Pathways of clonal progression from MGUS to multiple myeloma.

Mutational patterns in V_H genes define diversity in MGUS, with some cases showing intraclonal heterogeneity. Plasma cells in these MGUS cases most likely derive by maturation of a less differentiated sIg⁺ cell that is undergoing somatic mutation and has acquired a chromosomal event 1 to gain a proliferative potential. Transformation to myeloma can clearly occur in MGUS displaying heterogeneity, but does so in a single cell in which somatic mutation is silent and that acquires neoplastic event 2. This transformation may be rapid, and residual MGUS clones can still be identified at this time but will eventually be lost by clonal outgrowth as myeloma is homogeneous. A self-cloning process may also lead to the MGUS cases identified by intraclonal stability of sequence, which are more common. These cases can then transform to myeloma as a result of event 2. VDJ indicates functionally rearranged variable-diversity–joining gene.