<h3>Background</h3> Patients (pts) with multiple myeloma (MM) refractory to lenalidomide (LEN) are a growing and clinically relevant patient population with a need for safe and effective therapies. In the OPTIMISMM trial (NCT01734928), pts with LEN RRMM who were treated with pomalidomide (POM), bortezomib (BORT), and dexamethasone (DEX; PVd) at first relapse had significantly improved median PFS (20.7 vs 11.6 mo; HR, 0.54; 95% CI, 0.36–0.82; P=0.0027) vs BORT and DEX (Vd; Richardson PG, et al. Lancet Oncol 2019;20:781–794). Treatment-emergent adverse events (TEAEs) reported with PVd were consistent with safety profiles of POM, BORT, or DEX alone. Here we report a safety analysis of TEAEs in the events of interest (EOI) category for PVd vs Vd administered at first relapse in OPTIMISMM. <h3>Methods</h3> Patients with RRMM and 1–3 prior lines of therapy were randomized 1:1 to receive PVd or Vd in 21-day cycles until disease progression, unacceptable toxicity, or withdrawal of consent. Key eligibility criteria included ≥2 cycles of prior LEN (LEN-refractory pts were included). AEs were graded according to the NCI CTCAE (v4.0) and summarized by system organ class and preferred term. <h3>Results</h3> The safety analysis included 221/559 pts (PVd, n=111; Vd, n=110) who had 1 prior line of therapy and received ≥1 dose of study drug. Baseline characteristics were balanced between Tx arms. All pts had prior LEN (57% were refractory); 59% had prior BORT. Median duration of treatment was longer with PVd (47.4 wk; range 4.7–147.0) vs Vd (27.1 wk; range 0.4–162.0). Grade (Gr) 3/4 TEAE EOI occurred in 57% of pts (PVd, 69%; Vd, 45%). The most common Gr 3/4 TEAE EOI were neutropenia (24%), infections and infestations (22%), and thrombocytopenia (20%). Gr 3/4 TEAE EOI more common with PVd vs Vd included neutropenia (37% vs 12%), infections and infestations (29% vs 15%), and peripheral neuropathy (12% vs 5%). Onset of neutropenia was mostly in the first 3 cycles and mainly Gr 3/4, with a median duration of 8 days with PVd and 5 days with Vd. Onset of infections and infestations commonly occurred during cycles 1–9, were mostly Gr 1/2, with a median duration of 12 days with both PVD and Vd. Among patients with ≥1 TEAE EOI, most were managed with dose reductions (PVd, 59%; Vd, 39%) or interruptions (PVd, 79%; Vd, 55%). POM discontinuations due to ≥1 any-grade TEAE EOI were low (9%), none due to neutropenia. In the PVd arm, 62% (31/50) of pts with any-grade neutropenia received G-CSF support. Infections and infestations were the main cause of PVd dose interruptions (54%). Peripheral neuropathy was the most common TEAE EOI leading to dose reduction (32%) and discontinuation (16%) with PVd. <h3>Conclusion</h3> The safety profile for PVd at first relapse in pts with RRMM is consistent with previous reports. Most TEAE EOI occurred in early cycles of treatment and were managed with dose modifications or appropriate treatment. <h3>Previous presentation</h3> Weisel K, et al. HemaSphere 2021;5:e464–465. EP988.