Evolution of multiple myeloma from a genomic perspective.

Area of Science:

• Oncology
• Genetics
• Immunology

Background:

• Multiple myeloma (MM) universally follows precursor states, such as monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM), often decades prior to diagnosis.
• Genetic predisposition, including germline variants and MM-specific loci, significantly influences initial transformation and risk.
• Disparities in MM and precursor condition incidence across racial groups underscore the importance of genetic predisposition and necessitate broader research cohorts.

Purpose of the Study:

• To explore the intricate interplay of genomic evolution, environmental exposures, genetic predispositions, and immune surveillance in the progression from MGUS and SMM to MM.
• To highlight the complexity of myelomagenesis and emphasize the need for advanced prediction strategies.

Main Methods:

• Review of existing literature on genomic events, environmental factors, and immune responses in MM development.
• Integration of genomic and transcriptomic data with immune profiling and clinical features for risk stratification.

Main Results:

• Early genomic events like translocations and hyperdiploidy are critical for precursor initiation.
• Progression to symptomatic MM requires additional factors, including the positive selection of subclonal populations, influenced by aging and environmental exposures (e.g., Agent Orange, agrochemicals).

Conclusions:

• Identifying patients at high risk of MM progression necessitates integrating genomic, transcriptomic, and immune profiling data with clinical features.
• State-of-the-art approaches are crucial for improving the prediction of MM development from precursor conditions.