Patients with refractory relapsed multiple myeloma (RRMM) respond to Elotuzumab (Elo) and lenalidomide (Len) combination treatment. The mechanisms underlying this observation are not fully understood. Furthermore, predictive biomarkers of response have not been revealed to date. To address these issues, we used a humanized myeloma mouse model and adoptive transfer of human NK cells to show that Elo and Len treatment controlled myeloma growth, and this was mediated through CD16 on NK cells. In co-culture studies, we showed that PBMCs from a subset of RRMM patients were effective killers of OPM2 myeloma cells when treated with Elo and Len, and this was associated with significantly increased expression of CD54 expression on OPM2 cells. Furthermore, Elo and Len induced OPM2 cell killing and increased OPM2 CD54 expression was dependent on both monocytes and NK cells, and was not mediated by soluble factors alone. At the transcript level, Elo and Len treatment significantly increased OPM2 myeloma cell expression of genes for trafficking and adhesion molecules, NK cell activation ligands and antigen presentation molecules. In conclusion, our findings suggest that MM patients require Elo and Len-mediated upregulation of CD54 on the autologous myeloma cells, in combination with NK cells and monocytes to mediate an effective anti-tumour response. Further, our data suggest that increased myeloma cell CD54 expression levels could be a powerful predictive biomarker for response to Elo and Len treatment.
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