Experimental approaches in the treatment of multiple myeloma.

Myeloma therapy has undergone significant advances in recent years resulting in a marked improvement in survival. Knowledge of the active pathways involved in myeloma pathogenesis has led to the discovery of novel agents and greatly expanded the potential armamentarium available for treatment. This better understanding of the disease and resistance mechanisms has resulted in new agent classes that are being evaluated in preclinical and early clinical studies. In addition, dosing for existing agents is being optimized, and they are being given in new combinations. In this article, we review experimental agents that are showing promise in multiple myeloma treatment. New biological agents in clinical trials hold the promise of efficacy through novel mechanisms of action, with a significant reduction of dose-limiting toxicities compared with classic cytotoxic chemotherapeutics. Second-generation proteasome inhibitors and immunomodulatory agents are furthest along in clinical development, and histone deacetylase inhibitors, heat shock protein 90 inhibitors, Akt inhibitors and monoclonal antibodies are some of the other agents entering later-phase clinical trials. We also review developments in targeting the myeloma stem cell as an exciting new treatment direction.