The term “multiple myeloma” was suggested by von Rustizky in 1873, when he identified multiple discrete bone marrow (myel-) tumors (-oma) during an autopsy. Multiple myeloma (MM) is an age-dependent monoclonal tumor of bone marrow (BM) plasma cells (PC), often with significant end-organ damage that can include lytic bone lesions, anemia, loss of kidney function, immunodeficiency, and amyloid deposits in various tissues. With a yearly incidence of 20 000 in the USA, it accounts for nearly 20% of deaths from hematopoietic malignancies and about 2% of all deaths from cancer. Despite recent therapeutic advances, MM continues as a mostly incurable disease, but with a median survival that has increased to more than six years (1–4).

Multiple myeloma is a plasmablast/plasma-cell tumor of post-germinal center B cells

Pre-germinal center (GC) B cells can generate short-lived PC that mostly remain in the primary lymphoid tissue (Figure 74.1). Post-GC B cells can generate plasmablasts (PBs) that have successfully completed multiple rounds of somatic hypermutation and antigen selection, followed by IgH switch recombination, with both B-cell-specific DNA modification processes having oncogenic potential (5). These PB typically migrate to the BM, where stromal cells facilitate terminal differentiation into long-lived PC (6,7). Despite an aberrant immunophenotype, MM tumor cells are similar to post-GC PB/long-lived PC, including strong BM dependence, extensive somatic mutation of Ig genes, and absence of IgM expression in all but 1% of tumors.