Faculty, Staff and Student Publications

Publication Date

1-20-2026

Journal

Journal of Clinical Oncology

DOI

10.1200/JCO-25-01733

PMID

41061199

PMCID

PMC12614327

PubMedCentral® Posted Date

10-8-2025

PubMedCentral® Full Text Version

Post-print

Abstract

Multiple myeloma (MM) is consistently preceded by monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM). While these precursor conditions are asymptomatic, they are not entirely benign and carry a lifelong risk of progression to MM. Unlike other cancers defined by pathology, malignant transformation from MGUS or SMM to MM has so far relied on demonstration of clinical end-organ damage as morphology and cytogenetics cannot reliably distinguish them. In this study, using genomic data from 374 patients with MGUS or SMM (277 training, 97 validation), to our knowledge, we demonstrate for the first time the ability to identify malignant transformation in MGUS and SMM. We introduce the concept of genomic MM and genomic MGUS to differentiate the subsets of MGUS and SMM that are biologically malignant with genomic features indistinguishable from MM from the subset that is premalignant and unlikely to progress to malignancy. Importantly, we find that most SMM has biological features of malignant transformation indistinguishable from MM. As expected, this subset that we consider having genomic MM is associated with a high risk of progression to MM although some patients remained progression-free beyond 5 years. Conversely, 60% of MGUS and 10% of SMM have no evidence of malignant transformation (genomic MGUS), with no progression during follow-up. Integration of genomic features with the 2/20/20 International Myeloma Working Group model significantly improved the prediction of progression among genomic MM. These findings support the use of genomic criteria to refine the classification and the risk stratification in myeloma precursor conditions.

Keywords

Humans, Monoclonal Gammopathy of Undetermined Significance, Cell Transformation, Neoplastic, Genomics, Multiple Myeloma, Male, Female, Middle Aged, Aged, Smoldering Multiple Myeloma, Disease Progression, Precancerous Conditions

Published Open-Access

yes

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