This multidrug resistant (MDR) phenotype due to the overexpression of MDR1/Pgp is a documented mechanism of drug resistance in patients with multiple myeloma. Several currently available compounds such as verapamil and Cyclosporin A can modulate MDR: however, clinical studies have demonstrated substantial toxicity and limited efficacy. PSC 833 is a non-immunosuppressive, non-nephrotoxic derivative of Cyclosporin D, specifically selected for its ability to modulate Pgp and reverse MDR. Forty-eight patients with relapsed myeloma were enrolled in a Phase I trial of PSC 833 in combination with Vincristine, Adriamycin, and Dexamethasone (VAD). PSC 833 was administered orally, either as a soft-gelatin capsule or an oral solution, according to five different dosing schedules. Thrity-three patients were treated at the final recommended dose (FRD) of PSC 833 plus VAD. The FRD of PSC 833 oral solution was 0.4 mg/kg qid. FRD for four days of vincristine was reduced from the standard does of 0.4 mg/day to 0.2 mg/day, and the FRD of doxorubicin was reduced from the standard of nine mg/m2/day to seven mg/m2/day. Signficant myelosuppression was observed at all dosing levels (77% of patients), with grades three or four granulocytopenia observed 35% of patients treated at FRD . Fifteen percent of the patients had neutropenic fevers. There were no toxic deaths, although there were three deaths on the study believed to be unrelated to the PSC. Unique non-hematologic toxicities, not usually associated with VAD, were transient ataxia (40%) with 8% grade 3 and no grade 4 ataxia noted at FRD; and hyperbilirubinemia (35%) with 15% grade 3 and 8% grade 4 bilirubin elevations at FRD. Pharmacokinetic analysis of whole blood concentrations of PSC 833 showed that 12 of 13 patients (92%) in 2% of 29 cycles (97%) receiving the FRD of PSC 833 (4 mg/kg/qid) achieved adequate concentrations of PSC 833 (>1000 ng/ml) known to reverse MDR in vitro. Of the inital 26 myeloma patients evaluable or response, five patients had a partial response and three patients had a minor response. Studies to determine the effects of PSC 833 on doxorubicin pharmacokinetics are currently being analyzed. Phase II and III studies of PSC 833 plus VAD in patients with myeloma are underway using the doses determined from this Phase I study.
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