Molecular Clusters and Tumor-Immune Drivers of IgM Monoclonal Gammopathies


 Purpose: IgM MGUS and Waldenstrom Macroglobulinemia (WM) represent a disease spectrum with highly varied therapeutic management ranging from observation to chemoimmunotherapy. The current classification relies solely on clinical features and does not explain the heterogeneity that exists within each of these conditions. Further investigation is warranted to shed light on the biology that may account for the clinical differences. Experimental Design: We used bone marrow (BM) clonal CD19+ and CD138+ sorted cells, matched BM supernatant and peripheral blood serum from 32 patients (7MGUS, 25 WM) to perform the first multi-omics approach including whole exam sequencing, RNA-sequencing, proteomics, metabolomics and mass cytometry. Results: We identified three clusters with distinct pathway activation, immune continent, metabolic and clinical features. Cluster 1 (C1) included only WM patients and was characterized by transcriptional silencing of genes involved in cell cycle and immune response, enrichment of mitochondrial metabolism, infiltration of senescent T effector memory cells and aggressive clinical behavior. Genetic/structural alteration of TNFAIP3 were distinct events of this cluster. C2 compromised both MGUS and WM patients with upregulation of inflammatory response, senescence and glycolysis signatures, increased activated T follicular helper and T regulatory cells, and indolent clinical behavior. C3 also included both MGUS and WM patients and exhibited intermediate features including proliferative and inflammatory signaling, as well as glycolysis and mitochondrial metabolism. Conclusions: We have identified three distinct molecular clusters, suggesting a potential biologic classification that may have therapeutic implications.