Multiple myeloma ontogeny's hypothesis exemplified by a 14q translocation–positive case. A naive B cell harboring an incomplete DJ_H and a functional VDJ_H rearrangement enters the GC where it undergoes SHM and antigen selection (eg, selection against VH4-34 IGH rearrangements), followed by CSR. During the process of physiological CSR, double-strand breaks on the switch regions of the nonfunctional allele (DJ_H in the example) can be resolved by joining with a different chromosome resulting in a 14q32 translocation. If this illegitimate recombination occurs prior to legitimate CSR on the functional IGH allele, a mixture of different subpopulations (eg, IgM⁺ and IgG⁺ or IgA⁺) will have a survival or proliferative advantage due to the translocation, which will make them long-lived memory B or plasma cells without becoming fully malignant. After one of these subpopulations leaves the GC to become a plasma cell homing to the BM (normally IgG⁺ or IgA⁺), secondary genetic hits may occur that render such cells malignant plasma cells.