Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Myeloma

Minor clone provides a reservoir for relapse in multiple myeloma

Abstract

Recent studies have provided direct evidence for genetic variegation in subclones for various cancer types. However, little is known about subclonal evolutionary processes according to treatment and subsequent relapse in multiple myeloma (MM). This issue was addressed in a cohort of 24 MM patients treated either with conventional chemotherapy or with the proteasome inhibitor, bortezomib. As MM is a highly heterogeneous disease associated with a large number of chromosomal abnormalities, a subset of secondary genetic events that seem to reflect progression, 1q21 gain, NF-κB-activating mutations, RB1 and TP53 deletions, was examined. By using high-resolution single-nucleotide polymorphism arrays, subclones were identified with nonlinear complex evolutionary histories. Such reordering of the spectrum of genetic lesions, identified in a third of MM patients during therapy, is likely to reflect the selection of genetically distinct subclones, not initially competitive against the dominant population but which survived chemotherapy, thrived and acquired new anomalies. In addition, the emergence of minor subclones at relapse appeared to be significantly associated with bortezomib treatment. These data support the idea that new strategies for future clinical trials in MM should combine targeted therapy and subpopulations’ control to eradicate all myeloma subclones in order to obtain long-term remission.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

Similar content being viewed by others

Accession codes

Accessions

Gene Expression Omnibus

References

  1. Barlogie B, Tricot G, Anaissie E, Shaughnessy J, Rasmussen E, van Rhee F et al. Thalidomide and hematopoietic-cell transplantation for multiple myeloma. N Engl J Med 2006; 354: 1021–1030.

    Article  CAS  PubMed  Google Scholar 

  2. Facon T, Mary JY, Hulin C, Benboubker L, Attal M, Pegourie B et al. Melphalan and prednisone plus thalidomide versus melphalan and prednisone alone or reduced-intensity autologous stem cell transplantation in elderly patients with multiple myeloma (IFM 99-06): a randomised trial. Lancet 2007; 370: 1209–1218.

    Article  CAS  PubMed  Google Scholar 

  3. San Miguel JF, Schlag R, Khuageva NK, Dimopoulos MA, Shpilberg O, Kropff M et al. Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J Med 2008; 359: 906–917.

    Article  CAS  PubMed  Google Scholar 

  4. Harousseau JL, Attal M, Avet-Loiseau H, Marit G, Caillot D, Mohty M et al. Bortezomib plus dexamethasone is superior to vincristine plus doxorubicin plus dexamethasone as induction treatment prior to autologous stem-cell transplantation in newly diagnosed multiple myeloma: results of the IFM 2005-01 phase III trial. J Clin Oncol 2010; 28: 4621–4629.

    Article  CAS  PubMed  Google Scholar 

  5. Rajkumar SV, Jacobus S, Callander NS, Fonseca R, Vesole DH, Williams ME et al. Lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone as initial therapy for newly diagnosed multiple myeloma: an open-label randomised controlled trial. Lancet Oncol 2010; 11: 29–37.

    Article  CAS  PubMed  Google Scholar 

  6. Greaves M, Maley CC . Clonal evolution in cancer. Nature 2012; 481: 306–313.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Fonseca R, Bergsagel PL, Drach J, Shaughnessy J, Gutierrez N, Stewart AK et al. International Myeloma Working Group molecular classification of multiple myeloma: spotlight review. Leukemia 2009; 23: 2210–2221.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Walker BA, Leone PE, Jenner MW, Li C, Gonzalez D, Johnson DC et al. Integration of global SNP-based mapping and expression arrays reveals key regions, mechanisms, and genes important in the pathogenesis of multiple myeloma. Blood 2006; 108: 1733–1743.

    Article  CAS  PubMed  Google Scholar 

  9. Avet-Loiseau H, Li C, Magrangeas F, Gouraud W, Charbonnel C, Harousseau JL et al. Prognostic significance of copy-number alterations in multiple myeloma. J Clin Oncol 2009; 27: 4585–4590.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Avet-Loiseau H, Facon T, Grosbois B, Magrangeas F, Rapp MJ, Harousseau JL et al. Oncogenesis of multiple myeloma: 14q32 and 13q chromosomal abnormalities are not randomly distributed, but correlate with natural history, immunological features and clinical presentation. Blood 2002; 99: 2185–2191.

    Article  CAS  PubMed  Google Scholar 

  11. Lin M, Wei LJ, Sellers WR, Lieberfarb M, Wong WH, Li C . dChipSNP: significance curve and clustering of SNP-array-based loss-of-heterozygosity data. Bioinformatics 2004; 20: 1233–1240.

    Article  CAS  PubMed  Google Scholar 

  12. Rozen S, Skaletsky HJ . Bioinformatics methods and protocols. In Krawetz S, Misener S, (eds) Methods in Molecular Biology. Humana Press: Totowa, NJ, pp 365–386, 2000.

    Google Scholar 

  13. Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci USA 2005; 102: 15545–15550.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Matsui W, Huff CA, Wang Q, Malehorn MT, Barber J, Tanhehco Y et al. Characterization of clonogenic multiple myeloma cells. Blood 2004; 103: 2332–2336.

    Article  CAS  PubMed  Google Scholar 

  15. Jakubikova J, Adamia S, Kost-Alimova M, Klippel S, Cervi D, Daley JF et al. Lenalidomide targets clonogenic side population in multiple myeloma: pathophysiologic and clinical implications. Blood 2011; 117: 4409–4419.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Hastings PJ, Ira G, Lupski JR . A microhomology-mediated break-induced replication model for the origin of human copy number variation. PLoS Genet 2009; 5: e1000327.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Hastings PJ, Lupski JR, Rosenberg SM, Ira G . Mechanisms of change in gene copy number. Nat Rev Genet 2009; 10: 551–564.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Conrad DF, Bird C, Blackburne B, Lindsay S, Mamanova L, Lee C et al. Mutation spectrum revealed by breakpoint sequencing of human germline CNVs. Nat Genet 2010; 42: 385–391.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Annunziata CM, Davis RE, Demchenko Y, Bellamy W, Gabrea A, Zhan F et al. Frequent engagement of the classical and alternative NF-kappaB pathways by diverse genetic abnormalities in multiple myeloma. Cancer Cell 2007; 12: 115–130.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Keats JJ, Fonseca R, Chesi M, Schop R, Baker A, Chng WJ et al. Promiscuous mutations activate the noncanonical NF-kappaB pathway in multiple myeloma. Cancer Cell 2007; 12: 131–144.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Keats JJ, Chesi M, Egan JB, Garbitt VM, Palmer SE, Braggio E et al. Clonal competition with alternating dominance in multiple myeloma. Blood 2012; 120: 1067–1076.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Egan JB, Shi CX, Tembe W, Christoforides A, Kurdoglu A, Sinari S et al. Whole genome sequencing of multiple myeloma from diagnosis to plasma cell leukemia reveals genomic initiating events, evolution and clonal tides. Blood 2012; 120: 1060–1066.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Walker BA, Wardell CP, Melchor L, Hulkki S, Potter NE, Johnson DC et al. Intraclonal heterogeneity and distinct molecular mechanisms characterize the development of t(4;14) and t(11;14) myeloma. Blood 2012; 120: 1077–1086.

    Article  CAS  PubMed  Google Scholar 

  24. Mullighan CG, Phillips LA, Su X, Ma J, Miller CB, Shurtleff SA et al. Genomic analysis of the clonal origins of relapsed acute lymphoblastic leukemia. Science 2008; 322: 1377–1380.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Anderson K, Lutz C, van Delft FW, Bateman CM, Guo Y, Colman SM et al. Genetic variegation of clonal architecture and propagating cells in leukaemia. Nature 2011; 469: 356–361.

    Article  CAS  PubMed  Google Scholar 

  26. Notta F, Mullighan CG, Wang JC, Poeppl A, Doulatov S, Phillips LA et al. Evolution of human BCR-ABL1 lymphoblastic leukaemia-initiating cells. Nature 2011; 469: 362–367.

    Article  CAS  PubMed  Google Scholar 

  27. Ding L, Ley TJ, Larson DE, Miller CA, Koboldt DC, Welch JS et al. Clonal evolution in relapsed acute myeloid leukaemia revealed by whole-genome sequencing. Nature 2012; 481: 506–510.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Lopez-Corral L, Gutiérrez NC, Vidriales MB, Mateos MV, Rasillo A, García-Sanz R et al. The progression from MGUS to smoldering myeloma and eventually to multiple myeloma involves a clonal expansion of genetically abnormal plasma cells. Clin Cancer Res 2011; 17: 1692–1700.

    Article  CAS  PubMed  Google Scholar 

  29. Hanamura I, Stewart JP, Huang Y, Zhan F, Santra M, Sawyer JR et al. Frequent gain of chromosome band 1q21 in plasma-cell dyscrasias detected by fluorescence in situ hybridization: incidence increases from MGUS to relapsed myeloma and is related to prognosis and disease progression following tandem stem-cell transplantation. Blood 2006; 108: 1724–1732.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Chiecchio L, Dagrada GP, Ibrahim AH, Dachs Cabanas E, Protheroe RK, Stockley DM et al. Timing of acquisition of deletion 13 in plasma cell dyscrasias is dependent on genetic context. Haematologica 2009; 94: 1708–1713.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Chapman MA, Lawrence MS, Keats JJ, Cibulskis K, Sougnez C, Schinzel AC et al. Initial genome sequencing and analysis of multiple myeloma. Nature 2011; 471: 467–472.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Morgan GJ, Walker BA, Davies FE . The genetic architecture of multiple myeloma. Nat Rev Cancer 2012; 12: 335–348.

    Article  CAS  PubMed  Google Scholar 

  33. Munshi NC, Anderson KC, Bergsagel PL, Shaughnessy J, Palumbo A, Durie B et al. International Myeloma Workshop Consensus Panel 2. Consensus recommendations for risk stratification in multiple myeloma: report of the International Myeloma Workshop Consensus Panel 2. Blood 2011; 117: 4696–4700.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This study was supported by IFM; the French National Research Agency, Grant R08079NS (to SM); the French Institute National du Cancer, Grant R09076NN (to HA-L); the National Institutes of Health, Grants PO1 CA155258-01 (to NCM, SM, HA-L and KCA), RO1-124929 (to NCM), P50-100007 and PO1-78378 (to NCM and KCA), and Department of Veterans Affairs Merit Review Awards. We thank Elise Douillard, Magali Devic, Emilie Maurenton and Nathalie Roi for excellent technical expertise. We also thank Marie C Béné for critical reading of the manuscript.

Author contributions

PM, OD, PG, LG, LV, TF, AMS, GM, CH, PC, MT, EV, ER and HA-L provided study materials or patients, and collected clinical follow-up data. FM, LL, HA-L, WG and SM analyzed the data. FM, HA-L, NCM, KCA and SM designed the study. SM and FM wrote the report. All investigators reviewed the final report.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to S Minvielle.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies the paper on the Leukemia website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Magrangeas, F., Avet-Loiseau, H., Gouraud, W. et al. Minor clone provides a reservoir for relapse in multiple myeloma. Leukemia 27, 473–481 (2013). https://doi.org/10.1038/leu.2012.226

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/leu.2012.226

Keywords

This article is cited by

Search

Quick links