Genomics Define Malignant Transformation in Myeloma Precursor Conditions

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.

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Publication Details

Journal
Journal of Clinical Oncology
Published
2025-10-08
DOI
https://doi.org/10.1200/jco-25-01733
Citations
3
Primary Topic
Multiple Myeloma Research and Treatments
Type
article
Field-Weighted Citation Impact
5.31
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article

Genomics Define Malignant Transformation in Myeloma Precursor Conditions

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Journal of Clinical Oncology
Multiple Myeloma Research and Treatments
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article

Genomics Define Malignant Transformation in Myeloma Precursor Conditions

Benjamin T. Diamond, Rafaël Fonseca, Alessio Marella, P. Leif Bergsagel, Kylee H. Maclachlan, Daniel Leongamornlert, Saad Z. Usmani, Praneeth Sudalagunta, Yusuke Yamashita, Giancarlo Castellano, Malin L. Hultcrantz, Antonio Matera, Claudio De Magistris, Yan W. Asmann, Shaji Kunnathu Kumar, Peter J. Campbell, Juan‐José Garcés, Robert Zygmunt Orlowski, Bachisio Ziccheddu, Jamie K. Teer, Andrew McPherson, Niccolò Bolli, Kenneth H. Shain, Marta Lionetti, Stefania Pioggia, Patrick Blaney, Krina K. Patel, Rafael Renatino Canevarolo, Marios Papadimitriou, Phaedra Agius, Erin M. Siegel, S. Vincent Rajkumar, Michael Durante, Akihiro Maeda, Rachid Baz, Andriy Derkach, Matteo Da Vià, Ola Landgren, Esteban Braggio, Ariosto S. Silva, Ross Firestone, Francesco Maura, Gareth Morgan, David M. DeAvila
article en
3 citations

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.

Journal of Clinical OncologyVol. 44(3)
National Institutes of Health (US), Memorial Sloan Kettering Cancer Center (US), The University of Texas MD Anderson Cancer Center (US), University of Miami (US), University of Milan (IT), Wellcome Sanger Institute (GB), Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (IT), Moffitt Cancer Center (US), NYU Langone Health (US), Mayo Clinic in Arizona (US), Sylvester Comprehensive Cancer Center (US), NYU Langone’s Laura and Isaac Perlmutter Cancer Center
Openalex Percentile: Top 4%
Multiple Myeloma Research and Treatments
5.31
DOIOpen Access PDFOpenAlex
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