melphalan and carfilzomib

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

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

The monoclonal gammopathies of renal significance (MGRS) are a group of disorders characterized by monoclonal Ig deposition in the kidney, but are not associated with systemic lymphoma or overt multiple myeloma. The prevailing hypothesis is that the pathogenic paraproteins in MGRS are produced by underlying B cell or plasma cell clones. However, in the MGRS literature, the yield of detecting a clone has been variable, and progression to ESRD is common. Here, we present an "onco-nephrologic" approach to the MGRS disorders by highlighting recent advances in lymphoma and multiple myeloma that can be used in the evaluation and management of these patients.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bendamustine Hydrochloride; Bortezomib; Cyclophosphamide; Dexamethasone; Humans; Immunoglobulins; Immunosuppressive Agents; Kidney Diseases; Lenalidomide; Melphalan; Oligopeptides; Paraproteinemias; Pentostatin; Rituximab; Thalidomide; Vidarabine

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

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

We report a case of a relapsed hemophagocytic intramedullary plasmacytoma, previously non-phagocytic, in conjunction with development of a new clone with different cytogenetic abnormalities forming a solitary plasmacytoma.

Topics: Adult; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Bone Neoplasms; Bortezomib; Carmustine; Cisplatin; Cyclophosphamide; Cytarabine; Dexamethasone; Doxorubicin; Etoposide; Female; Humans; Magnetic Resonance Imaging; Melphalan; Neoplasm Recurrence, Local; Oligopeptides; Plasmacytoma; Positron Emission Tomography Computed Tomography; Pubic Bone; Rare Diseases; Stem Cell Transplantation; Thalidomide; Transplantation, Autologous; Treatment Outcome

The heparan sulfate-degrading enzyme heparanase promotes the progression of many cancers by driving tumor cell proliferation, metastasis and angiogenesis. Heparanase accomplishes this via multiple mechanisms including its recently described effect on enhancing biogenesis of tumor exosomes. Because we recently discovered that heparanase expression is upregulated in myeloma cells that survive chemotherapy, we were prompted to investigate the impact of anti-myeloma drugs on exosome biogenesis. When myeloma cells were exposed to the commonly utilized anti-myeloma drugs bortezomib, carfilzomib or melphalan, exosome secretion by the cells was dramatically enhanced. These chemotherapy-induced exosomes (chemoexosomes) have a proteome profile distinct from cells not exposed to drug including a dramatic elevation in the level of heparanase present as exosome cargo. The chemoexosome heparanase was not found inside the chemoexosome, but was present on the exosome surface where it was capable of degrading heparan sulfate embedded within an extracellular matrix. When exposed to myeloma cells, chemoexosomes transferred their heparanase cargo to those cells, enhancing their heparan sulfate degrading activity and leading to activation of ERK signaling and an increase in shedding of the syndecan-1 proteoglycan. Exposure of chemoexosomes to macrophages enhanced their secretion of TNF-α, an important myeloma growth factor. Moreover, chemoexosomes stimulated macrophage migration and this effect was blocked by H1023, a monoclonal antibody that inhibits heparanase enzymatic activity. These data suggest that anti-myeloma therapy ignites a burst of exosomes having a high level of heparanase that remodels extracellular matrix and alters tumor and host cell behaviors that likely contribute to chemoresistance and eventual patient relapse.. We find that anti-myeloma chemotherapy dramatically stimulates secretion of exosomes and alters exosome composition. Exosomes secreted during therapy contain high levels of heparanase on their surface that can degrade ECM and also can be transferred to both tumor and host cells, altering their behavior in ways that may enhance tumor survival and progression.

Topics: Animals; Antineoplastic Agents; Bortezomib; Cell Line, Tumor; Drug Resistance, Neoplasm; Drug Therapy; Exosomes; Extracellular Matrix; Gene Expression Regulation, Neoplastic; Glucuronidase; Humans; Melphalan; Mice; Multiple Myeloma; Oligopeptides; RAW 264.7 Cells; Signal Transduction; Up-Regulation

Venetoclax (ABT-199), a specific inhibitor of the anti-apoptotic protein Bcl-2, is currently in phase I clinical trials for multiple myeloma. The results suggest that venetoclax is only active in a small cohort of patients therefore we wanted to determine its efficacy when used in combination. Combining venetoclax with melphalan or carfilzomib produced additive or better cell death in four of the five cell lines tested. The most striking results were seen with dexamethasone (Dex). Co-treatment of human myeloma cell lines and primary patient samples, with Dex and venetoclax, significantly increased cell death over venetoclax alone in four of the five cell lines, and in all patient samples tested. The mechanism by which this occurs is an increase in the expression of both Bcl-2 and Bim upon addition of Dex. This results in alterations in Bim binding to anti-apoptotic proteins. Dex shifts Bim binding towards Bcl-2 resulting in increased sensitivity to venetoclax. These data suggest that knowledge of drug-induced alterations of Bim-binding patterns may help inform better combination drug regimens. Furthermore, the data indicate combining this novel therapeutic with Dex could be an effective therapy for a broader range of patients than would be predicted by single-agent activity.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Apoptosis Regulatory Proteins; Bcl-2-Like Protein 11; Bridged Bicyclo Compounds, Heterocyclic; Cell Line, Tumor; Dexamethasone; Humans; Melphalan; Middle Aged; Multiple Myeloma; Oligopeptides; Protein Binding; Proto-Oncogene Proteins c-bcl-2; Sulfonamides; Tumor Cells, Cultured

High heparanase expression is associated with enhanced tumor growth, angiogenesis, and metastasis in many types of cancer. However, the mechanisms driving high heparanase expression are not fully understood. In the present study, we discovered that drugs used in the treatment of myeloma upregulate heparanase expression. Frontline anti-myeloma drugs, bortezomib and carfilzomib activate the nuclear factor-kappa B (NF-κB) pathway to trigger heparanase expression in tumor cells. Blocking the NF-κB pathway diminished this chemotherapy-induced upregulation of heparanase expression. Activated NF-κB signaling was also found to drive high heparanase expression in drug resistant myeloma cell lines. In addition to enhancing heparanase expression, chemotherapy also caused release of heparanase by tumor cells into the conditioned medium. This soluble heparanase was taken up by macrophages and triggered an increase in TNF-α production. Heparanase is also taken up by tumor cells where it induced expression of HGF, VEGF and MMP-9 and activated ERK and Akt signaling pathways. These changes induced by heparanase are known to be associated with the promotion of an aggressive tumor phenotype. Importantly, the heparanase inhibitor Roneparstat diminished the uptake and the downstream effects of soluble heparanase. Together, these discoveries reveal a novel mechanism whereby chemotherapy upregulates heparanase, a known promoter of myeloma growth, and suggest that therapeutic targeting of heparanase during anti-cancer therapy may improve patient outcome.

Topics: Antineoplastic Agents; Bortezomib; Cell Line, Tumor; Doxorubicin; Enzyme Induction; Gene Expression Regulation, Neoplastic; Glucuronidase; Humans; Melanoma; Melphalan; Oligopeptides; Phenotype

The novel agents including thalidomide, bortezomib and lenalidomide have been incorporated into combination regimens which are moving from the advanced/refractory setting to first-line treatment. For the majority of elderly patients, the following regimens are considered standard: melphalan+prednisone in combination with bortezomib or thalidomide and the combination of lenalidomide+low-dose dex. For transplant-eligible patients novel agents are included in the induction phase before and in the consolidation/maintenance phase after transplant. In the relapsed/refractory setting, combinations of novel agents generate the best results but cumulative toxicity is limiting. Several newer agents such as carfilzomib, pomalidomide and deacetylase inhibitors are entering phase II and III clinical trials. The place of allogeneic stem cell transplantation in the treatment of myeloma remains controversial.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Boronic Acids; Bortezomib; Humans; Lenalidomide; Medical Oncology; Melphalan; Multiple Myeloma; Oligopeptides; Prednisone; Pyrazines; Quality of Life; Salvage Therapy; Stem Cell Transplantation; Thalidomide