The presence of circulating clonal CD19+ cells in multiple myeloma

Multiple myeloma (MM) is a B-cell malignancy characterized by the expansion of mature plasma cells (PC) localized in the bone marrow (BM). Several studies have identified circulating clonotypic CD19(+) cells at a differentiation stage preceding the PC. The level of circulating clonotypic CD19(+) cells is highly variable but generally low. Circulating clonotypic cells respond well to induction therapy, although a small subset within the CD19 compartment is resistant even to high-dose chemotherapy. The clonal CD19(+) cells represent an ongoing differentiating population ranging from memory B-cells to plasmablasts. However, a clonal relationship gives no proof of malignant potential, and whether or not clonotypic precursor cells are involved in the disease process is a subject of intense debate. Translocations involving the immunoglobulin locus (14q32) are an early non-transforming event common to both monoclonal gammopathy of undetermined significance (MGUS) and MM introduced at the memory B-cell level. At the plasmablast stage, a phenotypic transformation occurs with downregulation of CD19 and upregulation of myeloma specific markers such as CD56, CD117 and CD28. Translocations involving the isotype-switch machinery and the introduction of tumor-specific markers at the plasmablast stage suggest that the clonal CD19(+) memory B-cells and CD19(+) plasmablasts are non-malignant, but immortalized relatives that gave rise to myeloma. A final proof of the malignant potential of CD19(+) clonotypic cells might await the identification of the molecular events causing the transformation in myeloma.