PURPOSE Thalidomide-dexamethasone (THAL-DEX) is standard induction therapy for multiple myeloma (MM). Tandem melphalan-based transplantations have yielded superior results to single transplantations. Phase II trial S0204 was designed to improve survival results reported for the predecessor, phase III trial S9321 by 50%. PATIENTS AND METHODS Newly diagnosed patients with MM were eligible for S0204 with THAL-DEX induction, tandem melphalan-based tandem transplantation, and THAL-prednisone maintenance. Results Of 143 eligible patients, 142 started induction, 73% completed first transplantation, 58% completed second transplantation, and 56% started maintenance. The quantity of stem cells required for two transplantations was reached in 88% of 111 patients undergoing collection, 74% of whom completed both transplantations. Partial response, very good partial remission, and complete response were documented after 12 months of maintenance therapy in 87%, 72%, and 22% of patients, respectively. During a median follow-up time of 37 months, 4-year estimates of event-free and overall survival were 50% and 64%, respectively. Survival outcomes were superior for International Staging System (ISS) stage 1 disease, when lactate dehydrogenase (LDH) levels were normal and a second transplantation was applied in a timely fashion. CONCLUSION Both overall survival (P = .0002) and event-free survival (P < .0001) were significantly improved with S0204 compared with S9321 when 121 and 363 patients, respectively, were matched on ISS stage and LDH.