Comprehensive molecular profiling of multiple myeloma identifies refined copy number and expression subtypes

Area of Science:

• Hematology
• Oncology
• Genetics

Background:

• Multiple myeloma is a plasma cell cancer with complex genetics, lacking precision medicine treatments.
• Understanding myeloma's genetic landscape is crucial for developing targeted therapies.

Purpose of the Study:

• To analyze the genetic profiles of newly diagnosed multiple myeloma patients.
• To identify molecular underpinnings and high-risk subtypes of multiple myeloma.
• To investigate genetic changes during disease progression.

Main Methods:

• Longitudinal observational study (NCT01454297) of 1,143 newly diagnosed multiple myeloma patients.
• Whole-genome, whole-exome, and RNA sequencing of tumor samples at diagnosis and progression.
• 3-month interval clinical data collection.

Main Results:

• Identified genes targeted by recurrent gain-of-function and loss-of-function events.
• Discovered 8 copy number and 12 expression subtypes of multiple myeloma.
• 25.5% of patients transitioned to a high-risk expression subtype at progression.
• Observed robust expression of immunotherapy targets in high-risk subtypes.

Conclusions:

• Multiple myeloma exhibits diverse genetic subtypes, including high-risk groups.
• Disease progression can lead to high-risk genetic subtypes.
• Immunotherapy targets are present in high-risk subtypes, offering potential therapeutic avenues.