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Monoallelic loss of\n                    <jats:italic>GPRC5D<\/jats:italic>\n                    is frequently observed in newly diagnosed MM patients, and the incidence of acquired\n                    <jats:italic>GPRC5D<\/jats:italic>\n                    alterations increases following exposure to GPRC5D-directed therapies. However, the functional consequences of both baseline monoallelic and therapy-induced biallelic\n                    <jats:italic>GPRC5D<\/jats:italic>\n                    alterations remain poorly understood. In this study, we modeled monoallelic versus biallelic loss of\n                    <jats:italic>GPRC5D<\/jats:italic>\n                    to investigate their impact on MM cell biology and responsiveness to GPRC5D-targeted immunotherapies. Our results demonstrate that monoallelic\n                    <jats:italic>GPRC5D<\/jats:italic>\n                    loss in OPM-2 cells reduces surface expression of the antigen and confers resistance to GPRC5D-directed therapies. Complete loss of\n                    <jats:italic>GPRC5D<\/jats:italic>\n                    alters the transcriptional state of MM cells and promotes reprogramming of the phosphoproteomic circuitry ultimately resulting in a pro-proliferative chemokine environment. As a result, GPRC5D deficiency increases the basal proliferation rate of MM cells thereby providing a competitive advantage which may further be amplified by selecting these aggressive phenotypes during ongoing treatment with anti-GPRC5D immunotherapies.\n                  <\/jats:p>","DOI":"10.1038\/s41375-026-02920-7","type":"journal-article","created":{"date-parts":[[2026,3,31]],"date-time":"2026-03-31T13:57:41Z","timestamp":1774965461000},"page":"1227-1239","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Loss of GPRC5D enhances the proliferative capacity and competitive fitness of myeloma upon anti-GPRC5D 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Lancet Haematol. 2024;11:e751\u2013e60.","journal-title":"Lancet Haematol"},{"key":"2920_CR26","doi-asserted-by":"crossref","unstructured":"Lim S-L, Augustson B, Mian HS, Stadtmauer EA, Iida S, Slade M, et al. A Phase I\/II study of AZD0305, a novel antibody-drug conjugate (ADC) targeting GPRC5D, in patients with relapsed\/refractory multiple myeloma (RRMM). Blood. 2024;144 Suppl 1:2000.2-2.","DOI":"10.1182\/blood-2024-207816"},{"key":"2920_CR27","doi-asserted-by":"crossref","unstructured":"Huang W, Luo J, Li Y, Fei D, Qin X, Li R Abstract 6020: Preclinical activity of LM-305 targeting G-protein-coupled receptor class 5 member D (GPRC5D) antibody drug conjugate for the treatment of multiple myeloma. Cancer Res. 2022;82 12_Supplement:6020-.","DOI":"10.1158\/1538-7445.AM2022-6020"}],"container-title":["Leukemia"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41375-026-02920-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41375-026-02920-7","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41375-026-02920-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T05:43:28Z","timestamp":1780465408000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41375-026-02920-7"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,31]]},"references-count":27,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2026,6]]}},"alternative-id":["2920"],"URL":"https:\/\/doi.org\/10.1038\/s41375-026-02920-7","relation":{},"ISSN":["0887-6924","1476-5551"],"issn-type":[{"value":"0887-6924","type":"print"},{"value":"1476-5551","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,31]]},"assertion":[{"value":"15 August 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"12 February 2026","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"10 March 2026","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"31 March 2026","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare the following competing interests: KMK reports personal fees from BMS, AbbVie, GSK, Takeda, Sanofi, and Menarini; grants and personal fees from Janssen. CH is a current employee and owner of MLL Munich Leukemia Laboratory. HE reports grants and other support from Janssen, BMS, Amgen, GSK, and Sanofi, as well as further support from Takeda and Novartis. LR reports personal fees from BMS, Janssen, Pfizer, Amgen, GSK, and Sanofi. JW reports personal fees from Janssen, Sanofi, Takeda, Pfizer, Oncopeptides, Menarini-Stemline, Skyline D,x and GSK, and research support from BMS. BK is co-founder and shareholder of MSAID. He has no operational role in the company. All other authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"All methods were performed in accordance with the relevant guidelines and regulations. All donors provided written informed consent to participate in research protocols approved by the Institutional Review Board of the University of Wuerzburg (287\/21-me).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}}]}}