Influence of Genetic Single Nucleotide Polymorphisms in CYP3A4, CYP3A5, GSTP1, GSTM1, GSTT1 and MDR1 Genes on Survival and Treatment Related Toxicity in Patients with Multiple Myeloma Treated in the HOVON 24 Trial.

Cytochromes P450 (CYP 450) and gluthatione-S-transferases (GSTs) are drug metabolizing enzymes involved in the detoxification of numerous chemotherapeutic agents.The Multidrug Resistance gene 1 (MDR1, ABCB1) is a transmembrane drug transporter present in tumor cells and mucosal epithelium. Genetic single nucleotide polymorphisms (SNP’s) in these genes are frequent and may alter the metabolism of certain anti-cancer drugs. The CYP3A4*1B (A-290G) polymorphism has not yet been proven to alter enzymatic activity. Polymorphisms in the CYP3A5*3 gene (A6986G) and the GSTP1 gene (Ile105Val) lead to decreased enzymatic activity. Homozygous deletions in the GSTM1 and GSTT1 genes lead to complete absence of the enzyme. Genetic polymorphism of MDR1 (C3435T) are frequent and associated with enhanced efflux function. We hypothesized that SNP haplotypes of these drug metabolizing enzymes may determine the interindividual differences of patients to treatment response and toxicity. We have investigated the presence of SNP’s of 211/345 previously untreated patients with multiple myeloma from whom diagnostic material was available and who were treated according to the HOVON-24 protocol, a clinical trial comparing myeloablative therapy with stem cell rescue added to intensified chemotherapy to intensified chemotherapy alone. Peripheral blood or bone marrow samples were analyzed by PCR or multiplex PCR. Patients with different haplotypes of CYP3A4, GSTP1, GSTM1, GSTT1 genes did not have significant differences of overall survival (OS), time to progression (TTP), progression free survival (PFS), event free survival (EFS), partial remission (PR), complete remission (CR) as determined by multivariate analysis with all clinical variables. Patients with mutant GSTP1(Ile/Val) had significantly more toxicity following high-dose melphalan (p=0.003). Patients with MDR1 C3435T mutation or absence of GSTP1 Ile105Val mutations had a lower probability to achieve at least a partial response(p=0.01). Patients genotyped homozygously for the mutant allele CYP3A5 gene had increased toxicity (p=0.040), improved OS (p=0.01) and PFS (p=0.04) and a decrease in TTP (p=0.03).

This study is part of an ongoing analysis and the results will be validated in the next HOVON trial. We conclude that in patients with multiple myeloma who are treated with intensive chemotherapy and stem cell transplantation, analysis of genetic polymorphisms of metabolic enzymes may improve our understanding of treatment associated toxicity and treatment outcome.