Lenalidomide

Multiple myeloma Lenalidomide is used to treat multiple myeloma. It is a more potent molecular analog of thalidomide, which inhibits tumor angiogenesis, tumor-secreted cytokines, and tumor proliferation through induction of apoptosis. Lenalidomide is effective at inducing a complete or "very good partial" response and improves progression-free survival. Adverse events more common in people receiving lenalidomide for myeloma include neutropenia, deep vein thrombosis, infections, and an increased risk of other hematological malignancies. The risk of second primary hematological malignancies does not outweigh the benefit of using lenalidomide in relapsed or refractory multiple myeloma. It may be more difficult to mobilize stem cells for autograft in people who have received lenalidomide. In 2017, the FDA approved lenalidomide as standalone maintenance therapy (without dexamethasone) for people with multiple myeloma following autologous stem cell transplant. In 2009, The National Institute for Health and Clinical Excellence issued a final appraisal determination approving lenalidomide in combination with dexamethasone as an option to treat people with multiple myeloma who have received two or more prior therapies in England and Wales. The use of lenalidomide combined with other drugs was evaluated. It was seen that the drug combinations of lenalidomide plus dexamethasone and continuous bortezomib plus lenalidomide plus dexamethasone probably increased overall survival. Myelodysplastic syndromes Lenalidomide was approved by the FDA in December 2005, for people with low- or intermediate-1-risk myelodysplastic syndromes who have chromosome 5q deletion syndrome (5q- syndrome) with or without additional cytogenetic abnormalities. It was approved on 17 June 2013 by the European Medicines Agency for use in patients with low- or intermediate-1-risk myelodysplastic syndromes who have 5q- deletion syndrome but no other cytogenetic abnormalities and are dependent on red blood cell transfusions, for whom other treatment options have been found to be insufficient or inadequate. Follicular Lymphoma The FDA approves Lenalidomide in combination with Rituximab in patients whose disease is CD20 positive and has relapsed or progressed after at least one prior therapy. This treatment is commonly known as R² ("R squared"). Mantle cell lymphoma The FDA approves Lenalidomide as a specialty drug requiring a specialty pharmacy distribution for mantle cell lymphoma in people whose disease has relapsed or progressed after at least two prior therapies, one of which must have included the medicine bortezomib. ==Adverse effects==

In addition to embryo-fetal toxicity, lenalidomide carries black box warnings for hematologic toxicity (including neutropenia and thrombocytopenia) and thromboembolism. Serious side effects include thrombosis, pulmonary embolus, hepatotoxicity, and bone marrow toxicity resulting in neutropenia and thrombocytopenia. Myelosuppression is the major dose-limiting toxicity, which is not the case with thalidomide. Lenalidomide may be associated with adverse effects as second primary malignancy, severe cutaneous reactions, hypersensitivity reactions, tumor lysis syndrome, tumor flare reaction, hypothyroidism, and hyperthyroidism. It cannot be prescribed for people who are pregnant or who are likely to become pregnant during therapy. Venous thromboembolism Lenalidomide, like its parent compound thalidomide, may cause venous thromboembolism, a potentially serious complication with their use. High rates of venous thromboembolism have been found in patients with multiple myeloma who received thalidomide or lenalidomide in conjunction with dexamethasone, melphalan, or doxorubicin. Stevens-Johnson syndrome In March 2008, the US Food and Drug Administration (FDA) included lenalidomide on a list of twenty prescription drugs under investigation for potential safety problems. The drug was investigated for possibly increasing the risk of developing Stevens–Johnson syndrome, a life-threatening skin condition. FDA ongoing safety review In 2011, the FDA initiated an ongoing review of clinical trials that found an increased risk of developing cancers such as acute myelogenous leukemia and B-cell lymphoma, though it did not advise patients to discontinue treatment with lenalidomide. ==Mechanism of action==

Lenalidomide changes the substrate specificity of the CRL4CRBN E3 ubiquitin ligase, a complex consisting of DNA-binding protein 1 (DDB1), cullin 4a (CUL4A), regulator of cullins 1 (ROC1), and cereblon (CRBN). In particular, loss of IKZF3 then decreases the expression of interferon regulatory factor 4 (IRF4). IRF4 is a master regulator of several cancer-promoting genes and is required for the survival of multiple myeloma. Loss of IKZF1 and IKZF3 also results in increased expression and secretion of interleukin 2 and interferon gamma, which stimulates a local immune response from T cells and NK cells. ==Synthesis==

The first synthesis of lenalidomide was disclosed in patents filed by Celgene. : Methyl 2-methyl-3-nitrobenzoate is brominated using N-bromosuccinimide and the product is treated with 3-amino-piperidine-2,6-dione, a cyclic derivative of glutamine to form a lactam. Catalytic hydrogenation then gives lenalidomide. ==History==

Legal status Lenalidomide was approved for medical use in the United States in 2005. Lenalidomide made almost $9.7bn for Celgene in 2018. Price increases Since its initial approval by the Food and Drug Administration (FDA) in December 2005 for the treatment of certain cancers, the price of Lenalidomide, manufactured by Celgene, has risen significantly. At its launch, the cost per pill was $218, equating to an annual cost of approximately $55,000 for a standard regimen. Following FDA approval for multiple myeloma in mid-2006, the price per pill increased to $280, or about $70,560 annually. As of 2023, the price per pill had reached $892. Since its approval, Revlimid cost has increased 26 times. In Australia, a 21-day course of 25 mg lenalidomide tablets costs Medicare A$2397, however, the patient only pays $30 due to the Pharmaceutical Benefits Scheme. In 2025, the generic version of Revlimid is only marginally cheaper than the branded version in the United States, $17,349 versus $19,660 per month. == References ==