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We aimed to explore the mechanism of daratumumab resistance in 1q+ MM. Our findings revealed significantly lower CD38 expression in patients with 1q+ MM than in those with 1q wild type (WT) MM. Next, we focused on the interleukin\u20106 receptor (IL6R) located in the 1q21 region because a previous report shows that interleukin\u20106 (IL\u20106) reduces CD38 expression via the IL\u20106\/Janus kinase (JAK)\/signal transducer and activator of transcription (STAT) pathway activation in MM. Indeed, IL6R expression was significantly higher in 1q+ MM than in 1q WT MM. We verified that the 1q+ human myeloma cell lines (HMCLs) expressed higher IL6R levels than the 1q WT HMCLs. IL\u20106 treatment induced CD38 downregulation in both the 1q+ HMCLs and primary bone marrow (BM) samples but not in their 1q WT HMCLs and BM samples. IL\u20106 also resulted in the upregulation of phosphorylated STAT3 in 1q+ HMCLs but not in the 1q WT HMCLs. Furthermore, inhibition of the IL\u20106\/JAK\/STAT pathway by treatment with ruxolitinib or tocilizumab restored CD38 expression in the 1q+ HMCLs and BM samples. These findings elucidate the mechanisms underlying daratumumab resistance in 1q+ MM and provide insights for future therapeutic strategies.<\/jats:p>","DOI":"10.1111\/bjh.20106","type":"journal-article","created":{"date-parts":[[2025,5,27]],"date-time":"2025-05-27T09:24:50Z","timestamp":1748337890000},"page":"1615-1626","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Multiple myeloma with 1q gain\/amplification exhibits reduced <scp>CD38<\/scp> expression via interleukin\u20106 receptor overexpression"],"prefix":"10.1111","volume":"206","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2738-9226","authenticated-orcid":false,"given":"Wataru","family":"Kuroki","sequence":"first","affiliation":[{"name":"Department of Hematology, Nephrology and Rheumatology Akita University Graduate School of Medicine  Akita 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