Correlation of changes in subclonal architecture with progression in the MMRF CoMMpass study

Area of Science:

• Hematology
• Cancer Genomics
• Evolutionary Biology

Background:

• Multiple myeloma (MM) is a complex plasma cell disorder originating from premalignant stages.
• Disease progression involves intricate interactions between clonal mutations and the microenvironment.
• Understanding MM's evolutionary trajectory is key for early detection and treatment.

Purpose of the Study:

• To evaluate clonal evolution in multiple myeloma patients.
• To identify actionable gene targets and vulnerabilities in early disease stages.
• To explore potential for early prognostication and personalized therapies.

Main Methods:

• Analysis of clonal evolution at multiple time points.
• Study included 76 multiple myeloma patients from the MMRF CoMMpass study.
• Evaluation of molecular events, including gene mutations and cytogenetic aberrations.

Main Results:

• Multiple myeloma predominantly progresses via branching evolution.
• Heterogeneous mutational landscapes show distinct actionable targets at diagnosis versus progression.
• Unique clonal gene gains/losses correlate with cytogenetic aberrations.
• Significant correlations observed between co-occurring oncogenic mutations (e.g., TP53+SYNE1) and anticorrelative gene dependencies (e.g., FAT3+FCGBP).

Conclusions:

• Clonal evolution patterns in multiple myeloma are established early and retained.
• Identification of actionable targets and co-occurring mutation trajectories can inform risk stratification.
• These findings support the development of personalized therapies for multiple myeloma.