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Here, we report that monocytes actively control MM cell metabolism by transferring mitochondria to MM cells, thereby increasing their mitochondrial content. Transfer of mitochondria required the expression of CD38 on the surface of MM cells and its ligand CD31 (PECAM\u20101) on monocytes. The mitochondrial increase in MM cells induced a boost in oxidative phosphorylation (OXPHOS). This monocyte\u2010mediated metabolic adjustment promoted growth, motility, and drug\u2010resistance in both MM cell lines and primary MM cells. Notably, the CD38\u2010targeting monoclonal antibody daratumumab prevented mitochondrial transfer via blocking CD38 on MM cells. Furthermore, in the presence of daratumumab, monocytes acquired a divergent role and obtained mitochondria from MM cells through the process of trogocytosis. Daratumumab\u2010mediated disruption of mitochondrial transfer reduced the mitochondrial content in MM cells, prevented the boost in OXPHOS, significantly impaired MM cell growth and migration, and mitigated drug\u2010resistance. In conclusion, we reveal a crucial metabolic interplay between monocytes and MM cells within the BM microenvironment that promotes tumor growth and induces therapy resistance, providing the rationale for treatment strategies that combine targeting tumor metabolism with existing anti\u2010MM agents.<\/jats:p>","DOI":"10.1002\/hem3.70358","type":"journal-article","created":{"date-parts":[[2026,4,16]],"date-time":"2026-04-16T11:06:11Z","timestamp":1776337571000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Monocyte\u2010mediated metabolic rewiring via CD31\u2010CD38 interactions promotes growth and drug\u2010resistance in multiple myeloma"],"prefix":"10.1002","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1038-5090","authenticated-orcid":false,"given":"Ramin","family":"Raoof","sequence":"first","affiliation":[{"name":"Cancer Center Amsterdam, Amsterdam Institute for Infection and Immunology Cancer Immunology Amsterdam The Netherlands"},{"name":"Department of Hematology Amsterdam UMC location Vrije Universiteit Amsterdam Amsterdam The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7348-370X","authenticated-orcid":false,"given":"Giada","family":"Dal Collo","sequence":"additional","affiliation":[{"name":"Cancer Center Amsterdam, Amsterdam Institute for Infection and Immunology Cancer Immunology Amsterdam The Netherlands"},{"name":"Department of Hematology Amsterdam UMC location Vrije Universiteit Amsterdam Amsterdam The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Helga","family":"Simon\u2010Molas","sequence":"additional","affiliation":[{"name":"Cancer Center Amsterdam, Amsterdam Institute for Infection and Immunology Cancer Immunology Amsterdam The Netherlands"},{"name":"Department of Hematology Amsterdam UMC location Vrije Universiteit Amsterdam Amsterdam The Netherlands"},{"name":"Department of Experimental Immunology Amsterdam UMC location University of Amsterdam Meibergdreef 9 Amsterdam The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Panagiota","family":"Tzortzi","sequence":"additional","affiliation":[{"name":"Cancer Center Amsterdam, Amsterdam Institute for Infection and Immunology Cancer Immunology Amsterdam The Netherlands"},{"name":"Department of Hematology Amsterdam UMC location Vrije Universiteit Amsterdam Amsterdam The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Konxhe","family":"Kulaj","sequence":"additional","affiliation":[{"name":"Department of Pathology, Cancer Center Amsterdam, Amsterdam UMC Vrije Universiteit Amsterdam Amsterdam The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elif N.","family":"Demirez","sequence":"additional","affiliation":[{"name":"Cancer Center Amsterdam, Amsterdam Institute for Infection and Immunology Cancer Immunology Amsterdam The Netherlands"},{"name":"Department of Hematology Amsterdam UMC location Vrije Universiteit Amsterdam Amsterdam The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Crescenzo","family":"Massaro","sequence":"additional","affiliation":[{"name":"Department of Pathology, Cancer Center Amsterdam, Amsterdam UMC Vrije Universiteit Amsterdam Amsterdam The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ren\u00e9e","family":"Poels","sequence":"additional","affiliation":[{"name":"Cancer Center Amsterdam, Amsterdam Institute for Infection and Immunology Cancer Immunology Amsterdam The Netherlands"},{"name":"Department of Hematology Amsterdam UMC location Vrije Universiteit Amsterdam Amsterdam The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-0191-4343","authenticated-orcid":false,"given":"Charlotte L. 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