Novel biological therapies for the treatment of multiple myeloma.
The therapeutic management of multiple myeloma (MM) for the last several decades has mainly involved regimens based on use of glucocorticoids and cytotoxic chemotherapeutics. Despite progress in delineating the activity of such regimens, at either conventional or high doses, MM has remained an incurable disease, without substantial improvement in the median overall survival. This has sparked major interest in the development of novel therapies that in part capitalize on recent advances in our understanding of the biology of MM, including the molecular mechanisms by which MM cell-host bone marrow (BM) interactions regulate tumor-cell growth, survival, and drug resistance in the BM milieu. The development of in vitro and in vivo models of MM-stromal interactions has allowed not only for better characterization of these molecular phenomena but also for identification of specific therapeutic strategies to overcome these interactions and achieve an enhanced anti-MM effect, even against MM resistant to conventional therapies. Herein, we review the latest progress in the development of these novel anti-MM therapies, with major focus on therapies which have translated from preclinical evaluation to clinical application, including thalidomide and its more potent immunomodulatory (IMiD) derivatives, the first-in-class proteasome inhibitor bortezomib (formerly known as PS-341), and arsenic trioxide (As2O3).
Richardson
Paul G
PG
Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Department of Medicine, Harvard Medical School, Boston, MA, USA. paul_richardson@dfci.harvard.edu
Mitsiades
Constantine S
CS
Hideshima
Teru
T
Anderson
Kenneth C
KC
D051017:Apoptosis Regulatory Proteins; D001691:Biological Therapy / Q000639:trends*; D016503:Drug Delivery Systems; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors; D006801:Humans; D008562:Membrane Glycoproteins / Q000627:therapeutic use; D009101:Multiple Myeloma / Q000628:therapy*; D053221:TNF-Related Apoptosis-Inducing Ligand; D013792:Thalidomide / Q000627:therapeutic use; D014409:Tumor Necrosis Factor-alpha / Q000627:therapeutic use; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors
D051017:Apoptosis Regulatory Proteins; D004791:Enzyme Inhibitors; D018841:HSP90 Heat-Shock Proteins; D008562:Membrane Glycoproteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; D042461:Vascular Endothelial Growth Factor A; D013792:Thalidomide