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Immunoparesis defined by heavy/light chain pair suppression in smoldering multiple myeloma shows initial isotype specificity and involves other isotypes in advanced disease

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Abstract

Smoldering multiple myeloma (SMM) is an asymptomatic and biologically heterogeneous plasma cell disorder, with a highly variable clinical course. Immunoparesis, defined by total immunoglobulin measurements, has been shown to be an independent risk factor for progression to symptomatic disease. The heavy/light chain (HLC) assay allows precise measurement of the polyclonal immunoglobulin of the same isotype, enabling the evaluation of isotype-matched immunoparesis (IMI). In this study, we prospectively characterized immunoparesis, as determined by HLC measurements, in 53 SMM patients. Severe IMI was present in 51% of patients, while severe IP of uninvolved isotypes (HLC IP) was present in 39%. Most of the patients with severe HLC IP presented with severe IMI, but not the other way around. Isotype specificity of immune suppression was suggested by lower relative values of isotype-matched HLC pairs, both for IgG and IgA SMM. Severe IMI was associated with other risk factors for progression while patients with severe IMI and severe HLC IP showed an even higher risk profile. Both severe IMI and severe IgM HLC IP showed a significantly shorter time to progression. Finally, gene expression analysis demonstrated differences in the bone marrow microenvironment between patients with IMI and IMI plus HLC IP, with an increased expression of genes associated with cytolytic cells. In conclusion, our data supports isotype specificity of early immunoglobulin suppression mechanisms. While suppression of both involved and uninvolved isotypes is associated with risk of progression, the later appears to develop with more advanced disease and could be mediated by different mechanisms.

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Availability of data and material

The datasets generated during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

We are very thankful to The Binding Site Group Ltd. (Birmingham, UK) for the technical and material support about HLC concentration using Hevylite™ assays.

Funding

This work was supported in part by grants PI16/00423, PI19/00669, and PI20/00436 from Instituto de Salud Carlos III (Ministerio de Economía y Competitividad, co-funded by Fondo Europeo de Desarrollo Regional (FEDER)-Una manera de Hacer Europa) and 2017SGR00792 (AGAUR; Generalitat de Catalunya).

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Authors and Affiliations

  1. Amyloidosis and Myeloma Unit, Department of Hematology, Hospital Clínic of Barcelona, August Pi I Sunyer Biomedical Research Institute (IDIBAPS), University of Barcelona, 08036, Barcelona, Spain

    Ignacio Isola, David F. Moreno, Mari-Pau Mena, Natalia Tovar, Luis Gerardo Rodríguez-Lobato, Aina Oliver-Caldés, M. Teresa Cibeira, Laura Rosiñol, Joan Bladé & Carlos Fernández de Larrea

  2. Department of Immunology, Hospital de La Santa Creu I Sant Pau, Biomedical Research Institute Sant Pau (IIB Sant Pau), Universitat Autònoma de Barcelona, Barcelona, Spain

    Esther Moga

  3. Amyloidosis and Myeloma Unit, Department of Biochemistry, Hospital Clínic of Barcelona, Barcelona, Spain

    M. Carmen Salgado

  4. Department of Medical Oncology, Hospital Clínic of Barcelona, August Pi I Sunyer Biomedical Research Institute (IDIBAPS), Translational Genomics and Targeted Therapies in Solid Tumors, University of Barcelona, Barcelona, Spain

    Fara Brasó-Maristany & Aleix Prat

  5. Amyloidosis and Myeloma Unit, Department of Immunology, Hospital Clínic of Barcelona, Barcelona, Spain

    Jordi Yagüe

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  1. Ignacio Isola
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  2. David F. Moreno
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Contributions

II designed and performed the research, collected and analyzed data, and wrote the manuscript. DM, MM, FB, and EM performed the research and analyzed data. NT, LGR, AO, MCS, JY, MTC, LR, and JB collected data. AP contributed essential tools for research and analysis. CFL designed the research and analyzed the data. All authors reviewed and approved the final version of the manuscript.

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Correspondence to Carlos Fernández de Larrea .

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Study protocol was approved by the Institutional Review Board at Hospital Clínic of Barcelona.

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Sample collection and clinical record review were performed after informed written consent in accordance with the Declaration of Helsinki.

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Sample collection and clinical record review were performed after informed written consent in accordance with the Declaration of Helsinki.

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C.F.L. has received research grants and consultancy by The Binding Site. All other authors declare no conflict of interest.

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Isola, I., Moreno, D.F., Moga, E. et al. Immunoparesis defined by heavy/light chain pair suppression in smoldering multiple myeloma shows initial isotype specificity and involves other isotypes in advanced disease. Ann Hematol 100, 2997–3005 (2021). https://doi.org/10.1007/s00277-021-04653-2

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