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Lookup NU author(s): Professor Graham Jackson
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND).
© 2025 American Society of Hematology. Published by Elsevier Inc. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.Functional high-risk (FHR) multiple myeloma (MM) is defined as an unexpected, early relapse (ER) of disease in the absence of baseline molecular or clinical risk factors (RF), making FHR MM inherently dependent on which RFs were assessed at diagnosis, and what treatment patients received. To establish the true incidence of FHR, we analyzed uniformly treated, transplant-eligible patients from the Myeloma-XI (MyXI) trial that had been profiled for the International Myeloma Society and Working Group (IMS/IMWG) defined high-risk cytogenetic aberrations (HRCA), and the SKY92 gene expression HR signature (GEP-HR). A total of 135 MyXI patients were studied, with a median follow-up of 88 months; 25 (18.5%) experienced ER, defined as relapse <18 months from maintenance randomization post–autologous stem-cell transplantation. Hereof, 15 (60%) were IMS/IMWG-HR at diagnosis, of whom 8 were also GEP-HR. Another 6 patients were GEP-HR only and would have been missed by IMS/IMWG-HR. Among 4 patients with IMS/IMWG– and GEP–standard risk, 2 had isolated HR markers at diagnosis, leaving only 2 patients (8% of ER; 1.5% of all) truly meeting all FHR-criteria. Combined IMS/IMWG-HR and GEP-HR profiling identified 84% of ER, and differentiated long-term outcome across all 135 patients: co-occurring IMS/IMWG and GEP-HR was associated with very short overall survival compared to the absence of both (HR = 13.1; 95% CI, 6.5-26.1, P < .0001), followed by GEP-HR only (HR = 5.1; 95% CI, 2.4-11.1, P < .0001) and IMS/IMWG-HR only (HR = 3.2; 95% CI, 1.6-6.2, P = .0007). Our results support more comprehensive baseline diagnostic profiling to identify those at risk of ER upfront. The trials were registered at the ISRCTN Registry as ISRCTN49407852 and atclinicaltrials.govas #NCT01554852.
Author(s): Beer SA, Cairns DA, Pawlyn C, Holroyd A, Ferris E, Cook G, Drayson M, Boyd K, Proszek P, Davies FE, de Tute R, Jenner M, Morgan GJ, Owen R, Hubank M, Houlston R, Jackson G, Kaiser MF
Publication type: Article
Publication status: Published
Journal: Blood
Year: 2025
Volume: 146
Issue: 22
Pages: 2670-2680
Print publication date: 26/11/2025
Online publication date: 22/08/2025
Acceptance date: 21/07/2025
Date deposited: 27/11/2025
ISSN (print): 0006-4971
ISSN (electronic): 1528-0020
Publisher: Elsevier B.V.
URL: https://doi.org/10.1182/blood.2025029987
DOI: 10.1182/blood.2025029987
Data Access Statement: Data are available from the corresponding author, Martin F. Kaiser (martin.kaiser@icr.ac.uk), on request. Only methodologically sound proposals whose proposed use of the data has been approved by the independent trial steering committee will be considered. Following approval, data requestors will need to sign a data access agreement
PubMed id: 40834881
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