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PubMed1981

Aggressive plasma cell myeloma. A terminal phase.

Seven patients with plasma cell myeloma experienced an aggressive, terminal phase. This phase is characterized by rapidly enlarging soft-tissue masses with tumor morphologic characteristics similar to a poorly differentiated or large-cell (histiocytic) lymphoma, with rapid death, and often with fever, pancytopenia, decreasing levels of myeloma protein, and younger age. Median survival from the onset of the phase was four months. There was no response to single-agent or combination chemotherapy. In view of the extremely poor prognosis and lack of response to conventional treatment, patients experiencing this characteristic terminal phase should be considered candidates for innovative therapy.

Adult↗
PubMed2006

Comparison of ancillary studies in the detection of residual disease in plasma cell myeloma in bone marrow.

Morphologic determination of residual plasma cell myeloma is often difficult. This study was conducted to evaluate the diagnostic value of several ancillary methods. A total of 121 bone marrow specimens from patients with myeloma after bone marrow transplantation or chemotherapy were studied. Of those, 49 cases were studied by conventional cytogenetics (CC), 86 by flow cytometry (FC), 50 by immunohistochemical analysis, 72 by molecular studies (MS) for immunoglobulin gene rearrangements, and 18 by standard fluorescence in situ hybridization (FISH) study. Of the patients, 70 were found to have residual myeloma. Residual disease was detected in 58 of 70 patients by morphologic examination (detection rate, 83%), 25 of 26 by immunohistochemical analysis (96%), 39 of 54 by FC (72%), 6 of 40 by CC (15%), 6 of 12 by FISH (50%), and 24 of 40 by MS (60%). Among the ancillary studies, immunohistochemical analysis and FC were the most helpful ancillary studies for detection of residual disease in myeloma, with immunohistochemical analysis the most effective single method.

Adult↗
PubMed2005

The phenotypic plasticity of myeloma plasma cells as expressed by dedifferentiation into an immature, resilient, and apoptosis-resistant phenotype.

PURPOSE: We previously showed the ability of osteoclasts to support myeloma plasma cell survival and proliferation in vivo and ex vivo. The aim of the current study was to investigate osteoclast-induced phenotypic changes associated with long-term survival of myeloma cells in coculture. EXPERIMENTAL DESIGN: CD138-selected myeloma plasma cells from 16 patients were cocultured with human osteoclasts for up to 20 weeks. RESULTS: Precultured cells were typically CD45(low/intermediate) CD38(high) CD138(high), CD19(-)CD34(-). After >6 weeks, the phenotype of cocultured myeloma cells consistently shifted to cells expressing CD45(intermediate/high) CD19(low) CD34(low). Expression of CD38 and CD138 were reduced to subpopulations with CD38(intermediate) and CD138(low) levels. Morphologically, cocultured plasma cells became plasmablastic. Blocking interleukin-6 activity did not affect the immature phenotype of myeloma cells. The effect of dexamethasone on myeloma cells cultured alone or in cocultures at baseline and after 6 weeks of coculture was determined. When baseline myeloma cells were cultured alone, dexamethasone significantly increased the percentage of apoptotic cells over the spontaneous rate. Conversely, myeloma cells recovered from cocultures had high survival rates and were resistant to dexamethasone-induced apoptosis. Long-term coculture of normal CD34-expressing hematopoietic stem cells (HSC) resulted in loss of CD34 expression, suggesting a common mechanism for osteoclast-induced myeloma and HSC plasticity. CONCLUSIONS: This study indicates that myeloma cells have plasticity expressed by their ability to reprogram, dedifferentiate, and acquire autonomous survival properties.

Antigens, CD19↗
PubMed2003

Presence of a bone marrow stromal cell line with myoid differentiation in reactive plasmacytosis and plasma cell myeloma.

The presence of myoid cells (MCs) - stromal cells with myogenic differentiation - in human bone marrow (BM) has been observed during hematopoiesis in embryonic life, whereas during adult life, it is strictly related to various pathologic conditions. The aim of this study was to examine the presence, distribution and quantitation of cells in the stroma of the BM expressing alpha-smooth muscle actin (alpha-SMA) in reactive BM plasmacytosis and plasma cell myeloma. For this reason, a series of 10 trephine BM biopsies from patients with plasma cell myeloma and 10 specimens from healthy controls with reactive plasmacytosis were examined for the presence of stromal cells with myoid differentiation, using a monoclonal antibody recognizing alpha-SMA. Our results suggest that the incidence of MCs and subsequent fibrosis rises in plasma cell myeloma and in a lesser degree in the BM stroma of individuals with reactive plasmacytosis.

Actins↗
PubMed2006

Immunohistochemical analysis identifies two cyclin D1+ subsets of plasma cell myeloma, each associated with favorable survival.

The significance of cyclin D1 expression in plasma cell myeloma was examined by immunohistochemical analysis using a newly available rabbit monoclonal antibody with superior staining properties. Two patterns of positive staining were observed, each associated with distinct pathologic features. Strong cyclin D1 staining was associated with increased plasma cells at diagnosis (P=.026), lymphoplasmacytic morphologic features (P=.029), CD20 expression (P=.040), and t(11;14)(q13;q32) as detected by interphase fluorescence in situ hybridization with simultaneous CD138 immunofluorescence (P<.001). In contrast, weak staining was associated with hyperdiploidy (P=.02) and gains of the CCND1 locus (P=.01). Overall survival was longer in the cyclin D1+ cases than in cyclin D1- cases (estimated 3-year survival, 73% vs 27%; P=.005). Improved survival was seen in the strongly positive and weakly positive groups compared with cyclin D1- cases (P=.005). This report shows for the first time that cyclin D1 immunohistochemical analysis can provide prognostic information in plasma cell myeloma.

Animals↗
PubMed1998

Specific detection of myeloma plasma cells using anti-idiotypic single chain antibody fragments selected from a phage display library.

Bone marrow plasma cells constitute the bulk of malignant cells in multiple myeloma patients. B-lymphocytes having immunoglobulin heavy chain gene rearrangements identical to those of the malignant clone (clonally related B-lymphocytes) may function as malignant plasma cell precursors. We and others proposed the use of anti-idiotypic antibodies to isolate and study clonally related B-lymphocytes. This strategy failed until now because anti-idiotypic antibodies raised by conventional hybridoma techniques proved to react frequently with epitopes shared by different idiotypes. Recently, we succeeded in selecting specific single chain Fv antibodies from phage libraries. To select single chain Fv bearing phages specifically directed against the immunoglobulin idiotype expressed by myeloma tumor cells we panned a semisynthetic phage library against purified myeloma paraprotein Fab fragments. The selection was performed in the presence of soluble polyclonal immunoglobulin as a competitor. Three independent selections for three myeloma patients yielded 10-26 clones. Between two and seven of the selected clones were reactive with patient Fab and not with polyclonal immunoglobulin in enzyme-linked immunosorbent assays. Five out of six anti-idiotypic single chain Fvs were able to specifically stain fixed monoclonal plasma cells in myeloma bone marrow. Idiotype specificity of these single chain Fvs was confirmed by flow cytometry since they did not react with monoclonal plasma cells of other patients, a panel of nine myeloma cell lines, isolated polyclonal bone marrow plasma cells and cultured B-lymphocytes. Using these anti-idiotypic reagents we were able to detect 25 myeloma plasma cells in a background of 50000 immunoglobulin isotype-matched cells of the myeloma cell line UM-1 or 50000 donor bone marrow cells (sensitivity 0.05%). This paper shows that highly specific anti-idiotypic single chain Fv antibody fragments selected from a phage display library can be used to detect rare idiotypic cells in patient samples.

Animals↗
PubMed1975

Diagnosis of plasma cell myeloma.

Diagnosis of myeloma depends on identification of malignant plasma cells and the product of these cells, a monoclonal immunoprotein. Of the clinical manifestations of plasma cell myeloma, skeletal pain and anemia are two of the more common. Unexplained anemia and osteoporosis noted in the elderly should suggest the possibility of myeloma; this combination of symptoms certainly warrants obtaining a protein electrophoresis. Hypercalcemia and renal insufficiency are frequent sequelae of myeloma.

Anemia↗
PubMed2004

Plasma cell myeloma of the skull base: report of two cases.

Plasma cell myeloma (PCM) of the skull base is rarely encountered in neurosurgical practice. PCM has a wide spectrum of pathology, including a quite benign, solitary plasmacytoma (SPC), and an extremely malignant, multiple myeloma (MM) at the two ends of the spectrum. We have described two patients with PCM of the skull base, of which one harbored SPC, and the other progressed to MM. In case 1, a 46-year-old man presented with left multiple cranial nerve impairments and had a large skull base tumor. Subtotal removal was performed. The specimen and general examination, including bone marrow aspiration, revealed SPC. Postoperatively 50Gy of external radiotherapy was administered. The patient has no manifestation of MM 24 months after the initial presentation. In case 2, a 53-year-old woman presented with left abducens palsy and had a left petroclival osteolytic mass. Gross total resection was performed. The specimen revealed a plasmablastic tumor, i.e., myeloma. General examination established the diagnosis of MM. She was administrated adjuvant chemotherapy and autologous bone marrow transplantation. She is alive without local recurrence 30 months after the initial presentation.

Diagnosis, Differential↗
PubMed1977

Intermittent melphalan and prednisolone therapy in plasma cell myeloma.

Thirty-two consecutive, previously untreated patients with plasma cell myeloma were treated with 4-day courses of melphalan (0.25 mg/kg/day) and prednisolone (2 mg/kg/day) every sixth week. The observation period ranged from 26 to 75 months and the total median survival time was 29 months. 75% of the patients responded to therapy and their median survival time was 42 months. Sex did not influence either the response rate or the survival time. Most patients were treated in an out-patient clinic and required a minimum of check-ups.

Aged↗
PubMed1982

Flow cytometric analysis of DNA content of bone marrow cells in patients with plasma cell myeloma: clinical implications.

DNA content analysis by flow cytometry was performed in 32 patients with plasma cell myeloma and 3 patients with Waldenstrom's macroglobulinemia to determine the biologic and potential clinical usefulness of this technique. Hyperdiploid tumor DNA content was found in 23 myeloma patients (72%) during the course of illness, including 16/28 at presentation, but in none of 3 patients with Waldenstrom's macroglobulinemia. There was no significant association of aneuploidy in myeloma patients with age, sex, race, or M-protein class. Myeloma patients with aneuploid tumor cells were more likely to have advanced stage (p = 0.032) than patients with diploid plasma cells, and all patients with renal failure had aneuploid tumors. Pretreatment factors significantly associated with survival included stage (p = 0.01), serum creatinine (p = 0.003), and tumor DNA content (p = 0.005). Multivariate analysis using the Cox life table regression procedure indicated that the significant relation of tumor DNA content with survival remained after adjusting for stage (p less than 0.005). Myeloma patients with diploid tumors at diagnosis frequently had aneuploid plasma cells at the time of relapse, indicating a possible relationship of chromosomal alterations in the tumor to clinical drug resistance. We conclude that aneuploid tumor cells at the time of diagnosis of myeloma are of independent prognostic significance, and the development of aneuploidy is a frequent occurrence at clinical relapse, suggesting the change in DNA content are of biologic and clinical significance.

Adult↗