BACKGROUND: Early continuous lenalidomide use for multiple myeloma (MM) treatment has led to more patients with lenalidomide-refractory disease at earlier lines of therapy (LOTs). Real-world treatment practices and outcomes in elderly patients with comorbidities are not well characterized. MATERIALS AND METHODS: Using the Surveillance, Epidemiology, and End Results-Medicare database, we analyzed data from patients who were diagnosed with MM between 2014 and 2019, had 1 to 3 prior LOTs, including a proteasome inhibitor and an immunomodulatory drug, and were lenalidomide refractory. Patients were followed from index (initiation of first subsequent LOT after meeting eligibility criteria and after January 1, 2016) until death, end of continuous Medicare enrollment, or December 31, 2020. RESULTS: This analysis included 1297 patients (median age, 75 years). The mean National Cancer Institute Comorbidity Index score was 0.87 and 81% had at least 1 comorbidity. Singlet, doublet, and triplet therapies each accounted for ∼30% of index regimens. The most common regimens, ± corticosteroid, were daratumumab-pomalidomide (15%), pomalidomide (13%), and daratumumab (12%). Median overall survival and time to next treatment (TTNT) were 29.3 and 8.5 months, respectively. TTNT decreased with successive LOTs (1 prior LOT, 11.0 months
3 prior LOTs, 6.1 months). CONCLUSION: Elderly patients with comorbidities and lenalidomide-refractory disease after 1 to 3 LOTs receive suboptimal regimens, have poor outcomes, and move rapidly through treatments, highlighting the need for new effective treatments for this difficult-to-treat population.