Association in Outcome of Advanced Multiple Myeloma with Polymorphisms of Inflammatory-Related Genes IL-1A, IL-1B, IL1RN, TNF-a and TNFRSF1B.
Authors: Buda Gabriele , Martino Alessandro , Orciuolo Enrico , Lupia Antonella , Galimberti Sara , Gentile Massimo , Brunori Marino , Morabito Fortunato , Rossi Anna Maria , Petrini Mario 
Published: October 2019

Abstract
Abstract 1723
Poster Board I-749
Proinflammatory cytokines are suspected to play a role in the pathogenesis of multiple myeloma (MM). Therefore, it is possible that inborn genetic variations leading to a modified expression of these cytokines will influence the outcome for these patients (1). Interleukin-1 (IL-1) is a cytokine involved in the maturation and proliferation of B cells and plays a significant role in the development of lytic bone lesions, a major clinical feature of MM patients (pts). Previous studies demonstrated that the polymorphism of IL1b-31 significantly influenced overall survival, as reported in patients undergoing high-dose melphalan treatment followed by autologous-stem cell transplant (2). TNF-a, a potent mediator of inflammation and bone resorption, seems to be involved in the malignant transformation of plasma cells, since mononuclear cells, obtained from MM patients and exposed in vitro to TNF-a and interleukin-4, produced monoclonal plasma cells. In addition, TNF-a can stimulate plasma cell proliferation, by triggering interleukin-6 secretion, and shows proangiogenic properties in vitro. In addition, TNF-a determination was reported to be a good parameter for estimating tumor mass and for monitoring therapy outcome during treatment with different protocols. TNF-a is also able to activate NF-kB, which is the main target of bortezomib. Variation in TNF-a levels can be related to gene expression, which is regulated at transcriptional level, as well as to genetic polymorphism (SNP). Single nucleotide SNPs have been identified at position -308 and -238 in the gene promoter. Specifically, a G to A substitution at position -308 is associated with higher levels of TNF-a (3). TNFRSF1B is a member of the TNF-receptor superfamily. This protein through the recruitment of two anti-apoptotic proteins upgrades TNF-induced apoptosis by the ubiquitination and degradation of TNF-receptor-associated factor 2. Knockout studies in mice also suggest a role of this protein in protecting neurons from apoptosis by stimulating antioxidative pathways (4). In this study, we investigated the correlation between the SNPs of IL1A -889, IL1B -511, IL1B -31, IL1RN -371 (interleukin 1 receptor antagonist), TNF-a -308 and TNFRSF1B -587 on the outcome of refractory and relapsed MM pts, receiving bortezomib containing regimen as second line therapy. From September 2005 to April 2009 we selected 98 MM pts, who received at least one cycle of chemotherapy before treatment with bortezomib and at least one cycle of high dose chemotherapy with peripheral blood stem cell transplantation in 25 pts. No associations between the SNPs at the loci regarding IL-1A, IL-1B, IL-1RN and clinical factors such as age, sex, clinical stage at onset and M-protein type were observed. TNF-a SNP at position -308 and TNFRSF1B SNP at position -587 were determined on genomic DNA extracted from blood samples. These genotypes frequencies obtained were in agreement with Hardy–Weinberg equilibrium. Patients were categorized as responders (complete + partial response = R) or non responders (stable + progression disease = NR) to treatment. The overall response in our patients was about 74.5% (73/98). In MM pts carrying the rarest A allele of TNF-a the overall response was reduced to 61% (14/23 pts), whilst GG carriers showed a better response rate of 79% (59/75pts)(OR=0.42). We obtained similar results from the analysis of TNFRSF1B SNP. Pts carrying the rarest G allele the overall response was reduced to 69% (27/39 pts), whilst TT carriers showed a better response rate of 79% (46/59pts). Our results indicate that the cytokines (IL-1A, IL-1B, IL-1RN) gene SNPs do not confer differences in the outcome of advanced MM. On the contrary TNF-a and TNFRSF1B SNPs seems to be independent factors to predict the response and the outcome in patients affected by MM and treated with bortezomib containing regimen. If these preliminary results will be confirmed, they may represent a rationale for targeting TNF-a in novel therapeutic approaches to MM.

Disclosures
No relevant conflicts of interest to declare.