The biological and clinical impact of deletions before and after large chromosomal gains in multiple myeloma
Open accessAbstract
Acquisition of a hyperdiploid (HY) karyotype or immunoglobulin heavy chain (IgH) translocations are considered key initiating events in multiple myeloma (MM). To explore if other genomic events can precede these events, we analyzed whole-genome sequencing data from 1173 MM samples. By integrating molecular time and structural variants within early chromosomal duplications, we indeed identified pregain deletions in 9.4% of patients with an HY karyotype without IgH translocations, challenging acquisition of an HY karyotype as the earliest somatic event. Remarkably, these deletions affected tumor suppressor genes (TSGs) and/or oncogenes in 2.4% of patients with an HY karyotype without IgH translocations, supporting their role in MM pathogenesis. Furthermore, our study points to postgain deletions as novel driver mechanisms in MM. Using multiomics approaches to investigate their biologic impact, we found associations with poor clinical outcome in newly diagnosed patients and profound effects on both the oncogene and TSG activity despite the diploid gene status. Overall, this study provides novel insights into the temporal dynamics of genomic alterations in MM.
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In mantle cell or follicular lymphomas, virtually all IGH translocations are driven by RAG.
“This is, for example, strikingly different from mantle cell or follicular lymphomas, where virtually all IGH translocations are driven by RAG.68”
From Evolution of Multiple Myeloma from a Genomic Perspective (2026) · cites this paper as [68]
Supplementary Figure 5 (Additional information; page unavailable) identifies IGH–BCL2 translocations in follicular lymphoma and CCND1–IGH translocations in mantle cell lymphoma. The passages do not say these translocations are driven by RAG or establish that virtually all IGH translocations in either lymphoma are RAG-driven. (LLM, conf=0.83)
Experimental — accuracy not yet measuredFocal deletions involving tumor suppressor genes or oncogenes can occur within odd-numbered chromosomes before HY events.
“Leveraging WGS and structural variants it has been shown that focal deletion involving tumor suppressor genes or oncogene can occur within odd-numbered chromosomes before the HY events.68”
From Evolution of Multiple Myeloma from a Genomic Perspective (2026) · cites this paper as [68]
The Additional information (Supplementary Figures 2 and 6; page unavailable) describes a deletion acquired before an 11q gain and reports pre-gain deletions involving HY chromosomes. It discusses tumor-suppressor genes and oncogenes near deletions, but does not establish that the pre-gain deletions on HY chromosomes involved those genes; its explicit assessment of their impact concerns post-gain deletions. (LLM, conf=0.79)
Experimental — accuracy not yet measuredRecent evidence significantly downsized the fraction of patients with RAG-mediated IGH translocation events.
“recent evidence significantly downsized the fraction of patients with RAG mediated events.68”
From Evolution of Multiple Myeloma from a Genomic Perspective (2026) · cites this paper as [68]
The Additional information section mentions IGH translocations and compares CSR- and VDJ-region profiles, but gives no fraction of patients with RAG-mediated events or evidence that an estimate was revised downward. Searches for RAG-mediated events, patient proportions, and VDJ/CSR translocations found no passage addressing that change; page numbers were unavailable. (LLM, conf=0.72)
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Cited by
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Temporal genomic dynamics shape clinical trajectory in multiple myeloma
Maura, F., Kaddoura, M., Poos, A. M., Baughn, L. B., Ziccheddu, B., Bärtsch, M.-A., Cirrincione, A., Maclachlan, K., Chojnacka, M., Diamond, B., et al. (2025) · Nature Genetics · doi:10.1038/s41588-025-02292-1 · Cited by 14 · see citing works
Self-citationEvolution of Multiple Myeloma from a Genomic Perspective
Maura, F., Samur, M., & Munshi, N. (2026) · Blood · doi:10.1182/blood.2024026313 · Cited by 8 · see citing works
Self-citation
- Authors
- Cirrincione, A. M., Poos, A. M., Ziccheddu, B., Kaddoura, M., Bärtsch, M.-A., Maclachlan, K., Chojnacka, M., Diamond, B., John, L., Reichert, P., Huhn, S., Blaney, P., Gagler, D., Rippe, K., Zhang, Y., Dogan, A., Lesokhin, A. M., Davies, F., Goldschmidt, H., Fenk, R., Weisel, K. C., Mai, E. K., Korde, N., Morgan, G. J., Usmani, S., Landgren, O., Raab, M. S., Weinhold, N., & Maura, F.
- Affiliations
- University of Miami (US)
- German Cancer Research Center (DE)
- 2Heidelberg Myeloma Center, Department of Medicine V, University Hospital and Medical Faculty Heidelberg, Heidelberg University, Heidelberg, Germany
- Memorial Sloan Kettering Cancer Center (US)
- NYU Langone Health (US)
- 8Hematopathology Service, Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY
- University Hospital Heidelberg (DE)
- Düsseldorf University Hospital (DE)
- University Medical Center Hamburg-Eppendorf (DE)
- Corresponding author
- Maura, Francesco
- ORCID
- Cirrincione, Anthony M.
- Poos, Alexandra M.
- Ziccheddu, Bachisio
- Kaddoura, Marcella
- Maclachlan, Kylee
- Chojnacka, Monika
- Diamond, Benjamin
- John, Lukas
- Reichert, Philipp
- Huhn, Stefanie
- Blaney, Patrick
- Gagler, Dylan
- Rippe, Karsten
- Zhang, Yanming
- Dogan, Ahmet
- Lesokhin, Alexander M.
- Davies, Faith
- Goldschmidt, Hartmut
- Fenk, Roland
- Weisel, Katja C.
- Mai, Elias K.
- Korde, Neha
- Morgan, Gareth J.
- Usmani, Saad
- Landgren, Ola
- Raab, Marc S.
- Weinhold, Niels
- Maura, Francesco
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2024-08-15
- Volume
- 144
- Issue
- 7
- Pages
- 771-783
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- PMC
- PMC11375460
- OpenAlex
- W4396789537
- Cited by
- 15
- References
- 2
- Citations by year
- 2026: 4 · 2025: 6 · 2024: 5
- FWCI
- 4.63
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Blood (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (P30CA008748, P30CA240139, P30CA016087)
- Topics
- Health Sciences › Medicine › Hematology › Multiple Myeloma Research and Treatments
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Health Sciences › Medicine › Genetics › Chronic Lymphocytic Leukemia Research
- Keywords
- multiple myeloma, hyperdiploidy, chromosomal duplication, tumor suppressor, oncogenes, IGH translocation, driver mutations, clinical outcomes, myeloma pathogenesis
- MeSH terms
- Chromosome Aberrations, Female, Humans, Immunoglobulin Heavy Chains, Male, Multiple Myeloma, Translocation, Genetic, Genes, Tumor Suppressor, Gene Deletion
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