From the bench to the bedside: emerging new treatments in multiple myeloma

Abstract

Within the last decade, several novel classes of anti-myeloma therapeutics have become available. The clinical successes achieved by thalidomide, lenalidomide, and the proteasome inhibitor bortezomib, and in particular the ability of these agents to lead to major clinical responses in patients resistant to conventional or high-dose chemotherapy, have highlighted the importance of expanding further the spectrum of classes of agents utilized for the treatment of myeloma. Herein, we review the current status for the development of novel anti-myeloma agents, with emphasis on classes of therapeutics which have already translated into clinical trials or those in advanced stages of preclinical development. These include second-generation proteasome inhibitors (NPI-0052 and PR-171), heat shock protein 90 (hsp90) inhibitors, 2-methoxyestradiol, histone deacetylase (HDAC) inhibitors (e.g. SAHA and LBH589), fibroblast growth factor receptor 3 (FGF-R3) inhibitors, insulin-like growth factor 1 receptor (IGF-1R) inhibitors, mTOR inhibitors, monoclonal antibodies, and agents specifically targeting the tumor microenvironment, such as defibrotide.

Figure 1

Schematic representation of the integration of key signal transduction cascades in multiple myeloma (MM) cells and their interaction with non-malignant cells of the bone-marrow microenvironment. The molecular and cellular levels of action of some of the novel anti-MM agents in clinical or preclinical development are highlighted. Hsp90, heat shock protein 90; FGFR3, fibroblast growth factor receptor 3; IL-6(R), interleukin 6 (receptor); IGF-1(R), insulin-like growth factor 1 (receptor); VEGF(R), vascular endothelial growth factor (receptor); IKK, IκB kinase; SDF-1 α, stromal cell-derived factor 1α; BAFF, B-cell-activating factor; APRIL, a proliferation-inducing ligand; TNF α, tumor necrosis factor α; TGFβ, tumor growth factor β; NF-κB, nuclear factor κB; BMSC, bone-marrow stromal cell; MUC-1, mucin 1; LFA-1, lymphocyte function-associated antigen 1; ICAM-1, intercellular adhesion molecule 1; VLA-4, very late antigen 4; VCAM-1, vascular cell adhesion molecule 1; HGF, hepatocyte growth factor; BMEC, bone-marrow microvascular endothelial cell; bFGF, basic fibroblast growth factor; 2ME2, 2-methoxyestradiol; MIP-1 α, macrophage inflammatory protein 1α; DKK1, dickkopf-1; HDAC, histone deacetylase.