A Phase II Study of Elotuzumab in Combination with Pomalidomide, Bortezomib, and Dexamethasone in Relapsed and Refractory Multiple Myeloma

Abstract

Background Elotuzumab is an approved monoclonal antibody targeting SLAMF7 on plasma and NK cells that enhances the activity of lenalidomide, pomalidomide, and bortezomib in multiple myeloma (MM). A recent study showed improved outcomes with the combination of pomalidomide, bortezomib, and dexamethasone vs. bortezomib and dexamethasone in relapsed or refractory MM (Richardson PG et al., Lancet Oncol 2019). We therefore studied elotuzumab with pomalidomide, bortezomib, and dexamethasone (elo-PVD) in relapsed and refractory MM. Methods The primary objective was to determine the overall response rate (ORR). Patients with relapsed and refractory disease and ≥1 prior lines of treatment (including lenalidomide and a proteasome inhibitor) were eligible to participate. Prior treatment with pomalidomide was permitted. Elotuzumab was weekly for the first 2 cycles and then every other week. Pomalidomide was given on days 1-21; bortezomib was on days 1, 8, 15; and dexamethasone was weekly. Each cycle was 28 days. Results The trial has completed accrual in September 2018 with 48 patients receiving treatment. The median age was 64 (range 40-80), and median number of prior regimens was 3 (range 1-9); 25% had high risk FISH. All patients had prior lenalidomide and proteasome inhibitor (bortezomib 96%, 29% carfilzomib) and were refractory to their last line of therapy. Other prior therapies included: autologous stem cell transplant (48%), pomalidomide (33%), daratumumab (25%), and isatuximab (4%). 46 patients were assessable for response (2 patients did not complete cycle 1 and were not evaluable for response: 1 due to rapid disease progression; 1 stroke. The median length of follow up was 18.8 months (range 0.5-23.4): 16 patients continue on study; 27 patients discontinued for progressive disease; 3 patients discontinued for adverse events (AEs) (sepsis, pneumonia, stroke); 1 patient underwent auto SCT; and 1 patient was lost to follow up. Best ORR was 61% (PR = 16, VGPR = 10, CR = 2). ORR for patients with prior anti-CD38 antibody, 46%; carfilzomib, 46%; pomalidomide, 43%. Median PFS was 9.8 months (95% CI 6.8-Inf). In patients with 1 prior line of therapy, ORR was 74% and median PFS was not reached (95% CI 12-Inf); 18 month PFS was 68%. Grade ≥ 3 hematologic AEs included anemia (10%), neutropenia (29%), and thrombocytopenia (15%). Additional common grade ≥ 3 AEs included lung infection (27%) and hypophosphatemia (15%). Common non-hematologic AEs all grades included fatigue (grade 1-2 only, 70%), upper respiratory infection (grade 1-2, 56%; grade 3, 2%), diarrhea (grade 1-2 only, 42%), constipation (grade 1-2 only, 35%), hyperglycemia (grade 1-2, 46%; grade 3, 4%), and sensory neuropathy (grade 1-2 only, 31%), with 2 possibly related deaths (sepsis, pneumonia). Conclusions Elo-PVD is one of the first trials of a quadruplet regimen in relapsed and refractory MM incorporating a monoclonal antibody. In patients with refractory disease, elo-PVD shows encouraging responses. With the limitations of cross trial comparisons and small patient numbers, for patients with 1 prior line of treatment and refractory disease, a PFS at 18 months of 68% with elo-PVD compares favorably with a median PFS of 17.8 months in a similar subgroup of PVD in the OPTIMISMM trial (Dimopoulos MA et al., ASH 2018). Patients who received prior pomalidomide, carfilzomib, and/or anti-CD38 monoclonal antibody also benefited. Treatment was well-tolerated with manageable toxicity and with attention to infectious AEs. Disclosures Yee: Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Karyopharm: Consultancy; Adaptive: Consultancy; Amgen: Consultancy, Honoraria. Lipe:Celgene: Consultancy; amgen: Research Funding; amgen: Consultancy. Nadeem:Janssen: Consultancy; Amgen: Consultancy; Celgene: Consultancy; Sanofi: Consultancy. O'Donnell:Celgene: Consultancy; Amgen: Consultancy; BMS: Consultancy; Sanofi: Consultancy; Takeda: Consultancy. Branagan:Pharmacyclics: Consultancy; Janssen: Consultancy; Surface Oncology: Consultancy. Lohr:Celgene: Research Funding; T2 Biosystems: Honoraria. Anderson:Sanofi-Aventis: Other: Advisory Board; Bristol-Myers Squibb: Other: Scientific Founder; Oncopep: Other: Scientific Founder; Amgen: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau. Richardson:Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees. Raje:Amgen Inc.: Consultancy; Bristol-Myers Squibb: Consultancy; Celgene Corporation: Consultancy; Takeda: Consultancy; Janssen: Consultancy; Merck: Consultancy. OffLabel Disclosure: The combination of elotuzumab, pomalidomide, bortezomib, and dexamethasone is an off-label use in relapsed and refractory multiple myeloma.

Elotuzumab, pomalidomide, and dexamethasone is a very well tolerated regimen associated with durable remission even in very advanced myeloma: a retrospective study from two academic centers

“…with pomalidomide-based combinations (Attal et al 2019;Richardson et al 2019) and will represent a formidable therapeutic challenge in the near future. A recent trial reported responses in 48% of daratumumab-exposed patients and acceptable toxicity with a quadruplet regimen of elo/pom/dex and bortezomib (Yee 2019), further corroborating our findings.…”

Cell-free DNA for the detection of emerging treatment failure in relapsed/ refractory multiple myeloma

“…Samples for our exploratory test cohort were acquired from patients at remission stage or while undergoing induction therapy (n=16, Table 1 ). Samples for our validation cohort were acquired from 45 patients ( Table S1 ) treated within a multi-center phase II trial testing elotuzumab with pomalidomide-bortezomib-dexamethasone (elo-PVD) for RRMM 37 . All samples for this portion of the trial were retrieved at screening and at cycle 3 day 1 (C3D1) of elo-PVD.…”

Pomalidomide- and dexamethasone-based regimens in the treatment of refractory/relapsed multiple myeloma

“…Prior pomalidomide exposure was permitted. 54 Results were released in 2019; 48 patients were enrolled, median number of prior lines of therapy was 3. At a median follow-up of 18.8 months in 46 evaluable patients, median PFS was 9.8 months, and ORR was 61%; ORR for patients with previous pomalidomide was 43%, previous carfilzomib 46% and previous anti-CD38 46%.…”