Bortezomib (Velcade®)-Thalidomide-Dexamethasone (VTD) vs Thalidomide-Dexamethasone (TD) in Preparation for Autologous Stem-Cell (SC) Transplantation (ASCT) in Newly Diagnosed Multiple Myeloma (MM).

In May 2006, the Italian Myeloma Network GIMEMA initiated a multicenter, randomized phase III study comparing VTD (arm A) with TD (arm B) incorporated into ASCT for newly diagnosed MM. Both VTD and TD were planned to be administered before (induction) and after (consolidation) double ASCT with melphalan 200 mg/m² (MEL-200). In both arms, induction therapy consisted of three 21-d courses [63 days (d)]. The VTD regimen included Vel, 1.3 mg/m² on d 1, 4, 8, and 11, plus Dex, 40 mg on each day of and after Vel administration; Thal was given at 200 mg/d from d 1 to 63. Patients randomized to TD received Thal as in arm A and Dex 40 mg/d on d 1–4 and 9–12 of every 21-d cycle. Primary study end point was complete response [either immunofixation negative (CR) or immunofixation positive (nCR)] to induction therapy. Secondary study end points included CR+nCR to consolidation therapy, time to progression, event-free survival, overall survival and toxicity. An interim analysis was planned to be performed after one year from study initiation to assess efficacy and toxicity of induction therapy. As of May 30, 2007, 234 patients entered the study and 187 were evaluated for response to induction therapy and adverse events (AEs). Of these patients, 92 were randomly assigned to receive VTD and 95 to receive TD. Efficacy and toxicity analyses were performed on an intention-to-treat basis. The rate of CR+nCR to VTD was 38% vs 7% to TD (P<0.001); 60% of patients in VTD arm and 25% of patients in the control group attained at least a very good partial response (P<0.001). Patients who failed at least a partial response to VTD were significantly less than those who failed on TD (7% vs 21%, respectively; P=0.004). Grade ≥ 2 and grade ≥ 3 AEs were similar in both arms, with the exception of grade ≥ 3 skin rash (6.5% in VTD arm vs 1% in TD arm; P=0.04). Grade 3 peripheral neuropathy was reported in 8% of patients randomly assigned to VTD and in 2% of patients treated with TD (P=0.07). All patients received acyclovir prophylaxis against reactivation of varicella zoster virus (VZV). VZV infection occurred in 2% of patients in VTD arm and in 1% of patients in the control group. Treatment discontinuation due to AEs was required in a single patient in each of the two treatment arms. No patient died for any cause during the induction phase. In a subgroup of patients with longer follow-up response to first ASCT was also evaluated. The rate of CR or CR+nCR to MEL-200 was significantly higher in VTD arm than in the control group (P=0.02 for CR comparison and P=0.05 for CR+nCR comparison between the two treatment arms). Preliminary analysis of this study provides demonstration that VTD is a highly active and well tolerated induction regimen, resulting in a significantly higher CR or CR+nCR rate compared to TD both before ASCT and after the first autologous transplantation with MEL-200.