TNF-a Polymorphism Modulates the Outcome of Multiple Myeloma Patients Treated with Bortezomib

TNF-a is a potent mediator of inflammation and bone resorption that seems to be involved in the malignant transformation of plasma cells, since mononuclear cells, obtained from Multiple Myeloma (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 (1). In addition, TNF-a determination was reported to be a good parameter for estimating tumour mass and for monitoring therapy outcome during treatment with different protocols (2). In particular, TNF-a is able to activate NF-kB, which is the main target of bortezomib (3). Variation in TNF-a levels can be related to gene expression, which is regulated at transcriptional level, as well as to genetic polymorphism. Single nucleotide polymorphisms (SNPs) have been identified at position -308 and -238 in the gene promoter. In particular, a G to A substitution at position -308 is associated with higher levels of TNF-a (1). The aim of this study was to investigate the effect of this TNF-a polymorphism on the outcome of refractory and relapsed MM patients (pts), receiving Bortezomib containing regimen as second line therapy. From September 2005 to April 2008 we selected 90 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. TNF a polymorphism at position -308 was determined on genomic DNA extracted from blood samples. The genotype frequencies obtained (71/90 G/G; 19/90 G/A) 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% (67/90). In MM pts carrying the rarest A allele the overall response was reduced to 58% (11/19 pts), whilst GG carriers showed a better response rate of 79% (56/71 pts) (OR = 0.37). Our data indicate that the SNP at position -308 of the TNF-a gene promoter may be associated with different outcome in patients affected by MM and treated with bortezomib containing regimen. Similar conclusion was reached in a previous study where TNF-a gene promoter could predict the outcome after thalidomide therapy (1). To investigate whether TNF-a SNP is an independent predictor for response to MM therapy, larger studies are necessary, however if these preliminary results will be confirmed, they may represent a rationale for targeting TNF-a in novel therapeutic approaches to MM (4).