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Multiple Myeloma, Gammopathies

Differentiation stage of myeloma plasma cells: biological and clinical significance

Leukemia volume 31, pages 382–392 (2017)Cite this article

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Abstract

The notion that plasma cells (PCs) are terminally differentiated has prevented intensive research in multiple myeloma (MM) about their phenotypic plasticity and differentiation. Here, we demonstrated in healthy individuals (n=20) that the CD19−CD81 expression axis identifies three bone marrow (BM)PC subsets with distinct age-prevalence, proliferation, replication-history, immunoglobulin-production, and phenotype, consistent with progressively increased differentiation from CD19+CD81+ into CD19−CD81+ and CD19−CD81− BMPCs. Afterwards, we demonstrated in 225 newly diagnosed MM patients that, comparing to normal BMPC counterparts, 59% had fully differentiated (CD19−CD81−) clones, 38% intermediate-differentiated (CD19−CD81+) and 3% less-differentiated (CD19+CD81+) clones. The latter patients had dismal outcome, and PC differentiation emerged as an independent prognostic marker for progression-free (HR: 1.7; P=0.005) and overall survival (HR: 2.1; P=0.006). Longitudinal comparison of diagnostic vs minimal-residual-disease samples (n=40) unraveled that in 20% of patients, less-differentiated PCs subclones become enriched after therapy-induced pressure. We also revealed that CD81 expression is epigenetically regulated, that less-differentiated clonal PCs retain high expression of genes related to preceding B-cell stages (for example: PAX5), and show distinct mutation profile vs fully differentiated PC clones within individual patients. Together, we shed new light into PC plasticity and demonstrated that MM patients harbouring less-differentiated PCs have dismal survival, which might be related to higher chemoresistant potential plus different molecular and genomic profiles.

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Acknowledgements

The authors acknowledge all the participants of the Spanish Myeloma Group. This study was supported by the Cooperative Research Thematic Network grants RD12/0036/0048, RD12/0036/0058, RD12/0036/0046, RD12/0036/0068, RD12/0036/0069, and RD12/0036/0061 of the Red de Cancer (Cancer Network of Excellence); Instituto de Salud Carlos III, Spain, Instituto de Salud Carlos III/Subdirección General de Investigación Sanitaria (FIS: PI060339; 06/1354; 02/0905; 01/0089/01-02; PS09/01897/01370; PI13/01469, PI14/01867, G03/136; Sara Borrell: CD13/00340 and CD12/00540); Fundació La Marató de TV3 (20132130-31-32) and Asociación Española Contra el Cáncer (GCB120981SAN). The study was also supported internationally by the International Myeloma Foundation (IMF) Junior Grant, the Black Swan Research Initiative of the IMF, the Multiple Myeloma Research Foundation research fellow award, the Qatar National Research Fund (QNRF) Award No. 7-916-3-237, Marie Curie (LincMHeM-330598), the AACR-Millennium Fellowship in Multiple Myeloma Research (15-40-38-PAIV), Leukemia Research Foundation and the European Research Council (ERC) 2015 Starting Grant.

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Authors and Affiliations

  1. Clinica Universidad de Navarra, Centro de Investigacion Medica Aplicada (CIMA), IDISNA, Pamplona, Spain

    B Paiva, D Alignani, J A Delgado, M Pascual, X Agirre, F Prosper & J F San-Miguel

  2. Hospital Universitario de Salamanca, Instituto de Investigacion Biomedica de Salamanca (IBSAL), Centro de Investigación del Cancer (IBMCC-USAL, CSIC), Salamanca, Spain

    N Puig, M-B Vidriales, N C Gutierrez & M V Mateos

  3. Hospital 12 de Octubre, Madrid, Spain

    M T Cedena, Y Ruiz, I Rapado, J Martinez-Lopez & J J Lahuerta

  4. Department of Immunology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands

    B G de Jong, M C van Zelm & J J M Van Dongen

  5. Hospital Universitario y Politécnico La Fe, Valencia, Spain

    L Cordon

  6. Department of Immunology and Pathology, Monash University, Melbourne VIC, Australia

    M C van Zelm

  7. Unidad de Hematopatología, Servicio de Anatomía Patológica, Hospital Clínic, Universitat de Barcelona, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain

    J I Martín-Subero

  8. Hospital Universitario de Canarias, Tenerife, Spain

    M T Hernandez

  9. Institut Català d’Oncologia, Institut Josep Carreras, Hospital Germans Trias I Pujol, Badalona, Spain

    A Oriol

  10. Hospital de Donostia, San Sebastian, Spain

    M A Echeveste

  11. Hospital Universitario Josep Trueta, Girona, Spain

    Y Gonzalez

  12. Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, AR, USA

    S K Johnson, J Epstein, B Barlogie & G J Morgan

  13. IBSAL and Department of Medicine, Servicio General de Citometría, Centro de Investigación del Cancer (IBMCC-USAL, CSIC), Universidad de Salamanca, Salamanca, Spain

    A Orfao

  14. Hospital Clínic, IDIBAPS, Barcelona, Spain

    J Blade

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  1. B Paiva
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on behalf of GEM (Grupo Español de MM)/PETHEMA (Programa para el Estudio de la Terapéutica en Hemopatías Malignas) cooperative study groups

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Correspondence to J F San-Miguel.

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Paiva, B., Puig, N., Cedena, M. et al. Differentiation stage of myeloma plasma cells: biological and clinical significance. Leukemia 31, 382–392 (2017). https://doi.org/10.1038/leu.2016.211

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