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    Myeloma Genomics and Microenvironment and immune profiling

    Deciphering the interplay of immune alterations and microbiome changes along multiple myeloma evolution from premalignant conditions

    P-204: Deciphering the interplay of immune alterations and microbiome changes along multiple myeloma evolution from premalignant conditions

    Thursday, September 26, 2024
    Introduction: Multiple myeloma (MM) is an incurable blood cancer marked by the abnormal growth of plasma cells in the bone marrow. It is always preceded by a premalignant stage known as monoclonal gammopathy of undetermined significance (MGUS), often progressing to smoldering MM (SMM). Growing evidence indicates that the immune microenvironment plays a pivotal role in disease progression. Therefore, understanding these immune alterations is crucial for developing immunotherapeutic strategies to prevent disease advancement and improve patient outcomes. This study evaluated changes in the immune landscape and variations in fecal microbiota during the transition from MGUS to MM.

    Methods: To assess the immune composition-including myeloid and lymphoid T, B, and NK cell subpopulations, as well as immune checkpoint distribution—in both bone marrow (BM) and peripheral blood, we analyzed samples from 13 MGUS patients, 12 SMM patients, and 63 newly diagnosed MM (NDMM) patients. This analysis employed 10-color and 8-color flow cytometry panels. Additionally, we measured cytokine and chemokine levels in BM and peripheral blood using a 48-plex Luminex plate on 72 samples from the same patients, along with 4 healthy donors. We also conducted fecal microbiome profiling on samples from 10 MGUS, 15 SMM, and 16 MM patients to explore potential correlations between bacterial composition and MM progression.

    Results: Through unsupervised analysis of T cells by FlowCT, we identified a substantial increase in circulating TEMRA CD8 T cells, particularly CD57+ cells, accompanied by a significant decrease in naïve TIGIT+ and TIGIT+ TIM3+ CD8 T cells. Within CD4 T subsets, a reduction in BM effector memory phenotype and an elevation in IL17-producing BM CD4 T cells were observed throughout disease progression. Concurrently, non-classical monocytes HLA-DR+ CD11c+ and BM mature granulocytes diminished as MM advanced. Subsequently, the evaluation of cytokines and chemokines levels within BM plasma indicated a reduction in GM-CSF, IFN-α2, IFN-γ, IL-1β, IL-2, IL-2Ra, IL-3, IL-10, IL-13, and MCP-1/CCL2 levels in MM patients, suggesting a potential impairment in their myeloid function and T cell effector activity. Finally, fecal microbiota analysis revealed that in SMM, the Coriobacteriaceae family, part of the Actinobacteria phylum, was prevalent, with a significant presence of the Collinsella species. In MGUS, the dominant bacteria were Clostridia, Enterocloster, Faecalibacillus, and CAG-274, all members of the Firmicutes phylum, contrasting with Ruminococcus prevalence in NDMM.

    Conclusions: This study unveils synchronized immune dysregulation and microbiota shifts in MM evolution, identifying significant indicators of tumor progression and potential therapeutic targets. Data on single cell RNAseq, Abseq, TCRseq and BCRseq from the same patients are currently ongoing and will be presented at the meeting.