FROM BENIGN TO MALIGNANT DISEASE

It is believed that every multiple myeloma (MM) case evolves from asymptomatic conditions called monoclonal gammopathy of undetermined significance (MGUS) or smoldering multiple myeloma (SMM), even if these are not actually diagnosed before MM. MGUS is considered a pre-malignant condition and SMM an indolent cancer. However, this distinction was based on the clinical observation of their different rate of progression towards MM more than on actual biological studies. Recent next-generation sequencing (NGS) studies on MGUS/SMM show that these asymptomatic conditions share many of the driver genomic abnormalities of MM, indicating that the plasma cell clone has accumulated a notable oncogenic burden already in early clinical stages. However, one question is whether NGS can be exploited clinically to identify, among MGUS and SMM, patients at the highest risk of progression. Indeed, non-progressing MGUS/SMM show a distinct genomic spectrum of events, namely fewer hotspot gene mutations, segmental chromosomal deletions, complex rearrangements, and lower activity of the APOBEC family of DNA deaminases. Conversely, progressing MGUS/SMM show a genomic profile that is not different -on average- to the one of active MM at diagnosis, suggesting that current diagnostic criteria, mostly based on clinical and laboratory surrogates of disease burden, do not capture the actual disease biology. Also, using genomic techniques to estimate the time of acquisition of the first clonal event in the patient, it can be extrapolated that non-progressing MGUS/SMM arose closer to the day of sampling than active MM, where a decades-long subclinical evolution can be inferred. Looking at evolution of SMM into MM, two main patterns can be observed: one where the tumor does not change, implying it biologically is a MM from the start and early treatment may be beneficial; and another where the genomic composition of the tumor changes, implying the tumor was actually indolent at the time of diagnosis and treatment strategy may be aimed at eradication before the acquisition of aggressive subclones. Recent evidence suggests there is an advantage when treating SMM early, and studies are evaluating whether a more aggressive diagnosis approach -or even MGUS screening- may be beneficial for the patient. However, this will need to be paralleled by a better understanding of the biology of the tumor, and genomic prognostication may help better prognostication and treatment choices in MGUS/SMM patients.