{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T16:38:02Z","timestamp":1790613482609,"version":"4.1.0"},"reference-count":44,"publisher":"American Society of Hematology","issue":"23","license":[{"start":{"date-parts":[[2024,3,1]],"date-time":"2024-03-01T00:00:00Z","timestamp":1709251200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2024,6,6]]},"abstract":"<jats:sec>\n                  <jats:title>Abstract<\/jats:title>\n                  <jats:p>It remains elusive how driver mutations, including those detected in circulating tumor DNA (ctDNA), affect prognosis in relapsed\/refractory multiple myeloma (RRMM). Here, we performed targeted-capture sequencing using bone marrow plasma cells (BMPCs) and ctDNA of 261 RRMM cases uniformly treated with ixazomib, lenalidomide, and dexamethasone in a multicenter, prospective, observational study. We detected 24 and 47 recurrently mutated genes in BMPC and ctDNA, respectively. In addition to clonal hematopoiesis\u2013associated mutations, varying proportion of driver mutations, particularly TP53 mutations (59.2% of mutated cases), were present in only ctDNA, suggesting their subclonal origin. In univariable analyses, ctDNA mutations of KRAS, TP53, DIS3, BRAF, NRAS, and ATM were associated with worse progression-free survival (PFS). BMPC mutations of TP53 and KRAS were associated with inferior PFS, whereas KRAS mutations were prognostically relevant only when detected in both BMPC and ctDNA. A total number of ctDNA mutations in the 6 relevant genes was a strong prognostic predictor (2-year PFS rates: 57.3%, 22.7%, and 0% for 0, 1, and \u22652 mutations, respectively) and independent of clinical factors and plasma DNA concentration. Using the number of ctDNA mutations, plasma DNA concentration, and clinical factors, we developed a prognostic index, classifying patients into 3 categories with 2-year PFS rates of 57.9%, 28.6%, and 0%. Serial analysis of ctDNA mutations in 94 cases revealed that TP53 and KRAS mutations frequently emerge after therapy. Thus, we clarify the genetic characteristics and clonal architecture of ctDNA mutations and demonstrate their superiority over BMPC mutations for prognostic prediction in RRMM. This study is a part of the C16042 study, which is registered at www.clinicaltrials.gov as #NCT03433001.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1182\/blood.2023022540","type":"journal-article","created":{"date-parts":[[2024,3,1]],"date-time":"2024-03-01T19:07:35Z","timestamp":1709320055000},"page":"2401-2413","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":16,"title":["ctDNA improves prognostic prediction for patients with relapsed\/refractory MM receiving ixazomib, lenalidomide, and dexamethasone"],"prefix":"10.1182","volume":"143","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1158-5131","authenticated-orcid":false,"given":"Yasunori","family":"Kogure","sequence":"first","affiliation":[{"name":"1Division of Molecular Oncology, National Cancer Center Research Institute, Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3753-9862","authenticated-orcid":false,"given":"Hiroshi","family":"Handa","sequence":"additional","affiliation":[{"name":"2Department of Hematology, Gunma University Graduate School of Medicine, Maebashi, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7259-4870","authenticated-orcid":false,"given":"Yuta","family":"Ito","sequence":"additional","affiliation":[{"name":"1Division of Molecular Oncology, National Cancer Center Research Institute, Tokyo, Japan"},{"name":"3Division of Clinical Oncology and Hematology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9617-486X","authenticated-orcid":false,"given":"Masaki","family":"Ri","sequence":"additional","affiliation":[{"name":"4Department of Hematology and Oncology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuichi","family":"Horigome","sequence":"additional","affiliation":[{"name":"5Department of Hematology, Kitasato University School of Medicine, Sagamihara, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3471-0890","authenticated-orcid":false,"given":"Masaki","family":"Iino","sequence":"additional","affiliation":[{"name":"6Department of Hematology, Yamanashi Prefectural Central Hospital, Kofu, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1299-616X","authenticated-orcid":false,"given":"Yoriko","family":"Harazaki","sequence":"additional","affiliation":[{"name":"7Department of Hematology, Miyagi Cancer Center, Natori, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9914-7517","authenticated-orcid":false,"given":"Takahiro","family":"Kobayashi","sequence":"additional","affiliation":[{"name":"8Department of Hematology, Nephrology and Rheumatology, Akita University Graduate School of Medicine, Akita, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9317-7133","authenticated-orcid":false,"given":"Masahiro","family":"Abe","sequence":"additional","affiliation":[{"name":"9Department of Hematology, Kawashima Hospital, Tokushima, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3219-3292","authenticated-orcid":false,"given":"Tadao","family":"Ishida","sequence":"additional","affiliation":[{"name":"10Department of Hematology, Japanese Red Cross Medical Center, Tokyo, 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Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4014-2815","authenticated-orcid":false,"given":"Hirohiko","family":"Shibayama","sequence":"additional","affiliation":[{"name":"14Department of Hematology, National Hospital Organization Osaka National Hospital, Osaka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazutaka","family":"Sunami","sequence":"additional","affiliation":[{"name":"15Department of Hematology, National Hospital Organization Okayama Medical Center, Okayama, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9515-0017","authenticated-orcid":false,"given":"Hiroyuki","family":"Takamatsu","sequence":"additional","affiliation":[{"name":"16Department of Hematology, Kanazawa University Hospital, Kanazawa, 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