OR9 Certain KIR-HLA genotypes show improved progression-free survival in patients with multiple myeloma treated with Isatuximab (SAR650984, Anti-CD38 MAB), lenalidomide and dexamethasone

Aim The functional competency of NK cell is determined by the interactions of germline-encoded killer cell immunoglobulin-like receptors (KIR) and their cognate HLA class I ligands, which are substantially variable between individuals. To determine if certain KIR-HLA interactions modulate the efficacy of Isatuximab (Isa), a chimeric anti-CD38 monoclonal antibody used in clinical trials treating multiple myeloma. Methods We characterized KIR and HLA class I types using luminex rSSO methods on a cohort of 57 patients with relapsed and/or refractory multiple myeloma (RRMM) enrolled on the Isa/Len/Dex trial (NCT01749969). We used Kaplan-Meier methods to estimate progression-free survival (PFS) between patients carrying different KIR genotypes, and between patients carrying or missing distinct KIR + HLA pairs. Results Patients with AA KIR genotypes (carrying more inhibitory KIR s and 0–1 activating KIR ) have higher median PFS compared to those carrying Bx ( AB or BB ) genotypes (carrying less inhibitory KIR s and 2–6 activating KIR s) (Fig. A). Moreover, patients carrying KIR2DL3 + and HLA-C1 + , KIR3DL1 + and HLA-B Bw4 I80+ , and/or KIR3DL2 + and HLA-A3/A11 + have higher median PFS compared to those that were missing these receptor-ligand combinations (Fig.D, E, F). In contrast, patients carrying KIR3DL1 + and HLA-B Bw4 T80+ , KIR2DL1 + and HLA-C2 + and/or KIR2DL2 + and HLA-C1 + showed worst PFS compared to those missing these KIR-HLA pairs (Fig.E, B, C). Carriers of KIR2DS2 and/or KIR2DS3 showed worst PFS compared to those missing these activating KIRs. Presence/absence of KIR2DS1, 2DS4, 2DS5 , and/or 3DS1 did not make any difference in PFS. Conclusions Our results demonstrate that certain KIR-HLA interactions are associated with improved progression free survival in patients with RRMM treated with Isa/Len/Dex. The beneficial impact of individual KIR-HLA combinations is likely due to differences in binding strength or specificity, which influence NK licensing and/or inhibition, and effects the ability to induce ADCC.