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  • Review Article
  • Published:

Evolutionary biology of high-risk multiple myeloma

Nature Reviews Cancer volume 17, pages 543–556 (2017)Cite this article

Subjects

Key Points

  • Treatment of myeloma has developed rapidly over the past two decades with the advent of proteasome inhibitors and immunomodulatory agents. Despite their dramatic impact on overall patient outcomes, there remains a high-risk group of patients, constituting 20–30% of all cases, who have not benefited to the same extent and continue to have poor outcomes.

  • There is no single pathogenic mechanism that can currently be used to unify and define high-risk disease; instead, the common features are clinically aggressive behaviours, including therapy resistance, proliferation and evasion of apoptosis, which are the consequences of following several evolutionary trajectories driven by distinct gene–gene interactions.

  • The key molecular hallmarks of high-risk disease biology include increased proliferation and the development of a high-risk ecosystem that facilitates both cancer cell survival and failure of the immune response.

  • Genetic lesions underlie the key hallmarks of high-risk disease states and may occur as tumour initiating or progression events. No one of these lesions explains all high-risk disease, and in order to effectively target high-risk disease, we need to understand how these drivers arise, interact with each other and mediate their downstream effects.

  • Pathologically, the high-risk biological states of multiple myeloma are the end stage of a multi-step clinical progression system typical of multiple myeloma comprising benign monoclonal gammopathy; an intermediate stage lacking clinical damage; multiple myeloma itself, which has a range of clinical behaviours; and an easily recognizable leukaemic phase wherein disease is no longer confined to the bone marrow. This progression system is driven by subclonal competition and selective pressures within the bone marrow microenvironment.

  • To improve the outcomes of patients with high-risk disease, it is important to recognize them at disease presentation and to enter them into specific risk-stratified clinical trials. The heterogeneous nature of the molecular mechanisms underlying high-risk disease makes this challenging and is discussed in detail.

Abstract

The outcomes for the majority of patients with myeloma have improved over recent decades, driven by treatment advances. However, there is a subset of patients considered to have high-risk disease who have not benefited. Understanding how high-risk disease evolves from more therapeutically tractable stages is crucial if we are to improve outcomes. This can be accomplished by identifying the genetic mechanisms and mutations driving the transition of a normal plasma cell to one with the features of the following disease stages: monoclonal gammopathy of undetermined significance, smouldering myeloma, myeloma and plasma cell leukaemia. Although myeloma initiating events are clonal, subsequent driver lesions often occur in a subclone of cells, facilitating progression by Darwinian selection processes. Understanding the co-evolution of the clones within their microenvironment will be crucial for therapeutically manipulating the process. The end stage of progression is the generation of a state associated with treatment resistance, increased proliferation, evasion of apoptosis and an ability to grow independently of the bone marrow microenvironment. In this Review, we discuss these end-stage high-risk disease states and how new information is improving our understanding of their evolutionary trajectories, how they may be diagnosed and the biological behaviour that must be addressed if they are to be treated effectively.

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Figure 1: A convergent evolutionary route to high-risk myeloma via dysregulation of the G1/S cell cycle checkpoint.
Figure 2: The interaction between genetic drivers and microenvironment changes drives high-risk disease states.
Figure 3: The structural changes to chromosome 1 involved in mediating high-risk multiple myeloma states.
Figure 4: Myeloma clonal evolution to high-risk.
Figure 5: Clonal sweeps and proposed model of regional evolution.

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Acknowledgements

C.P. is a Wellcome Trust clinical research fellow (102363/Z/13/Z). The authors would like to thank F. Davies, M. Greaves, J. Jones, C. Messiou, L. Rasche, J. Sawyer, C. Stein, B. Walker, N. Weinhold and S. Yaccoby for contributing to the figures, helpful discussions and/or critical reading of the manuscript.

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Authors and Affiliations

  1. The Institute of Cancer Research, 15 Cotswold Road, Sutton, SM2 5NG, UK

    Charlotte Pawlyn

  2. The Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, 72205, Arkansas, USA

    Gareth J. Morgan

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C.P. and G.J.M. researched data for the article, made substantial contributions to discussions of the content, wrote the article and reviewed and/or edited the manuscript before submission.

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Correspondence to Charlotte Pawlyn.

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Competing interests

C.P. has participated in advisory boards for Celgene and Takeda Oncology and has received travel support from Celgene and Janssen. G.J.M. has participated in advisory boards for, received payment for lectures and the development of educational presentations from, and received travel support from Celgene, Novartis, Merck and Johnson & Johnson.

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Glossary

V(D)J recombination

A process occurring in the primary lymphoid organs and involving the somatic recombination of different segments of the heavy- and light-chain immunoglobulin genes, variable (V), joining (J) and diversity (D, heavy chain only), resulting in a diverse repertoire of antigen-binding regions.

Class-switch recombination

A process that enables the production of immunoglobulins (Igs) of different isotypes (IgG, IgM, IgE or IgD) by removing portions of the antibody heavy-chain locus. This occurs after V(D)J recombination and thus results in antibodies with the same antigenic specificity but with the ability to mediate different downstream effects.

Somatic hypermutation

Targeted nucleotide mutations affecting the variable regions of immunoglobulin genes in B cells to mediate affinity maturation.

Plasma cell leukaemia

(PCL). Myeloma circulating in the bloodstream. Defined by the World Health Organization as a condition in which plasma cells constitute more than 20% of the cells in peripheral blood, with an absolute plasma cell count of more than 2 × 109 per litre.

Extramedullary disease

(EMD). Myeloma existing outside the bone marrow, in the soft tissue or organs.

Convergent evolution

Different clonal populations evolving the same traits as a result of having to adapt to similar environments. The phenotype confers a selective advantage to such an extent that different molecular lesions leading to the same phenotype are selected for in different populations.

International Staging System

(ISS). Staging system for myeloma based on the plasma level of β2-microglobulin and albumin, yielding three groups associated with survival outcomes.

Interphase fluorescence in situ hybridization

(iFISH). A cytogenetic test that maps fluorescent probes to specific parts of the chromosome with the cell in interphase.

Revised International Staging System

(R-ISS). A revised risk score of the initial ISS that incorporates the high-risk cytogenetic markers 17p- and t(4;14) together with lactate dehydrogenase.

Immunoparesis

Reduced levels of uninvolved immunoglobulins, occurring as a consequence of the displacement of normal plasma cells from their bone marrow niche by malignant plasma cells better adapted to the niche.

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Pawlyn, C., Morgan, G. Evolutionary biology of high-risk multiple myeloma. Nat Rev Cancer 17, 543–556 (2017). https://doi.org/10.1038/nrc.2017.63

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