Mechanism of action of immunomodulatory drugs (IMiDS) in multiple myeloma

Abstract

Immunomodulatory drugs (IMiDs) are thalidomide analogues, which possess pleiotropic anti-myeloma properties including immune-modulation, anti-angiogenic, anti-inflammatory and anti-proliferative effects. Their development was facilitated by an improved understanding in myeloma (MM) biology and initiated a profound shift in the therapeutic approach towards MM. Despite the diverse effects of IMiDs in vitro, the relative contribution of each effect towards their ultimate anti-MM activity is still unclear. Based on in vitro data, it appears that anti-proliferative effects and downregulation of crucial cytokines are their most important anti-MM attributes. Although the co-stimulatory effects on T and NK cells have been heralded as a unique and important property of IMiDs towards enhancing anti-MM immune activity, these in vitro effects have yet to be firmly corroborated in vivo. Much is yet to be elucidated regarding the complex interplay of immunomodulatory cytokines that occurs in vivo, which ultimately dictates the net effects of IMiDs in MM-the understanding of which is necessary to facilitate optimal manipulation of these drugs in future MM management.

Figure 1

Chemical structure of thalidomide and its analogues, lenalidomide (CC-5013) and pomalidomide (CC-4047). The two first-in-class immunomodulatory drugs were lenalidomide and pomalidomide. Both are derived by adding an amino group to the fourth carbon of the phthaloyl ring of thalidomide. Pomalidomide essentially has a combined chemical structure of thalidomide and lenalidomide.

Figure 2

Multiple Myeloma induces immunoparesis. Plasma cell derived cytokines including transforming growth factor (TGF)-β, interleukin (IL)-10, IL-6 and VEGF mediate suppression of B and T lymphocytes, and impair T-cell co-stimulation by dendritic cells (DC), ultimately leading to poor tumor-specific immune response.

Figure 3

Summary of the immunomodulatory effects of immunomodulatory drugs. BMSC: bone marrow stromal cells; APC: antigen-presenting cells; IL: interleukin; TGF: transforming growth factor; TNF: tumor necrosis factor; VEGF: vascular endothelia growth factor; ADCC: antibody-dependent cellular toxicity; MHC: major histocompatibility complex; TCR: T cell receptor; NF-κB: Nuclear factor kappa B; PI3k: phosphoinositide 3-kinase; NFAT: nuclear factor of activated T cell; IFN: interferon; NK: natural killer.

Figure 4

Disruption of plasma cell–microenvironment interactions by immunomodulatory drugs. Anti-myeloma activity is mediated via downregulation of adhesion molecules, cytokine modulation, anti-angiogenesis, anti-osteoclastogenesis, as well as having direct anti-proliferative effects on malignant plasma cells.

Figure 5

Inhibition of caspase-8 by IMiDs. TNF: tumor necrosis factor, TRAIL: TNF-related apoptosis-inducing ligand; FasL: Fas ligand; NF-κB: Nuclear factor kappa B; IL:interleukin; IGF: insulin-like growth factor.