Phase II Trial of Lenalidomide, Bortezomib, and Dexamethasone In Patients (pts) with Relapsed and Relapsed/Refractory Multiple Myeloma (MM): Updated Efficacy and Safety Data After >2 Years of Follow-up

Single-agent bortezomib (btz) and lenalidomide (len)-dexamethasone (dex) are associated with higher rates of response and improved survival vs dex alone in relapsed MM, and both are approved for treatment of MM pts with ≥1 prior therapy. As frontline therapy, combined len 25 mg, btz 1.3 mg/m² and dex 20/10 mg (RVD) generated high response rates in a phase 1/2 study (Richardson et al Blood 2010). In relapsed/refractory MM, this combination was well tolerated in a phase I study, with 58% ≥ minimal response (MR) and maximum tolerated doses (MTD) of btz 1.0 mg/m² and len 15 mg (Richardson et al J Clin Oncol 2009). The aim of this prospective, multicenter, phase II study was to further evaluate the efficacy of RVD in pts with relapsed or relapsed/refractory MM at the MTD. Here we present updated and mature data after >2 years' follow up.

Eligibility criteria: relapsed or relapsed/refractory MM following 1–3 prior therapies, age ≥18 yrs, and KPS ≥60%. Pts with grade ≥2 PNY were excluded. Pts received up to eight 21-day cycles of btz 1.0 mg/m², d 1, 4, 8, 11; len 15 mg/day, d 1–14; dex 40/20 mg/day (cycles 1–4); and 20/10 mg/day (cycles 5–8), d 1, 2, 4, 5, 8, 9, 11, 12. Responding pts could receive maintenance therapy (21-day cycles of btz on d 1, 8; len on d 1–14; dex on d 1, 2, 8, 9; at doses tolerated at end of cycle 8). Pts were required to take anticoagulation therapy (daily aspirin 81 or 325 mg) and prophylactic antivirals. The primary endpoint was the proportion of patients alive and progression free (PFS) at 6 mos. Secondary endpoints included objective response rate (modified EBMT criteria), time to response (TTR), duration of response (DOR), time to progression (TTP), overall survival (OS), and safety/tolerability.

In total, 64 pts were treated; median age was 65 yrs (range 32–83), 66% were men, 58% had relapsed and 42% relapsed/refractory MM, and 59% had DSS III MM at diagnosis. Median number of prior therapies was 2, and 53%, 73%, and 6% of pts received prior btz, thalidomide, and len, respectively. Pts received a median of 11 cycles (range 1–48), including medians of 11 (1–48), 9 (1–48), and 9 (1–48) cycles of len, btz, and dex, respectively. 42 (66%) pts received ≥8 cycles (maintenance); reasons for discontinuation before cycle 8 included progressive disease (PD; n=11) and toxicity (n=3). 18 (28%) pts were on study for >1 yr and 6 pts remain on study at 16–34 mos from start of treatment. Dex start dose was 40 mg in 19 and 20 mg in 45 pts. In total, 40 (62%) pts required dose reductions. 48 (75%) pts are alive without PD at ≥6 mos from the start of treatment (90% CI: 65, 84). 50 (78%) pts achieved ≥ MR and 41 (64%) ≥ partial response (PR); 16 (25%) pts achieved complete response (CR)/near CR. No difference (p=0.8) was detected in ≥ PR rate between relapsed (62%) and relapsed/refractory (67%) pts. In pts with ≥ MR or ≥ PR, median TTR was 1.9 and 2.1 mos, and median DOR was 8.3 and 8.4 mos, respectively. After median follow-up of 26 mos, 55 pts have PD, and 32 have died. Median TTP was 9.5 mos; estimated 6-, 12-, and 24-mo TTP rates were 76%, 37%, and 16%, respectively. Median PFS was 9.5 mos; with respective 6-, 12- and 24-mo rates of 75%, 36%, and 15%. Median OS was 26 mos, with respective 12- and 24-mo OS rates of 86% and 55%. Preliminary analysis suggests no significant difference in outcome (PFS/OS) between pts with abnormal cytogenetics by metaphase karyotyping or FISH. Common treatment-related toxicities included sensory PNY (64%; 19% G2), fatigue (48%), neutropenia (42%), diarrhea, muscle pain (both 39%), and hyperglycemia (36%); most common G3/4 toxicities included neutropenia (30%), thrombocytopenia (22%), lymphopenia (11%), hyperglycemia, leucopenia (both 9%), hyponatremia, and hypophosphatemia (both 8%). No G3/4 sensory PNY or neuropathic pain was reported; 3% G3 motor PNY (2 pts) was observed. One pt (2%) developed thrombosis (G2). PNY was manageable and reversible in most pts, with only 5 (8%) pts discontinuing treatment due to toxicity of any cause.

RVD combination therapy is very active and well tolerated in pts with relapsed and relapsed/refractory MM, despite prior therapy with novel agents. OS data were encouraging in this population, with 32 pts alive at data cut-off. Further investigation of this regimen at the higher len and btz doses explored in the frontline setting, with subsequent dose reductions and schedule change as required for potential toxicities, as well as in combination with other agents, is warranted.

Richardson:Millennium Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees. Off Label Use: Bortezomib and lenalidomide in novel combination. Jagannath:Millennium Pharmaceuticals, Inc.: Consultancy, Honoraria; Merck: Consultancy, Honoraria. Jakubowiak:Millennium Pharmaceuticals, Inc.: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Centocor Ortho Biotech: Consultancy, Honoraria; Exelixis: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Research Funding. Lonial:Millennium Pharmaceuticals, Inc.: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Onyx: Consultancy, Research Funding. Raje:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; Astra Zeneca: Research Funding; Acetylon: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees. Alsina:Millennium Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Ortho Biotech: Research Funding. Ghobrial:Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Millennium Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees. Mazumder:Millennium Pharmaceuticals, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Munshi:Celgene: Consultancy; Millennium Pharmaceuticals, Inc.: Consultancy; Novartis: Consultancy; Onyx: Consultancy. Vesole:Celgene: Speakers Bureau; Millennium Pharmaceuticals, Inc.: Speakers Bureau. Hideshima:Acetylon Pharmaceuticals: Consultancy. Knight:Celgene: Employment, Equity Ownership. Esseltine:Millennium Pharmaceuticals, Inc.: Employment; Johnson & Johnson: Equity Ownership. Mitsiades:Millennium Pharmaceuticals, Inc.: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Merck: Consultancy, Honoraria; Kosan Pharmaceuticals: Consultancy, Honoraria; Pharmion: Consultancy, Honoraria; Centrocor: Consultancy, Honoraria; Amgen: Research Funding; AVEO Pharma: Research Funding; EMD Serono: Research Funding; Sunesis and Gloucester Pharmaceuticals: Research Funding; Genzyme: Research Funding; PharmaMar: Patents & Royalties; OSI Pharmaceuticals: Research Funding. Anderson:Millennium Pharmaceuticals, Inc.: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Onyx: Consultancy; Merck: Consultancy; BMS: Consultancy; Acetylon Pharmaceuticals: Equity Ownership, Membership on an entity's Board of Directors or advisory committees.