Despite significant advancements in therapy of multiple myeloma (MM) over the past 20 years, most patients experience relapse, necessitating new treatment approaches. This study aims to compare the real-world effectiveness of lenalidomide (LEN)-based triplet therapies, specifically daratumumab (DRD), carfilzomib (KRD), and ixazomib (IRD), in relapsed/refractory multiple myeloma (RRMM).A retrospective registry-based study analyzed 538 RRMM patients undergoing therapy for their first to third relapse. The primary endpoints were overall response rate (ORR), progression-free survival (PFS), and overall survival (OS), with a matching-adjusted indirect comparisons (MAIC) employed to address cohort differences.ORR was highest for DRD at 91.4%, followed by KRD (89.6%) and IRD cohorts (Early-IRD: 79.6%, Late-IRD: 70.8%). Median PFS for DRD was greater at 23.64 months compared to KRD (16.52 months) and IRD groups (Early-IRD: 19.97 months, Late-IRD: 11.57 months). The MAIC confirmed better outcomes for the DRD regimen. High-risk features were not overcome by any of the LEN-based regimens.The findings underscore the superior efficacy of DRD in achieving sustained responses in RRMM patients. The composition of the cohort is a crucial factor, extending beyond selection criteria. This study highlights the importance of real-world evidence in assessing treatment modalities in clinical settings.

1st Medical Department Clinical Department of Haematology 1st Faculty of Medicine and General Teaching Hospital Charles University Prague Czech Republic

4th Department of Internal Medicine Hematology University Hospital Hradec Kralove Faculty of Medicine Hradec Kralove Charles University Hradec Kralove Czech Republic

Department of Hemato Oncology Faculty of Medicine and Dentistry Palacky University Olomouc and University Hospital Olomouc Olomouc Czech Republic

Department of Hematooncology Faculty of Medicine University of Ostrava Ostrava Czech Republic

Department of Hematooncology University Hospital Ostrava Ostrava Czech Republic

Department of Internal Medicine and Hematology 3rd Faculty of Medicine Charles University and Faculty Hospital Kralovske Vinohrady Prague Czech Republic

Department of Internal Medicine Hematology and Oncology University Hospital Brno and Faculty of Medicine Masaryk University Brno Czech Republic

Hematology and Oncology Department Charles University Hospital Pilsen Pilsen Czech Republic

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