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Cited by 128Multiple Myeloma Research and TreatmentsChronic Lymphocytic Leukemia ResearchAcute Myeloid Leukemia Research

The molecular make up of smoldering myeloma highlights the evolutionary pathways leading to multiple myeloma

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Boyle, Eileen M., Deshpande, Shayu, Tytarenko, Ruslana, Ashby, Cody, Wang, Yan, Bauer, Michael A., Johnson, Sarah K., Wardell, Christopher P. +15 more·2021·Nature Communications
DOI 10.1038/s41467-020-20524-2PMC PMC7804406
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Abstract

Smoldering myeloma (SMM) is associated with a high-risk of progression to myeloma (MM). We report the results of a study of 82 patients with both targeted sequencing that included a capture of the immunoglobulin and MYC regions. By comparing these results to newly diagnosed myeloma (MM) we show fewer NRAS and FAM46C mutations together with fewer adverse translocations, del(1p), del(14q), del(16q), and del(17p) in SMM consistent with their role as drivers of the transition to MM. KRAS mutations are associated with a shorter time to progression (HR 3.5 (1.5–8.1), p = 0.001). In an analysis of change in clonal structure over time we studied 53 samples from nine patients at multiple time points. Branching evolutionary patterns, novel mutations, biallelic hits in crucial tumour suppressor genes, and segmental copy number changes are key mechanisms underlying the transition to MM, which can precede progression and be used to guide early intervention strategies.

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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 [76]

    The Results (pages unavailable in our copy) link KRAS mutations to shorter time to progression, report a higher APOBEC contribution in MM than SMM, and describe changes in sub-clonal structure before progression. They also document an acquired MYC translocation in one patient, but did not find MYC translocations associated with adverse outcome in their SMM cohort. The paper does not establish that these four are the most commonly reported alterations in progression. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • Either decreased efficacy of the immune system or selection of more aggressive and fit clones will eventually allow MGUS/SMM to progress into MM.

    “Either the decreased efficacy of the immune system or the selection of more aggressive and fit clones will eventually allow the MGUS/SMM to progress into MM.76,78,79,104”

    From Evolution of Multiple Myeloma from a Genomic Perspective (2026) · cites this paper as [76]

    The Discussion reports subclonal expansion and a proliferation advantage preceding progression from SMM to MM, supporting the selection-of-fitter-clones part of the claim. It does not establish declining immune efficacy as an alternative cause, extend that finding to MGUS, or say that all MGUS/SMM cases will eventually progress; the Results report 69.9% five-year progression-free survival for SMM. (LLM, conf=0.86)

    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 [76]

    The Results section ('Copy-number abnormalities and translocation frequency differs between SMM and MM'; page unavailable) reports fewer adverse-risk cytogenetic groups in SMM than in newly diagnosed MM (9.8% versus 20%). That comparison covers the SMM cohort overall, not specifically the high-risk SMM subgroup named in the claim. A separate Results passage discusses features enriched in high-risk SMM but does not compare that subgroup with newly diagnosed MM. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

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Authors
Boyle, E. M., Deshpande, S., Tytarenko, R., Ashby, C., Wang, Y., Bauer, M. A., Johnson, S. K., Wardell, C. P., Thanendrarajan, S., Zangari, M., Facon, T., Dumontet, C., Barlogie, B., Arbini, A., Rustad, E. H., Maura, F., Landgren, O., Zhan, F., van Rhee, F., Schinke, C., Davies, F. E., Morgan, G. J., & Walker, B. A.
Affiliations
  • Centre National de la Recherche Scientifique (FR)
  • University of Arkansas for Medical Sciences (US)
  • Centre Hospitalier Universitaire de Lille (FR)
  • Mount Sinai Hospital (US)
  • NYU Langone Health (US)
  • Memorial Sloan Kettering Cancer Center (US)
  • Indiana University Indianapolis (US)
Corresponding author
  • Morgan, Gareth J.
  • Walker, Brian A.
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2021-01-12
Volume
12
Issue
1
Pages
293-293
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-020-20524-2
PMC
PMC7804406
OpenAlex
W3119245920
Cited by
128
References
4
Citations by year
2026: 11 · 2025: 27 · 2024: 31 · 2023: 15 · 2022: 28 · 2021: 15
FWCI
14.54
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • HAL (submittedVersion, other-oa)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • UCL Discovery (University College London) (submittedVersion)
  • IUScholarWorks (Indiana University) (submittedVersion, cc-by)
Funders
Leukemia and Lymphoma Society (6020-20)
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, clonal evolution, KRAS mutation, NRAS mutation, chromosomal translocation, 17p deletion, immunoglobulin gene mutation, MYC mutations, clonal architecture, tumor suppressor, copy number alterations, time to progression
MeSH terms
APOBEC Deaminases, Smoldering Multiple Myeloma, Progression-Free Survival, Adult, Aged, Aged, 80 and over, Alleles, Clone Cells, Female, Humans, Male, Middle Aged, Mutation, Time Factors, Translocation, Genetic, Biomarkers, Tumor, Genome, Human, Gene Expression Regulation, Neoplastic, Multivariate Analysis, Genes, Tumor Suppressor, Proto-Oncogene Proteins p21(ras), Disease Progression, Evolution, Molecular, DNA Copy Number Variations, Mutation Rate

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