Background: We present the updated safety and efficacy of upfront belantamab mafodotin (belamaf) plus lenalidomide and dexamethasone (Rd) in transplant ineligible (TI) pts with newly diagnosed multiple myeloma (NDMM). Methods: The ongoing, prospective, open-label, phase 1/2 BelaRd study (NCT04808037) aims to enroll 66 pts with TI NDMM, with ECOG PS < 2 and adequate organ function. In Part 1, 36 pts are randomized (1:1:1) to receive belamaf 2.5, 1.9, or 1.4 mg/kg Q8W plus Rd. Eye exams include Snellen best corrected visual acuity (BCVA) and corneal exam (slit lamp examination). Ocular adverse evets (OAEs) are classified by CTCAE v5.0. This descriptive analysis presents the updated safety and efficacy findings for all Part 1 pts (cutoff date 15/12/22). Results: The analysis included 36 pts [median age: 73 years (64–86); male: 19 (53%)], of whom 31 (86%) were still on treatment and 5 (14%) had discontinued [4 pts due to belamaf-unrelated adverse events (AEs); 1 pt withdrew consent]. At baseline, 32 (89%) pts were intermediate fit as per International Myeloma Working Group frailty score and 34 (94%) had ECOG PS≤1. Median follow up was 15 months (3–23); median belamaf administrations and number of cycles reached were 6 (2–10) and 15 (3–22). Thirty-four (94%) pts experienced ≥1 grade (Gr) ≥3 treatment-emergent AEs (TEAEs). Most common (≥ 10% of pts) non ocular Gr ≥3 TEAEs were fatigue (21 pts, 58%), rash (6 pts, 17%), diarrhoea (5 pts, 14%) and COVID-19 infection (4 pts, 11%); no Gr ≥3 thrombocytopenias and any Gr infusion-related reactions were reported. Regarding pts visual acuity, out of a total of 499 BCVA assessments, 164 (33%) were Gr 2 and 54 (11%) were Gr 3. Notably, a meaningful BCVA decline (worse than 20/50 in better seeing eye) was observed in 38 (8%) assessments, with a median time to resolution of 1 month. Regarding clinically relevant Gr≥2 ocular symptoms, blurred vision, dry eye and visual impairment were observed in 38 (8%), 96 (20%) and 98 (20%) assessments, with a median time to resolution of 2, 3 and 2 months. Slit lamp examinations by the ophthalmologist (N = 501) revealed a Gr 2 keratopathy in 55 (11%) assessments and Gr 4 keratopathy in 2 ( < 1%) assessments, with a median time to resolution of 4 months. Overall response rate [partial response (PR) or better] was 100.0% [36 pts; stringent complete response: 14% (5 pts); complete response: 19% (7 pts); very good partial response: 47% (17 pts); PR: 19% (7 pts)]. Median time to first response was 1 month. Conclusions: Part 1 of the BelaRd study showed that in TI pts with NDMM, the safety profile of belamaf plus Rd was manageable and a meaningful BCVA decline was noted in a minority ( < 10%) of assessments which resolved quickly (1 month). The combination induced rapid and deep responses, with all pts achieving ≥PR and first response observed at a median of 1 month. Clinical trial information: NCT04808037.