Hematologist based management of ocular adverse events using the VRA tool in newly-diagnosed myeloma patients, ineligible for ASCT who received belantamab mafodotin plus lenalidomide/dexamethasone: Updated results from the randomized part 2 of bela-rd Study

Abstract

Abstract Introduction Belantamab mafodotin (belamaf) combinations showed superior efficacy over standard regimens in relapsed/refractory multiple myeloma (MM) in the DREAMM-7/-8 trials. In this trial (BelaRd) we evaluated the safety, tolerability & efficacy of an extended belamaf dosing schedule with lenalidomide & dexamethasone (Rd), in transplant-ineligible (TI) newly diagnosed MM (NDMM). Part 2 introduced a hematologist-led ocular management strategy, using the Vision-Related Anamnestic (VRA) tool to guide dosing in the presence of Ocular Adverse Events (OAEs). Methods BelaRd is a Phase 1/2 open-label trial (NCT04808037). Part 1 evaluated belamaf at 2.5/1.9/1.4 mg/kg Q8W with Rd in 36 patients (pts) (n=12/dose), establishing the recommended phase 2 dose (RP2D) as 1.9 mg/kg Q8W extendable to Q12W for ocular toxicity, based on ophthalmologist-assessed Keratopathy & Visual Acuity (KVA) scale. Belamaf was withheld for Grade ≥2 OAEs & resumed upon resolution to Grade ≤1. Part 2 enrolled 30 pts at the RP2D, comparing two ocular management strategies: Group (Gr.) A (15 pts) used ophthalmologist-guided dosing as in Part 1; Gr.B (15 pts) employed a hematologist-led approach using the VRA tool (a 9-item pt-reported questionnaire for ocular symptoms & impact on daily function). Belamaf was withheld if pts reported OAEs for >50% of the time in the last 24 hours (substantial time) through the VRA & if Grade ≥3 OAEs were ophthalmologist-confirmed. This analysis presents updated RP2D safety/efficacy results, focusing on the VRA implementation. Results As of the data cut-off (01 March 2025), 42 pts overall received belamaf at the RP2D with Rd. All had baseline ocular comorbidities; 35 (85.7%) had cataract. At a median follow-up of 24.6 months (range: 3.9-47.3), 31 (73.8%) remained on treatment; 2 (4.8%) had disease progression. Median dose intensity (DI) was 1.2 mg/kg/Q8W; 1.2 in Gr.A vs 1.4 mg/kg/ Q4W in Gr.B. Belamaf was withheld in 72/219 (32.9%) of the Part 1 doses planned, 40/151 (26.5%) in Gr.A & 23/136 (16.9%) in Gr.B; most due to OAEs (110/135). Median time to belamaf re-infusion was 12.8 weeks (range 8.3-19.1), with high variability in re-infusion intervals: 29/39 pts (Part.1: 11/12, Gr.A: 10/14; Gr.B: 8/13) had a coefficient of variation [CV]>20. Among pts completing 12 months of treatment, median re-infusion time was 14.9 weeks (range: 8.3-26.5), with more consistent intervals (only 8/29 pts had a CV>20%). ORR (PR or better) was 97.6% (41/42 pts); 93.3% in Gr.A vs 100% in Gr.B. Overall median time to first response of 1.0 month (range: 0.9-3.8). Median PFS/OS were not reached. 18-month PFS was 82.9% (95%CI: 67.5-91.5); 86.7% (95%CI: 56.4–96.5) in Gr.A vs 78.6% (95%CI: 47.3–92.5) in Gr.B. 18-month TTP was 97.2% (95%CI: 81.9-99.6) overall. CR rate was 76.2% in the below median DI subgroups & 28.6% in the above median DI subgroup; TTP events were 0 & 2 (9.6%) respectively. Most common (>10%) Grade ≥3 non-ocular TEAEs were fatigue (69%), rash (19.0%) & diarrhea (11.9%). Grade ≥3 Infections & infestations occurred in 14.3% of RP2D pts. No new safety signals emerged. In Part 2, Grade≥3 OAEs occurred at similar rates across the 2 Groups. Grade ≥3 BCVA decline was reported in 5.3% (Gr.A) & 2.0% (Gr.B) of assessments. Grade ≥3 keratopathy in 0.3% & 0.0% respectively. Only 3.3% (10/300) of Gr.A & 0.8% (2/251) of Gr.B ophthalmologist assessments detected Grade ≥3 OAEs without “substantial time” reported in the VRA. None of the 121 VRA-guided dosing decisions were withheld by ophthalmologist evaluation (Grade ≥3 OAEs). Vision-related activity limitations (e.g. stopping driving or reading) were reported in only 0.0%-0.6% of assessments in both groups. Conclusions The BelaRd RP2D demonstrated substantial clinical activity, with rapid, deep & durable responses in TI NDMM. Most pts achieved ORR within 1 month & the majority remained progression-free at 18 months. Extended dosing intervals and hematologist-led ocular management via the VRA tool enabled personalized treatment. The VRA-guided approach allowed symptom-based dosing, resulting in more consistent dosing intervals and minimal impact on vision-related daily activities, without compromising safety or efficacy. These findings support the continued evaluation of belamaf in 1st line MM setting & suggest the VRA tool as a feasible model for decentralized ocular AE management and dosing guide in clinical practice.