Simple SummaryRefractoriness to the five main myeloma treatments, including lenalidomide, pomalidomide, bortezomib, carfilzomib, and either daratumumab or isatuximab, define penta-refractory myeloma. Pent-refractory myeloma is a challenging disease that does not respond adequately to standard treatment approaches. However, clinical trials offer hope for innovative approaches. B-cell maturation antigen (BCMA) is a novel target for plasma cells. Initial clinical trials showed promising results in refractory myeloma. Nevertheless, measuring the benefits specifically for pent-refractory myeloma is required. In this retrospective analysis, we demonstrate that the BCMA-targeted approach has changed the outcomes of penta-refractory myeloma. While penta-refractory myeloma patients may benefit from BCMA-targeted therapy, more novel treatment options are needed to overcome its resistance.AbstractDespite advances in treatment, outcomes remain poor for patients with penta-relapsed refractory multiple myeloma (RRMM). In this retrospective analysis, we evaluated the survival outcomes of penta-RRMM patients treated with (BCMA)- directed therapy (BDT). We identified 78 patients with penta-RRMM. Median age was 65 years, 29 (37%) had R-ISS stage III disease, 63 (81%) had high-risk cytogenetics, and 45 (58%) had extra-medullary disease. Median LOT prior to penta-refractory state was 5 (3–12). Amongst penta-RRMM, 43 (55%) were treated with BDT, 35 (45%) were not treated with BDT. Type of BDT received included belantamab mafadotin 15 (35%), Chimeric Antigen Receptor T-cell therapy 9 (21%), BCMA monoclonal antibody 6 (14%), and Bispecific T-cell engager 2 (5%). Eleven (25%) patients received more than one BDT. No significant differences were identified between baseline characteristics for the two groups. Patients treated with a BDT had better median overall survival, 17 vs. 6 months, HR 0.3p-value < 0.001. Poor performance status, white race, and high-risk cytogenetics were associated with worse outcomes, whereas using a BDT was associated with better outcomes. Patients with penta-refractory MM have poor outcomes. Our retrospective analysis showed a significant survival benefit using BDT when compared to non-BDT for patients with penta-RRMM.