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Background: RRMM patients(pts)who have exhausted treatment(Tx)with bortezomib(BORT)and lenalidomide(LEN)or thalidomide have a poor prognosis with short overall survival(OS).HiDEX is a well-established standard Tx in RRMM.POM has demonstrated clinical efficacy in pts refractory to LEN and BORT.MM-003 compared POM + LoDEX vs.HiDEX in RRMM pts who failed LEN and BORT and who progressed on their last Tx.Methods: Pts must have been refractory to last prior Tx(progressive disease [PD] during Tx or within 60 days)and failed LEN and BORT after ≥ 2 consecutive cycles of each(alone or in combination).Pts were randomized 2:1 to receive 28-day cycles of POM 4 mg D1–21 + DEX 40 mg(20 mg for pts aged > 75 y)weekly or DEX 40 mg(20 mg for pts aged > 75 y)D1–4,9–12,and 17–20.Tx continued until PD or unacceptable toxicity.The primary endpoint was progression-free survival(PFS).Secondary endpoints included OS,overall response rate(ORR; ≥ partial response),and safety.Analyses were based on intent to treat.Results: 455 pts were randomized to POM + LoDEX(n = 302)or HiDEX(n = 153).The median number of prior Tx was 5(range 1-17).72%were refractory to LEN and BORT.Median follow-up was 4 months.POM + LoDEX significantly extended median PFS(3.6 vs.1.8 months,HR = 0.45,P <.001)and OS(not reached vs.7.8 months,HR = 0.53,P <.001)vs.HiDEX.The OS benefit was observed despite 29%of HiDEX pts receiving POM after PD.The trial met the primary endpoint of PFS,crossed the upper boundary for OS superiority,and the Data Monitoring Committee recommended crossover from HiDEX to POM ± DEX.With updated data,the ORR was 21%for POM + LoDEX vs.3%for HiDEX(P <.001)and 24%vs 3%for pts randomized ≥ 6 months post-enrollment(P <.001).The most frequent grade 3/4 adverse events(AEs)for POM + LoDEX vs.HiDEX were neutropenia(42%vs.15%),anemia(27%vs.29%),and infection(24%vs.23%).Discontinuation due to AEs was infrequent(7%vs.6%).Updated data will be presented.Conclusions: POM + LoDEX significantly extended PFS and OS vs.HiDEX in pts who failed LEN and BORT.POM + LoDEX should become a standard of care in RRMM pts who have exhausted Tx with LEN and BORT.