Temporal genomic dynamics shape clinical trajectory in multiple myeloma

Area of Science:

• Genomics
• Cancer Biology
• Hematology

Background:

• Multiple myeloma (MM) is a plasma cell malignancy.
• MM evolution involves accumulating genomic alterations.
• Understanding the timeline of these alterations is crucial for prognosis.

Purpose of the Study:

• To determine the timeline of genomic driver acquisition in multiple myeloma.
• To investigate the impact of the timing of specific genetic events on clinical outcomes.

Main Methods:

• Whole-genome sequencing of 421 samples from 382 multiple myeloma patients.
• Analysis of mutational signatures to estimate event timing.
• Correlation of genomic event timing with patient survival data.

Main Results:

• A significant time lag of 20-40 years exists between initial genomic events and MM diagnosis.
• Odd-numbered chromosome trisomies can arise concurrently with other gains, such as 1q gain.
• Hyperdiploidy acquisition occurs after immunoglobulin heavy chain translocations when co-occurring.
• Early 1q gain is associated with adverse outcomes, comparable to 1q amplification, and worse than late 1q gain.

Conclusions:

• The timing of genomic alterations, particularly 1q gain, is a critical determinant of clinical outcome in multiple myeloma.
• This study provides insights into the evolutionary history of multiple myeloma.
• Findings may inform prognostic stratification and therapeutic strategies for multiple myeloma patients.