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    Myeloma Genomics and Microenvironment and immune profiling

    Category: Myeloma Genomics and Microenvironment and immune profiling

    Integrated multi-omic profiling of immune, soluble, and microbial signatures identifies predictors of multiple myeloma evolution

    (PA-220) Integrated Multi-omic Profiling of Immune, Soluble, and Microbial Signatures Identifies Predictors of Multiple Myeloma Evolution

    Wednesday, September 17, 2025

    • Anna Maria Corsale (she/her/hers)

      Post-doctoral Researcher
      University of Palermo, Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (ProMISE), Palermo, Italy.

    Introduction: Multiple myeloma (MM) is a clonal plasma cell malignancy that develops through precursor stages, including monoclonal gammopathy of undetermined significance (MGUS) and smoldering MM (SMM). Despite well-established clinical criteria, the biological drivers of evolution remain incompletely understood. Here, we applied a multi-omic approach to dissect immune cell phenotypes, cytokine networks, and microbial composition across the MGUS–SMM–MM continuum, aiming to identify early determinants of evolution.

    Methods: We comprehensively characterized the immune landscape by performing scRNAseq and flow cytometric analysis of both BM and peripheral blood (PB) samples from a cohort of 26 and 46 patients, respectively, including MGUS, SMM, and MM. To complement the cellular data, we assessed cytokine and chemokine profiles using 48-plex Luminex assays on 72 patient samples, alongside 4 healthy donors (HDs). Additionally, fecal microbiota profiling was conducted on samples collected from 10 MGUS, 15 SMM, and 16 MM patients.

    Results:

    scRNAseq analysis revealed a progressive upregulation of immune checkpoint-related genes, including CD266, TIGIT, and members of the KIR family, accompanied by a concomitant downregulation of CD96 expression during MM evolution. In parallel, flow cytometric profiling indicated a significant depletion of PB transitional memory CD8⁺ T cells in MM patients, accompanied by an increase in both PB and BM TEMRA CD57⁻ CD8⁺ T cells, compared to MGUS and SMM. The evaluation of cytokine and chemokine levels revealed a marked reduction of multiple immune mediators (including GM-CSF, IFN-α2, IFN-γ, IL-1β, IL-2, IL-2Rα, IL-3, IL-10, IL-13, LIF, and MCP-1/CCL2) in BM plasma of MM patients compared to MGUS, SMM, and HDs, indicating impaired T cell activation, reduced immune cell recruitment, and an overall immunosuppressive milieu. A similar profile of immune mediator reduction was observed in PB plasma. Notably, this immune dysfunction is detectable not only in MM but also in MGUS and SMM patients, when compared to HDs. Complementary gut microbiota profiling identified a shift towards dysbiosis in MM patients, characterized by expansion of pro-inflammatory taxa (Proteobacteria, Enterobacteriaceae, Streptococcaceae) and depletion of beneficial microbial families (e.g., Lachnospiraceae, Bifidobacteriaceae). Notably, microbiota composition correlated with disease stage: MGUS samples retained a eubiotic profile, while SMM showed an intermediate state, mirroring the immune alterations observed in systemic compartments.

    Conclusions:

    Through an integrated multi-omic approach encompassing single-cell transcriptomics, immunophenotyping, cytokine profiling, and gut microbiota analysis, we delineated the progressive immune dysregulation occurring across the spectrum from MGUS to MM. These alterations may serve as predictive biomarkers of evolution and potential targets for preventive or therapeutic interventions.