Interleukin-6 is the central tumor growth factor in vitro and in vivo in multiple myeloma

When bone-marrow cells from patients with multiple myeloma (MM) were seeded in short-term cultures, a spontaneous proliferation of the myeloma cells occurred for most of the patients with active disease and proliferating myeloma cells in vivo. In all cases, this spontaneous proliferation was inhibited by anti-IL-6 monoclonal antibodies (mabs). Moreover, myeloma cell lines, completely dependent upon exogenous IL-6 for their growth, could be reproducibly established by initially stimulating the myeloma cells with both IL-6 and GM-CSF. These results demonstrate that IL-6 is a major paracrine myeloma-cell growth factor in vitro. High serum IL-6 levels were observed in MM patients with active disease, especially patients with terminal disease. High IL-6 mRNA levels were found in bone-marrow cells of MM patients, mainly in myeloid and monocytic cells, in vivo. The myeloma cells did not express IL-6 mRNA. Injection of anti-IL-6 mabs to MM patients with terminal disease and extramedullary proliferation, completely blocked the myeloma-cell proliferation in vivo and completely inhibited the serum IL-6 bioactivity and the serum CRP levels. One patient with plasma cell leukemia and hypercalcemia was treated for two months with anti-IL-6 mabs and maintain in remission for 2 months without major side effects. Interestingly, the serum calcium levels also decreased in these patients. All these results show that IL-6 is the main cytokine responsible not only for the myeloma-cell proliferation in vivo, but presumably also for the large bone resorption processes observed in human MM.(ABSTRACT TRUNCATED AT 250 WORDS)