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Background: Daratumumab (DARA) introduced in the multiple myeloma (MM) treatment strategy, producing a direct antitumor activity and immunomodulatory effects in phase I-II trial GEN501. In the POLLUX trial, the combination of DARA with lenalidomide and dexamethasone (DRd) reported impressive response rates. In Taiwan, the Dara-based regimen was supported by National Health Insurance recently, but there were no real-world data in Taiwan. Materials and Methods: We described a heavily pretreated group of 31 patients with MM who had received one or more lines of therapy to receive DRd therapy after Taiwan Food and Drug Administration approval. The primary end point was progression-free survival (PFS). Results: After a median follow-up of 22.87 (95% confidence interval [CI]: 16–29.73) months, the median time to first response was 59 days (95% CI: 24.8–81.6). Median PFS was 24.082 months (95% CI: 14–33) in patients who received DRd therapy. Twelve-month PFS showed 80.7% in the DRd group. Patients who achieved at least very good partial response (VGPR) had longer median PFS (39.8 months) than those who achieved partial response (7.35 months). The complete response rate and VGPR were 35.5% and 29%, respectively. About 22.6% of patients had a partial response. The average treatment duration was 11.48 ± 7 months. Patient experienced biological relapse at 5.88 months after discontinuing DRd treatment. Conclusion: After DRd treatment for 11.48 months, most of the patients showed biological relapse at 5.88 months, suggesting the good efficacy; however, the need of a longer maintenance treatment of DARA. The median PFS in real-world setting was consistent with the POLLUX trial regardless of more patients with high cytogenetic risks. Patient who could achieve deep response above VGPR had better PFS than those who did not. [ABSTRACT FROM AUTHOR]