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 African American. Disease was refractory to lenalidomide in all patients, and refractory to both bortezomib and lenalidomide in 3 patients. Six patients were previously exposed to anti-CD38 mAb. Eleven (73%) patients had presence of high-risk cytogenetics including del 17p, t (4;14), t (14;16) and 1q gain/amp. All 6 patients in in the safety lead-in cohort completed at least 2 cycles of treatment (DLT window), while the remaining patients completed at least 1 cycle of treatment. The median follow up was 8.5 months (1-16.6). None of the patients experienced DLT in the safety lead-in phase. Grade 3-4 treatment emergent adverse events (TEAEs) occurred in 15 (100%) of patients with most common being lymphopenia (93%), neutropenia (93%) and leucopenia (40%). Grade 3-4 infections occurred in 1(7%) patient. No grade 5 TEAEs occurred. Infusion related reactions occurred in 1 patient, maximum grade 2. All patients were evaluable for response with an ORR of 80% (12/15) (6 VGPR or better, 6 PR), and 100% in anti-CD38 mAb naive. The 12-month PFS rate was 67% (45%-99%). 5 patients discontinued the study (4 due to disease progression and 1 withdrew consent). Lymphocyte subpopulations showed a decrease in relative and absolute NK cells and an increase in monocytes (Figure 1 A, B). NK cell cytolytic activity was maintained in patient samples obtained over the course of the study (Figure 1C).

Conclusions: This is the first ever report combining two different mAbs with dual targeting of CD38 and SLAMF7 in RRMM. The results demonstrate that Isa-EloPD combination is both safe and feasible with high frequency and durability of responses. Despite an anticipated reduction in number, NK cell cytotoxicity remain unaffected with the combination. The study is ongoing and results from additional patients and longer follow up will be presented.