Whole-genome sequencing reveals progressive versus stable myeloma precursor conditions as two distinct entities

Area of Science:

• Genomics
• Oncology
• Hematology

Background:

• Multiple myeloma (MM) development is preceded by clinical precursor conditions such as monoclonal gammopathy of undetermined significance (MGUS) and smoldering myeloma (SMM).
• Understanding the genomic differences between stable and progressive precursor conditions is crucial for early detection and intervention.

Purpose of the Study:

• To investigate the whole genome sequence (WGS) profiles of MGUS, SMM, and MM.
• To identify genomic markers that differentiate stable myeloma precursor conditions from those that progress to MM.

Main Methods:

• Whole genome sequencing (WGS) was performed on 18 MGUS samples.
• WGS data from MGUS were compared with existing data from 14 SMM and 80 MM cases.
• Genomic events including chromothripsis, gene mutations, aneuploidy, and APOBEC activity were analyzed.

Main Results:

• Fifteen clinically stable myeloma precursor cases were characterized by later onset and absence of myeloma-defining genomic events.
• Progressive precursor conditions exhibited genomic hallmarks such as chromothripsis, driver gene mutations, aneuploidy, and APOBEC mutational activity.
• WGS can differentiate between biologically distinct, stable and progressive myeloma precursor entities.

Conclusions:

• Whole genome sequencing provides a powerful tool for distinguishing between stable and progressive myeloma precursor conditions.
• The absence of specific genomic events in stable precursor conditions suggests different biological mechanisms compared to progressive disease.
• These findings support the potential for WGS in identifying patients at risk of progressing to multiple myeloma.