Abstract
In this review, we explore the role of complex interactions between genomic evolution, environmental and genetic predispositions, and immune surveillance in disease progression from precursor conditions smoldering multiple myeloma and monoclonal gammopathy of undetermined significance to multiple myeloma (MM). MM has been described to be universally preceded by precursor states, often decades before it is even diagnosed. Genetic predisposition plays an important role in the initial transformation, and is driven by both germline variants and MM-specific loci influencing risk. The reported disparities in occurrence of precursor conditions and MM among racial groups highlights the role of predisposition and the need for broader cohort studies. Early genomic events, such as translocations and hyperdiploidy, are essential in precursor initiation. However, additional factors are usually needed to transform the precursor stages into symptomatic disease, such as positive selection of subclonal populations. This process is affected by aging and environmental factors, such as exposures to Agent Orange and agrochemicals. Therefore, integrating genomic and transcriptomic data with immune profiling or other clinical features is essential for identifying patients with high risk of progressing into MM. Here, we highlight the complexity of myelomagenesis, and underline the importance of state-of-the-art approaches for improved disease prediction.