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To investigate acquisition of CNAs and their prognostic relevance in context of first-line therapy, we profiled tumor diagnosis\u2013relapse pairs from 178 NCRI Myeloma XI (ISRCTN49407852) trial patients using digital multiplex ligation-dependent probe amplification. CNA profiles acquired at relapse differed substantially between MM subtypes: hyperdiploid (HRD) tumors evolved predominantly in branching pattern vs. linear pattern in t(4;14) vs. stable pattern in t(11;14). CNA acquisition also differed between subtypes based on <jats:italic>CCND<\/jats:italic> expression, with a marked enrichment of acquired del(17p) in <jats:italic>CCND2<\/jats:italic> over <jats:italic>CCND1<\/jats:italic> tumors. Acquired CNAs were not influenced by high-dose melphalan or lenalidomide maintenance randomization. A branching evolution pattern was significantly associated with inferior overall survival (OS; hazard ratio (HR) 2.61, <jats:italic>P<\/jats:italic>\u2009=\u20090.0048). As an individual lesion, acquisition of gain(1q) at relapse was associated with shorter OS, independent of other risk markers or time of relapse (HR\u2009=\u20092.00; <jats:italic>P<\/jats:italic>\u2009=\u20090.021). There is an increasing need for rational therapy sequencing in MM. Our data supports the value of repeat molecular profiling to characterize disease evolution and inform management of MM relapse.<\/jats:p>","DOI":"10.1038\/s41375-020-01096-y","type":"journal-article","created":{"date-parts":[[2020,12,1]],"date-time":"2020-12-01T18:34:36Z","timestamp":1606847676000},"page":"2043-2053","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":40,"title":["Copy number evolution and its relationship with patient outcome\u2014an analysis of 178 matched presentation-relapse tumor pairs from the Myeloma XI trial"],"prefix":"10.1038","volume":"35","author":[{"given":"James","family":"Croft","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sidra","family":"Ellis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy L.","family":"Sherborne","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kim","family":"Sharp","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy","family":"Price","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew W.","family":"Jenner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1528-7564","authenticated-orcid":false,"given":"Mark T.","family":"Drayson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roger G.","family":"Owen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sally","family":"Chown","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jindriska","family":"Lindsay","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4708-8092","authenticated-orcid":false,"given":"Kamaraj","family":"Karunanithi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hannah","family":"Hunter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2641-8416","authenticated-orcid":false,"given":"Walter M.","family":"Gregory","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Faith E.","family":"Davies","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gareth J.","family":"Morgan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1717-0412","authenticated-orcid":false,"given":"Gordon","family":"Cook","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lilit","family":"Atanesyan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suvi","family":"Savola","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2338-0179","authenticated-orcid":false,"given":"David A.","family":"Cairns","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Graham","family":"Jackson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5268-0242","authenticated-orcid":false,"given":"Richard S.","family":"Houlston","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3677-4804","authenticated-orcid":false,"given":"Martin F.","family":"Kaiser","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,12,1]]},"reference":[{"key":"1096_CR1","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1001\/jamaoncol.2019.4659","volume":"6","author":"F Maura","year":"2020","unstructured":"Maura F, Bolli N, Rustad EH, Hultcrantz M, Munshi N, Landgren O. 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