Polymorphisms of the tumor necrosis factor-α gene promoter predict for outcome after thalidomide therapy in relapsed and refractory multiple myeloma

Thalidomide (Thai) is a drug with antiangiogenic, anti-inflammatory, and immunomodulatory properties that was found to inhibit the production of tumor necrosis factor-alpha (TNF-alpha) in vitro. We studied single nucleotide polymorphisms at positions -308 and -238 of the TNF-a gene promoter and measured the corresponding TNF-alpha cytokine levels in 81 patients (pts) with refractory and relapsed multiple myeloma (MM) who were treated with Thai. In myeloma pts carrying the TNF-238A allele (n=8), we found a correlation with higher pretreatment TNF-alpha levels in peripheral blood (P=.047). After Thai administration, this TNF-238A group had a prolonged 12-month progression-free and overall survival of 86% and 100% versus 44% and 84% (P=.003 and P=.07) in pts with the TNF-238G allele, respectively. These findings suggest that regulatory polymorphisms of the TNF-alpha gene can affect TNF-alpha production and predict the outcome after Thai therapy, particularly in those MM pts who are genetically defined as "high producers" of TNF-alpha.