Few effective treatments are available for patients with multiple myeloma that is resistant to vincristine-doxorubicin by continuous infusion with high dose dexamethasone (VAD). In order to modulate p-glycoprotein, the multidrug resistance gene product, we administered a VAD-cyclosporine combination to patients with confirmed resistance to VAD. Twenty-five patients with multiple myeloma resistant to VAD received cyclosporine 4 mg/kg infused over 2 hours followed by a continuous infusion of 10 mg/kg/24 hrs for a total of 108 hours. VAD was given concurrently as a continuous infusion of vincristine 0.3 mg and doxorubicin 9 mg/m2 daily for 4 days with oral dexamethasone 20 mg/m2/day for 4 days beginning on days 1, 9 and 17. Clinical response and toxicity were correlated with MDR expression in plasma cells and the effects of cyclosporine on liver function. Six of 25 patients responded (24%; 95% CI 9-45%) with a median remission time of 7 months. Clinical response did not correlate with either the measured or the calculated MDR expression in plasma cells. Responses occurred more frequently in patients who developed high cyclosporine blood levels and paralytic ileus. The occasional benefit from VAD-cyclosporine for resistant multiple myeloma appeared to be due to a higher bioeffective dose of VAD rather than successful modulation of MDR.