Arsenic Trioxide with Ascorbic Acid and High-Dose Melphalan Is Safe and Effective for Autotransplantation for Multiple Myeloma.

Background: Arsenic trioxide (ATO) has been shown to be synergistic with melphalan both in vitro and in vivo. We conducted a randomized phase II trial to determine the safety and efficacy of a combination of ATO, melphalan, and ascorbic acid (AA) as a preparative regimen in patients undergoing autologous hematopoietic progenitor cell transplantation for multiple myeloma (MM). We also assessed the impact of ATO levels on melphalan pharmacokinetics, engraftment, and toxicity. Methods: Forty-eight patients with secretory myeloma (23 females, 25 males; median age, 54; range 35–70) were treated between 4/04 and 8/05. All patients received melphalan 100 mg/m 2 IV on days -4 and -3 and AA 1000 mg/day IV on days -9 to -3. Patients were randomized to 3 arms: no ATO (arm 1), ATO 0.15 mg/kg IV on days -9 to -3 (arm 2), and ATO 0.25 mg/kg IV on days -9 to -3 (arm 3). Twelve patients had received a prior autograft, with a median 4.5 x 10 6 /kg (range 2.3–10.9) CD34+ cells infused. Results: Patients in all 3 arms were evenly matched. Twenty-nine patients (60%) were transplanted for consolidation of first remission and 19 patients (40%) for relapsed disease. With a median follow-up of 26 months (range 10–37) post-autograft, no dose-limiting toxicity, or nonrelapse mortality was reported. Toxicity was limited to grade 1 or 2 nausea, vomiting, and diarrhea and was comparable in all 3 arms. Melphalan pharmacokinetics was not altered by ATO pretreatment. Median time to neutrophil engraftment (absolute neutrophil count >500/dL) was 9 days, with no engraftment failures or delays in either the control or ATO arms. The complete response (CR) rate for all patients was 25% (12/48), and the partial response rate was 60% (29/48) for an overall response rate (ORR = CR + PR) of 85%. Progression-free survival (PFS) and overall survival (OS) after 24 months of follow-up were 59% and 91%, respectively. Median PFS was 29 months; median OS has not been reached. There was no significant difference in CR, ORR, PFS, or OS among the 3 arms ( P =.9, .9, .5, and .6, respectively). PFS and OS were comparable among patients with chromosomal abnormalities or relapsed disease at transplant and patients undergoing a second autotransplant for salvage. Conclusions: Addition of ATO + AA to high-dose melphalan is safe and well tolerated as a preparative regimen for autotransplants in patients with MM, including high-risk patients. There was no adverse impact of ATO on engraftment. Longer follow-up is necessary to assess the efficacy of this combination on PFS and OS.