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Dr. Jonathan Keats- Interim analysis of the MMRF Compass Trial, a longitudinal study in MM relating clinical outcomes to genomic and immunophenotypic profiles

Jonathan Keats, MD
Assistant Professory, Integrated Cancer Genomics
Translational Genomics Research Institute (Tgen)
Phoenix, AZ

12.11.13

Program: Oral and Poster Abstracts
Type: Oral
Session: 651. Myeloma: Biology and Pathophysiology, excluding Therapy: Genomics

Monday, December 9, 2013: 3:30 PM, 388-390 (Ernest N. Morial Convention Center)

Jonathan J Keats, PhD1, David W Craig, PhD2*, Winnie Liang, PhD3*, Yellapantula Venkata, MSc4*, Ahmet Kurdoglu, BS5*, Jessica Aldrich, MSc6*, Daniel Auclair, PhD7*, Kristi Allen, BS1*, Beverly Harrison7*, Scott Jewell, PhD8*, Pamela G. Kidd, MD9, Mick Correll10*, Sundar Jagannath, MD11, David S. Siegel, MD, PhD12, Ravi Vij, MD13, Gregory Orloff, MD14, Todd M. Zimmerman, MD15, Mmrf CoMMpass Network16*, Walter Capone17*, John Carpten, PhD18* and Sagar Lonial, M.D.19

1Integrated Cancer Genomics, Translational Genomics Research Institute, Phoenix, AZ
2Neurogenomics, The Translational Genomics Research Institute, Phoenix, AZ
3Collaborative Sequencing Center, Translational Genomics Research Institute, Phoenix, AZ
4Integrated Cancer Genomics, TGen, Phoenix, AZ
5Neurogenomics, Translational Genomics Research Institute, Phoenix, AZ
6Neurogenomics, TGen, Phoenix, AZ
7Multiple Myeloma Research Foundation, Norwalk, CT
8Van Andel Research Institute, Grand Rapids, MI
9Spectrum Health, Grand Rapids, MI
10Genospace, Boston, MA
11Multiple Myeloma Program, Tisch Cancer Institute, Mount Sinai School of Medicine, New York, NY
12John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, NJ
13Department of Medicine, Division of Oncology, Washington University School of Medicine, Saint Louis, MO
14Fairfax Northern Virginia Hematology Oncology, Fairfax, VA
15University of Chicago, Chicago, IL
16The Multiple Myeloma Research Foundation, Norwalk, CT
17Multiple Myeloma Research Consortium, Norwalk, CT
18Integrative Cancer Genomics, Translational Genomics Research Institute, Phoenix, AZ
19Winship Cancer Institute, Emory University, Atlanta, GA

 
The Multiple Myeloma Research Foundation (MMRF) CoMMpass trial is the cornerstone of the MMRF Personalized Medicine Initiative.  The accrual goal is 1000 patients with newly-diagnosed active multiple with sufficient tumor material for the comprehensive analysis of each tumor genome. Each eligible patient will be followed from initial diagnosis longitudinally for a minimum of 8 years.  Additional tumor samples will be collected and comprehensively analyzed when possible for each patient at time of suspect CR, recurrence or progression of disease. The clinical study (NCT0145429) opened in July 2011 and now includes 56 sites in the US and Canada that have enrolled over 300 patients as of Aug. 1, 2013. The frontline treatments permitted in this study include current standard of care therapies containing a proteasome inhibitor, an IMiD or both.

The comprehensive analysis of each tumor and matched normal genome involves; Long-Insert Whole Genome Sequencing (WGS) to identify somatic copy number alterations and structural changes, Whole Exome Sequencing (WES) to identify somatic single nucleotide variants and indels, and RNA sequencing (RNAseq) to define transcript expression levels and fusion transcripts.  In addition, BRAF pyrosequencing and immunophenotyping analysis are being done in CAP-CLIA certified labs. An extensive, open-access, public clinical and molecular database, the CoMMpass Researcher Gateway (RG) (https://research.themmrf.org), is being developed to facilitate the rapid dissemination of the results and provides the myeloma community with a mechanism to analyze the results. The clinical endpoints and outcomes also include Quality of Life measures and health care resource utilization.

An initial interim analysis on the first 178 cases has just been completed and made publicly available through the CoMMpass RG. At the molecular level, BRAF analysis on this serial sample set of newly diagnosed patients identified V600E mutations at rate of 5.7%, confirming our previous observations from a mixture of non-consecutive treated and untreated patient samples in our previous genomic efforts. The flow cytometry panel was designed to provide a comprehensive immunofingerprint of each patient that could be used for minimal residual disease monitoring and to monitor potentially therapeutic options; MS4A1/CD20, CD52, KIT/CD117, and FGFR3.  These studies have identified tumors which are 100% positive for these actionable antigens at frequencies of; 16.0% for CD20, 5.7% for CD52, 49.7% for CD117, and 8.5% for FGFR3.  Of the 178 cases, 34 were profiled through WGS, WES and RNAseq before this interim analysis. We identified 553 variants (median 19 per patient, range 11-55) were the variant allele detected by WES was also detected by RNAseq, suggesting the variant is potentially biologically relevant.  Of these genes, 36 were seen more than once and 7 were identified in three or more patients.  This includes NRAS (23.5%), KRAS (14.7%), BRAF (8.8%), DIS3 (8.8%), FAM46C (8.8%), TRAF3 (8.8%), and ZNF100 (8.8%).  Interestingly, all three ZNF100 variants show preferential expression of the mutant allele.  Within this cohort the only recurrent fusion gene identified is the classic IgH-MMSET fusion transcripts associate with t(4;14).    

The MMRF CoMMpass is providing unprecedented molecular characterization and correlating clinical datasets that will help define the determinants of response to anti-myeloma agents, reveal new, actionable targets and/or those shared with other cancers and facilitate future clinical trial designs, thus serving as a stepping stone toward personalized medicine for myeloma patients.


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