Multiple myeloma remains a universally fatal malignancy with a median survival time not exceeding 3 years. A clinical trial was undertaken to determine feasibility and efficacy of marrow-ablative chemoradiotherapy supported by unpurged autologous bone marrow (ABMT) and to define prognostic variables. Total body irradiation and either melphalan or thiotepa were administered to 55 patients (median age 53 years; range 20 to 66 years). The group of 21 patients with resistance to standard melphalan-prednisone and to continuous infusions of vincristine and Adriamycin with high dose dexamethasone (VAD) included 7 with primary unresponsive disease and 14 with resistant relapse; among the 34 patients achieving remission with the VAD regimen, 14 were in first and 20 in a subsequent remission. Marked cytoreduction by greater than or equal to 75% was observed among all 21 patients with refractory myeloma, whereas further cytoreduction of this magnitude was noted in only 56% of the 34 patients already in remission after VAD. Five of the 6 early deaths among all 55 patients occurred in the 14 patients with resistant relapse, none of whom achieved complete remission and who, as a group, had median durations of relapse-free and overall survival of only 8 and 7 months, respectively. Among the 41 remaining patients, there was only one early death, and 27% achieved complete remission including a 36% incidence among the 14 patients treated in first remission; their projected 4-year survival rate was 82% regardless of their disease status (first or later remission or primary resistance). When information about sensitivity to prior therapy is unavailable, the presence before ABMT of both high beta-2-microglobulin levels (greater than 3 mg/L) and non-IgG isotype helped identify 9 among the 55 patients with a very poor prognosis: all 8 responders relapsed within 9 months, and 8 patients died within 15 months. By contrast, a 4-year projected survival rate of over 70% for the other patients (about 80% of this series) justifies further investigation of this novel treatment approach in comparison with standard dose regimens. Our results indicate that marrow-ablative therapy cannot be recommended for myeloma patients with resistant relapse or those with a combination of risk factors (advanced tumor burden, absence of IgG isotype). The apparent lack of an adverse effect of even marked plasmacytosis in autografts (up to 30%) emphasizes the need for better cytoreduction rather than bone marrow purging.