Phase I study of combined vorinostat (V), lenalidomide (L), and dexamethasone (D) in patients (pts) with relapsed or refractory multiple myeloma (MM).

8031 Background: MM remains incurable despite recent therapeutic advances. Although novel treatment combinations have improved outcome, new combinations are urgently needed. V, an oral histone deacetylase inhibitor, enhances anti-MM activity of other small molecule pro-apoptotics, with preclinical synergy seen when combined with L. This ongoing phase I multicenter, open-label study evaluated V plus L and D. Maximum tolerated dose (MTD; primary objective), safety, tolerability, and response rate (RR) were assessed. Methods: Relapsed and/or refractory MM pts were enrolled into 1 of 5 escalating doses of combination regimen using standard 3+3 design. Toxicity and response were evaluated using NCI c3.0 CTC and EBMT/UC. Results: Median prior therapies was 3 (range 1-12, N=31). Most pts received prior bortezomib (65%), thalidomide (68%), or L (45%). The majority ofadverse events(AEs) were mild/moderate; most common ≥G3 drug-related AEs (all cycles) were neutropenia (23%), thrombocytopenia (16%), diarrhea (13%), and fatigue (10%). One dose-limiting toxicity was seen (Table), with MTD not reached. Of 30 pts evaluable for efficacy, 26 (87%) experienced ≥ stable disease (SD); best single responses were 2 complete, 2 very good partial (VGPR), 10 partial (PR), 5 minimal (MR), 7 SD, and 4 progressive disease, for RR (≥ MR) of 63%. Of 13 evaluable pts who received prior L, ≥ SD was seen in 9 (69%), with 1 VGPR, 3 PR, 1 MR, and 4 SD, for RR (≥MR) of 38%. Conclusions: Preliminary results suggest V, L, and D may be a convenient, effective, and generally well tolerated oral regimen for relapsed/refractory MM pts. Activity was also seen in pts who received prior L. Further analysis of this study is ongoing and a phase II study is planned. Dosing Dose level (DL) V(mg qd)7 days on 7 off(days 1-7 and 15-21) L(mg qd)× 21 days(day 1-21) D(mg qd)(days 1, 8, 15, and 22) Evaluable for DLT† Maximum cycles‡ DLT 1 300 10 40 3 19 0 2 400 10 40 3 15 0 3 400 15 40 3 11 0 4 400 20 40 3 12 0 5 400 25 40 6 (+10§) 12 Diarrhea (G3) Cycles: 28 days. Concomitant daily aspirin recommended. † 10/31 pts (across all DLs) remain ongoing. ‡ Maximum treatment cycle for which ≥1 pt received ≥1 dose. § 10-pt expansion cohort enrolled at DL 5 with no formal DLT assessment. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Celgene, Dana-Farber Cancer Institute, Merck Bristol-Myers Squibb, Celgene, Merck, Millennium, Novartis, Ortho Biotech, Pharmion Merck Celgene, Janssen-Ortho, Merck, Millennium, Novartis, Onyx, Ortho Biotech, Pharmion Celgene, Gloucester Pharmaceuticals, Merck, Merck Serono, Millennium, Novartis