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  • Review Article
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The genetic architecture of multiple myeloma

Nature Reviews Cancer volume 12, pages 335–348 (2012)Cite this article

Subjects

Key Points

  • The initiation of myeloma is mediated by the interaction of environmental factors and inherited genetic events that, when combined with the normal physiological processes that are necessary to generate antibody diversity, result in genetic changes that lead to the immortalization of a myeloma-propagating cell. Chief among these events are chromosomal translocations and hyperdiploidy.

  • Based on their distribution in most clonal cells, chromosomal translocations that are generated by aberrant class switch recombination have been suggested to be initiating events occurring early in the disease process. As a result of these translocations, oncogenes can be placed under the control of the strong enhancers of the immunoglobulin gene loci, leading to their increased expression.

  • The interaction of normal plasma cells with their supportive microenvironment is crucial for plasma cell longevity. A characteristic feature of myeloma cells is the requirement for an intimate relationship with the bone marrow microenvironment, where plasma cells are nurtured in specialized niches that facilitate the growth of the myeloma clone. Derangement of these interactions is important in the immortalization of a myeloma-propagating cell.

  • The basic premise underlying the progression of myeloma is that multiple mutations in different pathways collaborate to deregulate the intrinsic biology of the plasma cell, changing it in ways that lead to the features of myeloma. The immortalized cell then acquires additional genetic hits over time, thus leading to the clinically recognized features of myeloma and eventually to the development of treatment resistance and an ability to grow in the peripheral blood as a leukaemic phase.

  • It is becoming increasingly clear that the molecular events acquired during myeloma progression are not acquired in a linear fashion but instead through branching, nonlinear pathways, similar to the mechanism suggested by Darwin to explain the evolution of species. Therefore, a further level of the genetic complexity of myeloma is based on intraclonal heterogeneity at the level of a myeloma-propagating cell.

  • The genetic lesions that lead to myeloma are best considered within the categories of inherited variation, translocations, copy number abnormalities, mutations, and methylation and miRNA abnormalities. The net biological impact of such events is to modify the behaviour of the myeloma-propagating cell, resulting in the key molecular hallmarks of myeloma.

  • The treatments that are used for myeloma include steroids, alkylating agents, the immunomodulatory drugs thalidomide and lenalidomide, proteasome inhibitors and autologous stem cell transplantation. Current therapeutic aims are to induce and maintain long-term remission. Future approaches based on personalized medicine strategies will involve targeted therapies combined with molecular-diagnostic strategies.

  • The presence of intraclonal heterogeneity has important effects on the clinical application of both standard and targeted treatment strategies but provides a model system within which to assess their optimum use.

Abstract

Based on the clinical features of myeloma and related malignancies of plasma cells, it has been possible to generate a model system of myeloma progression from a normal plasma cell through smouldering myeloma to myeloma and then plasma cell leukaemia. Using this model system we can study at which points the genetic alterations identified through whole-tumour molecular analyses function in the initiation and progression of myeloma. Further genetic complexity, such as intraclonal heterogeneity, and insights into the molecular evolution and intraclonal dynamics in this model system are crucial to our understandings of tumour progression, treatment resistance and the use of currently available and future treatments.

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Figure 1: The B cell immune response.
Figure 2: Initiation and progression of myeloma.
Figure 3: Pathways to myeloma.
Figure 4: A cellular wiring diagram of a typical myeloma cell.
Figure 5: The key genetic changes in the myeloma genome.
Figure 6: The impact of treatment on intraclonal diversity.

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Acknowledgements

We would like to acknowledge Myeloma UK for programme funding. F.E.D. is a Cancer Research UK Senior Cancer Fellow. In addition, we would also like to thank M. Greaves, L. Melchor, M. Kaiser and D. Gonzalez for their helpful discussions.

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  1. Division of Molecular Pathology, Haemato-oncology Research Unit, The Institute of Cancer Research and the Royal Marsden Hospital, 15 Cotswold Road, Sutton, SM2 5NG, Surrey, UK

    Gareth J. Morgan, Brian A. Walker & Faith E. Davies

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  1. Gareth J. Morgan
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  2. Brian A. Walker
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Correspondence to Gareth J. Morgan.

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Glossary

Paraproteinaemias

The clinical diseases that produce a paraprotein (immunoglobulin from a single clone that is present at high levels in the serum) and include myeloma, monoclonal gammopathy of undetermined significance (MGUS) and Waldenstrom's macroglobulinaemia (WM).

Plasma cell

A terminally differentiated quiescent B cell that secretes large amounts of antibodies.

Germinal centre

The site within a lymph node where B cells undergo affinity maturation of their antibody through somatic hypermutation (SHM). During this process the B cells rapidly proliferate and differentiate and are selected for increasingly specific antibodies against the antigen.

Class switch recombination

(CSR). A region-specific deletional recombination reaction that replaces one switch region with another. This allows the production of different immunoglobulin isotypes.

Immunoglobulin isotypes

Immunoglobulin (Ig) isotypes are defined by the heavy and light chain locus constant regions used by the Ig. These constant regions are encoded within the IGH@ locus (heavy chain) on chromosome 14 or the IGK@ and IGL@ loci (light chain) on chromosomes 2 and 22, respectively. There are nine heavy chain isotypes: IgM, IgD, IgE, IgA1, IgA2, IgG1, IgG2, IgG3 and IgG4. Two light chain isotypes exist, kappa and lambda.

Centroblast

A lymphocyte that has a large, non-cleaved nucleus. B cells that are proliferating and undergoing affinity maturation in response to stimulus, within the germinal centre, are termed centroblasts. These cells mature to centrocytes within the germinal centre before they leave to become plasmablasts.

Unfolded protein response

(UPR). This is a cellular stress pathway that is activated in response to an accumulation of unfolded or misfolded proteins. In myeloma plasma cells this pathway is crucial for dealing with the large quantities of immunoglobulin (or paraprotein) that are produced by the cells. Disruption of this pathway in plasma cells can lead to apoptosis.

Serological memory

The presence of immunoglobulin in the serum, usually from mature B cells that have undergone somatic hypermutation and class switch recombination in a germinal centre.

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Morgan, G., Walker, B. & Davies, F. The genetic architecture of multiple myeloma. Nat Rev Cancer 12, 335–348 (2012). https://doi.org/10.1038/nrc3257

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