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INTRODUCTION

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The therapeutic options for the treatment of multiple myeloma (MM) have expanded over the past decade with the introduction of novel biologically targeted agents, which in turn have resulted in significantly improved outcomes (1). The use of the immunomodulatory drug thalidomide in the 1990s and subsequently its analogue lenalidomide and more recently pomalidomide has been a major advance in the field. The proteasome inhibitor, bortezomib, was FDA approved in 2003, and the next-generation proteasome inhibitors are now undergoing evaluation in clinical trials. Antibodies targeting membrane-bound receptors are another promising class of agents.

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IMMUNOMODULATORY DRUGS (IMiDs)

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Thalidomide was originally developed as an antihistamine, but produced significant sedation and was marketed as a hypnotic. It alleviated symptoms of morning sickness due to pregnancy. However, in 1963 it was withdrawn when its use was associated with stunted limb growth (dysmelia) in children born of women exposed to the drug during pregnancy. Three decades later it was found to improve signs and symptoms of erythema nodosum leprosum. This approval reawakened interest in its antiangiogenic and immunomodulatory effects and led to its successful trial for the treatment of patients with refractory MM (2).

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Lenalidomide was developed as a thalidomide analogue that more effectively inhibited TNF-α. Pomalidomide is the newest IMiD.

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STRUCTURE

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Thalidomide is piperidinyl isoindole ([±]-α-[N-phthalimido]) glutarimide. It is a neutral racemic compound derived from glutamic acid, and is structurally related to the analeptic drug bemegride (α-ethyl-α-methyl-glutarimide, C18H13NO2), and to a sedative and antiepileptic drug, glutethimide (β-ethyl-β-phenyl-glutarimide, C15H23NO4). It has two ring systems: a left-sided phthalimide, and a right-sided glutarimide with an asymmetric carbon atom at position 3′ of the glutarimide ring. The drug consists of equimolar amounts of (+)-R- and (–)-(S)-enantiomers. Thalidomide is sparingly soluble in water (<0.1 g/l) and spontaneously hydrolyses in solution at pH 6.0 or higher to produce at least 12 different products. The structure of thalidomide was modified through the addition of an amino group at the 4 position of the phthaloyl ring, to generate pomalidomide and with the further removal of a carbonyl on the ring to form lenalidomide (Figure 6-1).

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FIGURE 6-1

The structure of thalidomide, hydroxylated metabolites with their hydrolytic products and analogs lenalidomide and pomalidomide. (A) Thalidomide, (B) its p450 hydroxylation product, (C) a spontaneous hydrolytic breakdown product, and (D) its analog, lenalidomide.

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MECHANISM OF ACTION

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IMiDs are hypothesized to act through multiple mechanisms including:

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  1. A direct antiproliferative/proapoptotic effect probably mediated by downregulation of TNFα, a tumor stimulating and immunomodulatory cytokine, and a suppressive effect on nuclear factor kappa B (NF-κB), a transcription factor that promotes a protective response to cell injury.

  2. An indirect antitumor effect mediated by downregulation of tumor cell adhesion molecules (I-CAM 1) and stimulatory cytokines such as IL-6.

  3. Inhibition of secretion of angiogenic cytokines such as basic FGF and VEGF.

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Its teratogenic activity is attributed to its binding to and inactivating a ubiquitin ligase, cereblon, the suppression of which aborts limb development in zebrafish (3...

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