Lenalidomide – Current Understanding of Mechanistic Properties

Nishant      Tageja

Abstract

The drug design of more effective and less toxic therapeutic agents for multiple myeloma (MM) is mushrooming in parallel to a better understanding of the underlying patho-physiology of this common hematological neoplasm. A decade back, the re-birth of Thalidomide as an anti-neoplastic agent completely transformed the treatment paradigm of patients with MM. Its effectiveness, though, has been jolted by significant adverse effects. IMiDs (immunodulatory compounds) are structural and functional analogs of thalidomide that were specifically designed to enhance immunomodulatory and anticancer properties and better tolerability profiles. Lenalidomide, a second generation IMiD, was created using thalidomide as a template by adding an amino group to the 4th carbon of the phthaloyl ring and removal of a carbonyl group. This novel drug possesses immunomodulatory, antiangiogenic, and direct apoptotic properties among others, which culminate in cancer cell death either through direct interference with key functions of tumor cells or indirectly through modulation of signaling pathways that regulate their interaction to bone marrow stromal cells. While recent preclinical and clinical studies put forward a dual mechanism of action for lenalidomide, involving both a direct tumoricidal activity and immunomodulation, it is presently unclear which mechanism(s) are responsible for clinical activity in patients responding to therapy; mechanisms themselves may also differ depending on the underlying malignancies and their tumor micro-environment. To make this riddle more complex, the relative contribution of each effect towards the eventual anti-tumor activity is very much unexplained. This research review elucidates the mechanistic properties of Lenalidomide - the understanding of which is indispensable to develop rational combination strategies for future management of hematological malignancies.

Keywords: Lenalidomide, thalidomide, IMiDs, multiple myeloma, CLL, MDS, mechanism of action, ENL, TNF-inhibitory activity, biological stability, immunomodulatory cytokines, antigen-presenting cells, CD19 B lymphocytes, pomalidomide, T-Cell Function