DEFICIENT DRUG TRANSPORTER FUNCTION OF BONE MARROW-LOCALIZED AND LEUKEMIC PLASMA-CELLS IN MULTIPLE-MYELOMA

Although chemotherapy effectively reduces the plasma cell burden in mu ltiple myeloma (MM), the disease recurs, MM includes circulating and b one marrow (BM) localized components. A large majority of circulating CD11b(+) MM B cells (81%) express an IgH VDJ rearrangement identical t o that of autologous BM plasma cells. Unlike plasma cells, these monoc lonal circulating B cells exhibit dye and drug transport activity befo re and throughout chemotherapy. Drug resistance was measured as the ab ility to export the fluorescent dye Rhodamine123 (Rh123) or the drug a driamycin, using flow cytometry. The role of P-glycoprotein 170 (P-gp) , the multidrug transporter, was defined by cyclosporin A (CsA)-sensit ive dye export. Only 8% to 11% of BM-localized plasma cells exported d ye with the majority retaining dye, identified as bright staining. Cir culating leukemic plasma cells were also unable to export dye and rema ined Rh123(bright). However, 53% of circulating clonotypic MM B cells exhibited CsA-sensitive dye export. BM plasma cells taken before or af ter initiation of first line chemotherapy were equally unable to expor t dye. Thus in myeloma, differentiation to the plasma cell stage is ac companied by a loss of P-gp function, although P-gp phenotypic express ion is retained. In contrast, for monoclonal gammopathy of undetermine d significance (MGUS), 54% of BM-localized plasma cells exported dye, comparable to the 53% of circulating MGUS B cells that also exported d ye, suggesting that the apparent defect in P-gp function is unique to myeloma plasma cells. Virtually all BM plasma cells in MM retained the drug adriamycin, consistent with their initial drug sensitivity in vi vo, in contrast to circulating MM B cells, or to T cells ire BM or blo od, Thus, circulating B cells appear to be the predominant drug resist ant component of the MM B-lineage hierarchy. This report suggests that successful therapeutic strategies will be those that target circulati ng B cells, Chemosensitization methods involving inhibition of P-gp ar e likely to improve depletion of these cells by compromising their abi lity to exclude drug. This work suggests that circulating clonotypic B cells should be monitored in clinical trials to confirm their depleti on and the overall efficacy of novel treatment strategies. (C) 1997 by The American Society of Hematology.