Phase 3b UPFRONT Study: Interim Results From a Community Practice-Based Prospective Randomized Trial Evaluating Three Bortezomib-Based Regimens in Elderly, Newly Diagnosed Multiple Myeloma Patients.

Abstract 129

In this US community-based, randomized, open-label, multicenter phase 3b study, we compare the safety and efficacy of three highly active bortezomib (Velcade®, Vc)-based regimens for multiple myeloma (MM), Vc–thalidomide–dexamethasone (VcTD), Vc–dexamethasone (VcD), and Vc–melphalan–prednisone (VcMP), in previously untreated MM patients (pts) ineligible for high-dose therapy and autologous stem cell transplantation. Use of these regimens is supported by data from phase 3 studies; only VcMP has been investigated specifically in elderly pts. Here we present data from a pre-specified interim analysis (IA) of 210 pts performed after the first 70 pts in each arm had the opportunity to complete four cycles of therapy. Pts with symptomatic, measurable MM were randomized (1:1:1) to receive 49 weeks of therapy: 24 weeks (eight 21-day cycles) of induction with VcD (Vc 1.3 mg/m², days 1, 4, 8, 11; D 20 mg, days 1, 2, 4, 5, 8, 9, 11, 12 [Cycles 1–4)], days 1, 2, 4, 5 [Cycles 5–8]), VcTD (Vc 1.3 mg/m², days 1, 4, 8, 11; T 100 mg/d, d1-21; D 20 mg, days 1, 2, 4, 5, 8, 9, 11, 12 [Cycles 1–4), days 1, 2, 4, 5 [Cycles 5–8]) or VcMP (Vc 1.3 mg/m², days 1, 4, 8, 11; M 9 mg/m² and P 60 mg/m², day 1–4, every other cycle), followed by 25 weeks (five 35-day cycles) of maintenance with Vc alone (1.6 mg/m², days 1, 8, 15, 22). Prophylactic aspirin, full dose warfarin, or low molecular weight heparin was administered to the VcTD arm unless medically contraindicated.The primary endpoint is progression-free survival; secondary endpoints include overall survival, duration of response, time to next therapy, quality of life (QoL) using the EORTC QLQ-C30 questionnaire, safety and tolerability, and efficacy (CR/nCR, VGPR, PR, and ORR). Responses were assessed by investigators using central laboratory data, applying the International Myeloma Working Group uniform criteria. An Independent Data Monitoring Committee (IDMC) assessed safety, tolerability, response rates and QoL data to determine which two of the three arms should continue enrolling pts. Pts in the VcD, VcTD, and VcMP arms had median ages of 74, 73, and 72 years, respectively; 83%, 58%, and 73% had ISS stage ll/lll and 21%, 22% and 32%, respectively, were non-Caucasian. In the VcD, VcTD, and VcMP arms, mean number of treatment cycles (for the first four cycles) and total Vc doses (16 doses for the first four cycles) were similar: 3.8, 3.6, and 3.7 cycles and 14.5, 13 and 13.8 Vc doses, respectively. The VcD arm had the lowest rate of adverse events (AEs) grade ≥3 (58% vs 71% each in the VcTD and VcMP arms, respectively), as well as the lowest rate of discontinuations due to AEs (10% vs 18% and 16% in the VcTD and VcMP arms, respectively). The VcTD arm had the highest rate of serious AEs (50% vs 39% and 36% in the VcD and VcMP arms, respectively), as well as peripheral neuropathy (PN) of any grade (48% vs 29% and 30% in the VcD and VcMP arms, respectively). PN grade ≥3 was 6%, 12% and 13% in the VcD, VcTD, and VcMP arms, respectively. The VcTD arm had higher rates of serious embolism/thrombosis (8% vs 6% and 3%) than in the VcD and VcMP arms, respectively. All three regimens demonstrated substantial activity. The overall response rate was 60%, 70%, and 52% in the VcD, VcTD, and VcMP arms, respectively (complete response (CR)/near CR: 13%, 18% and 15%; ≥very good partial response 15%, 23% and 24%, respectively). QoL functional scores improved in all arms, except for physical, role function and global health status, which worsened in the VcTD arm only. At a preplanned IA, the three Vc-based regimens were evaluated as having similar risk/benefit considerations after four cycles. The regimens were active with well-characterized and predictable toxicities. The study continues to enroll in all three arms as recommended by the IDMC. The UPFRONT trial demonstrates the feasibility of conducting a large, randomized, outpatient, phase 3b trial in community-based oncology centers in the United States.