Clinical modulation of multidrug resistance in multiple myeloma: effect of cyclosporine on resistant tumor cells

In multiple myeloma (MM) refractory to doxorubicin (DXR) and/or vincristine (VCR), myeloma cells frequently express the multidrug resistance (MDR) phenotype, associated with overexpression of P-glycoprotein (Pgp), which acts as a drug efflux pump. Recently, studies have shown that clinical resistance can be modulated by drug resistance modifiers. The present study was performed to investigate if MDR modulation in vivo is caused by a direct effect of cyclosporine (CSA) on resistant myeloma plasma cells (PC). Eight patients with VAD-refractory MM were treated with DXR, VCR, and dexamethasone (VAD) plus CSA. Pgp expression in PC was determined by flow cytometry/immunocytochemistry before and after clinical treatment. Functional Pgp expression was determined by the effect of CSA on the intracellular accumulation of DXR and VCR. Five of eight patients responded to VAD/CSA. The percentage of Pgp-positive (Pgp+) PC was 30% to 100% (median, 90%) before treatment and 4 to 90% (median, 40%) after treatment. CD56+/- or CD38+/- PC had identical Pgp expression. CSA, as well as SDZ PSC 833, but not dexamethasone, increased pretreatment intracellular accumulation of DXR and VCR in Pgp+ PC in three of four and six of six patients, respectively. After clinical treatment, in vitro drug accumulation in residual Pgp-negative (Pgp-) PC of four of four responding patients was not further modulated by CSA or SDZ PSC 833. At later relapse, PC of two of four patients remained Pgp-. These data indicate that Pgp overexpression is functional in refractory myeloma and that clinical modulation of MDR by CSA is mediated through an inhibition of Pgp-associated drug efflux. Pgp-expressing PC can be eliminated by clinical treatment with VAD/CSA.