Immunomodulation as a therapeutic strategy in the treatment of multiple myeloma

Growth and survival of multiple myeloma (MM) cells depend on intrinsic, cell-autonomous parameters, such as the genetic lesions harboured by the MM cells, as well as extracellular, cell-non-autonomous factors, including the interaction between MM cells and bone-marrow stromal cells and the suppression of the host's anticancer immune responses. Thalidomide and the immunomodulatory agents lenalidomide and pomalidomide have pleiotropic effects on MM cells and their microenvironment, including promotion of direct mechanisms of MM-cell apoptosis, as well as indirect mechanisms mediated by perturbation of cell adhesion, modulation of cytokine production, and inhibition of tumor-associated angiogenesis. The immunomodulatory properties of these agents are mediated by effects on T-cell proliferation and function, stimulation of natural killer cells, and inhibition of regulatory T cells. Thalidomide and lenalidomide have established roles in the treatment of patients with newly diagnosed MM and those with relapsed/refractory disease. Pomalidomide is currently being evaluated in clinical trials, and preliminary clinical data suggest that it is active in patients with MM that is refractory to lenalidomide and bortezomib treatment. This article provides an overview of the current and potential future roles of immunomodulation in the management of MM, and how improved anticancer immune responses may improve treatment outcomes.