Background: POM, a standard-of-care treatment (Tx) in RRMM, has demonstrated synergistic anti-myeloma activity with dexamethasone (DEX) and proteasome inhibitors (PIs). POM + DEX is indicated for RRMM after ≥ 2 prior Txs including LEN and a PI, and is the only Tx to be investigated exclusively after LEN. As LEN becomes increasingly established in up-front Tx of MM, pts who have exhausted the benefit of LEN represent a clinically relevant unmet medical need. In preclinical studies, POM inhibited proliferation of LEN-resistant cells. Here we report final PFS and safety data from the first phase 3 POM triplet trial comparing PVd vs Vd in an entirely post-LEN treated population. Methods: Pts with RRMM, 1-3 prior Tx lines, and ≥ 2 cycles (c) of prior LEN were randomized 1:1 to receive PVd or Vd. In 21-d c, pts received POM 4 mg/d on d 1-14 (PVd arm only); BORT 1.3 mg/m² on d 1, 4, 8, and 11 of c 1-8 and on d 1 and 8 of c 9+; and DEX 20 mg/d (10 mg if aged > 75 yrs) on the days of and after BORT. The primary endpoint was PFS. Results: 559 pts were enrolled: 281 PVd and 278 Vd. Median age was 67 and 68 yrs, respectively. All pts had prior LEN (71% vs 69% LEN refractory), 72% vs 73% had prior BORT, and 70% vs 66% were refractory to last Tx. Median prior Tx lines was 2; 40% in PVd and 41% in Vd arm had 1 prior Tx line. After a median follow-up of 16 mos, PVd significantly reduced the risk of progression or death by 39% vs Vd (Table). OS data are not mature. Most common grade 3/4 treatment-emergent AEs were neutropenia (42% vs 9%), infections (31% vs 18%), and thrombocytopenia (27% vs 29%). Conclusions: To date, OPTIMISMM is the only phase 3 study in early RRMM to report a significant and clinically meaningful PFS improvement in pts who were entirely LEN exposed and 70% LEN refractory. Furthermore, the results showed improved benefit in pts with only 1 prior Tx line. POM safety remained manageable, consistent with its known profile. Clinical trial information: NCT01734928