MODULATION OF INTERLEUKIN-6 INTERLEUKIN-6 RECEPTOR CYTOKINE LOOP IN THE TREATMENT OF MULTIPLE-MYELOMA/

Interluekin-6 (IL-6)/IL-6 receptor (IL-6R) play a major role in autocr ine/paracrine growth regulation of myeloma cells and are the central m ediators for bone destruction and other systemic manifestations of mul tiple myeloma. Modulation of the IL-6/IL-6R cytokine loop thus represe nts a rational therapeutic approach. We updated and reviewed the studi es on the agents that targeted IL-6/IL-6R modulation and the results o f selected clinical trials. Extensive in vitro studies with human myel oma cell lines or primary myeloma explants have shown that components of this cytokine loop could be modulated by various agents, and such m odulation is associated with inhibition of myeloma cell growth. The pu rported mechanisms of action of these agents, down-regulation or neutr alization of IL-6 and/or IL-6R and the interruption of IL-6 binding to IL-6R or gp130 signal transducer, with possible exception for glucoco rticoids and specific antibodies, remain to be formally proven. Clinic al trials showed largely limited benefits of these agents. Given tumor cell heterogeneity and the complexity of inter-connected cytokine net work in vivo, the future emphasis should be on the strategy of combina tion treatment that would modulate this cytokine loop at multiple site s. Further advances in delineating IL-6 and related cytokine signal tr ansduction pathways should also suggest other targets for therapeutic intervention.