text: Thalidomide was originally released in the Federal Republic of Germany (West Germany) under the label of Contergan on October 1, 1957, by Chemie Grünenthal (now Grünenthal). The drug was primarily prescribed as a sedative or hypnotic, but it was also used as an antiemetic for morning sickness in pregnant women. The drug was banned in 1961 after its teratogenic properties were observed. The problems with thalidomide were, aside from the teratogenic side effects, both high incidence of other adverse reactions along with poor solubility in water and absorption from the intestines. Adverse reactions include peripheral neuropathy in large majority of patients, constipation, thromboembolism along with dermatological complications.
  Four years after thalidomide was withdrawn from the market for its ability to induce severe birth defects, its anti-inflammatory properties were discovered when patients with erythema nodosum leprosum (ENL) used thalidomide as a sedative and it reduced both the clinical signs and symptoms of the disease. Thalidomide was discovered to inhibit tumour necrosis factor-alpha (TNF-α) in 1991 (5a Sampaio, Sarno, Galilly Cohn and Kaplan, JEM 173 (3) 699–703, 1991) . TNF-α is a cytokine produced by macrophages of the immune system, and also a mediator of inflammatory response. Thus the drug is effective against some inflammatory diseases such as ENL (6a Sampaio, Kaplan, Miranda, Nery..... JID 168 (2) 408-414 2008). In 1994 Thalidomide was found to have anti-angiogenic activity and anti-tumor activity which propelled the initiation of clinical trials for cancer including multiple myeloma. The discovery of the anti-inflammatory, anti-angiogenic and anti-tumor activities of thalidomide increased the interest of further research and synthesis of safer analogs.
  Lenalidomide is the first analog of thalidomide which is marketed. It is considerably more potent than its parent drug with only two differences at a molecular level, with an added amino group at position 4 of the phthaloyl ring and removal of a carbonyl group from the phthaloyl ring.
  Development of lenalidomide began in the late 1990s and clinical trials of lenalidomide began in 2000. In October 2001 lenalidomide was granted orphan status for the treatment of MM. In mid-2002 it entered phase II and by early 2003 phase III. In February 2003 FDA granted fast-track status to lenalidomide for the treatment of relapsed or refractory MM.
  In 2006 it was approved for the treatment of MM along with dexamethasone and in 2007 by European Medicines Agency (EMA). In 2008, phase II trial observed efficacy in treating Non-Hodgkin's lymphoma.
  Pomalidomide (3-aminothalidomide) was the second thalidomide analog to enter the clinic being more potent than both of its predecessors. 
  First reported in 2001, pomalidomide was noted to directly inhibit myeloma cell proliferation and thus inhibiting MM both on the tumor and vascular compartments. This dual activity of pomalidomide makes it more efficacious than thalidomide both in vitro and in vivo. This effect is not related to TNF-α inhibition since potent TNF-α inhibitors such as rolipram and pentoxifylline did not inhibit myeloma cell growth nor angiogenesis. Upregulation of interferon gamma, IL-2 and IL-10 have been reported for pomalidomide and may contribute to its anti-angiogenic and anti-myeloma activities.