Plasma cell myeloma--new biological insights and advances in therapy

Abstract

Plasma cell myeloma is a more complex neoplasm than suggested by the relative uniformity of its dominant plasma cells, which represent the terminal stage of normal B-cell differentiation. Phenotypic, molecular, and cellular genetic data favor the presence of a myeloma stem cell early in hematopoietic development so that, as in chronic myelogenous leukemia (CML), a far distance exists between the primordial malignant cell that was the target of malignant transformation and the dominant clinical phenotype. Traces of pre-B, myeloid, and T cells are coexpressed with the mature B-cell phenotype, an occurrence unknown in normal B-cell differentiation. Analogous to CML, disease progression is marked by disease dedifferentiation, occasionally with cessation of myeloma protein production and development instead of extramedullary lymphomalike features with high LDH or myelodysplasia/acute myelogenous leukemia (AML) syndromes. The prognostic importance of serum LDH levels even in newly diagnosed myeloma suggests the early presence of tumor cells with “LDH phenotype,” which, as a result of drug resistance and proliferative advantage, expand preferentially during disease progression. Further characterization of these cells may provide important clues about the ontogeny of multiple myeloma. Myeloma cells express many receptors for different biological signals that might be exploitable for therapy with immunotoxins or radioisotopes. Plasma cells and their precursors also produce a variety of cytokines, some of which have putatively autostimulatory functions (eg, IL-1, IL-5, IL-6) and/or are related to disease manifestations (eg, IL-1 and TNF-beta as OAF). The wealth of cellular expression by plasma cells provides clues for understanding the mechanisms of gene activation and the nature of abnormal growth and differentiation. The accuracy of prognostically relevant staging systems has been refined with the use of new quantitative parameters that reflect tumor mass (ie, serum B2M levels) and biology. Further studies of cellular and molecular biology (ie, CAL- LA, H-ras) may reveal those tumor cell features that define clinical entities, response to therapy, and long-term prognosis. The lack of a major advance in prognosis despite the use of more drugs and more intensive regimens justifies the continued use of standard melphalan- prednisone for patients with a highly favorable prognosis, for the very aged, and for those with a short life expectancy due to other major medical problems. However, a radical departure from standard practice is required to improve the prognosis for younger patients with poor risk features.(ABSTRACT TRUNCATED AT 400 WORDS)

Normal and clonal B lineage cells can be distinguished by their differential expression of B cell antigens and adhesion molecules in peripheral blood from multiple myeloma (MM) patients—diagnostic and clinical implications

“…Accordingly, homing specificity of circulating clonal PC could be determined by the integrin CD49d and the BM endothelial addressin CD106. Since the appearance of new bone lesions is a well known factor associated with disease progression [1], it is conceivable that these few circulating PC may be selected for re-entry into the BM to generate new focal lesions.…”

“…MM is a plasma cell neoplasia in which large amounts of monoclonal immunoglobulin are generally produced by malignant plasma cells [1]. Although this disease has long been regarded as a neoplasia localized to the BM [1], recent evidence shows a subset of circulating B cells in the peripheral blood (PB) that is clonally related to the malignant plasma cell [2]. Phenotypic and immunoglobulin gene rearrangement methods have been used to detect clonality in PB B cells [2,3].…”

Prediction of survival using absolute lymphocyte count for newly diagnosed patients with multiple myeloma: a retrospective study

“…The ISS [based on albumin (g/l) and b 2 -microglobulin (mg/l)], age, albumin (<35 g/l), b 2 -microglobulin ( ‡3AE5 mg/l), bone marrow plasma cells (BMPC ‡40%) (Corrado et al, 1989), circulating plasma cells (Witzig et al, 1996), lactate dehydrogenase (LDH) (U/l) (Barlogie et al, 1989) and plasma cell labelling index ( ‡1%) (Greipp et al, 1993) were used in the study.…”

MPC‐1−CD49e− immature myeloma cells include CD45+ subpopulations that can proliferate in response to IL‐6 in human myelomas

“…Myeloma cells from myeloma patients are heterogenous in the expression of surface antigens and their biological character (Barlogie et al, 1989). The expression of CD45 on human myeloma cells has been reported on immature myeloma cells but not on mature myeloma cells (Hata et al, 1994;Witzig et al, 1996;Joshua et al, 1996;Schneider et al, 1997).…”