No abstract

Background. The regimens of therapy with bortezomib have significantly improved the survival among patients with multiple myeloma (MM). However, the development of peripheral polyneuropathy (PP) resulting from treatment using proteasome inhibitors is still an undesirable event. Risk factors for PP in MM patients include old age, previous neuropathy and use of neurotoxic drugs. Recent studies have established the presence of a genetic component in the mechanism of developing bortezomib-induced neurotoxicity. However, there are conflicting opinions on the role of genetic characteristics in predicting the risk of treatment-induced neuropathy development.Aim. To identify the risk group of bortezomib-induced PP based on the analysis of gene polymorphism of the immune response in patients with newly-diagnosed MM.Materials and methods. A study of the association of 20 polymorphic loci of 14 immune response genes in 46 MM patients was conducted using a candidate gene identification approach. All the patietns were receiving VCD therapy with bortezomib.Results. The distribution of single nucleotide polymorphisms was compared in groups of patients with the presence and absence of PP. It is found that homozygous carriers of the wild type allele of the genes TLR6 (Ser249Pro) (p = 0.006), IL1β (G-1473C) (p = 0.04), IL4 (C-589T) (p = 0.04), as well as haplotype carriers with the mutant allele of the gene IL10 (G-1082A) (p = 0.04) and with the wild type allele gene IL2 (T-330G) (p = 0.01) were significantly more frequent among PP patients.Сonclusion. Our results have confirmed the contribution of the genetic component to the risk of developing bortezomibinduced neuropathy. These findings can be used for individualization of therapeutic approaches to the treatment of MM patients.

Aim. To determine the value of polymorphisms of the immune response genes for the treatment efficacy in MM patients receiving high-dose chemotherapy and autologous hematopoietic stem cell transplantation (autoHSCT). Methods. The overall of 20 ММ patients (8 men and 12 women) were included in the study. The median age was 51.5 years (range 32-67). Clinical laboratory tests had been performed before melphalan high-dose (200 mg/m²) conditioning therapy. In accordance with the achieved anticancer response to induction treatment the patients were divided into 3 groups: patients with partial remission (group 1; n = 7); patients with very good partial remission (group 2; n = 9); patients with complete remission (group 3; n = 4). Genotyping of 20 polymorphic loci of 14 immune response genes was performed using PCR. Results. The study showed that group 2 had no AA mutant homozygotes of IL10 in the G-1082A polymorphic locus compared to group 3 and no TT mutant homozygotes of TLR6 (Ser249Pro) compared to group 1. The patients with more pronounced mucositis (grade 2/3) compared to patients with minor mucositis (grade 0/1) had no CC mutant homozygotes of IL1ß in the G-1473C position and a smaller number of (CT+TT) heterozygous and homozygous haplotype carriers of IL10 with the T mutant allele in the C-819T mutation point. The multivariate analysis showed that the genetic marker statistically effecting the progression-free survival rates in MM patients after high-dose chemotherapy and autoHSCT was the polymorphous status of the IL10 (G-1082A), TNF (G-308A), TLR4 (Thr399Ile), and TLR9 in the T-1237C and A2848 polymorphic loci. Progression-free survival rates correlated with the mutation status of IL1ß (T-511C), IL2 (T-330G), IL6 (C-174G), CD14 (C-159T), TLR3 (Phe421Leu), and TLR4 (Asp299Gly). Conclusion. The obtained data show the correlation of 14 polymorphisms of 10 immune response genes with the immediate results of the induction treatment, and also with the severity of mucositis during the early post-transplant period, as well as overall and progression-free survival rates in MM patients. Due to a small sample volume further studies will be planned with the aim to verify the identified trends. The suggested hypothesis for immune response gene polymorphism effecting a disease prognosis can substantially contribute to developing of individualized approach to MM treatment.