{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T09:57:52Z","timestamp":1790848672376,"version":"4.1.0"},"reference-count":90,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T00:00:00Z","timestamp":1790812800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"<jats:p>Multiple myeloma (MM) outcomes have improved with proteasome inhibitors, immunomodulatory drugs, anti-CD38 antibodies, and transplantation, yet a subset of patients with high-risk MM (HRMM) continues to relapse early and die prematurely. Immune effector therapies (IET)\u2014B-cell maturation antigen (BCMA)- and G protein\u2013coupled receptor class C group 5 member D (GPRC5D)-directed chimeric antigen receptor T cells (CAR-T) and bispecific antibodies\u2014have transformed the treatment of relapsed\/refractory MM. However, their benefit in HRMM remains incompletely defined. This review describes how HRMM is defined in the IET-era distinguishing baseline biological\/genomic risk, clinical high-risk phenotypes, and IET-specific adverse predictors. The International Myeloma Society\/International Myeloma Working Group consensus integrates adverse cytogenetics and beta-2 microglobulin, whereas functional high-risk disease, extramedullary disease (EMD), plasma cell leukemia (PCL), high tumor burden, inflammation, and prior BCMA exposure identify aggressive disease in relapsed patients. Across pivotal trials, CAR-T therapy, particularly ciltacabtagene autoleucel, and selected bispecific antibodies retain activity in high-risk cytogenetic subgroups, whereas EMD and PCL remain associated with inferior responses and short progression-free survival. Emerging dual-antigen and trispecific engagers, along with novel targets such as FcRH5 and CD70, aim to overcome antigen escape. Prospective, biology-informed studies are needed to achieve durable disease control in HRMM.<\/jats:p>","DOI":"10.3389\/fonc.2026.1956522","type":"journal-article","created":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T09:38:14Z","timestamp":1790847494000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Reshaping the definition of high-risk disease in the immune effector therapy era in multiple myeloma"],"prefix":"10.3389","volume":"16","author":[{"given":"Yoshito","family":"Nishimura","sequence":"first","affiliation":[{"name":"Division of Hematology, Department of Medicine, Mayo Clinic","place":["Rochester, MN, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gunjan","family":"Gaur","sequence":"additional","affiliation":[{"name":"Division of Hematology, Department of Medicine, Mayo Clinic","place":["Rochester, MN, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Cottini","sequence":"additional","affiliation":[{"name":"Division of Hematology, Department of Internal Medicine, The Ohio State University Wexner Medical Center, James Cancer Hospital and Solove Research Institute","place":["Columbus, OH, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saurabh","family":"Zanwar","sequence":"additional","affiliation":[{"name":"Division of Hematology, Department of Medicine, Mayo Clinic","place":["Rochester, MN, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,10,1]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1002\/ajh.70070","article-title":"European myeloma network consensus statement on functional high-risk multiple myeloma","volume":"100","author":"Lim","year":"2025","journal-title":"Am J 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