In order to ascertain whether multiple myeloma patients resistant to one alkylating agent would respond to a second one, high-dose intermittent cyclophosphamide was administered to 12 patients showing resistance to melphalan and prednisone. On the other hand, intermittent melphalan and prednisone treatment was employed in eight myeloma patients resistant to intermittent cyclophosphamide. Only one objective response was achieved among 12 patients on cyclophosphamide therapy, in spite of having employed high doses of this alkylating agent. No responses were achieved with melphalan in the group of cyclophosphamide-resistant patients. The median survival probability was 8.7 months (SD +/- 2.9) for all patients after starting the second alkylating agent. These results suggest cross-resistance between melphalan and cyclophosphamide in myeloma. The authors conclude that a single second alkylating agent cannot be recommended as a treatment of patients with multiple myeloma who are truly refractory to one alkylating agent.