INTRINSIC EXPRESSION OF THE MULTIDRUG TRANSPORTER, P-GLYCOPROTEIN-170, IN MULTIPLE-MYELOMA - IMPLICATIONS FOR TREATMENT

Multidrug resistance, mediated by the P-glycoprotein 170 transport pum p, is a serious problem in multiple myeloma. In this review we discuss the expression of P-gp as a differentiation antigen on normal T and B lymphocytes. In myeloma, circulating presumptively malignant B cells express P-gp prior to chemotherapy. A variety of evidence characterize s these circulating B cells as members of the malignant clone in myelo ma, including the demonstration that they share immunoglobulin heavy c hain (IgH) rearrangements with bone marrow plasma cells, and their ext ensive DNA aneuploidy. In some patients the only components of the clo nal populations that express P-gp are the circulating B cells suggesti ng that they represent a reservoir of multidrug resistant cells that m aintain malignant growth and spread in myeloma. We speculate that expo sure to chemotherapy alters clonal homeostasis and exerts positive sel ection pressure on generative components of the myeloma clone. Thus th e possibility exists that chemotherapy perpetuates rather than eradica tes myeloma stem cells. P-gp is detectable on bone marrow plasma cells in myeloma but appears to be in an inactive form that is unable to me diate efflux of marker dyes. A similar phenomenon is seen for normal h uman monocytes which have surface P-gp but lack any functional export of P-gp substrates. P-gp appears to vary depending in a cell-type spec ific manner suggesting that it may be feasible to design inhibitors of P-gp which selectively block P-gp export by malignant cells and spare the function of P-gp on normal tissue, including lymphocytes and norm al hematopoietic stem cells.