Lenalidomide

Lenalidomide, sold under the trade name Revlimid among others, is a medication used to treat multiple myeloma (MM) and myelodysplastic syndromes (MDS).[1] For MM it is used after at least one other treatment and generally together with dexamethasone.[1] It is taken by mouth.[1]

Lenalidomide
Clinical data
Pronunciation/ˌlɛnəˈlɪdmd/
Trade namesRevlimid
AHFS/Drugs.comMonograph
MedlinePlusa608001
License data
Pregnancy
category
  • AU: X (High risk)
  • US: X (Contraindicated)
    Routes of
    administration
    By mouth (capsules)
    ATC code
    Legal status
    Legal status
    Pharmacokinetic data
    BioavailabilityUndetermined
    Protein binding30%
    MetabolismUndetermined
    Elimination half-life3 hours
    ExcretionKidney (67% unchanged)
    Identifiers
    CAS Number
    PubChem CID
    IUPHAR/BPS
    DrugBank
    ChemSpider
    UNII
    KEGG
    ChEMBL
    CompTox Dashboard (EPA)
    ECHA InfoCard100.218.924
    Chemical and physical data
    FormulaC13H13N3O3
    Molar mass259.261 g/mol g·mol−1
    3D model (JSmol)
    ChiralityRacemic mixture
      (verify)

    Common side effects include diarrhea, itchiness, join pain, fever, headache, and trouble sleeping.[1] Severe side effects may include low blood platelets, low white blood cells, and blood clots.[1] Use during pregnancy may harm the baby.[1] The dose may need to be adjusted in people with kidney problems.[1] It has a chemical structure similar to thalidomide but has a different mechanism of action.[2][1] How it works is not entirely clear as of 2019.[1]

    Lenalidomide was approved for medical use in the United States in 2005.[1] It is on the World Health Organization's List of Essential Medicines, the safest and most effective medicines needed in a health system.[3] In the United States it costs about US$16,000 to US$21,000 per month as of 2019.[4] In the United Kingdom this amount costs the NHS about £3,400 to 4,400.[5]

    Medical uses

    Multiple myeloma

    Lenalidomide is used to treat multiple myeloma.[6] It is a more potent molecular analog of thalidomide, which inhibits tumor angiogenesis, tumor secreted cytokines and tumor proliferation through the induction of apoptosis.[7][8][9]

    Lenalidomide is effective at inducing a complete or "very good partial" response as well as improving progression-free survival. Adverse events more common in people receiving lenalidomide for myeloma were neutropenia (a decrease in the white blood cell count), deep vein thrombosis, infections, and an increased risk of other hematological malignancies.[10] The risk of second primary hematological malignancies does not outweigh the benefit of using lenalidomide in relapsed or refractory multiple myeloma.[11] It may be more difficult to mobilize stem cells for autograft in people who have received lenalidomide.[7]

    In 2006, lenalidomide received U.S. Food and Drug Administration (FDA) clearance for use in combination with dexamethasone in people with multiple myeloma who have received at least one prior therapy.[12] In 2017, the FDA approved lenalidomide as standalone maintenance therapy (without dexamethasone) for people with multiple myeloma following autologous stem cell transplant.[13]

    In 2009, The National Institute for Health and Clinical Excellence (NICE) issued a Final Appraisal Determination (FAD) 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.[14]

    Myelodysplastic syndromes

    With myelodysplastic syndromes (MDS), the best results of lenalidomide were obtained in patients with the Chromosome 5q deletion syndrome (5q- syndrome).[15] The syndrome results from deletions in human chromosome 5 that remove three adjacent genes, granulocyte-macrophage colony-stimulating factor, Platelet-derived growth factor receptor B, and Colony stimulating factor 1 receptor.[16][17]

    It was approved by the FDA on 27 December 2005, for patients with low or intermediate-1 risk MDS with 5q- with or without additional cytogenetic abnormalities. A completed Phase II, multi-centre, single-arm, open-label study evaluated the efficacy and safety of Revlimid monotherapy treatment for achieving haematopoietic improvement in red blood cell (RBC) transfusion dependent subjects with low- or intermediate-1-risk MDS associated with a deletion 5q cytogenetic abnormality.

    63.8% of subjects had achieved RBC-transfusion independence accompanied by a median increase of 5.8 g/dL in blood Hgb concentration from baseline to the maximum value during the response period. Major cytogenetic responses were observed in 44.2% and minor cytogenetic responses were observed in 24.2% of the evaluable subjects. Improvements in bone marrow morphology were also observed. The results of this study demonstrate the efficacy of Revlimid for the treatment of subjects with Low- or Intermediate-1-risk MDS and an associated del 5 cytogenetic abnormality.[15][18][19]

    Lenalidomide was approved on 17 June 2013 by the European Medicines Agency for use in low- or intermediate-1-risk myelodysplastic syndromes (MDS) patients who have the deletion 5q cytogenetic abnormality and no other cytogenetic abnormalities, are dependent on red blood cell transfusions, and for whom other treatment options have been found to be insufficient or inadequate.[20]

    Mantle cell lymphoma

    Lenalidomide is approved by FDA for mantle cell lymphoma in patients whose disease has relapsed or progressed after at least two prior therapies.[2] One of these previous therapies must have included bortezomib.

    In 2013, the FDA designated lenalidomide as a specialty drug requiring a specialty pharmacy distribution for "use in mantle cell lymphoma (MCL) in people whose disease has relapsed or progressed after two prior therapies, one of which included bortezomib."

    Adverse effects

    In addition to embryo-fetal toxicity, lenalidomide also carries Black Box Warnings for hematologic toxicity (including significant neutropenia and thrombocytopenia) and venous/arterial thromboembolisms.[2]

    Serious potential side effects are thrombosis, pulmonary embolus, and hepatotoxicity, as well as bone marrow toxicity resulting in neutropenia and thrombocytopenia. Myelosuppression is the major dose-limiting toxicity, which is contrary to experience with thalidomide.[21] Lenalidomide may also be associated with adverse effects including second primary malignancy, severe cutaneous reactions, hypersensitivity reactions, tumor lysis syndrome, tumor flare reaction, hypothyroidism, and hyperthyroidism.[2]

    Teratogenicity

    Lenalidomide is related to thalidomide which is known to be teratogenic. Tests in monkeys have suggested lenalidomide is also teratogenic.[22] It therefore has the pregnancy category X and cannot be prescribed for women who are pregnant or who may become pregnant during therapy. For this reason, the drug is only available in the United States (under the brand name Revlimid) through a restricted distribution system called RevAssist. Females who may become pregnant must use at least two forms of reliable contraception during treatment and for at least four weeks after discontinuing treatment with lenalidomide.[2]

    It is only available through a specialty pharmacy, "a restricted distribution program in conjunction with a risk evaluation and mitigation strategy (REMS) due to potential for embryo-fetal risk."[23]

    Venous thromboembolism

    Lenalidomide, like its parent compound thalidomide, may cause venous thromboembolism (VTE), a potentially serious complication with their use. Bennett et al. have reviewed incidents of lenalidomide-associated VTE among patients with multiple myeloma.[24] They have found that there are high rates of VTE when patients with multiple myeloma received thalidomide or lenalidomide in conjunction with dexamethasone, melphalan, or doxorubicin. When lenalidomide and dexamethasone are used to treat multiple myeloma, a median of 14% of patients had VTE (range,3-75%). In patients who took prophylaxis to treat lenalidomide-associated VTE, such as aspirin, thromboembolism rates were found to be lower than without prophylaxis, frequently lower than 10%. Clearly, thromboembolism is a serious adverse drug reaction associated with lenalidomide, as well as thalidomide. In fact, a black box warning is included in the package insert for lenalidomide, indicating that lenalidomide-dexamethasone treatment for multiple myeloma is complicated by high rates of thromboembolism.

    Currently, clinical trials are under way to further test the efficacy of lenalidomide to treat multiple myeloma, and to determine how to prevent lenalidomide-associated venous thromboembolism.

    Stevens-Johnson syndrome

    In March 2008, the U.S. Food and Drug Administration (FDA) included lenalidomide on a list of 20 prescription drugs under investigation for potential safety problems. The drug is being investigated for possibly increasing the risk of developing Stevens–Johnson syndrome, a life-threatening condition affecting the skin.[25]

    FDA ongoing safety review

    As of 2011, the FDA has initiated an ongoing review which will focus on clinical trials which found an increased risk of developing cancers such as acute myelogenous leukemia (AML) and B-cell lymphoma,[26] though the FDA is currently advising all people to continue their treatment.[27]

    Mechanism of action

    Lenalidomide has been used to successfully treat both inflammatory disorders and cancers in the past ten years. There are multiple mechanisms of action, and they can be simplified by organizing them as mechanisms of action in vitro and in vivo.[28] In vitro, lenalidomide has three main activities: direct anti-tumor effect, inhibition of angiogenesis, and immunomodulation. In vivo, lenalidomide induces tumor cell apoptosis directly and indirectly by inhibition of bone marrow stromal cell support, by anti-angiogenic and anti-osteoclastogenic effects, and by immunomodulatory activity. Lenalidomide has a broad range of activities that can be exploited to treat many hematologic and solid cancers.

    On a molecular level, lenalidomide has been shown to interact with the ubiquitin E3 ligase cereblon[29] and target this enzyme to degrade the Ikaros transcription factors IKZF1 and IKZF3.[30] This mechanism was unexpected as it suggests that the major action of lenalidomide is to re-target the activity of an enzyme rather than block the activity of an enzyme or signaling process, and thereby represents a novel mode of drug action. A more specific implication of this mechanism is that the teratogenic and anti-neoplastic properties of lenalidomide, and perhaps other thalidomide derivatives, could be disassociated.

    History

    Lenalidomide was approved for medical use in the United States in 2005.[1]

    Price

    Lenalidomide costs $163,381 per year for the average person in the United States.[26] Lenalidomide made almost $9.7bn for Celgene in 2018.[31]

    In 2013, the UK National Institute for Health and Care Excellence (NICE) rejected lenalidomide for "use in the treatment of people with a specific type of the bone marrow disorder myelodysplastic syndrome (MDS)" in England and Scotland, arguing that Celgene "did not provide enough evidence to justify the £3,780 per month (US$5746.73) price-tag of lenalidomide for use in the treatment of people with a specific type of the bone marrow disorder myelodysplastic syndrome (MDS)".[32]

    Research

    Lenalidomide is undergoing clinical trial as a treatment for Hodgkin's lymphoma,[33] as well as non-Hodgkin's lymphoma, chronic lymphocytic leukemia and solid tumor cancers, such as carcinoma of the pancreas.[34] One Phase 3 clinical trial being conducted by Celgene in elderly patients with B-cell chronic lymphocytic leukemia was halted in July 2013, when a disproportionate number of cancer deaths were observed during treatment with lenalidomide versus patients treated with chlorambucil.[35]

    References

    1. "Lenalidomide Monograph for Professionals". Drugs.com. Retrieved 27 October 2019.
    2. "DailyMed - Revlimid- lenalidomide capsule". dailymed.nlm.nih.gov. Retrieved 27 October 2019.
    3. Organization, World Health (2019). "World Health Organization model list of essential medicines: 21st list 2019". hdl:10665/325771. Cite journal requires |journal= (help)
    4. "Revlimid Prices, Coupons & Patient Assistance Programs". Drugs.com. Retrieved 27 October 2019.
    5. British national formulary : BNF 76 (76 ed.). Pharmaceutical Press. 2018. p. 935. ISBN 9780857113382.
    6. Armoiry X, Aulagner G, Facon T (June 2008). "Lenalidomide in the treatment of multiple myeloma: a review". Journal of Clinical Pharmacy and Therapeutics. 33 (3): 219–26. doi:10.1111/j.1365-2710.2008.00920.x. PMID 18452408.
    7. Li S, Gill N, Lentzsch S (November 2010). "Recent advances of IMiDs in cancer therapy". Curr Opin Oncol. 22 (6): 579–85. doi:10.1097/CCO.0b013e32833d752c. PMID 20689431.
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    11. Dimopoulos MA, Richardson PG, Brandenburg N, et al. (22 March 2012). "A review of second primary malignancy in patients with relapsed or refractory multiple myeloma treated with lenalidomide". Blood. 119 (12): 2764–7. doi:10.1182/blood-2011-08-373514. PMID 22323483.
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    13. "Approved Drugs - Lenalidomide (Revlimid)". Food and Drug Administration (FDA). 3 November 2018.
    14. "REVLIMID Receives Positive Final Appraisal Determination from National Institute for Health and Clinical Excellence (NICE) for Use in the National Health Service (NHS) in England and Wales". Reuters. 23 April 2009. Cite journal requires |journal= (help)
    15. List A, Kurtin S, Roe DJ, et al. (February 2005). "Efficacy of lenalidomide in myelodysplastic syndromes". The New England Journal of Medicine. 352 (6): 549–57. doi:10.1056/NEJMoa041668. PMID 15703420.
    16. "PDGFRB platelet derived growth factor receptor beta [Homo sapiens (human)] - Gene - NCBI".
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    29. Zhu YX, Braggio E, Shi CX, et al. (2011). "Cereblon expression is required for the antimyeloma activity of lenalidomide and pomalidomide". Blood. 118 (18): 4771–9. doi:10.1182/blood-2011-05-356063. PMC 3208291. PMID 21860026.
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