Influence of GST Gene Polimorphisms in the Develovement of Liver Sinusoidal Obstructive Syndrome in Patients with Multiple Myeloma Undergoing Hematopoietic Stem Cell Transplantation.

Introduction: Liver metabolism has two fundamental types of enzymes. Phase two enzymes include GlutathioneS-transferases (GST), with three main variants: GST-M1, GST-T1 and GST-P1. Individual differences in these enzymes could influence their detoxificating capacity.

Aim: To study the influence of several genetic GST liver enzymes variants in the development of liver Sinusoidal Obstruction Syndrome (SOS) in patients with multiple myeloma (MM) that received BUMEL as conditioning regimen for Autologous Stem Cell Transplantation (ASCT).

Patients: 91 patients with MM - included in Spanish protocol Myeloma 2000 that had received BUMEL as conditioning schedule for ASCT - have been studied; 12 of them had developed SOS. 62 healthy individuals as well as 12 patients with monoclonal gammapathy of uncertain significance (MGUS) were also studied.

Methods: Three genotype variants of GST enzymes were studied: presence or absence of GST-M1, GST-T1 and GST-P1 polymorphism Ile105Val by real time PCR in light cycler v2 or ABI PRISM 7900HT thermocyclers. Associations between variables were studied by X² and exact Fisher test. Logistic regression analysis was performed to calculate Odds ratios and relative risk of SOS development.

Results: Significant differences (p>0.0001) were found in the prevalence of homozygous genotype GST-P1 Ile105Val comparing the group of patients with MM and SOS (5 of 12, 41%) and the rest of MM patients without SOS (5 of 79, 6%). This genotype was present in 17% of healthy individuals and MGUS. The genotype absence of GST-M1 was observed in 33% (4/ 12) of MM patients with SOS, 46% (37/79) of MM patients without SOS (p=0.38), 56% of controls and 71% of MGUS. The genotype absence of GST-T1 was observed in 50% (6/ 12) of MM patients with SOS, 27% (22/79) without SOS (p=012), 19% (16/62) of healthy individuals and 21% of MGUS. 33% (4/12) of MM patients with SOS presented the absence of GST-T1 genotype and the presence of homozygous GST-P1 Ile105Val and none of the patients with MM without SOS (p=0,000) presented these genotypes. The only factor associated to development of SOS in regression study was the presence of genotype GST-P1 Ile105Val in homozygosis (OR 10.57 CI 2.45–45.6 p=0.002).

Conclusions: The genotype absence of GST-T1 together with the homozygous GST-P1 Ile105Val polymorphism, especially the latter, should be considered as new risk factors in the development of SOS in MM undergoing ASCT conditioning regimen with BUMEL.