High Response Rates and Encouraging Time-to-Event Data with Lenalidomide, Bortezomib, and Dexamethasone in Newly Diagnosed Multiple Myeloma: Final Results of a Phase I/II Study.

The combination of lenalidomide (Len, Revlimid^®), bortezomib (Bz, Velcade^®), and dexamethasone (dex; RVD) has shown excellent efficacy in relapsed/refractory multiple myeloma (MM) patients, with overall response rates (ORR; ≥partial response [PR]) of 69%, including 26% complete/near complete responses (CR/nCR), and manageable toxicities (Anderson et al. ASCO 2009). The phase I portion of the study (Richardson et al. IMW 2009) found the maximum tolerated dose (MTD) of this combination in newly diagnosed MM patients to be Len 25 mg/day, Bz 1.3 mg/m², and dex 20 mg. In all phase I patients, the ORR was 100%, including 31% CR, 9% nCR, and 75% ³very good PR (VGPR). Results reported here are for patients treated in the phase II portion of the study.

Patients were treated with Len 25 mg/day (days 1–14), Bz 1.3 mg/m² (days 1, 4, 8, 11), and dex 20 mg (cycles 1–4) and 10 mg (cycles 5–8) on the day of and day after Bz for up to eight 21-day cycles. Patients received prophylactic anticoagulants. Responses were assessed by modified EBMT and Uniform criteria to include nCR and VGPR. Patients with at least PR could proceed to ASCT after ³4 cycles; responding patients who did not go on to ASCT could continue therapy at their physician's discretion. Patients with ³grade 2 peripheral neuropathy (PNY) by CTCAE v3 were excluded. Thirty five patients were enrolled in the phase II portion of this study and were evaluable for both efficacy and safety.

Median age was 59 years (range 22-86), 54% were men, 34% / 54% / 11% were ISS Stage I / II / III, and 57% / 31% had IgG / IgA MM, respectively. Patients received a median of 8 cycles of Bz and dex and 11 cycles of Len; 11 (31%) patients remain on therapy. Among the 24 patients who have gone off therapy, 5 (21%) completed treatment per protocol, 8 (33%) proceeded to ASCT, 3 (13%) had progressive disease (all during cycle 14 or later), 1 (4%) withdrew due to toxicities, 1 (4%) received non-protocol therapy, and the remaining (n=6; 25%) withdrew consent or stopped treatment due to physician decision. All patients (100%) had a best confirmed pre-ASCT response of ³PR, with 54% CR/nCR and 69% ³VGPR (Table). Response rates in the 31 and 24 patients who completed 4 and 8 cycles, respectively, are shown in the Table. Among the 24 patients without CR at cycle 4, response improved between cycles 4 and 8 in 16 (67%) patients. Fifteen of the 35 (43%) patients were mobilized for ASCT, with a median stem cell yield of 4.4 × 10⁶ (2.3–6.6 × 10⁶) CD34+ cells/kg. After median follow-up of 19.3 months, median time to progression (TTP), progression-free survival (PFS), and overall survival (OS) have not been reached; the estimated 1-year TTP and PFS are 76% and the estimated OS is 100%. Treatment-emergent grade 3 and 4 adverse events that occurred in >1 patient included lymphopenia (n=7; 20%), hypokalemia (n=3; 9%), and fatigue and neutropenia (n=2; 6% each). Sensory PNY of any grade occurred in 27 (77%) patients, which was grade 1 (n=18; 67%) and grade 2 (n=8; 30%) in the majority of patients; only one patient had grade 3 sensory PNY. Neuropathic pain and motor PNY were reported in 10 (29%; all grade 1 and 2) and 6 (17%; 1 grade 3) patients, respectively, with no grade 3 PNY seen. Importantly, PNY was reversible with dose reduction, supportive care, and/or completion of therapy. Thrombosis/thromboembolism was reported in just 2 (6%) patients. No treatment-related mortality was seen.

These phase II results suggest that RVD is a highly effective combination, with a pre-ASCT ORR of 100% and high rates of CR/nCR, and encouraging time-to-event analyses to date. RVD was well tolerated, with limited rates of grade 3 PNY and DVT/PE despite prolonged use of Bz and Len. Data from patients treated at the MTD in phase I and the impact of adverse risk factors (including advanced stage and high-risk cytogenetics) on outcome, as well as following ASCT, will be reported at the meeting. Based upon these promising results, phase II/III studies of RVD and RVD-based combinations are either planned or ongoing.

Richardson:Keryx: Membership on an entity's Board of Directors or advisory committees; Millennium Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees; Johnson and Johnson: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Lonial:BMS: Consultancy; Gloucester: Research Funding; Millennium Pharmaceuticals, Inc.: Consultancy, Research Funding; Novartis: Consultancy; Celgene: Consultancy. Jakubowiak:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Exelixis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Centocor Ortho Biotech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol-Myers-Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Jagannath:Merck: Consultancy, Honoraria; Millennium Pharmaceuticals, Inc.: Consultancy, Honoraria. Raje:AstraZeneca: Research Funding; Novartis: Research Funding; Celgene: Research Funding. Ghobrial:Millennium Pharmaceuticals, Inc.: Honoraria, Research Funding, Speakers Bureau; Celgene: Honoraria, Speakers Bureau. Schlossman:Millennium Pharmaceuticals, Inc.: Speakers Bureau; Celgene: Speakers Bureau. Mazumder:Millennium Pharmaceuticals, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Munshi:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium Pharmaceuticals, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Laubach:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Vesole:Celgene: Consultancy, Equity Ownership. Rosenblatt:Celgene: Research Funding. Doss:Millennium Pharmaceuticals, Inc.: Speakers Bureau; Celgene: Speakers Bureau. Mitsiades:Millennium Pharmaceuticals, Inc.: Consultancy; Novartis Pharmaceuticals: Consultancy; Bristol-Myers Squibb: Consultancy; Merck & Co.: Consultancy; Kosan Pharmaceuticals: Consultancy; Pharmion: Consultancy; Amgen Pharmaceuticals: Research Funding; AVEO Pharma: Research Funding; EMD Serono: Research Funding; Sunesis Pharmaceuticals: Research Funding; PharmaMar: Licensing royalties. Hideshima:Biotest AG: Consultancy. Knight:Celgene: Employment, Equity Ownership. Esseltine:Millennium Pharmaceuticals, Inc.: Employment, Equity Ownership. Anderson:Millennium Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding.