Influence of Genetic Polymorphisms in CYP1A2, CYP2C19, CYP3A4, GSTP1, MDR1 and PSMB5 Genes in Toxicity and Response to Induction Therapy in Multiple Myeloma Patients Included in the Trial of the Spanish PETHEMA/GEM 05 for Newly Diagnosed MM Elderly Patients (Age 65 or More)
Authors: Castilla-Llorente Cristina , de Arriba Felipe , Pérez-Andreu Virginia , Mateos Maria Victoria , González-Conejero Rocio , Rivera Pozo José , Oriol Albert , Martínez-López Joaquin , Teruel Ana Isabel , de Paz Raquel , García-Laraña José , Bengoechea Enrique , Martín Alejandro , Díaz-Mediavilla Joaquín , Palomera Luis , Gonzalez Yolanda , Hernández Jose Mariano , Sureda Anna , Bello Jose Luis , Bargay Joan , Peñalver Francisco Javier , Martin Mateos Maria Luisa , Cibeira María Teresa , Lahuerta Juan José , Blade Joan , San Miguel Jesús F. 
Published: October 2019

Abstract
Abstract 1412
Over the last decade, numerous new drugs have been incorporated in the treatment armamentarium of multiple myeloma (MM). However, there is not much information on the role of single nucleotide polymorphisms (SNPs) regarding toxicity and efficacy of the new myeloma therapies. Aims: to analyze the influence of genetic polymorphisms on toxicity and outcome of induction therapy on patients included in the trial of the Spanish PETHEMA/GEM 05 for newly diagnosed MM elderly patients (age 65 or more, “GEM05mas65”). (Lancet Oncol 2010; 11: 934). Patients and Methods: Between March, 2006, and October, 2008, 260 patients with untreated multiple myeloma, 65 years and older, from 63 Spanish centres, were randomly assigned to receive six cycles of botezomib plus melphalan and prednisone VMP (n=130) or bortezomib plus thalidomide and prednisone (VTP; n=130) as induction therapy. Genetic studies were performed in blood samples from 169 patients among the 260 included in the original trial (VMP: 84 patients; VTP: 85 patients). Toxicity and outcome parameters were analyzed and related to the genotype of polymorphisms in genes involved in bortezomib (CYP1A2 *1C, CYP1A2 *1F, CYP3A4), thalidomide (CYP2C19 *2, CYP2C19 *17) and melphalan metabolism (GSTP1 I105V) as well as bortezomib transport (MDR1 −3435C>T) and drug target (PSMB5 1042G>A). Results: Clinical results in our cohort reproduced those of the 260 patients of the original trial already published. The most frequent non haematological toxicity was peripheral neuropathy, similar in both arms. Among the 169 patients included in our study CYP2C19 *17 T carriers had worse overall response (p=0.033). Likewise, MRD1 −3435TT carriers presented less incidence of grade 3–4 neutropenia (p=0.041) meanwhile patients AA for CYP2C19 *2 genotype presented more grade 3–4 thrombopenia (p=0.009). The impact of the different genotypes among the two arms and inside each one was also analyzed. Wild type patients for MRD1 −3435T SNP displayed higher rate of severe neutropenia only in the VMP arm and in a genetic load depending manner (CC=71%, CT=38%, TT=22%; p= 0.012). Conclusions: Our results suggest that polymorphisms in genes involved in the metabolism of thalidomide, (CYP2C19 *17 y *2) or bortezomib transport (MDR1 −3435C>T) may result in a thalidomide modified metabolism rate or in a lower efficacy in the bortezomib transport, suggesting a potential influence in the haematological toxicity (neutropenia and thrombopenia) and overall response rates in MM patients treated with VMP or VTP. These results together with the relative elevated frequency of these SNPs in this population (>20%) justifies the interest of studying the genetic profile since it can become a step forward on the individualized management of MM patients.

Disclosures:
Mateos: Celgene: Honoraria; Janssen: Honoraria. Lahuerta:Janssen: Honoraria; Celgene: Honoraria. Blade:Janssen: Honoraria; Celgene: Honoraria.