Multiple myeloma is currently considered incurable1. However, immunotherapies have shown great promise in the refractory/relapse setting2. The combination of Elotuzumab (a monoclonal antibody targeting SLAMF7 on multiple myeloma tumour cells) and Lenalidomide (an immunomodulatory drug) has shown synergistic effects in the clinical trials, resulting in an 86% objective response rate with 16% complete remission, compared to 25% response with Elotuzumab alone3. Elotuzumab recruits NK cells for antibody dependent cell-mediated cytotoxicity4, while Lenalidomide has a wide variety of modulatory effects on various immune compartments. The exact interaction between Lenalidomide and the NK cell in the context of Elotuzumab induced killing forms the focus of this study, addressing why we see such an enhanced response in the clinic. Herein, we hypothesise that Elotuzumab potently activates NK cell killing of myeloma cells, and that this killing efficacy is greatly enhanced by Lenalidomide, directly through the modulation of the immune synapse, and indirectly through modulating the surrounding tumour milieu and immune infiltrate. We have shown it is essential that Elotuzumab engages FcRIII (CD16) on the NK cell for anti-myeloma activity, and that this engagement leads to secretion of cytokines IFNγ and TNF as well as various chemokines, implying recruitment of other immune cells to the tumour. Lenalidomide enhances cytokine/chemokine secretion and anti-myeloma activity in-vitro when using multiple myeloma patient PBMCs, but does not appear to enhance killing activity using healthy donor PBMCs. This implies a recovery of function or repaired defect, as patient NK cell production and function are compromised by the presence of tumour in the bone marrow. Further defining the mechanisms underlying this combinational therapy is critical to understanding the varied patient responses to the treatment, identifying new NK cell biology in the context of disease, and to better inform new therapeutic approaches in the future.