Dual Targeting of Slamf-7 and CD38 in Mulitple Myeloma (MM): A Phase II Study of Isatuximab, Elotuzumab, Pomalidomide and Dexamethasone (Isa-EloPD) in Relapsed and/or Refractory MM (RRMM)

Background: Elotuzumab (Elo) is a humanized IgG1 mAb that targets SLAMF7, an antigen highly expressed on malignant plasma cells. Isatuximab (Isa) is a humanized IgG1 mAb that binds to the unique CD38 epitope present on MM cells. Both mAbs have independently shown to be safe and effective when combined with pomalidomide and dexamethasone (PD) in patients with RRMM. Dual targeting of CD38 and SLAMF7 could be synergistic as the simultaneous expression of both antigens has been identified in 97% of primary MM cells, even among heavily treated patients (PMID 33420283). Further evaluation is necessary to assess the anticipated decline in lymphocyte subsets, particularly NK cells (express CD38 and SLAMF7), resulting from the combination. Here we report the safety and preliminary activity of the first ever combination of Isa, Elo, PD in patients with RRMM (IMPEDE-NCT04835129). Methods: This is a single arm, multi-center, phase II study with safety lead-in in patients with RRMM with 2 prior therapies including lenalidomide and a proteasome inhibitor (PI) and refractory to the last line of therapy. Patients with prior Elo and pomalidomide are excluded while prior anti-CD38 mAb is permitted with adequate washout and non-refractory status. A safety run-in phase was performed in 6 patients to assess for potential dose limiting toxicities (DLTs). Isa-EloPD was given on a 28-day cycle, and Elo was given per the EloPD schedule. To allow proper correlative assays informing the impact of Isa and Elo on lymphocyte subpopulations, Isa was sequentially introduced after Elo-PD in the safety run-in on cycle 2. For the first dose, Isa was given on day 2 after Elo and the same day subsequently. Treatment was given until progression or unacceptable toxicity occurred. The primary end point was overall response rate (ORR). Secondary end points included overall safety, duration of response, progression free (PFS) and overall survival (OS). Correlative analyses included changes in lymphocyte sub-populations and NK cell cytolysis for the first 2 cycles in the safety lead in phase. For NK cell cytolysis, PBMCs from individual patients were co-cultured with K562 target cells at serial effector: target (E: T) cell ratios. Peak cytolysis during the first 24 hours represents NK cell-mediated cytolysis. Based on Simon's two-stage design, a total accrual of 53 patients is planned. Results: At the time of data cut-off, 15 patients were enrolled. Median age was 68 years (range, 54-79) and 3 were