PF568 INVESTIGATING MECHANISMS OF ELOTUZUMAB AND LENALIDOMIDE THERAPY IN MULTIPLE MYELOMA

Abstract

Background:Multiple myeloma (MM) is currently incurable. To investigate new treatment options, patients with refractory relapsed (RR) MM were treated with combination of Elotuzumab (Elo, anti‐SLAMF7 antibody) and Lenalidomide (Len, IMiD) and had a 84% objective response rate. We hypothesized this Elo+Len clinical efficacy was due to repair of NK dysfunction in MM patient NK cells.Aims:To explore the mechanisms whereby Elo+Len rescued MM patient NK cell function.Methods:We co‐cultured MM patient PBMCs with myeloma cells and drug combinations in vitro, and compared changes in NK cell activation, cytotoxicity, cytokine/chemokine levels, and adhesion molecule expression between healthy donor (HD) and MM patient cohorts. We also used a humanized MM model to explore the in vivo efficacy of the Elo+Len combination.Results:We showed that Elo engaged NK cell FcγRIIIa, initiated anti‐myeloma cell cytotoxicity and NK cell secretion of pro‐inflammatory cytokines (IFNγ, TNFα) and chemokines (CCL3, CCL4, CCL5), suggesting recruitment of other immune effector cells to the tumour. Elo+Len treatment significantly enhanced in‐vitro Elo‐induced cytotoxicity of healthy donor (HD) and newly diagnosed MM (NDMM) patient PBMCs. In contrast, RRMM patient NK cells had divergent responses to Elo+Len treatment, including impaired cytotoxicity (7/11 patients), and normal cytotoxicity (4/11 patients) (Fig 1A). Len significantly increased the chemokine secretion of HD PBMCs and to a lesser extent, NDMM and RRMM patient PBMCs, with the exception of CCL5 which was upregulated similarly between all groups. Interestingly, both MM‐derived NK cells and OPM2 myeloma cells upregulated CD54 following Elo and Len therapy, strongly correlated with myeloma cell killing (P = 0.002, R2 = 0.76). This was most evident on the 4 responding RRMM patient PBMCS and their OPM2 targets (Fig 1A‐B, data points highlighted in red). Surprisingly, NK cell CD107a was upregulated equally on all groups in response to Elo, regardless of killing activity. This suggests MM patient dysfunctional NK cells are sufficiently activated to degranulate, but are unable to kill myeloma cells due to inefficient adhesion and synapse formation. We also found that Elo induced in‐vivo therapeutic efficacy of human NK cells against RPMI8226.huSLAMF7 (RPMI8226 cells engineered to express human SLAMF7) multiple myeloma tumors, this was further enhanced with Len co‐treatment (Fig 1C).Summary/Conclusion:Our data suggests that Len improved Elo‐induced tumor control via increased cytotoxicity, chemotactic recruitment of effector cells and enhanced NK‐target synaptic adhesion. These data also suggest that monitoring an increase in CD54 expression on MM patient myeloma cells and NK cells may be a useful biomarker that tracks with Elo+Len efficacy.image