Source: DGNews  |  Posted 1 year ago

By Jenny Powers

BARCELONA, Spain -- June 16, 2010 -- The response to standard therapeutics used for the treatment of patients with multiple myeloma (MM) is tempered by genetic variations in drug metabolism, inflammatory response, and DNA repair, researchers said here at the 15th Congress of the European Hematology Association (EHA).

Sophie Corthals, MD, Erasmus University Medical Center, Rotterdam, the Netherlands, presented the findings here on June 13.

The study was prompted by the observation that patients with MM who are treated with thalidomide plus melphalan experience improved overall response and progression-free survival (PFS), but not increased overall survival (OS) because of relapse-associated inferior survival.

Researchers collected peripheral white blood cell DNA from 532 patients with MM who participated in a trial comparing vincristine/doxorubicin/dexamethasone (VAD) with thalidomide plus doxorubicin and dexamethasone (TAD).

Genetic variations were analysed by a custom-built molecular inversion probe (MIP) single-nucleotide polymorphism (SNP) chip that contained 3,404 SNPs selected in "functional regions" within 983 genes that represent cellular functions and pathways thought to influence disease response, toxicities, complications, and survival.

The responses to both TAD and VAD treatment were associated with the drug absorption, distribution, metabolism, and excretion (ADME) genes ABCC1 and ABCC, as demonstrated by SNP association analyses.

The TAD response associated with ABCB11 (P = .002) and ABCC4 (P = .01), genes coding for factors in the inflammatory response, whereas genes involved in cell death associated with the VAD response.

TAD-treated patients had significant associations for both PFS and OS as observed by SNPs located in the DNA repair genes LIG3 and SHFM1 (P = .003 and P = .002, respectively) and the inflammatory genes coding for TNF, SELE, and F13A1 (P = .002 and P = .03, respectively).

SNPs associated with PFS were located in the ADME genes CYP39A1, ABCC2, and CYP2F1.

[Presentation title: Genetic Variations Associated With Treatment Response, Progression Free Survival and Overall Survival in Patients With Multiple Myeloma in the HOVON 50/Gmmg-Hd3 Trials Genetic Variations Associated With Treatment Response, Progression Free Survival and Overall Survival in Patients With Multiple Myeloma in the HOVOn 50/Gmmg-Hd3 Trials. Abstract 0527]