REVIEW Targeted therapies in multiple myeloma Efstathios Kastritis & Andreas Charidimou & Andreas Varkaris & Meletios A. Dimopoulos Received: 11 December 2008 / Accepted: 30 December 2008 / Published online: 17 January 2009 # Springer-Verlag 2009 Abstract Increasing knowledge of the biology of multiple myeloma led the way for the development of novel drugs that have changed the management of the disease. New treatments target not only to the malignant plasma cell but also target the interactions of myeloma cells with their microenvironment. Several preclinical studies have identi- fied potential targets and drugs are developed that act on pathways crucial for myeloma cell survival, proliferation, migration and drug resistance. The identification of active agents in the laboratory is followed by rationally designed clinical studies that validate these drugs, either as single agents or in combinations with other active drugs. These novel agents may be either small molecules or monoclonal antibodies targeting receptors, kinase activity of receptors or key molecules within critical pathways, intracellular maintenance mechanisms and immune modulation. Keywords Proteasome inhibitors . Histone deacetylase inhibitors . Heat shock protein 90 inhibitors . mTOR . IMiDs . Lenalidomide . Thalidomide . Pomalidomide . Angiogenesis . Bcl-2 Introduction In recent years, accumulated knowledge of the biology of multiple myeloma (MM) has led the way to the introduc- tion of novel drugs that have changed the management of this disease. Advances in the treatment of MM have been more pronounced over the last decade, when the introduc- tion of thalidomide, lenalidomide and bortezomib resulted in a significant improvement in the survival of myeloma patients [1]. However, MM remains an incurable disease and eventually almost all patients relapse, and their disease becomes resistant to treatment. Thus, novel treatments and innovative strategies are required to overcome drug resis- tance. New treatments target not only to the malignant plasma cell but also target to the interactions of MM cells with their microenvironment: BM stromal cells, extracellular matrix proteins, osteoclasts, endothelial cells, other accessory cells, immunocompetent cells, cytokines and growth factors. Several preclinical studies have identified potential targets and an increasing number of drugs are being developed that act on crucial pathways necessary for MM cell survival, proliferation, migration, and drug resistance. The identifica- tion of active agents in the laboratory is followed by rationally designed clinical studies that validate these drugs, either as single agents or in combinations with other active drugs. In this review we will focus on agents who are either in the phase of preclinical development or are being tested in clinical trials, and which have been developed to target specific pathways or molecules that are significant for the evolution of the disease (Table 1). Bone marrow microenvironment in multiple myeloma The bone marrow (BM) microenvironment supports growth, survival, migration and confers drug resistance to neoplasmatic plasma cells. This plasma cell—BM micro- environment interaction is accomplished through several signaling pathways that regulate critical components of plasma cell biology. These pathways have been studied Targ Oncol (2009) 4:23–36 DOI 10.1007/s11523-008-0102-9 E. Kastritis (*) : A. Charidimou : A. Varkaris : M. A. Dimopoulos Department of Clinical Therapeutics, University of Athens School of Medicine, Alexandra Hospital, 80 Vas Sofias Ave, 115 28 Athens, Greece e-mail: stathiskastritis@yahoo.com