Targeted Genomic Mutation Panel (M3 P) Results from 504 Multiple Myeloma (MM) Patients

Abstract

Introduction: Customized gene panel sequencing is an attractive approach to genomic tumor characterization in clinical care. Based on published MM exome data we developed a MM Mutation Panel (M3 P) that includes the most commonly mutated genes, actionable drug targets, genes targeted by current standard of care (SOC) therapies and which allows tracking of clonal evolution, copy number and sample purity. Methods and Material: M3 P (v3.0) covers 88 genes (1327 amplicons, 181kb). MM samples from 504 patients (pts) have been analyzed (corresponding germline in 81%) through collaborations between Mayo Clinic and Hospital-12-de-Octubre (Madrid, Spain), the DSMM and GMMG (Wurzburg, Ulm, Freiburg and Heidelberg, Germany) and the HOVON trial groups (Rotterdam, The Netherlands). The investigated cohort includes 410 untreated pts (81%), which includes a high risk cohort of 72 pts with del17p, 25 paired samples with later follow up from the same cohort, and 94 relapsed patients, of which 50 were relapsed and refractory. Results: Overall coverage per mutation averaged >500x depth. We identified 945 variants (1.9 per pt) and in 83% of the pts a mutation was found. Clonal heterogeneity was assessed with mutations ranging from 3%-100% variant reads suggesting the presence of a significant number of subclones (e.g. 21% of mutations were in Significant differences in DIS3 and FAM46C mutation incidences were observed across cohorts: DIS3 mutations are more common in untreated pts with a 1.7 fold increased predominance (14% untreated and 8% treated). FAM46C has an expected incidence of 8% but was rarely mutated in untreated del17p high risk disease with only one of 100 patients harboring both mutations. The significance of this finding needs to be determined but implies a possible overlap in function. Finally we assessed impact on survival of the mutation variants identified in 142 untreated Mayo patients and found STAT3 mutations negatively impacting PFS (p=0.034) and OS (p=0.001). This gene is rarely mutated in MM (2% of the total cohort) thus the sample size was small and this finding needs further validation. Conclusion: We here describe 504 MM patients sequenced using the M3 P gene panel, which identified mutations in >80% of investigated patients, overlaps well with published whole exome sequence data and provides clinically relevant information. New findings were the high frequency of minor clones, the relative lack of overlap of del17 and FAM46C mutation, a higher frequency of DIS3 mutation at diagnosis compared to relapse, the prognostic significance of STAT3 mutation and the frequent presence of CRBN pathway mutation in drug resistant relapsed patients. Disclosures Sonneveld:Janssen-Cilag, Celgene, Onyx, Karyopharm: Honoraria, Research Funding; novartis: Honoraria. Mai:Janssen-Cilag: Other: Travel Grant; Onyx: Other: Travel Grant; Mundipharma: Other: Travel Grant; Celgene: Other: Travel Grant. Goldschmidt:Takeda: Consultancy, Membership on an entity9s Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity9s Board of Directors or advisory committees; Onyx: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau; Millenium: Honoraria, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Membership on an entity9s Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Chugai: Honoraria, Research Funding, Speakers Bureau; Janssen-Cilag: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding, Speakers Bureau. Knop:Celgene Corporation: Consultancy. Kull:Bristol-Myers Squibb: Membership on an entity9s Board of Directors or advisory committees. Martinez-Lopez:Novartis: Honoraria, Research Funding; Bristol-Meyer Squibb: Honoraria; Celgene: Honoraria; Janssen: Honoraria. Einsele:Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Amgen/Onyx: Consultancy, Honoraria, Speakers Bureau. Raab:Novartis: Research Funding. Stewart:Oncospire Inc.: Equity Ownership; Celgene: Consultancy; Novartis: Consultancy; BMS: Membership on an entity9s Board of Directors or advisory committees.