Background Belantamab mafodotin (belamaf) is a first-in-class antibody-drug conjugate (ADC) targeting B-cell maturation antigen (BCMA) that has demonstrated clinically meaningful activity as monotherapy in RRMM. Pre-clinical studies demonstrate that the immune mediated anti-myeloma activities of belamaf are enhanced by immunomodulatory drugs providing the rationale for combining Belamaf with POM. Methods A Phase 1/2 multicenter, dose-escalation study evaluated the maximum tolerated does (MTD), recommended phase 2 dose (RP2D), safety and activity of Belamaf plus POM and DEX (B-Pd) in patients (pts) with RRMM. Eligibility required > 1 prior line of treatment (LoT), exposure to lenalidomide (LEN) and a proteasome inhibitor (PI) and refractoriness to the last LoT. POM was administered at 4 mg days 1-21, with weekly dexamethasone (DEX) and various doses and schedules of IV Belamaf on 28-day cycles. Responses were assessed by IMWG criteria and adverse events (AEs) were graded by CTCAE except for corneal findings which were graded by a pre-specified keratopathy and visual acuity (KVA) scale. To better inform the RP2D for Part 2, up to 12 pts could be enrolled in each dose cohort not exceeding the MTD. Results Here we report the tolerability and efficacy of 32 pts treated at each cycle with Belamaf, 1.92 mg/kg (n=12) or 2.5 mg/kg (n=20) in combination with Pd with a median follow up of 13.6 months. The 2.5 mg/kg B-Pd cohort included pts treated with belamaf Q4W (n=7), a 2.5 mg/kg LOADING dose followed by 1.92 mg/kg Q4W from cycle 2+ (n=5) or 2.5 mg/kg SPLIT equally on days 1 and 8 of each cycle (n=8). The median age was 64 (range 36-81) and median prior LoT 3 (1-5). Prior therapies (exposed/refractory) included stem cell transplant (62.5%), PI (100%/78%), LEN (100%/91%) and daratumamb (DARA) (37.5%/100%). 72% were refractory to LEN and a PI and 31% to LEN, a PI and DARA. Grade 3/4 non-ocular AEs reported in >25% of pts treated in the 1.92 and 2.5 mg/kg cohorts respectively, were neutropenia (50% and 50%), thrombocytopenia (42% and 25%), dyspnea (25 and 15%) and lung infection (25% and 10%). At 12 months of treatment =>G3 keratopathy (an eye exam finding) or =>G3 symptomatic blurred vision were observed in 42.9%/93.3% and 28.6%/13.3% of pts treated in the 1.92mg/kg (n=7)/2.5 mg/kg (n=15) groups, respectively. No patients discontinued treatment for AEs and no grade 5 AEs were observed. The ORR/=>VGPR rates for the 1.92 and 2.5 mg/kg cohorts, were 81.8%/63.6% and 95%/85%, respectively. As of May 20, 2021, the median PFS was 14.2 months for the 1.92 mg/kg cohort and 24.2 months for the 2.5 mg/kg group. Conclusions The safety profile of B-Pd is consistent with that observed for Pd or Belamaf individually. Both dose cohorts demonstrate deep and durable responses however the 2.5 mg/kg dose appears to have better efficacy. Alternative dosing schedules are under evaluation to optimize efficacy and safety.