.

Topics: Adult; Aged; Aged, 80 and over; Denmark; Drug Administration Schedule; Follow-Up Studies; Hospitals, County; Hospitals, University; Humans; Interferon alpha-2; Interferon-alpha; Melphalan; Middle Aged; Multiple Myeloma; Norway; Patient Selection; Quality Control; Randomized Controlled Trials as Topic; Recombinant Proteins; Sweden; Time Factors

The expression of the Bcl-2 oncoprotein was studied in pre-treatment bone-marrow samples from 63 patients with multiple myeloma, using an immunohistochemistry technique. A variable expression of the Bcl-2 protein was found in myeloma cells. 43% of the patients had strong expression of the Bcl-2 protein in the malignant cells. Forty patients received alpha-interferon, whereas 23 patients received melphalan/prednisone therapy. A significant association (p = 0.012) was found between high levels of Bcl-2 expression in myeloma cells and resistance to interferon therapy. No such correlation was found in the melphalan/prednisone treated patients. The data indicate that over-expression of Bcl-2 may be a cause for resistance to interferon therapy in myeloma and that staining for Bcl-2 expression in myeloma cells may have a predictive value for this treatment.

Topics: Antineoplastic Agents, Alkylating; Antineoplastic Agents, Hormonal; Humans; Interferon-alpha; Melphalan; Multiple Myeloma; Neoplasm Proteins; Prednisone; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-bcl-2

In 1988, a prospective, randomized multicenter study was initiated to determine the efficacy of a combined induction regimen with recombinant interferon-alpha-2b (IFN-alpha) and maintenance with IFN-alpha on the response and survival rates in multiple myeloma (MM) patients. Induction therapy consisted of VMCP (vincristine, melphalan, cyclophosphamide, prednisone), randomized to combine IFN-alpha at a dose of 2 x 10(6) U, 5 days per week throughout the induction period of 12 months. Patients who achieved plateau phase were subsequently randomized again between IFN alpha maintenance (2 x 10(6) U, 3 days a week) for 12 months and no maintenance therapy. Of the previously untreated patients, 84 were initially randomized for induction therapy, and 31 for the maintenance phase with IFN-alpha. Results of the cohort median survival, based on the intention to treat, have shown that those on the VMCP/IFN-alpha arm had a median survival of 53 months, compared with patients on the VMCP induction arm who a median survival of 26 months (P = 0.052). The median survival of stage 3 evaluable patients who were on the VMCP/IFN induction arm was 43 months, and 13 months for patients treated by VMCP alone (P = 0.008). No significant difference in survival was detected among patients in partial remission (after induction) who had a second IFN-alpha randomization at the plateau phase. Hematologic toxicity, mild to moderate fever, and fatigue were more common in the VMCP/IFN induction arm. The results show that VMCP/IFN is a well-tolerated treatment regimen, and is superior to VMCP for patients with stage 3 myeloma.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Drug Administration Schedule; Humans; Interferon alpha-2; Interferon-alpha; Israel; Melphalan; Middle Aged; Multiple Myeloma; Prednisone; Prognosis; Prospective Studies; Recombinant Proteins; Survival Analysis; Vincristine

To investigate the prognostic value of therapy at 6 months on survival in multiple myeloma, to develop a new criterion assessing response to initial therapy at 6 months, and to compare it to a current criterion. The types of initial and 6-month therapy were considered in a prognostic factor analysis in 70 patients treated in routine practice. Using the response to initial therapy defined by the clinician's decision as grouping variable in this group, a discriminant analysis identified the characteristics of responder patients. The validity of the resulting criterion was tested in another test group. Its prognostic ability was compared to the CLMTF criterion (50% M-component reduction from baseline). The therapy at 6 months, reflecting the clinician's appraisal of response to initial therapy, predicted survival significantly. A criterion combining two variables (M-component change and haemoglobin level at 6 months) classified 70% and 72.4% of patients correctly regarding response status in the training and test groups respectively. This criterion was shown to perform better than the CLMTF criterion in predicting survival.. A new criterion for response to therapy at 6 months, also presented in a nomogram, combines M-component change and haemoglobin level at 6 months.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Cyclophosphamide; Dexamethasone; Doxorubicin; Female; Humans; Immunoglobulin A; Immunoglobulin G; Male; Melphalan; Middle Aged; Multiple Myeloma; Neoplasm Staging; Prednisolone; Prednisone; Prognosis; Survival Rate; Vincristine

To determine whether interferon maintenance therapy improves overall survival and response duration in patients with multiple myeloma who have responded to induction therapy with melphalan and prednisone.. In a multicenter trial, patients with symptomatic clinical stage I and stage II and III multiple myeloma were registered at diagnosis and those who responded to melphalan-prednisone (MP) were randomized either to receive interferon (2 mU/m2) subcutaneously three times per week or no maintenance. MP was discontinued in both groups once a stable response plateau of the monoclonal protein was reached. Interferon was continued until relapse, and then was restarted on subsequent response to MP. Interferon toxicity was recorded using a self-report diary. Survival and response duration were calculated using life-table methods, and were adjusted in the analysis for imbalances in baseline prognostic factors.. Four hundred two patients were registered and 176 responders were randomized (85 to interferon and 91 to control). At a median follow-up time of 43 months, the median survival duration was 43 months for interferon and 35 months for control (P = .16), but when adjusted for chance imbalances in baseline prognostic factors (mainly performance status), the median survival duration was 44 months and 33 months for interferon and control, respectively (P = .049). Progression-free survival from randomization to first relapse also favored interferon (unadjusted P < .002; adjusted P < .003). Interferon toxicity caused 58% of patients to reduce their dose, of which 84% were able to return to the initial dose; 14% had to discontinue interferon treatment.. Interferon maintenance therapy improves progression-free and overall survival of patients with multiple myeloma who respond to melphalan and prednisone. Toxicity is substantial and must be weighed by patients against the potential benefits in response duration and survival.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Canada; Chi-Square Distribution; Combined Modality Therapy; Disease-Free Survival; Female; Follow-Up Studies; Humans; Interferon alpha-2; Interferon-alpha; Life Tables; Male; Melphalan; Middle Aged; Multiple Myeloma; Prednisone; Prognosis; Proportional Hazards Models; Recombinant Proteins; Remission Induction; Survival Rate

Interferon (IFN) treatment trials in multiple myeloma have yielded discordant results regarding response rates, maintenance duration, and survival times. Further randomized trials and global evaluations of available data are urgently needed for clarification.. 256 patients participated in a randomized trial, 125 on IFN + VMCP, and 131 on VMCP alone. 100 patients were randomized to IFN maintenance (n = 46) or were untreated controls (n = 54). Global evaluations are based on 1,518 patients in induction and 924 in maintenance trials.. The induction trial demonstrated a significantly (p < 0.05) lower rate of progressive disease under IFN + VMCP (10.6%) than under VMCP (22.9%), but this benefit was limited to stage I or II patients. Median progression-free survival was longer in the IFN + VMCP arm (23.2 months vs. 15.8 months); median overall survival did not differ significantly (38.9 vs. 30.2 months). The IFN maintenance treatment trial showed significantly superior results in the IFN arm versus controls (median maintenance duration: 17.8 months and 8.2 months (p < 0.01), survival: 50.6 and 34.4 months (p < 0.05), respectively). Previous IFN treatment increased the benefits of IFN maintenance therapy. Adverse effects of IFN during induction were hematologic toxicity, fever, and infections, requiring dose reductions. Toxic effects of IFN maintenance treatment were mild. Global evaluations of randomized trials showed small but significant benefits of combined IFN induction therapy and significantly prolonged maintenance duration and survival under IFN maintenance.. Presently available data support the use of IFN maintenance treatment because it significantly prolongs maintenance duration and survival. IFN added to induction chemotherapy resulted in minor improvements at the expense of increased toxicity, highlighting the need for better induction regimens.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Cyclophosphamide; Disease-Free Survival; Europe; Female; Humans; Interferon alpha-2; Interferon-alpha; Male; Melphalan; Middle Aged; Multiple Myeloma; Prednisone; Recombinant Proteins; Remission Induction; Survival Rate; Vincristine

406 untreated multiple myeloma patients of stage I (n = 54), II (n = 148) and III (n = 204) were enrolled in the trial. 51/54 stage I and 60/148 stage II patients were asymptomatic and followed without treatment until disease progression (progression free survival: 60% after 4 years for stage I versus 50% after 1 year for stage II). Symptomatic patients of stage I (n = 3/54) and II (n = 88/148) presenting with tumour progression, received melphalan 15 mg/m2 intravenously (i.v.) and prednisone 60 mg/m2 oral days 1-4 (MP). Stage II disease remission rate was 59%, and 50% tumour related survival (TRS) was 59 months. Stage III patients were randomised to receive MP or VBAMDex (vincristine/BCNU/doxorubicin/melphalan/dexamethasone) treatment. 43% of MP treated patients responded compared with 64% of the VBAMDex group. 50% TRS was 36 months in both groups without a detectable difference. 117 responders of stage II and III with stable disease were randomised to receive either IFN-alpha (5 x 10(6) IU, subcutaneous (S.C.) 3 times per week) or no maintenance treatment. The relapse rate in both groups was 50% after 13 months. No survival benefit for IFN alpha treated patients was observed (50% TRS: 45 months).

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Dexamethasone; Doxorubicin; Female; Humans; Interferon-alpha; Male; Melphalan; Middle Aged; Multiple Myeloma; Prednisone; Prospective Studies; Remission Induction; Survival Rate; Vincristine

This clinical trial was designed to investigate if maintenance therapy with alfa-interferon could prolong the plateau phase in patients with multiple myeloma. In addition, the tolerability of interferon treatment and its effect on survival were evaluated. From September 1987 to September 1989 a total of 314 patients were accrued to a multi-institutional randomized clinical trial. All patients entered into the protocol received standard melphalan-prednisone (MP) induction therapy. Response was noted in 184 (59%) and a plateau phase achieved in 155 (49%). From the latter group, 125 eligible patients were randomized to either interferon alfa-2b or no maintenance. The patients were followed for an average of 51 months (minimum 36 months) from the time of randomization. The plateau phase was significantly prolonged in the group of patients treated with interferon (median 13.9 v 5.7 months from the time of randomization; P < 0.0001). The interferon therapy was tolerated fairly well, moderate granulocytopenia and a chronic fatigue syndrome being the most frequent side-effects (22% v 18% W.H.O. grade 3 toxicity). The median survival from randomization was almost identical in both groups (36 v 35 months). The study shows that interferon maintenance therapy given to multiple myeloma patients who have achieved a response to initial treatment with MP prolongs the plateau phase duration with tolerable toxicity. The clinical value of this finding should be interpreted with caution, because survival was not prolonged. Further studies are required to clarify the role of interferon in the treatment of multiple myeloma.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Cause of Death; Combined Modality Therapy; Drug Administration Schedule; Humans; Interferon alpha-2; Interferon-alpha; Melphalan; Middle Aged; Multiple Myeloma; Prednisone; Recombinant Proteins; Survival Rate; Time Factors

This report describes the clinical characteristics, treatment associated toxicity, and follow-up of fifty-eight patients with plasma cell--dyscrasias treated with high dose chemotherapy and total body irradiation (TBI) at a single institution. Following TBI, 36 patients received anti-B cell monoclonal antibody (MoAb)-treated autologous bone marrow, 21 patients received anti-CD6 cell MoAb-treated allogeneic bone marrow to deplete T cells, and one patient received unpurged bone marrow from a syngeneic donor. Evaluation after high dose chemotherapy and bone marrow transplantation (BMT) demonstrated 26 complete responses (CR), 26 partial responses (PR), 2 non-responders, 1 not yet evaluated, and three toxic deaths. Fourteen of 36 patients who underwent autologous BMT are alive free from progression at 18 (range 5 to 68) months post transplant (post-BMT); of these, 11 remain in continuous complete response at 16 (range 5 to 68) months post-BMT. Seven of 21 patients who underwent allogeneic BMT are alive free from progression at 30 (range 4 to 44) months post-BMT; of these, three patients remain in continuous complete response at 43 (range 33 to 45) months post-BMT. These data suggest that high dose chemotherapy with TBI followed by MoAb purged BM can be performed with acceptable toxicity and high tumor response rates.

Topics: Adult; Aged; Antibodies, Monoclonal; Bone Marrow Purging; Bone Marrow Transplantation; Combined Modality Therapy; Cyclophosphamide; Disease Progression; Feasibility Studies; Female; Follow-Up Studies; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Whole-Body Irradiation

Eighty-four patients with myeloma were randomized to receive maintenance Intron A (Schering-Plough, Suffolk, UK), 3 mega units/m2 s.c. three times weekly or no treatment following induction therapy with cyclophosphomide, vincristine, doxorubicin, methyl prednisolone (C-VAMP), consolidated with high-dose melphalan (HDM) 200 mg/m2 + autologous bone marrow transplantation (ABMT). The patients have been followed up for a median of 52 months. Overall, median progression-free survival (PFS) from HDM was 27 months in the control group and 46 months in the Intron A group (< 0.025). For the 65 patients who achieved complete remission (CR) with HDM, there was a significant prolongation of remission (p = 0.02) for those who received Intron A and 49% of these patients remained in remission four years after high-dose treatment. However, for partial responders (PR) and nonresponders to HDM there was no significant prolongation of PFS. Overall, survival was also significantly better for the Intron A group, with 5 deaths versus 14 deaths in the control group (p = 0.006). Subsequently, 54 consecutive patients received the same HDM followed by rescue with peripheral blood stem cells after induction chemotherapy which included C-VAMP. Intron A was started in 45 of these patients at a median of 62 days which was comparable to the ABMT arm. The overall response rate in these patients was 79.62% (43/54-CR+PR) and the probability of survival at 18 months was 74.2% by the Kaplan Meier method.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Combined Modality Therapy; Hematopoietic Stem Cell Transplantation; Humans; Interferon alpha-2; Interferon-alpha; Melphalan; Multiple Myeloma; Recombinant Proteins; Transplantation, Autologous

In an attempt to offset the impaired hematopoietic progenitors' mobilization and collection which are frequently encountered in multiple myeloma (MM), we have started a pilot study to evaluate the ability of a combination of high-dose melphalan (HDM) and sequential s.c. administration of recombinant human interleukin 3 (rhIL-3) and rh-granulocyte colony-stimulating factor (G-CSF) to mobilize blood cells (BC) in MM patients. Two different schedules for administration were successively tested. Schedule A consisted of IL-3 (5 micrograms/kg/d) from day 7 to day 11 after HDM followed by G-CSF (5 micrograms/kg/d) from day 12 to day 20. Under schedule B, HDM was followed by IL-3 alone at the same dosage from day 1 to day 3, IL-3 and G-CSF (idem) from day 4 to day 7 and G-CSF alone from day 8 until completion of apheresis. Two patients (one previously untreated, one having received prior chemotherapy for one year) underwent schedule A; three patients (one previously untreated, two pretreated) underwent schedule B. The post-HDM aplasia was not shortened in schedule A patients in comparison to what we usually observed following HDM alone (25 days) correlated with a very moderate two- to three-fold CD34+ cell increase. Only one patient was further transplanted with apheresis products: the post-transplant granulocyte recovery was slower than usual (16 days versus 12 days) while platelet count never recovered over 20 x 10(9)/l. In contrast, the post-HDM aplasia was significantly shortened in two of the schedule B patients (3 to 10 days) and was followed by a 25- to 165-fold increase in CD34+ cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Combined Modality Therapy; Female; Granulocyte Colony-Stimulating Factor; Hematopoiesis; Hematopoietic Stem Cell Transplantation; Hematopoietic Stem Cells; Humans; Interleukin-3; Leukocyte Count; Male; Melphalan; Middle Aged; Multiple Myeloma; Recombinant Proteins

The aim of the study was to evaluate the feasibility and the efficacy of high-dose chemoradiotherapy followed by autologous hematopoietic stem cell support with peripheral blood progenitor cells (PBPC) harvested after high-dose cyclophosphamide (HDCYC) treatment in patients with high-risk multiple myeloma (MM). Inclusion criteria were: age less than 65 years and high-risk MM defined as stage II MM, stage III MM, refractory or relapsed MM. The design of the study was: 1) HDCYC +/- hematopoietic growth factors followed by PBPC collection, and 2) high-dose melphalan combined with total body irradiation (or busulfan for previously irradiated patients) followed by PBPC reinfusion (ABPCT). All 60 patients completed the procedure except two who died from infection after HDCYC and another of acute cardiac failure after reinfusion of PBPC. Out of the 60 evaluable patients, three failed to respond while the other 57 achieved either a partial (n = 33) or complete (n = 24) response. Thirty-one patients progressed or relapsed after a median duration of response of 15 months (range: 3-43). The median follow-up for the other 26 responder patients was 24 months (range: 2-66). Twenty-one patients died, 18 of MM (2 after failure, 16 after relapse) and three responders of lung cancer (n = 1) and infection (n = 2). In conclusion, this study shows that this therapeutic approach is feasible and efficient.

Topics: Adult; Aged; Combined Modality Therapy; Cyclophosphamide; Female; Hematopoietic Cell Growth Factors; Hematopoietic Stem Cell Transplantation; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Risk Factors; Survival Analysis; Transplantation, Autologous; Whole-Body Irradiation

A recent randomized multicentric French study has shown that intensification with stem cell rescue improves the response rate and progression-free survival in multiple myeloma. Transplantation with primed peripheral blood stem cells (PBSC) displays a faster hematological recovery, especially for platelets, as compared with a bone marrow stem cell graft. In multiple myeloma, the optimal mobilization method for PBSC is unknown. The present study compares mobilization with cyclophosphamide 4 g/m2 + G-CSF 5 micrograms/kg versus G-CSF 5 micrograms/kg alone versus G-CSF 10 micrograms/kg alone in two cases of multiple myeloma, using an intrapatient controlled evaluation of the amount of CD34-positive cells obtained during each leukapheresis. In both cases, the highest CD34-positive cells yield was obtained with G-CSF at 10 micrograms/kg. Despite the low number of cases, this method, devoid of life-threatening toxicity, might be of greatest interest in multiple myeloma.

Topics: Antigens, CD; Antigens, CD34; Belgium; Blood Transfusion; Combined Modality Therapy; Cyclophosphamide; Dose-Response Relationship, Drug; Drug Synergism; Drug Therapy, Combination; Flow Cytometry; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cells; Humans; Leukapheresis; Male; Melphalan; Middle Aged; Multiple Myeloma

In 1990 the Italian Non-Hodgkin's Lymphoma Cooperative Study Group (NHLSG) started a multicenter study on the role of interferon (IFN) in multiple myeloma (MM). The schedule of treatment was based on the assumption that melphalan plus prednisone (MP) would be better for good-prognosis patients, whereas poor-prognosis patients would benefit from polychemotherapy. Accordingly, IFN was included randomly for the induction treatment of good-prognosis patients and randomly as maintenance of the response achieved in both groups. Up to now 78 patients of the 124 enrolled have completed the induction treatment and are evaluable for response and response duration. The overall response rate was 59%. Sixty-two percent of good-prognosis patients obtained objective response, 9/14 (64%) with MP and 9/15 (60%) with MP+IFN. Up to now, with a median follow-up of 9 months from the evaluation of response, no difference has been recorded between the maintenance and no maintenance groups on relapse rate, neither in good- nor in poor-prognosis patients.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Female; Humans; Interferons; Male; Melphalan; Middle Aged; Multiple Myeloma; Prednisone; Prognosis

We report the complications and outcome of high-dose melphalan and TBI combined with ABMT used in the treatment of multiple myeloma at a single centre. Twenty-three patients, aged 65 years or less, who underwent the procedure are reviewed. All had chemosensitive disease. Response to ABMT assessed at 3 months showed 75% of evaluable patients to have further tumour cytoreduction of at least 50%, with 24% of patients who entered ABMT with residual disease eventually achieving CR. There was one toxic death. The overall survival is 60% and the progression-free survival is 49.8% at a median follow-up time of 17 months. Relapse or disease progression has occurred in 27% of patients, of whom half have died. No significant prognostic factors affecting survival were found although those patients with IgG myeloma had a better outcome. Patients transplanted in first plateau appeared to do significantly better if they had been resistant to their first-line chemotherapy but had then responded to further conventional chemotherapy (p = 0.029).

Topics: Adult; Bone Marrow Transplantation; Combined Modality Therapy; Disease Progression; Dose-Response Relationship, Drug; Female; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Treatment Outcome; Whole-Body Irradiation

This paper reports the experience of a single investigator team on the use of autografting in support of myeloablative therapy for multiple myeloma. This demonstrates continued progress toward decreased morbidity, and virtual elimination of mortality, as a result of rapid hematopoietic recovery, due to the use of peripheral blood stem cell grafts in newly diagnosed patients receiving several non-cross-resistant induction regimens followed by two autologous transplants, complete remission rates in excess of 50% can be achieved. Prognostic factors have also been identified for event-free and overall survival.

Topics: Anti-Bacterial Agents; Blood Transfusion; Bone Marrow Transplantation; Combined Modality Therapy; Dose-Response Relationship, Drug; Follow-Up Studies; Growth Substances; Hematopoietic Stem Cell Transplantation; Humans; Immunoglobulins, Intravenous; Melphalan; Middle Aged; Multiple Myeloma; Prognosis; Transplantation, Autologous

Standard therapy for multiple myeloma consists of cytotoxic chemotherapy plus glucocorticoids. Interferon (IFN) alfa maintenance is reported to prolong chemotherapy-induced remissions and survival. This study evaluates induction chemotherapy, glucocorticoids, and interferon maintenance in myeloma.. Five hundred twenty-two previously untreated myeloma patients were randomized to three chemotherapy regimens with differing glucocorticoid intensities. Patients who achieved remission were randomized to receive IFN or observation until relapse. Patients who failed to respond to chemotherapy received IFN alfa plus dexamethasone (DEX).. Five hundred nine patients were eligible for induction chemotherapy. Chemotherapy with higher dose-intensity glucocorticoids yielded higher response rates and improved survival (P = .02 for the three-group comparison; P < .05 for each higher glucocorticoid arm v vincristine, melphalan, cyclophosphamide, and prednisone alternating with vincristine, carmustine [BCNU], doxorubicin, and prednisone [VMCP/VBAP]). One hundred ninety-three patients who achieved remission were randomized to receive IFN alfa 3 MU three times weekly or observation. IFN was not superior to observation for relapse-free (P = .95) or overall survival (P = .39) from start of maintenance. Eighty-eight induction failures received 5 MU of IFN three times weekly plus DEX. Patients who received IFN/DEX had a median survival duration of 48 months from start of IFN/DEX.. Higher-dose glucocorticoids increases frequency of response to chemotherapy and prolong survival in myeloma. IFN maintenance with the dose schedule used in this trial did not prolong relapse-free or overall survival. We cannot exclude a small effect of IFN, as most individual trials do not have sufficient statistical power. Meta-analysis of randomized trials evaluating IFN maintenance in myeloma might be of value. While IFN appeared ineffective, addition of higher-dose glucocorticoids improved outcome in myeloma.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Cyclophosphamide; Dexamethasone; Doxorubicin; Female; Follow-Up Studies; Glucocorticoids; Humans; Interferon-alpha; Male; Melphalan; Middle Aged; Multiple Myeloma; Prednisone; Remission Induction; Survival Analysis; Vincristine

Topics: Administration, Oral; Adult; Cryotherapy; Female; Hodgkin Disease; Humans; Lymphoma, Non-Hodgkin; Male; Melphalan; Middle Aged; Mouth Mucosa; Multiple Myeloma; Prospective Studies; Stomatitis

A study was undertaken adding the alkylating agent sensitizer etanidazole to intravenous melphalan and oral prednisone for patients with multiple myeloma. This study explored the toxicity profile of these agents when given together and assessed the ability to attain adequate serum levels of etanidazole to permit sensitization to occur.. Etanidazole was administered intravenously in two doses of 3 g/m2 and 5 g/m2 90 min apart immediately prior to the administration of intravenous melphalan and oral prednisone for three consecutive cycles (total dose 24 g/m2). Patients received three additional cycles without etanidazole, allowing a comparison of hematologic toxicity from melphalan with and without etanidazole.. Hematologic toxicity was moderate (Grade 3 or 4), but severity was similar during cycles with and without etanidazole. Only one patient developed a Grade 1 peripheral neuropathy questionably related to etanidazole. Most patients had etanidazole levels of > or = 70 ug/ml for 7 h, a level felt to be necessary for sensitization to occur.. Etanidazole, administered as described, results in adequate serum levels for potential alkylating agent sensitization, without significant toxicity.

Topics: Antineoplastic Combined Chemotherapy Protocols; Etanidazole; Humans; Infusions, Intravenous; Melphalan; Multiple Myeloma; Peripheral Nervous System Diseases; Prednisone

From January 1988 until December 1990, 99 previously untreated patients with multiple myeloma (MM) were enrolled in a randomized prospective study comparing two combination chemotherapies with and without MCNU as induction therapy for MM; 49 patients with vindesine, melphalan and prednisolone (VMP therapy) versus 50 patients with MCNU, vindesine, melphalan and prednisolone (MCNU-VMP therapy). Seventy-two evaluable patients (34 patients in the VMP group, 38 in the MCNU-VMP group) were analyzed. The response rate was slightly higher with MCNU-VMP than with VMP (81.6% vs. 64.7%). In 43 responders (21 patients in the VMP group and 22 in the MCNU-VMP group) who were treated with the same regimen as the induction therapy to maintain remission, the remission duration was significantly longer in patients treated with MCNU-VMP than in those treated with VMP (median > 10.1 vs. 8.0 months, P = 0.018), particularly in patients with PS 3-4. The remission duration in the MCNU-VMP group was also slightly longer in the patients with stage III disease and who were older than 65 years. The median survival time showed no significant difference between the VMP group (20.3 months) and the MCNU-VMP group (> 15 months). Leukopenia, thrombocytopenia and nausea/vomiting were found to be somewhat severe in the MCNU-VMP group. In summary, MCNU-VMP therapy is effective as induction therapy for MM.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Female; Humans; Japan; Male; Melphalan; Middle Aged; Multiple Myeloma; Nitrosourea Compounds; Prednisolone; Prospective Studies; Remission Induction; Survival Rate; Vindesine

We report the results of intensive chemotherapy with high-dose melphalan (HDM) following conventional-dose cytoreductive chemotherapy in previously untreated patients with myeloma.. From 1986 to 1991, 53 previously untreated patients with myeloma received HDM 200 mg/m2 plus methylprednisolone 1.5 g daily (MP) for 5 days with autologous bone marrow transplantation (ABMT) after cytoreductive chemotherapy.. At the time of HDM administration, responses to induction therapy were complete remission (CR) in nine patients, partial remission (PR) in 38, and no response (NR) in six. Following HDM, all but one patient responded, with 40 patients achieving a CR (75%). There was one treatment-related death following HDM. The median time to reach a WBC count more than 1,000/microL and platelet count more than 25,000/microL was 19 days (range, 13 to 30) and 24 days (range, 15 to 55), respectively. The median duration of response has not been reached at 20 months, and it is significantly longer for patients in CR than for those in PR (P < .025). Currently, with a median follow-up duration of 31 months (range, 6 to 58), 12 patients are dead and 40 are alive, and the estimated probability of survival at 54 months is 63%. Multivariate analysis found hemoglobin (Hb) more than 10 g/dL (P = .012), and stage A disease (P = .001) at diagnosis to be favorable indicators for survival.. Myeloma patients who are able to receive HDM plus ABMT following conventional chemotherapy achieve a high proportion of CRs, which may be associated with prolonged survival.

Topics: Adult; Aged; Bone Marrow Transplantation; Combined Modality Therapy; Female; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Prognosis; Remission Induction; Survival Analysis; Treatment Outcome

One-hundred-and-fifty-one patients with previously untreated multiple myeloma were allocated to treatment with either NOP regimen (mitoxantrone 16 mg/m2 and vincristine 2 mg day 1 and prednisolone 250 mg day 1-4 and 17-20) or M+P regimen (melphalan 0.25 mg/kg and prednisolone 100-200 mg/day day 1-4). Both regimens were repeated every 4 weeks and were scheduled for 1 year. Seventy-seven patients were treated with NOP and 74 patients with M+P. No major clinical differences were recorded between the groups before treatment. Sixty percent of the patients responded (CR+PR) to NOP versus 64% to M+P (NS). The time to progression was 16 months (95% C.L. 14-51) in the NOP group versus 21 months (95% C.L. 15-27) in the M+P group (NS). The median survival was 14 months (7-21) in the NOP group and 31 months (21-43) in the M+P group (p = 0.02). NOP was significantly more toxic than M+P. Seven patients treated with NOP died due to infection and neutropenia and 1 patient died of cardiac toxicity, in contrast to 1 death due to infection and neutropenia in the M+P group. Gastrointestinal toxicity was acceptable in both groups. In conclusion, NOP was inferior to M+P as primary treatment of multiple myeloma.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Denmark; Female; Humans; Male; Melphalan; Middle Aged; Mitoxantrone; Multiple Myeloma; Norway; Prednisolone; Remission Induction; Survival Rate; Vincristine

In a randomised multicentre trial a combination of methylprednisolone, vincristine, lomustine, cyclophosphamide and melphalan (MOCCA) was compared with the same regimen omitting methylprednisolone after the first course (COLA) in previously untreated patients with multiple myeloma. The MOCCA arm showed a response rate of 72% among 79 patients and the COLA arm a response rate of 60% among 59 patients. This difference was not statistically significant. The median survival time was 56 months in the MOCCA arm and 61 months in the COLA arm. There was a slight increase of early deaths (within the first 6 months) in the MOCCA arm as compared with the COLA arm. We conclude that, in multidrug therapies, the continuation of corticosteroid at conventional dosage beyond the first course does not improve response rate or survival time in multiple myeloma.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Female; Humans; Leukemia, Myeloid, Acute; Lomustine; Male; Melphalan; Methylprednisolone; Middle Aged; Multiple Myeloma; Myelodysplastic Syndromes; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Remission Induction; Survival Rate; Vincristine

The significance of serum thymidine kinase (STK) as a prognostic indicator for patients with myeloma has been evaluated by determining the pre-treatment level of STK in a retrospective study of 547 patients from the Medical Research Council (MRC) V Myeloma Trial. Overall, STK was a highly significant prognostic factor (Chi 2 = 7.91; P = 0.005). At the time of censor, 23.4% of patients with a presentation STK of < 6 U/l but only 7.9% of the patients with an STK of > 11 U/l were still alive. STK proved to be a highly significant prognostic indicator for the 270 melphalan-treated patients (Chi 2 = 12.37; P = 0.0004) but had no prognostic significance for the 277 ABCM (adriamycin, BCNU, cyclophosphamide and melphalan) treated patients (Chi 2 = 0.29; P = 0.59). When the STK data was stratified for serum B-2-microglobulin (SB2M) it was demonstrated that STK was independent of SB2M and provided additional prognostic information for patients who were treated with melphalan. Thus patients with both a low STK and SB2M had the best prognosis (median survival 1677 d) and those patients with a high STK and SB2M had the worst prognosis (median survival 519 d). STK is a good prognostic marker for patients treated with melphalan but the prognostic significance of STK may disappear with the introduction of new chemotherapy regimens.

Topics: Antineoplastic Combined Chemotherapy Protocols; Humans; Melphalan; Multiple Myeloma; Prognosis; Retrospective Studies; Survival Rate; Thymidine Kinase

This clinical trial was designed to compare the effectiveness of the standard melphalan and prednisone regimen to that of melphalan, prednisone, and interferon in patients with untreated multiple myeloma.. Between October 1985 and March 1988, 278 patients were accrued to a multi-institutional, randomized clinical trial. Responding patients were treated for 2 years before termination of therapy.. After a median follow-up of 23 months, the overall remission rate for the melphalan/prednisone treatment group was 44% compared with 33% for the group receiving melphalan/prednisone/interferon alfa-2b. The durations of response and survival were identical for the two treatment groups. Median survival was 3.17 years on melphalan/prednisone treatment and 3.0 years on melphalan/prednisone/interferon alfa-2b treatment. Both hematologic and nonhematologic toxicities were greater in the melphalan/prednisone/interferon alfa-2b treatment group, but were usually of a mild or moderate degree and did not interfere with the completion of therapy. The frequency of deaths in the two treatment groups attributable to the treatment itself was similar.. This study shows no advantage to the concomitant delivery of interferon alfa-2b with standard melphalan and prednisone as initial treatment for patients with multiple myeloma.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Female; Humans; Interferon alpha-2; Interferon-alpha; Male; Melphalan; Middle Aged; Multiple Myeloma; Prednisone; Recombinant Proteins; Survival Analysis

In August 1988 we began a program in which multiple myeloma patients achieving < or = 10% marrow plasma cells and > or = 50% reduction in paraprotein levels after the VAD (vincristine, doxorubicin, dexamethasone) regimen underwent bone marrow harvest, ex vivo marrow purging with 4-hydroperoxycyclophosphamide (4-HC) and marrow cryopreservation. Conditioning with a regimen of high-dose busulfan (total dose 16 mg/kg), cyclophosphamide (120 mg/kg) and melphalan (90 mg/m2) (BU + CY + MEL) followed by autologous BMT was then carried out. Seventeen of the 24 patients who received VAD (71%, 95% confidence interval [CI] 49 to 87%) were eligible for bone marrow harvest. One patient was not harvested because of non-medical reasons; two patients who underwent marrow harvest had gross plasmacytosis present in biopsies performed intraoperatively and did not undergo BMT. Fourteen patients (58%, 95% CI 37 to 78%) received BU + CY + MEL and 4-HC-purged autologous BMT. The median time to recovery of 0.5 x 10(9)/l neutrophils was 19 days (range 14 to 26) while the last platelet transfusion was given on a median of day 32 (range 10 to 46) post-BMT in the evaluable patients. The major non-hematologic toxicity was hepatic; two patients in complete remission died of hepatic veno-occlusive disease. Another patient succumbed to fungal infection despite neutrophil recovery. The remaining 11 patients achieved responses (complete in six and partial in five) associated with a normal performance status.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Purging; Bone Marrow Transplantation; Busulfan; Clinical Protocols; Combined Modality Therapy; Cyclophosphamide; Cytarabine; Dexamethasone; Female; Humans; Life Tables; Male; Melphalan; Middle Aged; Multiple Myeloma; Survival Analysis; Transplantation, Autologous; Vincristine

From October 1983 until December 1988, 50 patients with asymptomatic multiple myeloma stage I were included in a prospective randomized multi-centre study comparing melphalan-prednisone (MP) therapy started at the time of diagnosis with deferred therapy where MP was started at the time of disease progression. Twenty-five patients were randomized to each group. The median time from diagnosis to start of therapy in the group with deferred therapy was 12 months. The reasons for starting therapy were increasing M-protein in 8 cases, symptomatic bone disease in 9 and anaemia in 5. In 2 cases, disease progression was complicated by vertebral fractures necessitating radiotherapy. Two patients in the group in which MP was started at the time of diagnosis developed acute leukaemia. No differences in response rate, response duration or survival were observed between the treatment groups. We conclude that in asymptomatic myeloma deferral of chemotherapy is feasible in well-informed and well-controlled patients but conveys no advantage in survival. In clinical practice the benefits of treatment deferral are to some extent outweighed by disease progression before start of treatment.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Drug Administration Schedule; Female; Humans; Leukemia, Myeloid, Acute; Male; Melphalan; Middle Aged; Multiple Myeloma; Prednisone; Prognosis

Three hundred thirty-five previously untreated patients with multiple myeloma in clinical stages II and III entered a randomized trial comparing intermittent oral melphalan and prednisone (MP) therapy (n = 171) with MP in combination with natural (leukocyte-derived) alpha-interferon (MP/IFN) (n = 164). The treatment groups were comparable with regard to major prognostic factors. The response frequency was 42% in the MP group and 68% in the MP/IFN group (P < .0001). Eighty-five percent of IgA myelomas and 71% of Bence-Jones myelomas responded to MP/IFN compared with 48% and 27%, respectively, to MP treatment (P = .001). There was no difference in the overall survival between the two treatment groups. However, the survival of 72 patients with IgA or Bence-Jones myeloma randomized to receive MP/IFN was significantly longer (median 32 months) than that of 71 patients treated with MP (median 17 months) (p < .05). No statistically significant difference in response frequency (60% v 46%) or survival was found for patients with IgG myeloma. Hematologic toxicity, WHO grades III and IV, was higher in the MP/IFN group (48%) than in the MP group (33%) (P < .05) during the induction treatment period. Flulike syndrome was observed in 68% of patients receiving MP/IFN. The results show that MP/IFN is a well-tolerated treatment regimen, superior to MP for remission induction, and it improves significantly the overall survival for patients with IgA and Bence-Jones myelomas.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Humans; Interferon-alpha; Melphalan; Middle Aged; Multiple Myeloma; Neoplasm Staging; Prednisone; Survival Rate

In 1989, a prospective randomized multicenter study was initiated in order to determine the safety and efficacy of oral clodronate in myeloma patients. The primary objective of this long-term trial is to evaluate whether supportive clodronate is able to prevent or retard the progression of bone disease and reduce the occurrence of characteristic complications: pain, pathologic fractures, and hypercalcemia. We now report first results as an interim analysis, including data obtained from 26 patients (total number of Tübingen patients n = 36) who entered the study at the Medizinische Universitätsklinik Tübingen. Patients were randomized to receive either chemotherapy alone (melphalan 15 mg/m2 i.v. on day 1 and prednisolone 60 mg/m2 orally on days 1-4 every 4 weeks (control group) or in combination with 1600 mg clodronate/day orally as a single dose for a period of at least 1 year. Repeated radiologic examinations in addition to hematologic and biochemical analysis were performed in order to evaluate the skeletal status with respect to lytic bone lesions and osteoporosis and the course of serum M protein and light chain excretion into urine. Clodronate treatment resulted in a significant decrease of serum calcium concentrations and of biochemical indices for bone resorption. No clodronate-related toxicity or hypocalcemia was observed. In patients treated with chemotherapy alone, this effect was less marked and discontinuous. Clodronate-treated patients developed fewer progressive bone lesions (significant for lytic, not for osteoporotic lesions). No hypercalcemic episodes occurred in the clodronate-treated patients, but there were six episodes in the control group. Whereas the number of vertebral fractures was evidently less is clodronate-treated patients, three of those patients suffered from multiple fractures of long bones and ribs. All together, 12 pathologic fractures occurred in five clodronate-treated patients, whereas in the control group 23 pathologic fractures occurred in the same number of patients during the whole observation period. The final analysis of all multicenter included patients should clarify these findings. There was a significant finding that clodronate proved to have an analgesic effect.

Topics: Adult; Aged; Analgesia; Bone Diseases; Bone Resorption; Calcium; Clodronic Acid; Female; Fractures, Bone; Humans; Hypercalcemia; Male; Melphalan; Middle Aged; Multiple Myeloma; Osteoporosis; Prednisolone; Prospective Studies

To determine whether combination chemotherapy with alternating cycles of vincristine, cyclophosphamide, melphalan, and prednisone (VCMP) and vincristine, carmustine (BCNU), Adriamycin (doxorubicin; Farmitalia, Carlo-Erba Laboratories, Spain), and prednisone (VBAP) is better than the standard melphalan-prednisone (MP) regimen in multiple myeloma (MM).. From January 1985 to December 1989, 28 institutions of the Spanish Cooperative Group for Hematological Malignancies Treatment, Spanish Society of Hematology (PETHEMA) entered 487 eligible patients with symptomatic MM into the study. Patients were randomized to receive either MP or alternating courses of VCMP and VBAP. Logistic regression and the Cox proportional hazards models were used to assess the association between patients' characteristics and response rate and survival, respectively.. Among 449 patients who were assessable for response, the overall response rate to MP was 51.8% (31.5% objective response plus 20.3% partial response) as compared with 62.7% (45.2% objective response plus 17.5% partial response) to VCMP/VBAP (P = .025). Also, a significantly higher proportion of objective responses was observed with combination chemotherapy (45.2% v 31.5%; P = .004). The factors associated with an unfavorable response rate in the overall series were low platelet count, treatment with MP, high creatinine level and immunoglobulin, (IgG) monoclonal (M)-component. No significant differences were found when survival rates of both groups of patients were compared. However, patients with IgA myeloma treated with VCMP/VBAP survived significantly longer than those who received MP (median, 20.2 v 38.4 months; P < .005).. These results indicate that combination chemotherapy improves response rate in MM. However, this does not result in a significantly different survival rate, except for patients with IgA myeloma, who survive significantly longer with combination chemotherapy.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Cyclophosphamide; Doxorubicin; Female; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Prednisone; Survival Rate; Vincristine

In two consecutive studies of a pilot study and a multicenter trial 16 patients and 61 patients, respectively, with multiple myeloma were treated with the combination chemotherapy (CMVM regimen; the same intermittent high dose dexamethasone as in VAD regimen, MCNU bolus injection of 1.2mg/m2 on day 1, melphalan 12mg/day on days 1-6) plus IFN alpha (HLBI 300MU every day or two) to assess the efficacy and the toxicity of this protocol. Both studies were achieved in the same regimen except for initial 12 days administration of IFN alpha in the multicenter trial. The treatment was repeated 3 times every 6-8 weeks. Complete remission (CR) in which serum and urine M protein disappeared and myeloma cells in bone marrow were eradicated was obtained in 6 in 16 patients (37.5%) in the pilot study and 16 in 61 patients (26.2%) in the multicenter trial. CR plus PR was 68.8% and 68.9% in two studies. The achievement of CR in such high proportion of patients may exhibit a significant advance in the myeloma therapy.

Topics: Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Drug Administration Schedule; Humans; Interferon-alpha; Melphalan; Middle Aged; Multiple Myeloma; Nitrosourea Compounds; Pilot Projects; Remission Induction; Survival Rate; Vincristine

Sixty-nine patients with multiple myeloma diagnosed during a five year period at the Belfast City Hospital were followed until death or for a minimum of one year in a retrospective study of survival. Although the patients were unselected, survival data was found to be similar to results from trials in which patient selection had occurred. Overall median survival was thirty-two months. Median survival fell with advancing disease and was 47, 27 and 18 months for Durie-Salmon stages I, II and III respectively. Those patients presenting with a platelet count of < 100 x 10(9)/1 had a median survival of eight months in contrast to those with a platelet count > 100 x 10(9)/1 whose median survival was 36 months. Patients presenting in renal failure had a shorter median survival of 28 months compared to 46 months for those with normal renal function.

Topics: Adult; Age Factors; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Dexamethasone; Doxorubicin; Female; Follow-Up Studies; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Northern Ireland; Prednisolone; Retrospective Studies; Survival Rate; Treatment Outcome; Vincristine

Both melphalan and cyclophosphamide increase life expectancy in patients with myelomatosis, but few large randomised studies have compared combination chemotherapy regimens with these single agents. In the Vth MRC myelomatosis trial, the survival of 314 patients randomised to receive ABCM (adriamycin, BCNU, cyclophosphamide, and melphalan) as first-line treatment was significantly longer than that of 316 patients given intermittent melphalan (M7) (p = 0.0003). The 75%, median, and 25% survivals were 7, 24, and 42 months, respectively, with M7 and 10, 32, and 56 months, respectively, with ABCM. Stable disease with few symptoms (plateau) was achieved by 61% of patients given ABCM and 49% of those given M7 (p = 0.004). Myelotoxicity was comparable between regimens. Cross-trial analysis suggests that M7 is comparable to melphalan and prednisone or melphalan, prednisone, and vincristine; that the efficacy of ABCM in the Vth trial and VIth MRC trials is comparable; and that ABCM gave better survival than intermittent melphalan regimens in the prognostic groups analysed. The results indicate that ABCM is an acceptable regimen that is more effective than melphalan, with or without prednisone, for first-line treatment of myelomatosis.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; beta 2-Microglobulin; Carmustine; Cause of Death; Cyclophosphamide; Doxorubicin; Drug Administration Schedule; Follow-Up Studies; Humans; Melphalan; Multiple Myeloma; Prognosis; Survival Analysis

The purpose of this single arm phase II study was to test a modified version of the three drug combination vincristine, adriamycin and dexamethasone (m-VAD), in which intravenous vincristine (0.4 mg/d) and adriamycin (9 mg/m2 per day) infusions are administered for only 2 h on days 1-4 of each 28 d cycle, in patients with refractory multiple myeloma. In addition, only two 4 d courses of dexamethasone 40 mg/d was given during each cycle. The entry criteria for 44 patients included plasma cell myeloma and a measurable monoclonal peak, either refractory to initial treatment with melphalan and prednisone, or resistant to melphalan and prednisone after initially responding (resistant relapsed disease, 27 patients). Patients treated previously with chemotherapy other than melphalan and prednisone were excluded. There were no complete responses. Of the 41 evaluable patients who completed at least one course of therapy 11 had a partial response (27%, 95% C.I. 14-40%). The response rates were 19% for primary refractory disease patients, and 32% for those with resistant relapsed disease. The median duration of response was 4 months. The median survival for all 44 patients was 7.6 months (5.5 months for primary refractory patients, and 10 months for relapsed resistant disease patients). Episodes of documented bacterial infection occurred in 12 patients, and 10 patients had minor viral infection. The dexamethasone dose was reduced in 12 patients. The median neutrophil nadir was 1.2 x 10(9)/l, and median platelet nadir was 147 x 10(9)/l. Five deaths were judged as treatment related and occurred during marrow cytopenia. The results of this modified form of VAD are inferior to that reported previously for 4 d continuous infusions of vincristine and doxorubicin. This could be related to either patient selection factors, or to a reduction of the efficacy of the drug combination produced by either the shortened intravenous infusions and/or omission of one 4 d course of dexamethasone.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Doxorubicin; Drug Resistance; Female; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Pilot Projects; Survival Analysis; Vincristine

A trial was initiated to determine the feasibility and efficacy of a three-phase treatment including: (1) induction chemotherapy (IC); (2) high-dose melphalan with total body irradiation supported by unpurged autologous bone marrow transplantation (ABMT); and (3) interferon (IFN) alpha maintenance treatment, in previously untreated aggressive myeloma. Thirty-five consecutive patients, ages under 65 years, were enrolled. Initial induction therapy was randomized between the VAD regimen (vincristine, doxorubicin, dexamethasone) or the VMCP regimen (vincristine, melphalan, cyclophosphamide, prednisone) that were found to give similar results as IC. Thirty-one of 35 (89%) patients, with good performance status and normal renal function after IC, received ABMT. IFN alpha was started soon after ABMT and was well tolerated. Fifteen of 35 (43%) patients achieved complete response (CR) and 14 of 35 (40%) achieved partial response (PR). Low pretreatment beta 2 microglobulin was the only predictive factor for accomplishing CR. The duration of response was significantly affected by the magnitude of response. The 33-month, post-ABMT probability of progression-free survival was 85% for patients in CR versus 24% for patients in PR. The 42-month, post-diagnosis probability of survival was 81%. This overall strategy may represent an advance in the management of multiple myeloma. Furthermore, the high rate and long duration of CR that we observed in patients with low beta 2 microglobulin suggest that such patients may preferentially benefit from this strategy.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Combined Modality Therapy; Cyclophosphamide; Dexamethasone; Doxorubicin; Female; Humans; Interferon-alpha; Male; Melphalan; Middle Aged; Multiple Myeloma; Prednisone; Prospective Studies; Recurrence; Salvage Therapy; Transplantation, Autologous; Vincristine; Whole-Body Irradiation

A randomized trial has been performed in which 91 patients with stage III myeloma and additional severe criteria were randomly allocated to either VAD or VMBCP. No significant difference was noted between these two groups using the following criteria: response rate (VMBCP: 54%; VAD: 39%), impact on symptoms, median survival (VMBCP: 14 months, VAD: 17 months). However, toxic effects and refusal to pursue treatment were more frequent with VAD than with VMBCP (12 v 6). Therefore, in this trial, VMBCP appears to be more useful than VAD.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Cyclophosphamide; Dexamethasone; Doxorubicin; Female; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Prednisone; Prognosis; Vincristine

80 patients with resistant or relapsing multiple myeloma received a combination of vincristine, cyclophosphamide, lomustine, melphalan and methylprednisolone (MOCCA) as a second-line chemotherapy. 27 of them were resistant to primary chemotherapy with alkylating agents, and 53 had relapsed after initially responding to these drugs. An objective response was achieved in 39 patients (49%): in 14 patients who were primarily resistant (52%) and in 25 patients who had a relapse (47%). Of 41 patients relapsing during maintenance chemotherapy 14 (34%) responded, while 11 of 12 patients (92%) treated for a relapse off-therapy responded. The median duration of response was 22 months. Severe complications, in most cases infections, occurred in 30% of patients, and were fatal in 9% of the cases. According to our experience the five-drug combination MOCCA is an effective second-line chemotherapy for myeloma patients primarily resistant to or relapsing after therapy with single alkylating agents.

Topics: Aged; Alkylating Agents; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Drug Resistance; Follow-Up Studies; Humans; Immunoglobulin A; Immunoglobulin G; Immunoglobulin Light Chains; Lomustine; Melphalan; Methylprednisolone; Middle Aged; Multiple Myeloma; Neoplasm Staging; Recurrence; Treatment Outcome; Vincristine

To study the efficiency of high-dose melphalan in previously untreated patients with advanced myeloma, we performed a Phase I-II trial. Twenty-eight patients were treated at dose level of 60-140 mg/m2. Each patient was first treated with a priming dose of cyclophosphamide (300 mg) followed by high-dose melphalen 1 week later. One course of therapy was given. Patients were then followed without further therapy until relapse. Clinical and laboratory features of the 28 patients in this study included: median age 63, performance status 0-2, hypercalcemia 21%, bone pain 82%, paraprotein types: IgG 76%, Iga 20%, and paraproteinuria 71%. Because none of the patients achieved complete remission (CR) at 60 mg/m2, despite life-threatening toxicity in all patients, the dose level was rapidly increased to 140 mg/m2, a dose previously reported to induce a high percentage of CR. At this dose, CR was achieved in only 1 of 11 patients (9%). This patient had multiple plasmacytomas without generalized bone marrow involvement. One additional patient at 100 mg/m2 achieved CR. Of the whole group, 12 achieved PR. Durations of remissions were generally short: CR 6.3 and 18+ months and PR 2.3-18 month, median 6.9 months. Life-threatening myelosuppression was universal with prolonged pancytopenia. Treatment-related deaths from sepsis were observed in 29% of patients. The median survival of the entire group was 15.6 months. Older patients in this trial did not tolerate high-dose melphalen therapy well; this resulted in a high proportion of toxic deaths and poor overall survival.

Topics: Adult; Aged; Aged, 80 and over; Drug Evaluation; Female; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Neoplasm Staging; Remission Induction

Eighteen patients with advanced multiple myeloma resistant to VAD chemotherapy (vincristine, Adriamycin, dexamethasone) were treated with intravenous melphalan in a single-pulse dose of 50-70 mg/m2. Objective response (greater than or equal to 50% reduction of the monoclonal protein) was observed in 9 patients. The median duration of remission in the responding patients was 6 months and the median survival 11.5 months. The main toxicity noted was bone marrow suppression. We conclude that intermediate doses of intravenous melphalan are a useful therapeutic modality in refractory or relapsing myeloma patients.

Topics: Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Doxorubicin; Female; Humans; Male; Melphalan; Multiple Myeloma; Vincristine

The present trial was designed to evaluate whether interferon (IFN) combined with standard induction chemotherapy and/or interferon remission maintenance treatment improve treatment results in patients with multiple myeloma. Up to now 89 patients have received IFN plus vincristine/melphalan/cyclophosphamide/prednisolone (VMCP) as induction therapy, and 86 conventional VMCP. The proportion of patients with progressive disease was significantly lower (P less than 0.005) under IFN + VMCP as compared to the VMCP treatment group. Survival times were significantly longer (P less than 0.02) after IFN + VMCP induction therapy than after VMCP alone. In the second phase of this investigation, 33 progression-free myeloma patients were assigned to receive IFN as maintenance therapy, and 41 patients served as untreated controls. Patients maintained with IFN showed a tendency towards increased progression-free survival. Haematological side effects were observed significantly more often in patients receiving IFN, with more severe haematological toxicity in patients on the combined IFN + VMCP regimen and an increased number of patients with mild haematological toxicity in the group maintained with IFN. Other side effects, such as fever and fatigue, remained within tolerable limits. In conclusion, the preliminary results of this current clinical trial indicate significant advantages of combined IFN + VMCP induction treatment in terms of reduced disease progression and prolonged survival and possible benefits of IFN maintenance therapy in patients with multiple myeloma.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Cyclophosphamide; Female; Humans; Interferon alpha-2; Interferon-alpha; Male; Melphalan; Middle Aged; Multiple Myeloma; Prednisone; Recombinant Proteins; Remission Induction; Vincristine

A multicentre clinical trial was carried out in order to evaluate the effect of interferon (IFN) in patients with multiple myeloma. Patients (n = 120) who had shown response to conventional intermittent melphalan-prednisone induction therapy, and achieved a plateau phase, were randomized at that point to receive either interferon alfa-2b in a dose of 5 million units (MU) three times per week or no therapy. This report presents the results of an interim analysis, performed when the patients had been followed for a median of 20 months. The duration of the plateau phase was significantly longer in the IFN arm (59 weeks), compared to the no therapy arm (26 weeks). A total of 34 deaths have occurred, 13 in the IFN arm and 21 in the no therapy arm. In spite of the high median age of the patients studied (70 years), most patients were able to tolerate a full or only slightly reduced IFN dose.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Female; Humans; Interferon alpha-2; Interferon-alpha; Male; Melphalan; Middle Aged; Multiple Myeloma; Prednisone; Recombinant Proteins

Topics: Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Humans; Interferon-alpha; Melphalan; Multiple Myeloma; Prednisone; Prospective Studies

The effectiveness of therapeutic plasmaphereses with antineoplastic chemotherapy was evaluated in 25 cases of plasmocytic myeloma in stage III of progression of the proliferative process. The indication to plasmapheresis was hypergelification of serum with clinical symptoms of central nervous system disturbances, renal failure in various stages of progression, intensification of coronary symptoms, bleeding tendency. Good effects with reduced level of total protein and monoclonal protein in serum by 30-80% with regression of clinical symptoms caused by serum hypergelification were obtained in 11 cases. In the remaining patients clinical improvement of varying degree was noted when the level of total and monoclonal protein in the serum fell by 10-29%.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Combined Modality Therapy; Cyclophosphamide; Female; Humans; Immunoglobulin kappa-Chains; Immunoglobulin lambda-Chains; Male; Melphalan; Middle Aged; Multiple Myeloma; Neoplasm Staging; Plasmapheresis; Prednisone; Vincristine

Prospective studies were carried out on the effectiveness of various treatment methods in 208 patients with plasmocytic myeloma. In 102 patients induction therapy was based exclusively on melphalan, in 106 cases polychemotherapy was used including vincristine, melphalan, carmustine, cyclophosphamide and prednisone. The differences in the per cent of patients with good response to treatment and in the survival time after treatment beginning were statistically not significant between these groups which suggests that polychemotherapy begun from the diagnosis of the disease is justified in patients with large mass of the neoplasm and poor prognostic factors. In 45 patients chemotherapy was supported by administration of immunomodulatory agents, including calf thymus extract in 25 cases, levamisole in 18 and interferon in 2. It was observed that maintenance of remission with chemotherapy and with immunomodulatory agents calf thymus extract or levamisole prolonged the survival of the patients. In cases of leucopenia the use of calf thymus extract facilitated chemotherapy by stimulation of myelopoiesis.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Cyclophosphamide; Doxorubicin; Female; Humans; Interferon-alpha; Levamisole; Male; Melphalan; Middle Aged; Multiple Myeloma; Prednisone; Remission Induction; Thymus Extracts; Vincristine

From September 1975 to December 1986, 115 consecutive previously untreated patients with multiple myeloma (MM) were treated with combination chemotherapy consisting of BCNU, cyclophosphamide, melphalan, vincristine, and prednisone (M-2). No patients were excluded or lost during follow-up. Forty-three percent of the patients were Stage I plus II, and 57% were Stage III. Thirty-eight patients (33%) had blood urea nitrogen greater than or equal to 40 mg/dl (substage B). Reaching an objective response treatment was stopped, generally after 1 year, and restarted at relapse. After induction therapy, 94 patients (82%) responded and had a median duration of response (MDR) of 22 months. After first relapse, 26 of 38 patients (69%) responded again to the same regimen and had an MDR of 11 months. This response rate and MDR are significantly lower than the ones achieved in induction chemotherapy. After second relapse, 7 of 16 patients (44%) again responded with an MDR of 3.5 months. The median survival time (MST) was 50.5 months for all patients. The most relevant side effect was leukopenia. No case of secondary leukemia was noticed. The authors conclude that patients with MM can be treated safely without maintenance therapy after reaching remission because a high response rate can be obtained in first and even second relapse. The planned treatment pause at remission does not adversely affect the survival time. Secondary leukemia is infrequent after this policy. Quality of life improves during the treatment pause.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Cyclophosphamide; Female; Follow-Up Studies; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Prednisone; Vincristine

IFN alpha is a biologic therapeutic agent with documented antitumoral effect in multiple myeloma. 15% of previously untreated myeloma patients achieve a clinical response to IFN alpha alone with a possible dose-response relationship. A particularly good effect is noted in IgA myelomas treated with natural IFN alpha. A randomized study was started in April 1986 comparing melphalan/prednisone (MP) therapy with MP plus natural IFN alpha (MP/IFN) in untreated patients with multiple myeloma stages II and III. 220 patients had entered the study by autumn 1989. An interim report is given here. The response frequency was 48% in the MP group and 66% in the MP/IFN group (P less than 0.02). Stage II patients responded better to MP/IFN (76%) than to MP alone (48%) (P less than 0.01). No significant difference was noted for stage III patients. 91% of all IgA myelomas responded to MP/IFN and 52% to MP (P less than 0.01). The difference in response frequency of IgG and BJ myelomas between the two treatment groups was not statistically significant. The observation period is still too short to draw firm conclusions on survival. However, a statistically significant longer response duration time and survival from response (P less than 0.01) was noted for stage II patients.

Topics: Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Humans; Interferon-alpha; Melphalan; Multiple Myeloma; Neoplasm Staging; Prednisone

This preliminary report focuses on the therapeutic role of interferon in a large randomized trial evaluating combination chemotherapy induction and interferon maintenance, as compared with no maintenance therapy, in patients with newly diagnosed multiple myeloma. The trial also included an evaluation of the combination of interferon and dexamethasone therapy for patients who failed to respond to induction chemotherapy or who had achieved only a partial remission. Case accrual is completed for remission induction with 505 eligible patients registered on study, but is still open for additional maintenance registrations. As of January 1991, 161 patients have been randomized to interferon versus observation, but the therapeutic results of this aspect of the study remain coded. Toxicity of interferon maintenance was generally of a mild to moderate degree, and less severe than that of the interferon/dexamethasone combination, which was due to the addition of steroid side effects. Among 41 patients who failed to achieve remission with chemotherapy, 13 (32%) achieved at least a partial remission with interferon/dexamethasone, and only five others (12%) have had progressive disease. Of 12 partial responders on induction chemotherapy, five (42%) achieved remission (75% tumor regression) with interferon/dexamethasone. To date, more than 65% of patients receiving interferon/dexamethasone remain alive, suggesting that this regimen will be useful for patients who fail to achieve remission with induction chemotherapy.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carmustine; Cyclophosphamide; Dexamethasone; Doxorubicin; Etoposide; Humans; Interferon-alpha; Melphalan; Multiple Myeloma; Prednisone; Remission Induction; Vincristine

Over the course of a 2-year period (September 1987 to September 1989) a total of 432 patients with multiple myeloma were registered in a study comprising 39 Swedish and one Italian clinics. Six of these were university hospitals, the others were county (community) hospitals. A total of 308 patients fulfilled the eligibility criteria of the protocol, and were started on traditional intermittent melphalan-prednisone therapy. Response, defined as a reduction in the concentration of the M-component in serum or urine, was observed in 58% of patients, and a clearly defined plateau phase was noted in 38% of the cases. Of the patients who achieved a plateau phase, 120 individuals (with a median age of 71 years) were at this point randomized between no further therapy and continuous interferon-alfa-2b at a dose of 5 x 10(6) IU subcutaneously three times per week. At relapse the interferon therapy was discontinued, and melphalan-prednisone restarted. Only preliminary data and interim results are at this point available. The final evaluation of the study will be performed after June 1, 1991. The treatment arms are comparable with regard to age, stage according to Durie-Salmon, renal function, immunoglobulin class, and type of response to the cytostatic therapy (rapid versus slow). A median number of six courses of melphalan-prednisone were administered before randomization. For those patients in whom pretreatment serum beta-2-microglobulin was analyzed, no difference in the median values between the treatment arms was found. The median observation time from randomization is 20 months. At the time of this analysis, 85 had relapsed: 33 of 59 (56%) in the interferon arm, and 52 of 61 (85%) in the no therapy arm. An interim analysis of the duration of the plateau phase (from the time of randomization) was performed in October 1990, showing a highly significant difference between the two treatment arms (P less than .001). The median duration of plateau was 59 weeks in the interferon arm, and 26 weeks in the no therapy arm. To date there have been 34 deaths, 13 in the interferon arm and 21 in the no therapy arm. All patients in the no therapy arm died from multiple myeloma (n = 19), or from another cause, but with the myeloma in an uncontrolled, progressive state (n = 2). In the interferon arm, only 10 patients died from progressive myeloma, and four of these either did not start interferon therapy at all (n = 1), or discontinued therapy early (n = 3).(ABSTRACT TRUNCATED

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Drug Administration Schedule; Female; Humans; Interferon alpha-2; Interferon-alpha; Male; Melphalan; Multiple Myeloma; Neoplasm Recurrence, Local; Prednisone; Recombinant Proteins; Sweden

The efficacy of alternating vincristine, melphalan (M), cyclophosphamide, prednisone/vincristine, carmustine, doxorubicin, and prednisone (VMCP/VBAP) polychemotherapy was compared with the M and prednisone (MP) regimen as induction treatment in multiple myeloma (MM). Three hundred four MM patients entered this study between March 1983 and July 1986; the analysis was performed in December 1989. The treatment groups did not show significant differences with respect to major prognostic factors. Median overall survival was 33.8 months. In the VMCP/VBAP and MP arms, after 12 induction chemotherapy cycles, 59.0% and 47.3% (P less than .068) of the patients achieved an M component reduction greater than 50%. No significant difference was observed in the two treatment arms in terms of remission duration (21.3 v 19.6 months, P less than .66) and survival (31.6 v 37.0 months, P less than .28). Patients younger than 65 years did not show any advantage from the alternating polychemotherapy. At diagnosis, the plasma cell labeling index (LI) and serum beta-2 microglobulin (beta 2-m) were evaluated in 173 and 183 patients, respectively. A significantly reduced survival was observed for patients with LI greater than or equal to 2% (16.4 months) or beta 2-m greater than or equal to 6 mg/L (20.4 months). Even in these poor-risk subgroups, VMCP/VBAP was not superior to MP.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; beta 2-Microglobulin; Carmustine; Cyclophosphamide; Doxorubicin; Drug Administration Schedule; Female; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Prednisone; Prognosis; Vincristine

A vincristine, melphalan, cyclophosphamide, and prednisone (VMCP) multi-drug regimen was used in 85 previously untreated patients with multiple myeloma (MM) (symptomatic Durie Stages II and III) until they became refractory. The prognostic significance of various pretreatment characteristics was evaluated in terms of therapeutic response (according to Southwest Oncology Group [SWOG] and Chronic Leukemia-Myeloma Task Force [TF] criteria) and survival. Therapeutic responses, obtained in 31.2% (SWOG) and 68.7% (TF) of patients, had a significant inverse correlation with myeloma cell mass, serum calcium, and bone status. Median survival time of Stage II and Stage III patients was 39 and 34 months, respectively. Serum B2 microglobulin greater than or equal to 6 micrograms/ml was the only variable correlating unfavorably with survival duration after multi-variate analysis (increased risk = 2.79), although therapeutic response as a time-dependent variable had no effect on survival. These data suggest no correlation between response and survival, partially because of inadequate response assessment criteria and partially because no existing treatment is curative (although current therapeutic approaches may prevent death from complications).

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; beta 2-Microglobulin; Calcium; Cyclophosphamide; Female; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Neoplasm Staging; Prednisone; Survival Rate; Vincristine

277 untreated multiple myeloma patients of stage 1 (n = 33), II (n = 106) and III (n = 138) entered the study. Patients of stage II presenting a progressive tumor (n = 64) initially or during observation (n = 14) were treated with MivP (remissions: 61%). 138 patients of stage III were randomized to receive MivP or VBAMDex treatment. 51% of MivP treated patients responded versus 70% of the VBAMDex group. 71 responders of stage II and III with stable disease were randomized on Ifn-alpha maintenance versus no maintenance treatment. The relapse rate in both groups was 50% after 7 months. 75% survival was greater than 36 months in stage II and 11 months in stage III patients.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carmustine; Combined Modality Therapy; Dexamethasone; Doxorubicin; Female; Humans; Interferon Type I; Male; Melphalan; Multiple Myeloma; Neoplasm Staging; Prednisone; Recombinant Proteins; Vincristine

A cooperative randomized clinical trial to compare the effectiveness of multi-drug combination chemotherapy (VMCP), vincristine-melphalan-cyclophosphamide-prednisolone) with CP (cyclophosphamide-prednisolone) for the treatment of multiple myeloma was performed. When the whole group of patients was evaluated, the choice of chemotherapy (VMCP or CP) was not a significant prognostic factor associated with response or survival by uni- or multivariate analysis, and the difference between the survival curves of the treatment groups was only marginally significant. However, when the analysis was confined to stage III patients, the choice of chemotherapy became a significant prognostic factor associated with both response rate and survival, and the statistical difference between survival curves was significant. Taking the disease characteristics of multiple myeloma into consideration, the better result obtained with multi-drug combination chemotherapy in the treatment of stage III patients is consistent with other studies supporting the superiority of multi-drug combination chemotherapy for patients with overt systemic disease.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Female; Humans; Male; Melphalan; Multiple Myeloma; Neoplasm Staging; Prednisolone; Prognosis; Survival Analysis; Vincristine

Six hundred fourteen previously untreated patients with multiple myeloma were evaluated on this phase III Southwest Oncology Group (SWOG) trial. For remission induction, two noncross-resistant drug combinations (vincristine, melphalan, cyclophosphamide, and prednisone [VMCP] and vincristine, carmustine [BCNU], Adriamycin [doxorubicin; Adria Laboratories, Columbus, OH], and prednisone [VBAP]) were administered with either a direct alternating or a syncopated schedule. Pretreatment serum beta-2 microglobulin (beta 2M) was the single most important prognostic factor for survival (P less than .0001). There was no difference in toxicity, response, or survival by induction chemotherapy schedule (P greater than .7). For consolidation, 180 eligible and responsive patients were randomized to receive either an additional year of VMCP or sequential hemibody radiation (HBI) with vincristine and prednisone (VP) administered between the two HBI courses. Relapse-free survival (26 months) and overall survival (median, 36 months) were better with VMCP than with HBI (median, 20 months and 28 months; P = .04 and .018, respectively). HBI was also evaluated on a nonrandomized basis in 66 patients who achieved either a partial response (PR) or who were nonresponders to induction therapy. While HBI converted 24% of the PR patients to remission status, this effect was only seen in 5% of nonresponding patients. The survival of responsive and nonresponding patients receiving HBI was similar. All HBI groups had an inferior outcome to those receiving VMCP consolidation. Myelosuppression was also significantly worse after HBI. Survival from the time of relapse did not differ between patients randomized to receive VMCP or HBI. Thus HBI induced less durable remissions, but did not render patients less amenable to postrelapse chemotherapy. Our findings do not support the use of HBI in either chemotherapy responsive or nonresponding patients with multiple myeloma.

Topics: Antineoplastic Combined Chemotherapy Protocols; beta 2-Microglobulin; Biomarkers, Tumor; Carmustine; Combined Modality Therapy; Cyclophosphamide; Doxorubicin; Female; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Prednisone; Randomized Controlled Trials as Topic; Remission Induction; Vincristine

From October 1983 until December 1986, 164 patients with multiple myeloma stage II-III were included in a prospective randomized multi-centre study comparing melphalan-prednisone (MP) with multidrug chemotherapy (MDC). The patients comprised 77% of all newly diagnosed myeloma stage II-III cases reported from 18 hospitals covering the entire Health Care Region of Western Sweden (1.5 million inhabitants). Patients randomized to MP (29 stage II and 55 stage III patients) were given oral melphalan and prednisone every 6 weeks. For patients randomized to MDC, stage II patients (n = 25) were given VMCP every 4 weeks and stage III patients (n = 53) VBAP and VMCP alternately every 4 weeks. For stage II patients, the response rate for MP compared to VMCP was 69 versus 56% and the median survival 46 versus 33 months. For stage III the response rate for MP compared to VBAP/VMCP was 58 versus 57% and the median survival 26 versus 24 months. No statistically significant differences were seen. The time to response and remission duration were also similar in both treatment arms. The dose intensity index (cumulative given/planned dose of myelosuppressive drugs) was greater than or equal to 0.8 in 89% of the MP patients and 81% of the MDC patients. Patients with index values less than 0.8 had the same response rate as patients with index greater than or equal to 0.8. This study has not demonstrated any advantage of MDC over traditional MP in multiple myeloma stage II-III.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Cyclophosphamide; Doxorubicin; Female; Humans; Male; Melphalan; Middle Aged; Multicenter Studies as Topic; Multiple Myeloma; Prednisone; Prospective Studies; Randomized Controlled Trials as Topic; Vincristine

136 untreated multiple myeloma patients of stage II and III were collected in the study. 37/51 stage II patients had progressive disease and were treated with melphalan and prednisone (MP). 85 patients were of stage III and randomized into MP and vincristine, BCNU, adriamycin, melphalan and dexamethasone (VBAMDex) treatment groups. 55% of MP treated patients responded versus 75% of the VBAMDex group. Since the study has been activated only 16 months ago, no difference in survival could be observed.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carmustine; Dexamethasone; Doxorubicin; Female; Follow-Up Studies; Humans; Male; Melphalan; Multicenter Studies as Topic; Multiple Myeloma; Neoplasm Staging; Prednisone; Vincristine

Between January 1985 and December 1988, 386 patients with multiple myeloma were randomized to receive either MP or combination chemotherapy based on alternating cycles of VCMP and VBAP. The major prognostic parameters did not differ significantly between both treatment groups. A significantly higher proportion of objective responses was observed with combination chemotherapy as compared to MP (47.8 vs 32.2, P = 0.01). The median survival for all patients was 33.5 months. So far no significant differences were found when comparing the survival curves from both groups of patients. However, the median survival of MP-treated patients is 26.8 months, whereas the median survival of patients receiving VCMP/VBAP has not yet been reached. The definitive analysis must await the evaluation of all patients entered into the study and a longer follow-up time.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carmustine; Cyclophosphamide; Doxorubicin; Drug Administration Schedule; Female; Humans; Male; Melphalan; Middle Aged; Multicenter Studies as Topic; Multiple Myeloma; Prednisone; Prospective Studies; Randomized Controlled Trials as Topic; Vincristine

Eighty-one previously untreated patients with multiple myeloma stage II entered a randomized trial comparing oral melphalan (0.25 mg/kg/day; n = 40) with intravenous melphalan (0.125 mg/kg/day; n = 41) in combination with oral prednisone (2 mg/kg/day). The courses were given for 4 days and repeated every sixth week. The treatment groups were well comparable with regard to major prognostic factors. There was no statistically significant difference in the response rates, the response duration times and the survival times. No significant difference in nonhematological and hematological toxicity was noted. Since intravenous administration of melphalan did not result in a substantial increase in response rate or survival, this study supports the use of oral melphalan/prednisone as first-line therapy for patients with multiple myeloma.

Topics: Actuarial Analysis; Administration, Oral; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Humans; Injections, Intravenous; Melphalan; Middle Aged; Multiple Myeloma; Neoplasm Staging; Prednisone; Prognosis; Sweden

Alpha-2a-interferon (IFN) has demonstrable activity in advance and refractory multiple myeloma (MM), because of the in vitro synergism between IFNs and cytotoxic agents we report the preliminary results of a therapeutic trial of 50 patients with MM. Twenty-eight patients were randomized to receive melphalan plus prednisone (MP) and 22 were randomized to receive IFN plus MP (IFN-MP). Criteria for response, progression and relapse were those of the Southwestern Oncology Group. 95% of the patients receiving IFN-MP responded to therapy as opposed to 68% of the patients receiving MP (P less than 0.05). Response was independent of M-component immunoglobulin class but in stage III it was higher in the IFN-MP group than in the MP group (P less than 0.05). The combination IFN-MP was well tolerated without unusual or unexpected toxic effects. The response duration time was longer in the IFN-MP group than in the MP group (P less than 0.025). The median survival was 80 weeks in the MP group and in the IFN-MP group the 93% of patients were still alive after 90 weeks (P less than 0.025). Our results show that the use of the IFN as an adjuvant to MP improves the percentage of responders, the response duration time and the median survival of untreated patients with MM.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Female; Humans; Interferon alpha-2; Interferon-alpha; Male; Melphalan; Middle Aged; Multiple Myeloma; Prednisone; Recombinant Proteins; Remission Induction; Time Factors

The influence of interferon-induced fever on oral melphalan pharmacokinetics has been studied in 10 myeloma patients in a randomized crossover design. The melphalan dose (0.25 mg/kg) was given alone and 5 hours after the administration of human interferon alpha (7 x 10(6) IU/m2), respectively. The plasma concentration of melphalan was determined by liquid chromatography with fluorometric detection after derivatization of melphalan with N-acetylcysteine. The area under the plasma concentration-time curve (AUC) was significantly lower (p = 0.02) when melphalan was given with interferon. There was a significant negative correlation (p = 0.008) between body temperature and dose normalized AUC, whereas no effect was noticed on the maximum plasma concentration (Cmax) and on the time to obtain Cmax. The rate of elimination showed a tendency (p = 0.06) to increase with increasing body temperature. It is suggested that the cytotoxicity of the drug is most probably enhanced because of the higher alkylating activity of the compound at elevated body temperatures.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Body Temperature; Drug Interactions; Female; Fever; Half-Life; Humans; Interferon Type I; Male; Melphalan; Metabolic Clearance Rate; Middle Aged; Multiple Myeloma; Prednisone

Patients aged 70 yr or older with multiple myeloma were treated, when suitable, according to concurrent trial protocols for younger patients, with the exception that the cytostatic regimen was not allocated at random. Intermittent melphalan and prednisone (MP) was given as the primary treatment to 42 patients and 5-drug combination MOCCA to 68 patients. The groups were comparable with each other, and the distribution of the clinical stages of the patients was similar to the younger patients in concurrent trials. An at least 50% response was achieved in 33% (SE 7.3) with MP and in 75% (SE 5.3) with MOCCA. The median survival times were 39 and 32 months, the relative age-adjusted survival times 45 and 41 months, respectively. Advanced age as such is thus no contraindication for active treatment of myeloma, and in suitable patients the results compare well with those achieved in younger patients.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Humans; Lomustine; Melphalan; Methylprednisolone; Multiple Myeloma; Vincristine

Fifty-two previously untreated patients with multiple myeloma were randomized to either a combination of recombinant interferon (rIFN) alpha-2 and chemotherapy or chemotherapy alone. Patients were treated with vincristine, melphalan, cyclophosphamide and prednisolone every 4-6 weeks. In the combined treatment arm rIFN was administered concurrently with chemotherapy as well as during chemotherapy free intervals. The combined regimen effected 17/21 (80.9%) responses as compared to 19/27 (70.4%) responses in VMCP treated patients. Addition of rIFN to chemotherapy did not enhance hematologic toxicity. These findings suggest a somewhat higher rate of objective response in the VPMC + rIFN group, although a significant improvement in median survival by adding rIFN to conventional first line polychemotherapy in myeloma patients has not yet been achieved.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Combined Modality Therapy; Cyclophosphamide; Female; Humans; Interferon alpha-2; Interferon Type I; Interferon-alpha; Male; Melphalan; Middle Aged; Multiple Myeloma; Prednisone; Prospective Studies; Random Allocation; Recombinant Proteins; Vincristine

Thirty-three previously untreated patients with multiple myeloma were randomized to either a combination of recombinant interferon-alpha-2C (rIFN-alpha-2C) plus vincristine/melphalan/cyclophosphamide and prednisone (VMCP) or VMCP chemotherapy alone. The combined regimen effected 67% responses and 26% minor responses, while 35 and 47% of VMCP-treated patients had a pathologically documented remission, respectively. Despite the somewhat earlier achievement and duration (12.0 vs. 8.0 months) of objective response, and the marginal survival benefit observed in the rIFN-alpha-2C + VMCP treatment arm, a significant improvement in therapeutic gain by adding a biologic response modifier to conventional first-line polychemotherapeutic drug treatment in myeloma patients has not yet been achieved. The combined regimen was well tolerated without unusual or unexpected toxic effects.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Cyclophosphamide; Female; Humans; Interferon Type I; Male; Melphalan; Middle Aged; Multiple Myeloma; Prednisone; Prospective Studies; Random Allocation; Recombinant Proteins; Vincristine

86 previously untreated patients with multiple myeloma stage III entered a randomized trial comparing combination chemotherapy (VMCP/VBAP) (n = 42) with intermittent oral melphalan and prednisone (MP) treatment (n = 44). The treatment gropus were well comparable with regard to major prognostic factors. There was no statistically significant difference in the response rates, 52% (VMCP/VBAP) vs 61% (MP); in the response duration times, median 19 months vs 22 months, or in the survival times, median 24 months vs 28 months. However, survival of patients older than 65 years was significantly shorter in the VMCP/VBAP group (median 15 months) compared to the MP group (median 23 months) (p = 0.03). No significant difference in non-hematological or hematological toxicity was noted. The study further supports the notion that MP therapy should be used as primary standard treatment for patients with multiple myeloma.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Clinical Trials as Topic; Cyclophosphamide; Doxorubicin; Humans; Melphalan; Middle Aged; Multiple Myeloma; Prednisone; Prospective Studies; Random Allocation; Sweden; Vincristine

Fifty previously untreated patients with myeloma were entered into a 2-phase treatment programme: vincristine, adriamycin and methyl prednisolone (VAMP) followed by high dose intravenous melphalan (HDM) with autologous bone marrow transplantation where possible. The complete remission rate of 50% was associated with very good quality of life and the reversal of humoral immunosuppression. Complete remission is important in younger patients with myeloma as it represents a first step in achieving long, symptom- free survival.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Clinical Trials as Topic; Combined Modality Therapy; Doxorubicin; Female; Humans; Male; Melphalan; Methylprednisolone; Middle Aged; Multiple Myeloma; Transplantation, Autologous; Vincristine

Reports of 13 prospective, randomized clinical trials comparing standard treatment with melphalan and prednisone (MP) versus various drug combinations in the treatment of myeloma patients are presented. These studies reveal that patients with Durie-Salmon Stage III disease respond significantly more frequently to MP and drug combinations than those with Stage I and II. Drug combinations may be more effective in inducing objective responses. The response rates were significantly better for the drug combinations in 3 of the 13 comparisons. There was little evidence that either form of treatment was superior in prolonging survival, for in one study the patients treated with a drug combination lived significantly longer than those treated with MP, while in another the reverse was true, and there was no difference in the survival of the two groups in the remaining 11 studies. In the Vth MRC myelomatosis trial, patients treated with a combination of adriamycin, carmustine, cyclophosphamide and melphalan are living significantly longer than those treated with melphalan alone, and this survival advantage persists after correction for the most important prognostic factor, beta 2 microglobulin. Attempts to increase the intensity of treatment by using syngeneic, allogeneic or autologous marrow transplantation to rescue patients following otherwise lethal chemoradiotherapeutic treatments, have not yet demonstrated conclusively that the myeloma clone can be eliminated by this form of treatment.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Combined Modality Therapy; Humans; Melphalan; Multiple Myeloma; Prednisone; Prospective Studies; Randomized Controlled Trials as Topic

A randomized study comparing melphalan/prednisone (M/P) therapy with MP + natural alpha-IFN in untreated patients with multiple myeloma stages II and III started April 1, 1986. By March 1989, 78 patients were evaluable in the MP group and 80 in the MP/IFN group. 48% of the MP patients achieved a response and 66% in the MP/IFN group (p = 0.04). Stage II patients responded better to MP/IFN (76%) than MP alone (47%) (p = 0.02), while no statistically significant difference was noted for stage III patients. 90% of the IgA myelomas responded to MP/IFN and 52% to MP (p = 0.02). Both for IgG and BJ myelomas the response rates of MP/IFN were higher than of MP, although the differences were not statistically significant. The observation period is still short. There was no difference in total survival between the two treatment groups. However, in patients less than or equal to 65 years a tendency to a longer survival was seen for those receiving the IFN combination (p = 0.12).

Topics: Antineoplastic Combined Chemotherapy Protocols; Humans; Interferon Type I; Melphalan; Multicenter Studies as Topic; Multiple Myeloma; Prednisone; Randomized Controlled Trials as Topic

Topics: Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Carmustine; Cell Cycle; Cyclophosphamide; Diagnosis, Differential; Doxorubicin; Drug Evaluation; Humans; Melphalan; Multiple Myeloma; Paraproteinemias; Plasma Cells; Prednisone; Prognosis; Random Allocation; Vincristine

In a prospective multicenter trial, 320 untreated myeloma patients of stage II and III were randomized for remission induction into two groups receiving six monthly courses of either MP or VCMP treatment. Response rates were equal in both groups: 72% remission, 21% no change, 7% progress for patients evaluable by TCM changes and 56% remission, 11% no change, 33% progress for BJ- and non-secretory myelomas. The overall survival rate was 60% after 4 years. An unexpected finding was the significantly longer survival of MP treated patients compared to the VCMP group. After successful remission induction, patients were randomized into one group receiving maintenance treatment using the induction scheme q 8 weeks, and another group without further chemotherapy. Although patients in the latter group relapsed significantly earlier, differences between both groups concerning acquired resistance to first line therapy or survival have not been noticed to date.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Cyclophosphamide; Humans; Melphalan; Multiple Myeloma; Prednisone; Prospective Studies; Random Allocation; Vincristine

A total of 589 patients with previously untreated multiple myeloma were randomized to receive daily oral melphalan, pulse-dose intravenous (IV) melphalan, carmustine (BCNU), or lomustine (CCNU). All patients received an initial tapering course of prednisone (Pred). During week 22 (day 154), patients were randomized to receive or not to receive additional therapy with vincristine (VCR) (1 mg/m2) and prednisone (0.6 mg/kg/d for seven days) at 8-week intervals. The influence of VCR/Pred was determined in 302 patients who remained on study beyond 22 weeks after initial therapy. VCR/Pred converted a significant percentage of nonresponders to responders in patients treated with melphalan (55% v 19%, P = .002), but not in patients treated with a nitrosourea (48% v 23%, P = .06). Survival beyond week 22 was significantly longer following the addition of VCR/Pred in patients receiving melphalan (median, 35.3 months v 27.0 months; P = .003) but not in patients receiving BCNU or CCNU (median, 28.1 months v 26.2 months; P = .91). These differences were seen both for oral and IV melphalan. A trend for beneficial effect of VCR/Pred was definitely seen in the good-risk patients (P = .03) but only suggestive for poor-risk patients (P = .12). Following adjustment for VCR/Pred effects, there were no differences in the survival of patients receiving any of the four initial treatments.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carmustine; Clinical Trials as Topic; Drug Administration Schedule; Female; Humans; Lomustine; Male; Melphalan; Middle Aged; Multiple Myeloma; Prednisone; Random Allocation; Vincristine

Topics: Antineoplastic Combined Chemotherapy Protocols; Argentina; Clinical Trials as Topic; Cyclophosphamide; Humans; Melphalan; Multiple Myeloma; Prednisone; Random Allocation; Semustine; Vincristine

Topics: Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Cyclophosphamide; Humans; Interferon Type I; Melphalan; Multiple Myeloma; Prednisone; Recombinant Proteins; Vincristine

Patients who have received radiation to localized areas of marrow eventually regenerate marrow in the irradiated area, if the dose is 2,400 centigrays (cGy) or less. This trial was designed to deliver a radiation dose of 1500 cGy to all marrow containing sites in patients with multiple myeloma, a technique we refer to as total bone marrow irradiation, or TBMI. Patients with previously untreated myeloma received 12 weeks of melphalan (L-PAM) and prednisone (pred) therapy. Four weeks later, sequential irradiation was administered using the 3-2 technique with rest periods to permit recovery from radiation-induced cytopenia. This was followed by electron beam irradiation of the rib and skull fields. Following completion of TBMI, patients were untreated until relapse. Twenty patients were entered. At entry 5, 8, and 7 patients had low, intermediate and high tumor cell loads, respectively. Two patients had a serum Ca in excess of 12 mg/dl; 3 had an increased creatinine. The median performance (ECOG) was 1. At week 16, immediately prior to TBMI, 5 of the 20 patients fulfilled the Myeloma Task Force criteria for response and 5 others had improved. Six patients did not begin the radiation therapy portion of the protocol. Three had rapidly progressive disease, one persistent leukopenia, one refused radiation therapy and one was withdrawn by his physician. Only 6 of the fourteen patients receiving the radiation treatment phase of the protocol were able to tolerate the intended course of 1500 cGy to all areas. Eight other patients received lower doses. Patients completing the radiation phase of the protocol failed to have further reductions in M-protein or improvement in other parameters beyond those obtained on the chemotherapy phase of the protocol. The median duration of response and survival was 12.0 and 42 months, respectively. We suggest possible reasons for the disappointing results of this trial and conclude that this approach to the primary treatment of myeloma holds little promise.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Combined Modality Therapy; Humans; Melphalan; Middle Aged; Multiple Myeloma; Prednisone; Prognosis

In order to assess the role of maintenance melphalan and prednisone (MP) in responding multiple myeloma patients, 185 eligible patients who responded to initial MP with stabilization for at least 4 months were randomized to either stop treatment and resume therapy at relapse or to continue MP until relapse. Time to first relapse was significantly shorter in the no maintenance group (P = 0.0011), however 57% of the no maintenance patients had a second response when MP was restarted and others had minor improvement. The time to final progression on MP, which reflects the duration of disease control by MP, was therefore longer for the no maintenance group (median = 39 months) compared to the maintenance group (median = 31 months) although the observed difference was not statistically significant (P = 0.086). Median survival from start of MP in the maintenance group (46 months) was also not significantly different than the no maintenance group (51 months) (P = 0.587). Multifactor analysis of the randomized patients demonstrated shorter total remission duration and shorter survival in patients who had an initially rapid response to therapy or a lesser reduction in serum M-protein concentration.

Topics: Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Female; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Myeloma Proteins; Prednisone; Prognosis; Random Allocation; Remission Induction; Time Factors

In a prospective study by the German Myeloma Treatment Group, 320 untreated patients with multiple myeloma, stage II and III, were randomized into 2 groups receiving courses of either MP or VCMP as induction treatment every 6 months. 72% of the patients evaluable by TCM changes remitted, 21% showed a no change, and progress occurred in 7%. The corresponding results in BJ and nonsecretory myelomas were 56% remissions, 11% no change, 33% progress. The response rates were equal in both treatment groups. The overall survival was 60% after 4 years. However, MP-treated patients lived significantly longer than patients in the VCMP group. After successful remission induction, patients were randomized into one group with maintenance treatment using the induction scheme Q 8 weeks, and another group without further chemotherapy. Although the relapse rate of the latter group was significantly higher, differences between both groups concerning survival have not been observed.

Topics: Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Drug Evaluation; Humans; Melphalan; Multiple Myeloma; Neoplasm Staging; Prednisone; Prognosis; Vincristine

An update of two consecutive randomized studies in previously untreated multiple myeloma was performed. The first study (10-M-73) began in 1973; 150 patients were treated with melphalan and prednisone (MP) or semustine, cyclophosphamide, and prednisone (MeCP). In a second randomized study (3-M-77), begun in 1977, 260 patients were treated with MP or melphalan, prednisone, cyclophosphamide, semustine, and vincristine (MPCCV). A total of 27 of the 67 patients (40%) treated with MP and 33 of the 83 patients (40%) treated with MeCP showed a good response in protocol 10-M-73; 48 of 145 patients (33%) treated with MP and 51 of the 115 patients (44%) treated with MPCCV in protocol 3-M-77 obtained a good response (P is not significant). Median survival in protocol 10-M-73 was 30 months for MeCP and 38 months for MP. At 84 months, 19% and 9% remain alive, respectively. Median survival for protocol 3-M-77 was 44 months for those treated with MPCCV and 42 months for MP. At 60 months, 9% and 11% remain alive; this difference was not significant. Also, there was no survival difference for favorable or unfavorable prognostic groups among the four treatment arms of both protocols. It can be concluded, with a long-term follow-up of both protocols, that the combination of MP is as effective as the three- and five-drugs combinations, and in view of its simplicity and cost-saving advantages, it should be favored for initial therapy of multiple myeloma patients.

Topics: Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Humans; Melphalan; Multiple Myeloma; Prednisone; Prognosis; Random Allocation

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Female; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Prednisone

Almost all patients with multiple myeloma still relapse or become refractory in 2 to 3 years. Interferon (IFN) therapy has clearly influenced the levels of abnormal serum proteins in some patients. A multi-institutional phase II clinical trial used alfa-2b recombinant interferon (Intron A, Schering, Kenilworth, NJ) in 38 evaluable patients with relapsing and refractory multiple myeloma; two thirds of the patient population had received extensive prior treatment. Seven responded, of whom three continued to do so beyond 1 year--one with an ongoing complete remission. An additional 13 had at least a 25% decrease in abnormal paraproteins. Of nine patients who were initially refractory to chemotherapy, two responded to IFN. Of nine relapsing patients returned to chemotherapy following IFN therapy, six then responded. Thirty previously untreated patients with multiple myeloma were treated with IFN followed by melphalan and prednisone; of 24 evaluable patients, 18 responded with a median duration of 10+ months. Alfa-2b IFN apparently does not antagonize melphalan or prednisone, nor does it appear to worsen the response of the two drugs alone. Effectiveness of recombinant alfa-2b IFN in pretreated relapsing patients suggests additional trials are needed to study its effects in previously untreated patients. A significant number of patients who relapsed on their original chemotherapy and subsequent interferon will apparently respond to the reinstitution of chemotherapy.

Topics: Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Combined Modality Therapy; Humans; Immunotherapy; Interferon Type I; Melphalan; Multiple Myeloma; Prednisone; Recombinant Proteins

Twelve of 648 patients in the Medical Research Council's first two trials in myelomatosis have developed myelodysplasia or acute leukaemia. This corresponds to a 5-year actuarial prevalence of 3% and an 8-year prevalence of 10%. Patients were randomised to treatment with either melphalan or cyclophosphamide and the relative capabilities of these two drugs to cause these conditions were examined as a function of duration of treatment. A significant relationship with length of melphalan treatment was found but no relationship was observed for cyclophosphamide treatment. The amount of melphalan treatment given in various intervals before diagnosis of myelodysplasia or leukaemia was studied and it was found that the amount of treatment in the most recent 3-year period was the most important determinant of risk (P = 0.0001). It is estimated that the risk of haemopoietic neoplasia after 10 years of follow-up is about 3% for each year of melphalan treatment and that much of this risk will occur within three years of the last treatment.

Topics: Aged; Clinical Trials as Topic; Cyclophosphamide; Female; Humans; Leukemia, Myeloid, Acute; Male; Melphalan; Middle Aged; Models, Biological; Multiple Myeloma; Myelodysplastic Syndromes; Random Allocation; Risk; Time Factors

The effects of pretreatment with cimetidine (200 mg three times daily, 400 mg at night) on the pharmacokinetics of oral melphalan (10 mg) have been investigated in patients with multiple myeloma. Cimetidine pretreatment reduced the bioavailability of oral melphalan by approximately 30% (P less than 0.05). The elimination rate of melphalan from plasma was significantly increased by cimetidine (P less than 0.05), the half-life being reduced from 1.94 +/- 0.55 h to 1.57 +/- 0.53 h. Cimetidine appeared to reduce the interindividual variability in melphalan absorption, but at the cost of reduced bioavailability.

Topics: Administration, Oral; Aged; Biological Availability; Cimetidine; Clinical Trials as Topic; Double-Blind Method; Drug Interactions; Female; Humans; Leukocyte Count; Male; Melphalan; Middle Aged; Multiple Myeloma; Platelet Count

In a randomised multicentre trial a combination of methylprednisolone, vincristine, CCNU, cyclophosphamide and melphalan (MOCCA) was compared with intermittent melphalan and prednisone (MP) as primary treatment in multiple myeloma. In the MP arm the refractory or relapsed patients were treated with regimen MOCCA. The MOCCA arm produced a response rate of 75% among 64 patients and the MP arm a response rate of 54% among 66 patients. The median survival was 41 months in the MOCCA arm and 45 months in the patients primarily randomised to the MP arm. The initial response to MOCCA improved the survival, while this effect was not statistically significant in the MP arm. The results show that the median survival does not increase if aggressive chemotherapy is employed as the first line treatment in multiple myeloma.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Drug Administration Schedule; Female; Humans; Immunoglobulins; Lomustine; Male; Melphalan; Methylprednisolone; Middle Aged; Multiple Myeloma; Prednisone; Vincristine

Topics: Antineoplastic Combined Chemotherapy Protocols; Bone and Bones; Clinical Trials as Topic; Cyclophosphamide; Drug Administration Schedule; Drug Resistance; Humans; Interferon Type I; Interferons; Melphalan; Multiple Myeloma; Prednisone; Radiography; Recombinant Proteins

A randomized, controlled trial was initiated in 1977 to evaluate the impact of three alternative approaches to consolidation and maintenance therapy after initial maximal response for multiple myeloma. All patients were treated initially with BCNU, cyclophosphamide, and prednisone (BCP) until a designated level of response was achieved. Responders were randomly assigned to either melphalan and prednisone (MP); prednisone, Adriamycin (Adria Laboratories, Columbus, Ohio), azathioprine, and vincristine (PAIV), or no therapy until relapse, then treatment with BCP. Initial response rates were comparable with previous trials. A small number of incremental responses were observed with both MP and PAIV. Survival was the same for all three maintenance approaches and the same as that observed in our previous continuous BCP or MP therapy. Additional or consolidation/maintenance therapy of the type administered here appears to offer little advantage once an initial response has been achieved.

Topics: Antineoplastic Combined Chemotherapy Protocols; Azathioprine; Carmustine; Clinical Trials as Topic; Cyclophosphamide; Doxorubicin; Drug Administration Schedule; Humans; Melphalan; Multiple Myeloma; Prednisone; Random Allocation; Risk; Time Factors; Vincristine

Polychemotherapy has improved prognostic parameters of survival in patients with plasmocytoma. The mean survival in patients given long-time prednisone and melphalan treatment is 20 months, in those given polychemotherapy over 30 months. In patients with a slow disease progression the combinations COPP and VMCP give satisfactory results in about 40%, but in a majority of patients more effective treatment is necessary. The authors compare the 5-year survival of two polychemotherapy groups with the prednisone and melphalan group. The mean survival after prednisone and melphalan was 33 months, after polychemotherapy (groups COPP, VMCP) 46 months and 57 months (VMCP + M2), respectively. Survival time was influenced by the clinical stage.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carmustine; Clinical Trials as Topic; Cyclophosphamide; Humans; Melphalan; Multiple Myeloma; Prednisone; Vincristine

Four hundred forty previously untreated patients with active multiple myeloma were entered into a randomized trial (Southwest Oncology Group [SWOG] study 7927/28) comparing vincristine, melphalan, Cytoxan (Mead Johnson & Company, Evansville, Ind), and prednisone (VMCP) alternating with vincristine, BCNU, Adriamycin (Adria Laboratories, Columbus, Ohio) and prednisone (VBAP) with or without levamisole with vincristine, Cytoxan, and prednisone (VCP) with or without levamisole for induction therapy. The treatment groups were well balanced for all of the known major prognostic factors. Patients receiving VMCP-VBAP responded (greater than or equal to 75% regression) more frequently to induction therapy, both without (54%) and with (44%) levamisole v VCP without (28%) or with (28%) levamisole (P less than .001). In addition, patients receiving VMCP-VBAP (+/- levamisole) had a survival duration determined to be significantly increased by all forms of analysis: 48 and 33 months for VMCP-VBAP without and with levamisole v 29 and 26 months for VCP without and with levamisole (P = .011 overall). Levamisole did not improve response rates or survival duration (P greater than or equal to .1), nor did it prolong remission in the maintenance phase (P = .85). Analysis of SWOG study 7704/05 (updated April 1985) confirmed improved survival for combination therapy v MP, but no benefit for levamisole. The overall findings support the use of VMCP-VBAP as an excellent treatment option for remission induction in patients with active myeloma of all stages and prognostic categories.

Topics: Actuarial Analysis; Aged; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Clinical Trials as Topic; Cyclophosphamide; Doxorubicin; Hematologic Diseases; Humans; Levamisole; Melphalan; Multiple Myeloma; Neoplasm Staging; Prednisone; Prognosis; Random Allocation; Vincristine

Four intravenous (IV) alkylating agent regimens were tested in 615 previously untreated patients with multiple myeloma. Patients were randomized to receive melphalan, cyclophosphamide, and carmustine in combination (MCBP), sequentially (Seq-MCBP), or in combination with doxorubicin (MCBPA). The fourth group received IV melphalan (MP) as the only alkylating agent. All groups received a tapering dose of prednisone. Toxicity was similar for all regimens although the nadir of cytopenia was reached more quickly for the regime including melphalan only. Response as measured by reduction in myeloma protein or other parameters were similar for the four treatments. Survival was significantly poorer for the group receiving the alkylating agents in sequence. The survival of high tumor cell load patients who were azotemic was better in the groups treated with IV MP or with the combination of IV MCBP. In view of the simplicity and probable cost savings attached to single-agent treatment, a melphalan/prednisone regimen should be considered as initial therapy for all patients with myeloma.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Clinical Trials as Topic; Cyclophosphamide; Doxorubicin; Drug Hypersensitivity; Female; Humans; Leukocyte Count; Male; Melphalan; Middle Aged; Multiple Myeloma; Myeloma Proteins; Platelet Count

257 untreated myeloma patients (stage II and III) were studied in a multicenter trial. The patients were randomized and received MP or VCMP therapy. No differences in remission rate could be found in both therapy arms. After successful remission induction those patients without maintenance therapy relapsed significantly earlier than those patients receiving maintenance therapy. In pilot studies an etoposide therapy was found ineffective and a multidrug therapy (VBAMDex) could induce high remission rates in high risk and pretreated patients.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carmustine; Clinical Trials as Topic; Cyclophosphamide; Dexamethasone; Doxorubicin; Drug Administration Schedule; Etoposide; Humans; Melphalan; Multiple Myeloma; Neoplasm Staging; Prednisone; Random Allocation; Vincristine

Forty-two previously untreated patients with multiple myeloma were entered in a prospective, randomised trial comparing recombinant interferon alfa-2C monotherapy with VMCP (vincristin, melphalan, cyclophosphamide and prednisolone). Both treatment arms were comparable for the stratification variables such as paraprotein type, stage of disease, and renal function. Rec. interferon effected 14% responses and 29% minor responses, while 57 and 32% of VMCP-treated patients achieved a pathologically documented remission (P less than 0.001). The time on initial treatment was significantly shorter in the IFN group (3.2 months) than in the VMCP group (7.6 months). In four patients in the IFN arm, primary treatment had to be changed according to progressive or severe stationary disease. Since all four patients responded to second line therapy (VMCP) no significant difference has been observed between the two groups in survival (median follow-up greater than 12 months). Despite this clear superiority of the conventional four-drug polychemotherapy, there was some suggestion that IFN might be particularly active in cases with low tumor-burden (stage I, II), and light-chain or IgA paraprotein type.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Cyclophosphamide; Humans; Interferon Type I; Melphalan; Middle Aged; Multiple Myeloma; Neoplasm Staging; Prednisone; Prospective Studies; Random Allocation; Recombinant Proteins; Vincristine

67 previously untreated patients with multiple myeloma were entered on a randomized clinical trial to determine whether the use of combination chemotherapy including vincristine, carmustine, alkylating agents, and prednisone was more effective than conventional therapy with melphalan and prednisone. The treatment groups did not show significant differences with respect to major prognostic factors. With the 2-drug combination therapy and 5-drug combination therapy, 67 and 74% of the patients achieved remission, respectively. Moreover, no significant difference was found between the two treatment schedules in terms of median survival (30+ months). The survival curves for stage III patients treated with the two regimens did not differ significantly. After 12 months, patients who had achieved remission were randomized to have treatment discontinued or to have maintenance treatment. 7 of 15 patients on maintenance therapy relapsed, whereas 9 of 14 patients who had their therapy discontinued relapsed, and the survival of the two groups was similar.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carmustine; Clinical Trials as Topic; Cyclophosphamide; Humans; Melphalan; Multiple Myeloma; Prednisone; Random Allocation; Vincristine

Seventy-five patients with previously untreated multiple myeloma were randomly treated with the association of Peptichemio, Vincristine and prednisone (PTC-VCR-P) or of melphalan and P (MPH-P) for first induction therapy. After induction, all responsive patients received MPH and P until relapse, while unresponsive patients received it until unequivocal evidence of disease progression was observed. A second induction therapy with PTC-VCR-P was then administered, except to patients resistant to this association at first induction (who received combination chemotherapy which included cyclophosphamide and adriamycin). The response rate was 58% in the PTC-VCR-P and 41% in the MPH-P group (P greater than 0.05). The PTC-VCR-P responsive patients experienced a median duration of response shorter than MPH-P responsive patients (20.3 vs 39.7, P = 0.041). Median survival from the start of treatment was 26.2 months in the PTC-VCR-P and 54.1 months in the MPH-P group of patients (P = 0.039). Stage I and II myelomas had the same response rate to PTC-VCR-P and to MPH-P, but their survival was shorter on PTC-VCR-P than on MPH-P (P = 0.014). Stage III myelomas responded more frequently to PTC-VCR-P than to MPH-P (P less than 0.02) and there was a trend to survive longer on PTC-VCR-P than on MPH-P (22.0 vs 12.5 months, P greater than 0.05).

Topics: Antineoplastic Combined Chemotherapy Protocols; Female; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Neoplasm Staging; Peptichemio; Prednisone; Vincristine

In the Medical Research Council's IVth trial in Myelomatosis the possible benefit of adding vincristine to first line treatment with intermittent melphalan and prednisone has been assessed. This was analysed in 530 patients who were randomly allocated to receive vincristine or not. Survival was not improved by the addition of vincristine. A total of 268 patients reached plateau phase on first line therapy. Of these 226 patients were rerandomised either to continue receiving first line therapy for a further year or to cease therapy. At the present time there is a slight but not significant survival advantage in the group which received no further treatment on reaching plateau.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Humans; Melphalan; Middle Aged; Multiple Myeloma; Prednisone; Prognosis; Random Allocation; Vincristine

To determine the impact of age upon the response to treatment, survival, and toxicity of chemotherapy for multiple myeloma, the results of a large cooperative group trial were examined. Patients were randomly assigned to induction therapy with either carmustine, cyclophosphamide, and prednisone or melphalan and prednisone; patients with response received two years of treatment. The age distribution of patients in this trial compared with the incidence figures from the Surveillance Epidemiology and End Results (SEER) study shows a degree of under-representation of the oldest patient groups. Prognostic factors were evenly distributed over the age range and treatment groups. Older patients had responses and survival rates equivalent to younger patients and with both treatment regimens regardless of prognostic factor characteristics. Hematologic toxicity was no greater for the older group in either regimen despite the presence of a nitrosourea in one. Gastrointestinal toxicity was increased in the older patients who received the regimen of melphalan and prednisone. The study suggests that in myeloma and perhaps other such chemotherapy-responsive malignancies treated with moderately intense chemotherapy, without bone marrow ablation, elderly and younger patients have similar outcomes.

Topics: Adult; Age Factors; Aged; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Clinical Trials as Topic; Cyclophosphamide; Humans; Melphalan; Middle Aged; Multiple Myeloma; Prednisone; Prognosis

The results of an Italian multicentric trial for treatment of symptomatic Multiple Myeloma (MM) are reported. One hundred and thirty-three previously untreated patients were singled out at random for three different chemotherapy schedules: Melphalan plus Prednisone (M.P.) X 6 monthly cycles; Vincristine plus Melphalan plus Cyclophosphamide plus Prednisone (VMCP) X 6 monthly cycles; Peptichemio, Cyclophosphamide, BCNU. Drugs in this latter schedule were administered sequentially, for a period of six months. Criteria for response, progression and relapse were those of the Southwestern Oncology Group. Fifteen patients in MP chemotherapy (35%) and 20 patients in VCMP chemotherapy (46%) achieved an objective response (decrease of at least 50% in the synthesis index of Monoclonal Component (M.C.], while only 3 out of the other 21 patients assigned to the third schedule responded to treatment. No significant differences were noted in the survival curves in either of the three treatment groups. The 38 responding patients did not receive maintenance therapy; no significant difference was found in remission duration between patients in MP and VCMP arms, with a median duration of 16 months for the whole group. No statistical difference was observed between survival and remission curves of patients with a 'response' (M. spike reduction greater than 75%) and those with 'improvement' (M. spike reduction between 75 and 50%). The authors conclude that the inclusion of Vintristine in a combination chemotherapy does not produce clear survival benefits; a longer induction period (12 cycles) could allow a better differentiation between MP and VMCP regimens.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bence Jones Protein; Carmustine; Clinical Trials as Topic; Cyclophosphamide; Drug Administration Schedule; Female; Humans; Immunoglobulin A; Immunoglobulin D; Leukopenia; Male; Melphalan; Middle Aged; Multiple Myeloma; Peptichemio; Prednisone; Prognosis; Random Allocation; Vincristine

A one-armed multicentre trial was conducted in Finland during the period from Jan. 1979 to Feb. 1980 to document the possible beneficial effect of aggressive combination chemotherapy MOCCA on the remission induction and survival in multiple myeloma. The regimen MOCCA consisted of vincristine, methylprednisolone and 3 alkylating agents. Of the 50 patients eligible for the for study, 39 (78%) achieved at least a 50% response. 27 (54%) achieved an excellent response. The median survival time for all patients was 49 months from the initiation of the treatment, but 23 of the 33 patients whose myeloma protein had shown a greater than or equal to or greater than or equal to 75% reduction were still alive at 4 yr. Advanced clinical stage and irreversible renal damage had a negative prognostic value. After 12 months on regimen MOCCA the patients with a greater than or equal to or greater than or equal to 75% reduction in myeloma protein were allocated at random to receive MOCCA courses bimonthly or no further chemotherapy. The maintenance chemotherapy did not prolong remission or survival.

Topics: Adult; Aged; Clinical Trials as Topic; Cyclophosphamide; Female; Humans; Lomustine; Male; Melphalan; Methylprednisolone; Middle Aged; Multiple Myeloma; Prognosis; Vincristine

A prospective randomized trial in 96 patients with previously untreated myelomatosis was performed comparing 3 regimens of chemotherapy: (i) Intermittent vincristine, BCNU, cyclophosphamide, melphalan, and prednisone (VBCMP) to (ii) intermittent vincristine, melphalan and prednisone (VMP) to (iii) intermittent melphalan and prednisone (MP). Induction response rates and survival were similar in all 3 regimens. An improvement in relapse-free survival was observed by adding vincristine to MP, but this did not achieve statistical difference (p = 0.10). Patients given VBCMP fared slightly worse than those given VMP. The haematologic toxicity was similar in all 3 regimens, but the tolerability of VBCMP was lower. Although showing no statistical differences between the 3 treatment regimens, the results support the view that a combination of MP 'standard' induction therapy in MM with frequently administered vincristine has a trend towards postponing treatment failure due to development of resistance to melphalan.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Clinical Trials as Topic; Cyclophosphamide; Drug Resistance; Female; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Prednisone; Vincristine

The effect of recombinant interferon-alpha-2C monotherapy was compared with the efficacy of VMCP-polychemotherapy in 42 patients with multiple myeloma in a prospective randomized multicenter trial. IFN-treatment induced remissions (R) in 2 (14%) and partial remissions (PR) in 4 (29%) out of 14 evaluable patients. 7 patients remained stable. Polychemotherapy induced R in 11 (57%) and PR in 6 (32%) of 19 evaluable patients. 2 (11%) patients remained stable. IFN was preferentially active in patients with low tumor burden and patients with IgA paraprotein. The proportion of responders (R + PR) was significantly lower in the IFN-arm (43%) compared to the polychemotherapy group (89%; p less than 0,001).

Topics: Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Combined Modality Therapy; Cyclophosphamide; Humans; Interferon Type I; Melphalan; Multiple Myeloma; Prednisone; Prospective Studies; Random Allocation; Recombinant Proteins; Vincristine

Thirty-two evaluable good risk patients with multiple myeloma received a 70-day tapering course of prednisone beginning at a dose of 1.2 mg/kg/day. Forty-four percent of the patients demonstrated objective evidence of response to this treatment. Although the median time to disease progression for the prednisone-treated group was shorter than for patients randomized to receive prednisone with alkylating agents or who were treated with alkylating agent alone, the results from this trial indicate that prednisone, by itself, may produce objective responses. Caution must be used interpreting trials of new agents in myeloma when such treatments are combined with corticosteroid administration.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carmustine; Female; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Prednisone; Prognosis; Random Allocation; Recurrence

During March 1980 to February 1982, 73 out of 80 patients in renal failure admitted to the fourth MRC myelomatosis trial were managed by a planned policy of high fluid intake (greater than or equal to 3 1/24 h) in addition to receiving one of the two chemotherapeutic regimens being tested in the main trial. Patients were also randomised to receive either sodium bicarbonate to render their urine neutral or no supplement. Follow up continued till death or to April 1983. Of 49 patients who survived more than 100 days, 39 achieved reversal of their renal failure (18 complete, 21 partial). Recovery of renal function, as assessed by a fall in the serum creatinine concentration, was achieved even when light chain proteinuria persisted. Partial recovery of renal function was associated with prolonged useful life in several patients. In only 14 of the 80 patients studied was death directly attributable to renal failure. Survival of patients in the study was appreciably better than in equivalent groups of patients in other MRC trials in which less stringent policies of fluid intake were used. Patients randomised to receive alkali fared marginally better than the others, but the difference was not significant. These results show that in many cases patients with myelomatosis who develop renal failure may have this complication reversed by taking a high fluid intake. Furthermore, though light chain is an essential component of renal disease in these patients, other factors are also important and are accessible to treatment.

Topics: Acute Kidney Injury; Adult; Aged; Bicarbonates; Clinical Trials as Topic; Cyclophosphamide; Fluid Therapy; Humans; Melphalan; Middle Aged; Multiple Myeloma; Sodium Bicarbonate; Vincristine

The effects of eight different drug combinations were evaluated in 256 patients with multiple myeloma. The response rate and time to remission were superior from regimens that added both vincristine and Adriamycin (doxorubicin) to an alkylating agent-prednisone combination. There was no improvement in response rate or survival time from two alternating drug combinations evaluated in an attempt to achieve more marked tumor reductions and to delay the emergence of resistant subclones. The addition of levamisole during remission maintenance did not improve survival time. Results supported the utility of unmaintained remission follow-up in selected patients with marked reductions in myeloma cell mass.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carmustine; Clinical Trials as Topic; Cyclophosphamide; Doxorubicin; Drug Administration Schedule; Humans; Levamisole; Melphalan; Multiple Myeloma; Prednisone; Prognosis; Random Allocation; Vincristine

The 2-cyanaziridin derivative, azimexon (E), has previously been shown to have certain immunomodulatory properties. In particular, the induction of leukocytosis, the stimulation of delayed-type hypersensitivity reactions and the synergistic effect of azimexon and antibiotics in the control of lethal bacterial and fungal infections in mice prompted us to test azimexon as an adjuvant to chemotherapy in 14 myeloma patients. In a randomized double-blind cross-over study 3 X 600 mg of azimexon were added to one of two consecutive, identical chemotherapy courses consisting of melphalan/prednisone (MP) or vincristine/cyclophosphamide/melphalan/prednisone (VCMP). Chemotherapy was given during days 1-4 and azimexon or placebo were added on days 6, 10 and 14. Blood counts and natural killer (NK) cell testing were performed on days 0 and 21 of each course. With the exception of a transient taste irritation in two patients, azimexon caused no subjective side-effects. White blood cell counts were not altered by the drug; red blood cells and hemoglobin showed a borderline depression after azimexon. NK activities measured against three target cell lines (K562, IGR3, L1210) tended to increase after azimexon treatment. When added in vitro to NK assays azimexon caused a slight increase of NK activity at concentrations of 0.01-0.25 mu/ml, whereas concentrations above 1 microgram/ml were inhibitory. The increase of NK activity by azimexon was not due to the induction of interferon in the effector lymphocyte population.

Topics: Adjuvants, Immunologic; Aziridines; Azirines; Clinical Trials as Topic; Cyclophosphamide; Double-Blind Method; Humans; Killer Cells, Natural; Leukocyte Count; Melphalan; Multiple Myeloma; Prednisone; Vincristine

In a randomized study with 234 previously untreated patients with multiple myeloma, 129 were treated with melphalan (8 mg/m2 perorally for four days) and prednisone (40 mg/m2 perorally for seven days, both every four weeks) and 105 with melphalan and prednisone at the same doses plus cyclophosphamide (600 mg/m2 intravenously every four weeks), MeCCNU (100 mg/m2 PO every eight weeks), and vincristine (MPCCV, 0.6 mg/m2 IV every four weeks). A total of 49 (38%) of the 129 patients treated with melphalan and prednisone (MP) and 48 (46%) of the 105 patients treated with MPCCV showed good response (GR) (P not significant); the overall response rates were 58% and 70%, respectively. Thirty-seven percent of the MP group and 39% of the MPCCV group remain alive at 48 months from first treatment (P not significant). The estimated 48-month survival from first treatment, according to different prognostic factors at diagnosis, in both groups was as follows: stage 1,56%; stage II, 46%, and stage III, 23% (I and II v III P less than .001). Survival at 48 months according to response was GR, 68%; partial response (PR), 33%; and null, 16% (GR v null, P less than .0005; GR v PR, P less than .0005). Survival according to renal function was 43% for a creatinine level less than 2 mg/100 mL and 27% for a creatine level greater than or equal to 2 mg/100 mL (P less than .0005). No significant difference has been found between the two treatment schedules in terms of response rate and survival time, in any stage of disease.

Topics: Antineoplastic Combined Chemotherapy Protocols; Blood Proteins; Clinical Trials as Topic; Cyclophosphamide; Humans; Immunoglobulins; Melphalan; Multiple Myeloma; Myeloma Proteins; Neoplasm Staging; Prednisone; Random Allocation; Semustine; Time Factors; Vincristine

In a randomized clinical trial intermittent high-dose melphalan/prednisone (MP) treatment has been compared with human leukocyte interferon (IFN) administration. Three to 6 X 10(6) IU of IFN was given im daily. Therapy was continued to progression of the disease. Fifty-five patients were randomized to receive MP and 75 were randomized to receive IFN. Forty-four percent of the patients receiving MP responded to therapy as opposed to only 14% of the patients receiving IFN (P less than 0.001). This difference was mainly due to a low response rate in IFN-treated IgG myelomas, while the response rate for IgA and Bence Jones myelomas did not differ significantly between the two treatment groups. Median duration of response was shorter for IFN-responding patients (23 months) as compared to patients in the MP group (35 months). During follow-up, second-line therapy was given more frequently in the IFN group (91%) than in the MP group (59%). Time on initial treatment was significantly shorter in the IFN group (3 months) than in the MP group (19 months). Since more patients responded to second-line therapy in the IFN group than in the MP group, total survival did not differ significantly between the two groups.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Female; Humans; Immunoglobulins; Interferon Type I; Male; Melphalan; Middle Aged; Multiple Myeloma; Prednisone; Random Allocation

Thirty-five previously untreated patients with multiple myeloma were treated with a 60-week course of alternating, potentially non-cross-resistant chemotherapy combinations (melphalan and prednisone; vincristine, cyclophosphamide, doxorubicin, and prednisone; and carmustine, melphalan, and prednisone), alternating every 15 weeks in an attempt to prevent the development of drug resistance. The overall objective response rate (greater than 50% decrease in M protein) was 60% and six patients (17%) had a complete disappearance of the M protein. After 60 weeks, chemotherapy was discontinued in 17 responding or stable patients until relapse occurred from 4 to 39 months later (median, 12 months). Patients relapsing late (greater than 12 months after discontinuation of therapy) responded more frequently than those relapsing earlier to the reinstitution of the same chemotherapy program. The overall response rate and the actuarial median survival of 26 months in the 35 patients do not differ from the results reported recently with nonalternating combinations given until clinical tumor progression. The failure of this study to prolong survival by using alternating regimens may be due to (a) the likely possibility that the initial two regimens are not actually non-cross-resistant in most myeloma patients, and (b) the long interval between the alternating regimens, particularly in the face of the low response rate to the initial regimen of melphalan and prednisone.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Clinical Trials as Topic; Cyclophosphamide; Doxorubicin; Drug Resistance; Female; Follow-Up Studies; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Myeloma Proteins; Neoplasm Staging; Prednisone; Vincristine

A randomized controlled trial was initiated in 1972 to compare two chemotherapeutic regimens [1-3-bis (2-chloroethyl) 1-nitrosourea (BCNU), cyclophosphamide, and prednisone versus melphalan and prednisone], to determine whether the two regimens are cross-resistant, and to evaluate the effectiveness of sodium fluoride, vitamin D, calcium gluconate, and fluoxymesterone in the promotion of bone healing. Initial responses (50%) and survival (36 mo median) for patients treated with the two chemotherapeutic regimens were the same. Patients on either regimen who failed to respond after 6 mo had a very low response rate to the alternative regimen (approximately 10%). Initially responding patients were randomly assigned to either an active drug regimen (sodium fluoride, vitamin D, calcium gluconate, fluoxymesterone) or placebo tablets. There was no significant difference in the low percentage of patients demonstrating bone improvement. Thus, the BCNU, cyclophosphamide, prednisone regimen is as effective as melphalan and prednisone. Fluoride, calcium, vitamin D, and androgenic steroids should not be routinely recommended in myeloma, as they seem to add little to effective chemotherapy and may contribute to morbidity.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Calcium Gluconate; Carmustine; Clinical Trials as Topic; Cyclophosphamide; Drug Resistance; Drug Therapy, Combination; Fluoxymesterone; Humans; Long-Term Care; Melphalan; Multiple Myeloma; Prednisone; Radiography; Sodium Fluoride; United States; Vitamin D

Topics: Antineoplastic Combined Chemotherapy Protocols; Carmustine; Cyclophosphamide; Female; Humans; Male; Melphalan; Multiple Myeloma; Prednisone; Vincristine

Patients with newly diagnosed multiple myeloma were randomly allotted to an intermittent high-dose melphalan/prednisone (MP) treatment (120 patients) or a continuous low-dose melphalan (M) regimen (99 patients). The median observation time was 59 months (range 33-84). Response to therapy was obtained in 45% of the MP group and 31% of the M group (P less than 0.05). No significant difference in response with regard to clinical stage was noted. Median survival was 36 months in the MP group and 29 months in the M group. Survival was longer in stage I and II myeloma than in the stage III cases, at least in the MP group. The median and 5-yr survival rates in stages I and II were significantly better in the MP than in the M group. Response to therapy was associated with length of survival, median survival being 62 months in responding patients and 20 months in non-responders. The MP and M groups did not differ in this respect.

Topics: Adult; Age Factors; Aged; Clinical Trials as Topic; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Neoplasm Staging; Prednisone; Prospective Studies

The pharmacokinetics of melphalan have been studied after intravenous and oral dosing (10 mg) in 6 patients with multiple myeloma. After intravenous administration, mean plasma t0.5 alpha was 8.0 +/- 2.3 min, t0,5 beta was 63.3 +/- 8.7 min, and total systemic clearance was 510.4 +/- 57.9 ml/min. After oral administration, the drug was rapidly absorbed (lag-time = 18.4 +/- 3.7 min, absorption rate constant = 0.0547 +/- 0.0166 min-1, Tmax = 59.3 +/- 6.6 min), but there was considerable variation in its bioavailability (61.5 - 102.0% mean 78.3 +/- 6.3%). Variability in drug absorption may be responsible, at least in part, for variation in response to this drug.

Topics: Administration, Oral; Adult; Aged; Humans; Injections, Intravenous; Kinetics; Male; Melphalan; Middle Aged; Multiple Myeloma

A prospective randomized trial in patients with previously untreated multiple myeloma was performed comparing carmustine (BCNU), cyclophosphamide, and prednisone (BCP) to melphalan (Alkeran) and prednisone (AP). Induction response rates, remission duration, and survival were similar with both regimens. Hematologic toxicity was greater with AP. Crossover studies in patients who relapsed did not illustrate any significant activity with either drug treatment program. Therefore, BCP can be utilized as initial therapy in myeloma because of comparable remission rates and less hematologic toxicity.

Topics: Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Clinical Trials as Topic; Cyclophosphamide; Drug Therapy, Combination; Female; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Prednisone; Prognosis; Prospective Studies; Random Allocation

Sixty-five patients with multiple myeloma resistant to melphalan were randomized to receive cyclophosphamide, doxorubicin (Adriamycin), and prednisone (CAP) (30 patients) or carmustine (BCNU), doxorubicin, and prednisone (BAP) (35 patients). Objective responses occurred in two patients in the CAP group and in seven in the BAP group. Indirect responses were noted in seven additional patients in the CAP group and in six additional patients in the BAP group. Toxic effects consisted mainly of leukopenia and thrombocytopenia. Median survival did not differ between the two treatment groups (CAP, 8.4 months; BAP, 7.7). Objective responders had a longer survival than nonresponders (14.5 vs 7.7 months).

Topics: Aged; Antineoplastic Agents; Carmustine; Cyclophosphamide; Doxorubicin; Drug Resistance; Drug Therapy, Combination; Female; Humans; Leukopenia; Male; Melphalan; Middle Aged; Multiple Myeloma; Prednisone; Random Allocation; Thrombocytopenia

The influence of renal insufficiency on melphalan-induced myelosuppression was examined during the initial 10 weeks of treatment in 295 patients with multiple myeloma. Patients were randomized to receive either oral melphalan (0.15 mg/kg/day for 7 days, followed by 0.05 mg/kg/day after recovery from the wbc count nadir) or iv melphalan (16 mg/m2 every 2 weeks for four doses, followed by a single dose every 4 weeks). All patients received a 6-week tapering course of prednisone. Patients with renal insufficiency (BUN greater than or equal to 30 mg/100 ml) had a significantly higher frequency of severe leukopenia (less than or equal to 1000 cells/mm3) following iv melphalan than did patients with normal renal function (50% vs 15%, respectively; P = 0.007). The latter effect resulted in an increased frequency of drug-related deaths secondary to infection. The frequency of severe thrombocytopenia (less than or equal to 25,000 cells/mm3) was also greater in patients with renal failure following iv melphalan therapy. Reduction of iv melphalan dose to 50% in patients with elevated BUN reduced the frequency of these complications to levels that were not significantly different from those observed in patients with normal renal function. The frequency of severe myelosuppression was independent of renal function in patients receiving oral melphalan. Possible explanations for these findings are discussed.

Topics: Blood Urea Nitrogen; Bone Marrow; Humans; Kidney; Kidney Diseases; Leukopenia; Melphalan; Multiple Myeloma; Random Allocation; Thrombocytopenia

A total of 361 evaluable patients with previously untreated multiple myeloma were randomized to receive oral melphalan (0.15 mg/kg/day for seven days, followed by 0.05 mg/kg/day after recovery from the nadir of the leukocytes), BCNU (150 mg/m2 intravenously every six weeks) or CCNU (100 mg/m2 orally every six weeks). All patients received a tapering six-weeks) or CCNU (100 mg/m2 orally every six weeks). All patients received a tapering six-week course of prednisone starting at 0.8 mg/kg for the first two weeks. At week 22, one-half of the patients were randomized to receive vincristine (1 mg/m2) and prednisone (0.6 mg/kg for seven days) every two months in addition to previous therapy. The melphalan treated patients showed a significantly higher overall objective response frequency (59%), according to Myeloma Task Force criteria, when compared to those treated with BCNU (40%) or CCNU (42%). The survivals for all patients were not statistically different for the three treatment programs. However, the good-risk patients treated with melphalan had significantly longer survival (P = 0.02) than the equivalent patients who received BCNU or CCNU. The addition of vincristine and prednisone at week 2 did not significantly increase the percentage of subsequent objective responses or prolong the subsequent survival of any treatment group. It is concluded that oral melphalan is superior to BCNU and CCNU in producing objective responses and in prolonging survival in good risk patients.

Topics: Antineoplastic Agents; Carmustine; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Leukopenia; Lomustine; Male; Melphalan; Middle Aged; Multiple Myeloma; Prednisone; Random Allocation; Thrombocytopenia; Vincristine

Topics: Adult; Aged; Clinical Trials as Topic; Drug Therapy, Combination; Female; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Peptichemio; Prednisone

Topics: Adult; Aged; Antineoplastic Agents; Carmustine; Clinical Trials as Topic; Cyclophosphamide; Drug Therapy, Combination; Female; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Prednisone; Vincristine

Topics: Carmustine; Clinical Trials as Topic; Cyclophosphamide; Drug Therapy, Combination; Humans; Melphalan; Multiple Myeloma; Prednisone; Vincristine

Of 139 evaluable and previously untreated patients with multiple myeloma, 67 received methyl-CCNU-cyclophosphamide-prednisone (group A) and 72 received melphalan-prednisone (group B); 48% and 33% respectively had good responses and the overall response rates (good plus partial) were 75% and 65% for groups A and B respectively. The survival curves for both groups of patients were similar, with a median survival of 32 months. At 36 months, 70% of those patients who obtained good response were alive, 29% of those with partial response were alive, and 13% of those with no response were alive. The clinical staging system described by Durie and Salmon shows a good prognosis for stage I patients, with 80% remaining alive at 48 months, while the survival curves for stage II and III patients were similar, with 33% and 28% respectively remaining alive at 48 months. The combination of methyl-CCNU-cyclophosphamide-prednisone is not more effective in terms of response rate or duration of survival than melphalan-prednisone.

Topics: Adult; Aged; Antineoplastic Agents; Clinical Trials as Topic; Cyclophosphamide; Drug Therapy, Combination; Humans; Melphalan; Middle Aged; Multiple Myeloma; Neoplasm Staging; Prednisone; Prognosis; Semustine; Time Factors

Three hundred and seventy-two patients were randomized between 3 regimens of chemotherapy: cyclophosphamide, intermittent melphalan, and melphalan with prednisone, and were followed up to death or for at least 5 years. There was no difference in survival between the treatments, either overall or in any subgroup of patients. Therefore, the choice among these 3 treatments should be guided by the patient's comfort and convenience. The most important prognostic feature at presentation was the quality of renal function. It was possible to define good, intermediate and poor renal-function groups which were highly correlated with prognosis (X2 for trend = 62.6). The haemoglobin level at presentation was strongly correlated with prognosis among patients in the good renal-function group. Among 107 patients who presented with good renal function and with haemoglobin above 100 g/l, the 5-year survival was 43%. Other prognostic features were much less important when account was taken of renal function and haemoglobin level.

Topics: Aged; Clinical Trials as Topic; Cyclophosphamide; Drug Therapy, Combination; Follow-Up Studies; Hemoglobinometry; Humans; Immunoglobulin M; Kidney Diseases; Melphalan; Middle Aged; Multiple Myeloma; Prednisone; Prognosis; Proteinuria; Urea

Results after an average follow-up of 3 years are presented on 485 patients in the 3rd MRC therapeutic trial in myelomatosis. The 353 non-azotaemic patients (199 now dead) were randomized between i.v. cyclophosphamide (CY) and oral melphalan with prednisone (M & P). THose treated with M & P fared slightly, but non-significantly, better. The 132 azotaemic patients (111 now dead) were randomized between i.v. CY and a 4-drug regimen, and both groups fared equally badly. Finally, after one year of the allocated treatment, 297 survivors (126 now dead) were randomized either to stop all treatment until evidence of relapse was obtained, or to continue treatment with azathioprine and vincristine, interrupted every 3 months for a course of the first-allocated treatment. The overall results suggested that maintenance therapy was beneficial, though the results were not statistically significant. Most of the difference was found among the few patients with unfavourable prognostic features who survived one year and were eligible for this randomization. In this, as in the two previous MRC trials, no striking differences have emerged between the therapeutic effects of different schedules of melphalan and/or CY. Consequently, a regimen of intermittent oral melphalan (with or without prednisone) seems satisfactory, because it is among the least toxic and most convenient. The 4th myeloma trial, now beginning, seeks to discover whether the addition of vincristine to the regimen can improve these results.

Topics: Aged; Clinical Trials as Topic; Cyclophosphamide; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Lomustine; Male; Melphalan; Middle Aged; Multiple Myeloma; Prednisone; Prognosis; Uremia

Topics: Adult; Aged; Bence Jones Protein; Clinical Trials as Topic; Cyclophosphamide; Drug Evaluation; Female; Humans; Immunoglobulin kappa-Chains; Immunoglobulin lambda-Chains; Immunoglobulin Light Chains; Male; Melphalan; Middle Aged; Multiple Myeloma

Ten patients developed allergic reactions to iv melphalan (L-PAM) during therapy for multiple myeloma. The incidence of such reactions was 2.4% among 425 patients receiving iv L-PAM with or without other drugs and 3.9% among 255 patients receiving iv L-PAM alone. Only one such reaction was demonstrated in 294 patients who initially received oral L-PAM. The median day of first reaction to iv L-PAM was Day 222 (range, Days 44-909) and the median total dose prior to a reaction was 185 mg (range, 51-250 mg). Of five patients who subsequently received oral L-PAM, four developed a reaction similar to that experienced with the iv drug.

Topics: Administration, Oral; Aged; Drug Hypersensitivity; Female; Humans; Infusions, Parenteral; Injections, Intravenous; Male; Melphalan; Middle Aged; Multiple Myeloma

Two hundred fifty-two previously untreated evaluable patients with multiple myeloma were entered into a study testing a regimen of three intravenous alkylating agents, melphalan, cyclophosphamide, and carmustine (BCNU), given in combination (BCMP) against a regimen employing oral melphalan (MP). Both regimens included a tapering course of prednisone. Objective responses based on the Myeloma Task Force criteria were significantly more frequent in the group receiving BCMP. Survival for the entire group of BCMP-treated patients was not significantly better than that for MP-treated patients (p = 0.62). However, when the survival of the poor-risk (high tumor cell load) group of patients treated with BCMP was compared with the survival of the poor-risk (high tumor cell load) group of patients treated with MP, an improvement in survival attributable to BCMP therapy was seen (p = 0.049 and 0.02, respectively). In the good-risk (low and intermediate tumor cell load) group, BCMP treatment resulted in a trend toward poorer survival, but this did not achieve statistical significance (p = 0.080 and 0.23, respectively). These results indicate that optimal therapy in myeloma may be dependent on the extent of disease at the time of first treatment. Additional studies to explore the effects of treatment intensity and duration are needed in order to design improved myeloma treatment based on the patient's extent of disease.

Topics: Alkylating Agents; Carmustine; Cyclophosphamide; Drug Therapy, Combination; Humans; Leukopenia; Melphalan; Multiple Myeloma; Prednisone; Prognosis

Eighty-nine patients with multiple myeloma resistant to melphalan were randomized to receive cyclophosphamide plus prednisone (CP) (47 patients) or cyclophosphamide plus BCNU plus prednisone (CBP) (42 patients). No differences were detected in the two groups prior to therapy. Objective responses occurred in three (7%) of the CP patients and in seven (17%) of the CBP patients. About 40% of the patients in each group achieved some response. Toxic reactions consisted mainly of leukopenia and thrombocytopenia. Median survival was not different in the two groups. The median survival time was 31 months among those patients with an objective response and 9.4 months among those without an objective response. The addition of BCNU to CP increased the frequency of objective response, but not significantly. This triple combination (CBP) cannot be recommended.

Topics: Carmustine; Cyclophosphamide; Drug Resistance; Drug Therapy, Combination; Humans; Melphalan; Multiple Myeloma; Prednisone

Previously untreated patients with myeloma were randomized to initial treatment with melphalan and prednisone (and to cyclophosphamide or carmustine if relapse or progression occurred)(Group A, 125 patients), melphalan, cyclophosphamide, carmustine and prednisone in alternating (Group B, 123 patients) or concurrent (Group C, 116 patients) schedules. The groups were similar with respect to known prognostic factors. Response rates and survival were also similar. We were unable to identify a subgroup of patients who responded or survived better on melphalan-cyclophosphamide-carmustine and prednisone than on melphalan and prednisone. We conclude that the combination of the four drugs is not better than melphalen and prednisone for inducing responses or prolonging the survival of patients with myeloma. Myelomas producing only gamma chains have a poorer prognosis (P greater than 0.001) than IgG, IgA, or kappa myeloma. Acute leukemia has developed in 14 patients. The actuarial risk of developing acute leukemia, has increased rapidly to 17.4 per cent at 50 months.

Topics: Acute Disease; Adult; Aged; Alkylating Agents; Carmustine; Cyclophosphamide; Drug Therapy, Combination; Female; Humans; Immunoglobulins; Leukemia; Male; Melphalan; Middle Aged; Multiple Myeloma; Prednisone; Prognosis; Prospective Studies; Risk

The effect of six different chemotherapy regimens were evaluated in 462 previously untreated patients with multiple myeloma. In comparison with other treatments, drug combinations that included vincristine and were given at 3-week intervals were associated with higher response rates and longer survival times. No gain was noted from the use of Adriamycin or from combinations of alkylating agents unless vincristine was given and the treatment intervals were short. Seventy-one responding patients were allocated at random to maintenance treatment with intermittent courses of either azathioprine--prednisone or a combination of melphalan--cyclophosphamide--carmustine (BCNU)--prednisone. The survival time was not prolonged with either maintenance treatment in comparison with that for responding patients continued on other therapies or on no therapy in previous studies. Attempts to reduce tumor was maximally with a change in the therapeutic modality, such as with immunotherapy or radiotherapy, remain to be evaluated.

Topics: Antineoplastic Agents; Azathioprine; Carmustine; Cyclophosphamide; Doxorubicin; Drug Therapy, Combination; Female; Humans; Male; Melphalan; Multiple Myeloma; Prednisone; Remission, Spontaneous; Time Factors; Vincristine

The authors report the results obtained from the treatment of 13 cases of myeloma by cyclic chemotherapy (melphalan) applied after cellular synchronization with vincristine. The clinical results (maximum 2 years after treatment) were good in 11 cases out of 13. The following laboratory values quickly returned to normal: sedimentation and calcaemia, but there was little change in the immunoglobulins.

Topics: Aged; Anemia; Blood Sedimentation; Bone Neoplasms; Clinical Trials as Topic; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Hypercalcemia; Male; Melphalan; Middle Aged; Mitosis; Multiple Myeloma; Pain; Periodicity; Vincristine

Topics: Aged; Bence Jones Protein; Clinical Trials as Topic; Cyclophosphamide; Diagnosis, Differential; Drug Evaluation; Drug Therapy, Combination; Female; Humans; Kidney Neoplasms; Melphalan; Multiple Myeloma; Nitrosourea Compounds

A randomized double-blind study was carried out in 26 patients with multiple myeloma to compare the therapeutic effect of sodium fluoride (50 mg twice daily) plus calcium carbonate (1 g four times daily) and placebo. All patients also received melphalan and prednisone for one week every six weeks. Bone biopsies for microradiography and histology, and videodensitometry as well as conventional roentgenograms, 99mTc-polyphosphate bone scans, and bone densitometry of the mid and distal radius, were done initially and one year after therapy. Microradiography and videodensitometry studies revealed significant increases in bone formation (P less than 0.01) and bone mass (P less than 0.005) in the fluoride-calcium group. Bone trabeculae appeared thickened on roentgenograms of six of 13 fluoride-calcium-treated patients (P less than 0.02). Technetium bone scans and bone densitometry determinations proved insensitive for detection of skeletal changes. Fluoride calcium should be considered a useful adjunct in the treatment for multiple myeloma.

Topics: Bone and Bones; Bone Diseases; Calcium Carbonate; Clinical Trials as Topic; Fluorides; Humans; Melphalan; Multiple Myeloma; Osteosclerosis; Prednisone; Prospective Studies

The effects of various regimens of melphalan combination chemotherapy were evaluated in 508 patients with multiple myeloma. No value was confirmed from the addition of procarbazine or vincristine sulfate to melphalan-prednisone combinations. Ninety-six patients who responded to treatment were allocated at random to one of three maintenance regimens, namely intermittent courses of carmustine with prednisone, continued courses of melphalan with prednisone, or no chemotherapy. There were no differences in the frequency of relapse, the remission duration, or the survival time among these maintenace groups. The frequencies of pneumonia and herpes zoster were higher in patients receiving continued chemotherapy. Continued melphalan-prednisone chemotherapy after the first year is of no major value to responding patients with multiple cyeloma. Attempts to reduce tumor mass maximally with a change in therapy are justified.

Topics: Bone Neoplasms; Carmustine; Drug Therapy, Combination; Female; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Prednisone; Procarbazine; Recurrence; Remission, Spontaneous; Time Factors; Vincristine

A randomized study compared the response of patients with multiple myeloma to chlorambucil, melphalan, and azathioprine. All patients also received a combination of prednisone and fluoxymesterone. Seventy-three of 86 patients entered on the study could have evaluations. The results indicate that melphatan produced more responses than either azathioprine or chlorambucil, but responses to both of these agents were observed. No difference was noted between survival curves for patients with no poor-risk factors as compared to those having at least one poor-risk factor. The only poor-risk factor affecting survival in this group of patients was the blood urea nitrogen level.

Topics: Azathioprine; Blood Urea Nitrogen; Bone Neoplasms; Chlorambucil; Drug Therapy, Combination; Fluoxymesterone; Humans; Melphalan; Multiple Myeloma; Prednisone; Remission, Spontaneous; Risk; Time Factors

A timed sequential chemotherapeutic regimen for multiple myeloma was desinged, based on plasma cell kinetics. A randomized study comparing this regimen with the combination of intermittent melphalan and prednisone was started after an adequate pilot study. Studies with tritiated thymidine labeling and mitotic indexes were performed on patients treated with sequential therapy. Of 13 patients treated with the combination therapy, the responses were as follows: two, objective improvement; nine, subjective improvement; and two, no responses. Of nine patients treated with sequential therapy, the responses in six patients who could have evaluations were as follows: one, objective improvement; two, subjective improvement; one, no response; one, with progressive disease; and one, cardiac death. The two studies showed differences in pertubation of cell kinetics of myeloma that may be related to exponential growth and immunoblobulin types.

Topics: Autoradiography; Bence Jones Protein; Bone Neoplasms; Cell Count; Drug Therapy, Combination; Humans; Immunoglobulins; Kinetics; Melphalan; Methotrexate; Mitosis; Multiple Myeloma; Plasma Cells; Prednisone; Risk; Thymidine; Time Factors; Tritium; Vincristine

The effect of certain disease parameters on remission and survial time was evaluated in 482 patients with multiple myeloma treated with intermittent courses of melphalan-prednisone combinations. Increasing degrees of anemia, hypercalcemia, azotemia, and high serum myeloma protein levels were associated with progressive lifespan shortening. The short survival of patients with anemia and hypercalcemia was associated with short remissions in responding patients with these abnormalities. The extent of tumor mass was defined from specific laboratory parameters reported by Durie to be associated with large numbers of plasma cells. More advanced stages of myeloma were associated with higher frequencies and degrees of normal immunoglobulin depression. The response rate was not affected by the tumor mass grade, but increasing tumor mass was associated with a shorter lifespan. Greater degrees of tumor reduction were associated with longer remission and survival times. Patients in whom a marked tumor reduction was rapid had shorter survival and remission times than patients who responded more slowly.

Topics: Aged; Anemia; Drug Therapy, Combination; Female; Humans; Hypercalcemia; Immunoglobulins; Male; Melphalan; Middle Aged; Multiple Myeloma; Myeloma Proteins; Plasma Cells; Prednisone; Prognosis; Remission, Spontaneous; Serum Albumin; Time Factors; Uremia

A study was designed to evaluate the effectiveness of prednisone therapy in poor-risk patients with multiple myeloma. Patients were treated with melphalan alone or in combination with prednisone at doses of either 0.6 mg/kg or 0.3 mg/kg. The group of patients receiving melphalan and prednisone 0.6 mg/kg had significantly improved responses in hemoglobin, lowering of the M-protein concentration, and reduction of azotemia. Significant benefits attributable to prednisone were not demonstrated in the group receiving 0.3 mg/kg. Good responses have been shown to produce improved survival. The combination of melphalan and prednisone is effective in producing good responses, but the dose of steroids is important. A dose of prednisone of 0.6 mg/kg in gradually decreasing doses has been found to be effective in production of good responses, especially in the uremic patient.

Topics: Dose-Response Relationship, Drug; Drug Therapy, Combination; Humans; Melphalan; Multiple Myeloma; Prednisone; Prognosis; Remission, Spontaneous; Risk; Uremia

Twenty-eight patients with multiple myeloma have been treated with a quadruple chemotherapeutic regimen consisting of 1, 3 bis (2-chloroethyl)-1-nitrosourea (BCNU), cyclophosphamide, melphalan, and prednisolone. Nineteen new patients and nine who had escaped from previous single-agent therapy were included in the study. The results to date, on eight criteria of response, seem to be superior to those obtained from previous chemotherapeutic regimens. The study has been in progress for 18 months and only three patients have died. Only one who had not received previous therapy died, and she had complicating hyperparathyroidism, which almost certainly contributed to her death.

Topics: Bone Marrow Examination; Calcium; Carmustine; Clinical Trials as Topic; Cyclophosphamide; Drug Therapy, Combination; Hemoglobins; Humans; Immunoglobulin Fragments; Immunoglobulins; Kidney Function Tests; Melphalan; Multiple Myeloma; Myeloma Proteins; Plasmacytoma; Prednisolone; Serum Albumin

Topics: Adult; Aged; Clinical Trials as Topic; Female; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Prognosis; Remission, Spontaneous

Topics: Androgens; Cyclophosphamide; Hemoglobinometry; Hemoglobins; Humans; Melphalan; Multiple Myeloma; Prednisone

Topics: Adult; Aged; Bone Neoplasms; Female; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Remission, Spontaneous; Time Factors

Topics: Adult; Aged; Alkaline Phosphatase; Bence Jones Protein; Calcium; Cyclophosphamide; Female; Hemoglobins; Humans; Immunoglobulin M; Male; Melphalan; Middle Aged; Multiple Myeloma; Prognosis; Proteinuria; Radiography; Serum Albumin; Urea

Topics: Anemia, Aplastic; Clinical Trials as Topic; Cyclophosphamide; Drug Combinations; Evaluation Studies as Topic; Humans; Leukopenia; Melphalan; Middle Aged; Multiple Myeloma; Palliative Care; Prospective Studies; Radiography, Thoracic; Retrospective Studies; Thrombocytopenia

Topics: Aniline Compounds; Antineoplastic Agents; Blood Sedimentation; Carmustine; Clinical Trials as Topic; Drug Synergism; Hemoglobinometry; Humans; Melphalan; Multiple Myeloma; Mustard Compounds; Prednisone; Procarbazine; Prognosis; Remission, Spontaneous

Topics: Antineoplastic Agents; Benzoates; Drug Combinations; Evaluation Studies as Topic; Humans; Immunoglobulin G; Melphalan; Multiple Myeloma; Prednisone; Procarbazine; Remission, Spontaneous

Topics: Bence Jones Protein; Blood Cell Count; Blood Platelets; Blood Protein Electrophoresis; Blood Proteins; Bone Marrow; Bone Marrow Cells; Clinical Trials as Topic; Follow-Up Studies; Hemoglobins; Humans; Leukocytes; Melphalan; Multiple Myeloma; Plasmacytoma; Staining and Labeling

UNTREATED PATIENTS SUFFERING FROM MYELOMATOSIS WERE ALLOCATED AT RANDOM FOR TREATMENT BY THE DAILY ORAL ADMINISTRATION OF EITHER CYCLOPHOSPHAMIDE OR MELPHALAN: 141 received cyclophosphamide and 133 melphalan. The trial began on 1 October 1964 and the intake of patients continued until 31 July 1968. The statistical analysis includes follow-up of the surviving patients to 31 May 1970.The most important single factor affecting the prognosis was the blood urea concentration at presentation. The median survival of the 125 patients whose blood urea concentration was less than 40 mg/100 ml was 33 months, compared with 20 months for the 96 patients whose blood urea concentration was 40-79 mg/100 ml and two months for the 55 patients whose blood urea concentration was 80 mg/100 ml or more.The median survival periods of the 114 patients in the cyclophosphamide group and of the 105 in the melphalan group whose blood urea concentration at presentation was less than 80 mg/100 ml were 27 and 23 months respectively. The difference is not statistically significant.

Topics: Clinical Trials as Topic; Cyclophosphamide; Humans; Melphalan; Multiple Myeloma; Prognosis; Time Factors; Urea

Topics: Aged; Bence Jones Protein; Blood Urea Nitrogen; Clinical Trials as Topic; Cyclophosphamide; Female; Follow-Up Studies; Humans; Hypercalcemia; Immunoglobulin A; Immunoglobulin G; Male; Melphalan; Middle Aged; Multiple Myeloma; Serum Albumin

Topics: Amyloid; Amyloidosis; Anemia; Antineoplastic Agents; Clinical Trials as Topic; Cyclophosphamide; Hodgkin Disease; Humans; Immunodiffusion; Immunoelectrophoresis; Immunoglobulin G; Immunoglobulin M; Immunoglobulins; Infections; Leukemia, Lymphoid; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Non-Hodgkin; Melphalan; Multiple Myeloma; Prognosis; Pyelonephritis

Topics: Adult; Aged; Bence Jones Protein; Blood Protein Electrophoresis; Blood Urea Nitrogen; Clinical Trials as Topic; Cyclophosphamide; gamma-Globulins; Hematocrit; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Placebos; Plasma Cells; Thrombocytopenia

Topics: Bence Jones Protein; Blood Protein Electrophoresis; Blood Proteins; Humans; Immunoelectrophoresis; Melphalan; Multiple Myeloma; Prednisone; Urea

Topics: Clinical Trials as Topic; Humans; Melphalan; Multiple Myeloma

Topics: Cyclophosphamide; Female; Humans; Male; Melphalan; Multiple Myeloma; Prognosis; Uremia

High-dose melphalan-based autologous stem cell transplant (ASCT) remains a standard of care for plasma cell disorders (PCDs). Currently, there is variability in the literature surrounding the timing of melphalan administration to avoid potential cytotoxic effects, although the administration has been safely proposed when given at least 8 hours prior to stem cell infusion. The objectives of this study were to assess differences in safety and efficacy outcomes between day -1 and day -2 single-dose melphalan administration in patients undergoing ASCT for PCDs. A retrospective chart review was performed at our institution comparing patients receiving melphalan on day -1 to an equal number of patients receiving melphalan on day -2. The primary endpoint was time to neutrophil engraftment from stem cell infusion. Univariate analyses were performed. Mean time to neutrophil engraftment from stem cell infusion was identical at 10.7 days for both cohorts (

Topics: Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Multiple Myeloma; Plasma Cells; Retrospective Studies; Stem Cell Transplantation; Transplantation Conditioning; Transplantation, Autologous

Rapidly progressing relapsed/refractory multiple myeloma (RRMM) patients with compromised marrow have limited treatment options. Thus, non-myeloablative chemotherapy with a stem cell boost (SCB) may provide disease control and hematopoietic improvement as bridge to subsequent therapies. We identified 96 patients who received a SCB between January 2011 and December 2019 at the Mount Sinai Hospital. Patients had a median age of 64 years, received a median of 7 prior lines of therapy and 68 and 42% were triple-class and penta-drug refractory, respectively. Chemotherapy included melphalan (MEL) (n = 16), melphalan + carmustine (BCNU/MEL) (n = 52) or a variant of DCEP (dexamethasone, cyclophosphamide, etoposide, cisplatin) (n = 28). Median time to neutrophil recovery was 10 days and was significantly lower with DCEP (8 days) compared to MEL and BCNU/MEL (10-11 days) (p = 0.0047). Time to progression, progression-free survival and overall survival were 3.19, 2.7 and 8.38 months, respectively. The BCNU/MEL group had the highest response rate of 85% (p = 0.05), clinical benefit rate of 94% (p = 0.0014), progression-free survival of 3.3 months (p = 0.4) and overall survival of 8.7 months (p = 0.5). Sixty-six patients (69%) were bridged to new lines of therapy, including clinical trials. Non-myeloablative chemotherapy with SCB provides rapid disease control and marrow recovery with potential to receive further therapy.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carmustine; Clinical Trials as Topic; Cyclophosphamide; Etoposide; Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Middle Aged; Multiple Myeloma; Transplantation, Autologous

Topics: Aged; Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Multiple Myeloma; Progression-Free Survival; Standard of Care; Transplantation Conditioning; Transplantation, Autologous

High-dose melphalan (HDM) with autologous hematopoietic cell transplantation (AHCT) after induction chemotherapy is considered standard of care in transplant-eligible patients with newly-diagnosed multiple myeloma (MM). Alkeran melphalan has propylene glycol as a solvent (PG-mel) while Evomela utilizes a propylene glyclol-free formulation (PGF-mel). We evaluated the differences in efficacy and safety of the 2 formulations as there are no prospective head-to-head trials.. We retrospectively reviewed the medical records of all 259 consecutive MM patients who received PGF-mel as part of HDM-AHCT at The Ohio State University (OSU). The comparator group was the preceding 255 patients who received PG-mel.. Baseline patient characteristics were similar between the 2 groups. Post-AHCT rates of relapse were comparable in the PG-mel and PGF-mel groups. Some adverse events were observed at a higher frequency in the PG-mel group compared to the PGF-mel group (grade ≥ 2 mucositis, febrile neutropenia, other infectious complications, and acute renal insufficiency). Time to neutrophil engraftment was slightly longer in the PG-mel group while time to platelet engraftment was longer in PGF-mel group. Red cell transfusion requirement was higher with the use of PG-mel but not platelet transfusion. Duration of hospitalization was slightly shorter with PGF-mel but readmission rates within 30 days of discharge were higher.. Considering possible confounding factors could possibly account for observed differences in some adverse events, the comparable treatment responses, and difference in cost of the 2 formulation, The OSU reverted to PG-mel as the preferred formulation for HDM-AHCT in MM.

Topics: Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Multiple Myeloma; Myeloablative Agonists; Neoplasm Recurrence, Local; Retrospective Studies; Transplantation Conditioning; Transplantation, Autologous

Topics: Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Humans; Melphalan; Multiple Myeloma; Prednisolone; Prednisone; Prognosis; Treatment Outcome; United Kingdom

We evaluated impact of melphalan dose on transplant outcomes for multiple myeloma. Between 1995 and 2019 459 consecutive patients received a transplant; 69(15%) received melphalan ≤150 mg/m2 (Mel 150 cohort) and 390 (85%) melphalan 200 mg/m2 (MEL 200 cohort). The primary outcome was overall survival (OS) from the date of transplant. Progression-free survival (PFS), engraftment, transplant response, and cumulative relapse at 2 years were secondary outcome measures. Patients in Mel 150 cohort had adverse clinical and laboratory parameters at base line. Transplant response was better for Mel 200 cohort (

Topics: Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Multiple Myeloma; Neoplasm Recurrence, Local; Stem Cell Transplantation; Transplantation Conditioning; Transplantation, Autologous; Treatment Outcome

Multiple myeloma is one of the most common hematological malignancies worldwide. Genetic alterations may lead to the progression from monoclonal gammopathy to multiple myeloma. Additionally, the genetic background of the disease might influence therapy outcomes, including survival time. SLCO1B1, belonging to the OATPs family, is a membrane protein that mediates the uptake of a wide range of endogenous and exogenous (including drugs) compounds.. In this study, the A388G single nucleotide polymorphism in the SLCO1B1 gene in Polish multiple myeloma patients was determined. This polymorphism affects the amino acid change of the protein, so it may be responsible for treatment effectiveness or risk of disease development. A388G was evaluated by the PCR-RFLP method. The presented study showed a statistically significant association between the GG genotype with longer survival of patients with multiple myeloma with Melphalan-Prednisone therapy compared to other treatment regimens (p = 0.0271). There was no statistically significant association in the frequency of genotypes (p = 0.8211) and alleles: allele A (p = 0.5442); allele G (p = 0.8020) between multiple myeloma patients and a control group.. The A388G polymorphism does not seem to affect the increased risk of the development of multiple myeloma. However, the occurrence of the GG genotype may prolong of patients overall survival in the case of Melphalan-Prednisone therapy.

Topics: Genotype; Humans; Liver-Specific Organic Anion Transporter 1; Melphalan; Multiple Myeloma; Poland; Polymorphism, Single Nucleotide; Prednisone

High-dose melphalan (HDM) improves progression-free survival in multiple myeloma (MM), yet melphalan is a DNA-damaging alkylating agent; therefore, we assessed its mutational effect on surviving myeloma cells by analyzing paired MM samples collected at diagnosis and relapse in the IFM 2009 study. We performed deep whole-genome sequencing on samples from 68 patients, 43 of whom were treated with RVD (lenalidomide, bortezomib, and dexamethasone) and 25 with RVD + HDM. Although the number of mutations was similar at diagnosis in both groups (7137 vs 7230; P = .67), the HDM group had significantly more mutations at relapse (9242 vs 13 383, P = .005). No change in the frequency of copy number alterations or structural variants was observed. The newly acquired mutations were typically associated with DNA damage and double-stranded breaks and were predominantly on the transcribed strand. A machine learning model, using this unique pattern, predicted patients who would receive HDM with high sensitivity, specificity, and positive prediction value. Clonal evolution analysis showed that all patients treated with HDM had clonal selection, whereas a static progression was observed with RVD. A significantly higher percentage of mutations were subclonal in the HDM cohort. Intriguingly, patients treated with HDM who achieved complete remission (CR) had significantly more mutations at relapse yet had similar survival rates as those treated with RVD who achieved CR. This similarity could have been due to HDM relapse samples having significantly more neoantigens. Overall, our study identifies increased genomic changes associated with HDM and provides rationale to further understand clonal complexity.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Chronic Disease; Dexamethasone; Humans; Lenalidomide; Melphalan; Multiple Myeloma; Neoplasm Recurrence, Local; Transplantation, Autologous

Renal impairment (RI) used to exclude multiple myeloma (MM) patients from autologous stem cell transplantation (ASCT) for safety concerns. Here, we retrospectively reviewed 34 consecutively transplanted patients with creatinine clearance < 60 ml/min at ASCT in recent 5 years at our institution. Busulfan/cyclophosphamide and high-dose melphalan were both employed as conditioning regimens. We found 62% grade 1-2 oral mucositis, 12% grade 3 oral mucositis, 48% grade 3 infection, 8% grade ≥ 4 infection, 50% grade 1 transient creatinine increase, 15% cardiac adverse events, and 12% engraftment syndrome. One case of secondary platelet graft failure and 1 case of transplantation-related mortality were observed. Interleukin-6 concentration was elevated among patients with increased body temperature and/or N-terminal pro-brain natriuretic peptide during engraftment, and close monitoring of these markers may help to predict susceptibility to cardiac events and engraftment syndrome. Adverse events occurred frequently, but the majority were manageable in this cohort. ASCT would further deepen the anti-myeloma efficacy and slightly ameliorated renal function. With a median follow-up of 26.2 months post transplantation (range: 1.6-74.8 months), the median progression-free survival (PFS) and overall survival (OS) post-transplantation of patients undergoing first-line transplantation were not reached; the median PFS post-transplantation of patients undergoing rescue transplantation was 19.2 months and the median OS was not reached.

Topics: Creatinine; Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Multiple Myeloma; Retrospective Studies; Stem Cell Transplantation; Stomatitis; Transplantation Conditioning; Transplantation, Autologous

The overall survival (OS) has improved significantly in multiple myeloma (MM) over the last decade with the use of proteasome inhibitor and immunomodulatory drug-based combinations, followed by high-dose melphalan and autologous hematopoietic stem cell transplantation (auto-HSCT) and subsequent maintenance therapies in eligible newly diagnosed patients. However, clinical trials using auto-HSCT followed by lenalidomide maintenance have shown an increased risk of second primary malignancies (SPM), including second hematological malignancies (SHM). We evaluated the impact of SPM and SHM on progression-free survival (PFS) and OS in patients with MM after auto-HSCT using CIBMTR registry data. Adult patients with MM who underwent first auto-HSCT in the United States with melphalan conditioning regimen from 2011 to 2018 and received maintenance therapy were included (n = 3948). At a median follow-up of 37 months, 175 (4%) patients developed SPM, including 112 (64%) solid, 36 (20%) myeloid, 24 (14%) SHM, not otherwise specified, and 3 (2%) lymphoid malignancies. Multivariate analysis demonstrated that SPM and SHM were associated with an inferior PFS (hazard ratio [HR] 2.62, P < .001 and HR 5.01, P < .001, respectively) and OS (HR 3.85, P < .001 and HR 8.13, P < .001, respectively). In patients who developed SPM and SHM, MM remained the most frequent primary cause of death (42% vs 30% and 53% vs 18%, respectively). We conclude the development of SPM and SHM leads to a poor survival in patients with MM and is an important survivorship challenge. Given the median survival for MM continues to improve, continued vigilance is needed to assess the risks of SPM and SHM with maintenance therapy post-auto-HSCT.

Topics: Adult; Hematologic Neoplasms; Humans; Lenalidomide; Melphalan; Multiple Myeloma; Neoplasms, Second Primary; Transplantation, Autologous; United States

Multiple Myeloma (MM) is an incurable plasma cell malignancy often treated by autologous stem cell transplant (ASCT). Clinical response to ASCT has been associated with DNA repair efficiency. Here we interrogated the role of the base excision DNA repair (BER) pathway in MM response to ASCT. Across 450 clinical samples and six disease stages, expression levels of genes in the BER pathway were found to be highly upregulated during the development of MM. In a separate cohort of 559 patients with MM treated with ASCT, expression of BER pathway members MPG and PARP3 was positively associated with overall survival (OS) while expression of PARP1, POLD1, and POLD2 was negatively associated with OS. In a validation cohort of 356 patients with MM treated with ASCT, PARP1 and POLD2 findings were replicated. In patients with MM who never received ASCT (n=319), PARP1 and POLD2 were not associated with OS, suggesting that the prognostic effect of these genes may be treatment-dependent. In preclinical models of MM, synergy was observed in anti-tumor activity when poly (ADPribose) polymerase (PARP) inhibitors (olaparib, talazoparib) were used in combination with melphalan. The negative prognosis associated with PARP1 and POLD2 expression along with the apparent melphalan-sensitizing effect of PARP inhibition may suggest this pathway as a potential biomarker in patients with MM in the setting of ASCT. Further understanding of the role of the BER pathway in MM is vital to improve therapeutic strategies related to ASCT.

Topics: DNA Polymerase III; Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Multiple Myeloma; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerase Inhibitors; Prognosis; Retrospective Studies; Stem Cell Transplantation; Transplantation, Autologous

Topics: Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Multiple Myeloma; Transplantation Conditioning; Transplantation, Autologous

Despite decades of development of treatments and the successful application of targeted therapies for multiple myeloma, clinical challenges remain for patients with relapsed/refractory disease. A drug designed for efficient delivery of an alkylating payload into tumor cells that yields a favorable therapeutic window can be an attractive choice. Herein we describe melphalan flufenamide (melflufen), a drug with a peptide carrier component conjugated to an alkylating payload, and its cellular metabolism. We further underline the fundamental role of enzymatic hydrolysis in the rapid and robust accumulation of alkylating metabolites in cancer cells and their importance for downstream effects. The formed alkylating metabolites were shown to cause DNA damage, both on purified DNA and on chromatin in cells, with both nuclear and mitochondrial DNA affected in the latter. Furthermore, the rapid intracellular enrichment of alkylating metabolites is shown to be essential for the rapid kinetics of the downstream intracellular effects such as DNA damage signaling and induction of apoptosis. To evaluate the importance of enzymatic hydrolysis for melflufen's efficacy, all four stereoisomers of the compound were studied in a systematic approach and shown to have a different pattern of metabolism. In comparison with melflufen, stereoisomers lacking intracellular accumulation of alkylating payloads showed cytotoxic activity only at significantly higher concentration, slower DNA damage kinetics, and different mechanisms of action to reach cellular apoptosis.

Topics: Antineoplastic Agents, Alkylating; Humans; Melphalan; Multiple Myeloma; Phenylalanine

Topics: Biosimilar Pharmaceuticals; Female; Filgrastim; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Transplantation; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Polyethylene Glycols; Prospective Studies; Recombinant Proteins; Retrospective Studies; Transplantation, Autologous

Topics: Cohort Studies; Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Multiple Myeloma; Neoplasm Recurrence, Local; Transplantation Conditioning; Transplantation, Autologous

Canine multiple myeloma (MM) is typically treated with melphalan chemotherapy. A protocol with repeated 10-day cyclical dosing of melphalan has been used at our institution but has not been described in the literature. Our objectives were to describe the outcome and adverse events of this protocol in a retrospective case series. We hypothesised the cyclical 10-day protocol would have similar outcomes compared to other reported chemotherapy protocols. Dogs diagnosed with MM that received melphalan treatment at Cornell University Hospital for Animals were identified through a database search. Records were retrospectively reviewed. Seventeen dogs met inclusion criteria. Lethargy was the most common presenting complaint. The median duration of clinical signs was 53 days (range, 2-150 days). Seventeen dogs had hyperglobulinemia with 16/17 having monoclonal gammopathies. Sixteen dogs had bone marrow aspiration and cytology performed at initial diagnosis and plasmacytosis was diagnosed in all. Based on serum globulin concentrations, 10 of 17 dogs (59%) achieved complete response (CR), and 3 dogs (18%) achieved partial response (PR), for an overall response rate of 76%. The median overall survival time was 512 days (range, 39-1065). Retinal detachment (n = 3) and maximum response of CR/PR (n = 13) were associated with overall survival on multivariate analysis (p = .045 and .046, respectively). Adverse events were minimal with diarrhoea being the most reported (n = 6). This cyclical 10-day protocol was better-tolerated with fewer adverse events than with other reported chemotherapy protocols, but response rate was also lower, likely due to a lower dosing intensity.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Dog Diseases; Dogs; Melphalan; Multiple Myeloma; Retrospective Studies

This study aimed to identify the risk factors of febrile neutropenia(FN)onset associated with melphalan(L-PAM)therapy. Thirty-nine patients(21 men, 18 women)were administered L-PAM intravenously for multiple myeloma(MM)from April 2011 to February 2022 at the Department of Hematology of Gifu Municipal Hospital. Patients were classified into those with and without FN(Grade 3 or higher), complete blood count and liver function tests were performed immediately before starting therapy. Univariate analysis with Fisher's exact probability test was performed. Factors with p<0.2 were considered as independent variables for multivariate analysis in the multiple logistic regression analysis. A multivariate analysis with 2 independent variables, lactate dehydrogenase(LD)level>222 U/L(upper limit of the facility reference value)and white <3.3×103/μL(lower limit of the facility reference value)from the univariate analysis, and FN onset(Grade 3 or higher)as the dependent variable showed that LD level>222 U/L(odds ratio: 6.33, 95% confidence interval: 1.12-35.8, p=0.037)was a significant factor. In conclusion, patients with LD levels >222 U/L immediately before starting therapy require adequate monitoring for FN onset following L-PAM administration.

Topics: Febrile Neutropenia; Female; Hospitals, Municipal; Humans; Male; Melphalan; Multiple Myeloma; Risk Factors

Melphalan flufenamide (melflufen), a first-in-class alkylating peptide-drug conjugate, plus dexamethasone demonstrated superior progression-free survival (PFS) but directionally different overall survival (OS) favoring pomalidomide (hazard ratio [HR], 1.10) in OCEAN.. These analyses further investigated prognostic subgroups impacting survival in updated data from the randomized, phase 3 OCEAN study (NCT03151811; date: February 3, 2022) and the phase 2 HORIZON study (NCT02963493; date: February 2, 2022).. In OCEAN, subgroups prognostic for OS were age (P = .011; <65 years favored pomalidomide) and no previous autologous stem cell transplant (ASCT) or progression >36 months after ASCT (P = .001; favored melflufen). Overall, 245 of 495 (49%) patients randomized had received a previous ASCT, of which 202 (82%) had progressed within 36 months following their ASCT. When excluding patients who had progressed <36 months post-ASCT (melflufen group, n = 145; pomalidomide group, n = 148), median OS was 23.6 months with melflufen and 19.8 months with pomalidomide (HR, 0.83 [95% CI, 0.62-1.12]; P = .22). Among patients with triple-class refractory disease in HORIZON, patients who had progressed <36 months post-ASCT (n = 58) had a lower response rate and shorter duration of response and PFS than the remaining patients (n = 52). Safety was consistent with previous reports.. These analyses demonstrate a consistent benefit for melflufen and dexamethasone in patients with relapsed/refractory multiple myeloma who have not received an ASCT or progressed >36 months after receiving an ASCT (ClinicalTrials.gov identifier: NCT03151811).

Topics: Antineoplastic Combined Chemotherapy Protocols; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Dexamethasone; Follow-Up Studies; Humans; Melphalan; Multiple Myeloma; Randomized Controlled Trials as Topic; Risk Assessment; Transplantation, Autologous

Autologous hematopoietic stem cell transplant (aHCT) has become standard care for patients with multiple myeloma (MM). Outpatient aHCT with high-dose melphalan conditioning has reduced costs and length of hospital stay. This study aimed to highlight the effectiveness, safety, and cost implications of outpatient vs inpatient aHCT at a tertiary academic medical center, as well as the utility of growth factor use in these patients.. Using an institutional HCT database, a total of 100 patients undergoing aHCT for MM were identified; 50 patients who underwent aHCT in the outpatient setting (chemotherapy and stem cell infusion followed by inpatient admission if needed) were compared with 50 patients in the inpatient setting (chemotherapy and stem cell infusion followed by discharge to outpatient setting). Patients were excluded if the melphalan dose was less than 200 mg/m. Time to neutrophil and platelet engraftment was shorter in the outpatient group than in the inpatient group (14 vs 16 days and 19 vs 21 days, respectively; P < 0.001). Median length of hospital stay was also shorter in the outpatient group (8.5 vs 15.5 days, respectively; P < 0.001). Ninety percent of the outpatient group required admission for neutropenic fever, and 60% of these patients received growth factor support starting at a median of 9 days after stem cell infusion, for a median duration of 4 days. Compared to 16 patients who did not receive growth factor support, these patients had a significantly shorter time to neutrophil recovery (13 days with vs 15 days without growth factor, P = 0.02) and no difference in the total length of hospital stay (8 days with vs 10 days without growth factor, P = 0.43).. For adult patients with MM undergoing aHCT, the outpatient setting is safe and reduces the total length of hospital stay and thus overall transplant costs. Growth factor support for patients with febrile neutropenia may not reduce length of stay for subsequent hospitalizations.

Topics: Adult; Febrile Neutropenia; Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Multiple Myeloma; Outpatients; Retrospective Studies; Transplantation, Autologous

Multiple myeloma (MM) is the second most common hematologic malignancy, with 34,470 estimated new cases in 2022. High-dose therapy followed by autologous hematopoietic cell transplantation (auto-HCT) remains a standard treatment for MM even in the era of novel therapies. This is usually performed in hospital-based settings, either in the inpatient or outpatient units. Advanced Care at Home (ACH) represents a virtual hybrid hospital-at-home program that combines a virtual provider-staffed command center with a vendor-mediated supply chain capable of delivering high-acuity care in the comfort of the patients' own homes. In our program, we used the existing ACH platform to deliver post-HCT care for recipients of auto-HCT.. Patients were discharged to their homes after completing the infusion on day 0 or day +1 at the latest. Post-infusion care was provided by the ACH team in coordination with the BMT team. The median time intervals to absolute neutrophil count and platelet engraftment were 12 (range, 11-13) and 11 (range, 9-16) days, respectively. All patients were successfully discharged from the ACH program at a median of day +14 (range, day +14 to day +15).. Our results highlight the feasibility of delivering post-HCT care for auto-HCT recipients in the home setting and confirm the generalizability of this approach.

Topics: Adult; Aged; Female; Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Middle Aged; Multiple Myeloma; Transplantation Conditioning; Transplantation, Autologous; Treatment Outcome

Despite the development of effective agents for multiple myeloma (MM), the management of patients with high-risk MM (HRMM) is challenging. High-dose treatment followed by autologous stem cell transplantation (ASCT) is regarded as upfront treatment for transplant-eligible patients with HRMM. In the present study, we retrospectively investigated the efficacies of two conditioning regimens for upfront ASCT in newly diagnosed patients with MM and high-risk features: high-dose melphalan (HDMEL; 200 mg/m

Topics: Antineoplastic Combined Chemotherapy Protocols; Busulfan; Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Multiple Myeloma; Retrospective Studies; Stem Cell Transplantation; Transplantation Conditioning; Transplantation, Autologous

Bortezomib-melphalan-prednisone (VMP) and lenalidomide-dexamethasone (Rd) remain the standard treatments for transplant-ineligible patients with newly diagnosed multiple myeloma (NDMM). This study aimed to compare real-world benefits between the two regimens. We also were interested in exploring efficacy according to subsequent therapy following VMP or Rd.. A total of 559 NDMM patients treated with VMP (n = 443, 79.2%) or Rd (n = 116, 20.8%) was recruited retrospectively from a multicenter database.. Rd provided more benefits than VMP-overall response rate: 92.2 vs. 81.8%, p = 0.018; median progression-free survival (PFS): 20.0 vs. 14.5 months, p <0.001; second PFS (PFS2): 43.9 vs. 36.9 months, p = 0.012; overall survival (OS): 100.1 vs. 85.0 months, p = 0.017. Multivariable analysis revealed significant benefits of Rd over VMP, with hazard ratios of 0.722, 0.627, and 0.586 for PFS, PFS2, and OS, respectively. In propensity score-matched cohorts with matched VMP (n = 201) and Rd (n = 67) arms to balance baseline characteristics, Rd still showed significantly better outcomes for PFS, PFS2, and OS than VMP. Following VMP failure, triplet therapy showed significant benefits for response and PFS2; after Rd failure, PFS2 with carfilzomib-dexamethasone was significantly better than bortezomib-based doublet treatment.. These real-world findings may assist with better selection between VMP and Rd as well as subsequent therapy for NDMM.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Dexamethasone; Humans; Lenalidomide; Melphalan; Multiple Myeloma; Prednisone; Registries; Retrospective Studies; Treatment Outcome

Oral mucositis is a frequently seen complication in the first weeks after hematopoietic stem cell transplantation recipients which can severely affects patients quality of life. In this study, a labelled and label-free proteomics approach were used to identify differences between the salivary proteomes of autologous hematopoietic stem cell transplantation (ASCT) recipients developing ulcerative oral mucositis (ULC-OM; WHO score ≥ 2) or not (NON-OM).. In the TMT-labelled analysis we pooled saliva samples from 5 ULC-OM patients at each of 5 timepoints: baseline, 1, 2, 3 weeks and 3 months after ASCT and compared these with pooled samples from 5 NON-OM patients. For the label-free analysis we analyzed saliva samples from 9 ULC-OM and 10 NON-OM patients at 6 different timepoints (including 12 months after ASCT) with Data-Independent Acquisition (DIA). As spectral library, all samples were grouped (ULC-OM vs NON-OM) and analyzed with Data Dependent Analysis (DDA). PCA plots and a volcano plot were generated in RStudio and differently regulated proteins were analyzed using GO analysis with g:Profiler.. A different clustering of ULC-OM pools was found at baseline, weeks 2 and 3 after ASCT with TMT-labelled analysis. Using label-free analysis, week 1-3 samples clustered distinctly from the other timepoints. Unique and up-regulated proteins in the NON-OM group (DDA analysis) were involved in immune system-related processes, while those proteins in the ULC-OM group were intracellular proteins indicating cell lysis.. The salivary proteome in ASCT recipients has a tissue protective or tissue-damage signature, that corresponded with the absence or presence of ulcerative oral mucositis, respectively.. The study is registered in the national trial register (NTR5760; automatically added to the International Clinical Trial Registry Platform).

Topics: Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Multiple Myeloma; Proteome; Proteomics; Quality of Life; Stomatitis; Stomatitis, Aphthous

Topics: Dysbiosis; Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Multiple Myeloma; Transplantation Conditioning; Transplantation, Autologous

Topics: Humans; Leukemia, Myeloid, Acute; Melphalan; Multiple Myeloma

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Antineoplastic Agents, Immunological; Biological Products; Clinical Trials as Topic; Drug Discovery; Humans; Lymphoma, Large B-Cell, Diffuse; Melphalan; Multiple Myeloma; Phenylalanine; Receptors, Antigen, T-Cell

Topics: Consolidation Chemotherapy; Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Multiple Myeloma; Stem Cell Transplantation; Transplantation Conditioning; Transplantation, Autologous

It has been reported that expression of OCT3 enhanced the sensitivity to melphalan in cells, indicative of potential roles of OCT3 in melphalan transport. Herein we investigated the association of select single nucleotide polymorphisms in SLC22A3 (gene encoding OCT3) with clinical outcomes in multiple myeloma (MM) patients with hematopoietic autologous stem cell transplants followed by high-dose melphalan therapy.. Melphlan concentrations in blood samples from 108 MM patients were measured using liquid chromatography-tandem mass spectrometry (LC-MS/ΜS); genotypes of rs2048327, rs1810126, and rs3088442 in these patients were determined using quatitive RT-PCR assays.. Rs3088442 A variant-carriers had a significantly increased risk of severe oral mucositis in comparison with homozygous rs3088442 G-carriers with adjusted odds ratio of 4.00 (95% CI=1.25-14.7; p=0.027). Rs3088442 A carriers tended to have lower creatinine clearance (p=0.10) and higher maximum plasma concentration of melphalan (p=0.07).. OCT3 might be involved in melphalan transport in MM patients.

Topics: Adult; Aged; Genetic Association Studies; Genetic Predisposition to Disease; Genotype; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Organic Cation Transport Proteins; Polymorphism, Single Nucleotide; Stem Cell Transplantation; Stomatitis; Transplantation, Autologous

Topics: Humans; Melphalan; Multiple Myeloma; Phenylalanine

Multiple myeloma (MM) is the second most common hematologic malignancy diagnosed in the United States. With a growing arsenal of novel therapies, patients are living longer and hence are at increased risk of secondary cancers such as myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). While MDS-associated cytogenetic abnormalities have been described in patients with a diagnosis of for decades, clonal hematopoiesis (CH) has been described only recently. CH has been shown to correlate with inferior survival in MM due to increased risk of disease progression in patients who are treated with high-dose melphalan without lenalidomide maintenance. When involving specific high-risk genes, multiple genes, or when present at high variant allelic frequencies, CH could also potentially elevate the risk of secondary MDS and/or AML, cardiovascular events, and venous thromboembolic events. Despite growing knowledge about CH in patients with MM, many questions remain unanswered. Further studies are needed to better understand the prognostic and therapeutic significance of CH in MM and its precursor conditions, as well as the effect of specific treatments on long-term outcome.

Topics: Clonal Hematopoiesis; Humans; Leukemia, Myeloid, Acute; Melphalan; Multiple Myeloma; Myelodysplastic Syndromes; Neoplasms, Second Primary

Topics: Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Humans; Melphalan; Multiple Myeloma; Prednisone; Treatment Outcome

Topics: Humans; Melphalan; Multiple Myeloma; Phenylalanine

Topics: Humans; Melphalan; Multiple Myeloma; Phenylalanine

A 71-year-old woman diagnosed with type II diabetes mellitus with severe iron deficiency anemia and positive fecal occult blood. Colonoscopy was performed, showing a soft mass in the ascending colon, with biopsies compatible with plasmacytoma and restriction for Kappa light chains. After bone marrow aspiration, associated IgG multiple myeloma was detected, so chemotherapy with VMP (bortezomib, melphalan and prednisone) was started. Colonoscopy six months later showed that the ulcerated lesion had a reduction in tumor size of up to 80%. A 27-year-old male with a history of kidney transplantation and symptoms of chronic diarrhea, colonoscopy was indicated with the finding of a large exophytic and ulcerated lesion in the cecum. Pathology revealed plasmacytoma with restriction of lambda light chains. After ruling out lesions in other locations, the patient was treated with immunochemotherapy according to the Bortezomib-Rituximab-Dexamethasone scheme, with subsequent complete clinical and endoscopic remission. Plasmacytoma accounts for < 4 % of plasma cell tumours. It may appear isolated or associated with another plasma cell neoplasm, mainly multiple myeloma. Its presence in the gastrointestinal tract is rare, being infrequent in the stomach or small intestine, and even rarer in the colonic tract (incidence 1/10,000,000). The clinical manifestations are similar to those of other colon neoplasms, while the treatment or prognosis may differ from those of other neoplasms. In patients with clinical suspicion, it is important to perform an early endoscopic study, especially in patients diagnosed with multiple myeloma.

Topics: Adult; Aged; Bortezomib; Dexamethasone; Diabetes Mellitus, Type 2; Female; Humans; Immunoglobulin G; Male; Melphalan; Multiple Myeloma; Plasmacytoma; Prednisone; Rituximab; Tertiary Care Centers

Mesenchymal stem/stromal cells (MSCs) are self-renewing and multipotent progenitors, which constitute the main cellular compartment of the bone marrow stroma. Because MSCs have an important role in the pathogenesis of multiple myeloma, it is essential to know if novel drugs target MSCs. Melflufen is a novel anticancer peptide-drug conjugate compound for patients with relapsed refractory multiple myeloma. Here, we studied the cytotoxicity of melflufen, melphalan and doxorubicin in healthy human bone marrow-derived MSCs (BMSCs) and how these drugs affect BMSC proliferation. We established co-cultures of BMSCs with MM.1S myeloma cells to see if BMSCs increase or decrease the cytotoxicity of melflufen, melphalan, bortezomib and doxorubicin. We evaluated how the drugs affect BMSC differentiation into adipocytes and osteoblasts and the BMSC-supported formation of vascular networks. Our results showed that BMSCs were more sensitive to melflufen than to melphalan. The cytotoxicity of melflufen in myeloma cells was not affected by the co-culture with BMSCs, as was the case for melphalan, bortezomib and doxorubicin. Adipogenesis, osteogenesis and BMSC-mediated angiogenesis were all affected by melflufen. Melphalan and doxorubicin affected BMSC differentiation in similar ways. The effects on adipogenesis and osteogenesis were not solely because of effects on proliferation, seen from the differential expression of differentiation markers normalized by cell number. Overall, our results indicate that melflufen has a significant impact on BMSCs, which could possibly affect therapy outcome.

Topics: Bone Marrow; Bortezomib; Doxorubicin; Humans; Melphalan; Mesenchymal Stem Cells; Multiple Myeloma; Phenylalanine

Autologous stem cell transplant (ASCT) is a standard therapy for transplant eligible patients of multiple myeloma (MM). To evaluate impact of time to transplant on subsequent outcomes, we analyzed data on consecutive MM patients who received novel agents-based induction prior to transplant.. Between 2006 and 2019, 363 MM patients underwent ASCT. Patients' median age was 52 years, ranging from 20 to 72 years, 233 (64.2%) were males. Median interval from diagnosis to transplant was 11.5 months (range, 4-67.5); 201 (55.4%) patients underwent ASCT within 12 months (early) and 162 (44.6%) beyond 12 months since diagnosis (delayed ASCT). Primary objective was progression-free survival. Secondary objectives were-response rate to transplant, overall survival (OS), and transplant-related mortality (TRM).. Post-ASCT complete response (CR) (77.1% vs. 64.8%; P < .025) and CR+ very good partial response rate (89% vs. 81.5%; P < .03) was higher for early ASCT cohort. Engraftment characteristics, regimen-related toxicities, and day +100 TRM (3.5% vs 3.7%; P = .564) were similar in 2 cohorts. Median OS for early versus late cohort from date of diagnosis is 127.0 (95% CI, 98.9-155.1) versus 104.5 months (95% CI, 79.3-129.6; P = .356) and from date of transplant is 119.0 (95% CI, 93.4-144.6) versus 89.5 months (95% CI, 57.4-121.6), P < .02. Median PFS is better for early transplant cohort; 69.5 (95% CI, 56.7-82.3) versus 50.0 months (95% CI, 35.6-64.4), P < .05, respectively.. Early transplant for myeloma is associated with higher response rate and better progression-free survival.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Female; Hematopoietic Stem Cell Transplantation; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Retrospective Studies; Transplantation, Autologous; Treatment Outcome; Young Adult

The use of non-cryopreserved hematopoietic stem cells (HSC) can be an alternative to the traditional cryopreserved infusions of HSCs in autologous stem cell transplantation (aHSCT). After high-dose melphalan conditioning (HDM), we sought to compare time to engraftment, overall survival, and safety in multiple myeloma (MM) patients undergoing a first aHSCT after high-dose melphalan conditioning (HDM). We conducted a cohort study from March 2018 to December 2019. Of all autologous transplants performed during this period, 105 were for MM as the first consolidation. Fifty-one patients received a cryopreserved graft; the remaining 54 patients received a fresh infusion. General clinical characteristics were similar between these two groups. Cell viability was higher in non-cryopreserved grafts (95% vs. 86% p < 0.01). Four deaths occurred during hospitalization in the cryopreserved group, one in the non-cryopreserved group. The cumulative incidence of neutrophil and platelet engraftment on D + 25 was higher in the non-cryopreserved compared to the cryopreserved group (98% vs 90% p < 0.01 and 96.2% vs 72.54% p < 0.01 respectively). Additionally, the hospital length of stay was reduced by 4 days for patients for the non-cryopreserved cohort. In summary, the use of non-cryopreserved HSCs after HDM is safe and effective compared to patients who received a cryopreserved graft.

Topics: Autografts; Cohort Studies; Hematopoietic Stem Cell Transplantation; Hematopoietic Stem Cells; Humans; Melphalan; Multiple Myeloma; Transplantation Conditioning; Transplantation, Autologous

Chemotherapy-induced nausea and vomiting (CINV) is common in patients with lymphoma and multiple myeloma (MM) receiving high-dose chemotherapy (HDC) followed by autologous stem cell transplantation (ASCT). Despite a standard triple antiemetic regimen of a neurokinin-1 (NK1) receptor antagonist (RA), a 5-hydroxytryptamine-3 (5-HT3) RA, and dexamethasone is recommended, how to control the protracted CINV in ASCT setting remains an intractable problem. Here, we retrospectively analyze CINV data of 100 patients who received either SEAM (semustine, etoposide, cytarabine, melphalan) or MEL140-200 (high-dose melphalan) before ASCT, evaluate the efficacy and safety of multiple-day administration of fosaprepitant combined with tropisetron and olanzapine (FTO), and compare the results to those of patients who received a standard regimen of aprepitant, tropisetron, and dexamethasone (ATD). The overall rate of complete response (CR), defined as no emesis and no rescue therapy, is 70% in the FTO group compared to 36% in the ATD group. Although CR rates are comparable in the acute phase between the two groups, significantly more patients treated by FTO achieve CR in the delayed phase than those treated by ATD (74% vs. 38%, p < 0.001). Moreover, FTO treatment significantly reduced the percentage of patients who are unable to eat, as well as the requirement for rescue medications. Both regimens are well tolerated and most adverse events (AEs) were generally mild and transient. In conclusion, the antiemetic strategy containing multiple-day administration of fosaprepitant is safe and effective for preventing CINV in lymphoma and MM patients, particularly in the delayed phase.

Topics: Antiemetics; Antineoplastic Agents; Dexamethasone; Hematopoietic Stem Cell Transplantation; Humans; Lymphoma; Melphalan; Morpholines; Multiple Myeloma; Nausea; Olanzapine; Retrospective Studies; Transplantation Conditioning; Transplantation, Autologous; Tropisetron; Vomiting

Melphalan flufenamide (melflufen) is a first-in-class peptide-drug conjugate that takes advantage of increased aminopeptidase activity inside tumor cells to rapidly release alkylating agents therein. Melflufen in combination with dexamethasone has been evaluated in multiple clinical trials in patients with relapsed/refractory multiple myeloma (MM).. This profile covers the unique mechanism of action of melflufen, the preclinical results supporting its activity in cellular models of resistance to chemotherapy, its activity in animal models of MM, and the clinical pharmacokinetics of melflufen. Findings from clinical trials evaluating melflufen, including the pivotal phase II HORIZON study and the phase III OCEAN study, are discussed.. Although MM treatment has improved, patients with disease refractory to multiple standard-of-care drug classes face a dismal prognosis. Melflufen demonstrated efficacy and tolerability in select populations, with an initial approval in the United States in patients with ≥ four previous lines of therapy and triple-class-refractory MM. Results from the phase III OCEAN study - currently under discussion with regulatory agencies in the United States and Europe - are more complex and have been put into context herein. Lastly, melflufen provides a proof-of-concept for the utility of the peptide-drug conjugate platform in relapsed/refractory MM.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Europe; Melphalan; Multiple Myeloma; Phenylalanine

Although patients with multiple myeloma (MM) have improved survival with current therapies, there remains a long-term risk of treatment-associated second primary malignancies. We present a case of a patient with IgG kappa MM undergoing treatment for relapsed disease who was noted to have progressive pancytopenia. For his MM, he had previously undergone autologous stem cell transplant with high-dose melphalan and had received immunomodulatory (IMiD) agents in induction, maintenance and relapse regimens. A peripheral blood smear showed abnormal lymphoid cells, and a bone marrow biopsy revealed B-cell acute lymphoblastic leukaemia (B-ALL). He underwent intensive induction chemotherapy with plans for possible allogeneic stem cell transplant. Secondary B-ALL is a rare occurrence in patients with MM, with exposure to alkylating and IMiD agents being potential risk factors.

Topics: Antineoplastic Combined Chemotherapy Protocols; Hematopoietic Stem Cell Transplantation; Humans; Male; Melphalan; Multiple Myeloma; Neoplasm Recurrence, Local; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Transplantation, Autologous

Topics: Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Clinical Trials, Phase II as Topic; Humans; Melphalan; Multiple Myeloma; Prednisolone; Randomized Controlled Trials as Topic

Peripheral neuropathy is a common treatment-emergent side effect during the treatment of newly diagnosed multiple myeloma. Although bortezomib is most commonly implicated, real-world data suggest that lenalidomide and dexamethasone (VRd) and autologous stem cell transplantation (ASCT) may also contribute to neuropathy and health-related quality of life (HRQoL).. The Multiple Myeloma Research Foundation (MMRF) CoMMpass Registry was queried for all patients who received frontline VRd or bortezomib, cyclophosphamide and dexamethasone (VCd). Incidence of neuropathy and patient-reported HRQoL outcomes over the first 12 months after diagnosis were compared between patients receiving VRd or VCd with or without early ASCT before 6 months.. There were 368 and 191 patients treated with VRd and VCd, respectively. VRd with early ASCT was associated with worse grade 1 neuropathy compared to VRd without early ASCT, as well as compared to VCd with early ASCT. There were no differences in neuropathy between VRd and VCd without early ASCT, and no differences in grade ≥2 neuropathy. There were significant improvements in HRQoL between baseline and 12 months in both VRd and VCd cohorts, regardless of early ASCT. Development of neuropathy was not associated with decrements in progression-free survival or overall survival.. In this longitudinal database analysis, there were no differences in grade ≥2 neuropathy between VRd and VCd frontline induction, and overall HRQoL significantly improved across all cohorts. However, differences in grade 1 neuropathy between VRd and VCd induction suggest that lenalidomide and high-dose melphalan may augment the risk of neuropathy in newly diagnosed multiple myeloma.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Cyclophosphamide; Dexamethasone; Hematopoietic Stem Cell Transplantation; Humans; Lenalidomide; Melphalan; Multiple Myeloma; Patient Reported Outcome Measures; Peripheral Nervous System Diseases; Quality of Life; Transplantation, Autologous

Dysgeusia is a common but understudied complication in patients undergoing autologous hematopoietic cell transplantation (auto-HCT). We assessed the feasibility of using chemical gustometry (CG) to measure dysgeusia and explored its associations with symptom burden, nutrition, chemotherapy pharmacokinetics (PK), and the oral microbiome.. We conducted a single-center, prospective feasibility study (NCT03276481) of patients with multiple myeloma undergoing auto-HCT. CG was performed longitudinally testing five flavors (sweet, sour, salty, bitter, umami) to calculate a total taste score (maximum score, 30). We measured caloric intake and patient-reported symptoms, assessing their correlation with oral microbiota composition and salivary and blood melphalan PK exposure.. Among all 45 patients, 39 (87%) completed at least four (>60%) and 22 (49%) completed all six CG assessments. Median total CG scores remained stable over time but were lowest at day +7 (27, range 24-30) with recovery by day +100. Symptom burden was highest by day +10 (area under the curve, 2.9; range, 1.0-4.6) corresponding with the lowest median overall caloric intake (1624 kcal; range, 1345-2267). Higher serum/salivary melphalan levels correlated with higher patient-reported dysgeusia and lower caloric intake. Oral microbiota α-diversity was stable early and increased slightly by day +100.. Assessment of dysgeusia by CG is feasible after auto-HCT. Most dysgeusia, symptom burden, and lowest caloric intake occurred during the blood count nadir. Higher melphalan concentrations correlated with more dysgeusia and poorer caloric intake. Future studies will aim to modulate melphalan exposure by PK-targeted dosing and characterize patient taste preferences to personalize diets for improved nutritional intake.. Taste changes after cancer treatments are very common. We used chemical gustometry (taste testing) to study taste changes and to better understand why patients with multiple myeloma experience this symptom after autologous hematopoietic cell transplantation. We found that taste testing was feasible, taste changes peaked when blood counts were lowest, and most patients recovered their taste by 100 days after transplantation. Taste changes correlated with lower food intake and with higher levels of chemotherapy in the body. Future work will focus on using personalized chemotherapy doses to reduce taste changes and to match patients' individual taste preferences with their diets.

Topics: Dysgeusia; Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Multiple Myeloma; Prospective Studies; Transplantation, Autologous

Topics: Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Multiple Myeloma; Taste; Transplantation Conditioning; Transplantation, Autologous

Despite the effectiveness of newer drugs for the treatment of multiple myeloma (MM), the outcomes are further improved by subsequent autologous stem cell transplantation (ASCT). Data on effectiveness in older patients are limited. We compared outcomes in patients aged 65-75 years depending on whether they were treated with ASCT or not and compared those to outcomes in patients <65 years.. This was a retrospective, single-center study. We compared progression-free survival (PFS) and overall survival (OS) for all MM patients below and above the age of 65 years treated ± ASCT at the Karolinska University Hospital between 2010 and 2020. PFS and OS were calculated by the Kaplan-Meier method. Variables affecting PFS and OS were evaluated using Cox regression model.. Both PFS and OS were improved in the group 65-75 years treated +ASCT compared to those treated pharmacologically (p = 0.008 and p < 0.001, respectively). There were no significant differences between patients <65 years and those 65-75 years treated with ASCT.. The findings indicate that even patients >65 years should be evaluated as candidates for ASCT. An individualized approach supported by a frailty/geriatric assessment score could assist clinicians to select the appropriate treatment for each patient.

Topics: Aged; Disease-Free Survival; Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Multiple Myeloma; Retrospective Studies; Standard of Care; Transplantation Conditioning; Transplantation, Autologous; Treatment Outcome

An 11 year old female-neutered Labrador presented for facial swelling. Clinicopathological abnormalities included hyperglobulinemia, azotemia, hypercalcemia, nonregenerative anemia, thrombocytopenia, and spurious hypoglycemia. Normoglycemia was subsequently confirmed using a cage-side analyzer (AlphaTRAK, Zoetis, UK). Serum and urine protein electrophoresis documented monoclonal (immunoglobulin M) gammopathy with Bence-Jones proteinuria. Computed tomography imaging revealed a monostotic osteolytic bone-lesion, and bone marrow cytology and histopathology documented plasmacytosis with multiple myeloma oncogene 1 / interferon regulatory factor 4 positivity, consistent with multiple myeloma. Infectious disease testing initially indicated seropositivity for Leishmania, Borrelia, and Anaplasma spp.; however, Leishmania PCR (splenic and bone marrow aspirates), and paired serological titers for Borrelia and Anaplasma were negative. Consequently, initial serological results were considered to be false positive because of paraproteinemia-associated assay interference. Chemotherapy (prednisolone and melphalan combination therapy) was initiated, but the dog was euthanased 30 days later because of the development of pericardial effusion. This is a report of spurious serological (and other laboratory) results occurring secondary to monoclonal gammopathy in a dog.

Topics: Animals; Bone Marrow; Dog Diseases; Dogs; Female; Immunoglobulin M; Melphalan; Multiple Myeloma; Proteinuria

For eligible patients with multiple myeloma (MM) and amyloid light chain (AL) amyloidosis, high-dose chemotherapy and autologous hematopoietic cell transplantation (HCT) is a standard and widely used consolidation therapy. Autologous HCT requires specialized care at a transplantation center and investment from patients and caregivers. We studied the safety and feasibility of delivering transplantation care in a homebound setting to decrease the burden of therapy and increase access to autologous HCT. Patients with MM and AL amyloidosis undergoing autologous HCT were eligible if they resided in designated ZIP codes and had a full-time caregiver, Wi-Fi connection, HCT Comorbidity Index ≤3, and Karnofsky Performance Status score ≥80. High-dose melphalan (on day -2) and hematopoietic cell reinfusion (day 0) were administered in the outpatient clinic. Protocol-specific home care was provided from day +1 through engraftment. Patients were assessed and blood was drawn daily by advanced practice providers. Interventions were delivered by registered nurses. Attending physicians communicated daily through telemedicine. Quality of life, patient and caregiver satisfaction, and fecal microbiota profiling data were collected. Fifteen patients were enrolled and received transplantation care at home starting on day +1 following hematopoietic cell infusion. Patients remained in the program for an average of 12 days and required an average of 2 outpatient visits while receiving home care. Seven of 15 patients were admitted for a median of 4 days (range, 3 to 10 days); admission occurred on day +7 in 5 patients, on day +8 in 1 patient, and on day +12 in 1 patient for neutropenic fever in 2 patients, fever attributed to engraftment syndrome in 2 patients, diarrhea in 2 patients, and dehydration in 1 patient. Only 1 patient had a documented infection (Clostridioides difficile). One patient admitted with neutropenic fever required intensive care unit admission for a gastrointestinal bleed. Forty-seven percent of the patients experienced a grade ≥3 nonhematologic toxicity. There were no deaths on the study. Patients and caregivers reported high satisfaction with care. Microbiota diversity patterns were similar to those of autologous HCT recipients who did not receive post-HCT care at home, although a subset of the cohort maintained microbiota diversity throughout. Homebound HCT in an urban setting is safe and feasible, with less than one-half of patients requiring inpatient adm

Topics: Hematopoietic Stem Cell Transplantation; Humans; Immunoglobulin Light-chain Amyloidosis; Melphalan; Multiple Myeloma; Pilot Projects; Quality of Life; Transplantation, Autologous

Myeloablative therapy with highdoses of the cytostatic drug melphalan (MEL) in preparation for hematopoietic cell transplantation is the standard of care for multiple myeloma (MM) patients. Melphalan is a bifunctional alkylating agent that covalently binds to nucleophilic sites in the DNA and effective in the treatment, but unfortunately has limited therapeutic benefit. Therefore, new approaches are urgently needed for patients who are resistant to existing standard treatment with MEL. Regulating the pharmacological activity of drug molecules by modifying their structure is one method for improving their effectiveness. The purpose of this work was to analyze the physicochemical and biological properties of newly synthesized melphalan derivatives (EE-MEL, EM-MEL, EM-MOR-MEL, EM-I-MEL, EM-T-MEL) obtained through the esterification of the carboxyl group and the replacement of the the amino group with an amidine group. Compounds were selected based on our previous studies for their improved anticancer properties in comparison with the original drug. For this, we first evaluated the physicochemical properties using the circular dichroism technique, then analyzed the zeta potential and the hydrodynamic diameters of the particles. Then, the in vitro biological properties of the analogs were tested on multiple myeloma (RPMI8226), acute monocytic leukemia (THP1), and promyelocytic leukemia (HL60) cells as model systems for hematological malignant cells. DNA damage was assessed by immunostaining γH2AX, cell cycle distribution changes by propidium iodide (PI) staining, and cell death by the activation of caspase 2. We proved that the newly synthesized derivatives, in particular EM-MOR-MEL and EM-T-MEL, affected the B-DNA conformation, thus increasing the DNA damage. As a result of the DNA changes, the cell cycle was arrested in the S and G2/M phases. The cell death occurred by activating a mitotic catastrophe. Our investigations suggest that the analogs EM-MOR-MEL and EM-T-MEL have better anti-cancer activity in multiple myeloma cells than the currently used melphalan.

Topics: Cell Death; Child; DNA Damage; Hematologic Neoplasms; Humans; Melphalan; Multiple Myeloma

Histone deacetylase inhibitors show synergy with several genotoxic drugs. Herein, we investigated the biological impact of the combined treatment of panobinostat and melphalan in multiple myeloma (MM). DNA damage response (DDR) parameters and the expression of DDR-associated genes were analyzed in bone marrow plasma cells (BMPCs) and peripheral blood mononuclear cells (PBMCs) from 26 newly diagnosed MM patients. PBMCs from 25 healthy controls (HC) were examined in parallel. Compared with the ex vivo melphalan-only treatment, combined treatment with panobinostat and melphalan significantly reduced the efficiency of nucleotide excision repair (NER) and double-strand-break repair (DSB/R), enhanced the accumulation of DNA lesions (monoadducts and DSBs), and increased the apoptosis rate only in patients’ BMPCs (all p < 0.001); marginal changes were observed in PBMCs from the same patients or HC. Accordingly, panobinostat pre-treatment decreased the expression levels of critical NER (DDB2, XPC) and DSB/R (MRE11A, PRKDC/DNAPKc, RAD50, XRCC6/Ku70) genes only in patients’ BMPCs; no significant changes were observed in PBMCs from patients or HC. Together, our findings demonstrate that panobinostat significantly increased the melphalan sensitivity of malignant BMPCs without increasing the melphalan sensitivity of PBMCs from the same patients, thus paving the way for combination therapies in MM with improved anti-myeloma efficacy and lower side effects.

Topics: DNA Repair; Humans; Leukocytes, Mononuclear; Melphalan; Multiple Myeloma; Panobinostat

Multiple myeloma (MM) is a hematologic cancer characterized by accumulation of malignant plasma cells in the bone marrow. To date, no definitive cure exists for MM and resistance to current treatments is one of the major challenges of this disease. The DNA helicase BLM, whose depletion or mutation causes the cancer-prone Bloom's syndrome (BS), is a central factor of DNA damage repair by homologous recombination (HR) and genomic stability maintenance. Using independent cohorts of MM patients, we identified that high expression of BLM is associated with a poor outcome with a significant enrichment in replication stress signature. We provide evidence that chemical inhibition of BLM by the small molecule ML216 in HMCLs (human myeloma cell lines) leads to cell cycle arrest and increases apoptosis, likely by accumulation of DNA damage. BLM inhibition synergizes with the alkylating agent melphalan to efficiently inhibit growth and promote cell death in HMCLs. Moreover, ML216 treatment re-sensitizes melphalan-resistant cell lines to this conventional therapeutic agent. Altogether, these data suggest that inhibition of BLM in combination with DNA damaging agents could be of therapeutic interest in the treatment of MM, especially in those patients with high BLM expression and/or resistance to melphalan.

Topics: DNA Repair; Drug Resistance; Humans; Melphalan; Multiple Myeloma; RecQ Helicases

Engraftment syndrome (ES) is a common complication of autologous hematopoietic cell transplantation (HCT). The difference in incidence of ES between melphalan formulations has not been widely reported throughout the literature and would allow for a more comprehensive understanding of the advantages and disadvantages of both melphalan formulations.. This retrospective, single-center, observational study evaluated 83 adult multiple myeloma and immunoglobulin light chain amyloidosis patients who received either propylene glycol-containing (PG) or propylene glycol-free (PG-free) melphalan 140 mg/m. The incidence of ES for PG and PG-free melphalan did not differ significantly, 14/39 (35.9%) and 12/44 (27.3%) (P = 0.4), respectively. No potential risk factors for ES were identified on multivariate logistic regression analysis. A statistically significant difference in number of days to engraftment was identified for PG and PG-free melphalan, 15.56 vs. 13.82 days (P = 0.01), respectively; although, this did not translate to a decrease in LOS, 19.9 vs. 18.59 days (P = 0.14).. The incidence of ES did not differ significantly between melphalan formulations. Future research is needed to determine whether the faster time to engraftment seen with PG-free melphalan may translate to a decrease in LOS.

Topics: Hematopoietic Stem Cell Transplantation; Humans; Immunoglobulin Light-chain Amyloidosis; Incidence; Melphalan; Multiple Myeloma; Retrospective Studies; Transplantation Conditioning; Transplantation, Autologous

Several international centres have published their experiences with outpatient autologous stem cell transplantation (ASCT) as treatment of haematological malignancies.. In this single-centre retrospective review, we aim to examine the outcomes of outpatient autograft and review healthcare resource utilisation in the pre-cytopenic period.. Patients undergoing ASCT in Royal Hobart Hospital, Tasmania between 2008 and 2018 had their records reviewed and key outcomes data collected based on whether they received inpatient/outpatient ASCT. An outpatient ASCT was defined as conditioning as an outpatient; patients could then be managed with an elective admission during the cytopenic period or admission only when clinically indicated.. Of 231 ASCT performed, 135 (58%) were as outpatients: 59 used carmustine-etoposide-cytarabine-melphalan conditioning for lymphoma (BEAM-ASCT) and 76 used high-dose melphalan for myeloma and amyloidosis (MEL-ASCT). Approximately one-third of patients undergoing outpatient ASCT were admitted electively during nadir period; the majority of patients required minimal interventions prior to this time. The most common causes for unplanned hospitalisation (which occurred in 71 (80%) of the 89 planned outpatient transplants) were febrile neutropenia (39%) and mucositis (35%). Age was the only risk factor identified to increase risk of requiring unplanned hospitalisation. Use of oral antibiotic prophylaxis reduced febrile neutropenia rates among melphalan outpatient ASCT. Outpatient ASCT led to significantly reduced inpatient bed-days and overall cost (approximately A$13 000-A$16 000) compared with inpatient autografts, with no significant differences in engraftment, rates of febrile neutropenia, intensive care admissions or mortality.. Outpatient autografts may save healthcare resources without compromising patient outcomes.

Topics: Antineoplastic Combined Chemotherapy Protocols; Australia; Febrile Neutropenia; Hematopoietic Stem Cell Transplantation; Hospitals; Humans; Melphalan; Multiple Myeloma; Outpatients; Retrospective Studies; Stem Cell Transplantation; Tasmania; Transplantation Conditioning; Transplantation, Autologous

Chemotherapy-induced nausea and vomiting (CINV) is one of the most frequent adverse events compromising quality of life (QoL) in patients undergoing autologous stem cell transplantation (ASCT). However, CINV prophylaxis is still lacking uniformity for high-dose melphalan (HDM), which is used to condition patients with multiple myeloma (MM). Netupitant/palonosetron (NEPA) is administered with dexamethasone (DEXA) for CINV prevention in several chemotherapy regimens. Our study aims to assess the efficacy of NEPA, without DEXA, in preventing CINV in 106 adult patients with MM receiving HDM and ASCT. All patients had antiemetic prophylaxis with multiple doses of NEPA 1 h before the start of conditioning and after 72 h and 120 h. A complete response (CR) was observed in 99 (93%) patients at 120 h (overall phase). The percentage of patients with complete control was 93%. The CR rate during the acute phase was 94% (n = 100). During the delayed phase, the CR rate was 95% (n = 101). Grade 1 nausea and vomiting were experienced by 82% and 12% of the patients, respectively. Grade 2 nausea was reported in 18% and vomiting in 10% of patients. Our results showed, for the first time, that NEPA, without DEXA, was a well-tolerated and effective antiemetic option for MM patients receiving HDM followed by ASCT.

Topics: Antiemetics; Dexamethasone; Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Multiple Myeloma; Nausea; Palonosetron; Pyridines; Quality of Life; Quinuclidines; Transplantation, Autologous; Vomiting

Topics: COVID-19 Vaccines; Humans; Immunotherapy; Melphalan; Multiple Myeloma

High-dose chemotherapy followed by autologous hematopoietic stem cell transplantation (auto-HSCT) represents a standard treatment regime for multiple myeloma (MM) patients. Common and potentially fatal side effects after auto-HSCT are infections due to a severely compromised immune system with hampered humoral and cellular immunity. This study delineates in depth the quantitative and functional B cell defects and investigates underlying extrinsic or intrinsic drivers.. Peripheral blood of MM patients undergoing high-dose chemotherapy and auto-HSCT (before high-dose chemotherapy and in early reconstitution after HSCT) was studied. Absolute numbers and distribution of B cell subsets were analyzed. Quantitative B cell defects including a shift in the B cell subset distribution occurred after auto-HSCT. Functionally, these patients showed an impaired TD as well as TI B cell immune response. Individual functional responses correlated with quantitative alterations of CD19+, CD4+, memory B cells and marginal zone-like B cells. The TD B cell function could be partially restored upon stimulation with CD40L/IL-21, successfully inducing B cell proliferation and differentiation into plasmablasts and immunoglobulin secreting cells.. Quantitative and functional B cell defects contribute to the compromised immune defense in MM patients undergoing auto-HSCT. Functional recovery upon TD stimulation and correlation with CD4+ T cell numbers, indicate these as extrinsic drivers of the functional B cell defect. Observed correlations of CD4+, CD19+, memory B and MZ-like B cell numbers with the B cell function suggest that these markers should be tested as potential biomarkers in prospective studies.

Topics: Adult; Antineoplastic Agents, Alkylating; B-Lymphocytes; Case-Control Studies; CD4-Positive T-Lymphocytes; Chemotherapy, Adjuvant; Female; Hematopoietic Stem Cell Transplantation; Humans; Immunocompromised Host; Lymphocyte Activation; Male; Melphalan; Middle Aged; Multiple Myeloma; Neoadjuvant Therapy; Phenotype; Recovery of Function; Transplantation, Autologous; Treatment Outcome

Revaccination after autologous hematopoietic cell transplantation (AHCT) is recommended in post-HCT survivorship guidelines to restore humoral immunity. Data on seroconversion after AHCT and vaccination in multiple myeloma (MM) patients are limited. We investigated the feasibility and effectiveness of vaccination post-AHCT and analyzed the restoration of humoral immunity and patient prognosis. Anti-pathogen titers were measured within a median of 2 days before and 96 days after AHCT and following revaccination in 139 MM patients who had a first AHCT from 2013 to 2016. Most (84%) patients received at least one dose of any planned vaccines. High-dose melphalan with AHCT restored measurable immunity in 18% of patients. In an additional >60% of patients, seroconversion occurred after vaccination; however, despite vaccination, 20% of patients remained seronegative for most pathogens. Attainment of MM complete response post-AHCT was associated with higher rates of seroconversion which yielded significantly longer progression-free and overall survival. Our study demonstrates the feasibility of post-AHCT vaccination, supporting measurement of post-vaccination titers to determine which patients should be considered for antimicrobial prophylaxis, as seroconversion does not occur in all patients. Titer seroconversion is a potential indicator of the immunological effects of AHCT, with restoration of humoral immunity demonstrating improved survival.

Topics: Disease-Free Survival; Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Multiple Myeloma; Transplantation, Autologous; Vaccination

Improvements in multiple myeloma therapy have led to deeper responses that are beyond the limit of detection by historical immunohistochemistry and conventional flow cytometry in bone marrow samples. In parallel, more sensitive techniques for assessing minimal residual disease (MRD) through next-generation flow cytometry and sequencing have been developed and are now routinely available. Deep responses when measured by these assays correspond with improved outcomes and survival. We review the data supporting MRD testing as well as its limitations and how it may fit in with current and future clinical practice.

Topics: Antineoplastic Agents, Alkylating; Disease Management; Female; Flow Cytometry; Humans; Melphalan; Middle Aged; Multiple Myeloma; Neoplasm, Residual; Stem Cell Transplantation

The objective of this research was to develop vitamin E oil (VEO)-loaded liposomes for intravenous delivery and to study the VEO effect on melphalan (MLN) loading, release, and stability. Further, the research aim was to determine the in vitro anticancer activity and in vivo systemic toxicity of MLN and simvastatin (SVN) combinations, for repurposing SVN in multiple myeloma. The liposomes were prepared by thin-film hydration technique. The optimized liposomes were surface modified with Pluronic F108, lyophilized, and evaluated for mean particle size, MLN content and release behavior, and in vitro hemolysis, cytotoxicity, and macrophage uptake characteristics. Further, in vivo acute toxicity of plain MLN + SVN combination was determined in comparison to their liposomal combination. The VEO alone and in combination with D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) has significantly increased the MLN and SVN loading. The reconstituted liposomes showed the mean particle size below 200 nm (cryo-transmission electron microscope analysis also revealed the liposome formation). In presence of VEO, the liposomes have shown substantially controlled drug release, lower hemolysis, sustained cytotoxicity, lower phagocytosis, and moderately improved chemical stability. Besides, the effect of liposomal combination on mice bodyweight is found substantially lower than the plain drug combination. In conclusion, the VEO could be used along with phospholipids and cholesterol to develop liposomal drugs with improved physicochemical characteristics. Further, the interesting cytotoxicity study results indicated that SVN could be repurposed in combination with anticancer drug MLN against multiple myeloma; liposomal drugs could be preferred to obtain improved efficacy with decreased systemic toxicity.

Topics: Animals; Liposomes; Melphalan; Mice; Multiple Myeloma; Particle Size; Polyethylene Glycols; Simvastatin; Vitamin E

Ankylosing spondylitis is an autoimmune disease with chronic inflammation of the spine and sacroiliac joints that is commonly treated with immunosuppressants including disease-modifying antirheumatic drugs and anti-tumor necrosis factor alpha therapy.. A 75-year-old female with active ankylosing spondylitis on treatment with etanercept was referred to us for newly diagnosed IgG kappa free light chain multiple myeloma. After failing induction with revlimid, bortezomib, and dexamethasone, she was initiated on carfilzomib. Following the achievement of adequate response to induction, she underwent an autologous hematopoietic stem cell transplant selected for CD34+ cells with melphalan 200mg/m. Although our patient had a coincident and unprecedented resolution of ankylosing spondylitis after receiving the hematopoietic stem cell transplant, this case consolidates the idea of transplant as a potential treatment option for ankylosing spondylitis and other rheumatological conditions.

Topics: Aged; Bortezomib; Dexamethasone; Female; Hematopoietic Stem Cell Transplantation; Humans; Lenalidomide; Melphalan; Multiple Myeloma; Remission Induction; Spondylitis, Ankylosing; Transplantation Conditioning; Transplantation, Autologous; Treatment Outcome

Most data on autologous hematopoietic cell transplantation (auto-HCT) in myeloma are based on the use of innovator formulation of melphalan. Comparative bioequivalence and efficacy studies of generic melphalan are lacking.. In this retrospective study, we report long-term outcomes of auto-HCT in myeloma using innovator (Alkeran, Aspen Pharma; n = 41) and generic melphalan (Alkacel, Celon Labs, India; n = 55) formulations. All consecutive patients at a single center from the period 2011-2018 were included.. The median follow-up in the innovator and generic groups was 61.7 and 32.5 months, respectively. Both groups were matched for age, sex, stage, and myeloma response. There were significantly more patients in the innovator melphalan group who were administered melphalan at a reduced dose at physician discretion (26.8% vs. 3.6%, p = .001). There were significantly more patients with grade 3 or higher mucositis (68.3% vs. 38.1%, p < .0001) and grade 3 or higher diarrhea (85.4% vs. 50.1%, p < .0001) in the innovator group. The median duration of hospital stay was significantly longer in the innovator group (19 days vs. 15.5 days, p < .0001). There were significantly more patients in the generic group who received standard maintenance (94.5% vs. 34.1%, p < .0001). Despite the differences in the melphalan dose and post-transplant strategies, the 4-year progression-free survival and overall survival were not significantly different in the two groups (58% vs. 63%, p = .7, 71% vs. 72%, p = .4, respectively).. Long-term efficacy comparison is helpful in the absence of postmarketing bioequivalence studies of generic melphalan.

Topics: Adult; Antineoplastic Agents, Alkylating; Disease-Free Survival; Drug Substitution; Drugs, Generic; Female; Hematopoietic Stem Cell Transplantation; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Myeloablative Agonists; Retrospective Studies; Transplantation, Autologous; Treatment Outcome

Topics: Amyloidosis; Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Multiple Myeloma; Transplantation Conditioning; Transplantation, Autologous

Topics: Adult; Aged; Aged, 80 and over; Angiogenesis Inhibitors; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Case-Control Studies; Dexamethasone; Female; Humans; Lenalidomide; Male; Melphalan; Middle Aged; Multiple Myeloma; Prednisone; Prospective Studies; Quality of Life; Registries; Safety; Stem Cell Transplantation

Daratumumab is a CD38-targeting monoclonal antibody approved for intravenous (IV) infusion for multiple myeloma (MM). We describe the Phase II PLEIADES study of a subcutaneous formulation of daratumumab (DARA SC) in combination with standard-of-care regimens: DARA SC plus bortezomib/lenalidomide/dexamethasone (D-VRd) for transplant-eligible newly diagnosed MM (NDMM); DARA SC plus bortezomib/melphalan/prednisone (D-VMP) for transplant-ineligible NDMM; and DARA SC plus lenalidomide/dexamethasone (D-Rd) for relapsed/refractory MM. In total, 199 patients were treated (D-VRd, n = 67; D-VMP, n = 67; D-Rd, n = 65). The primary endpoints were met for all cohorts: the ≥very good partial response (VGPR) rate after four 21-day induction cycles for D-VRd was 71·6% [90% confidence interval (CI) 61·2-80·6%], and the overall response rates (ORRs) for D-VMP and D-Rd were 88·1% (90% CI 79·5-93·9%) and 90·8% (90% CI 82·6-95·9%). With longer median follow-up for D-VMP and D-Rd (14·3 and 14·7 months respectively), responses deepened (ORR: 89·6%, 93·8%; ≥VGPR: 77·6%, 78·5%), and minimal residual disease-negativity (10

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Combined Modality Therapy; Dexamethasone; Female; Follow-Up Studies; Hematologic Diseases; Humans; Immunotherapy; Lenalidomide; Male; Melphalan; Middle Aged; Multiple Myeloma; Prednisone; Standard of Care; Treatment Outcome

Structural chromosomal changes including copy number aberrations (CNAs) are a major feature of multiple myeloma (MM), however their evolution in context of modern biological therapy is not well characterized. To investigate acquisition of CNAs and their prognostic relevance in context of first-line therapy, we profiled tumor diagnosis-relapse pairs from 178 NCRI Myeloma XI (ISRCTN49407852) trial patients using digital multiplex ligation-dependent probe amplification. CNA profiles acquired at relapse differed substantially between MM subtypes: hyperdiploid (HRD) tumors evolved predominantly in branching pattern vs. linear pattern in t(4;14) vs. stable pattern in t(11;14). CNA acquisition also differed between subtypes based on CCND expression, with a marked enrichment of acquired del(17p) in CCND2 over CCND1 tumors. Acquired CNAs were not influenced by high-dose melphalan or lenalidomide maintenance randomization. A branching evolution pattern was significantly associated with inferior overall survival (OS; hazard ratio (HR) 2.61, P = 0.0048). As an individual lesion, acquisition of gain(1q) at relapse was associated with shorter OS, independent of other risk markers or time of relapse (HR = 2.00; P = 0.021). There is an increasing need for rational therapy sequencing in MM. Our data supports the value of repeat molecular profiling to characterize disease evolution and inform management of MM relapse.

Topics: Cyclin D1; DNA Copy Number Variations; Humans; Lenalidomide; Melphalan; Multiple Myeloma; Nerve Tissue Proteins; Prognosis; Recurrence

Autologous stem cell transplantation (ASCT) has been used for treating multiple myeloma (MM) for over three decades and is generally reserved for patients younger than 65. Herein we report on outcomes of outpatient ASCT in a cohort of patients with MM aged ≥75 years. Between October 2005 and August 2020, 50 patients aged ≥75 years, received an ASCT at Mayo Clinic, Rochester. Median time from diagnosis to ASCT was 6.85 months (IQR 5.2-10.52) and 50%. received reduced intensity conditioning with melphalan 140 mg/m

Topics: Disease-Free Survival; Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Multiple Myeloma; Stem Cell Transplantation; Transplantation Conditioning; Transplantation, Autologous; Treatment Outcome

Autologous stem cell transplantation (ASCT) conditioned with melphalan 200 mg/m

Topics: Disease-Free Survival; Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Multiple Myeloma; Retrospective Studies; Transplantation Conditioning; Transplantation, Autologous

In multiple myeloma, drug-resistant cells underlie relapse or progression following chemotherapy. Cell adhesion-mediated drug resistance (CAM-DR) is an established mechanism used by myeloma cells (MMC) to survive chemotherapy and its markers are upregulated in residual disease. The integrin very late antigen 4 (VLA4; α. We synthetized 20 nm VLA4-targeted micellar nanoparticles (V-NP) carrying DiI for tracing or a novel camptothecin prodrug (V-CP). Human or murine MMCs, alone or with stroma, and immunocompetent mice with orthotopic multiple myeloma were used to track delivery of NPs and response to treatments.. V-NPs selectively delivered their payload to MMCs. V-CP may be a safe and effective strategy to prevent or treat relapsing or refractory myeloma. V-NP targeting of resistant cells may suggest a new approach to environment-induced resistance in cancer.

Topics: Animals; Camptothecin; Cell Adhesion; Cell Line, Tumor; Dexamethasone; Drug Resistance, Neoplasm; Humans; Integrin alpha4beta1; Melphalan; Mice; Mice, Inbred C57BL; Multiple Myeloma; Nanoparticles; Topoisomerase I Inhibitors

The aim of this multicentre, longitudinal study was to determine salivary changes in relation to oral mucositis (OM) in multiple myeloma patients following high-dose melphalan and autologous hematopoietic stem cell transplantation (ASCT). Unstimulated and stimulated whole-mouth saliva samples (UWS and SWS) were collected before ASCT, 1×/wk during the hospitalisation phase, and 3 and 12 months post-ASCT. During the hospitalisation period OM was scored 3×/wk (WHO system). Flow rate, pH, total protein concentration (Nanodrop), albumin, lactoferrin, neutrophil defensin-1 (HNP1), total IgA and S100A8/A9 (ELISA) were determined. Mixed models were used to evaluate differences between ulcerative (u)OM (≥2 WHO, n = 20) and non-uOM (n = 31) groups. Until 18 days after ASCT, flow rate, pH, total IgA and HNP1 levels decreased in UWS and/or SWS, while log lactoferrin levels were significantly increased (UWS: p = 0.016 95% CI [0.36, 3.58], SWS: p < 0.001 95% CI [1.14, 3.29]). Twelve months post-ASCT, salivary protein levels were similar to baseline except for log total IgA, which was higher (UWS: p < 0.001 95% CI [0.49, 1.29], SWS: p < 0.001 95% CI [0.72, 1.45]). No differences between uOM and non-uOM groups were observed. Changes in salivary proteins indicated an inflammatory reaction in salivary glands coinciding with mucosal and systemic reactions in response to high-dose melphalan.

Topics: Hematopoietic Stem Cell Transplantation; Humans; Longitudinal Studies; Melphalan; Multiple Myeloma; Stomatitis; Transplantation, Autologous

Topics: Animals; Antineoplastic Agents, Alkylating; Humans; Melphalan; Multiple Myeloma; Phenylalanine; Treatment Outcome

Topics: Aged; Clonal Hematopoiesis; Female; Hematopoietic Stem Cell Transplantation; Humans; Immunologic Factors; Lenalidomide; Maintenance Chemotherapy; Male; Melphalan; Middle Aged; Multiple Myeloma; Prognosis; Retrospective Studies; Salvage Therapy; Transplantation Conditioning; Transplantation, Autologous; Venous Thrombosis

The metabolome, which is the final down-stream global product of metabolic processes in organisms, is not sufficiently described in multiple myeloma (MM) patients. The aim of this study was, therefore, to study the serum metabolomic profile using proton nuclear magnetic resonance (

Topics: Adult; Aged; Antineoplastic Agents, Alkylating; Female; Hematopoietic Stem Cell Transplantation; Humans; Male; Melphalan; Metabolome; Middle Aged; Multiple Myeloma; Neoplasm Staging; Transplantation, Autologous; Treatment Outcome

The ALCYONE trial found that daratumumab in combination with bortezomib, melphalan, and prednisone (D-VMP) can significantly improve progression-free survival (PFS) and overall survival (OS) for patients with transplant-ineligible, newly diagnosed multiple myeloma (MM) in China. In the present study, we evaluated the cost-effectiveness of D-VMP versus VMP for patients with newly diagnosed MM in China.. A Markov model was used to estimate the cost-effectiveness of frontline D-VMP versus VMP for MM. The life years (LYs), quality-adjusted LYs (QALYs), and incremental cost-effectiveness ratio (ICER) were calculated. A series of sensitivity analyses was performed to assess the robustness of the model and address uncertainties in variable estimates. Subgroup analysis was also performed.. D-VMP provided an additional 2.99 LYs and 1.67 QALYs compared with VMP, with incremental $64,920 per LY and $116,015 per QALY gained. The results of the univariable sensitivity analysis showed that the parameter that had the greatest impact on the ICER was the cost of subsequent treatment and daratumumab. When the cost of daratumumab was 100%, 70%, 50%, and 30% of the current price, the probability of D-VMP being cost-effective was 2.49%, 16.11%, 39.09%, and 70.73% at the willingness-to-pay (WTP) threshold of $30,950/QALY, respectively. The results demonstrated that the ICER in all subgroups remained > $30,950/QALY.. D-VMP versus VMP is likely to exceed the commonly accepted values of cost-effectiveness in patients with transplant-ineligible, newly diagnosed MM in China.

Topics: Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Bortezomib; China; Cost-Benefit Analysis; Humans; Melphalan; Multiple Myeloma; Prednisone; Quality-Adjusted Life Years

Progression of multiple myeloma is regulated by factors intrinsic to the clonal plasma cells (PC) and by the immune effector cells in the tumor microenvironment. In this study, we investigated the interaction between CD304 expression on myeloid-derived suppressor cells (MDSC) and galectin-1 from malignant PCs in the context of autologous stem cell transplantation (ASCT) for multiple myeloma. Using high-throughput screening, CD304 expression on circulating monocytic MDSCs (M-MDSC; CD14

Topics: Antineoplastic Agents, Alkylating; Cell Line, Tumor; Galectin 1; Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Monocytes; Multiple Myeloma; Myeloid-Derived Suppressor Cells; Neuropilin-1; Transplantation, Autologous; Tumor Microenvironment

The incidence of multiple myeloma (MM), a bone marrow (BM) resident hematological malignancy, is increasing globally. The disease has substantial morbidity and mortality and remains largely incurable. Clinical studies show that autologous stem cell transplantation (ASCT) remains efficacious in eligible patients, providing a progression free survival (PFS) benefit beyond novel therapies alone. Conventionally, improved PFS after ASCT is attributed to cytoreduction from myeloablative chemotherapy. However, ASCT results in immune effects beyond cytoreduction, including inflammation, lymphodepletion, T cell priming

Topics: Animals; Combined Modality Therapy; Disease Models, Animal; Disease Progression; Graft vs Tumor Effect; Hematopoietic Stem Cell Transplantation; Humans; Immune Checkpoint Inhibitors; Immunogenic Cell Death; Immunotherapy, Adoptive; Melphalan; Mice; Multiple Myeloma; Myeloablative Agonists; Progression-Free Survival; Receptors, Chimeric Antigen; Transplantation, Autologous; Tumor Microenvironment

Despite the significant proportion of older patients with newly diagnosed multiple myeloma (MM), most clinical trials driving therapeutic decisions in routine practice include younger and presumably healthier patients than those in the real world. Furthermore, longitudinal studies suggest that elderly, transplant-ineligible patients with MM are not benefitting enough from new anti-MM agents. We retrospectively analyzed the profile of and treatment patterns and outcomes in 675 transplant-ineligible patients with MM who started frontline therapy in routine practice. The mean (SD) age was 75.6 (6.7) years; 152 (47.4%) had Eastern Cooperative Oncology Group performance status (ECOG PS) 2-4, and 73 (25.1%) had high cytogenetic risk. The most frequent frontline therapy was non-VMP bortezomib-based regimens (n=207; 30.7%), which were more frequent among patients with ECOG PS 0/1 and higher risk (e.g., international staging system (ISS) stage III, severely impaired glomerular filtrate rate (GFR), high lactate dehydrogenase (LDH), and high-risk cytogenetics); 185 patients (27.4%) started an attenuated (lite) VMP regimen, and 159 (23.6%) a VMP (VISTA) regimen. Median progression-free survival and overall survival (OS) were 15.3 months (95%CI 14.0-16.9) and 33.5 months (95%CI 29.1-37.2), respectively; 405 patients (78.2%) achieved partial response or better. Age, ECOG PS, ISS stage, serum LDH, GFR, cytogenetic risk, and treatment regimen significantly influenced OS. In this study, a remarkable proportion of transplant-ineligible patients with MM were older, frontline regimens were highly heterogeneous, and patients at higher risk often received less efficacious combinations. These findings suggest that clinicians have limited objective criteria for therapeutic decisions for this patient group.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Cyclophosphamide; Dexamethasone; Doxorubicin; Female; Humans; Kaplan-Meier Estimate; Lenalidomide; Male; Melphalan; Multiple Myeloma; Prednisone; Progression-Free Survival; Retrospective Studies; Treatment Outcome

Topics: Antineoplastic Combined Chemotherapy Protocols; Autografts; Bortezomib; Cyclophosphamide; Dexamethasone; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Mobilization; Humans; Immune Reconstitution; Melphalan; Multiple Myeloma; Retrospective Studies

The aim of this study was to determine risk factors for development of acute myeloid leukemia/myelodysplastic syndromes (AML/MDS) in patients with multiple myeloma (MM).. We identified all patients diagnosed with MM in Sweden from January 1st, 1958 to December 31, 2011. A total of 26 627 patients were diagnosed with MM with during the study period. Of these, 124 patients (0.5%) developed subsequent AML/MDS. For each patient with MM and a subsequent AML/MDS diagnosis, we randomly selected a matched (age, sex, and date of MM diagnosis) MM patient without a subsequent second malignancy diagnosis.. The cumulative melphalan exposure was significantly higher (OR = 2.8, 95% CI 1.7-5.2; P < .001) among cases (median 988 mg; IQR 644-1640) compared with controls (median 578 mg; IQR 360-967). Median time to AML/MDS development was 3.8 years (IQR 2.8-5.8). Risk of AML/MDS was not statistically altered by M protein isotype, anemia, renal failure, hypercalcemia, lytic bone lesions, or radiation therapy.. In this nationwide population-based study, we show that increased cumulative doses of alkylating therapy with melphalan increases the subsequent risk of developing AML/MDS in patients with MM. Given improved survival in MM patients over the last decade future studies will be important to better define long-term risks.

Topics: Antineoplastic Agents, Alkylating; Disease Susceptibility; Humans; Leukemia, Myeloid, Acute; Melphalan; Multiple Myeloma; Myelodysplastic Syndromes; Neoplasms, Second Primary; Public Health Surveillance; Risk Assessment; Risk Factors; Sweden

Multiple myeloma is an incurable hematological malignancy that impacts tens of thousands of people every year in the United States. Treatment for eligible patients involves induction, consolidation with stem cell rescue, and maintenance. High-dose therapy with a DNA alkylating agent, melphalan, remains the primary drug for consolidation therapy in conjunction with autologous stem-cell transplantation; as such, melphalan resistance remains a relevant clinical challenge. Here, we describe a proteometabolomic approach to examine mechanisms of acquired melphalan resistance in two cell line models. Drug metabolism, steady-state metabolomics, activity-based protein profiling (ABPP, data available at PRIDE: PXD019725), acute-treatment metabolomics, and western blot analyses have allowed us to further elucidate metabolic processes associated with melphalan resistance. Proteometabolomic data indicate that drug-resistant cells have higher levels of pentose phosphate pathway metabolites. Purine, pyrimidine, and glutathione metabolisms were commonly altered, and cell-line-specific changes in metabolite levels were observed, which could be linked to the differences in steady-state metabolism of naïve cells. Inhibition of selected enzymes in purine synthesis and pentose phosphate pathways was evaluated to determine their potential to improve melphalan's efficacy. The clinical relevance of these proteometabolomic leads was confirmed by comparison of tumor cell transcriptomes from newly diagnosed MM patients and patients with relapsed disease after treatment with high-dose melphalan and autologous stem-cell transplantation. The observation of common and cell-line-specific changes in metabolite levels suggests that omic approaches will be needed to fully examine melphalan resistance in patient specimens and define personalized strategies to optimize the use of high-dose melphalan.

Topics: Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Metabolomics; Multiple Myeloma; Transplantation, Autologous

Topics: Gabapentin; Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Multiple Myeloma; Pregabalin; Prospective Studies; Retrospective Studies; Transplant Recipients; Transplantation Conditioning; Transplantation, Autologous

A post hoc subgroup analysis of two phase III trials (NCT00416273, NCT00416208) was carried out to investigate the influence of 100/140 and 200 mg/m² melphalan as well as single/double autologous stem cell transplantation (ASCT) on progression-free survival (PFS). Additionally, the effect of bortezomib consolidation on PFS was analyzed.. Following induction therapy and high-dose melphalan with subsequent ASCT, patients with newly diagnosed multiple myeloma (NDMM) were randomized 1:1 to either four 35-day cycles of bortezomib consolidation (1.6 mg/m² IV on days 1, 8, 15, 22) or observation.. Of the 340 patients included in this analysis, 13.5% received 1 × MEL100/140, 22.9% 2 × MEL100/140, 31.2% 1 × MEL200, and 32.4% 2 × MEL200. With higher cumulative melphalan dose, PFS improved (P = .0085). PFS curves of patients treated with 2 × MEL100/140 and 1 × MEL200 were very similar. The superior dose effect of MEL200 over MEL100/140 was non-existent in the bortezomib consolidation arm but pronounced in the observation arm (P = .0015). Similarly, double ASCT was only beneficial in patients without bortezomib consolidation (P = .0569).. Full dose melphalan and double transplantation seem advantageous only as long as patients are not receiving bortezomib consolidation afterwards.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Combined Modality Therapy; Consolidation Chemotherapy; Dose-Response Relationship, Drug; Female; Hematopoietic Stem Cell Transplantation; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Retrospective Studies; Transplantation, Autologous

This study compared the use of bortezomib in different combination regimens in newly diagnosed multiple myeloma (NDMM) patients who were transplant ineligible.. We analyzed data from the Registry of Monoclonal Gammopathies (RMG) of the Czech Myeloma Group (CMG) to provide real-world evidence of outcome for 794 newly diagnosed MM transplant ineligible patients. The most frequently used regimen was VCd (bortezomib-cyclophosphamide-dexamethasone) (47.5%) over VMP (bortezomib-melphalan-prednisone) (21.7%), BDd (bortezomib-doxorubicin-dexamethasone) (9.8%), and VTd (bortezomib-thalidomide-dexamethasone) (2.9%).. The overall response rate (ORR) was 69.2% (478/691), including 12.6% (≥ CR); 34.7% very good partial responses (VGPR); and 21.9% partial responses (PR). Among triplet regimens, VMP was the most effective regimen compared to VCd, BDd, and VTd. Median PFS was 22.3 vs. 18.5 vs. 13.7 vs. 13.8 mo, (P = .275), respectively, and median OS was 49 vs. 41.7 vs. 37.9 vs. 32.2 mo (P = .004), respectively. The most common grade 3-4 toxicities were anemia in 17.4% and infections in 18% of patients.. Our study confirmed that bortezomib-based treatment is effective and safe in NDMM transplant ineligible patients, especially VMP, which was identified as superior between bortezomib-based induction regimens not only in clinical trials, but also in real clinical practice.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Cyclophosphamide; Czech Republic; Dexamethasone; Disease-Free Survival; Doxorubicin; Female; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Prednisone; Registries; Thalidomide; Treatment Outcome

In the phase 3 ALCYONE study, daratumumab plus bortezomib/melphalan/prednisone (D-VMP) versus bortezomib/melphalan/prednisone (VMP) significantly improved progression-free survival (PFS) and overall survival (OS) in transplant-ineligible, newly diagnosed multiple myeloma (NDMM) patients. We present a subgroup analysis of ALCYONE by patient frailty status.. Frailty assessment was performed retrospectively using age, Charlson comorbidity index, and baseline Eastern Cooperative Oncology Group performance status score. Patients were classified as fit (0), intermediate (1), or frail (≥2); a nonfrail category combined fit and intermediate patients.. Our findings support the clinical benefit of D-VMP in transplant-ineligible NDMM patients enrolled in ALCYONE, regardless of frailty status.

Topics: Aged; Aged, 80 and over; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Female; Humans; Male; Melphalan; Multiple Myeloma; Prednisone

Consolidative autologous hematopoietic stem cell transplantation (AHCT) is commonly used for patients with multiple myeloma (MM). We studied AHCT use and outcomes in patients with MM ≥75 years old.. Patients with MM ≥75 years old receiving AHCT between 2013 and 2017 in the United States were identified using the Center for International Blood and Marrow Transplant Research database. Relapse and/or progression (REL), progression-free survival (PFS), and overall survival (OS) were modeled using Cox proportional hazards models. Covariates used were age, sex, Karnofsky performance score (KPS), HCT-comorbidity index (HCT-CI), International Staging System and/or Durie-Salmon stage, high-risk cytogenetics, melphalan dose, and disease status at and 1 year after transplant. AHCT utilization rate using the Surveillance, Epidemiology, and End Results database was used to estimate specific incidence among ≥75 years old by race and gender.. Of 360 patients, 63% were male, 84% were White, 56% had KPS <90, and 57% had HCT-CI ≥3. The 100-day transplant-related mortality was 1% (0%-2%) with a 2-year REL rate of 27% (95% confidence interval [CI], 22%-33%), PFS of 66% (95% CI, 60%-72%), and OS of 83% (95% CI, 78%-87%). On multivariate analysis, only high-risk cytogenetics was associated with REL risk and decreased PFS. In White males, transplant utilization rate was 5.2%-5.8% compared to 3.5%-4.0% in African American males (P = .02). There was 3.37-3.79% transplant utilization in White females compared to 1.88-2.12% in African American females (P < .01).. The use of AHCT was associated with excellent 2-year outcomes in this selected MM population ≥75 years old. Transplant utilization for patients ≥75 years old remains low with significant racial and gender disparities.

Topics: Aged; Female; Hematopoietic Stem Cell Transplantation; Humans; Male; Melphalan; Multiple Myeloma; Neoplasm Recurrence, Local; Transplantation Conditioning; Transplantation, Autologous; Treatment Outcome; United States

Topics: Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Multiple Myeloma; Stem Cell Transplantation; Transplantation Conditioning; Transplantation, Autologous

Autologous stem cell transplant (ASCT) is a feasible treatment option for multiple myeloma (MM) patients with renal insufficiency; however, these patients tend to experience higher rates of drug toxicity and transplant-related mortality (TRM) during ASCT. Recent adoption of bortezomib-based induction regimens and dose reduction of melphalan during conditioning may improve outcomes in this population. In this single center retrospective study, we compared the toxicity and survival outcomes of 96 MM patients with renal insufficiency undergoing ASCT between two eras: 1998-2007 and 2008-2016. The proportion of dialysis dependent patients was similar in both groups (49 and 45%). We found no TRM in those transplanted more recently as compared with 13% in the older era of ASCT. There were significantly more high grade (grades 3-4) toxicities in the older era of ASCT including high grade electrolyte abnormalities, mucositis, delirium, and bleeding. Patients transplanted more recently had significantly higher overall response rate (ORR) as well as deeper responses to ASCT (≥VGPR in 79% vs 39%). Progression-free survival (PFS) was prolonged by 26 months in the more recent era compared with the older era. Overall, improvements in treatment regimens have resulted in reduced TRM and toxicities for patients with renal insufficiency undergoing ASCT.

Topics: Disease-Free Survival; Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Multiple Myeloma; Renal Insufficiency; Retrospective Studies; Stem Cell Transplantation; Transplantation, Autologous; Treatment Outcome

Multiple myeloma (MM) is the second most common hematologic malignancy. In spite of the development of new therapeutic agents, MM remains incurable due to multidrug resistance (MDR) and the 5-year survival rate is approximately 50%. Thus, further study is needed to investigate the mechanism of MDR and improve MM prognosis. Heat shock protein 90 (HSP90) is a molecular chaperone that is responsible for the stability of a number of client proteins, most of which are involved in tumor progression. Therefore, HSP90 inhibitors represent potential new therapeutic agents for cancer. Furthermore, inhibition of HSP90 leads to degradation of client proteins, overcoming acquired anti-cancer drug resistance. In this study, we assessed the role of HSP90 in MDR using established melphalan-resistant MM cells. We found that expression of HSP90 was higher in melphalan-resistant MM cells than in parent cells and that HSP90 inhibitors KW-2478 and NUV-AUY922 restored drug sensitivity to the level observed in parent cells. Activation of the unfolded protein response is a hallmark of MM, and expression of endoplasmic reticulum stress signaling molecules is reduced in melphalan-resistant cells; however, KW-2478 did not affect endoplasmic reticulum stress signaling. We demonstrated that treatment with KW-2478 decreased expression of Src, a client of HSP90, and suppressed the activity of ERK, Akt, and NF-κB. Our findings indicate that inhibition of HSP90 results in suppression of Src and its downstream effectors, including ERK, Akt, and NF-κB, and therefore that HSP90 inhibitors could be useful for treatment of MDR MM.

Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Cell Survival; Down-Regulation; Drug Resistance, Neoplasm; Drug Synergism; Endoplasmic Reticulum Stress; Gene Expression Regulation, Neoplastic; HSP90 Heat-Shock Proteins; Humans; Isoxazoles; Melphalan; Morpholines; Multiple Myeloma; Resorcinols; Signal Transduction; src-Family Kinases; Unfolded Protein Response

D-VMP is a novel treatment for transplant-ineligible newly diagnosed multiple myeloma (TIE NDMM). D-VMP significantly prolonged PFS versus VMP in the ALCYONE trial. The FIRST trial investigated Rd given in 28-day cycles until disease progression, Rd for 18 cycles, and MPT for 12 cycles for TIE NDMM. As no randomized controlled trials comparing D-VMP to standard-of-care regimens such as those in FIRST are available, an MAIC was performed to assess relative OS and PFS for D-VMP from ALYCONE and Rd continuous, Rd 18, and MPT from FIRST. Individual patient data for D-VMP in ALCYONE were weighted to match aggregated baseline patient characteristics for each arm of FIRST. D-VMP significantly improved OS versus MPT and Rd 18, with a trend favoring D-VMP versus Rd continuous. D-VMP performed significantly better than all FIRST comparators for PFS. This MAIC demonstrates OS and PFS benefits for D-VMP versus Rd continuous, Rd 18, and MPT.

Topics: Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Dexamethasone; Humans; Lenalidomide; Melphalan; Multiple Myeloma; Prednisone; Thalidomide; Treatment Outcome

Multiple myeloma (MM) is the second most prevalent hematologic malignancy after non-Hodgkin lymphoma and is currently considered incurable. Clinical ophthalmic manifestations of MM are rare but at the same time diverse. Ocular surface manifestations of multiple myeloma are uncommon. Conjunctival 'salmon patch' is a typical ocular surface ophthalmological sign with a distinct set of differential diagnoses, including most often ocular adnexal lymphoma. This case report presents a 33-year-old female with a relapse of MM manifesting as a conjunctival 'salmon patch'. The patient initially responded well to medical management including high dose melphalan supported by a third autologous stem cell transplantation (ASCT) and did not require further surgical excision of the ocular lesion. It is suggested that MM should be included in the differential diagnosis of 'salmon patch' conjunctival lesions.

Topics: Adult; Antineoplastic Agents, Alkylating; Combined Modality Therapy; Conjunctiva; Conjunctival Neoplasms; Diagnosis, Differential; Female; Humans; Magnetic Resonance Imaging; Melphalan; Multiple Myeloma; Stem Cell Transplantation; Transplantation, Autologous

The AAA-ATPase TRIP13 drives multiple myeloma progression. Here, we present the crystal structure of wild-type human TRIP13 at a resolution of 2.6 Å. A small-molecule inhibitor targeting TRIP13 was identified on the basis of the crystal structure. The inhibitor, designated DCZ0415, was confirmed to bind TRIP13 using pull-down, nuclear magnetic resonance spectroscopy, and surface plasmon resonance-binding assays. DCZ0415 induced antimyeloma activity

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; ATPases Associated with Diverse Cellular Activities; Cell Cycle Proteins; Cell Proliferation; Crystallography, X-Ray; Disease Progression; Enzyme Inhibitors; Humans; Melphalan; Mice; Mice, Inbred BALB C; Mice, Nude; Multiple Myeloma; Panobinostat; Protein Conformation; Pyridines; Small Molecule Libraries; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

High-dose melphalan (MEL) is the standard conditioning regimen used for autologous stem cell transplantation (ASCT) in patients with multiple myeloma (MM). Generic MEL is routinely used in various transplant centers across the world including ours due to its reduced cost and ease of availability. We compared the pharmacokinetics (PK) and the clinical efficacy of generic MEL with that of the innovator formulation in MM patients undergoing ASCT.. Sixty-three patients diagnosed with MM receiving high-dose MEL were included in this study. MEL levels in plasma were measured using a liquid chromatography tandem mass spectrometry (HPLC/MS-MS) protocol and non-linear mixed effects modeling was used to evaluate the PK of the data.. The interindividual variability (IIV) in MEL area under the concentration versus time curve (AUC) and clearance (CL) were 4.39, 5.88-fold for generic, and 4.34, 6.85-fold for the innovator formulation, respectively. The median MEL AUC and CL were comparable between the 2 formulations. The population PK analysis showed age and creatinine CL as the only significant covariates explaining IIV in MEL AUC/CL. Analysis of MEL PK parameters with clinical outcome showed no significant differences in terms of onset and severity of mucositis, day to neutrophil and platelet engraftment, as well as response status on day 100 post ASCT between patients receiving generic or innovator formulations of MEL. In addition, neither MEL AUC nor CL was found to be associated with day +100 response.. Our study suggests that the PK and efficacy of the generic MEL is comparable to the innovator formulation.

Topics: Adult; Aged; Antineoplastic Agents, Alkylating; Female; Hematopoietic Stem Cell Transplantation; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Transplantation, Autologous; Young Adult

Topics: Antibodies, Monoclonal; Bortezomib; Humans; Melphalan; Multiple Myeloma; Prednisone

Topics: Antibodies, Monoclonal; Bortezomib; Humans; Melphalan; Multiple Myeloma; Prednisone

Topics: Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Busulfan; Humans; Melphalan; Multiple Myeloma; Transplantation Conditioning; Treatment Outcome

Topics: Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Bridged Bicyclo Compounds, Heterocyclic; Busulfan; Cell Line, Tumor; Cytotoxins; Deoxycytidine; DNA Fragmentation; Drug Screening Assays, Antitumor; Endoplasmic Reticulum Chaperone BiP; Endoplasmic Reticulum Stress; Gemcitabine; Humans; Melphalan; Membrane Potential, Mitochondrial; Multiple Myeloma; Neoplasm Proteins; Panobinostat; Signal Transduction; Sulfonamides

Topics: Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Multiple Myeloma; Prednisone

Topics: Adult; Humans; Melphalan; Multiple Myeloma; Obesity; Transplantation, Autologous

Topics: Antineoplastic Agents, Alkylating; Humans; Melphalan; Multiple Myeloma

High dose melphalan (HDM) and autologous stem cell transplant (ASCT) is standard of care for multiple myeloma (MM), but there is significant variability in melphalan exposure (area under the plasma drug concentration-time curve, AUC) when using body surface area-based dosing. Our aim was to establish a method of pharmacokinetic (PK) testing for real-time melphalan dose adjustments.. We performed a prospective PK study of melphalan 140 or 200 mg/m. Less than 20% interpatient variation in the day -2 and - 1 AUC was observed. The day -2 range in AUC (4.95-11.28 mg h/L) confirmed significant interpatient variability. The hypothetical total dose ranged from 133-302 mg/m. Here we outline the methods to establish novel melphalan dosing using PK testing in MM patients undergoing ASCT to target a desired melphalan AUC.

Topics: Autografts; Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Multiple Myeloma; Prospective Studies

The objective of this study is to evaluate the toxicity of autologous transplantation of non-frozen peripheral blood stem cells in Moroccan patients with multiple myeloma.. This was a bicentric retrospective study conducted in the Clinical Haematology Department of Mohammed V Military Teaching Hospital and at the Al Madina Clinic in Casablanca. The study period was from January 2015 to June 2019. All patients with multiple myeloma who had undergone an autologous peripheral stem cell transplant without freezing were included. Mobilisation was performed with lenograstim alone and the collected stem cells were stored for 24-48hours in a blood bank refrigerator at a temperature of 4°C. After standard conditioning with high-dose melphalan, the peripheral blood stem cells were reinjected 24 h following conditioning.. Our study finds good feasibility and low toxicity of autologous peripheral stem cell transplantation without freezing in patients with multiple myeloma.

Topics: Adult; Aged; Blood Cell Count; Blood Preservation; Female; Graft Survival; Hematopoietic Stem Cell Mobilization; Humans; Lenograstim; Male; Melphalan; Middle Aged; Morocco; Multiple Myeloma; Peripheral Blood Stem Cell Transplantation; Retrospective Studies; Transplantation Conditioning; Transplantation, Autologous

Topics: Antineoplastic Agents, Alkylating; Betacoronavirus; Coronavirus Infections; COVID-19; Disease Management; Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Multiple Myeloma; Outpatients; Pandemics; Pneumonia, Viral; Risk Factors; SARS-CoV-2; Steroids; Transplantation, Autologous

We conducted a retrospective study comparing posttransplant outcomes between myeloma patients receiving conditioning melphalan on day-2 vs day-1 for autologous stem cell transplant. Between January 2017 and December 2018, 201 patients received melphalan on day-2 and 166 on day-1 prior to stem cell infusion. Baseline disease and clinical characteristics between the two groups were similar. Although rates of hospitalization were similar between the cohorts, duration of hospital admission was longer for day-1 (median 7 days for day-1 vs 5 days for day-2, p = 0.003). Rates of fever were higher in the day-1 cohort (69% vs 49%, p = 0.0002). Time to platelet and neutrophil engraftment was significantly longer in the day-1 cohort (platelet engraftment median days 17 for day-1 vs 15 for day-2, p < 0.0001, neutrophil engraftment median days 16 for day-1 vs 16 for day-2, p = 0.025). Overall response rate was similar between the cohorts (99% for day-1, vs 100% for day-2). Day-2 melphalan infusions should be considered in preference for day-1 protocols, given the clinically significant delay in platelet and neutrophil engraftment and longer duration of hospitalization with day-1 infusions.

Topics: Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Multiple Myeloma; Retrospective Studies; Stem Cell Transplantation; Transplantation Conditioning; Transplantation, Autologous

The public subsidy in Australia of bortezomib (Velcade) for untreated non-transplant multiple myeloma patients was based on the VISTA trial.. To ascertain the health outcomes of bortezomib in 'real world' transplant-ineligible elderly patients, compared to trial data.. Patient and treatment data were extracted from an oncology information system, laboratory information system and medical chart audits for three Queensland public hospitals.. We identified 74 patients; the median age was 75 years. Our cohort comprised 47% patients who were International Staging System stage III, 45% at stage II and 8% at stage I. Patients who had comorbidities, such as cardiac disease (41%), pulmonary disease (14%), diabetes (22%), peripheral neuropathy (14%) and other comorbidities (41%) at baseline were included. The common regimens prescribed were VMP, CVD and VD, and most patients (n = 73) received bortezomib on a once-weekly or twice-a-week basis. The overall response rate was 81%. Half (53%) of the patients did not complete their planned therapy due to toxicity (30%), suboptimal response or disease progression (15%), or death on treatment (8%). Overall survival was 40.7 months and progression free survival was 17.7 months.. Our patients were older, had worse disease characteristics and more comorbidities than patients in the VISTA trial. While response rates were similar, survival outcomes appeared worse. Bortezomib-based treatment in the real world setting still carries a high risk of toxicity in the elderly population.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Australia; Bortezomib; Humans; Melphalan; Multiple Myeloma; Prednisone; Queensland; Treatment Outcome

High-dose melphalan and autologous hematopoietic stem cell transplantation (AHSCT) is the standard treatment strategy for multiple myeloma (MM) patients who are eligible for it. The recommended dose of CD34+ hematopoietic progenitor cells (HPCs) for adequate engraftment is above 2 × 106/kg. The aim of this study was to evaluate the relationship between the dose of CD34+HPCs and survival in MM patients who underwent AHSCT at a tertiary care center.. Enrolled in this study were 271 MM patients who underwent AHSCT between 2003 and 2019. Clinical characteristics of the patients, disease status pre-AHSCT, reinfused CD34+ cell doses, and neutrophil and platelet engraftment days were recorded, retrospectively. The patients were divided into 2 groups according to whether the dose of reinfused CD 34+ HPCs was <5 × 106/kg or ≥5 × 106/kg. The groups were compared in terms of engraftment and overall survival (OS) times.. The median age of the patients was 54.8 (33–76) years. The median dose of infused CD34+ HPCs was 5.94 × 106/kg (1.47–59.5 × 106/kg). The median follow-up period was 54 months (4–211). The median OS of the patients was 103 months (11–144). The median neutrophil and platelet engraftment time was 10 (8–24) and 11 (7–40) days. Doses of <5 × 106/kg and ≥5 × 106/kg CD34+ HPC were reinfused in 38.1% and 61.9% of the patients, respectively. There was a negative significant correlation between the reinfused CD34+cell level and neutrophil/platelet engraftment times (r = –0.32, P < 0.001; r = –0.27, P < 0.001, respectively). The median OS times were observed as 103 months (11–144) and 145 months (123–166) for patients who had been administered <5 × 106/kg and ≥5 × 106/kg of CD34+ HPCs, respectively (P = 0.009).. The increased amount of CD34+ autologous hematopoietic stem cell dose after high dose melphalan chemotherapy in MM patients shortened the platelet and neutrophil engraftment time and increased OS. Early platelet engraftment and administration of a CD34+ HPC count that is ≥5 × 106/kg can be considered as predictors of better survival in patients.

Topics: Adult; Aged; Antineoplastic Agents, Alkylating; Female; Follow-Up Studies; Graft Survival; Hematopoietic Stem Cell Transplantation; Hematopoietic Stem Cells; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Transplantation, Autologous

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Combined Modality Therapy; Cyclophosphamide; Dexamethasone; Fatal Outcome; Female; Humans; Lenalidomide; Melphalan; Multiple Myeloma; Pleural Neoplasms; Prednisolone; Thalidomide

Topics: Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Multiple Myeloma; Transplantation Conditioning; Transplantation, Autologous

We compared the efficacy and toxicity of busulfan and melphalan (BUMEL) and those of high-dose melphalan (HDMEL) as conditioning regimens for autologous stem cell transplantation (ASCT) in patients with multiple myeloma (MM) through a propensity score-matched analysis. No significant difference in the complete response and overall response rate after ASCT was observed between BUMEL and HDMEL. After a median follow-up of 37.3 months in the BUMEL group and 50.8 months in the HDMEL group, the median progression-free survival was calculated to be 32.9 months and 25.2 months (

Topics: Antineoplastic Combined Chemotherapy Protocols; Busulfan; Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Multiple Myeloma; Propensity Score; Stem Cell Transplantation; Transplantation Conditioning; Transplantation, Autologous

Topics: Adult; Aged; Antiemetics; Dexamethasone; Drug Therapy, Combination; Female; Hematopoietic Stem Cell Transplantation; Humans; Induction Chemotherapy; Male; Melphalan; Middle Aged; Multiple Myeloma; Nausea; Palonosetron; Prospective Studies; Pyridines; Transplantation Conditioning; Transplantation, Autologous; Vomiting

Multiple myeloma (MM) progression is characterized by the seeding of cancer cells in different anatomic sites. To characterize this evolutionary process, we interrogated, by whole genome sequencing, 25 samples collected at autopsy from 4 patients with relapsed MM and an additional set of 125 whole exomes collected from 51 patients. Mutational signatures analysis showed how cytotoxic agents introduce hundreds of unique mutations in each surviving cancer cell, detectable by bulk sequencing only in cases of clonal expansion of a single cancer cell bearing the mutational signature. Thus, a unique, single-cell genomic barcode can link chemotherapy exposure to a discrete time window in a patient's life. We leveraged this concept to show that MM systemic seeding is accelerated at relapse and appears to be driven by the survival and subsequent expansion of a single myeloma cell following treatment with high-dose melphalan therapy and autologous stem cell transplant.

Topics: Antineoplastic Combined Chemotherapy Protocols; Cell Survival; Clonal Evolution; Disease Progression; Dose-Response Relationship, Drug; Hematopoietic Stem Cell Transplantation; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Mutation; Neoplasm Invasiveness; Neoplasm Recurrence, Local; Positron Emission Tomography Computed Tomography; Single-Cell Analysis; Spatio-Temporal Analysis; Transplantation, Autologous; Whole Genome Sequencing

Melphalan at a dose of 200 mg/m

Topics: Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Busulfan; Follow-Up Studies; Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Multiple Myeloma; Transplantation Conditioning; Transplantation, Autologous

High-dose chemotherapy with melphalan followed by autologous transplantation is a first-line treatment for multiple myeloma. Here, we present preclinical evidence that this treatment may be significantly improved by the addition of exportin 1 inhibitors (XPO1i). The XPO1i selinexor, eltanexor, and KOS-2464 sensitized human multiple myeloma cells to melphalan. Human 8226 and U266 multiple myeloma cell lines and melphalan-resistant cell lines (8226-LR5 and U266-LR6) were highly sensitized to melphalan by XPO1i. Multiple myeloma cells from newly diagnosed and relapsed/refractory multiple myeloma patients were also sensitized by XPO1i to melphalan. In NOD/SCIDγ mice challenged with either parental 8226 or U266 multiple myeloma and melphalan-resistant multiple myeloma tumors, XPO1i/melphalan combination treatments demonstrated stronger synergistic antitumor effects than single-agent melphalan with minimal toxicity. Synergistic cell death resulted from increased XPO1i/melphalan-induced DNA damage in a dose-dependent manner and decreased DNA repair. In addition, repair of melphalan-induced DNA damage was inhibited by selinexor, which decreased melphalan-induced monoubiquitination of FANCD2 in multiple myeloma cells. Knockdown of FANCD2 was found to replicate the effect of selinexor when used with melphalan, increasing DNA damage (γH2AX) by inhibiting DNA repair. Thus, combination therapies that include selinexor or eltanexor with melphalan may have the potential to improve treatment outcomes of multiple myeloma in melphalan-resistant and newly diagnosed patients. The combination of selinexor and melphalan is currently being investigated in the context of high-dose chemotherapy and autologous transplant (NCT02780609). SIGNIFICANCE: Inhibition of exportin 1 with selinexor synergistically sensitizes human multiple myeloma to melphalan by inhibiting Fanconi anemia pathway-mediated DNA repair.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; DNA Damage; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Exportin 1 Protein; Fanconi Anemia Complementation Group D2 Protein; Humans; Hydrazines; Karyopherins; Melphalan; Mice, Inbred NOD; Multiple Myeloma; Nestin; Receptors, Cytoplasmic and Nuclear; Triazoles; Ubiquitination; Xenograft Model Antitumor Assays

Therapeutic strategies designed to tinker with cancer cell DNA damage response have led to the widespread use of PARP inhibitors for BRCA1/2-mutated cancers. In the haematological cancer multiple myeloma, we sought to identify analogous synthetic lethality mechanisms that could be leveraged upon established cancer treatments. The combination of ATR inhibition using the compound VX-970 with a drug eliciting interstrand cross-links, melphalan, was tested in in vitro, ex vivo, and most notably in vivo models. Cell proliferation, induction of apoptosis, tumor growth and animal survival were assessed. The combination of ATM inhibition with a drug triggering double strand breaks, doxorucibin, was also probed. We found that ATR inhibition is strongly synergistic with melphalan, even in resistant cells. The combination was dramatically effective in targeting myeloma primary patient cells and cell lines reducing cell proliferation and inducing apoptosis. The combination therapy significantly reduced tumor burden and prolonged survival in animal models. Conversely, ATM inhibition only marginally impacted on myeloma cell survival, even in combination with doxorucibin at high doses. These results indicate that myeloma cells extensively rely on ATR, but not on ATM, for DNA repair. Our findings posit that adding an ATR inhibitor such as VX-970 to established therapeutic regimens may provide a remarkably broad benefit to myeloma patients.

Topics: Animals; Apoptosis; Ataxia Telangiectasia Mutated Proteins; Cell Line, Tumor; Cell Survival; DNA Damage; DNA Repair; Humans; Melphalan; Multiple Myeloma

Experimental evidence suggests that ubiquitin-protein ligases regulate a number of cellular processes involved in tumorigenesis. We analysed the role of the E3 ubiquitin-protein ligase HUWE1 for pathobiology of multiple myeloma (MM), a still incurable blood cancer. mRNA expression analysis indicates an increase in HUWE1 expression levels correlated with advanced stages of myeloma. Pharmacologic as well as RNAi-mediated HUWE1 inhibition caused anti-proliferative effects in MM cell lines in vitro and in an MM1.S xenotransplantation mouse model. Cell cycle analysis upon HUWE1 inhibition revealed decreased S phase cell fractions. Analyses of potential HUWE1-dependent molecular functions did not show involvement in MYC-dependent gene regulation. However, HUWE1 depleted MM cells displayed increased DNA tail length by comet assay, as well as changes in the levels of DNA damage response mediators such as pBRCA1, DNA-polymerase β, γH2AX and Mcl-1. Our finding that HUWE1 might thus be involved in endogenous DNA repair is further supported by strongly enhanced apoptotic effects of the DNA-damaging agent melphalan in HUWE1 depleted cells in vitro and in vivo. These data suggest that HUWE1 might contribute to tumour growth by endogenous repair of DNA, and could therefore potentially be exploitable in future treatment developments.

Topics: Animals; Antineoplastic Agents, Alkylating; Cell Line, Tumor; Disease Progression; DNA Repair; Female; Gene Expression Regulation, Neoplastic; Humans; Melphalan; Mice, SCID; Multiple Myeloma; Neoplasms, Experimental; Primary Cell Culture; Proto-Oncogene Proteins c-myc; Tumor Suppressor Proteins; Ubiquitin-Protein Ligases

Autologous stem cell transplantation (ASCT) remains the standard of care for young multiple myeloma (MM) patients; indeed, at-home ASCT has been positioned as an appropriate therapeutic strategy. However, despite the use of prophylactic antibiotics, neutropenic fever (NF) and hospital readmissions continue to pose as the most important limitations in the outpatient setting. It is possible that the febrile episodes may have a non-infectious etiology, and engraftment syndrome could play a more significant role. The aim of this study was to analyze the impact of both G-CSF withdrawal and the addition of primary prophylaxis with corticosteroids after ASCT.. Between January 2002 and August 2018, 111 MM patients conditioned with melphalan were managed at-home beginning +1 day after ASCT. Three groups were established: Group A (n = 33) received standard G-CSF post-ASCT; group B (n = 32) avoided G-CSF post-ASCT; group C (n = 46) avoided G-CSF yet added corticosteroid prophylaxis post-ASCT.. The incidence of NF among the groups was reduced (64%, 44%, and 24%; P<0.001), with a non-significant decrease in hospital readmissions as well (12%, 6%, and 2%; P = 0.07). The most important variables identified for NF were: HCT-CI >2 (OR 6.1; P = 0.002) and G-CSF avoidance plus corticosteroids (OR 0.1; P<0.001); and for hospital readmission: age ≥60 years (OR 14.6; P = 0.04) and G-CSF avoidance plus corticosteroids (OR 0.07; P = 0.05).. G-CSF avoidance and corticosteroid prophylaxis post ASCT minimize the incidence of NF in MM patients undergoing at-home ASCT. This approach should be explored in a prospective randomized clinical trial.

Topics: Adrenal Cortex Hormones; Adult; Age Factors; Aged; Antineoplastic Agents, Alkylating; Female; Fever; Granulocyte Colony-Stimulating Factor; Humans; Incidence; Male; Melphalan; Middle Aged; Multiple Myeloma; Odds Ratio; Patient Readmission; Progression-Free Survival; Risk Factors; Stem Cell Transplantation; Transplantation, Autologous

Topics: Humans; Melphalan; Multiple Myeloma; Neoplasms, Plasma Cell