melphalan and Osteolysis

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

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

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

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

Bone loss in multiple myeloma (MM) is caused by an uncoupling of bone formation to resorption trigged by malignant plasma cells. Increasing evidence indicates that the bone remodelling compartment (BRC) canopy, which normally covers the remodelling sites, is important for coupled bone remodelling. Loss of this canopy has been associated with bone loss. This study addresses whether the bone remodelling in MM is improved by high-dose therapy. Bone marrow biopsies obtained from 20 MM patients, before and after first-line treatment with high-dose melphalan followed by autologous stem cell transplantation, and from 20 control patients with monoclonal gammopathy of undetermined significance were histomorphometrically investigated. This investigation confirmed that MM patients exhibited uncoupled bone formation to resorption and reduced canopy coverage. More importantly, this study revealed that a good response to anti-myeloma treatment increased the extent of formative bone surfaces with canopy, and reduced the extent of eroded surfaces without canopy, reverting the uncoupled bone remodelling, while improving canopy coverage. The association between improved coupling and the canopy coverage supports the notion that canopies are critical for the coupling of bone formation to resorption. Furthermore, this study supports the observation that systemic bone disease in MM can be reversed in MM patients responding to anti-myeloma treatment.

Topics: Autografts; Bone Marrow; Bone Remodeling; Female; Humans; Male; Melphalan; Multiple Myeloma; Osteogenesis; Osteolysis; Stem Cell Transplantation

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Boronic Acids; Bortezomib; Cesarean Section; Chemoradiotherapy; Cisplatin; Combined Modality Therapy; Contraindications; Cyclophosphamide; Cytarabine; Dexamethasone; Doxorubicin; Etoposide; Fatal Outcome; Female; Hematopoietic Stem Cell Transplantation; Humans; Hypercalcemia; Idarubicin; Infant, Newborn; Lenalidomide; Male; Melphalan; Methylprednisolone; Multiple Myeloma; Myeloma Proteins; Osteolysis; Plasmacytoma; Postpartum Period; Pregnancy; Pregnancy Complications, Neoplastic; Pregnancy Outcome; Pyrazines; Remission Induction; Spinal Cord Compression; Thalidomide; Thoracic Vertebrae; Transplantation, Autologous

A 74-year-old woman with refractory IgG-κ multiple myeloma developed massive melena caused by hemorrhagic submucosal tumors in the duodenum and middle jejunum. A biopsy revealed the tumor to be marked AL amyloid deposition. Treatment with bortezomib did not improve the melena or the underlying disease. The patient also developed multiple amyloidomas in the bilateral femoral heads, which caused a fracture in the left femoral head. Treatment with lenalidomide, as the final therapeutic option, resolved the intractable melena and improved both the intestinal lesions and myeloma. This case shows that successful treatment of multiple myeloma leads to marked improvement of accompanying AL amyloidosis.

Topics: Aged; Amyloid; Amyloidosis; Angiogenesis Inhibitors; Antineoplastic Combined Chemotherapy Protocols; Blood Transfusion; Bone Diseases; Boronic Acids; Bortezomib; Carpal Tunnel Syndrome; Dexamethasone; Disease Progression; Doxorubicin; Duodenal Diseases; Female; Femur Head; Fractures, Spontaneous; Gastrointestinal Hemorrhage; Hip Fractures; Humans; Jejunal Diseases; Lenalidomide; Melphalan; Multiple Myeloma; Osteolysis; Prednisolone; Pyrazines; Thalidomide; Vincristine

Topics: Antibodies, Monoclonal, Murine-Derived; Antineoplastic Combined Chemotherapy Protocols; Bone Density Conservation Agents; Bone Resorption; Boronic Acids; Bortezomib; Combined Modality Therapy; Dexamethasone; Diphosphonates; Hematopoietic Stem Cell Transplantation; Humans; Imidazoles; Male; Melphalan; Middle Aged; Multimodal Imaging; Osteolysis; Positron-Emission Tomography; Pyrazines; Recurrence; Remission Induction; Rituximab; Tomography, X-Ray Computed; Waldenstrom Macroglobulinemia; Zoledronic Acid

To prospectively assess molecular imaging of multiple myeloma (MM) by using the radiolabeled amino acid carbon 11 ((11)C) methionine and positron emission tomography (PET)/computed tomography (CT).. The study was approved by the institutional local ethics committee and the national radiation protection authorities. All patients with MM and control patients gave written informed consent. Nineteen patients with MM (11 women, eight men; age range, 42-64 years) and 10 control patients with hyperparathyroidism without hematologic diseases (six women, four men; age range, 43-75 years) underwent PET/CT 20 minutes after injection of a mean of 1.0 GBq +/- 0.2 (standard deviation) (11)C-methionine. Presence and extent of CT-assessed tumor manifestations and (11)C-methionine bone marrow (BM) uptake were determined on the basis of maximum standardized uptake value (SUV(max)). BM imaging patterns, normal BM, and maximal lesion (11)C-methionine uptake in patients with MM were compared with those in control patients. In two patients with MM, sulfur 35 ((35)S) methionine uptake in freshly isolated BM plasma cells was measured. Values for SUV(max) of groups were compared by using the Mann-Whitney test on a per-patient basis.. (35)S-methionine uptake of plasma cells was five- to sixfold higher than in normal BM cells. (11)C-methionine BM uptake in control patients was homogeneous and low. All patients with MM except one with exclusively extramedullary myeloma had (11)C-methionine-positive lesions. Maximal lesion and normal BM (11)C-methionine mean SUV(max) were 10.2 +/- 3.5 and 4.3 +/- 2.0, respectively, and thus were significantly higher than that of BM in the control group (mean, 1.8 +/- 0.3; P < .001). Extramedullary MM was clearly visible in three patients (mean SUV(max), 7.2 +/- 2.4). Additional (11)C-methionine-positive lesions in normal cancellous bone were found in nearly all patients with MM. In pretreated patients with MM, a moderate fraction of osteolytic lesions had no (11)C-methionine uptake.. On the basis of increased methionine uptake in plasma cells, active MM can be imaged with (11)C-methionine PET/CT.

Topics: Adult; Aged; Antineoplastic Agents, Alkylating; Bone and Bones; Bone Marrow; Carbon Radioisotopes; Cohort Studies; Female; Follow-Up Studies; Humans; Hyperparathyroidism; Image Processing, Computer-Assisted; Male; Melphalan; Methionine; Middle Aged; Multiple Myeloma; Osteolysis; Plasma Cells; Positron-Emission Tomography; Prospective Studies; Radiopharmaceuticals; Sulfur Radioisotopes; Syndecan-1; Tomography, X-Ray Computed

Supporting roles of stromal cells in preferential colonization of myeloma cells in bone marrow and development of associated osteoclastic osteolysis through cell-cell interactions have been indicated. Here we examined the effects of a monoclonal antibody to alpha4 integrin (anti-alpha4 Ab) that disrupts myeloma cell-stromal cell interactions mediated via alpha4beta1 integrin and vascular cell adhesion molecule-1 (VCAM-1) on myeloma cell growth in bone marrow and accompanying osteolysis. The anti-alpha4 Ab decreased VCAM-1-stimulated 5TGM1/luc cell growth in culture. The 5TGM1 murine myeloma cells stably transfected with the firefly luciferase (5TGM1/luc) were inoculated from tail vein in bg/xid/nd mice. Preventative administration of the anti-alpha4 Ab suppressed the elevation of serum IgG2b levels, decreased 5TGM1/luc tumor burden with increased apoptosis in bone and spleen, reduced bone destruction with diminished number of osteoclasts, and prolonged survival of 5TGM1/luc-bearing mice. In contrast, therapeutic administration of the antibody failed to show these effects. However, therapeutic administration of the antibody combined with melphalan significantly suppressed serum IgG2b levels and tumor burden in bone. Our results suggest that the interactions with stromal cells via alpha4beta1/VCAM-1 are critical to the development of myeloma and associated osteolysis and that disruption of these interactions using anti-alpha4 Ab is a potential therapeutic approach for myeloma.

Topics: Animals; Antibodies; Antibodies, Monoclonal; Apoptosis; Bone and Bones; Bone Marrow Cells; Cell Communication; Cell Division; Cell Line, Tumor; Cell Survival; Immunoglobulin G; Integrin alpha4; Integrin alpha4beta1; Luciferases; Melphalan; Mice; Multiple Myeloma; Osteoclasts; Osteolysis; Recombinant Proteins; Spleen; Time Factors; Vascular Cell Adhesion Molecule-1

Topics: Fatal Outcome; Graft Survival; Humans; Male; Melphalan; Multiple Myeloma; Organometallic Compounds; Organophosphorus Compounds; Osteolysis; Peripheral Blood Stem Cell Transplantation; Radioisotopes; Radiopharmaceuticals; Salvage Therapy; Samarium; Transplantation Conditioning; Transplantation, Autologous; Treatment Outcome

Topics: Antineoplastic Combined Chemotherapy Protocols; B-Lymphocytes; CD4 Antigens; CD4 Lymphocyte Count; CD4-Positive T-Lymphocytes; Cell Line, Tumor; Clone Cells; Combined Modality Therapy; Culture Media, Conditioned; Cyclophosphamide; Disease Progression; Female; Humans; Leukemia, Lymphoid; Melphalan; Middle Aged; Multiple Myeloma; Neoplastic Stem Cells; Osteolysis; Paraproteinemias; Prednisone; Vincristine

Pleural effusion caused by plasma cell involvement in multiple myeloma has been reported unfrequently, and has been described at a frequency below 1% of multiple myeloma. In this study, we report an observation with pleural effusion as first symptom of multiple myeloma. The analysis of the pleural liquid showed plasma cells with a monoclonal IgG Kappa immunoglobulin. In addition, there was a bone marrow infiltration by plasma cells, a serum monoclonal immuno-globulin of the same type and osteolytic lesions. Our patient has received one course of chemotherapy with: vincristine, melphalan, cyclophosphamide and prednisone. The patient did not respond to the therapy and died one month later. Pleural effusion seems to be an expression of aggressive myeloma. Survival exceeds rarely 4 months.

Topics: Antibodies, Monoclonal; Antineoplastic Agents, Alkylating; Antineoplastic Agents, Hormonal; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Cyclophosphamide; Fatal Outcome; Female; Humans; Immunoglobulin G; Immunoglobulin kappa-Chains; Melphalan; Middle Aged; Multiple Myeloma; Osteolysis; Plasma Cells; Pleural Effusion; Prednisone; Vincristine

We report here the youngest known IgM myeloma patient to have presented with a mandibular mass. A 22-year-old Chinese man sought medical attention due to a mass over his right mandible that had been growing progressively for 6 months. A solitary osteolytic lesion in the right mandible was identified radiologically. Incisional biopsy revealed the presence of plasma cells of monoclonal origin, as evidenced by the exclusively positive staining of the kappa light chain. The diagnosis of multiple myeloma with mandibular involvement was confirmed by bone marrow examination. Further tests, including immunoglobulin electrophoresis and assay of the serum levels of kappa and lambda light chains, demonstrated that his myeloma was of the IgM, kappa subtype. The patient achieved a nonsustained partial response to six courses of melphalan and prednisolone therapy and palliative radiotherapy.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Humans; Immunoglobulin kappa-Chains; Immunoglobulin M; Male; Mandibular Neoplasms; Melphalan; Multiple Myeloma; Myeloma Proteins; Osteolysis; Palliative Care; Prednisolone

The association of leukemia and multiple myeloma is well described usually as a complication of chemotherapy but also in the absence of chemotherapy or at diagnosis. Such leukemias are typically acute myeloid leukemia (AML), particularly myelomonocytic subtype, and cases of acute promyelocytic leuke (APL) are rarely reported. Controversy exists as to whether myeloma and AML originate from a single haematopoietic progenitor or arise from different cell lineages. We report a case of a 58 year old female who developed APL 10 months following diagnosis of nonsecretory light chain (kappa) myeloma which had been treated with local spinal irradiation and low dose oral melphalan and prednisone. Clonality had originally been demonstrated by light chain restriction (kappa) of her bone marrow plasma cells whilst immunoglobulin heavy chain and T cell receptor genes were germ line. At development of APL cytogenetics revealed t(15;17) and PML-RAR fusion gene was detected by RT-PCR. The patient was treated with all-trans retinoic acid (ATRA) and received 2 cycles of consolidation chemotherapy with Idarubicin. Following this therapy the t(15;17) and PML-RAR were both undetectable whilst the clonal population of kappa staining plasma cells persisted. This particular patient represents a rare case of APL complicating multiple myeloma with persistence of the myeloma clone but disappearance of PML-RAR alpha RNA following therapy. This case study appears to support the argument that the APL and myeloma originated from distinct cell lineages.

Topics: Antibiotics, Antineoplastic; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Cell Lineage; Chromosomes, Human, Pair 15; Chromosomes, Human, Pair 17; Clone Cells; Combined Modality Therapy; Diphosphonates; Embryonal Carcinoma Stem Cells; Female; Gene Rearrangement, B-Lymphocyte, Light Chain; Humans; Idarubicin; Immunoglobulin kappa-Chains; Leukemia, Promyelocytic, Acute; Melphalan; Middle Aged; Multiple Myeloma; Myeloma Proteins; Neoplasm Proteins; Neoplasms, Multiple Primary; Neoplastic Stem Cells; Oncogene Proteins, Fusion; Osteolysis; Pamidronate; Prednisone; Remission Induction; Translocation, Genetic; Tretinoin

Topics: Bone Neoplasms; Combined Modality Therapy; Diabetic Neuropathies; Diagnosis, Differential; Humans; Ischium; Male; Melphalan; Middle Aged; Osteolysis; Plasmacytoma; Polyneuropathies; Tomography, X-Ray Computed

It is reported on the symptomatology, diagnostics and therapy in a 54-year-old patient with a micromolecular plasmocytoma of kappa-type. Here particularly the impressionable improvement of the clinical picture after an intermitting impact therapy with melphalan (alkeran) - prednisolone in a period of treatment of approximately 2 years is emphasized.

Topics: Bence Jones Protein; Humans; Immunoglobulin kappa-Chains; Lumbar Vertebrae; Male; Melphalan; Middle Aged; Neoplasm Metastasis; Osteolysis; Plasmacytoma; Prednisolone; Radiography

A case of nonproductor myeloma is reported. The diagnosis was supported by the radiological findings, the heavy marrow infiltration of malignant plasma cells, the absence of a monoclonal component in the serum or urine and the failure to demonstrate intracytoplasmic immunoglobulins with immunoifluorescent techniques. The clinical findings of our patient are similar to those reported for the 5 cases of nonproductor myeloma described so far, indicating that there are no characteristic features differentiating nonproductor myeloma from productor myelomas.

Topics: Bone Marrow; Drug Therapy, Combination; Female; Humans; Immunoglobulins; Melphalan; Middle Aged; Multiple Myeloma; Osteolysis; Plasma Cells; Prednisone; Radiography; Skull

A report on two patients with osteoclerotic myeloma is presented (myeloma with osteoblastic lesions). In case one, metastatic bone tumor of unknown origin was wrongly diagnosed initially. Because of increasing neurological symptoms laminectomy was performed. Biopsy led to the correct diagnosis of multiple myeloma of IgA-type. Patient also had a very severe peripheral neuropathy. The second patient had pancytopenia and osteosclerotic lesions of the pelvis. Bone marrow aspiration revealed so-called "empty marrow". Based on these findings, myelofibrosis was wrongly diagnosed at another hospital. Bone marrow aspiration, paper- and immunoelectrophoresis subsequently produced the correct diagnosis of multiple myeloma of IgG-type. Multiple myeloma usually is characterized by osteolytic lesions of the bones. However, the literature contains some 50 cases with osteosclerotic multiple myeloma, three different forms of which are described. In a fairly large percentage osteosclerotic multiple myeloma is combined with periphereal polyneuropathy. It would appear that in IgE-myeloma the incidence of sclerotic lesions is higher. Osteosclerotic multiple myeloma is very rare. It should however be considered if the differential diagnosis of osteosclerotic bone lesions is established.

Topics: Aged; Cyclophosphamide; Female; Humans; Immunoglobulin A; Immunoglobulin G; Male; Melphalan; Multiple Myeloma; Osteolysis; Osteosclerosis; Prednisone

The treatment of rapidly progressive skeletal demineralisation in myelomatosis has been studied with the help of metabolic calcium balance in two patients; In one, osteoporosis accelerated during treatment with melphalan and prednisolone, although he remained normocalcaemic throughout, suggesting that osteoporosis was aggravated by corticosteroid therapy. In the other patient, who was initially hypercalcaemic, conventional treatment produced clinical remission before eventual relapse with more hypercalcaemia and skeletal dissolution. Both patients were then treated with mithramycin alone, and, although neither obtained haematological remission, bone pain was relieved, hypercalciuria and hypercalcaemia were abolished, and calcium balances proved that mithramycin was effective in restoring calcium equilibrium. The results indicate that mithramycin may abolish excessive bone resorption in myelomatosis and that severe bone dissolution may occur in the absence of hypercalcaemia. Regular determination of 24-hour urinary calcium excretion as well as of plasma-calcium is important in monitoring process. Mithramycin should be considered in the early treatment not only of hypercalcaemia but also of severe hypercalciuria, if these complications do not rapidly remit during the first course of conventional myeloma therapy, with or without steroids. Finally, these results add to evidence that a humoral factor may be responsible for osteoclast stimulation in myelomatosis.

Topics: Aged; Calcium; Cyclophosphamide; Drug Therapy, Combination; Female; Humans; Hypercalcemia; Injections, Intravenous; Male; Melphalan; Middle Aged; Multiple Myeloma; Osteolysis; Phosphorus; Plicamycin; Prednisolone; Water-Electrolyte Balance