Polymorphisms of the tumor necrosis factor-alpha gene promoter predict for outcome after thalidomide therapy in relapsed and refractory multiple myeloma.
Thalidomide (Thal) 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-alpha 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 Thal. 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 Thal 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 Thal therapy, particularly in those MM pts who are genetically defined as "high producers" of TNF-alpha.
Department of Internal Medicine V, University of Heidelberg, Hospitalstrasse 3, 69115 Heidelberg, Germany.
Kai
K
Neben
Joannis
J
Mytilineos
Thomas M
TM
Moehler
Astrid
A
Preiss
Alwin
A
Kraemer
Anthony D
AD
Ho
Gerhard
G
Opelz
Hartmut
H
Goldschmidt
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D005787:Gene Frequency; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics*; D016879:Salvage Therapy; D016019:Survival Analysis; D013792:Thalidomide / Q000627:therapeutic use*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*
D014409:Tumor Necrosis Factor-alpha; D013792:Thalidomide