In Multiple Myeloma, High-Risk Secondary Genetic Events Observed at Relapse Are Present from the Diagnosis in Tiny Undetectable Subclones

In multiple myeloma (MM), among the anomalies associated with shorter survival, it should be noted recurrent copy number variations (CNV), such as del(17p13), del(1p32), or 1q gains. These abnormalities are considered secondary, thus acquired during the course of the disease. Although they can be observed from diagnosis, they are only detected at the time of relapses in some patients. It is now clearly demonstrated that MM is a molecular subclonal disease, with the coexistence of different subclones of varying size. As in other cancers, it has also been shown that these different subclones can vary in size according to the different relapses, suggesting that an unnoticed minor subclone at diagnosis could become the major one at the time of relapse. Although subclonality has been largely reported at the mutational level, little is known about this phenomenon at the CNV level. Since a few CNV are associated with a poor outcome, and assuming they will impact the disease course, it would be clinically highly valuable to track these abnormalities at the time of diagnosis in minor subclones. Here, we report the first analysis at the single cell level of CNV of tumor cells from 81 patients with MM analyzed at the time of diagnosis, relapse or pre-symptomatic stages.