Detailed immunophenotypic and genetic characterization of bone marrow clonal plasma cells and B-cells in early-stage monoclonal gammopathies

Monoclonal gammopathy (MG) of undetermined significance (MGUS) is the earliest and most prevalent stage of MG that may progress to symptomatic multiple myeloma (MM) or Waldenström's macroglobulinemia (WM) through intermediate smoldering forms of both diseases. We used next-generation flow cytometry (NGF) to identify and purify bone marrow (BM) clonal plasma cells (cPC) and B-cells/lymphoplasmacytic cells (cB-cells) from 25 asymptomatic individuals with MG diagnosed within the population-based iStopMM screening program for further molecular analysis by next-generation sequencing (NGS). IgM-MGUS cases consistently exhibited WM-like phenotypes by NGF, and MYD88 p.L265P and/or CXCR4 mutations in the coexisting cPC and cB-cells. Conversely, cPC from non-IgM MGUS and smoldering MM (SMM) displayed a MM-like phenotype associated with genetic drivers -i.e., t(11;14)-, frequently coexisting with genetically unrelated cB-cells. Interestingly, recurrent RUNX1 single nucleotide variants were detected in cPC, but not coexisting cB-cells, from WM-like cases, suggesting a role for RUNX1 in PC differentiation. In summary, NGF enabled detailed immunophenotypic characterization of BM cPC and cB-cell populations in all cases analyzed, subdivided in IgM vs non-IgM cases with WM-like or MM-like phenotypic and genetic profiles, respectively. These findings underscore the potential contribution of NGF and NGS for accurate classification or early-stage disease, beyond conventional criteria.

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Publication Details

Journal
Blood Cancer Journal
Published
2026-07-18
DOI
https://doi.org/10.1038/s41408-026-01579-8
Primary Topic
Multiple Myeloma Research and Treatments
Type
article
Field-Weighted Citation Impact
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article

Detailed immunophenotypic and genetic characterization of bone marrow clonal plasma cells and B-cells in early-stage monoclonal gammopathies

Sigurður Y. Kristinsson, Elín Ruth Reed, Jón Þórir Óskarsson, Luzalba Sanoja-Flores et al.
Blood Cancer Journal
Multiple Myeloma Research and Treatments
article

Detailed immunophenotypic and genetic characterization of bone marrow clonal plasma cells and B-cells in early-stage monoclonal gammopathies

Sigurður Y. Kristinsson, Elín Ruth Reed, Jón Þórir Óskarsson, Luzalba Sanoja-Flores, Maria Gonzalez-Gonzalez, María Jara‐Acevedo, Quentin Lécrevisse, Sigrún Þorsteinsdóttir, Sæmundur Rögnvaldsson, Juan Flores‐Montero, Anton W. Langerak, Þorvarður Jón Löve, Oihane Pérez‐Escurza, Alberto Órfão, Julio Pozo, Silvia Martín, Brian Durie, Stephen Harding, P. Martijn Kolijn, Albert Orfao, ECRIN-M3, on behalf of the iStopMM
article en

Abstract

Monoclonal gammopathy (MG) of undetermined significance (MGUS) is the earliest and most prevalent stage of MG that may progress to symptomatic multiple myeloma (MM) or Waldenström's macroglobulinemia (WM) through intermediate smoldering forms of both diseases. We used next-generation flow cytometry (NGF) to identify and purify bone marrow (BM) clonal plasma cells (cPC) and B-cells/lymphoplasmacytic cells (cB-cells) from 25 asymptomatic individuals with MG diagnosed within the population-based iStopMM screening program for further molecular analysis by next-generation sequencing (NGS). IgM-MGUS cases consistently exhibited WM-like phenotypes by NGF, and MYD88 p.L265P and/or CXCR4 mutations in the coexisting cPC and cB-cells. Conversely, cPC from non-IgM MGUS and smoldering MM (SMM) displayed a MM-like phenotype associated with genetic drivers -i.e., t(11;14)-, frequently coexisting with genetically unrelated cB-cells. Interestingly, recurrent RUNX1 single nucleotide variants were detected in cPC, but not coexisting cB-cells, from WM-like cases, suggesting a role for RUNX1 in PC differentiation. In summary, NGF enabled detailed immunophenotypic characterization of BM cPC and cB-cell populations in all cases analyzed, subdivided in IgM vs non-IgM cases with WM-like or MM-like phenotypic and genetic profiles, respectively. These findings underscore the potential contribution of NGF and NGS for accurate classification or early-stage disease, beyond conventional criteria.

Blood Cancer Journal
Reykjavík University (IS), Cedars-Sinai Medical Center (US), University of Iceland (IS), Universidad de Salamanca (ES), Sahlgrenska University Hospital (SE), Instituto de Salud Carlos III (ES), Erasmus MC (NL), Rigshospitalet (DK), National University Hospital of Iceland (IS), Instituto de Investigación Biomédica de Salamanca (ES), Centro de Investigación del Cáncer (ES), Medical Research Network (US)
Cancer Research UK, Erasmus Medisch Centrum, Ministerio de Ciencia e Innovación, Associazione Italiana per la Ricerca sul Cancro, Consejería de Educación, Junta de Castilla y León, Instituto de Salud Carlos III
Good health and well-being
Openalex Percentile: Top 8%
Multiple Myeloma Research and Treatments
DOIOpen Access PDFOpenAlex
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