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The mutagenic impact of melphalan in multiple myeloma

Leukemia volume 35, pages 2145–2150 (2021)Cite this article

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Abstract

The introduction of whole genome and exome sequencing partnered with advanced bioinformatic pipelines has allowed the comprehensive characterization of mutational processes (i.e., mutational signatures) in individual cancer patients. Studies focusing on multiple myeloma have defined several mutational processes, including a recently identified mutational signature (called “SBS-MM1”) directly caused by exposure to high-dose melphalan (i.e., autologous stem cell transplant). High-dose melphalan exposure increases both the overall and nonsynonymous mutational burden detected between diagnosis and relapse by ~10–20%. Nevertheless, most of these mutations are acquired within the heterochromatin and late-replicating regions, rarely involving key myeloma driver genes. In this review, we summarize key studies that made this discovery possible, and we discuss potential clinical implications.

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Fig. 1: History of melphalan mutational signature in multiple myeloma.
Fig. 2: Melphalan mutational signatures.
Fig. 3: SBS-MM1 is detectable only in relapsed multiple myeloma exposed to melphalan.
Fig. 4: Scheme summarizing the single cell expansion and engraftment models.

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Acknowledgements

This work was supported by the Sylvester Comprehensive Cancer Center NCI Core Grant (P30 CA 240139), by the Memorial Sloan Kettering Cancer Center NCI Core Grant (P30 CA 008748), by the Multiple Myeloma Research Foundation (MMRF), by the Perelman Family Foundation, and by the Riney Family Multiple Myeloma Research Program Fund. FM is supported by the American Society of Hematology, the International Myeloma Foundation and The Society of Memorial Sloan Kettering Cancer Center. BD is supported by Myeloma Crowd and Conquer Cancer.

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Author notes

  1. These authors contributed equally: Francesco Maura, Niels Weinhold

  2. These authors jointly supervised this work: Gareth Morgan, Ola Landgren

Authors and Affiliations

  1. Myeloma Program, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA

    Francesco Maura, Dickran Kazandjian & Ola Landgren

  2. Department of Internal Medicine V, Heidelberg University Hospital, Heidelberg, Germany

    Niels Weinhold

  3. Clinical Cooperation Unit (CCU) Molecular Hematology/Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany

    Niels Weinhold

  4. Myeloma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Benjamin Diamond

  5. Multiple Myeloma Program, Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

    Dickran Kazandjian

  6. Department of Internal Medicine II, Division of Oncology and Hematology, Würzburg University Hospital, Würzburg, Germany

    Leo Rasche

  7. Perlmutter Cancer Center, New York University Langone Health, New York, NY, USA

    Gareth Morgan

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  1. Francesco Maura
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FM, NW, GM, LR, DK, BD and OL designed and supervised the study, collected and analyzed the data and wrote the paper.

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Correspondence to Francesco Maura or Ola Landgren.

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Maura, F., Weinhold, N., Diamond, B. et al. The mutagenic impact of melphalan in multiple myeloma. Leukemia 35, 2145–2150 (2021). https://doi.org/10.1038/s41375-021-01293-3

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