Background: Belantamab mafodotin (belamaf) is a B-cell maturation antigen-binding antibody-drug conjugate that eliminates myeloma cells via direct cell killing and anti-myeloma immune responses. DREAMM-9 (NCT04091126) is an ongoing Phase 1, randomized, dose and schedule evaluation study. It aims to evaluate belamaf plus bortezomib, lenalidomide, and dexamethasone (VRd) in adult patients (pts) with transplant-ineligible (TI) newly diagnosed MM (NDMM) and to establish the recommended dose for future development of belamaf combination therapies in the 1^st-line setting. Herein, we report updated interim-analysis data. Methods: Belamaf dose cohorts (Co1–7) are shown in the Table. VRd was given every 3 weeks (Q3W) until cycle 8, and Rd Q4W thereafter. Following safety data from Co2–5, Co6–7 were opened in parallel (randomized 1:1) and have shorter follow-up (Table). Safety was the primary endpoint; efficacy and tolerability were secondary endpoints. Minimal residual disease (MRD) was assessed by next-generation sequencing (10^-5). Results: As of data cutoff (Oct 20, 2022), 93 pts were treated across Co1–7. Median age (range) was 73 (51–88) years, 55% of pts were male, and 84% were white. The most commonly reported non-ocular adverse events (AEs) across all Co were thrombocytopenia (46%), constipation (36%), diarrhea (34%), and peripheral sensory neuropathy (31%). Overall, belamaf-related Grade ≥3 AEs occurred in 35% of pts and led to belamaf dose reductions in 7% and dose delays in 63% of all treated patients. Grade ≥3 ocular AEs (keratopathy and visual acuity [KVA] scale) occurred in 53% of all pts and led to dose reductions in 12% and dose delays in 52% of overall pts. Fatal AEs occurred in 7 pts, all unrelated to study treatment. Efficacy results and ocular AEs are summarized in the Table: 100% of pts responded in Co1 (1.9 mg/kg Q3/4W) and Co3 (1.9 mg/kg Q6/8W). Median time to very good partial response or better (≥VGPR) ranged from 2.1 to 3.1 months (mo) across cohorts. Highest MRD negativity (MRD[-]) rates (≥VGPR) were seen in Co1 (83%) and Co3 (67%). Conclusions: This updated interim analysis demonstrates that belamaf plus VRd has no new safety signals and provides early and deep anti-myeloma responses in pts with TI NDMM, with high MRD[-] rates. Clinical trial information: NCT04091126.