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Molecular basis of clonal evolution in multiple myeloma

Abstract

The treatment outcome of multiple myeloma (MM) is worse than expected from the average numbers of non-synonymous mutations, which are roughly correlated with the prognosis of cancer patients. The refractoriness of MM may be ascribed to the complex genomic architecture and clonal behavior of the disease. In MM, disease progression is accomplished by branching patterns of subclonal evolution from reservoir clones with a propagating potential and/or the emergence of minor clones, which already exist at the MGUS stage and outcompete other clones through selective pressure mainly by therapeutic agents. Each subclone harbors novel mutations and distinct phenotypes including drug sensitivities. In general, mature clones are highly sensitive to proteasome inhibitors (PIs), whereas immature clones are resistant to PIs but could be eradicated by immunomodulatory drugs (IMiDs). The branching evolution is a result of the fitness of different clones to microenvironment and their evasion of immune surveillance; therefore, IMiDs are effective for MM with this pattern of evolution. In contrast, ~ 20% of MM evolve neutrally in the context of strong oncogenic drivers, such as high-risk IgH translocations, and are relatively resistant to IMiDs. Further understanding of the genomic landscape and the pattern of clonal evolution may contribute to the development of more effective treatment strategies for MM.

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Adapted from Walker et al. [13] with permission through Copyright Clearance Center, Inc

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Adapted from Bolli et al. [14] with permission through Copyright Clearance Center, Inc

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Adapted from Johnson et al. [69] with permission through Copyright Clearance Center, Inc

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Adapted from Rasche et al. [70] with permission through Copyright Clearance Center, Inc

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Acknowledgments

YF received the Award in Aki’s Memory from the International Myeloma Foundation Japan. JK received the Kano Foundation Research Grant and a grant from the International Myeloma Foundation Japan.

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Correspondence to Yusuke Furukawa.

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YF received research funding and honoraria from AbbVie Inc., Bristol–Myers Squibb Co., Celgene Co., Janssen Pharmaceutical K.K. and Takeda Pharmaceutical Co. JK declares no conflict of interest.

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Furukawa, Y., Kikuchi, J. Molecular basis of clonal evolution in multiple myeloma. Int J Hematol (2020). https://doi.org/10.1007/s12185-020-02829-6

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Keywords

  • Clonal dynamics
  • Bone marrow microenvironment
  • Branching evolution
  • Neutral evolution
  • Drug sensitivity