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The introduction of proteasome inhibitors (PIs) and lenalidomide as treatment for newly diagnosed multiple myeloma (MM) has led to an increased population of lenalidomide-refractory patients. Limited data are available characterizing current treatments and outcomes in this difficult-to-treat population. Individual patient-level data were analyzed from the treatment arms of multiple daratumumab studies, including APOLLO, CASTOR, CANDOR, EQUULEUS, ALCYONE, MAIA, GRIFFIN, POLLUX, and CASSIOPEIA. Included patients were PI exposed and lenalidomide refractory, received 1–3 prior lines of therapy (LOT), and had an Eastern Cooperative Oncology Group performance status < 2. Treatments and outcomes were analyzed by number of prior LOT in the lenalidomide-refractory population. Time to next treatment (TTNT), progression-free survival (PFS), and overall survival (OS) were estimated using the Kaplan-Meier method. Out of 4764 patients, 915 patients (prior LOT, one [n = 114]; two [n = 462]; three [n = 339]) met inclusion criteria. Median follow-up was 29·7 months (range 28·0–31·7). The overall response rate was 55·4 %. Estimated median TTNT was 9·7 months, median PFS was 10·0 months, and median OS was 27·5 months. Response rates and PFS decreased as number of prior LOT increased. Prognostic factors for response, TTNT, PFS, and OS included International Staging System stage, baseline plasmacytoma status, baseline hemoglobin, anti-CD38–refractory status, and cytogenetic risk status. Lenalidomide-refractory patients treated with 1–3 prior LOT have poor PFS and OS, which generally worsen with each additional LOT, highlighting the need for new and effective treatments for this population. • Outcomes were analyzed in patients with lenalidomide-refractory multiple myeloma. • Data represent treatment arms and subsequent therapies from 9 trials (2014–2022). • Outcomes were suboptimal: 55 % response rate, 10-mo median PFS, and 28-mo median OS. • New, effective therapies are needed for this difficult-to-treat population. [ABSTRACT FROM AUTHOR]