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

Abstract

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 KIRs and 0–1 activating KIR) have higher median PFS compared to those carrying Bx (AB or BB) genotypes (carrying less inhibitory KIRs and 2–6 activating KIRs) (Fig. A). Moreover, patients carrying KIR2DL3+ and HLA-C1+, KIR3DL1+ and HLA-B Bw4I80+, 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 Bw4T80+, 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.