High-producer haplotypes of tumor necrosis factor alpha and lymphotoxin alpha are associated with an increased risk of myeloma and have an improved progression-free survival after treatment

Purpose: To determine the effect of polymorphic variations in the tumor nec rosis factor alpha (TNF alpha) and lymphotoxin alpha (LT alpha) genes on th e predisposition to myeloma and the effect of these polymorphisms on respon se to treatment and overall survival. Patients and Methods: Genotype distribution was determined in 63 patients w ith monoclonal gammopathy of uncertain significance (MGUS) and 198 patients with myeloma and compared with that in 250 age- and sex-matched population -based controls. The effect on treatment response and survival was determin ed in 171 myeloma patients treated with either conventional or high-dose ch emotherapy. Results: Comparison of the extended TNF alpha/LT alpha haplotype in the mye loma cases and controls showed a significant excess of high-producer allele s in the cases. The double heterozygotes TNF1/2 and LT10.5/5.5 were present in 35.8% of cases but in only 18% of the controls; this presence was assoc iated with a significant increased risk of myeloma (odds ratio, 2.05; 95% c onfidence interval, 1.26 to 3.35). A similar odds ratio was seen in the MGU S cases, suggesting that this genotype is associated with the initiation of plasma-cell disorders rather than the progression of MGUS to myeloma. The median overall survival time of myeloma patients was 53.8 months and showed no difference with regard to TNF alpha/LT alpha polymorphic status. A tren d toward an improved progression-free survival was apparent in cases with a high-producer haplotype, although this effect was seen only in patients re ceiving high-dose chemotherapy. Conclusion: individuals with polymorphisms associated with a high productio n of TNF alpha/LT alpha are at a significantly increased risk of developing MGUS and myeloma. The impact of polymorphic status on overall survival is minimal, although there is a trend toward an increased progression-free sur vival in the high-producer group. J Clin Oncol 18:2843-2851, (C) 2000 by Am erican Society of Clinical Oncology.