A Novel Hypothesis: Certain KIR/Cognate Ligand Containing Genotypes Differ in Frequency Among Patients With Myeloma and Have an Effect on Age of Disease Onset

KIR and KIR-ligand frequencies, alone or in combination, among MM (n:204) and healthy subjects (n:424) showed "cAB1" as a specificity delaying onset of MM in the presence of "C1C2" and "AA" as a predisposing one in the presence of "C1C1" to be associated with earlier onset. Findings independent of R-ISS suggesting an immune modulating role of KIR plus ligand genotypes. Background: Natural killer (NK) cells are known to have cytotoxic effects mediated through killer immunoglobulin-like receptors (KIRs) and their cognate ligands. Role of KIRs in myeloma is yet unresolved. Patients and Methods: KIR genotypes and ligands of 204 newly diagnosed MM patients are compared with 424 healthy subjects. Statistical analysis included t-test, chi-square and binary logistic regression. Results: KIR ligands were significantly more (C2C2: 27.5% vs 15.1%; OR 2.128; 95% CI, 1.417-3.196; P < .001) or less (C1C2: 40.2% vs 51.9%; OR 0.623; 95% CI, 0.444-0.874; P = .006) frequent among MM. Co-occurrence of genotype AA with C2C2 was also higher in frequency among MM (OR 2.509; 95% CI, 1.171-5.378; P = .015) likewise cAB1 with C1C2 was less frequent (OR 0.553; 95% CI, 0.333-0.919; P = .021). Genotypes AA with C1C1, cAB1 with C1C2 or C1C2 alone were associated with a delay (median age: 61 [48-73]; P = .044; 62 [31-81]; P = .030 or 59 [31-85]; P = .028), but AA with C2C2 with an earlier age of onset (48 [29-77]; P = .042). In multivariate analysis including R-ISS, light chain, KIR genotype/ligands; ligand C1C2 ( P = .02) and genotype AA-C1C1 ( P = .037) were independently associated with age of onset & GE;60. Conclusion: C1C2 and C2C2 alone or in combination with KIR genotype (cAB1 and AA, respectively), is observed in less or higher frequency among MM cases and associated with delayed/earlier age of onset, respectively. Genotype AA-C1C1 although in similar frequency between patients and healthy subjects, is also associated with delay. To our knowledge, this is the first study demonstrating an association between KIR and MM onset age, independent from R-ISS or light chain type.