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Introduction: Multiple Myeloma (MM) is a complex malignancy of plasma cells well-described hyperdyploidy, and immunoglobulin gene rearrangements. To promote rapid advances in the field, Multiple Myeloma Research Foundation (MMRF) initiative is an intensive and comprehensive longitudinal study (CoMMpass) designed to create a rich discovery ecosystem to through in-depth clinical and molecular profiling to understand the molecular perturbations of the disease in the context of therapy. The large study population empowered us to stratify mutational landscapes among different ethnicities to influence on broader disparities in tumor dynamics. Methods: Clinical data, tumor/normal sample collection, and mutational landscape analysis described in this abstract are derived from MMRF CoMMpass IA7 release that is composed of self-identified 93 African American (AA) and 377 European American (EA). The post-processing and primary analysis was done on baseline samples only. Whole exome sequencing was analyzed for the detection of somatic events. Secondary analysis was performed using MutSigCV (Mutation Significance) algorithm and GISTIC (The Genomic Identification of Significant Targets in Cancer) to determine the significance of coding mutations and copy number events. Results: Our preliminary comparison analysis of CoMMpass IA7 data demonstrated that overall there was no statistical difference (p=0.5973) in nonsilent mutation burden between the two stratified groups, AA (μ=63.9 mutations/patient) vs EA (μ=73.7 mutations/patient). However, we have observed several notable differences. The most notable population difference (p Furthermore, MutSig analysis also revealed a novel candidate PTCHD3 (p = 7.07E-06, q = 3.33E-02) with 6% occurrence in AA compared to only 0.04% in EA. Furthermore, we looked at mutation occurrence difference of at least 5 fold between the two stratified populations. We have identified several additional genes that have higher mutation frequencies in tumors from AA patients including: ANKRD26, BCL7A, BRWD3. Interestingly, majority is implicated in epigenetic regulatory mechanisms. Moreover, despite the complex karyotype in MM translocations, our analysis demonstrated a lower frequency of 14q32 translocations in tumors from AA patients (10%) compared to tumors from EA patients (37%). These data would independently validate our previously reported differences in 14q32 breakpoints between these two populations. Conclusion: Data from this comprehensive diverse multi-institutional longitudinal study has afforded us the opportunity to study population differences among MM patients in an unprecedented way. Taking advantage of high quality, high-resolution whole exome and whole-genome data has allowed us to identify potential differences in the genomic and molecular landscape of MM from AA and EA patients. These data may help us further understand the incidence and outcomes among patients from these populations. As CoMMpass continues to mature these datasets will be retested that may result in some of these preliminary reported events to either level off, or increase in power. Disclosures Mulligan: Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Lonial:Janssen: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Onyx: Consultancy, Research Funding. Keats:Translational Genomic Research Institute: Employment.

The Multiple Myeloma Research Foundation (MMRF) CoMMpass trial (NCT145429) is a longitudinal study of 1000 patients with newly-diagnosed multiple myeloma from clinical sites in the United States, Canada, Spain, and Italy. Each patient receives a treatment regimen containing a proteasome inhibitor, immunumodulatory agent, or both. Clinical parameters are collected at study enrollment and every three months through the five-year observation period. To identify molecular determinants of clinical outcome each baseline and progression tumor specimen is characterized using Whole Genome Sequencing, Exome Sequencing, and RNA sequencing. This will be the first public presentation of the interim analysis seven cohort with 760 enrolled patients of whom 565 are molecularly characterized. This cohort of patients includes 14 patients with baseline and secondary samples along with 7 patients with characterized tumor samples from the bone marrow and peripheral blood. Although the median follow-up time for the cohort is only 260 days the patients on proteasome and IMiD based combinations are currently showing a PFS and OS benefit compared to those receiving combinations with each agent alone. From the raw mutational analysis we identified 24 significant genes that are recurrently mutated and the mutated allele is detectably expressed in all but one, DNAH5. Suggesting these mutations are likely contributing to myelomagenesis through an unconventional mechanism. Interestingly, DIS3 mutations are independent of KRAS, NRAS, and BRAF indicating a potential mechanistic link while PRKD2 mutations are associated with t(4;14). To identify events driving the initiation of myeloma we performed a detailed clonality analysis using a bayesian clustering method that corrects for copy number abnormalities and tumor purity to assign mutations into distinct clonal branches versus the initiating trunk mutations. On average 63.8% of mutations are trunk mutations and in 86.7% of patients at least one trunk mutation is associated with somatic hypermutation of an immunoglobulin gene as expected in a late stage B-cell malignancy. This identified many expressed trunk mutations that did not come out in the classic significance analysis like ATM, EGR1, and CCND1. To identify molecular subtypes we performed unsupervised clustering using a consensus clustering approach on independent discovery and validation cohorts, which identified 12 distinct subtypes, using a combination of silhouette score and cumulative distribution of consensus scores. This analysis identified two distinct groups associated with t(4;14) with mutations in FGFR3 and DIS3 being exclusive to one subgroup. In addition, this analysis separates patients with cyclin D translocations into three different groups, with one group having the second lowest PFS proportion. Three patients without CCND1 or CCND3 translocations were found to have IgH translocations targeting CCND2. The MAF subgroup was associated with the lowest OS and PFS proportion, and the three MAF/MAFB translocation negative patients in the subgroup all had MAFA translocations. The remaining 6 subgroups are associated with hyperdiploid copy number profiles and harbor the majority of the IgH-MYC translocation events. Two of the hyperdiploid groups are associated with a low level of NFKB activation compared to the remaining four, one of these is defined by the highest proliferation index but paradoxically the other has the second worst OS proportion. Another group is enriched with FAM46C and NRAS mutations. The genomic profiles of the paired tumors isolated from the peripheral blood and bone marrow are highly similar indicating these are not genetically distinct tumor compartments, at least in this subset of seven patients. Applying our bayesian clustering method to the serial samples resolved additional clonal clusters as mutations with similar cancer cell fractions at diagnosis clearly diverged at later timepoints. These analyses have identified tumor initiating mutations and new subtypes of myeloma, which are associated with distinct molecular events and clinical outcomes. Disclosures Jagannath: Novartis: Honoraria; Bristol Myers Squibb: Honoraria; Celgene: Honoraria; Merck: Honoraria; Janssen: Honoraria. Siegel:Celgene Corporation: Consultancy, Speakers Bureau; Amgen: Speakers Bureau; Takeda: Speakers Bureau; Novartis: Speakers Bureau; Merck: Speakers Bureau. Vij:Takeda, Onyx: Research Funding; Celgene, Onyx, Takeda, Novartis, BMS, Sanofi, Janssen, Merck: Consultancy. Zimmerman:Amgen: Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Millennium: Honoraria, Speakers Bureau; Onyx: Honoraria. Niesvizky:Celgene: Consultancy, Speakers Bureau. Rifkin:Onyx Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Consultancy, Membership on an entity's Board of Directors or advisory committees. Lonial:Millennium: Consultancy, Research Funding; Onyx: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding.

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. Disclosures: Auclair: MMRC: Employment. Harrison:MMRC: Employment. Jagannath:Celgene: Honoraria; Millennium: Honoraria. Siegel:Celgene: Honoraria, Speakers Bureau; Millennium: Honoraria, Speakers Bureau; Onyx: Honoraria, Speakers Bureau. Vij:Celgene: Honoraria, Research Funding, Speakers Bureau; Millennium: Honoraria, Speakers Bureau; Onyx: Honoraria, Research Funding, Speakers Bureau. Zimmerman:Celgene: Honoraria; Millenium: Honoraria; Onyx: Honoraria. Capone:MMRC: Employment. Lonial:Millennium: Consultancy; Celgene: Consultancy; Novartis: Consultancy; BMS: Consultancy; Sanofi: Consultancy; Onyx: Consultancy.

Abstract 3980 The Multiple Myeloma Research Foundation (MMRF) CoMMpassSM trial plans to analyze the tumor genome from 1000 patients with newly-diagnosed active multiple myeloma (ND-MM) from initial diagnosis over a period of 8 yrs [http://clinicaltrials.gov/ct2/show/NCT01454297]. Eligible patients include those with symptomatic MM who have not received prior therapy and provide consent for submission of paired specimens of bone marrow aspirate containing tumor cells and peripheral blood specimens for molecular analysis and biobanking. Individual tumor genomes will be sequenced to reveal the molecular and genetic changes underpinning tumor response and clinical benefit of therapies for MM and to facilitate future clinical trial designs. An extensive clinical and molecular database is being developed to facilitate association studies. The clinical endpoints and outcomes also include Quality of Life measures and health care resource utilization. The molecular database includes data from Whole Genome Sequencing, Whole Exome Sequencing and RNA sequencing comparing tumor to normal health mononuclear cells as part of the longitudinal profile of MM disease progression and clinical response in individual patients. The clinical study opened in July 2011 and includes 55 sites in the US contributing over 180 patients as of Aug 8, 2012. The frontline treatments permitted in this study include current standard of care therapies containing a proteasome inhibitor, an IMiD or both. Screening of 1500 individuals presenting with suspected myeloma in primary care community and academic centers is expected to identify individuals with asymptomatic MGUS, SMM and active MM patients. Patients with a confirmed diagnosis of asymptomatic myeloma or MGUS will be invited to re-enroll in CoMMpassSM Study upon conversion to active disease. Centralized bone marrow aspirate and peripheral blood specimen processing is being conducted to support profiling of the patient samples. The workflow for biospecimens includes real time analysis of bone marrow aspirates by multiplex flow cytometry to identify patient-specific immunophenotypic markers to follow evidence of Minimal Residual Disease (MDR), recurrence of disease and emergence or expansion of new tumor cell clonal populations3. B-raf pyrosequencing and immunophenotyping are performed in CAP-CLIA certified labs and results are provided to physicians. Included in these assays are potentially actionable drug targets include the following proteins: CD52 [CAMPATH-1], CD117 [c-kit], FGFR3, B-raf V600E and CD20. CD138-positive tumor cells purified from BM aspirates and paired healthy cells undergo sequencing analysis comprising Shallow Whole Genome and Whole Exome sequencing and transcriptome analysis. Chromosomal alterations and ploidy will be assessed by cytogenetic and FISH analysis. Altogether, these efforts will provide an unprecedented myeloma dataset on structural and copy number variation, mutation and gene expression. Samples collected at suspected Complete Response will also be evaluated by flow cytometry using multiple markers to follow immunophenotypic changes and to monitor minimal residual disease (MRD) and clonal evolution of the tumor population over time. The MMRF CoMMpassSM study will comprehensively catalog genomic alterations in patients treated with standard-of-care 1st line agents at significant clinical events, such as suspected CR, recurrence or progression of disease. The knowledge base developed from CoMMpassSM will fuel key insights into mechanisms of disease and drug response in myeloma, new drug targets and pathways, prognostic and predictive biomarkers for clinical validation and development and refine molecular classification of MM subtypes. The MMRF CoMMpassSM Research database and Myeloma Community portal will serve as a foundation to build personalized medical care strategies for MM patients. Disclosures: Keats: Tgen: Employment. Carpten:Life Technologies: Research Funding. Anderson:celgene: Membership on an entity's Board of Directors or advisory committees; millennium: Membership on an entity's Board of Directors or advisory committees; onyx: Membership on an entity's Board of Directors or advisory committees; bristol myers squibb: Membership on an entity's Board of Directors or advisory committees; acetylon: Membership on an entity's Board of Directors or advisory committees; oncopep: Membership on an entity's Board of Directors or advisory committees. Lonial:Millennium: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Bristol-Myers Squibb: Consultancy; Onyx: Consultancy; Merck: Consultancy.