Temporal genomic dynamics shape clinical trajectory in multiple myeloma

Francesco Maura^#^{1

2}, Marcella Kaddoura^#³, Alexandra M Poos^#^{4

5}, Linda B Baughn⁶, Bachisio Ziccheddu³, Marc-Andrea Bärtsch^{4

5}, Anthony Cirrincione³, Kylee Maclachlan⁷, Monika Chojnacka³, Benjamin Diamond³, Marios Papadimitriou³, Patrick Blaney⁸, Lukas John^{4

5}, Philipp Reichert⁴, Stefanie Huhn⁴, Dylan Gagler⁸, Yanming Zhang⁹, Ahmet Dogan¹⁰, Alexander M Lesokhin⁷, Faith Davies⁸, Hartmut Goldschmidt¹¹, Roland Fenk¹², Katja C Weisel¹³, Elias K Mai⁴, Neha Korde⁷, Gareth J Morgan⁸, S Vincent Rajkumar¹⁴, Shaji Kumar¹⁴, Saad Usmani⁷, Ola Landgren³, Marc S Raab^#^{4

5}, Niels Weinhold^#^{15

16}

Affiliations

¹ Myeloma Institute, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA. mauraf@mskcc.org.
² Myeloma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York City, NY, USA. mauraf@mskcc.org.
³ Myeloma Institute, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA.
⁴ Heidelberg Myeloma Center, Department of Medicine V, University Hospital Heidelberg, Medical Faculty, Heidelberg University, Heidelberg, Germany.
⁵ Clinical Cooperation Unit Molecular Hematology/Oncology, Department of Internal Medicine V, Heidelberg University Hospital, Heidelberg University and German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁶ Division of Hematopathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
⁷ Myeloma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York City, NY, USA.
⁸ Myeloma Research Program, NYU Langone, Perlmutter Cancer Center, New York City, NY, USA.
⁹ Cytogenetics Laboratory, Department of Pathology, Memorial Sloan Kettering Cancer Center, New York City, NY, USA.
¹⁰ Hematopathology Service, Department of Pathology, Memorial Sloan Kettering Cancer Center, New York City, NY, USA.
¹¹ Internal Medicine V, Hematology, Oncology and Rheumatology, GMMG Study Group, Heidelberg University Hospital and the National Center for Tumor Diseases (NCT), Heidelberg, Germany.
¹² Department of Hematology, Oncology and Clinical Immunology, University Hospital Duesseldorf, Duesseldorf, Germany.
¹³ Department of Oncology, Hematology, and Blood and Marrow Transplant, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
¹⁴ Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA.
¹⁵ Heidelberg Myeloma Center, Department of Medicine V, University Hospital Heidelberg, Medical Faculty, Heidelberg University, Heidelberg, Germany. niels.weinhold@med.uni-heidelberg.de.
¹⁶ Clinical Cooperation Unit Molecular Hematology/Oncology, Department of Internal Medicine V, Heidelberg University Hospital, Heidelberg University and German Cancer Research Center (DKFZ), Heidelberg, Germany. niels.weinhold@med.uni-heidelberg.de.

^# Contributed equally.

PMID: 40835892
DOI: 10.1038/s41588-025-02292-1

Temporal genomic dynamics shape clinical trajectory in multiple myeloma

Francesco Maura et al. Nat Genet. 2025 Sep.

. 2025 Sep;57(9):2203-2214.

doi: 10.1038/s41588-025-02292-1. Epub 2025 Aug 20.

Authors

Affiliations

¹ Myeloma Institute, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA. mauraf@mskcc.org.
² Myeloma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York City, NY, USA. mauraf@mskcc.org.
³ Myeloma Institute, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA.
⁴ Heidelberg Myeloma Center, Department of Medicine V, University Hospital Heidelberg, Medical Faculty, Heidelberg University, Heidelberg, Germany.
⁵ Clinical Cooperation Unit Molecular Hematology/Oncology, Department of Internal Medicine V, Heidelberg University Hospital, Heidelberg University and German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁶ Division of Hematopathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
⁷ Myeloma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York City, NY, USA.
⁸ Myeloma Research Program, NYU Langone, Perlmutter Cancer Center, New York City, NY, USA.
⁹ Cytogenetics Laboratory, Department of Pathology, Memorial Sloan Kettering Cancer Center, New York City, NY, USA.
¹⁰ Hematopathology Service, Department of Pathology, Memorial Sloan Kettering Cancer Center, New York City, NY, USA.
¹¹ Internal Medicine V, Hematology, Oncology and Rheumatology, GMMG Study Group, Heidelberg University Hospital and the National Center for Tumor Diseases (NCT), Heidelberg, Germany.
¹² Department of Hematology, Oncology and Clinical Immunology, University Hospital Duesseldorf, Duesseldorf, Germany.
¹³ Department of Oncology, Hematology, and Blood and Marrow Transplant, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
¹⁴ Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA.
¹⁵ Heidelberg Myeloma Center, Department of Medicine V, University Hospital Heidelberg, Medical Faculty, Heidelberg University, Heidelberg, Germany. niels.weinhold@med.uni-heidelberg.de.
¹⁶ Clinical Cooperation Unit Molecular Hematology/Oncology, Department of Internal Medicine V, Heidelberg University Hospital, Heidelberg University and German Cancer Research Center (DKFZ), Heidelberg, Germany. niels.weinhold@med.uni-heidelberg.de.

^# Contributed equally.

PMID: 40835892
DOI: 10.1038/s41588-025-02292-1

Abstract

Multiple myeloma evolution is characterized by the accumulation of genomic drivers over time. To unravel this timeline and its impact on clinical outcomes, we analyzed 421 whole-genome sequences from 382 patients. Using clock-like mutational signatures, we estimated a time lag of two to four decades between the initiation of events and diagnosis. We demonstrate that odd-numbered chromosome trisomies in patients with hyperdiploidy can be acquired simultaneously with other chromosomal gains (for example, 1q gain). We show that hyperdiploidy is acquired after immunoglobulin heavy chain translocation when both events co-occur. Finally, patients with early 1q gain had adverse outcomes similar to those with 1q amplification (>1 extra copy), but fared worse than those with late 1q gain. This finding underscores that the 1q gain prognostic impact depends more on the timing of acquisition than on the number of copies gained. Overall, this study contributes to a better understanding of the life history of myeloma and may have prognostic implications.

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Conflict of interest statement

Competing interests: O.L. has received research funding from NIH, NCI, U.S. Food and Drug Administration, MMRF, International Myeloma Foundation, LLS, Myeloma Solutions Fund, Paula and Rodger Riney Multiple Myeloma Research Program Fund, the Tow Foundation, Perelman Family Foundation, Rising Tide Foundation, Amgen, Celgene, Janssen, Takeda, Glenmark, Seattle Genetics, Karyopharm; Honoraria/ad boards: Adaptive, Amgen, Binding Site, Bristol Myers Squibb (BMS), Celgene, Cellectis, Glenmark, Janssen, Juno, Pfizer; and serves on Independent Data Monitoring Committees for clinical trials lead by Takeda, Merck, Janssen, Theradex. G.J.M. has received funding from NIH, NCI, MMRF, LLS, Perelman Family Foundation, Amgen, Celgene, Janssen and Takeda; has received honoraria or advisory board fees from Adaptive, Amgen, BMS, Celgene and Janssen; and serves on Independent Data Monitoring Committees for clinical trials led by Takeda, Karyopharm and Sanofi. E.K.M. reports consulting or advisory role, honoraria, research funding, travel accommodation and expenses from BMS (Celgene), GlaxoSmithKline (GSK), Janssen-Cilag, Oncopeptides, Pfizer, Sanofi, Stemline and Takeda. K.C.W. reports research grant from AbbVie, Amgen, BMS/Celgene, Janssen, GSK and Sanofi; and has received honoraria and consulting fees from AbbVie, Amgen, Adaptive Biotech, AstraZeneca, BMS/Celgene, BeiGene, Janssen, GSK, Karyopharm, Novartis, Oncopeptides, Pfizer, Roche Pharma, Sanofi, Stemline and Takeda. R.F. reports consulting or advisory role, honoraria, travel accommodation and expenses from Amgen, BMS (Celgene), GSK, Janssen-Cilag, Sanofi, Stemline and Takeda. K.H.S. has served on an advisory board for AbbVie, Amgen, BMS, GSK and Janssen; received honoraria for Adaptive Biotechnologies Corporation, Amgen, BMS, GSK, Janssen and Sanofi Genzyme; and has received research funding from AbbVie and Karyopharm Therapeutics. H.G. has received grants and/or provision of investigational medicinal product from BMS/Celgene, Dietmar-Hopp-Foundation, Janssen and Sanofi; research support from Amgen, BMS, Celgene, GlycoMimetics, GSK, Heidelberg Pharma, Hoffmann-La Roche, Janssen, Millenium Pfizer, Sanofi and Novartis; advisory board fees from BMS, GSK, Janssen and Sanofi; honoraria from Amgen, BMS, GSK, Janssen, Oncopeptides, Sanofi and Pfizer; and support for attending meetings and/or travel form Amgen, BMS, GSK, Janssen, Oncopeptides, Sanofi and Pfizer. N.K. has received research funding from Janssen and AbbVie, and has served on an advisory board for Janssen. K.H.M. has received funding from the Multiple Myeloma Research Foundation, the American Society of Hematology and the IMS. L.B.B. served as a consultant for Genentech. F.M. has received consulting fees from Medidata and Sanofi. B.D. reports consulting via an independent data review committee for Janssen. All other authors declare no competing interests.

Update of

Temporal Genomic Dynamics Shape Clinical Trajectory in Multiple Myeloma.
Maura F, Kaddoura M, Poos AM, Baughn LB, Ziccheddu B, Bärtsch MA, Cirrincione A, Maclachlan K, Chojnacka M, Diamond B, Papadimitriou M, Blaney P, John L, Reichert P, Huhn S, Gagler D, Zhang Y, Dogan A, Lesokhin AM, Davies F, Goldschmidt H, Fenk R, Weisel KC, Mai EK, Korde N, Morgan GJ, Rajkumar SV, Kumar S, Usmani S, Landgren O, Raab MS, Weinhold N. Maura F, et al. bioRxiv [Preprint]. 2024 Sep 4:2024.08.30.610457. doi: 10.1101/2024.08.30.610457. bioRxiv. 2024. Update in: Nat Genet. 2025 Sep;57(9):2203-2214. doi: 10.1038/s41588-025-02292-1. PMID: 39282268 Free PMC article. Updated. Preprint.

References

1. Maura, F. et al. Moving from cancer burden to cancer genomics for smoldering myeloma: a review. JAMA Oncol. 6, 425–432 (2020). - PubMed - PMC
1. Morgan, G. J., Walker, B. A. & Davies, F. E. The genetic architecture of multiple myeloma. Nat. Rev. Cancer 12, 335–348 (2012). - PubMed
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1. Kyle, R. A. et al. Long-term follow-up of monoclonal gammopathy of undetermined significance. N. Engl. J. Med. 378, 241–249 (2018). - PubMed - PMC

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Temporal genomic dynamics shape clinical trajectory in multiple myeloma

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Temporal genomic dynamics shape clinical trajectory in multiple myeloma

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