Bortezomib, Melphalan, Prednisone and Thalidomide (VMPT) Followed by Maintenance with Bortezomib and Thalidomide for Initial Treatment of Elderly Multiple Myeloma Patients.

Abstract 128

Background. In newly diagnosed myeloma patients the combination of bortezomib with melphalan-prednisone (VMP) was superior to MP. In relapsed-refractory patients the 4 drug combination bortezomib-melphalan-prednisone-thalidomide (VMPT) induced a high proportion of complete responses (CR). Aims. This prospective, randomized, phase III trial, compared VMPT with a maintenance regimen including bortezomib and thalidomide with VMP without a maintenance regiment. The primary end point was PFS. Methods. Patients (N=511) older than 65 years were randomly assigned to receive VMPT followed by maintenance with bortezomib and thalidomide (N=254) or VMP (N=257). Initially, patients were treated with nine 6-week cycles of VMPT (induction: bortezomib 1.3 mg/m² days 1,4,8,11,22,25,29,32 in cycles 1–4 and days 1,8,22,29 in cycles 5–9; melphalan 9 mg/m² days 1–4; prednisone 60 mg/m² days 1–4 and thalidomide 50 mg days 1–42; maintenance: bortezomib 1.3 mg/m² every 15 days and thalidomide 50 mg/day) or VMP (bortezomib, melphalan and prednisone at the same doses and schedules previously described without maintenance). In March 2007, the protocol was amended: both VMPT and VMP induction schedules were changed to nine 5-week cycles and bortezomib schedule was modified to weekly administration (1.3 mg/m² days 1,8,15,22 in cycles 1–9). Results. All patients have been evaluated in intention-to-treat. Patient characteristics were similar in both groups, median age was 71 years. The response rates were always superior in the VMPT group: at least PR rate (86% vs 79%, p=0.02), at least VGPR rate (55% vs 47%, p=0.07) and CR rate (34% vs 21% p=0.0008), respectively. Maintenance treatment did not increase the best response achieved during VMPT induction. After a median follow-up of 17.8 months, the 2-year PFS was 70.0% in the VMPT group and 58.2% in the VMP group (HR=0.62, 95% CI 0.44–0.88, p=0.008). The achievement of CR significantly prolonged PFS in both VMPT (p<0.0001) and VMP (p=0.003) patients. Chromosomal abnormalities, such as del13, t(4;14), t(14;16) or del17, did not affect 2-year PFS in both VMPT (p=0.51) and VMP (p=0.41) patients. The 2-year overall survival (OS) was 89.6% in the VMPT group and 89.0% in the VMP group (HR=0.94, 95% CI 0.51–1.72, p=0.84). The incidence of grade 3–4 neutropenia (37% vs 28%, p=0.02) and cardiac complications (10% vs 5%, p=0.04) was higher in the VMPT group. The incidence of other grade 3–4 adverse events was similar in the VMPT group and in the VMP group: thrombocytopenia (21% vs 19%), peripheral neuropathy (5% vs 8%), infections (12% vs 9%), and gastrointestinal complications (6% vs 8%), respectively. From twice-weekly, the weekly infusion of bortezomib significantly decreased the incidence of grade 3–4 peripheral neuropathy in the VMPT group (from 18% to 4%, p=0.0002) and in the VMP (from 13% to 2%, p=0.0003), without any significant change in CR rates and 2-year PFS. Conclusion. VMPT followed by maintenance with bortezomib and thalidomide was superior to VMP for response rates and PFS. The weekly infusion of bortezomib significantly reduced the incidence of peripheral neuropathy without affecting outcome. This is the first report showing the superiority of a 4-drug combination followed by maintenance in comparison with the most recent standard therapy, VMP. These data will be updated at the meeting.