Target antigen density may impact clinical response in patients with relapsed/refractory multiple myeloma undergoing treatment with elotuzumab and belantamab mafodotin

Abstract

Abstract Background: NCT05002816 is an ongoing phase Ib/II trial evaluating the safety, tolerability and preliminary efficacy of the unique combination of Elotuzumab and Belantamab mafodotin in patients with relapsed/refractory myeloma (RRMM). Combining monoclonal antibodies simultaneously targeting SLAMF7 and BCMA could prevent antigen loss and development of resistance. Here we present interim biologic correlatives on the first 20 patients from this trial exploring patient's bone marrow (BM) myeloma -intrinsic and -extrinsic factors impacting clinical response. Methods: This single-arm phase Ib/II study has enrolled thus far 20 patients with triple-class refractory RRMM as of Aug 1, 2025. Patients with progression after prior BCMA-targeted therapy are eligible. Elotuzumab is administered via intravenous (IV) infusion at an established dose of 10 mg/kg on days 1, 8, 15, 22 every 28 days for cycles 1 and 2; followed by 20mg/kg on day 1 of each 28-day cycle. Belantamab mafodotin is administered via IV infusion with the starting dose of 1.9 mg/kg IV at every 4-week interval, with subsequent dose-reduction based on toxicity. Immune profiling of tumor biological samples is performed via flow cytometry. We define the expression levels of multiple immunotherapeutic targets such as SLAMF7 and BCMA on patient's BM CD138+ myeloma cells collected at multiple time points (at screening, after 3 cycles and at the end of treatment) as well as cellular changes within the BM CD138-negative cell populations by flow-cytometry. Results: Median age of patients is 66.5 years (range 59-79). The patient population is heavily pretreated with 5 prior median lines of therapy (range 2-8). Phase I part of the study was completed after 10 patients concluded safety follow-up. The safety and preliminary efficacy of the phase I part of this study were previously reported and were notable for an encouraging preliminary with partial responses (PR) in 4/10 (40%) and stable disease (SD) in additional 3/10 (30%) of patients.1 Notably, 40% (4/10) of patients were refractory to prior BCMA-targeted therapy (2 post-BCMA bispecific antibody, 2 post-BCMA chimeric antigen receptor T-cell therapy [CART]). We find that SLAMF7 expression levels decrease in 8/10 (80%) of patients who progressed over time with this treatment, while no significant change in BCMA expression is noted. Quantitative profiling of SLAMF7 density shows a statistically significant decrease upon treatment (average number of SLAMF7 molecules per cell before treatment is 2,675 compared to 1,382 at the end of treatment) based on n=16 patients analyzed thus far. The association with clinical responses will be performed at the time of completion of the trial accrual. Further, we observe a significant increase in CD19+ B-cells after starting treatment and decreased PD1+ T cells upon continued treatment. No significant differences were observed in myeloid cell populations. Conclusion: In summary, combination therapy with belantamab mafodotin and elotuzumab has shown an encouraging safety profile and a promising preliminary efficacy including among those with prior failure of BCMA-targeted therapy, as previously reported.1 Our preliminary data suggest that decreased SLAMF7 density may predicts inferior clinical response among poor responders, likely representing one mechanism of escape while the impact on B-cell and T-cell compartments may contribute to disease response in patients with heavily pretreated RRMM. Funding and Product for this study was provided by GSK . GSK was provided the opportunity to provide a courtesy review of the preliminary version of this publication for accuracy only, but the authors are solely responsible for final content and interpretation. Please ensure the legal entity name is as per the contract with GSK. Ref:Sabrina Browning, Terri Parker, Natalia Neparidze, et al. Poster Presentation. Open-label, single-arm phase Ib/II study of immune combination therapy with elotuzumab and belantamab mafodotin in patients with relapsed refractory multiple myeloma. ASCO June 2024, Chicago, IL