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However, disease progression remains inevitable due to the emergence of drug-resistant myeloma cell populations, often culminating in extramedullary disease manifestations. In this study, we identified CD70-expressing myeloma cells as critical drivers of disease progression and propagation. CD70 expression in MM cells is an independent negative prognostic factor for overall survival. Mechanistically, CD70\/CD27 signaling activates the MAPK\/ERK and Wnt signaling pathways in MM cell lines and primary patient-derived MM samples, promoting increased cell cycling and proliferation. This proliferative advantage results in elevated CD70 expression in advanced MM stages, particularly in extramedullary myeloma. Functional inhibition of CD70\/CD27 signaling, achieved either by generating CD70-knockout primary MM cells or with blocking monoclonal antibodies, completely abrogated tumor growth in xenotransplantation models. Furthermore, the ADCC-enhanced anti-CD70 antibody, cusatuzumab, demonstrated high efficacy in treating myeloma in xenotransplantation\u00a0models. Collectively, these findings underscore the critical role of CD70\/CD27 signaling in activating MAPK\/ERK and Wnt pathways essential for MM progression. Targeting CD70 with blocking or ADCC-enhanced antibodies represents a promising therapeutic strategy, particularly for advanced MM stages characterized by high CD70 expression.<\/jats:p>","DOI":"10.1038\/s41375-026-02899-1","type":"journal-article","created":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T10:58:00Z","timestamp":1774263480000},"page":"1163-1175","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["CD70\/CD27 signaling promotes the pathogenesis of multiple myeloma and represents a promising therapeutic target"],"prefix":"10.1038","volume":"40","author":[{"given":"Stefan","family":"Forster","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chantal","family":"Reinhardt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maxime","family":"Boy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-1203-2990","authenticated-orcid":false,"given":"Adrian","family":"Wegm\u00fcller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessio","family":"Hinrichsen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1792-1768","authenticated-orcid":false,"given":"Christian M.","family":"Sch\u00fcrch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6409-0824","authenticated-orcid":false,"given":"Frido K.","family":"Br\u00fchl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5496-293X","authenticated-orcid":false,"given":"Falko","family":"Fend","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandar","family":"Tzankov","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie-No\u00eblle","family":"Kronig","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michaela","family":"R\u00f6mmele","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-5883-6120","authenticated-orcid":false,"given":"Ang\u00e9line","family":"Gl\u00fcck","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin","family":"L\u00fcscher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Myriam","family":"Legros","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ulrike","family":"Bacher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katja","family":"Seipel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6055-5257","authenticated-orcid":false,"given":"Thomas","family":"Pabst","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5632-7833","authenticated-orcid":false,"given":"Ramin","family":"Radpour","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7512-513X","authenticated-orcid":false,"given":"Carsten","family":"Riether","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1773-5436","authenticated-orcid":false,"given":"Adrian F.","family":"Ochsenbein","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,3,23]]},"reference":[{"key":"2899_CR1","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1007\/s00117-021-00926-z","volume":"62","author":"A Vogelsberg","year":"2022","unstructured":"Vogelsberg A, Sch\u00fcrch CM, Fend F. 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AFO and CR are listed on the Patents No. US20200222532A1 and GB1709677.7A.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"All methods were carried out in accordance with relevant guidelines and regulations and the Declaration of Helsinki. This study was approved by the Ethics Committee, University of T\u00fcbingen (approvals 522\/2015BO2 and 462\/2022BO2) and the local ethical committee of the Canton of Bern, Switzerland (approval 2019-01627). Written informed consent was obtained from all participants prior to inclusion in the study. Animal experiments were approved by the local animal committee of the Canton of Bern and performed according to the Swiss laws for animal protection (BE12\/21).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}}]}}