We compared the efficacy of intensified chemotherapy followed by myeloablative therapy and autologous stem cell rescue with intensified chemotherapy alone in patients newly diagnosed with multiple myeloma. There were 261 eligible patients younger than 66 years with stage II/III multiple myeloma who were randomized after remission induction therapy with vincristine, adriamycin, dexamethasone (

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Summary. Patients with multiple myeloma (MM) refractory to alkylating agents frequently express P-glycoprotein (Pgp), which is associated with the multidrug resistance (MDR) phenotype. We have conducted a randomized phase II/III study of the MDR reversal agent cyclosporin A combined with VAD (vincristine, doxorubicin, dexamethasone) compared with standard VAD in patients with MM stage IIA/IIIA who were refractory to or progressive after treatment with alkylating agents. Out of 81 patients who were randomized, 75 were eligible and evaluable: 34 in the VAD 1 cyclosporin A arm versus 41 in the VAD arm. Toxicities of grade 2±3 were observed more often with VAD 1 cyclosporin A than with VAD only: nausea (30% versus 8%, P 0´015), mucositis (18% versus 5%, P 0´13), infection (45% versus 35%, P 0´50). The treatment results were similar in the two arms: 53% versus 49% responded [95% CI (218´5%, 26´9%)]. The median progression-free survival (PFS) was 8´6 months (VAD 1 cyclosporin A) versus 5´8 months (VAD): [log rank P 0´16, hazard ratio 0´71, 95% CI (0´44, 1´15)], and median overall survival was 13 months versus 14´6 months [log rank P 0´89, hazard ratio 0´96, 95% CI (0´62, 1´72)]. The cause of death was progressive disease (85%), toxicity (10%) or other (5%). Bone marrow analysis performed in 23 patients showed that the response rate was 67% in Pgppositive versus 55% in Pgp-negative patients. Cyclosporin A combined with VAD is relatively well tolerated. There is no effect of cyclosporin A on the overall response rate, PFS and overall survival with VAD.