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Modified adriamycin-vincristine-dexamethasone (m-VAD) in primary refractory and relapsed plasma cell myeloma: an NCI (Canada) pilot study. The National Cancer Institute of Canada Clinical Trials Group.

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.

Aged↗

Plasma cell myeloma of the orbit.

An 80-year-old woman had a left superior temporal orbital mass that displaced the globe downward and forward. Restriction of motion was present in all fields of gaze. Radiologic and ultrasound evaluation revealed an orbital mass extending posteriorly, with erosion of the superior orbital rim. Biopsy diagnosis was plasma cell myeloma, a rare orbital tumor. The patient was subsequently found to have multiple myeloma, treated with local radiotherapy and chemotherapy. Three-and-one-half years after diagnosis, she is alive and in remission.

Aged↗

Testicular and epididymal plasmacytoma: a report of 7 cases, including three that were the initial manifestation of plasma cell myeloma.

We report the cases of six men, 40 to 89 years of age, with testicular (6 cases) or epididymal (1 case) plasmacytoma. Patients presented with a mass in five cases. One tumor was found during evaluation of progressive myeloma. In the final case, the testicular lesion was identified when the patient presented with pathologic fractures. Gross inspection revealed discrete or, less often, ill-defined lesions. Microscopic examination disclosed masses of atypical plasma cells, including binucleated and multinucleated cells and, occasionally, anaplastic cells that obliterated the underlying parenchyma or invaded between seminiferous or epididymal tubules. Immunohistochemical stains on paraffin sections in five cases showed tumor cell expression of monotypic cytoplasmic immunoglobulin. The cells were positive for the leukocyte common antigen (CD45) in three of five cases. All four cases tested were negative for B (CD20) and T (CD3) cell specific antigens and for CD30 and placental alkaline phosphatase. Expression of CD43, CD45RO, and epithelial membrane antigen was found in three, two, and one of four cases respectively. All the patients also had plasma cell neoplasia distant from the testis, identified before (3 cases), concurrent with (3 cases) or after (1 case) the testicular or epididymal plasmacytoma. In one patient a plasmacytoma developed in the contralateral testis three years later; he was alive with plasma cell myeloma 51 months after diagnosis. Another had a plasmacytoma in the contralateral epididymis 8 years later; he also had a nasal cavity plasmacytoma and multiple subcutaneous plasmacytomas, and was alive and well after 26 years. One additional patient was alive with myeloma 6 months later, and four final patients died between 2 months and 3 years after orchiectomy. Three of the four consultation cases in this series were submitted with diagnoses of spermatocytic seminoma, anaplastic seminoma and lymphoma. The diagnosis of plasmacytoma should be borne in mind when examining testicular or paratesticular tumors with a diffuse pattern without glandular differentiation, particularly in men 40 years of age or older.

Adult↗

Intraoral corroboration of systemic plasma-cell myeloma. Abbreviated case report.

A patient with a previously diagnosed case of multiple myeloma was readmitted for a pathologic fracture of the hip. Intraoral examination revealed a soft-tissue swelling over the right posterior mandibular ridge. Radiographs showed multiple radiolucent areas of the maxilla and mandible. A needle-biopsy technique was used to confirm the diagnosis of intraoral manifestations of plasma-cell myeloma.

Female↗

Fas-L up-regulation by highly malignant myeloma plasma cells: role in the pathogenesis of anemia and disease progression.

Highly malignant myeloma cells up-regulate their Fas-ligand (Fas-L) to escape immune surveillance by Fas(+) cytotoxic cells. Here it is demonstrated that this abnormality is involved in the pathogenesis of the severe anemia associated with progression of multiple myeloma (MM). By measuring Fas and Fas-L in plasma cells and erythroblasts from 19 MM patients and 5 with monoclonal gammopathies of undetermined significance (MGUS), it was found that both Fas-L(+) myeloma cells and Fas(+) erythroid progenitors were significantly increased in patients with stage III MM whose erythroblasts, cultured in the presence of autologous plasma cells or their supernatant, underwent prompt apoptosis as evaluated by propidium iodide staining, the TUNEL assay, and detection of the APO2.7-reactive mitochondrial antigen. Flow cytometry of fresh erythroblasts revealed a considerable expression of the caspases CPP32 and FLICE in both their constitutive proenzymatic forms and in cleaved subunits. By contrast, their intracytoplasmic expression was defective in patients with inactive disease and MGUS controls. The evidence that Fas-L(+) myeloma clones directly prime erythroblast apoptosis in vivo was further supported by the occurrence of fluorescein isothiocyanate-TUNEL(+) erythroblasts juxtaposed to myeloma cells in bone marrow smears. These results strongly suggest that the deregulated apoptosis in myeloma clones plays an active role in the progressive destruction of the erythroid matrix by a cytotoxic mechanism based on up-regulation of Fas-L.

Anemia↗

Spontaneous spinal epidural hematoma with spinal cord compression complicating plasma cell myeloma. A case report.

STUDY DESIGN: A case is reported in which a patient had acute paraplegia with sensory loss caused by a spontaneous epidural hematoma that was ascribed to bleeding of pre-existing myeloma lesions of the thoracic vertebrae. OBJECTIVES: To highlight the causes of secondary epidural hematomas with special attention to pre-existing vertebral or epidural lesions. SUMMARY OF BACKGROUND DATA: There are no apparent previous reports of epidural spinal hematomas ascribed to underlying malignant diseases. Benign dysplasia, such as hemangioma or Paget's disease, has been implicated in a few cases. METHODS: A case of spontaneous dorsal epidural hematoma is reported in a patient followed up for plasma cell myeloma with osteolytic lesions in the lower thoracic spine. There was no history of major trauma or coagulation disorders. Complete loss of motor and sensory function in both lower limbs was noted, with sphincter dysfunction. Magnetic resonance imaging of the thoracic spine showed a large posterolateral epidural hematoma responsible for spinal cord compression. RESULTS: The patient failed to improve despite surgical decompression within 6 hours of symptom onset. He died 13 days later of refractory bacterial pneumonia. A large epidural hematoma adjacent to myelomatous lesions of the thoracic vertebrae was found at autopsy. CONCLUSIONS: This is the first reported case of spontaneous epidural hematoma ascribed to underlying malignant disease, with confirmation of the diagnosis by postmortem examination. Possible mechanisms include tumor-related epidural inflammation and fragility of epidural venous plexuses.

Aged↗

Light chain myeloma plasma cells induce a strong cell-mediated immune response mainly directed against the monoclonal light chain determinants in a murine experimental model.

An important goal for the treatment of human B cell malignancies lies in the induction of an active immune response directed against the tumoral clone, and more particularly against antigenic determinants of the monoclonal immunoglobulin (Ig). The presence of idiotype-reactive T-cells in patients with multiple myeloma has been previously reported, and strategies to increase their responsiveness towards the malignant plasma cells are being actively explored. Light chain (LC) myeloma is often an aggressive form of the disease, regarding which antitumoral immunity has not yet been studied. Here, we investigated in an experimental murine model a secreted monoclonal LC that may behave as a strong tumor antigen after immunization of animals with mitomycin C-treated malignant plasma cells producing monoclonal Ig. Non-dividing plasma cells were utilized as a cell suspension to immunize the mice intraperitoneally (i.p.). The immunized mice produced anti-Ig LC antibodies, mounted a cell-mediated response mainly directed against the monoclonal LC determinants, and survived tumor challenge with significant frequency. These results suggest that plasma cells are capable of presenting antigenic determinants derived from a secreted monoclonal LC in an MHC class I context, and of predominantly inducing a monoclonal Ig-specific T-cell response which can contribute to tumor rejection.

Animals↗

Myeloma bone marrow plasma cells: evidence for their capacity as antigen-presenting cells.

Myeloma plasma cells constitute 10% to 90% of the total bone marrow cell count in patients with multiple myeloma (MM). These cells express a variety of cell surface markers, such as HLA-ABC and HLA-DR, and surface antigens that are necessary for professional antigen-presenting cells, including adhesion and costimulatory molecules. In this study, we examined the expression of major histocompatability complex (MHC) and costimulatory molecules on CD38(bright,++) plasma cells in bone marrow aspirates from eight MM patients. Small percentages of plasma cells expressed weak but detectable levels of HLA-DR, HLA-DQ, CD40, CD80, and CD86, which could be upregulated by interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha. CD38++ plasma cell and CD38(dim,+) cells were sorted from freshly isolated bone marrow mononuclear cells and tested for their capacity to act as antigen-presenting cells. Indeed, both CD38++ plasma cells and CD38+ cells were able to stimulate allogeneic T cells and present the soluble antigens purified protein derivative and tetanus toxoid to autologous T cells. Recognition of the antigens led to T-cell proliferation and secretion of IFN-gamma and was MHC class-I and -II restricted. Antigen processing and presentation by CD38++ and CD38+ cells were abolished by treatment of the cells with chloroquine. Hence, our study provides for the first time evidence that myeloma plasma cells may act as antigen-presenting cells. Further studies are warranted to examine in detail the molecules required for inducing T-cell stimulation.

ADP-ribosyl Cyclase↗