Phase I/II Dose Expansion Of a Multi-Center Trial Of Carfilzomib and Pomalidomide With Dexamethasone (Car-Pom-d) In Patients With Relapsed/Refractory Multiple Myeloma

[Graphic][1] Background Carfilzomib, a novel proteasome inhibitor (PI), and pomalidomide, an IMiD® immunomodulatory agent, have both demonstrated efficacy as single agents or in combination with dexamethasone in relapsed/refractory multiple myeloma(RRMM). IMiD compound+PI combinations including lenalidomide/dex and thalidomide/dex in combination with bortezomib and carfilzomib, have had high response rates and good tolerability. We aimed to combine carfilzomib and pomalidomide with dexamethasone (Car-Pom-d) for the first time and hypothesized that this regimen would be highly effective in patients RRMM. In the Phase I, dose-escalation of carfilzomib started with 27mg/m2 carfilzomib/4mg pomalidomide/40 mg dexamethasone using a standard 3+3 schema based on dose-limiting toxicities (DLTs) occurring in cycle 1. The MTD presented previously was 27mg/m2 Carfilzomib /4mg pomalidomide/40 mg dexamethasone. Here, we report our combined findings from the additional Phase II expansion cohort of the first phase I/II trial of Car-Pom-d in patients with RRMM ([NCT01464034][2]). Methods The primary objective of the phase II portion was to determine the overall response rate (ORR). Secondary objectives included time to progression(TTP), progression free survival(PFS), overall survival (OS)and time to next therapy. All patients had to be refractory to prior lenalidomide, and must have relapsed or were refractory to their most recent therapy. Phase II patients had to be both pomalidomide and Carfilzomib naive. Treatment consisted of 28-day cycles of oral pomalidomide once daily on days 1-21, intravenous (IV) carfilzomib over 30 minutes on days 1, 2, 8, 9, 15, and 16, and oral or IV dexamethasone 40 mg on days 1, 8, 15, and 22 Carfilzomib was initiated at 20 mg/m2 for Cycle 1, days 1-2 at all dose levels. Investigators were permitted to adjust the dose of dexamethasone at any point based on their discretion. Adverse events (AEs) were graded by NCI-CTCAE v4. Response was assessed by the modified International Uniform Response Criteria. Results In the Phase I dose-escalation portion of the trial a total of 12 patients were enrolled. The MTD was established as the starting dose level (carfilzomib 20/27 mg/m2, pomalidomide 4mg, dexamethasone 40 mg). We enrolled an expansion cohort of 20 patients at MTD for a total of 30 toxicity-evaluable patients from 8 centers. In Phase II we enrolled 40 of 82 planned patients resulting in a total study population of 72 patients, with 29 still receiving treatment. Five patients out of the 72 were not yet evaluable for efficacy. Data cut-off was June 15, 2013. The median age was 64 years (range 41–78), 63% were male. The median number of prior regimens was 6 (range 2–15), median time from diagnosis was 5.1 years and median follow-up was 6.0 months (range: .5 to 16.1 months). Two-thirds of patients had a prior stem cell transplant, 87% had prior bortezomib, and all were lenalidomide-refractory. Cytogenetic abnormalities included 16 patients with del(17p), 6 patients with t(4;14), and 23, 14, and 5 patients each with del(13), t(11;14), and t(14;16), respectively. Patients received a median of 5 cycles (range 1–18 cycles). Ten patients have died, 6 from progressive multiple myeloma. Best response assessments in 67 out of 72 patients showed 1 CR, 18 VGPR, 24 PR, 11 MR, 11 SD, and 2 PD for an ORR of 64% and a ≥MR rate of 81%. Grade ≥3 drug-related AEs occurring in >20% of patients included fatigue (48%), neutropenia (40%), anemia (34%), thrombocytopenia (34%), and diarrhea (20%). Sixty-two percent of patients experienced grade ≥3 AEs including neutropenia, anemia, and diarrhea. Median PFS and OS were 12.0 and 16.3 months, respectively, for the entire cohort. Patients with intermediate- or high-risk cytogenetics (mSMART criteria, N=33) had a median PFS of 9.6 months and a ≥MR rate of 84%. Conclusions The Car-Pom-d regimen is a well-tolerated regimen and achieves a high response rate (ORR of 64%; ≥MR rate of 81%) in a heavily pre-treated Lenalidomide-refractory population with prior bortezomib exposure, with a median of 6 lines of prior therapy. Importantly, we have seen responses in patients with poor risk cytogenetics, specifically del (17p) with prolonged disease control. We would like to acknowledge Onyx Pharmaceuticals, Inc. and Celgene Corporation for their support of this study. Disclosures: Shah: Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Array BioPharma: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Onyx Pharmaceuticals: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Research Funding; Millennium Pharmaceuticals: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Stadtmauer: Celgene: Consultancy, Speakers Bureau; Millenium: Consultancy, Speakers Bureau. Abonour: Onyx: Honoraria, Research Funding; Millennium: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Cohen: Millennium: Honoraria; Onyx: Honoraria; Bristol Myers Squibb: Honoraria, Research Funding; Celgene: Membership on an entity’s Board of Directors or advisory committees. Bensinger: Celgene: Consultancy, Honoraria, Research Funding. Gasparetto: Onyx: Membership on an entity’s Board of Directors or advisory committees; Celgene: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Millennium: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau. Kaufman: Onyx: Consultancy; Novartis: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Millennium Pharmaceuticals: Consultancy; Jansenn: Consultancy; Merck: Research Funding. Lentzsch: Celgene: Research Funding. Vogl: Acetylon Pharmaceuticals, Inc: Research Funding; Millennium: Research Funding; Celgene: Consultancy; Otsuka: Consultancy. Orlowski: Bristol-Myers Squibb: 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, Research Funding; Millennium: The Takeda Oncology Company: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Onyx: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Resverlogix: Research Funding; Array Biopharma: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Genentech: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Merck: Membership on an entity’s Board of Directors or advisory committees. Durie: Celgene: Consultancy; Onyx: Consultancy; Millennium: Consultancy; Amgen: Consultancy. 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