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Although therapeutic interventions have substantially improved the outcome for standard- and intermediate-risk multiple myeloma, the survival for HRMM has not improved to the same extent. To address this poor outcome requires a strategy to define and identify HRMM in a standardized fashion, determine its biology, and identify novel strategies for treatment. A recognized driver of HR biology is loss of 17p and mutation of P53, but beyond this we are making significant inroads into breaking down the remaining monolith of HRMM into its component biologic subgroups. In this article, we provide a framework within which to understand the biology of HRMM and to clinically define it so that patients can be entered into clinical trial programs designed to systematically improve outcomes. We explore the evolving definitions of HRMM and investigate the role of personalized therapeutic strategies using conventional targeted agents and novel immunotherapies to address whether they can overcome adverse high-risk biology.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1200\/edbk-26-517494","type":"journal-article","created":{"date-parts":[[2026,5,28]],"date-time":"2026-05-28T19:59:13Z","timestamp":1779998353000},"source":"Crossref","is-referenced-by-count":0,"title":["High-Risk Multiple Myeloma: Redefining Risk and Rethinking Therapy"],"prefix":"10.1200","volume":"46","author":[{"given":"Gareth J.","family":"Morgan","sequence":"first","affiliation":[{"name":"Perlmutter Cancer Center, NY Langone Health, New York, NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dennis D.","family":"Lee","sequence":"additional","affiliation":[{"name":"New York University Langone Health, New York, NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nisha S.","family":"Joseph","sequence":"additional","affiliation":[{"name":"Cancer Center Cl\u00ednica Universidad de Navarra, Cima, IDISNA, CIBERONC, Universidad de Navarra, Pamplona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sagar","family":"Lonial","sequence":"additional","affiliation":[{"name":"Cancer Center Cl\u00ednica Universidad de Navarra, Cima, IDISNA, CIBERONC, Universidad de Navarra, Pamplona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paula","family":"Rodriguez-Otero","sequence":"additional","affiliation":[{"name":"Cancer Center Cl\u00ednica Universidad de Navarra, Cima, IDISNA, CIBERONC, Universidad de Navarra, Pamplona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jes\u00fas F.","family":"San-Miguel","sequence":"additional","affiliation":[{"name":"Cancer Center Cl\u00ednica Universidad de Navarra, Cima, IDISNA, CIBERONC, Universidad de Navarra, Pamplona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"233","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1200\/JCO-24-01893"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrc3257"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrc.2017.63"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-11680-1"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.26269"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-017-00296-y"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2017-06-788786"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2018-03-840132"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41375-018-0196-8"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1038\/nri3795"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2013.12.015"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-025-02196-0"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms7997"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.23.01277"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2005-11-013458"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2006-07-038430"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.15718"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1111\/bjh.17670"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13046-021-02185-1"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-48327-9"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1158\/2643-3230.BCD-20-0132"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcdb.2021.04.014"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-017-01793-w"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41408-019-0226-4"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1080\/10245330512331390140"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2021014391"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-22-3209"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2015.02.014"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.21.02614"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","unstructured":"Wang Y Liu S Ghamlouch H et al: Study of NSD2 using a dTAG system reveals their molecular mechanism and oncogenic implications in t(4;14) multiple myeloma. 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