This report summarizes a broad experience in the treatment of patients with multiple myeloma resistant to standard chemotherapy. The VAD regimen has induced remissions in about 50% of relapsing patients but in only about 25% of previously unresponsive patients. In patients resistant to VAD, high-dose therapies with intravenous melphalan, a CBV combination (cyclophosphamide-BCNU-VP-16) or an EDAP regimen (VP-16 -platinum) produced responses in about 40% of patients. However, these treatments usually required autologous bone marrow or blood stem cell support and the median duration of control was only 6 months. With an even more intensive program using high-dose melphalan and total body irradiation supported by autologous bone marrow, all patients who survived the early treatment period responded for a median duration of about 1 year. Results indicated a dose-response effect of chemoradiotherapy on VAD-resistant myeloma with the potential that such intensive regimens will prolong disease-free survival time.