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Cited by 222Multiple Myeloma Research and TreatmentsCancer Genomics and DiagnosticsAcute Myeloid Leukemia Research

Genomic patterns of progression in smoldering multiple myeloma

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Bolli, Niccolò, Maura, Francesco, Minvielle, Stephane, Gloznik, Dominik, Szalat, Raphael, Fullam, Anthony, Martincorena, Inigo, Dawson, Kevin J. +16 more·2018·Nature Communications
DOI 10.1038/s41467-018-05058-yPMC PMC6105687
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Abstract

We analyzed whole genomes of unique paired samples from smoldering multiple myeloma (SMM) patients progressing to multiple myeloma (MM). We report that the genomic landscape, including mutational profile and structural rearrangements at the smoldering stage is very similar to MM. Paired sample analysis shows two different patterns of progression: a “static progression model”, where the subclonal architecture is retained as the disease progressed to MM suggesting that progression solely reflects the time needed to accumulate a sufficient disease burden; and a “spontaneous evolution model”, where a change in the subclonal composition is observed. We also observe that activation-induced cytidine deaminase plays a major role in shaping the mutational landscape of early subclinical phases, while progression is driven by APOBEC cytidine deaminases. These results provide a unique insight into myelomagenesis with potential implications for the definition of smoldering disease and timing of treatment initiation.

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  • Virtually all documented HY cases exhibit clear germinal-center mutagenesis acquired before the duplication, which excludes a pre-germinal-center origin.

    “Virtually all HY cases documented so far exhibit clear GC mutagenesis acquired before the duplication, which excludes a pre-GC origin.9,12,13,69”

    From Evolution of Multiple Myeloma from a Genomic Perspective (2026) · cites this paper as [69]

    The Results (The genomic landscape of smoldering myeloma; page unavailable) identify seven hyperdiploid cases, and the Discussion (page unavailable) reports an early AID mutational contribution in all studied samples, consistent with germinal-center activity. The paper does not establish that this mutagenesis preceded chromosome duplication in virtually all documented hyperdiploid cases or that it excludes a pre-germinal-center origin. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • 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 [69]

    The Results (Progression to multiple myeloma; page not provided) report that MYC rearrangements generally increased in clonality at progression, and the mutational-signatures Results identify APOBEC activity. The Discussion describes genomic heterogeneity but names gain 1q, del13q, hyperdiploidy, and IGH translocations—not the claimed list—as the most common aberrations. The passages do not establish RAS mutations as part of that list or show that these four features are the most commonly reported alterations. (LLM, conf=0.84)

    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 [69]

    The Results (The genomic landscape of smoldering myeloma; page unavailable) describe genomic features in 11 SMM cases, and the Discussion (page unavailable) says their cytogenetic, mutational, and rearrangement profiles are very similar to those described in MM. Neither passage compares the prevalence of high-risk features specifically in high-risk SMM with newly diagnosed MM; a broadly similar profile does not settle that narrower claim. (LLM, conf=0.72)

    Experimental — accuracy not yet measured

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Research works printed but not linked: 37

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Authors
Bolli, N., Maura, F., Minvielle, S., Gloznik, D., Szalat, R., Fullam, A., Martincorena, I., Dawson, K. J., Samur, M. K., Zamora, J., Tarpey, P., Davies, H., Fulciniti, M., Shammas, M. A., Tai, Y. T., Magrangeas, F., Moreau, P., Corradini, P., Anderson, K., Alexandrov, L., Wedge, D. C., Avet-Loiseau, H., Campbell, P., & Munshi, N.
Affiliations
  • University of Milan (IT)
  • Wellcome Sanger Institute (GB)
  • Harvard University (US)
  • Centre National de la Recherche Scientifique (FR)
  • University of California San Diego (US)
  • University of Oxford (GB)
Corresponding author
  • Campbell, Peter
  • Munshi, Nikhil
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2018-08-22
Volume
9
Issue
1
Pages
3363-3363
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-018-05058-y
PMC
PMC6105687
OpenAlex
W2885104676
Cited by
222
References
5
Citations by year
2026: 14 · 2025: 19 · 2024: 23 · 2023: 28 · 2022: 30 · 2021: 44 · 2020: 40 · 2019: 20 · 2018: 3
FWCI
19.17
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • HAL (submittedVersion, other-oa)
  • Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, other-oa)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Research Explorer (The University of Manchester) (submittedVersion, cc-by)
Funders
  • U.S. Department of Veterans Affairs (I01 BX001584, I01BX001584-01)
  • Leukemia and Lymphoma Society
  • Cancer Research UK (21777)
  • Associazione Italiana per la Ricerca sul Cancro (17658)
  • Associazione Italiana Contro le Leucemie-Linfomi e Mieloma
  • Società Italiana di Ematologia Sperimentale
  • National Institutes of Health (P01-155258, I01BX001584-01, I01-BX001584, CA100707)
  • National Cancer Institute (P50CA100707, P01CA155258)
Topics
  • Health Sciences › Medicine › Hematology › Multiple Myeloma Research and Treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
  • Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
Keywords
smoldering multiple myeloma, progression to multiple myeloma, myelomagenesis, subclonal architecture, mutational landscape, structural rearrangement, APOBEC cytidine deaminases, AID, clonal evolution, paired tumor samples, disease burden, time to treatment
MeSH terms
Smoldering Multiple Myeloma, Aged, Female, Humans, Male, Middle Aged, Multiple Myeloma, Mutation, Risk Factors, Gene Expression Regulation, Neoplastic, Disease Progression, Gene Expression Profiling, Genomics, Databases, Genetic

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