A Journey Through Myeloma Evolution: From the Normal Plasma Cell to Disease Complexity

Area of Science:

• Oncology
• Molecular Biology
• Cancer Genomics

Background:

• Tracking cancer evolution and origin are critical unmet needs in clinical oncology.
• Personalized treatment strategies require understanding cancer biology throughout its lifecycle.
• Multiple myeloma (MM) offers a model for applying evolutionary insights due to its multi-stage progression.

Purpose of the Study:

• To review the molecular pathogenesis of multiple myeloma (MM) from an evolutionary perspective.
• To highlight how understanding MM initiation, preclinical, and pre-malignant phases can improve patient stratification.
• To discuss drivers of MM evolution and their relation to refractory disease and treatment resistance.

Main Methods:

• Review of current literature on multiple myeloma molecular pathogenesis.
• Analysis of genomic data and microenvironment composition in MM.
• Integration of evolutionary biology principles with clonal heterogeneity in MM.

Main Results:

• Novel insights into the timing and modes of MM disease initiation.
• Identification of genomic and microenvironmental factors for risk stratification in preclinical/pre-malignant MM.
• Elucidation of cell-intrinsic and cell-extrinsic drivers of MM progression to symptomatic disease.

Conclusions:

• An evolutionary approach to MM biology, considering clonal heterogeneity, can guide clinical management.
• Stratifying patients based on detailed biological features, rather than disease burden surrogates, is feasible.
• This approach promises to enhance personalized treatment strategies for multiple myeloma patients.