Drug Insight: thalidomide as a treatment for multiple myeloma

Abstract

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.

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Figure 1: Chemical structure of thalidomide.
Figure 2: Potential mechanisms of action of thalidomide and its immunomodulatory derivatives.

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Author information

Correspondence to Kenneth C Anderson.

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Competing interests

KC Anderson declared competing interests. He receives research support from Celgene, Novartis and Millennium.

Glossary

POST-GERMINAL-CENTER B CELLS

The centrocytes that survive in the germinal center and mature into enduring class-switched plasma cells or memory B cells

STROMAL CELLS

Connective tissue cells of an organ found in the loose connective tissue; usually associated with the uterine mucosa, ovary, and hematopoietic system

OSTEOBLASTS

Cells that arise from fibroblasts and which, as they mature, are associated with the production of bone

OSTEOCLASTS

Large multinuclear cells associated with the absorption and removal of bone

SEVERE COMBINED IMMUNODEFICIENT (SCID) MICE

Mice homozygous for the mutant autosomal recessive gene scid; these mice lack mature, functional lymphocytes and are susceptible to lethal opportunistic infections

ERYTHEMA NODOSUM LEPROSUM

An acute type of lepromatous reaction displaying tender deep cutaneous and subcutaneous nodules of the face, thighs, and arms

ENANTIOMERS

A pair of chiral isomers (stereoisomers) that are direct, non-superimposable mirror images of each other

TANDEM TRANSPLANTS

Surgical procedures to collect sufficient stem cells to perform two consecutive transplants each preceded by a course of high-dose chemotherapy

SMOLDERING/INDOLENT MM

Asymptomatic myeloma; patients are usually observed without treatment until evidence of disease progression

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