VAD is the most active regimen in refractory myeloma patients; however, the role of vincristine and doxorubicin remains unclear. Relatively high doses of cyclophosphamide (3.6 g/sqm) increased the response rate and survival in resistant MM. Cyclophosphamide and dexamethasone were administered to 28 patients with advanced refractory myeloma. Thirteen patients received cyclophosphamide 1.2 g/sqm on days 1 and 3 and dexamethasone 40 mg/day from day 1 to day 4, every 4 weeks for 6 cycles (schedule A); 15 patients were treated with cyclophosphamide 0.5 g/sqm on days 1 and 3 and dexamethasone 40 mg/day from day 1 to day 4, every two weeks for 12 cycles (schedule B). Overall, 21 patients (75%) responded and 10 achieved an objective response (36%), while 11 reached a partial response. Twenty patients died (68%), most of them of disease progression, and 8 are still alive (32%). Median length of response and survival is 6 and 8 months, respectively. Therapy was easily applied and well tolerated. The overall response rate (75%) compares favorably with the best published results in this setting. The two schedules proved to be equally effective but patients treated with schedule B had more infections, which may have been related to the higher dosage of steroids.