P913: low-dose belantamab mafodotin (belamaf) in combination with nirogacestat vs belamaf monotherapy in patients with relapsed/refractory multiple myeloma (rrmm): phase 1/2 dreamm-5 platform sub-study 3

Topic: 14. Myeloma and other monoclonal gammopathies - Clinical Background: Belantamab mafodotin (belamaf), a B-cell maturation antigen (BCMA)-targeting antibody-drug conjugate, is being developed to address an unmet need in patients with relapsed/refractory multiple myeloma (RRMM). DREAMM-5 (NCT04126200) is an ongoing Phase 1/2 platform study that incorporates a master protocol evaluating multiple belamaf-containing combinations in distinct sub-studies to identify efficacious combinations. Preclinical data suggest nirogacestat, a gamma-secretase inhibitor, may enhance anti-BCMA agent activity by increasing cell-surface BCMA levels. Aims: To compare the efficacy and safety of low-dose belamaf + nirogacestat versus belamaf alone in triple-class refractory patients with RRMM. Methods: Patients were randomized (1:1) to belamaf 0.95 mg/kg every three weeks (Q3W, low-dose) + nirogacestat 100 mg once daily (BID) or belamaf 2.5 mg/kg Q3W monotherapy. The primary objective was to assess the clinical activity (overall response rate [ORR]) of low-dose belamaf + nirogacestat combination in comparison with the monotherapy control arm. Results: Data from 34 patients with low-dose belamaf + nirogacestat and 37 patients with belamaf monotherapy are presented. Patients had a median (range) age of 68 (48–81) years and a median (range) of 5 (3–14) prior lines of therapy. As of the data cutoff (Dec 9, 2022), patients received a median (range) of 4 (1–20) cycles of the combination and 3 (1–9) monotherapy cycles. For the combination and monotherapy arms, respectively, ORR was 29% (95% CI 15.1, 47.5) and 38% (22.5, 55.2) (Table). Incidence of Grade ≥3 adverse events was 76% and 65%. Grade 3 ocular events were less frequent for low-dose belamaf + nirogacestat (29% vs 59%); no Grade 4 ocular events or new toxicities occurred in either arm. Four patients discontinued study treatment (combination therapy n=3; monotherapy n=1) due to adverse events unrelated to study treatment. Summary/Conclusion: Despite utilizing a belamaf dose and schedule that are expected to have limited activity as a monotherapy, low-dose belamaf + nirogacestat demonstrated an encouraging ORR with a substantial reduction of high-grade ocular events, indicating an increase in BCMA target density by nirogacestat. Furthermore, the efficacy and safety data from the monotherapy arm were consistent with DREAMM-2, DREAMM-3, and real-world evidence observed to date. These data support ongoing exploration in DREAMM-5 of belamaf + nirogacestat + standard of care agents in patients with RRMM. Funding: GSK (208887); drug linker technology licensed from Seagen Inc.; mAb produced using POTELLIGENT Technology licensed from BioWa; nirogacestat is manufactured and provided by SpringWorks Therapeutics as part of a collaborative agreement with GSK.Keywords: Multiple myeloma, B-cell maturation antigen, Relapse, Phase I/II