Lenalidomide

Lenalidomide (initially known as CC-5013 and marketed as Revlimid® by Celgene) is a derivative of thalidomide introduced in 2004. It was initially intended as a treatment for multiple myeloma, for which thalidomide is an accepted therapeutic modality, but has also shown efficacy in the hematological disorders known as the myelodysplastic syndromes.

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The exact mechanism of the immunomodulatory drugs (i.e. thalidomide, CC-4047/Actimid and lenalidomide) is not known. Apart from interfering with the immune system, they are also thought to act on angiogenesis.

Lenalidomide and bortezomib are considered therapeutic breakthroughs in myeloma, which generally carries a poor prognosis.

With myelodysplastic syndromes, the best results of lenalidomide were obtained in patients with deletion 5q (List et al 2005).

It was approved by the FDA on December 27, 2005 for patients with low or intermediate-1 risk MDS with 5q- with or without additional cytogenetic abnormalities. On June 29, 2006, Revlimid (lenalidomide) received FDA clearance for use in combination with dexamethasone in patients with multiple myeloma who have received at least one prior therapy.

Mechanism of action

The exact mechanism by which Lenalidomide acts as an immunomodulatory agent is unknown. However, recent evidence suggests that it enhances ligand-dependent expansion of a subset of T cell, the Natural killer T cell, that responds to lipid antigens and is thought to be involved in immune tolerance, tumor immunosurveilance, modulation of autoimmunity, and protection from infection.

It is currently being tested in at least one study for treating some types of amyloidosis.

Risks

Lenalidomide is related to Thalidomide, and considered to be teratogenic. It has the pregnancy category X and cannot be prescribed for women who are pregnant or who might be conceiving. For this reason, the drug is only available through a restricted distribution system called RevAssistSM.

Other potential side effects are thrombosis, pulmonary embolus, and hepatotoxicity, as well as bone marrow toxicity resulting in neutropenia and thrombocytopenia.

References

• List A, Kurtin S, Roe DJ, Buresh A, Mahadevan D, Fuchs D, Rimsza L, Heaton R, Knight R, Zeldis JB. Efficacy of lenalidomide in myelodysplastic syndromes. N Engl J Med 2005;352:549-57. PMID 15703420.
• Chang DH, Liu N, Klimek V, Hassoun H, Mazumder A, Numer SD, Jagannath S, Dhodapkar MV. Enhancement of ligand dependent activation of human natural killer T cells by lenalidomide: therapeutic implications. Blood 2006;epub ahead of print. PMID 16569772.
• Anderson KC. Lenalidomide and thalidomide: mechanisms of action--similarities and differences. Semin Hematol 2005;42(4 Suppl 4):S3-8. PMID 16344099.