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Myeloma

Phenotypic identification of subclones in multiple myeloma with different chemoresistant, cytogenetic and clonogenic potential

Leukemia volume 29, pages 1186–1194 (2015)Cite this article

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Abstract

Knowledge about clonal diversity and selection is critical to understand multiple myeloma (MM) pathogenesis, chemoresistance and progression. If targeted therapy becomes reality, identification and monitoring of intraclonal plasma cell (PC) heterogeneity would become increasingly demanded. Here we investigated the kinetics of intraclonal heterogeneity among 116 MM patients using 23-marker multidimensional flow cytometry (MFC) and principal component analysis, at diagnosis and during minimal residual disease (MRD) monitoring. Distinct phenotypic subclones were observed in 35/116 (30%) newly diagnosed MM patients. In 10/35 patients, persistent MRD was detected after 9 induction cycles, and longitudinal comparison of patient-paired diagnostic vs MRD samples unraveled phenotypic clonal tiding after therapy in half (5/10) of the patients. After demonstrating selection of distinct phenotypic subsets by therapeutic pressure, we investigated whether distinct fluorescence-activated cell-sorted PC subclones had different clonogenic and cytogenetic profiles. In half (5/10) of the patients analyzed, distinct phenotypic subclones showed different clonogenic potential when co-cultured with stromal cells, and in 6/11 cases distinct phenotypic subclones displayed unique cytogenetic profiles by interphase fluorescence in situ hybridization, including selective del(17p13). Collectively, we unravel potential therapeutic selection of preexisting diagnostic phenotypic subclones during MRD monitoring; because phenotypically distinct PCs may show different clonogenic and cytogenetic profiles, identification and follow-up of unique phenotypic-genetic myeloma PC subclones may become relevant for tailored therapy.

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Acknowledgements

This work was supported by the Cooperative Research Thematic Network (RTICC) RD12/0036/0048, RD12/0036/0058, RD12/0036/0046, RD12/0036/0069 and G03/136, Instituto de Salud Carlos III/ Subdirección General de Investigación Sanitaria (FIS: PI060339; 06/1354; 02/0905; 01/0089/01-02; PS09/01897/01370; Sara Borrell: CD13/00340; Miguel Servet: CP13/00080) and Consejería de Sanidad, Junta de Castilla y León, Valladolid, Spain (HUS396A12-1), Asociación Española Contra el Cáncer (AECC; GCB120981SAN), Spain. The study was also supported internationally by the International Myeloma Foundation (IMF) Junior Grant Proposal and the Multiple Myeloma Research Foundation (MMRF) research fellow award.

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Author notes

  1. T Paíno and B Paiva: These authors contributed equally to this work.

Authors and Affiliations

  1. Centro de Investigación del Cáncer, Instituto de Biología Molecular y Celular del Cáncer/Consejo Superior de Investigaciones Científicas-Universidad de Salamanca (IBMCC, USAL-CSIC), Salamanca, Spain

    T Paíno, L A Corchete, E M Ocio & L San-Segundo

  2. Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain

    T Paíno, J M Sayagués, L A Corchete, E M Ocio, L San-Segundo, M E Sarasquete, R García-Sanz, M-B Vidriales, A Orfao, M-V Mateos & N C Gutiérrez

  3. Clínica Universidad de Navarra, Centro de Investigaciones Médicas Aplicadas (CIMA), Pamplona, Spain

    B Paiva & J F San-Miguel

  4. Servicio General de Citometría y Departamento de Medicina, Universidad de Salamanca, Salamanca, Spain

    J M Sayagués, I Mota, M L Sanchez, P Barcena & A Orfao

  5. Centro do Sangue e da Transplantação de Coimbra, Instituto Português do Sangue e da Transplantação, Coimbra, Portugal

    T Carvalheiro & A Paiva

  6. Hospital Universitario de Salamanca, Salamanca, Spain

    I Aires-Mejía, J J Pérez, E M Ocio, M E Sarasquete, R García-Sanz, M-B Vidriales, M-V Mateos & N C Gutiérrez

  7. Hospital Germans Trias i Pujol, Badalona, Spain

    A Oriol

  8. Hospital Universitario de Canarias, Santa Cruz de Tenerife, Spain

    M-T Hernández

  9. Hospital de Donostia, San Sebastian, Spain

    M-A Echeveste

  10. Hospital Clínic, IDIBAPS, Salamanca, Spain

    J Blade

  11. Hospital 12 de Octubre, Madrid, Spain

    J-J Lahuerta

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  1. T Paíno
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Consortia

on behalf of the GEM (Grupo Español de MM)/PETHEMA (Programa para el Estudio de la Terapéutica en Hemopatías Malignas) cooperative study group

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Correspondence to J F San-Miguel.

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Paíno, T., Paiva, B., Sayagués, J. et al. Phenotypic identification of subclones in multiple myeloma with different chemoresistant, cytogenetic and clonogenic potential. Leukemia 29, 1186–1194 (2015). https://doi.org/10.1038/leu.2014.321

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