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Genomic Profiling of Smoldering Multiple Myeloma Identifies Patients at a High Risk of Disease Progression
Open accessAbstract
PURPOSE: Smoldering multiple myeloma (SMM) is a precursor condition of multiple myeloma (MM) with a 10% annual risk of progression. Various prognostic models exist for risk stratification; however, those are based on solely clinical metrics. The discovery of genomic alterations that underlie disease progression to MM could improve current risk models. METHODS: We used next-generation sequencing to study 214 patients with SMM. We performed whole-exome sequencing on 166 tumors, including 5 with serial samples, and deep targeted sequencing on 48 tumors. RESULTS: We observed that most of the genetic alterations necessary for progression have already been acquired by the diagnosis of SMM. Particularly, we found that alterations of the mitogen-activated protein kinase pathway ( KRAS and NRAS single nucleotide variants [SNVs]), the DNA repair pathway (deletion 17p, TP53, and ATM SNVs), and MYC (translocations or copy number variations) were all independent risk factors of progression after accounting for clinical risk staging. We validated these findings in an external SMM cohort by showing that patients who have any of these three features have a higher risk of progressing to MM. Moreover, APOBEC associated mutations were enriched in patients who progressed and were associated with a shorter time to progression in our cohort. CONCLUSION: SMM is a genetically mature entity whereby most driver genetic alterations have already occurred, which suggests the existence of a right-skewed model of genetic evolution from monoclonal gammopathy of undetermined significance to MM. We identified and externally validated genomic predictors of progression that could distinguish patients at high risk of progression to MM and, thus, improve on the precision of current clinical models.
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“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 [78]
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“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 [78]
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“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 [78]
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Citations
Cites
International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma
Rajkumar, S. V., Dimopoulos, M. A., Palumbo, A., Blade, J., Merlini, G., Mateos, M.-V., Kumar, S., Hillengass, J., Kastritis, E., Richardson, P., et al. (2014) · The Lancet Oncology · doi:10.1016/s1470-2045(14)70442-5 · Cited by 4,978
Self-citationUno, H., Cai, T., Pencina, M. J., D'Agostino, R. B., & Wei, L. J. (2011) · Statistics in Medicine · doi:10.1002/sim.4154 · Cited by 1,535
Clinical Course and Prognosis of Smoldering (Asymptomatic) Multiple Myeloma
Kyle, R. A., Remstein, E. D., Therneau, T. M., Dispenzieri, A., Kurtin, P. J., Hodnefield, J. M., Larson, D. R., Plevak, M. F., Jelinek, D. F., Fonseca, R., et al. (2007) · New England Journal of Medicine · doi:10.1056/nejmoa070389 · Cited by 921
A monoclonal gammopathy precedes multiple myeloma in most patients
Weiss, B. M., Abadie, J. M., Verma, P. S., Howard, R. S., & Kuehl, W. M. (2009) · Blood · doi:10.1182/blood-2008-12-195008 · Cited by 568
Dispenzieri, A. A., Kyle, R. A., Katzmann, J. A., Therneau, T. M., Larson, D. R., Benson, J. T., Clark, R. J., Melton, L. J., Gertz, M. A., Kumar, S. K., et al. (2007) · Blood · doi:10.1182/blood-2007-08-108357 · Cited by 432
Self-citationRisk stratification of smoldering multiple myeloma incorporating revised IMWG diagnostic criteria
Lakshman, A., Rajkumar, S. V., Buadi, F. K., Binder, M., Gertz, M. A., Lacy, M. Q., Dispenzieri, A. A., Dingli, D., Fonder, A. L., Hayman, S. R., et al. (2018) · Blood Cancer Journal · doi:10.1038/s41408-018-0077-4 · Cited by 299
Self-citationChromosome abnormalities clustering and its implications for pathogenesis and prognosis in myeloma
Debes-Marun, C. S., Dewald, G., Bryant, S., Picken, E. B., Santana-Dávila, R., Gonzalez-Paz, N. C., Winkler, J. M., Kyle, R. A., Gertz, M. A., Witzig, T. E., et al. (2003) · Leukemia · doi:10.1038/sj.leu.2402797 · Cited by 227
Genomic patterns of progression in smoldering multiple myeloma
Bolli, N., Maura, F., Minvielle, S., Gloznik, D., Szalat, R., Fullam, A., Martincorena, I., Dawson, K. J., Samur, M. K., Zamora, J., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-05058-y · Cited by 222
Self-citationDhodapkar, M. V., Sexton, R., Waheed, S., Usmani, S., Papanikolaou, X., Nair, B., Petty, N., Shaughnessy, J. D., Hoering, A., Crowley, J., et al. (2014) · Blood · doi:10.1182/blood-2013-07-515239 · Cited by 192
MYC dysregulation in the progression of multiple myeloma
MMRF CoMMpass Network, Misund, K., Keane, N., Stein, C. K., Asmann, Y. W., Day, G., Welsh, S., Van Wier, S. A., Riggs, D. L., Ahmann, G., et al. (2020) · Leukemia · doi:10.1038/s41375-019-0543-4 · Cited by 161
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Malard, F., Neri, P. E., Bahlis, N. J., Terpos, E., Moukalled, N. M., Hungria, V., Manier, S., & Mohty, M. (2024) · Nature Reviews Disease Primers · doi:10.1038/s41572-024-00529-7 · Cited by 387
Self-citationInternational Myeloma Working Group risk stratification model for smoldering multiple myeloma (SMM)
Mateos, M.-V., Kumar, S., Dimopoulos, M. A., González-Calle, V., Kastritis, E., Hajek, R., De Larrea, C. F., Morgan, G. J., Merlini, G., Goldschmidt, H., et al. (2020) · Blood Cancer Journal · doi:10.1038/s41408-020-00366-3 · Cited by 291
Self-citationGenomic profiling for clinical decision making in lymphoid neoplasms
de Leval, L., Alizadeh, A. A., Bergsagel, P. L., Campo, E., Davies, A. J., Doǧan, A., Fitzgibbon, J., Horwitz, S. M., Melnick, A. M., Morice, W. G., et al. (2022) · Blood · doi:10.1182/blood.2022015854 · Cited by 176
Self-citationChromosome 1q21 abnormalities in multiple myeloma
Schmidt, T. M., Fonseca, R., & Usmani, S. Z. (2021) · Blood Cancer Journal · doi:10.1038/s41408-021-00474-8 · Cited by 154
Zhao, A., Zhou, H., Yang, J., Li, M., & Niu, T. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01342-6 · Cited by 153
Metadata
- Authors
- Bustoros, M., Sklavenitis-Pistofidis, R., Park, J., Redd, R., Zhitomirsky, B., Dunford, A. J., Salem, K., Tai, Y.-T., Anand, S., Mouhieddine, T. H., Chavda, S. J., Boehner, C., Elagina, L., Neuse, C. J., Cha, J., Rahmat, M., Taylor-Weiner, A., Van Allen, E., Kumar, S., Kastritis, E., Leshchiner, I., Morgan, E. A., Laubach, J., Casneuf, T., Richardson, P., Munshi, N. C., Anderson, K. C., Trippa, L., Aguet, F., Stewart, C., Dimopoulos, M.-A., Yong, K., Bergsagel, P. L., Manier, S., Getz, G., & Ghobrial, I. M.
- Affiliations
- Broad Institute (US)
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA
- Dana-Farber Cancer Institute (US)
- Harvard University (US)
- University College London (GB)
- Mayo Clinic (US)
- National and Kapodistrian University of Athens (GR)
- Brigham and Women's Hospital (US)
- Janssen (Belgium) (BE)
- Université de Lille (FR)
- Corresponding author
- Ghobrial, Irene M.
- ORCID
- Bustoros, Mark
- Park, Jihye
- Redd, Robert
- Zhitomirsky, Benny
- Dunford, Andrew J.
- Salem, Karma
- Tai, Yu-Tzu
- Anand, Shankara
- Mouhieddine, Tarek H.
- Chavda, Selina J.
- Boehner, Cody
- Neuse, Carl Jannes
- Cha, Justin
- Rahmat, Mahshid
- Taylor-Weiner, Amaro
- Kumar, Shaji
- Leshchiner, Ignaty
- Morgan, Elizabeth A.
- Laubach, Jacob
- Casneuf, Tineke
- Richardson, Paul
- Munshi, Nikhil C.
- Anderson, Kenneth C.
- Trippa, Lorenzo
- Aguet, François
- Stewart, Chip
- Dimopoulos, Meletios-Athanasios
- Yong, Kwee
- Bergsagel, P. Leif
- Manier, Salomon
- Getz, Gad
- Ghobrial, Irene M.
- Venue
- Journal of Clinical Oncology
- Published
- 2020-07-20
- Volume
- 38
- Issue
- 21
- Pages
- 2380-2389
- ISSN
- 0732-183X (ISSN-L)
- 1527-7755
- PMC
- PMC7367550
- OpenAlex
- W3027407129
- Cited by
- 187
- References
- 10
- Citations by year
- 2026: 14 · 2025: 29 · 2024: 35 · 2023: 26 · 2022: 32 · 2021: 35 · 2020: 16
- FWCI
- 17.20
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Oncology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Multiple Myeloma Research Foundation
- Leukemia and Lymphoma Society
- Dr. Miriam and Sheldon G. Adelson Medical Research Foundation
- Celgene
- European Hematology Association (TRTH177)
- Cancer Research UK
- National Institutes of Health
- Stand Up To Cancer
- Pharmacyclics
- National Human Genome Research Institute (T32HG002295)
- National Cancer Institute (R01CA195688, R01CA205954, R01CA168762, P50CA186781)
- Topics
- Health Sciences › Medicine › Hematology › Multiple Myeloma Research and Treatments
- Health Sciences › Medicine › Hematology › Chronic Lymphocytic Leukemia Research
- Health Sciences › Medicine › Pathology and Forensic Medicine › Lymphoma Diagnosis and Treatment
- Keywords
- smoldering multiple myeloma, progression to multiple myeloma, KRAS mutation, NRAS mutation, TP53 mutation, ATM mutations, 17p deletion, MYC translocation, MAPK signaling, DNA repair pathways, monoclonal gammopathy of undetermined significance, time to progression
- MeSH terms
- Smoldering Multiple Myeloma, Adult, Aged, Aged, 80 and over, Female, Humans, Male, Middle Aged, Risk Factors, Disease Progression, Genomics, High-Throughput Nucleotide Sequencing
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