Drug insight: thalidomide as a treatment for multiple myeloma.
Multiple myeloma (MM)--a malignancy of the bone marrow--remains incurable by current therapies, and there is an urgent need for new drugs based on a better understanding of the underlying disease biology. MM is characterized by monoclonal plasma cells that accumulate in the bone marrow, which provides a microenvironment that promotes tumor cell growth and survival and protection against various therapeutic agents. The MM cell interacts with bone marrow stromal cells and endothelial cells, as well as osteoblasts and osteoclasts. Our understanding of the tumor microenvironment has already prompted the development of new agents that are aimed at disrupting the multiple facets of these interactions. It has also enabled the development of a comprehensive and rational approach to preclinical evaluation of new agents, facilitating the translation of in vitro studies to in vivo tumor models and, subsequently, to clinical trials. In this review, we describe the preclinical studies that led to the development of clinical trials of thalidomide and its immunomodulatory derivatives as therapeutic agents for MM. These drugs, alone or in combination, have shown impressive activity at all stages of the disease, and these demonstrations of clinical benefit have in turn validated our model systems for drug discovery in MM. Integration of data from clinical trials and laboratory studies will allow the design of future clinical trials that combine thalidomide and its derivatives with other drugs, ultimately leading to more effective therapies and better outcomes in patients with MM.
Kumar
Shaji
S
Mayo Clinic College of Medicine and , Division of Hematology, Mayo Clinic, Rochester, MN, USA.
Anderson
Kenneth C
KC
D000818:Animals; D001854:Bone Marrow Cells / Q000502:physiology; D002448:Cell Adhesion; D049109:Cell Proliferation; D002470:Cell Survival; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D051379:Mice; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000276:immunology* / Q000503:physiopathology; D015398:Signal Transduction; D013792:Thalidomide / Q000627:therapeutic use*
D007166:Immunosuppressive Agents; D013792:Thalidomide