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Multiple Myeloma Risk and Outcomes Are Associated with Pathogenic Germline Variants in DNA Repair Genes
Open accessPublished version of a preprint
Abstract
First-degree relatives of patients with multiple myeloma are at increased risk for the disease, but the contribution of pathogenic germline variants (PGV) in hereditary cancer genes to multiple myeloma risk and outcomes is not well characterized. To address this, we analyzed germline exomes in two independent cohorts of 895 and 786 patients with multiple myeloma. PGVs were identified in 8.6% of the Discovery cohort and 11.5% of the Replication cohort, with a notable presence of high- or moderate-penetrance PGVs (associated with autosomal dominant cancer predisposition) in DNA repair genes (3.6% and 4.1%, respectively). PGVs in BRCA1 (OR = 3.9, FDR < 0.01) and BRCA2 (OR = 7.0, FDR < 0.001) were significantly enriched in patients with multiple myeloma when compared with 134,187 healthy controls. Five of the eight BRCA2 PGV carriers exhibited tumor-specific copy number loss in BRCA2, suggesting somatic loss of heterozygosity. PGVs associated with autosomal dominant cancer predisposition were associated with younger age at diagnosis, personal or familial cancer history, and longer progression-free survival after upfront high-dose melphalan and autologous stem-cell transplantation (P < 0.01). Significance: Our findings suggest up to 10% of patients with multiple myeloma may have an unsuspected cancer predisposition syndrome. Given familial implications and favorable outcomes with high-dose melphalan and autologous stem-cell transplantation in high-penetrance PGV carriers, genetic testing should be considered for young or newly diagnosed patients with a personal or family cancer history. See related commentary by Walker, p. 375
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In patients with germline variants predisposing to cancer, multiple myeloma prevalence and incidence are increased, but the tumor genomic landscape differs from that observed in solid tumors.
“Interestingly, while MM prevalence and incidence are increased in this population, the tumor genomic landscape in patients harboring these variants differs from what observed in solid tumor.”
From Evolution of Multiple Myeloma from a Genomic Perspective (2026) · cites this paper as [45]
The Discussion reports pathogenic germline variants in patients with multiple myeloma, and the Results section on PGV enrichment finds BRCA1/2 variants more common in those patients than in healthy controls. That supports an association with myeloma risk, but the study does not measure myeloma incidence among variant carriers. Its tumor-genomic analysis is limited to selected carriers and does not establish that their tumors’ genomic landscape differs from solid tumors (no page numbers are available in our copy). (LLM, conf=0.85)
Experimental — accuracy not yet measuredGermline variants of genes predisposing to several different cancer types, including multiple myeloma (e.g., CHECK2, BRCA, TP53), form one group of germline events associated with MM and MGUS.
“The first includes germline variants of genes predisposing to the risk of several different cancer types, including MM (e.g. CHECK2, BRCA, TP53).45”
From Evolution of Multiple Myeloma from a Genomic Perspective (2026) · cites this paper as [45]
The Results section reports pathogenic germline variants in CHEK2 (spelled “CHECK2” in the citing sentence), BRCA1/2, and TP53 among patients with multiple myeloma, and finds significant enrichment only for BRCA1/2. The Discussion describes the TP53 association as suggestive, not established; the paper does not establish these variants as predisposing to MGUS. No page numbers are available in our copy. (LLM, conf=0.87)
Experimental — accuracy not yet measuredGenetic predisposition plays an important role in the initial transformation and is driven by both germline variants and multiple myeloma-specific loci influencing risk.
“Genetic predisposition plays an important role in the initial transformation and is driven by both germline variants and MM-specific loci influencing risk.”
From Evolution of Multiple Myeloma from a Genomic Perspective (2026) · cites this paper as [45]
The Introduction says germline genetic variation contributes to multiple myeloma risk, and the Discussion reports enrichment of pathogenic BRCA1/2 variants in patients with multiple myeloma. The paper does not establish a role in initial transformation or identify MM-specific risk loci; its study population comprised patients with active myeloma and excluded precursor conditions (Results, Study Population; page unavailable). (LLM, conf=0.86)
Experimental — accuracy not yet measuredA list of loci specific to multiple myeloma and MGUS/SMM exists.
“The second group included a list of loci that are specific to multiple myeloma and MGUS/SMM .43-46”
From Evolution of Multiple Myeloma from a Genomic Perspective (2026) · cites this paper as [45]
The Discussion reports an association between pathogenic variants in BRCA1/2 and multiple myeloma. But the Results (Study Population; page unavailable) say the study explicitly excluded people with MGUS or smoldering multiple myeloma, so it does not establish loci specific to those precursor conditions. (LLM, conf=0.85)
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Citations
Cites
BRCA locus-specific loss of heterozygosity in germline BRCA1 and BRCA2 carriers
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Evolution of Multiple Myeloma from a Genomic Perspective
Maura, F., Samur, M., & Munshi, N. (2026) · Blood · doi:10.1182/blood.2024026313 · Cited by 8
Metadata
- Authors
- Thibaud, S., Subaran, R. L., Newman, S., Lagana, A., Melnekoff, D. T., Bodnar, S., Ram, M., Soens, Z., Genthe, W., Brander, T., Mouhieddine, T. H., Van Oekelen, O., Houldsworth, J., Cho, H. J., Richard, S., Richter, J., Rodriguez, C., Rossi, A., Sanchez, L., Chari, A., Moshier, E., Jagannath, S., Parekh, S., & Onel, K.
- Affiliations
- Icahn School of Medicine at Mount Sinai (US)
- Sema4 (United States) (US)
- St. Jude Children's Research Hospital (US)
- 3Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.
- University of California, San Francisco (US)
- Tisch Cancer Institute (US)
- Roswell Park Comprehensive Cancer Center (US)
- Corresponding author
- Parekh, Samir
- Onel, Kenan
- ORCID
- Thibaud, Santiago
- Subaran, Ryan L.
- Newman, Scott
- Lagana, Alessandro
- Melnekoff, David T.
- Bodnar, Saoirse
- Ram, Meghana
- Soens, Zachry
- Genthe, William
- Brander, Tehilla
- Mouhieddine, Tarek H.
- Van Oekelen, Oliver
- Houldsworth, Jane
- Cho, Hearn Jay
- Richard, Shambavi
- Richter, Joshua
- Rodriguez, Cesar
- Rossi, Adriana
- Sanchez, Larysa
- Chari, Ajai
- Moshier, Erin
- Jagannath, Sundar
- Parekh, Samir
- Onel, Kenan
- Venue
- Blood Cancer Discovery
- Published
- 2024-09-16
- Volume
- 5
- Issue
- 6
- Pages
- 428-441
- ISSN
- 2643-3230 (ISSN-L)
- 2643-3249
- PMC
- PMC11528192
- OpenAlex
- W4402582274
- Cited by
- 22
- References
- 1
- Citations by year
- 2026: 5 · 2025: 13 · 2024: 4
- FWCI
- 6.80
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Blood Cancer Discovery (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by-nc-nd)
- Funders
- American Society of Hematology (ASH Bridge Grant)
- Bristol Myers Squibb Foundation (Robert A. Winn Diversity in Clinical Trials: Career Development Award (Winn CDA) - Cohort 2)
- National Cancer Institute (R01CA244899, R01CA252222, P30CA196521)
- National Center for Advancing Translational Sciences (KL2TR004421)
- Multiple Myeloma Research Foundation (MMRF 2023 Scholars Grant)
- Topics
- Health Sciences › Medicine › Hematology › Multiple Myeloma Research and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › BRCA gene mutations in cancer
- Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
- Keywords
- multiple myeloma, germline pathogenic variants, DNA repair genes, BRCA1, BRCA2, hereditary cancer predisposition, loss of heterozygosity, progression-free survival, high-dose melphalan, autologous stem cell transplantation, family history of cancer, genetic testing
- MeSH terms
- Adult, Aged, DNA Repair, Female, Humans, Male, Middle Aged, Multiple Myeloma, Germ-Line Mutation, Genetic Predisposition to Disease
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