CHIP is clonally unrelated to multiple myeloma and associates with specific microenvironmental changes

Multiple myeloma (MM) initiation is dictated by genomic events at the expense of a post-germinal center B- cell. However, its progression from asymptomatic stages to an aggressive also depends on changes of the tumor microenvironment (TME). Clonal hematopoiesis of indeterminate potential (CHIP) is a prevalent clonal condition of the hematopoietic stem cell whose presence is causally linked to a more incamed TME. Here, we show that CHIP is frequently co- existing with MM at diagnosis, associates with a more advanced ISS stage, trends towards higher age, increased BM PC inRltration and lower median hemoglobin. In our cohort analyzed by single cell RNA- sequencing, the two conditions do not share a clonal origin but, when present, correlate with signiRcant TME changes: a decrease in naïve T-cells, a more pro- incammatory TME, decreased antigen-presenting function by dendritic cells and expression of exhaustion markers in CD8 T-cells. The interaction within TME cells is much thicker in the presence of CHIP, and monocytes especially show a prominent role in mediating incammation and immune evasion signals. Altogether, our data show that, in the presence of CHIP, the TME of MM at diagnosis is signiRcantly disrupted. The changes we found are in line with what usually seen in more advanced disease and in cases that fail to respond to immunotherapies. Our data highlight the relevance of this association and prompt for further studies on the mechanistic link between MM and CHIP.