Tandem Cycle High-Dose Melphalan and Busulfan/Cyclophosphamide Followed by Maintenance Interferon Alpha-2 (IF) with or without Thalidomide (Thal) Is Associated with High Complete and Very Good Partial Response Rates, Improved Progression-Free, and Overall Survival.

Tandem cycle high-dose melphalan (Mel) followed by Mel +/− total body radiation therapy improves progression-free (PFS) and overall survival (OS) in comparison to single cycle Mel, but is associated with 3% treatment-related mortality (TRM). We tested a new tandem regimen (THDCT) followed by maintenance therapy in order to lower TRM, while enhancing efficacy. Between 5/94 and 8/04, 114 patients (pts) were enrolled on 2 sequential studies. First, pts received Mel 150 mg/m² [cycle 1 (C1)], oral busulfan (bu 16 mg/kg; 46 pts), and cyclophosphamide 120 mg/kg (Cy; C2); the next cohort received the same THDCT but bu was given intravenously (i.v. 12.8 mg/kg; 68 pts). All pts were to receive maintenance IF 3 million units/m² given subcutaneously, 3 times/week. Pts participating on the 2nd study were to receive thal together with IF provided that they were not in CR at 6 months post-THDCT. Peripheral blood progenitor cell mobilization consisted of G-CSF 10 microgram/kg to procure 4 x 10⁶ CD34+ cells/kg without (first 46 pts) or with Cy 1.5 g/m² (last 68 pts). Pts ≤65 years, with responsive or stable MM, with <40% marrow involvement, with a creatinine clearance of 70 cc/min and Karnofsky performance status of 70% were enrolled. Median age was 52 years (range: 29–65); 70% of pts were diagnosed with stage III MM, and 4 pts presented with plasma cell leukemia; 40% received prior radiation therapy. Pts received a median of 1(1–3) induction chemotherapy regimens; the median time from diagnosis to THDCT was 8 months (range: 2–73); 89% of pts received both C-s at a median of 76 days (range, 29–134). Among the first 46 pts (treated with oral bu) there were 7 cases of veno-occlusive disease (VOD): 3 were fatal, resulting in TRM of 7%. There were 8 cases of VOD in the 68 pt cohort treated with i.v. bu, one of whom died of multi-organ failure/sepsis (TRM:1.5%). Eighty nine percent of pts tolerated at least 1 million units/m² of IF 2–3 times/week. Of pts receiving concomitant IF and thal (median dose of thal: 100 mg/day[range, 50–400]), only 7 pts tolerated both (median: 4 months; range: 1.6–18 months), 3 of whom converted to CR. At best response 44% pts were in CR and 12% achieved 90% reduction (very good partial remission (VGPR). For the entire group, 3-year PFS is 50% (95% CI, 40–59%) and OS is 71% (95%CI, 61–78%). Three-year PFS is 66% (95% CI 52–76%) vs. 29% (95% CI 16–42%) and OS is 87% (95% CI 76–93%) vs. 49% (95% CI 35–63%) favoring pts in CR and VGPR vs. all others. THDCT with Mel and i.v. bu /Cy and maintenance IF can be given safely, and may provide an alternative regimen to tandem Mel. Concomitant administration of IF and thal is not feasible. Thal should be used either in sequence or in lieu of IF as maintenance.