Phase 3b UPFRONT Study: Safety and Efficacy of Weekly Bortezomib Maintenance Therapy After Bortezomib-Based Induction Regimens In Elderly, Newly Diagnosed Multiple Myeloma Patients

The UPFRONT study is a US community-based, randomized, open-label, multicenter phase 3b trial comparing the safety and efficacy of three bortezomib (Velcade®, Vc)-based regimens, VcD (Vc-dexamethasone), VcTD (Vc-thalidomide-dexamethasone), and VcMP (Vc-melphalan-prednisone), followed by Vc maintenance, in newly diagnosed multiple myeloma (MM) patients ineligible for high-dose therapy and stem cell transplantation. Patients with previously untreated, symptomatic, measurable MM were randomized (1:1:1) to receive 49 weeks of therapy: 24 weeks (eight 21-day cycles) of induction with VcD, VcTD, or VcMP (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]); 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 weekly Vc (1.6 mg/m², days 1, 8, 15, 22). Here we present updated results after 300 patients had the opportunity to undergo the entire 13-cycle treatment period (8 induction + 5 maintenance cycles). The primary study endpoint is progression-free survival (PFS); secondary endpoints include efficacy (overall response rate [ORR], complete response [CR]/near-CR [nCR] and very good partial response [≥VGPR] rates), safety and tolerability, and response duration. Responses were assessed by investigators using central laboratory data, applying modified International Myeloma Working Group (IMWG) criteria. Patients in the VcD, VcTD, and VcMP arms had median ages of 73.5, 73.0, and 72.0 years, respectively; 85%, 64%, and 74% had ISS stage II/III, and 22%, 27%, and 28% were non-Caucasian. Patients received a median of 9 (VcD), 6 (VcTD), and 7 (VcMP) treatment cycles (induction + maintenance); 56%, 33%, and 43% of patients, respectively, received Vc maintenance. In the VcD, VcTD, and VcMP arms, Vc dose intensity (mean ratio of doses received/doses planned) was 76%, 63%, and 69% during induction, and 73%, 77%, and 85% during maintenance, respectively. All three Vc-based induction regimens exhibited substantial efficacy after 8 cycles, with ORRs (≥PR; best confirmed response) of 68%, 78%, and 71% for VcD, VcTD, and VcMP, respectively. After 5 cycles of Vc maintenance, the ORR was increased to 71%, 79%, and 73% in the VcD, VcTD, and VcMP arms, respectively. Similar trends were seen in CR+nCR and ≥VGPR rates after Vc maintenance in the VcD, VcTD, and VcMP arms: CR+nCR rates were 24%, 36%, and 31% after induction versus 31%, 38%, and 34% after Vc maintenance, and ≥VGPR rates were 36%, 44%, and 40% after induction versus 39%, 47%, and 44% after Vc maintenance, respectively (Table). After 13 treatment cycles, the rates of grade ≥3 adverse events (AEs) were 74%, 86%, and 80% for patients in the VcD, VcTD, and VcMP arms, respectively; similar to the rates reported after 8 cycles, 70%, 84%, and 79%, respectively. After 13 cycles, the five most common grade ≥3 AEs were peripheral neuropathy (PN) (18%, 28%, and 21% for VcD, VcTD, and VcMP, respectively), fatigue (10%, 15%, 8%), diarrhea (11%, 5%, 10%), neutropenia (1%, 3%, 21%), and pneumonia (11%, 6%, 6%). The incidence of serious AEs was highest in the VcTD arm (61%, vs 57% with VcD and 51% with VcMP). All-grade PN was most frequently reported in the VcTD arm (61%), versus the VcD (49%) and VcMP (45%) arms; these rates are similar to those reported after 8 induction cycles (59%, 45%, and 43% for the VcTD, VcD, and VcMP arms). Rates of deep vein thrombosis and pulmonary embolism were 7%, 4%, and 2%, and 4%, 3%, and 1%, respectively, in the VcD, VcTD, and VcMP arms. Study drug discontinuation due to AEs was highest in the VcTD arm (41%, vs 29% with VcD and 35% with VcMP). In conclusion, maintenance with Vc monotherapy is well tolerated when administered after VcD, VcTD, and VcMP induction regimens. Response rates, including CR and ≥VGPR, improved after Vc maintenance with no concomitant increase in the incidence of PN. Patients continue to be monitored for PFS and response duration.

Niesvizky:Celgene: Consultancy, Research Funding; Millennium Pharmaceuticals, Inc.: Consultancy, Research Funding; Onyx: Consultancy, Research Funding. Off Label Use: Discussion of Velcade in a novel combination in frontline myeloma is included. Flinn:Millennium Pharmaceuticals, Inc.: Research Funding. Rifkin:Millennium Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Speakers Bureau; Amgen: Speakers Bureau; Cephalon: Speakers Bureau; Dendreon: Speakers Bureau. Gabrail:Millennium Pharmaceuticals, Inc.: Research Funding. Charu:Amgen: Equity Ownership, Research Funding; Pfizer: Equity Ownership; GSK: Equity Ownership, Research Funding; Lilly: Equity Ownership, Research Funding; Millennium Pharmaceuticals, Inc.: Research Funding; Roche: Research Funding; Bristol-Myers Squibb: Equity Ownership. Neuwirth:Millennium Pharmaceuticals, Inc.: Employment. Corzo:Millennium Pharmaceuticals, Inc.: Employment. Reeves:Celgene: Common stock in Celgene.