Tumor necrosis factor-alpha and interleukin 4 in myeloma cell precursor differentiation

Multiple myeloma is a B-cell malignancy characterized by the accumulation of a clonal population of plasma cells in the bone marrow that secrete a monoclonal immunoglobulin protein. It has been regarded as a tumor arising at the B, pre-B lymphocyte, or even stem cell level. Precursor cells are presumed to proliferate and differentiate, giving rise to clonal expansion in plasma cells. Peripheral blood mononuclear cells (PBMC) from 36 patients with multiple myeloma, 12 with monoclonal gammopathy of undetermined significance (MGUS), and 21 healthy controls were cultured in vitro in the presence of tumor necrosis factor-alpha (TNF-alpha) and interleukin 4 (IL-4). We have demonstrated that monoclonal plasma cells can be induced in different proportions from PBMC obtained from myeloma patients when exposed in vitro to TNF-alpha and IL-4. Although myeloma cell precursors cannot be distinguished from other cells by morphology, a high number of monoclonal plasma cells was detected in our culture system on day 4 even when plasma cells accounted for less than 0.2% of the cells seeded on day 0. In 16 of the 36 patients with myeloma, monoclonal plasma cells appeared after 4 days. These changes were not observed in PBMC from patients with MGUS or from controls. These findings thus suggest that circulating myeloma cell precursors differentiate into plasma cells in the presence of TNF-alpha and IL-4, and the variation in the number of myeloma cell precursors in peripheral blood could therefore be used as a prognostic parameter in response to chemotherapy in myeloma patients.