Analysis of Sequential Patient Samples from the Mmrf Commpass Study Identifies a High Risk Progression Phenotype

Multiple myeloma (MM) is a hematological malignancy of plasma cells accounting for ~2% of new cancer cases each year in the United States. The Multiple Myeloma Research Foundation CoMMpass Study (NCT01454297) is a fully accrued, longitudinal, observational clinical trial with 1143 newly diagnosed MM patients from sites in the United States, Canada, Spain, and Italy. Tumor samples are collected and characterized using whole genome (WGS), exome (WES), and RNA (RNAseq) sequencing at diagnosis and each progression event. Clinical parameters are collected at baseline and every three months through the eight-year observation period. Although ongoing, longitudinal collection of molecular and clinical data from CoMMpass patients has aided in our understanding of the molecular mechanisms underpinning relapse in MM. The CoMMpass IA13 dataset includes 136 patients with longitudinal time points, including 25 patients with multiple progression events. We analyzed 100 patients with WES data at baseline and at least one progression event and identified 7 genes (KRAS, NRAS, SPEN, SRCAP, MACF1, ANK3, and RPRD2) with acquired non-synonymous mutations in at least 3% of patients at progression. We identified five patients with KRAS mutations at baseline in whom a clonal shift to NRAS Q61 mutations occurred at progression and four additional patients with novel NRAS Q61 mutations becoming detectable at progression. Patients with NRAS Q61 mutations at baseline exhibit poor OS outcomes as compared to patients with other NRAS mutations (p An integrated analysis leveraging WGS, WES, and RNAseq data identified gain- (GOF) and loss-of-function (LOF) genes for each sample. Longitudinal changes in gene functional status was determined for 47 patients with 57 paired time points. TRAF3 and CDKN2C/FAF1 were found to be the most common complete LOF events acquired at progression, found in 5 (10.6%) and 4 (8.5%) patients, respectively. Acquired complete LOF events are enriched for genes involved in cell cycle regulation (15% of patients, p 4% of longitudinal patients. In addition, 5 (10.6%) patients acquired GOF events in genes either up- or downstream of RAS, including HIST2H3C, OSMR, PAK2, PIK3R6, and STAT3, highlighting the complexity of targeting RAS in MM. Unsupervised consensus clustering of RNAseq data for 714 patients at baseline identified 12 expression subtypes of MM, which generally correspond with known subgroups. The proliferation (PR) group consists of patients whose tumors have an array of genetic backgrounds but a similar RNA expression profile, and exhibit poor OS (HR = 3.996, 95% CI = 2.632 - 6.067, p These observations suggest that progression in MM is often driven by marked shifts in gene expression and molecular events that further deregulate RAS and cell cycle pathways, highlighting the need for novel inhibitors in MM; protocols, such as MyDRUG, which aim to treat patients based on their tumor genetic profile; and molecular profiling of patients throughout their disease course. Disclosures Lonial:Amgen: Research Funding.