Modulation of multidrug resistance in multiple myeloma

Primary or acquired drug resistance is the major cause of failure of chemotherapy in MM. MDR is associated with expression of a membrane P-gp, which acts as an efflux pump for natural product drugs, such as doxorubicin and vincristine. P-gp expression is observed in extensively treated patients and is a cause of refractoriness to VAD chemotherapy. Among several other non-cytotoxic drugs, cyclosporins modulate the function of P-gp in refractory myeloma cells. Early clinical trials with verapamil and cyclosporin have shown that these can be combined with VAD. In patients treated with drug-resistance modifiers, there is, besides an effect on the tumour cell, also an increased plasma exposure to several cytostatic drugs, which is mediated through inhibition of biliary efflux. Thus, the clinical effect of drug modulation may result from inhibition of tumour P-gp and from altered drug pharmacokinetics. Several trials are now in progress in order to evaluate the clinical benefit of resistance modulators in myeloma.