Initiation and progression of myeloma. A postgerminal centre B cell receives a genetic “hit” which immortalizes the cell and initiates transition to the indolent phase of monoclonal gammopathy of undetermined significance (MGUS). MGUS clones may then transition through the other disease phases of smouldering multiple myeloma (SMM), myeloma, and plasma cell leukemia (PCL) as genetic “hits”, which confer a survival advantage and are acquired over time. Clonal evolution develops through branching pathways whereby numerous ecosystems composed of multiple subclones exist at each disease phase, as represented by the differing shapes. At the end of this process, proliferative clones no longer become confined to the bone marrow and expand rapidly as a leukemic phase. At each disease phase, the precursor clones are present only at a low level as they have been outcompeted by more advantageous clones. It should be noted that the above figure represents an oversimplification of myeloma initiation and progression, as the process is highly complex with multiple pathways possible at any one time (adapted from Morgan et al., 2012 [8]).
