This article reports the efficacy of two salvage programs for primary resistant and relapsed multiple myeloma. Employing high dose dexamethasone alone or combined with continuous infusions of vincris-tine and adriamycin (VAD) in 83 patients, ½ achieved a ≥ 75 % tumor cytoreduction. The highest response rate of 65 % was observed among previously responding patients receiving VAD compared to approximately ¼ among those receiving VAD for primary resistant disease or dexamethasone alone regardless of prior response status. Tumor halving times were short with values of 0.5 months for VAD and 1.3 months for dexamethasone alone. The single most important pretre’atment variable associated with failure to achieve remission was a low RNA content of myeloma plasma cells in the bone marrow. The second program evaluated high dose melphalan with or without autologous bone marrow transplantation in 23 patients resistant to VAD salvage treatment. Ten of 23 patients responded for at least 2 months, and 4 others had a comparable anti-tumor effect but died between 4–6 weeks from disseminated infection. Unlike the VAD regimen, responses occurred regardless of prior response or plasma cell RNA content, and tumor halving times were extremely short with a median of 0.3 months. With autologous bone marrow support, the higher melphalan dose (140 vs. 100 mg/m2) could be more safely administered to an older patient population (median of 63 vs. 44 years) with 1 of 7 vs 6 of 16 drug-related deaths in the absence of marrow support. Thus, two probably non-cross resistant regimens have been developed which are currently being evaluated in previously untreated patients with myeloma, where VAD-induced remissions are consolidated with high dose melphalan and total body irradiation in conjunction with autologous marrow support harvested in remission.