The CoMMpass study (NCT01454297) is a prospective, longitudinal observational trial involving 1,141 newly diagnosed, treatment-naïve multiple myeloma (NDMM) patients. Bone marrow aspirates from the study participants were collected, separated into CD138 negative and CD138 positive fractions for comprehensive molecular characterization of tumor (using bulk RNA sequencing and whole genome sequencing) and tumor immune microenvironment using 3' single-cell RNA sequencing (scRNA-seq). To support exploration of this rich multi-omic dataset, we developed CoMMpass Explorer (CE), an intuitive interactive platform that enables real-time analysis of clinical and genomic data from these study participants.

CE provides four main views: Overall Summary for clinical feature distribution and Kaplan-Meier curves; Mutational Profile for visualizing and comparing somatic mutations; Tumor Profile for differential expression and gene set enrichment; and Immune Microenvironment for comparing cell type abundance and cell cycle dynamics between cohorts using scRNA-seq data. A central feature of CE is cohort building, where users can filter and stratify patients by clinical, genomic, and survival data elements to create custom cohorts for analysis.

We validated CE by reproducing findings from two prior CoMMpass-based studies. In the first study by Simhal et al, we stratified patients using transcript-level expression by WEE1 into tertiles and confirmed that high WEE1 expression is associated with poorer progression-free survival across multiple genomic subgroups. In the second study by Manojlovic et al, we replicated mutation frequencies between African American and Caucasian patients by creating race-based cohorts.

We further demonstrate CE's utility by identifying and comparing two NDMM cohorts of patients at baseline who have not received autologous stem cell transplant: cohort 1 includes patients that received up-front triplet therapy (N=342) and cohort 2 includes those who did not receive a triplet up-front (N=235). While survival differences between these two cohorts were not statistically significant (p>0.05), CE revealed elevated epithelial-mesenchymal transition (EMT) pathway activity in cohort 1. Immune profiling showed lower abundance of CD8+ T cells (p < 0.05) and NK cells (p = 0.01), but a higher abundance of B cells (p < 0.05) in cohort 1. Genomic data showed fewer EIF2AK3 mutations and higher transcript-level expression of EIF2AK3 in cohort 1. Notably, patients in cohort 1 with lower transcript-level expression of EIF2AK3 had better survival outcomescompared to patients in cohort 2.

CE democratizes access to the CoMMpass multi-omic resource, allowing researchers to interrogate clinical and molecular heterogeneity with ease. By enabling hypothesis generation and replication of published results, CE serves as a valuable tool for identifying meaningful patterns in gene expression, mutation profiles, and immune contexture. It also highlights potential prognostic biomarkers, such as EIF2AK3 expression, that may inform treatment decisions in NDMM, especially in the context of triplet-based regimens.

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2025
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