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These PCDs include subtypes with distinct clinical features. Multiple myeloma (MM) and monoclonal gammopathy of undetermined significance (MGUS) are more common and relatively well-studied. In contrast, primary light-chain amyloidosis (AL) and POEMS syndrome (POEMS) are rare and remain less understood. To investigate the role of clonal hematopoietic (CH) mutations and potential interconnections in these diseases, we sequenced CH mutations in lymphoid and myeloid lineages, as well as myeloma driver gene mutations, in BMPCs from affected patients. Recurrent lymphoid CH mutations (in FAT1, KMT2D, MGA, and SYNE1) and myeloma driver gene mutations (in ZFHX3 and DIS3) were found in the dominant clonal and subclonal plasma cell populations. These moderately aging-associated lymphoid CH mutations had a higher burden in MM than in AL or POEMS. Binary matrix factorization of these mutations revealed the subgroups associated with progression-free survival (PFS) (observed in MM, AL, and POEMS), age at diagnosis (in AL and POEMS), serum differential free light chain (dFLC) levels, plasma cell burden (in AL), and serum vascular endothelial growth factor (VEGF) levels (in POEMS). Moreover, the poor PFS associated with MGA or SYNE1 mutations was confirmed across MM, AL, and POEMS. CH mutations partially explained the shared pathogenesis of MM, AL, POEMS, and MGUS, and helped identify patient subgroups with specific clinical features.<\/jats:p>","DOI":"10.1093\/gpbjnl\/qzaf027","type":"journal-article","created":{"date-parts":[[2025,3,30]],"date-time":"2025-03-30T23:51:41Z","timestamp":1743378701000},"source":"Crossref","is-referenced-by-count":3,"title":["Clonal Hematopoietic Mutations in Plasma Cell Disorders: Clinical Subgroups and Shared Pathogenesis"],"prefix":"10.1093","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9424-6540","authenticated-orcid":false,"given":"Xuezhu","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Hematology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College , Beijing 100730,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6268-8790","authenticated-orcid":false,"given":"Liping","family":"Zuo","sequence":"additional","affiliation":[{"name":"Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology , Wuhan 430022,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1133-7501","authenticated-orcid":false,"given":"Yanying","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Hematology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College , Beijing 100730,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-9123-393X","authenticated-orcid":false,"given":"Xinyi","family":"Xiong","sequence":"additional","affiliation":[{"name":"Department of Hematology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College , Beijing 100730,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-3762-492X","authenticated-orcid":false,"given":"Jian","family":"Xu","sequence":"additional","affiliation":[{"name":"Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology , Wuhan 430022,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5696-3357","authenticated-orcid":false,"given":"Bing","family":"Qiao","sequence":"additional","affiliation":[{"name":"Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology , Wuhan 430022,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3486-7705","authenticated-orcid":false,"given":"Jia","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Hematology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College , Beijing 100730,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2153-9470","authenticated-orcid":false,"given":"Hao","family":"Cai","sequence":"additional","affiliation":[{"name":"Department of Hematology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College , Beijing 100730,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7093-5050","authenticated-orcid":false,"given":"Qi","family":"Yan","sequence":"additional","affiliation":[{"name":"School of Life Sciences, Tsinghua University , Beijing 100084,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-1426-1718","authenticated-orcid":false,"given":"Hongxiao","family":"Han","sequence":"additional","affiliation":[{"name":"Department of Hematology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College , Beijing 100730,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-3125-5794","authenticated-orcid":false,"given":"Xin-xin","family":"Cao","sequence":"additional","affiliation":[{"name":"Department of Hematology, Peking Union Medical College Hospital, Chinese 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