Clonal hematopoiesis is clonally unrelated to multiple myeloma and is associated with specific microenvironmental changes

• - CHIP and myeloma derive from unrelated clones and their co-existence seems to confer only a mild clinical impact in our cohort

• - The myeloma tumor microenvironment shows more inflammation and dysfunctional immune cells in the presence of CHIP

Multiple myeloma (MM) initiation is dictated by genomic events. However, its progression from asymptomatic stages to an aggressive disease that ultimately fails to respond to treatments is also dependent 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 inflamed microenvironment. Here, we show in 106 patients with MM that CHIP is frequently co-existing with MM at diagnosis, associates with a more advanced R-ISS stage, higher age and shows a non-significant trend towards lower median hemoglobin. In our cohort the two conditions do not share a clonal origin. Single cell RNA-sequencing in 16 MM patients highlights significant TME changes when CHIP is present: decreased naïve T cells, a pro-inflammatory TME, decreased antigen-presenting function by dendritic cells and expression of exhaustion markers in CD8 cells. Inferred interactions between cell types in CHIP-positive TME suggested that especially monocytes, T cells and clonal plasma cells may have a prominent role in mediating inflammation, immune evasion and pro-survival signals in favor of MM cells. Altogether, our data show that, in the presence of CHIP, the TME of MM at diagnosis is significantly disrupted in line with what usually seen in more advanced disease, with potential translational implications. Our data highlight the relevance of this association and prompt for further studies on the modifier role of CHIP in the MM TME.