A trial was initiated to determine the feasibility and efficacy of a three-phase treatment including: (1) induction chemotherapy (IC); (2) high-dose melphalan with total body irradiation supported by unpurged autologous bone marrow transplantation (ABMT); and (3) interferon (IFN) alpha maintenance treatment, in previously untreated aggressive myeloma. Thirty-five consecutive patients, ages under 65 years, were enrolled. Initial induction therapy was randomized between the VAD regimen (vincristine, doxorubicin, dexamethasone) or the VMCP regimen (vincristine, melphalan, cyclophosphamide, prednisone) that were found to give similar results as IC. Thirty-one of 35 (89%) patients, with good performance status and normal renal function after IC, received ABMT. IFN alpha was started soon after ABMT and was well tolerated. Fifteen of 35 (43%) patients achieved complete response (CR) and 14 of 35 (40%) achieved partial response (PR). Low pretreatment beta 2 microglobulin was the only predictive factor for accomplishing CR. The duration of response was significantly affected by the magnitude of response. The 33-month, post-ABMT probability of progression-free survival was 85% for patients in CR versus 24% for patients in PR. The 42-month, post-diagnosis probability of survival was 81%. This overall strategy may represent an advance in the management of multiple myeloma. Furthermore, the high rate and long duration of CR that we observed in patients with low beta 2 microglobulin suggest that such patients may preferentially benefit from this strategy.