Dose-escalation Study of Carfilzomib (CFZ) Plus Lenalidomide (LEN) Plus Low-Dose Dexamethasone (dex) (crd) in Relapsed/refractory Multiple Myeloma (R/R MM).

8029 Background: CFZ, a specific, irreversible proteasome inhibitor, is highly active with a favorable side effect profile in R/R MM. This open-label, phase Ib dose-escalation study evaluated the safety and maximum recommended dose of CFZ + LEN+ low-dose Dex, (CRd). Methods: Eligible patients (pts) included those with relapsed or progressive MM after 1–3 prior therapies. CRd was given on 28 day cycles (C) in 6 cohorts as shown in the Table. Primary endpoints included safety and establishment of the maximum recommended dose. Other endpoints included overall response rate (ORR) and clinical benefit response (CBR). Results: To date, 40 pts were enrolled in cohorts 1–6 and 27 in a cohort 6 expansion. 27/32 pts in cohorts 1–5 were evaluable for safety and 29/32 for response. Pts were heavily pretreated; 72% received prior BTZ and 87.5% received prior IMiD. 47% of pts were refractory to their last therapy; 84% had a history of neuropathy (67% related to prior BTZ or thalidomide). No treatment emergent fatigue, neuropathy, or thrombotic events ≥ Grade (G) 3 were observed. Hematological AEs ≥G3 (thrombocytopenia [n=6], anemia [n=4], and neutropenia [n=6]) were reversible. 4 pts had drug-related SAEs (transient G3 sinus bradycardia, G3 upper respiratory tract infection, febrile neutropenia, and G3 diarrhea + G3 urinary infection). ORR and CBR for 29 evaluable pts are 59% and 72%, respectively which included 21% CR/nCR, 17% VGPR, and 21% PR. Initial responses improved with continued therapy, up to 18 C. 43/67 pts remain on study. No dose- limiting toxicities or deaths have been reported. Conclusions: CRd is well-tolerated in pts with R/R MM, even in those with a history of neuropathy. Nonoverlapping toxicity profiles of CFZ and LEN allow their combination at full doses for extended durations up to 18 C. Prior therapy with either BTZ or an IMiD, or disease refractory to the immediately preceding regimen does not preclude achieving MR, PR, VGPR or CR to CRd. Authors wish to acknowledge support from Celgene Corp. Cohort Administration day 1 2 3 4 5 6/E C1-4 C5-8 C9-16 CFZ IV bolus (mg/m2) 15 20 20→27* 1, 2, 8, 9, 15, 16 1, 2, 15, 16 LEN po (mg) 10 15 20 25 1-21 Dex po (mg) 40 1, 8, 15, 22 1 * 20 mg/m2 on C1 days 1 and 2; 27 mg/m2 thereafter. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Onyx Pharmaceuticals Celgene, Millennium, Onyx Onyx, Onyx Pharmaceuticals Celgene, Millennium, Onyx Pharmaceuticals Celgene, Millennium, Novartis, Onyx, Seattle Genetics