The incidence of multiple myeloma is higher in males. The underlying mechanisms may be related to differences in immune system orchestration in males and females. LAG3 and CTLA4 are immune checkpoint proteins and inhibitory regulators of T cells. Here, we analyzed the prevalence of the common LAG3 gene variant rs870849 and the common CTLA4 gene variant rs231775 in myeloma patients eligible for autologous stem cell transplantation. CTLA4 rs231775 was prevalent at normal allele frequencies. In contrast, LAG3 rs870849 was prevalent at elevated allele frequencies in myeloma patients, with allele frequency 0.61 in male and 0.53 in female patients compared to 0.39 in the European population. The gene risk analysis of rs870849 indicated an odds ratio 6.8 in male and 3.6 in female patients. Moreover, treatment outcomes differed in the three genetic LAG3 subgroups with median progression-free survival of 2.6, 3.3 and 3.4 and median overall survival of 7, 15 and 18 years in the I455hom, I455Thet and T455hom subgroups, respectively. LAG3 rs870849 may affect survival and treatment outcome after autologous stem cell transplantation in myeloma patients with favorable outcomes in rs870849 carriers.

Background: Clinical outcomes for multiple myeloma are highly variable. Inherited genetic variants of immune regulatory genes can modulate disease susceptibility and clinical outcomes. The germline variant CTLA4 rs231775 polymorphism may alter T-cell function and affect clinical outcomes. Methods: We conducted a retrospective single-center study including 156 consecutive myeloma patients who underwent first-line ASCT. The patients were stratified according to the CTLA4 rs231775 genotype and disease stage (ISS I–III). Results: The CTLA4 rs231775 AA genotype was associated with inferior PFS in ISS I–II and superior PFS in ISS III. In the multivariate analysis, the CTLA4 rs231775 AA genotype emerged as a potential risk factor in ISS I-II and a potential protective factor in ISS III. Conclusions: This germline CTLA4 polymorphism may serve as biomarker to refine post-transplant risk stratification and enable personalized treatment management.