{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T21:31:11Z","timestamp":1785533471448,"version":"3.56.0"},"posted":{"date-parts":[[2025,12,11]]},"group-title":"Cancer Biology","reference-count":67,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,12,11]],"date-time":"2025-12-11T00:00:00Z","timestamp":1765411200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/publicdomain\/zero\/1.0\/"}],"funder":[{"name":"NIH-NCI","award":["P30CA076292"],"award-info":[{"award-number":["P30CA076292"]}]},{"name":"NIH-NCI","award":["R01CA244328-03"],"award-info":[{"award-number":["R01CA244328-03"]}]},{"name":"NIH-NCI","award":["P30 CA 240139"],"award-info":[{"award-number":["P30 CA 240139"]}]},{"name":"NIH-NCI","award":["P30 CA 008748"],"award-info":[{"award-number":["P30 CA 008748"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,12,11]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  Chimeric antigen receptor T-cell (CART) and T-cell engager (TCE) therapies targeting B-cell maturation antigen (BCMA) are transforming the treatment landscape for relapsed multiple myeloma (MM). However, despite impressive initial response rates, most patients eventually relapse. To investigate this unmet medical need, we applied whole-genome sequencing (WGS) to MM cells from cohorts of 102 relapsed patients treated with anti-BCMA CART and TCE therapies. Several genomic alterations were associated with clinical outcomes, particularly primary refractoriness, including high genomic complexity and mutations in genes regulating plasma cell identity, which predicted resistance to therapy. Single-cell RNA sequencing further revealed that MM cells from refractory patients exhibited high proliferation signatures and reduced expression of\n                  <jats:italic>TNFRSF17<\/jats:italic>\n                  (encoding BCMA), while were less enriched for plasma cell\u2013associated transcriptional programs, a phenomenon we term \u201cplasma cell identity escape.\u201d This profile was strongly associated with immune dysregulation of CD8 T cells including increased activation and exhaustion. This evolution of MM toward a more proliferative and lineage-divergent state, refractory to the anti-BCMA T-cell redirecting therapies, was functionally validated in preclinical MM mouse models. Collectively, our results comprehensively define the cellular and molecular mechanisms underlying primary resistance to anti-BCMA therapies.\n                <\/jats:p>","DOI":"10.64898\/2025.12.08.692978","type":"posted-content","created":{"date-parts":[[2025,12,15]],"date-time":"2025-12-15T07:55:17Z","timestamp":1765785317000},"source":"Crossref","is-referenced-by-count":2,"title":["Plasma cell identity escape drives resistance to anti-BCMA T-cell\u2013redirecting therapy in multiple myeloma"],"prefix":"10.64898","author":[{"given":"Francesco","family":"Maura","sequence":"first","affiliation":[{"name":"Myeloma Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA"},{"name":"Myeloma Service, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ciara L.","family":"Freeman","sequence":"additional","affiliation":[{"name":"Moffitt Cancer Center, Tampa, FL, 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