Drug resistance in multiple myeloma: novel therapeutic targets within the malignant clone.

Myeloma is incurable because the malignant stem cell is not eradicated by treatment. Thus, identification of the malignant hierarchy of B lineage cells in myeloma is required to identify potentially generative components and to evaluate their drug resistance properties. BM plasma cells are usually depleted by chemotherapy, but clonotypic B cells survive melphalan/prednisone as well as combination chemotherapy. In vitro, circulating and bone marrow-localized myeloma plasma cells show defective drug export, despite their phenotypic expression of P-glycoprotein, the mdr1 gene product. In contrast to plasma cells, circulating myeloma clonotypic B cells exhibit very efficient drug export. This suggests that circulating clonotypic MM B cells comprise a reservoir of drug resistant disease in myeloma although their stem cell potential remains to be confirmed. The malignant clone in each myeloma patient is defined by a unique IgH VDJ gene rearrangement. Using methods that exclude the possibility that a frequent but non-malignant clone has inadvertently been identified, and after confirming that the sequence identified is expressed by nearly all bone marrow plasma cells, we show that the drug resistant set of myeloma B cells is clonally related to the malignant plasma cells in myeloma. Clonotypic MM B cells survive chemotherapy, persist during clinically defined "minimal residual disease" and remain after autologous transplantation. Thus their malignant status is an important consideration. If malignant, they must be considered in the design of therapy. If non-malignant, they would be expected to have minimal impact on the disease process. A variety of evidence provides strong support for the view that clonotypic drug resistant B cells are malignant and may include the generative compartment of myeloma. The P-gp+ set of clonotypic B cells is extensively DNA aneuploid, an attribute of malignancy. All clonotypic B cells overexpress RHAMM, a novel oncogene involved in malignant spread. Finally, the population of clonotypic B cells lacks intraclonal heterogeneity. Since intraclonal heterogeneity is driven by the response to antigens, its absence in these cells indicates that they are no longer antigen-responsive. Since antigen-independent clonal expansion is characteristic of lymphoid malignancies, these observations provide further proof that clonotypic B cells in myeloma are malignant. Thus, the drug resistance of these cells is highly relevant to understanding why myeloma remains incurable despite the initial chemosensitivity of most bone marrow plasma cells.