Journal of Clinical Oncology, Vol 12, 1584-1591, Copyright © 1994 by American Society of Clinical Oncology
Clinical modulation of multidrug resistance in multiple myeloma: effect of cyclosporine on resistant tumor cells
P Sonneveld, M Schoester and K de Leeuw
Department of Hematology, Erasmus University Rotterdam, The Netherlands.
PURPOSE: 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). PATIENTS AND METHODS: 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. RESULTS: 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-. CONCLUSION: 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.
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