Senescence profiling of monoclonal gammopathies reveals paracrine senescence as a crucial defense against disease progression.

Multiple myeloma (MM) is a plasma cell (PC) malignancy that is preceded by monoclonal gammopathy of undetermined significance (MGUS) and/or smoldering multiple myeloma (SMM). MGUS and SMM PCs exhibit the same primary oncogenic abnormalities as MM but lack the end-organ damage that defines proliferative disease, suggesting that clonal PCs in these precursor conditions could exhibit senescence or senescence-like growth arrest. Herein we identified monoclonal gammopathy patient-derived PCs that exhibit senescence features and found that senescent PCs were significantly increased in MGUS patients compared to SMM or MM. Spatial analysis of senescent PCs in stable MGUS and SMM patient biopsies demonstrated the activation of local paracrine senescence in the bone marrow microenvironment. Stable MGUS and SMM patients also exhibited disease-specific senescence-associated secretory phenotype (SASP) signatures that significantly correlated with PC burden and clonal antibody. In contrast, progressing MGUS, SMM, and new MM patients lacked local paracrine senescence responses and robust activation of disease specific SASP signatures. Overall, these data suggest that failure to activate tumor-specific paracrine senescence responses is key to disease progression in monoclonal gammopathies.