Multiple myeloma, the second most common haematopoietic cancer, represents a collection of plasma-cell neoplasms that invariably become fatal when self-renewing myeloma cells begin unrestrained proliferation. Myeloma cells are arrested as intermediates in plasma-cell differentiation as a consequence of transformation. Unlike normal plasma cells, myeloma cells retain the self-renewing potential. Although impaired apoptosis accounts for the accumulation of myeloma cells in the bone marrow during the plateau phase of the disease, cell-cycle deregulation underlies unrestrained proliferation of self-renewing myeloma cells in aggressive myelomas and during relapse. The mechanism that governs deregulated cell-cycle re-entry and progression in multiple myeloma is unknown, and the relationship between myeloma cells and their normal counterparts is undefined. Plasma-cell differentiation is a complex multi-step process. This chapter will address recent advances in the mechanism of normal plasma-cell differentiation and our current understanding of the relationship between plasma-cell differentiation and myeloma pathogenesis.
