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Cited by 70Multiple Myeloma Research and TreatmentsCancer Genomics and DiagnosticsAcute Myeloid Leukemia Research

Genome-wide somatic alterations in multiple myeloma reveal a superior outcome group

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Samur, Mehmet Kemal, Aktas Samur, Anil, Fulciniti, Mariateresa, Szalat, Raphael, Han, Tessa, Shammas, Masood, Richardson, Paul, Magrangeas, Florence +8 more·2020·Journal of Clinical Oncology
DOI 10.1200/jco.20.00461PMC PMC7499613
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Abstract

PURPOSE: Multiple myeloma (MM) is accompanied by heterogeneous somatic alterations. The overall goal of this study was to describe the genomic landscape of myeloma using deep whole-genome sequencing (WGS) and develop a model that identifies patients with long survival. METHODS: We analyzed deep WGS data from 183 newly diagnosed patients with MM treated with lenalidomide, bortezomib, and dexamethasone (RVD) alone or RVD + autologous stem cell transplant (ASCT) in the IFM/DFCI 2009 study (ClinicalTrials.gov identifier: NCT01191060 ). We integrated genomic markers with clinical data. RESULTS: We report significant variability in mutational load and processes within MM subgroups. The timeline of observed activation of mutational processes provides the basis for 2 distinct models of acquisition of mutational changes detected at the time of diagnosis of myeloma. Virtually all MM subgroups have activated DNA repair–associated signature as a prominent late mutational process, whereas APOBEC signature targeting C>G is activated in the intermediate phase of disease progression in high-risk MM. Importantly, we identify a genomically defined MM subgroup (17% of newly diagnosed patients) with low DNA damage (low genomic scar score with chromosome 9 gain) and a superior outcome (100% overall survival at 69 months), which was validated in a large independent cohort. This subgroup allowed us to distinguish patients with low- and high-risk hyperdiploid MM and identify patients with prolongation of progression-free survival. Genomic characteristics of this subgroup included lower mutational load with significant contribution from age-related mutations as well as frequent NRAS mutation. Surprisingly, their overall survival was independent of International Staging System and minimal residual disease status. CONCLUSION: This is a comprehensive study identifying genomic markers of a good-risk group with prolonged survival. Identification of this patient subgroup will affect future therapeutic algorithms and research planning.

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  • Different patients might experience different exposure in time and intensity in the germinal center, potentially reflecting unique interaction with the external environment.

    “Importantly, based on the different number of GC mutations observed across hundreds of WGS, it has been shown that different patients might experience different exposure in time and intensity, potentially reflecting unique interaction with the external environment.12,13,15,72,73”

    From Evolution of Multiple Myeloma from a Genomic Perspective (2026) · cites this paper as [73]

    The Results describe somatic-hypermutation mutations and variation in mutational processes across myeloma samples; the Discussion places AID-related mutations predominantly at an early, clonal stage. These passages do not establish that individual patients experienced different durations or intensities of germinal-center exposure, or link such exposure to interactions with the external environment. Page numbers were not available in our copy. (LLM, conf=0.78)

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Authors
Samur, M. K., Aktas Samur, A., Fulciniti, M., Szalat, R., Han, T., Shammas, M., Richardson, P., Magrangeas, F., Minvielle, S., Corre, J., Moreau, P., Thakurta, A., Anderson, K. C., Parmigiani, G., Avet-Loiseau, H., & Munshi, N. C.
Affiliations
  • Harvard University (US)
  • Department of Data Sciences, Dana Farber Cancer Institute, Boston, MA
  • Dana-Farber Cancer Institute (US)
  • Centre National de la Recherche Scientifique (FR)
  • Inserm UMR892, CNRS 6299, Université de Nantes, and Centre Hospitalier Universitaire de Nantes, Unité Mixte de Genomique du Cancer, Nantes, France
  • University Cancer Center of Toulouse Institut National de la Santé, Toulouse, France
  • Celgene (United States) (US)
Corresponding author
Samur, Mehmet Kemal
ORCID
Venue
Journal of Clinical Oncology
Publisher
American Society of Clinical Oncology (ASCO)
Published
2020-09-20
Volume
38
Issue
27
Pages
3107-3118
ISSN
  • 0732-183X (ISSN-L)
  • 1527-7755
DOI
10.1200/jco.20.00461
PMC
PMC7499613
OpenAlex
W3043473017
Cited by
70
References
4
Citations by year
2026: 2 · 2025: 10 · 2024: 18 · 2023: 12 · 2022: 11 · 2021: 14 · 2020: 3
FWCI
6.32
Type
journal article
Language
en
Open access
Licence
cc-by-nc-nd
Locations
  • Journal of Clinical Oncology (publishedVersion, cc-by-nc-nd)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • HAL (submittedVersion)
  • HAL (submittedVersion, other-oa)
Funders
  • U.S. Department of Veterans Affairs (I01 BX001584)
  • Celgene
  • Agence Nationale de la Recherche (ANR-16-IDEX-0007)
  • 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
multiple myeloma, somatic alterations, mutational signatures, APOBEC signature, mutational load, NRAS mutation, prognostic subgroups, overall survival, progression-free survival, autologous stem cell transplantation
MeSH terms
Bortezomib, Whole Genome Sequencing, Lenalidomide, Progression-Free Survival, Adult, Aged, Antineoplastic Combined Chemotherapy Protocols, Combined Modality Therapy, Dexamethasone, DNA Mutational Analysis, DNA, Neoplasm, Female, Humans, Male, Membrane Proteins, Middle Aged, Multiple Myeloma, Biomarkers, Tumor, Survival Rate, Treatment Outcome, GTP Phosphohydrolases, Stem Cell Transplantation, INDEL Mutation

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