Thirty-five previously untreated patients with multiple myeloma were treated with a 60-week course of alternating, potentially non-cross-resistant chemotherapy combinations (melphalan and prednisone; vincristine, cyclophosphamide, doxorubicin, and prednisone; and carmustine, melphalan, and prednisone), alternating every 15 weeks in an attempt to prevent the development of drug resistance. The overall objective response rate (greater than 50% decrease in M protein) was 60% and six patients (17%) had a complete disappearance of the M protein. After 60 weeks, chemotherapy was discontinued in 17 responding or stable patients until relapse occurred from 4 to 39 months later (median, 12 months). Patients relapsing late (greater than 12 months after discontinuation of therapy) responded more frequently than those relapsing earlier to the reinstitution of the same chemotherapy program. The overall response rate and the actuarial median survival of 26 months in the 35 patients do not differ from the results reported recently with nonalternating combinations given until clinical tumor progression. The failure of this study to prolong survival by using alternating regimens may be due to (a) the likely possibility that the initial two regimens are not actually non-cross-resistant in most myeloma patients, and (b) the long interval between the alternating regimens, particularly in the face of the low response rate to the initial regimen of melphalan and prednisone.