(1) National and Kapodistrian University of Athens, (2) Institut Català d’Oncologia and Institut Josep Carreras, Hospital Germans Trias i Pujol, (3) Karolinska Institute, Department of Medicine, Division of Hematology, Karolinska University Hospital at Huddinge, (4) Clínica Universidad de Navarra, Centro de Investigación Médica Aplicada (CIMA), Instituto de Investigación Sanitaria de Navarra (IDISNA), CIBER-ONC, (5) Arnie Charbonneau Cancer Research Institute, University of Calgary, (6) Memorial Sloan Kettering Cancer Center, (7) Department of Haematology, University College London Hospitals NHS Trust, (8) Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, (9) Japanese Red Cross Medical Center, Department of Hematology, (10) Vejle Hospital and University of Southern Denmark, (11) Department of Internal Medicine, Seoul National University College of Medicine, (12) Hematology Department, Hadassah Medical Center, Faculty of Medicine, Hebrew University, (13) Dana-Farber Cancer Institute, (14) University Hospital Heidelberg, Internal Medicine V and National Center for Tumor Diseases (NCT), (15) Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, (16) Genmab US, Inc., (17) Janssen Research & Development, LLC, (18) Janssen Research & Development, LLC, (19) Janssen Research & Development, LLC, (20) Hematology, University Hospital Hôtel-Dieu Introduction: Daratumumab (DARA) is a human IgGκ monoclonal antibody targeting CD38 that is approved in combination with standard-of-care regimens for pts with newly diagnosed multiple myeloma (NDMM) and as monotherapy and in combination with standard-of-care regimens for pts with relapsed/refractory multiple myeloma (RRMM). In the primary analysis of the phase 3 POLLUX study (median follow-up, 13.5 months), DARA plus lenalidomide and dexamethasone (D-Rd) provided a significant progression-free survival (PFS) benefit versus lenalidomide and dexamethasone (Rd) alone, and key secondary endpoints (including time to disease progression, rate of very good partial response or better, overall response rate, and minimal residual disease [MRD]–negativity rate) showed a statistically significant benefit favoring D-Rd. Here, we report final overall survival (OS) and updated MRD-negativity and safety results after >6 years of follow-up. Methods: Pts with RRMM and ≥1 prior line of therapy were randomized 1:1 to receive D-Rd or Rd. All pts received 28-day cycles of Rd (R 25 mg PO on Days 1-21; d 40 mg QW). Pts in the D-Rd group also received DARA (16 mg/kg IV QW in Cycles 1-2, Q2W in Cycles 3-6, and Q4W thereafter). In both groups, pts were treated until disease progression or unacceptable toxicity. The primary endpoint was PFS; OS was a secondary endpoint. Results: In total, 569 pts were randomized (D-Rd, n=286; Rd, n=283). The median (range) age was 65 (34-89) years; pts had received a median (range) of 1 (1-11) prior lines of therapy. At a median (range) follow-up of 79.7 (0.0-86.5) months, the POLLUX study showed a statistically significant and clinically meaningful improvement in OS with D-Rd versus Rd (hazard ratio, 0.73; 95% confidence interval [CI], 0.58-0.91; P=0.0044 [crossing the prespecified stopping boundary of P<0.0331]), representing a 27% reduction in the risk of death in the D-Rd group (Figure). The median OS was 67.6 (95% CI, 53.1-80.5) months in the D-Rd group versus 51.8 (95% CI, 44.0-60.0) months in the Rd group. Prespecified subgroup analyses showed an OS improvement with D-Rd versus Rd in most subgroups, including pts aged ≥65 years; pts who had received 1, 2, or 3 prior lines of therapy; pts with International Staging System stage III disease; and pts who were refractory to a proteasome inhibitor or to their last prior line of therapy. D-Rd achieved significantly higher rates of MRD negativity (10–5) versus Rd (33.2% vs 6.7%; P<0.0001). The most common (≥10%) grade 3/4 treatment-emergent adverse events (TEAEs; D-Rd/Rd) were neutropenia (57.6%/41.6%), anemia (19.8%/22.4%), pneumonia (17.3%/11.0%), thrombocytopenia (15.5%/15.7%), and diarrhea (10.2%/3.9%). Rates of discontinuation due to TEAEs were comparable between treatment groups (D-Rd, 19.1%; Rd, 16.0 %). There were no new safety concerns identified with extended follow-up. Conclusion: Treatment with D-Rd significantly prolonged OS compared with Rd alone. These results, together with the OS results observed with DARA in combination with bortezomib and dexamethasone in the phase 3 CASTOR study, demonstrate for the first time an OS benefit with DARA-containing regimens in RRMM. Our results support the use of DARA in pts with RRMM.