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Gene expression-based dissemination score predicts early spread and poor outcomes in multiple myeloma
Arwa Bohra1, Surendra Dasari2, Saurabh Zanwar1
1Division of Hematology, Mayo Clinic, Rochester, MN, USA.
Abstract:
Multiple myeloma progresses from bone marrow-confined disease to systemic forms through processes linked to loss of adhesion and EMT-related programs. We analyzed baseline plasma cell RNA-seq, microarray, and single-cell datasets to derive and validate a dissemination score. In the newly diagnosed MMRF CoMMpass cohort (n = 754), differential expression analyses of circulating plasma cells (n = 592) and PET-CT-confirmed plasmacytomas (n = 118), integrated with 1114 EMTome genes, identified 1357 dissemination-associated genes. Elastic Net Cox regression derived a 30-gene Dissemination Score (DS) that stratified overall survival (54.5 vs 102.5 mo; C-index 0.71) and improved prognostic performance when added to UAMS70 and EMC92 in bootstrap analyses. DS was associated with Adverse stromal interaction (ASI) and stratified high-risk ASI interactions. In an independent Mayo Clinic cohort (n = 133), DS reproduced prognostic discrimination (52.1 vs 113.6 mo, p < 0.01) and predicted earlier dissemination events (2.1 vs 6.8 yrs, p < 0.01). In GSE117156, circulating plasma cells showed consistently higher DS than marrow plasma cells across MGUS, SMM, MM, and AL, with progressive DS increase from controls to MM. In GSE106218, CD138⁺ extramedullary plasma cells had higher DS than marrow plasma cells (p < 0.01). Collectively, DS quantifies dissemination biology.
Insights
A new 30-gene Dissemination Score (DS) accurately predicts multiple myeloma patient survival and disease spread. This score quantifies cancer dissemination biology, aiding in risk stratification for better patient outcomes.
Area of Science:
- Oncology
- Molecular Biology
- Genomics
Background:
- Multiple myeloma progression involves bone marrow confinement loss and epithelial-mesenchymal transition (EMT).
- Understanding the molecular drivers of myeloma dissemination is crucial for prognostic assessment.
Purpose of the Study:
- To derive and validate a gene expression-based score to quantify multiple myeloma cell dissemination.
- To assess the prognostic value of this score in predicting patient survival and disease spread.
Main Methods:
- Analysis of plasma cell RNA-seq, microarray, and single-cell datasets from multiple myeloma cohorts.
- Differential gene expression analysis integrating EMTome genes to identify dissemination-associated genes.
- Elastic Net Cox regression to derive a 30-gene Dissemination Score (DS) and validate its prognostic performance.
Main Results:
- Identified 1357 dissemination-associated genes and derived a 30-gene DS.
- DS significantly stratified overall survival in newly diagnosed and independent cohorts.
- DS predicted earlier dissemination events and was higher in circulating and extramedullary myeloma cells compared to bone marrow cells.
Conclusions:
- The Dissemination Score (DS) effectively quantifies multiple myeloma dissemination biology.
- DS serves as a robust prognostic biomarker for overall survival and disease spread.
- DS enhances prognostic models by incorporating dissemination-associated gene expression patterns.
