BACKGROUND. Today, intensive therapy that includes high-close melphalan with autologous stein cell transplantation (ASCT) is considered standard therapy in younger patients with newly diagnosed myeloma. When the current trial was initiated, combined vincristine, doxorubicin, and dexamethasone (VAD) was the most commonly used induction therapy before ASCT and yielded rapid major responses without interfering with stein cell harvest. However, the administration of VAD demands a central venous access, and well-described toxicities are associated with the therapy. This randomized trial, which was initiated in 2001 by the Nordic Myeloma Study Group, was an attempt to bring a larger portion of patients to ASCT more quickly. METHODS. Patients were randomized to receive either 3 cycles of VAD or 2 courses of cyclophosphamide plus dexamethasone (Cy-Dex) (cyclophosphamide at a dose of 1000 mg/m(2) on Day 1 and dexamethasone at a dose of 40 mg per day on Days 1-4 and 9-12, repeated on Day 22) as initial therapy followed by stein cell mobilization, harvest, and finally ASCT. RESULTS. No significant difference was observed in the proportion of patients undergoing ASCT (VAD [86%] vs Cy-Dex [87%]). During the first 4 months after the initiation of therapy, the mortality rates were 5.8% for VAD and 1.9% for Cy-Dex (P =.08). The response rates after ASCT were comparable (partial response or better: VAD: 80% vs Cy-Dex: 81%). In both groups, the median event-free survival was 29 months, and the overall survival rate at 3 years was 75%. CONCLUSIONS. The current results indicated that Cy-Dex before ASCT has efficacy comparable to that of VAD. It also demonstrated that a short course of alkylater therapy using cyclophosphamide does not affect stem cell harvest or transplantation.