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Cited by 35Multiple Myeloma Research and TreatmentsChronic Lymphocytic Leukemia ResearchAcute Myeloid Leukemia Research

Genetic subtypes of smoldering multiple myeloma are associated with distinct pathogenic phenotypes and clinical outcomes

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Bustoros, Mark, Anand, Shankara, Sklavenitis-Pistofidis, Romanos, Redd, Robert, Boyle, Eileen M., Zhitomirsky, Benny, Dunford, Andrew J., Tai, Yu-Tzu +19 more·2022·Nature Communications
DOI 10.1038/s41467-022-30694-wPMC PMC9200804

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Abstract

Smoldering multiple myeloma (SMM) is a precursor condition of multiple myeloma (MM) with significant heterogeneity in disease progression. Existing clinical models of progression risk do not fully capture this heterogeneity. Here we integrate 42 genetic alterations from 214 SMM patients using unsupervised binary matrix factorization (BMF) clustering and identify six distinct genetic subtypes. These subtypes are differentially associated with established MM-related RNA signatures, oncogenic and immune transcriptional profiles, and evolving clinical biomarkers. Three genetic subtypes are associated with increased risk of progression to active MM in both the primary and validation cohorts, indicating they can be used to better predict high and low-risk patients within the currently used clinical risk stratification models.

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  • RAS mutations, MYC translocations, APOBEC mutagenesis, and patterns of genomic complexity are the most commonly reported alterations in progressing multiple myeloma.

    “Among these, RAS mutations, MYC translocations, APOBEC mutagenesis, and patterns of genomic complexity are the most commonly reported.8,9,11,69,76-83,84”

    From Evolution of Multiple Myeloma from a Genomic Perspective (2026) · cites this paper as [77]

    The Results (pages not provided) identify a subtype with KRAS mutations and MYC translocations, find APOBEC activity enriched in two subtypes, and associate high-risk genetic subtypes with progression. The Introduction says that copy-number alterations are the most common events in smoldering multiple myeloma, followed by single-nucleotide variants and translocations. The paper does not establish that the four listed features are the most commonly reported alterations in progressing multiple myeloma. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • High-risk features are underrepresented among high-risk smoldering multiple myeloma (SMM) compared with newly diagnosed multiple myeloma (MM).

    “Specifically, it is peculiar that these high-risk features are underrepresented among high-risk SMM compared to newly diagnosed MM.9,11,69,76-79”

    From Evolution of Multiple Myeloma from a Genomic Perspective (2026) · cites this paper as [77]

    The Results section reports that high-risk genetic subtypes of SMM are enriched for alterations including TP53, t(4;14), and 1q gain. The Introduction and Discussion passages do not compare the frequency of those features in high-risk SMM with newly diagnosed MM; searches for that comparison found no supporting passage in our copy. No page numbers were available. (LLM, conf=0.73)

    Experimental — accuracy not yet measured

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Cited by

Sorted by citations

Authors
Bustoros, M., Anand, S., Sklavenitis-Pistofidis, R., Redd, R., Boyle, E. M., Zhitomirsky, B., Dunford, A. J., Tai, Y.-T., Chavda, S. J., Boehner, C., Neuse, C. J., Rahmat, M., Dutta, A., Casneuf, T., Verona, R., Kastritis, E., Trippa, L., Stewart, C., Walker, B. A., Davies, F. E., Dimopoulos, M.-A., Bergsagel, P. L., Yong, K., Morgan, G. J., Aguet, F., Getz, G., & Ghobrial, I. M.
Affiliations
  • Dana-Farber Cancer Institute (US)
  • Broad Institute (US)
  • NYU Langone Health (US)
  • University College London (GB)
  • University of Münster (DE)
  • Janssen (Belgium) (BE)
  • National and Kapodistrian University of Athens (GR)
  • Indiana University Indianapolis (US)
  • Mayo Clinic (US)
Corresponding author
  • Getz, Gad
  • Ghobrial, Irene M.
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2022-06-15
Volume
13
Issue
1
Pages
3449-3449
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-022-30694-w
PMC
PMC9200804
OpenAlex
W4282944983
Cited by
35
References
6
Citations by year
2026: 7 · 2025: 11 · 2024: 7 · 2023: 5 · 2022: 5
FWCI
5.09
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • IUScholarWorks (Indiana University) (submittedVersion, cc-by)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • UCL Discovery (University College London) (submittedVersion)
Funders
  • American Association for Cancer Research
  • Multiple Myeloma Research Foundation
  • Leukemia and Lymphoma Society
  • Dr. Miriam and Sheldon G. Adelson Medical Research Foundation
  • Entertainment Industry Foundation
  • Cancer Research UK (28770, A28770)
  • National Institute for Health and Care Research
  • University College London
  • University College London Hospitals NHS Foundation Trust
  • National Institutes of Health
  • Stand Up To Cancer (SU2C-AACR-DT28-18, AACR-DT-28-18)
  • Medical Research Council
  • National Cancer Institute (R01CA205954, P50CA186781)
  • National Institute of General Medical Sciences (P20GM121176)
Topics
  • Health Sciences › Medicine › Hematology › Multiple Myeloma Research and Treatments
  • Health Sciences › Medicine › Genetics › Chronic Lymphocytic Leukemia Research
  • Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
Keywords
smoldering multiple myeloma, multiple myeloma, genetic subtypes, disease progression, progression risk, gene expression profiling, immune signatures, clinical risk stratification, clinical biomarkers, RNA signatures
MeSH terms
Smoldering Multiple Myeloma, Humans, Multiple Myeloma, Phenotype, Risk, Risk Factors, Disease Progression

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