Authors
Ryosuke Shirasaki
Published in
[Rinsho ketsueki] The Japanese journal of clinical hematology. Volume 67. Issue 9. Pages 1233-1241.
Abstract
Multiple myeloma (MM) is a plasma cell malignancy whose genomic architecture is largely established during a prolonged premalignant phase (MGUS/SMM) preceding diagnosis by 20 to 40 years, providing a biological rationale for early intervention. Recurrent genomic aberrations-including IGH translocations (t(11;14), t(4;14), t(14;16), t(14;20)), del(17p)/TP53 abnormalities, 1q gain/amplification, del(1p32), and MYC rearrangements-directly determine therapeutic responsiveness and resistance to specific drug classes. Specifically, t(11;14) confers BCL2 dependence amenable to venetoclax, t(4;14)-driven NSD2 overexpression imposes proteostatic stress that sensitizes cells to proteasome inhibition, and t(14;16)/MAF aberrations induce APOBEC mutational signatures that drive accelerated genomic evolution. In relapsed/refractory MM, resistance to anti-CD38 antibodies, IMiDs/CELMoDs, and BCMA/GPRC5D-targeted immunotherapies reflects a unifying framework of target aberrations comprising point mutations, copy loss, biallelic inactivation, and acquired DNA hypermethylation of the cognate antigen or substrate receptor. This review synthesizes contemporary myeloma genomics from a treatment-oriented perspective, incorporating the 2025 IMS-IMWG consensus definition of MM, and outlines emerging strategies to address the convergent mechanisms of high-risk genomic and epigenomic resistance.
PMID:
42951639
Bibliographic data and abstract were imported from PubMed on 29 Oct 2026.
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