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Although daratumumab and isatuximab target the same antigen, accumulating evidence indicates that they differ in epitope recognition, biological activity, and immunomodulatory properties, suggesting these agents may not be therapeutically interchangeable. This review summarizes the molecular and immunological mechanisms underlying their distinct antitumor effects and their implications for treatment selection. Isatuximab binds near the catalytic site of CD38, resulting in potent enzymatic inhibition, enhanced antibody internalization, FOXM1 suppression, and reactive oxygen species-mediated cytotoxicity, which may preferentially target MM cells harboring 1q21 amplification. In contrast, daratumumab exerts prominent Fc-dependent immune effects, including trogocytosis-mediated downregulation of CD38 and VLA-4, suppression of cell adhesion-mediated drug resistance, and modulation of the immune microenvironment, potentially enhancing subsequent T-cell-redirecting therapies. We further discuss the relevance of these mechanistic differences to measurable residual disease, extramedullary disease, and sequencing with BCMA- and GPRC5D-directed immunotherapies. Finally, we propose a biology-guided treatment-selection model integrating genomic alterations, tumor biology, and immune remodeling to support precision medicine for patients with MM.<\/jats:p>","DOI":"10.3390\/cells15151331","type":"journal-article","created":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T01:26:23Z","timestamp":1785115583000},"page":"1331","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Mechanistic and Clinical Differences Between Daratumumab and Isatuximab in Multiple Myeloma: Emerging Roles of 1q Gain and Immune Remodeling"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-8791-3263","authenticated-orcid":false,"given":"Jiro","family":"Kikuchi","sequence":"first","affiliation":[{"name":"Division of Emerging Medicine for Integrated Therapeutics (EMIT), Center for Molecular Medicine, Jichi Medical University, Shimotsuke 329-0498, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0905-6855","authenticated-orcid":false,"given":"Hiroshi","family":"Yasui","sequence":"additional","affiliation":[{"name":"Department of Hematology and Oncology, St. Marianna University School of Medicine, Kawasaki 216-8511, Japan"},{"name":"The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Yasui, H., Idogawa, M., Ishida, T., and Imai, K. 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