P-068: Haplotypes rich in activating killer-cell immnuglobulin-like receptor genes are associated with delay on age of myeloma onset

Abstract

<h3>Background</h3> Natural killer (NK) cells are known for their anti-tumoral cytotoxic effects. Effector NK-cell functions are controlled by interactions between inhibitory and activating killer-cell immnuglobulin-like receptors (iKIRs and aKIRs) on NK cells in the presence of human leukocyte antigen (HLA) class I ligands on target cells. The aim of this study was to investigate the frequency of KIR genotypes with/without their cognate ligands among myeloma (MM) patients compared to a healthy population. <h3>Methods</h3> 178 MM patients diagnosed between 2007-2018 enrolled into the study. The median age of patients was 63 (range, 33-95) with ISS:I/II/III:49/36/37; IgG/IgA/Light chain: 58/22/40 and median lines of treatment of three (range, 1-6) (38% history of transplant). As a control group, 449 healthy subjects screened for HLA and KIR genotyping aged median: 42 (7-82) as related/unrelated hematopoietic stem cell donors were included. The Olerup SSP KIR Genotyping Kit (Olerup, Stockholm, Sweden) and Olerup KIR HLA Ligand Detection Kit was used to type KIR and KIR ligands: For KIR genotype comparisons total AA, AB and BB, their telomeric and centromeric motifs were chosen. <h3>Results</h3> Among aKIR genotypes 2DL5B and 2DS3 were found to be less frequent among MM patients compared to healthy subjects (p=0.001; p=0.04). When KIR receptor genes were evaluated along with their cognate ligands, the frequencies of KIR2DL2 and C1, KIR2DL3 and C1 as well as KIR2DS2 and C1 were found to be less frequent among MM patients (p=0.002; p=0.03; p=0.002). The frequency of patients with aKIR ≥5 was significantly lower among MM patients (P<0.0001). When the total haplotype was compared,AB is more and BB less frequent among patients with similar inheritance of AA (p=0.001). Among MM patients, haplotype AA (with ligands C2+Bw4+) frequency is significantly higher compared to healthy controls (p=0.005). BB haplotype carrying male patients had a four years delay in onset age of diagnosis. This effect was in the opposite direction for females. AA haplotype carrying males had MM diagnosed seven years earlier than negative patients, an effect not visible among females. When the predictors for age at diagnosis was assessed, tAB1 haplotype appears to be a stronger factor (p=0.06) than gender (p=0.76). When impact on early relapse was analyzed cAB1 (n=7) was the only motif to have a minor effect. <h3>Conclusion</h3> This study is the first to demonstrate activating KIR containing haplotypes to be less frequent among myeloma patients when compared to healthy subjects. Furthermore specifically this effect was confirmed in the presence of their ligands and the haplotypes rich in activating KIRs. Haplotype BB which includes the highest and haplotype AA which has the least number of a KIRs were found to influence the age of onset mainly among males delaying (haplotype BB) or earlier onset (Haplotype AA). Similar analysis among smoldering MM is warranted to provide further evidence.