A Non-Myeloablative Regimen of Fludarabine and Melphalan Is Safe and Well Tolerated for Allogeneic Transplantation in Multiple Myeloma.

Background: Allogeneic transplantation is a potentially curative approach in patients with myeloma. The potential benefit is offset by a higher risk of transplant-related mortality (TRM), graft-vs.host disease (GVHD) and opportunistic infections. The success of reduced intensity conditioning approaches has renewed interest in allogeneic transplantation. In this randomized phase II trial we evaluated whether lowering the dose of melphalan in a nonablative preparative regimen can lower the toxicity and TRM. Two reduced intensity regimens:

• fludarabine + melphalan 140 mg/m2 (FM 140) and

• fludarabine + melphalan 100 mg/m2 (FM 100) were compared in patients undergoing allogeneic stem cell transplantation.

Methods: We enrolled 22 patients, 11 in each arm, who were 70 years of age or younger and had an HLA-identical sibling donor. Patients underwent allogeneic transplantation between April 2002 and January 2007. Median age was 52.5 years (Range: 32–63). GVHD prophylaxis consisted of tacrolimus and methotrexate 5mg/m2 on days 1, 3, 6 and 11. Median interval between diagnosis and transplant was 28 months (9–232). Only 6 patients (27%) received transplant for the consolidation of first remission, the rest had relapsed or refractory disease (73%). Twenty-one patients had a prior autotransplant; 3 of these had 2 prior autotransplants. Median number of prior treatment regimens was 5 (1–10). Cytogenetic abnormalities were observed in 8/22 patients (36%).

Results: The 2 groups were comparable in terms of age, disease status, prior therapy and other prognostic factors. Median time to neutrophil engraftment in both arms was 12 days. TRM in the first 100 days was zero in both arms. Response rate (CR 18% + PR 64%) was 82%, with no significant difference between the 2 arms. After a median follow up of 25 months (26 months in FM 100, 21 months in FM 140), Kaplan-Meier estimates of 2-year PFS in FM 100 vs. FM 140 were 41% vs. 42%, respectively. Kaplan-Meier estimates of 2-year OS in FM 100 vs. FM 140 were 60 vs. 36%, (p=0.4), respectively. There was no significant difference in the incidence of grade II-IV acute GVHD (27 vs. 36%) or chronic GVHD (50 vs. 43%) between the 2 arms. There was a decrease in overall grade II-IV toxicity in the FM 100 arm (45% vs. 73%) that did not reach statistical significance (p=0.2) Patients transplanted in relapse had shorter PFS (0.09).

Conclusions: The dose of melphalan in preparative regimen can be safely reduced without adversely impacting the engraftment in this heavily pretreated patient population. There was a trend towards lower grade II-IV toxicity and prolonged OS in the FM 100 arm. This approach may be more beneficial when used early in the course of treatment.