{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,14]],"date-time":"2026-11-14T05:41:35Z","timestamp":1794634895967,"version":"4.9.1"},"reference-count":14,"publisher":"American Society of Hematology","issue":"2","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2021,1,14]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Emergence of drug resistance to all available therapies is the major challenge to improving survival in myeloma. Cereblon (CRBN) is the essential binding protein of the widely used immunomodulatory drugs (IMiDs) and novel CRBN E3 ligase modulator drugs (CELMoDs) in myeloma, as well as certain proteolysis targeting chimeras (PROTACs), in development for a range of diseases. Using whole-genome sequencing (WGS) data from 455 patients and RNA sequencing (RNASeq) data from 655 patients, including newly diagnosed (WGS, n = 198; RNASeq, n = 437), lenalidomide (LEN)-refractory (WGS, n = 203; RNASeq, n = 176), and pomalidomide (POM)-refractory cohorts (WGS, n = 54; RNASeq, n = 42), we found incremental increases in the frequency of 3 CRBN aberrations, namely point mutations, copy losses\/structural variations, and a specific variant transcript (exon 10 spliced), with progressive IMiD exposure, until almost one-third of patients had CBRN alterations by the time they were POM refractory. We found all 3 CRBN aberrations were associated with inferior outcomes to POM in those already refractory to LEN, including those with gene copy losses and structural variations, a finding not previously described. This represents the first comprehensive analysis and largest data set of CBRN alterations in myeloma patients as they progress through therapy. It will help inform patient selection for sequential therapies with CRBN-targeting drugs.<\/jats:p>","DOI":"10.1182\/blood.2020007081","type":"journal-article","created":{"date-parts":[[2020,8,4]],"date-time":"2020-08-04T20:03:32Z","timestamp":1596571412000},"page":"232-237","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":175,"title":["Multiple cereblon genetic changes are associated with acquired resistance to lenalidomide or pomalidomide in multiple myeloma"],"prefix":"10.1182","volume":"137","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1549-7043","authenticated-orcid":false,"given":"Sarah","family":"Gooding","sequence":"first","affiliation":[{"name":"MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom;"},{"name":"Department of Haematology, Oxford University Hospitals NHS Trust, Oxford, United Kingdom;"},{"name":"NIHR Oxford Biomedical Research Centre,"},{"name":"Oxford Centre for Translational Myeloma Research, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naser","family":"Ansari-Pour","sequence":"additional","affiliation":[{"name":"NIHR Oxford Biomedical Research Centre,"},{"name":"Big Data Institute, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fadi","family":"Towfic","sequence":"additional","affiliation":[{"name":"Bristol Myers Squibb, San Diego, CA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda","family":"Ortiz Est\u00e9vez","sequence":"additional","affiliation":[{"name":"Celgene Institute for Translational Research Europe, Sevilla, Spain;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6407-7344","authenticated-orcid":false,"given":"Philip P.","family":"Chamberlain","sequence":"additional","affiliation":[{"name":"Bristol Myers Squibb, San Diego, CA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kao-Tai","family":"Tsai","sequence":"additional","affiliation":[{"name":"Bristol-Myers Squibb, Berkeley Heights, NJ;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erin","family":"Flynt","sequence":"additional","affiliation":[{"name":"Bristol-Myers Squibb, Summit, NJ;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marissa","family":"Hirst","sequence":"additional","affiliation":[{"name":"Rancho Biosciences, San Diego, CA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dan","family":"Rozelle","sequence":"additional","affiliation":[{"name":"Rancho Biosciences, San Diego, CA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paula","family":"Dhiman","sequence":"additional","affiliation":[{"name":"NIHR Oxford Biomedical Research Centre,"},{"name":"Centre for Statistics in Medicine, Nuffield Department of Orthopaedics, Rheumatology, and Musculoskeletal Sciences, Botnar Research Centre, University of Oxford, Oxford, United Kingdom; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paola","family":"Neri","sequence":"additional","affiliation":[{"name":"Tom Baker Cancer Center, University of Calgary, Calgary, AB, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3385-3707","authenticated-orcid":false,"given":"Karthik","family":"Ramasamy","sequence":"additional","affiliation":[{"name":"MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom;"},{"name":"Department of Haematology, Oxford University Hospitals NHS Trust, Oxford, United Kingdom;"},{"name":"NIHR Oxford Biomedical Research Centre,"},{"name":"Oxford Centre for Translational Myeloma Research, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nizar","family":"Bahlis","sequence":"additional","affiliation":[{"name":"Tom Baker Cancer Center, University of Calgary, Calgary, AB, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3931-0914","authenticated-orcid":false,"given":"Paresh","family":"Vyas","sequence":"additional","affiliation":[{"name":"MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom;"},{"name":"Department of Haematology, Oxford University Hospitals NHS Trust, Oxford, United Kingdom;"},{"name":"NIHR Oxford Biomedical Research Centre,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0415-1706","authenticated-orcid":false,"given":"Anjan","family":"Thakurta","sequence":"additional","affiliation":[{"name":"Bristol-Myers Squibb, Summit, NJ;"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"234","reference":[{"issue":"5971","key":"2021011416210667700_B1","doi-asserted-by":"crossref","first-page":"1345","DOI":"10.1126\/science.1177319","article-title":"Identification of a primary target of thalidomide teratogenicity","volume":"327","author":"Ito","year":"2010","journal-title":"Science"},{"issue":"9","key":"2021011416210667700_B2","doi-asserted-by":"crossref","first-page":"803","DOI":"10.1038\/nsmb.2874","article-title":"Structure of the human cereblon-DDB1-lenalidomide complex reveals basis for responsiveness to thalidomide analogs","volume":"21","author":"Chamberlain","year":"2014","journal-title":"Nat Struct Mol Biol"},{"issue":"5","key":"2021011416210667700_B3","doi-asserted-by":"crossref","first-page":"1129","DOI":"10.1038\/leu.2013.315","article-title":"Absence of mutations in cereblon (CRBN) and DNA damage-binding protein 1 (DDB1) genes and significance for IMiD therapy","volume":"28","author":"Thakurta","year":"2014","journal-title":"Leukemia"},{"issue":"suppl 1","key":"2021011416210667700_B4","article-title":"A molecular analysis of cereblon-related immunomodulatory drug resistance in CoMMpass multiple myeloma patients [abstract]","volume":"130","author":"Skerget","year":"2017","journal-title":"Blood"},{"issue":"9","key":"2021011416210667700_B5","doi-asserted-by":"crossref","first-page":"1226","DOI":"10.1182\/blood-2016-02-698092","article-title":"Targeted sequencing of refractory myeloma reveals a high incidence of mutations in CRBN and Ras pathway genes","volume":"128","author":"Kort\u00fcm","year":"2016","journal-title":"Blood"},{"issue":"5","key":"2021011416210667700_B6","doi-asserted-by":"crossref","first-page":"748","DOI":"10.1111\/bjh.12291","article-title":"Extramedullary myeloma whole genome sequencing reveals novel mutations in Cereblon, proteasome subunit G2 and the glucocorticoid receptor in multi drug resistant disease","volume":"161","author":"Egan","year":"2013","journal-title":"Br J Haematol"},{"issue":"8","key":"2021011416210667700_B7","doi-asserted-by":"crossref","first-page":"e368","DOI":"10.3324\/haematol.2017.186601","article-title":"Cereblon loss and up-regulation of c-Myc are associated with lenalidomide resistance in multiple myeloma patients","volume":"103","author":"Franssen","year":"2018","journal-title":"Haematologica"},{"issue":"22","key":"2021011416210667700_B8","doi-asserted-by":"crossref","DOI":"10.1182\/blood.V128.22.120.120","article-title":"Cereblon splicing of exon 10 mediates IMiDs resistance in multiple myeloma: clinical validation in the CoMMpass trial [abstract]","volume":"128","author":"Neri","year":"2016","journal-title":"Blood"},{"issue":"4","key":"2021011416210667700_B9","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1182\/blood-2016-02-700872","article-title":"Safety and efficacy of pomalidomide plus low-dose dexamethasone in STRATUS (MM-010): a phase 3b study in refractory multiple myeloma","volume":"128","author":"Dimopoulos","year":"2016","journal-title":"Blood"},{"issue":"suppl","key":"2021011416210667700_B10","article-title":"First clinical (phase 1b\/2a) study of iberdomide (CC-220; 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