Multiple myeloma (MM) is a haematological malignancy characterised by an uncontrolled clonal proliferation of malignant plasma cells in the bone marrow, invariably preceded by asymptomatic precursor conditions MGUS and smouldering myeloma (SMM). Progression is accompanied by an increasingly dysfunctional immune system that potentially contributes to the loss of immune surveillance. Whilst NK cell dysfunction has been described in MM, no clear picture has emerged of the way in which NK cell function is altered in MM progression.

Using primary patient samples, this study aims to elucidate the effect of MM disease progression on patient NK cell function. In comparison to precursor conditions, we observed functional impairment of MM patient NK cells to both cytokine and tumour target stimulation. NK cell function was consistently impaired in bone marrow NK cells when compared to matched peripheral blood NK cells for all patients. Analysis of NK cell metabolism revealed no differences in mitochondrial mass; but markedly elevated long-chain fatty acid uptake in bone marrow NK cells when compared to matched peripheral blood NK cells. This was particularly evident in bone marrow CD56^bright NK cells, where uptake positively correlated with patient tumour burden. This was accompanied by an increase in the expression of a number of fatty acid receptors on NK cells in the bone marrow. Further work will elucidate the link between fatty acid uptake and NK cell function; however, our findings suggest that the diseased bone marrow environment may play a role in altering NK cell metabolic function that contributes to their dysfunctional state.