Belantamab mafodotin (belamaf) in combination with bortezomib, lenalidomide, and dexamethasone (VRd) for patients (pts) with transplant-ineligible (TI) newly diagnosed multiple myeloma (NDMM): A focus on treatment efficacy and management/resolution of ocular events in the Phase 1 dreamm-9 study

Abstract

Abstract Introduction: Belamaf is an antibody-drug conjugate approved in multiple countries as part of combination regimens for relapsed/refractory multiple myeloma. DREAMM-9 is evaluating belamaf plus VRd (BVRd) in TI NDMM. Treatment with belamaf can cause keratopathy which is managed with dose/schedule modifications. We examined ocular event occurrence and resolution alongside efficacy in DREAMM-9. Methods: Pts aged ≥18 years with TI NDMM received BVRd in 1 of 8 belamaf dosing cohorts at a Q3/4W (SHORT: 1.9, 1.4, or 1.0 mg/kg), Q6/8W (STRETCH: 1.9 or 1.4 mg/kg), Q9/12W step-down (S/D: 1.9 for 1 dose then S/D to 1.4 mg/kg or 1.4 for 1 dose then S/D to 1.0 mg/kg), or Q12W (1.0 mg/kg) schedule. VRd was administered per US prescribing information for Cycles 1‒8 (21-day cycle), then Rd for Cycles 9+ (28-day cycle). Primary endpoint was safety and tolerability. Ocular examination findings (OEF) were measured using the Keratopathy and Visual Acuity (KVA) scale comprising changes in best corrected visual acuity (BCVA) and slit lamp findings. OEFs were managed through dose reductions and schedule extensions. Changes in bilateral BCVA to 20/50 or worse in pts who had BCVA of 20/25 or better in at least 1 eye at baseline were assessed. Objective response rate (ORR), complete response (CR), and minimal residual disease negativity (MRD-; 10-5 threshold by next-generation sequencing) were assessed (IMWG criteria, 2016). In exposure-response (ER) analyses, logistic regression models were used to assess the probability of efficacy/safety endpoints and Cox proportional hazard models were used to assess time-to-event endpoints. Results: As of March 4, 2024, 108 pts were enrolled across the 8 dosing cohorts (Usmani et al. Blood 2024), with median duration of follow-up 7.8‒37.6 months. Across all cohorts, ORR was ≥71% (100% in 1.9 SHORT, 1.9 STRETCH, 1.4 STRETCH, 1.0 Q12W). MRD- in pts with CR+ was 75% (1.9 SHORT), 67% (1.9 STRETCH), 54% (1.4 SHORT), 45% (1.4 STRETCH), 29% (1.9 S/D to 1.4), 43% (1.0 SHORT), 27% (1.4 S/D to 1.0), 0% (1.0 Q12W). Grade (Gr) ≥2 OEF were seen in 74% of pts and decrease in BCVA to 20/50 or worse was seen in 27% of pts overall. Both Gr≥2 OEF and decrease in BCVA to 20/50 or worse in pts with 20/25 or better in ≥1 eye at baseline had a trend towards lower incidence in lower-dose-intensity cohorts (Usmani et al. Blood 2024). The first Gr≥2 OEF resolved in 90% of total affected pts. Resolution rates were: 92% 1.9 SHORT; 91% 1.9 STRETCH; 91% 1.4 STRETCH; 92% 1.4 SHORT; 100% 1.9 S/D to 1.4; 91% 1.0 SHORT; 100% 1.4 S/D to 1.0; 40% 1.0 Q12W (shorter follow-up than the other cohorts). The first decrease in BCVA to 20/50 or worse resolved in 89% of pts overall; resolution rates were: 100% 1.9 SHORT; 100% 1.9 STRETCH; 67% 1.4 STRETCH; 100% 1.4 SHORT; 100% 1.9 S/D to 1.4; 100% 1.0 SHORT; 0% in 1.4 S/D to 1.0 (only 1 patient had an event); in 1.0 Q12W, no pts had an event. Discontinuation rates due to Gr≥2 OEF events were low at 6% across the study (range: 0% [1.9 STRETCH, 1.4 STRETCH, 1.9 S/D to 1.4, and 1.0 Q12W] to 15% [1.4 SHORT]). ER analyses (Carreño et al. Blood 2024) found a positive correlation between belamaf cycle 1 average concentration (Cavg) and probability of response, but not probability of safety events. A Q6/8W schedule was associated with higher probability of CR+ (odds ratio [OR] 3.11 [95% CI 0.856–14.9]), while Q9/12W was associated with lower probability of Gr≥2 OEFs (OR 0.114 [95% CI 0.0301–0.348]) and longer time to Gr≥2 OEFs (OR 0.0674 [95% CI 0.0338–0.134]) but also lower probability of CR+ (OR 0.333 [95% CI 0.13–0.818]). Conclusions: While BVRd demonstrated high ORRs across all cohorts, MRD- rates were higher in the 1.9 SHORT/1.9 STRETCH cohorts, consistent with ER data correlating belamaf Cavg and deep responses. Across cohorts, ocular events were manageable via dose reductions/schedule extensions. Although lower-dose-intensity cohorts trended to lower OEF incidence, ocular events were successfully managed across all cohorts; the 1.9 SHORT/1.9 STRETCH cohorts achieved high OEF resolution rates while inducing high MRD- rates with low discontinuation rates due to OEF. In line with clinical observations, ER analyses indicated the potential for higher doses to optimize responses and longer schedules to optimize tolerability. Together, an initial 1.9 mg/kg dose of belamaf with a Q6/8W schedule in pts with NDMM may induce deeper responses, and subsequent schedule extensions may improve tolerability.