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Background and Importance Multiple myeloma (MM) is the second most common haematologic malignancy, with an increasing incidence in patients over 75 years. Frail individuals who are ineligible for autologous stem cell transplantation require effective and safe therapeutic strategies to delay disease progression. The addition of daratumumab (D) to standard first-line regimens–VMP (bortezomib/melphalan/prednisone) and Rd (lenalidomide/dexamethasone)–has shown improved progression-free survival (PFS) and overall survival (OS) in pivotal trials ( ALCYONE and MAIA).Aim and Objectives This study aimed to evaluate the real-world effectiveness and safety of daratumumab-based regimens in patients aged ≥80 years with newly diagnosed MM (NDMM).Material and Methods A retrospective, observational study was conducted including NDMM patients aged ≥80 years treated with daratumumab from its introduction until January 2025. Baseline variables included ISS/R-ISS stage, cytogenetics, renal function, albumin, and β2-microglobulin. Effectiveness was assessed by progression-free survival (PFS), overall survival (OS), and progression rate using Kaplan–Meier analysis. Safety was evaluated according to CTCAE v5.0 and treatment-related modifications.Results 33 patients (mean age 84.1±3.7 years; 51.5% female) were analysed: 60.6% received D-VMP, 30.3% D-Rd, and 9.1% D-VCP. Median treatment duration was 16.8±14.4 months, and median follow-up was 5.4 years. Seven patients (21.2%) progressed and seven (21.2%) died, three due to disease progression. Median PFS was 40.7 months (95% CI: 36.8–NA); 1-year PFS was 88.6%, and 2-year PFS was 79%. Median OS was not reached; 1-year OS was 78%, and 2-year OS was 73.4%. Adverse events (AEs) occurred in 85.8% of patients, predominantly grade 1–2 (87.3%). The most frequent AEs were haematologic (32.7%; anaemia 20%, neutropenia 5.5%), infectious (29.1%; pneumonia 16.4%), and neurological (18.2%; sensory neuropathy). Severe AEs included grade 4 cholestasis and grade 5 fatal septic shock. Treatment adjustments were required in 53.8% of cases, mainly temporary interruptions or drug discontinuations.Abstract 5PSQ-163 Figure 1Conclusion and Relevance Daratumumab-based triplet or quadruplet regimens demonstrated favourable safety and effectiveness in patients ≥80 years with NDMM, with toxicity predominantly mild to moderate. Outcomes were consistent with pivotal trials, supporting daratumumab as a viable treatment option for this vulnerable population.References and/or Acknowledgements 1. Mateos MV, Spencer A, et al. Haematologica. 2020;105(2):468–477.2. Moreau P, Facon T, et al. Leukemia. 2025:10.1038/s41375-024-02506-1.3. Dimopoulos MA, Moreau P, et al. Multiple myeloma: EHA-ESMO Clinical Practice Guidelines. Ann Oncol. 2021;32(3):309–22.Conflict of Interest No conflict of interest