Lenalidomide is a synthetic compound derived by modifying the chemical structure of thalidomide. It belongs to the second generation of immunomodulatory drugs (IMiDs) and possesses pleiotropic properties. Even if lenalidomide has been shown to be active in the treatment of several hematologic malignancies, this review article is mostly focalized on its mode of action in multiple myeloma. The present paper is about the direct and indirect antitumor effects of lenalidomide on malignant plasmacells, bone marrow microenvironment, bone resorption and host’s immune response. The molecular mechanisms and targets of lenalidomide remain largely unknown, but recent evidence shows cereblon (CRBN) as a possible mediator of its therapeutical effects. 1. Introduction Lenalidomide and pomalidomide are synthetic compounds derived by modifying the chemical structure of thalidomide [1]. In particular, as shown in Figure 1, lenalidomide has been synthesized from the structural bone of thalidomide molecule. Lenalidomide has been developed by adding an amino group (NH2–) at 4th position of phthaloyl ring and by removing the carbonyl group (C=O) of the 4-amino-substituted phthaloyl ring. This drug is the result of the pressing need to develop molecules with enhanced immunomodulatory and antitumor activity in comparison to thalidomide. Lenalidomide, which possesses pleiotropic properties, belongs to the second generation of immunomodulatory drugs (IMiDs). Figure 1: Lenalidomide and thalidomide structure. Lenalidomide and its parental molecule thalidomide have shown therapeutical activity in various malignancies [2–21]. The US Food and Drug Administration (FDA) first approved lenalidomide for the treatment of patients suffering from 5q-myelodysplastic syndrome [22]. However, because of the proven activity of thalidomide in multiple myeloma (MM), the clinical activity of lenalidomide has been evaluated more extensively in this neoplasia [7–12], in respect to other B-cell neoplasia. The favourable toxic profile of lenalidomide and its antitumor activity emerged from phase I and phase II studies in relapsed or refractory MM patients [23–25]. These encouraging results led to the design of two large, phase III, multinational, randomized, double-blind, placebo-controlled, registration trials (MM-009 in US and Canada and MM-010 in Europe, Australia, and Israel) in this setting of patients. In both studies, patients were randomly assigned to receive 25？mg of lenalidomide or placebo on days 1 to 21 of 28-day cycles plus dexamethasone (40？mg on days 1 to 4, 9 to 12 and 17 to 20 for the
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