Phase I Study of Belantamab Mafodotin in Combination with Standard of Care in Transplant-Ineligible Newly Diagnosed Multiple Myeloma: Dreamm-9 Updated Interim Analysis

Introduction DREAMM-9 (NCT04091126) is an ongoing randomized Phase 1 dose optimization study evaluating belantamab mafodotin (belamaf) plus bortezomib, lenalidomide, and dexamethasone (VRd) in autologous stem cell transplant (ASCT)-ineligible newly diagnosed multiple myeloma (TI NDMM). A previous interim analysis reported no unexpected safety signals and early and deep anti-myeloma responses (Usmani et al. JCO, 2023). Here we report data on all cohorts explored in the trial in the TI NDMM setting. Methods Patients (pts) ≥18 years (yrs) ineligible for ASCT and with no prior MM treatment were dosed in one of 8 cohorts (C1-8) with differing belamaf doses (mg/kg) and schedules and follow-up: C1, 1.9 Q3/4W (N=12); C2, 1.9 Q6/8W (N=12); C3, 1.4 Q3/4W (N=13); C4, 1.4 Q6/8W (N=12); C5, 1.9 for 1 dose and then 1.4 Q9/12W (N=19); C6, 1.0 Q3/4W (N=15); C7, 1.4 for 1 dose and then 1.0 Q9/12W (N=15); C8, 1.0 Q12W (N=10). Cohorts with lower doses and longer schedules were opened to inform on the potential to improve tolerability while maintaining efficacy. All cohorts received belamaf with standard VRd for Cycles 1‒8 (21-day cycle), followed by Rd for Cycles 9+ (28-day cycle). Primary endpoint was safety/tolerability (dose-limiting toxicities [DLTs] and adverse events [AEs]). Efficacy endpoints included overall response rate (ORR, % of pts with a confirmed partial response or better); complete response rate (CRR, % of pts with a complete response or better [CR+]); and minimal residual disease negativity rate (MRD[-], % of pts with very good partial response or better [VGPR+] and reached MRD negativity at 10-5 threshold by next generation sequencing). Responses were assessed per International Myeloma Working Group criteria (2016). Results As of Mar 4, 2024, 108 pts were treated in 8 cohorts. Median age (range) was 74.0 (51‒88) yrs; 44% (n=47) were ≥75 yrs old, 86% were White, and 46% female. Overall duration of follow-up ranged from 0.1-49.8 months, and by cohort (months, interquartile range) was: C1, 37.6 (21.9‒43.1); C2, 32.3 (31.4‒33.4); C3, 20.2 (14.0‒33.0); C4, 32.4 (18.8‒33.6); C5, 17.1 (2.8‒20.3); C6, 31.0 (16.3‒33.4); C7, 18.2 (8.7‒20.6); C8, 7.8 (7.0‒8.7). Of the pts who received ≥1 dose of belamaf, 100% (n=105) experienced AEs. Grade 3+ (Gr3+) belamaf-related AEs ranged from 67% (n=8) for C1 to 10% (n=1) for C8. Ocular events (Gr3+) based on keratopathy and visual acuity scale (KVA) were reported in 55% (n=58) of pts across cohorts; dose interruptions/delays were seen in 95% (n=55) and dose reductions in 33% (n=19) of affected pts. Cohorts 1-3 had the highest proportion of pts with Gr3+ KVA events (% [n]): C1, 83 (10); C2, 92 (11); C3, 85 (11), while the lowest was reported for C7, 7 (1) and C8, 20 (2). The most common non-ocular Gr3+ AEs (% [n]) across all cohorts were thrombocytopenia, 30 (32), neutropenia, 26 (27), and COVID-19 pneumonia, 14 (15). A total of 28 pts (27%) had a decrease in best correct visual acuity (BCVA) score from baseline (20/25 or better) to 20/50 or worse, with a median (range) time of 194 (42-713) days to onset of the first occurrence, of which 89% (n=25) resolved in a median (range) of 85 (22-421) days. The longest median time to onset was reported for the cohorts with the longer dosing intervals (days [n]): C7 (Q9/12W), 337 (1); C4 (Q6/8W), 263.5 (6); C2 (Q6/8W), 245.5 (6). The shortest median time to onset was 76 days for C1 (Q3/4W). Across the cohorts ORR (% [range]) was 90 (71-100); CRR (% [range]) was 63 (30-92) and median time to VGPR+ ranged from 2.1‒3.2 months. ORR % (CRR %) by cohort was C1, 100 (75); C2, 100 (92); C3, 92 (62); C4, 100 (91); C5, 71 (41); C6, 86 (71); C7, 87 (53); C8, 100 (30). MRD[-] rate in pts with VGPR+ ranged from 10% (C8) to 83% (C1). MRD[-] rate in pts with CR+ ranged from 0% (C8) to 75% (C1) and was highest in (% [n]): C1, 75 (9); C2, 67 (8), and C3, 54 (7). Conclusions These results show that belamaf plus VRd in patients with TI NDMM delivered highly effective tumor responses across all dosing schedules. Regardless of dosing interval, higher belamaf doses were associated with higher rates of MRD negativity. Longer dosing intervals were associated with fewer ocular events and increased time to onset of clinically meaningful BCVA changes; follow-up is ongoing. Across the cohorts, ocular events were effectively managed with dose holds/reductions maintaining patients on treatment. These data are consistent with prior clinical studies of belamaf in the relapsed/refractory setting.

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