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  • Review Article
  • Published:

Genomic complexity of multiple myeloma and its clinical implications

Nature Reviews Clinical Oncology volume 14, pages 100–113 (2017)Cite this article

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This article has been updated

Key Points

  • The development of multiple myeloma is preceded by pre-malignant stages, and therefore constitutes a well-defined model of disease progression that is appropriate for studies of clonal evolution and heterogeneity

  • Whole-exome sequencing studies have enabled the characterization of the genomic alterations underlying the pathogenesis of multiple myeloma

  • The primary genomic events involved in multiple myeloma are the acquisition of hyperdiploidy or translocations affecting the IGH genes; these events are mutually exclusive

  • Secondary genomic events include chromosomal translocations, copy-number variations and single-nucleotide variants

  • Genomic events underlying multiple myeloma affect multiple signalling pathways including the MYC, NF-κB, and MAPK pathways, plasma-cell differentiation, cell-cycle regulation or DNA-damage repair

Abstract

Multiple myeloma (MM) is a genetically complex disease that evolves from pre-malignant stages, such as monoclonal gammaopathy of undetermined significance and smouldering multiple myeloma, and progresses to symptomatic MM; this continuum provides a unique framework to study the sequential genomic evolution of MM. In the past 5 years, results from large-scale whole-exome sequencing studies have provided new insights into the clonal heterogeneity and evolution of the disease. Moreover, the recurrent co-occurrence of genomic events helps to dissect the genomic complexity underlying tumour progression. According to the primary genetic events involved in tumorigenesis, MM tumours are hierarchically subdivided into hyperdiploid and non-hyperdiploid subtypes; subsequently, secondary genetic events lead to tumour progression. In this Review, we describe the 'driver' gene alterations involved in the development and progression of MM, with a focus on the sequential acquisition of the main genomic aberrations. We also provide valuable insight into the clonal heterogeneity and clonal evolution of the disease, as well as into the therapeutic implications of a comprehensive understanding of the genomic complexity of MM.

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Figure 1: Translocations involved in multiple myeloma.
Figure 2: Copy-number variations in multiple myeloma.
Figure 3: Most frequent somatic mutations in patients with multiple myeloma.
Figure 4: Recurrent genetic alterations affecting key pathways involved in multiple myeloma.
Figure 5: Clonal heterogeneity in multiple myeloma.
Figure 6: Proposed model of clonal evolution in multiple myeloma.

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Change history

  • 24 August 2016

    In Figure 4, in the MYC activation subpanel, the genes depicted should be MYC and MAX instead of BIRC2 and NRAS. This error has been corrected in the print and online versions of the article.

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Acknowledgements

We acknowledge funding from the Leukaemia & Lymphoma Society, the Multiple Myeloma Research Foundation and the US NIH.

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Authors and Affiliations

  1. Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, HIM 237, 77 Avenue Louis Pasteur, Boston, 02115, Massachusetts, USA

    Salomon Manier, Karma Z. Salem, Jihye Park & Irene M. Ghobrial

  2. Cancer Program, Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, 02142, Massachusetts, USA

    Salomon Manier, Karma Z. Salem, Jihye Park, Gad Getz & Irene M. Ghobrial

  3. New York Genome Center, 101 Avenue of the Americas, Room 621, New York, 10013, New York, USA

    Dan A. Landau

  4. Weill Cornell Medicine, Belfer Research Building, Room 1428, New York, 10021, New York, USA

    Dan A. Landau

  5. Cancer Center and Department of Pathology, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Boston, 02114, Massachusetts, USA

    Gad Getz

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  1. Salomon Manier
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Contributions

S.M., K.Z.S. and J.P. researched data for the article. S.M., D.A.L., G.G. and I.M.G. contributed to discussions of content. All authors were involved in writing the article, and reviewed and edited the manuscript before submission.

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Correspondence to Irene M. Ghobrial.

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Manier, S., Salem, K., Park, J. et al. Genomic complexity of multiple myeloma and its clinical implications. Nat Rev Clin Oncol 14, 100–113 (2017). https://doi.org/10.1038/nrclinonc.2016.122

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