Optimization of Multiple Myeloma Patient Stratification and Drug Development with Insights from a Targeted NGS Panel  – the M3P (Multiple Myeloma Mutation Panel)

Written by: Anna Israyelyan, MD, PhD
Manager, Clinical Affairs

Published on:
March 18th, 2016

Anna Israyelyan, MD, PhD
Dr. Israyelyan joined CGI in 2015. She has over 15 years of extensive cancer research and management experience in industry and academia covering wide range of medical areas, including basic, translational, and clinical research. Anna is an active member of the American Society of Hematology (ASH), the American Association for Cancer Research (AACR), and American Association for the Advancement of Science (AAAS). Dr. Israyelyan has a scientific advisory role with matrix management of scientific, technical, and operational aspects related to various biopharma projects and collaborations involving biomarkers in solid tumors and hematologic malignancies.

The identification and characterization of the molecular alterations of individual cancer patients is critical for the development of more effective personalized therapies. Next-generation sequencing (NGS) has revolutionized cancer genomics research by providing a comprehensive method of detecting genomic alterations associated with somatic cancer, especially hematological malignancies. This powerful technology has resulted in major advances associated with disease diagnosis, risk stratification, monitoring clonal evolution, and therapeutic decision making.

CGI’s joint venture with Mayo Clinic, Oncospire Genomics, presented oral and poster abstracts at the recent Annual Meeting of the American Society of Hematology (ASH) discussing studies utilizing NGS for multiple myeloma (MM). Launched in 2013, Oncospire was established to focus on developing and commercializing NGS panels as gold standards for areas of critical unmet need in oncology, including MM, a disease desperate for improved diagnostic, management and treatment selection strategies.

There were 26,850 estimated new cases of MM in 2015 with 11,240 deaths in US [1]. There are over 300 open MM clinical trials in US from which about 100 started in the last year [2]. In 2015, five drugs were granted approval by the U.S. Food and Drug Administration (FDA) for the treatment of MM.

The current testing paradigm for MM requires multiple tests using different technologies, often requiring multiple biopsies, leading to discordant results and diagnostic uncertainty in many cases. Oncospire Genomics has developed a custom targeted NGS diagnostic 91-gene panel M3P for MM, which may be able to replace the complexity of current diagnostic testing on various platforms with one NGS-based panel. Encompassing comprehensive mutation detection, detailed information on copy number variations (CNV), key translocations, and clonal architecture, this important new test can improve early detection by predicting transformation to MM and be utilized for better prognosis of patients already confirmed with the disease. The panel can provide valuable information on rational drug combination and lead optimization of the investigational compound into the clinical trial phase successfully.

One of the studies presented at ASH (723 Targeted Sequencing of Relapsed/Refractory Myeloma Patients Identifies an Enrichment of Mutations in Cereblon and MAPK Pathways; https://ash.confex.com/ash/2015/webprogram/Paper78047.html) discussed the screening of a homogenous cohort of heavy pretreated refractory MM (rMM) patients utilizing the M3P panel. The targeted sequencing give key insights in the landscape of the rMM genome, uncovering an increasing frequency of MAPK, TP53 and CRBN mutations. Importantly, it was the first study showing recurrent mutations in CRBN in patients unresponsive to immunomodulatory agent (IMiD) treatment, supporting a potential association with resistance to IMiD-based therapies.

In another study presented (1795 Targeted Genomic Mutation Panel (M3P) Results from 504 Multiple Myeloma (MM) Patients; https://ash.confex.com/ash/2015/webprogram/Paper86384.html), the M3P gene panel was employed to sequence samples from 504 MM patients and identified mutations in >80% of investigated patients, overlaping well with published whole exome sequence data and providing clinically relevant information.  The study’s new findings were the high frequency of minor clones, the relative lack of overlap of del17 and FAM46C mutation, the 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.

The third study utilizing the M3P panel (2984 M3P Sequencing Panel Identifies TP53 Mutational Status As a Prognostic Factor in Chemotherapy-Naive Multiple Myeloma https://ash.confex.com/ash/2015/webprogram/Paper83967.html) was able to confirm the published prevalence of recurrently somatically mutated genes (RSMGs) in a cohort of newly diagnosed chemotherapy-naïve 103 MM patients. NRAS, KRAS, DIS3, FAM46C, TP53, and BRAF were the most frequently mutated genes. TP53 mutational status was the strongest unfavorable prognostic factor in the cohort studied and seemed to be associated with greater mutational burden. Validation in a more extensive population is planned. The findings warrant further investigation of the mutational status of the mentioned genes in larger clinical trial cohorts, enabling a more robust comparison with conventional prognostic markers.

To summarize, M3P was developed by Oncospire Genomics and combines three tests in one: analysis of mutations, translocations and copy number changes, generating relevant information about actionable targets, drug resistance pathways, and clonal evolution of MM. M3P has utilized the extensive expertise of clinically informed teams becoming a suitable and cost-effective tool that could be simultaneously utilized by biopharma to drive targeted drug development and provide information needed to guide precision therapy and individually tailored treatment for MM patients in the clinic.

Oncospire is looking for additional collaboration and validation partners to help realize its ultimate goal to develop the gold standard NGS tests for critical oncologic diseases, including MM, lung cancer, and follicular lymphoma.

To learn more about Oncospire Genomics, please visit our website www.oncospire.com.

[1] SEER Stat Fact Sheets: Myeloma. Surveillance, Epidemiology, and End Results Program, National Cancer Institute. http://seer.cancer.gov/statfacts. (Accessed on 2-5-2016)

[2] ClinicalTrials.gov, A service of the U.S. National Institutes of Health. https://clinicaltrials.gov. (Accessed on 2-5-2016)

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