Biological heterogeneity is a characteristic of multiple myeloma. A dysregulated cytokine network underlies the various phases of the disease. Numerous cytokines, either promoting or inhibiting plasma cell growth, are involved in tumor control. Interferon-γ (IFN-γ) showed the most powerful inhibiting activity on myeloma cell proliferation. This effect was demonstrated on IL-6 dependent myeloma cell lines, but not on IL-6 independent ones. It was also evident on fresh explanted bone marrow myeloma cells. The antiproliferative effect of IFN-γ seems mainly due to the inhibition of IL-6, the central myeloma growth factor. IL-6 inhibition may occur at various levels: a downregulation of IL-6 receptor has been reported, and also a block of the IL-6 signal trasduction pathway via interaction with cytoplasmic proteins such as p91 has been suggested. Our findings showed that IFN-γ strongly inhibited myeloma cell proliferation to the same extent as dexamethasone (DEX), whereas interferonce (IFN-α) inhibited Ig secretion. The combined use of interferons (IFNs) showed inhibitory activities both on proliferation and Ig synthesis that paralleled the effects of DEX. In some cases, IFN-γ was also shown to augment monoclonal immunoglobulin secretion suggesting a possible differentianting activity on plasma cells.

The in vitro data encouraged pilot studies to evaluate the in vivo antitumor effects of IFN-γ. Preliminary data are rather controversial and the lack of large and control studies has not yet allowed definition of the real role of this cytokine, either as single agent or in combination with IFN-a or other not cytotoxic inhibitory agents such as all-trans retinoic acid, cis-retinoic acid, DEX. The ideal candidates for this non-cytotoxic treatment seem low tumor mass patients, who have no need for immediate onset of chemotherapy.