{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T04:00:59Z","timestamp":1792036859415,"version":"4.4.0"},"reference-count":40,"publisher":"American Society of Hematology","issue":"2","license":[{"start":{"date-parts":[[2024,10,7]],"date-time":"2024-10-07T00:00:00Z","timestamp":1728259200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2025,1,9]]},"abstract":"<jats:sec>\n                  <jats:title>Abstract<\/jats:title>\n                  <jats:p>Chimeric antigen receptor (CAR) T cells and bispecific antibodies targeting B-cell maturation antigen (BCMA) have significantly advanced the treatment of relapsed and refractory multiple myeloma. Resistance to BCMA-targeting therapies, nonetheless, remains a significant challenge. BCMA shedding by \u03b3-secretase is a known resistance mechanism, and preclinical studies suggest that inhibition may improve anti-BCMA therapy. Leveraging a phase 1 clinical trial of the \u03b3-secretase inhibitor (GSI), crenigacestat, with anti-BCMA CAR T cells (FCARH143), we used single-nuclei RNA sequencing and assay for transposase-accessible chromatin sequencing to characterize the effects of GSI on the tumor microenvironment. The most significant impacts of GSI involved effects on monocytes, which are known to promote tumor growth. In addition to observing a reduction in the frequency of nonclassical monocytes, we also detected significant changes in gene expression, chromatin accessibility, and inferred cell-cell interactions after exposure to GSI. Although many genes with altered expression are associated with \u03b3-secretase\u2013dependent signaling, such as Notch, other pathways were affected, indicating GSI has far-reaching effects. Finally, we detected monoallelic deletion of the BCMA locus in some patients with prior exposure to anti-BCMA therapy, which significantly correlated with reduced progression-free survival (PFS; median PFS, 57 vs 861 days). GSIs are being explored in combination with the full spectrum of BCMA-targeting agents, and our results reveal widespread effects of GSI on both tumor and immune cell populations, providing insight into mechanisms for enhancing BCMA-directed therapies.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1182\/blood.2024025231","type":"journal-article","created":{"date-parts":[[2024,10,7]],"date-time":"2024-10-07T20:57:12Z","timestamp":1728334632000},"page":"220-233","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":16,"title":["Single-cell analysis of the multiple myeloma microenvironment after \u03b3-secretase inhibition and CAR T-cell therapy"],"prefix":"10.1182","volume":"145","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3544-8836","authenticated-orcid":false,"given":"David G.","family":"Coffey","sequence":"first","affiliation":[{"name":"1Myeloma Division, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9462-4241","authenticated-orcid":false,"given":"Pinar","family":"Ataca Atilla","sequence":"additional","affiliation":[{"name":"2Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, WA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8613-2105","authenticated-orcid":false,"given":"Erden","family":"Atilla","sequence":"additional","affiliation":[{"name":"3Immunotherapy Integrated Research Center, Fred Hutchinson Cancer Center, Seattle, WA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6485-4839","authenticated-orcid":false,"given":"Ola","family":"Landgren","sequence":"additional","affiliation":[{"name":"1Myeloma Division, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew J.","family":"Cowan","sequence":"additional","affiliation":[{"name":"2Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, WA"},{"name":"3Immunotherapy Integrated Research Center, Fred Hutchinson Cancer Center, Seattle, WA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sylvain","family":"Simon","sequence":"additional","affiliation":[{"name":"3Immunotherapy Integrated Research Center, Fred Hutchinson Cancer Center, Seattle, WA"},{"name":"4Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margot J.","family":"Pont","sequence":"additional","affiliation":[{"name":"3Immunotherapy Integrated Research Center, Fred Hutchinson Cancer Center, Seattle, WA"},{"name":"4Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA"},{"name":"5Galapagos B.V., Oegstgeest, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-0393-9571","authenticated-orcid":false,"given":"Melissa L.","family":"Comstock","sequence":"additional","affiliation":[{"name":"4Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Geoffrey R.","family":"Hill","sequence":"additional","affiliation":[{"name":"3Immunotherapy Integrated Research Center, Fred Hutchinson Cancer Center, Seattle, WA"},{"name":"4Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stanley R.","family":"Riddell","sequence":"additional","affiliation":[{"name":"3Immunotherapy Integrated Research Center, Fred Hutchinson Cancer Center, Seattle, WA"},{"name":"4Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0477-1446","authenticated-orcid":false,"given":"Damian J.","family":"Green","sequence":"additional","affiliation":[{"name":"3Immunotherapy Integrated Research Center, Fred Hutchinson Cancer Center, Seattle, WA"},{"name":"4Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA"},{"name":"6Division of Transplantation and Cellular Therapy, Department of Medicine, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"234","reference":[{"issue":"8","key":"2025010916210704100_bib1","doi-asserted-by":"crossref","first-page":"705","DOI":"10.1056\/NEJMoa2024850","article-title":"Idecabtagene vicleucel in relapsed and refractory multiple myeloma","volume":"384","author":"Munshi","year":"2021","journal-title":"N\u00a0Engl J 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