Background: We report the belantamab mafodotin (belamaf)-associated ocular adverse events (OAEs) in transplant ineligible (TI) patients (pts) with newly diagnosed multiple myeloma (NDMM) treated with belamaf plus lenalidomide and dexamethasone (Rd). Methods: BelaRd (NCT04808037), an ongoing, prospective, open-label, phase 1/2 study, aims to enroll 66 TI pts with NDMM. In Part 1, assessing the safety/clinical activity of belamaf plus Rd, 36 pts are randomized (1:1:1) to receive belamaf 1.4, 1.9, or 2.5 mg/kg doses Q8W. Eye exams include Snellen best corrected visual acuity (BCVA) and corneal exam. Ocular symptoms are graded by CTCAE v5.0, and dry eye disease severity/activities of daily living (ADLs) are assessed with the Ocular Surface Disease Index (OSDI). This descriptive analysis included all Part 1 pts (cutoff: 15/12/2022). Results: Pts (N = 36) were followed up for a median 15 months. At baseline all pts had ocular comorbidities. Regarding pts visual acuity, out of a total of 499 BCVA assessments, 164 (33%) were Gr 2 [1.4, 1.9, 2.5 mg/Kg: 46/157 (29%), 49/182 (27%), 69/160 (43%)] and 54 (11%) were Gr 3 [1.4, 1.9, 2.5 mg/Kg: 18/157 (11%), 16/182 (9%), 20/160 (13%)]. Notably, a meaningful BCVA decline (worse than 20/50 in better seeing eye) was observed in 38 (8%) assessments [1.4, 1.9, 2.5 mg/Kg: 12/151 (8%), 13/182 (7%), 13/160 (8%)], 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, respectively. Slit lamp examinations by the ophthalmologist (N = 501) revealed a Gr 2 keratopathy in 55 (11%) assessments [1.4, 1.9, 2.5 mg/Kg: 17/158 (11%), 18/183 (10%), 20/160 (13%)] and Gr 4 keratopathy in 2 ( < 1%) assessments [1.4, 2.5 mg/Kg: 1/158 ( < 1%), 1/160 (1%)], with a median time to resolution of 4 months. The proportion of belamaf doses withheld /planned due to OAEs was 26% (24/94), 26% (28/106) and 36% (35/98) in the 1.4, 1.9 and 2.5 mg/Kg cohorts. Regarding OSDI findings, in the ocular symptoms category (Q1–5), the proportions of assessments with ‘all’ or ‘most’ of the time worst answers were 0%, 1% (1/173), 0% and 6% (8/146), 2% (4/173), 3% (5/146), in the 1.4, 1.9, 2.5 mg/Kg cohorts, respectively. The proportions of assessments with ‘all’ or ‘most’ of the time worst answers to ADLs (Q6–9) were 1% (1/146), 0%, 1% (1/146) and 1% (2/146), 2% (3/173), 3% (5/146) in the 1.4, 1.9, 2.5 mg/Kg cohorts. Conclusions: No new ocular safety signals were observed with belamaf plus Rd in the upfront treatment of TI pts with NDMM. A meaningful BCVA decline was observed in a minority ( < 10%) of assessments which resolved quickly (1 month). Most importantly, a minor impact on daily functioning, ‘all’ or ‘most’ of the time, was noted with the combination. Clinical trial information: NCT04808037.