View source for Lenalidomide

{{Short description|Pair of enantiomers}}
{{Use dmy dates|date=September 2023}}
{{cs1 config |name-list-style=vanc |display-authors=6}}
{{Infobox drug
| Watchedfields = changed
| verifiedrevid = 459429828
| image = Lenalidomide enantiomers.svg
| width = 200
| alt = 
| chirality = Racemic mixture

<!-- Clinical data -->
| pronounce = {{IPAc-en|ˌ|l|ɛ|n|ə|ˈ|l|ɪ|d|oʊ-|m|aɪ|d}}
| tradename = Revlimid, Linamide, others
| Drugs.com = {{drugs.com|monograph|lenalidomide}}
| MedlinePlus = a608001
| licence_EU = yes
| DailyMedID = Lenalidomide
| pregnancy_AU = X
| pregnancy_AU_comment = <ref name="Drugs.com pregnancy">{{cite web | title=Lenalidomide (Revlimid) Use During Pregnancy | website=Drugs.com | date=13 March 2020 | url=https://www.drugs.com/pregnancy/lenalidomide.html | access-date=13 August 2020 | archive-date=9 October 2020 | archive-url=https://web.archive.org/web/20201009143932/https://www.drugs.com/pregnancy/lenalidomide.html | url-status=live }}</ref>
| pregnancy_category = 
| routes_of_administration = [[Oral administration|By mouth]]
| class = 
| ATC_prefix = L04
| ATC_suffix = AX04
| ATC_supplemental =

<!-- Legal status -->
| legal_AU = S4
| legal_AU_comment =<ref>{{cite web|url=https://www.tga.gov.au/resources/prescription-medicines-registrations/lenalidomide-viatris-alphapharm-pty-ltd|access-date=1 April 2023|website=Department of Health and Ages Care|title=LENALIDOMIDE VIATRIS (Alphapharm Pty Ltd)|archive-date=13 November 2022|archive-url=https://web.archive.org/web/20221113203021/https://www.tga.gov.au/resources/prescription-medicines-registrations/lenalidomide-viatris-alphapharm-pty-ltd|url-status=live}}</ref><ref>{{cite web|url=https://www.tga.gov.au/resources/prescription-medicines-registrations/lenalidomide-sunlenalidomide-rbxlenalidomide-ran-sun-pharma-anz-pty-ltd|access-date=1 April 2023|website=Department of Health and Ages Care|title=Lenalidomide Sun/Lenalidomide Rbx/Lenalidomide Ran (Sun Pharma ANZ Pty Ltd)|archive-date=18 March 2023|archive-url=https://web.archive.org/web/20230318025026/https://www.tga.gov.au/resources/prescription-medicines-registrations/lenalidomide-sunlenalidomide-rbxlenalidomide-ran-sun-pharma-anz-pty-ltd|url-status=live}}</ref>
| legal_BR = C3
| legal_BR_comment = <ref>{{cite web |author=Anvisa |author-link=Brazilian Health Regulatory Agency |date=31 March 2023 |title=RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial |trans-title=Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control|url=https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 |url-status=live |archive-url=https://web.archive.org/web/20230803143925/https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 |archive-date=3 August 2023 |access-date=15 August 2023 |publisher=[[Diário Oficial da União]] |language=pt-BR |publication-date=4 April 2023}}</ref>
| legal_CA = <!-- OTC, Rx-only, Schedule I, II, III, IV, V, VI, VII, VIII -->
| legal_CA_comment = 
| legal_DE = <!-- Anlage I, II, III or Unscheduled -->
| legal_DE_comment = 
| legal_NZ = <!-- Class A, B, C -->
| legal_NZ_comment = 
| legal_UK = POM
| legal_UK_comment = 
| legal_US = Rx-only
| legal_US_comment = <ref name=PI2019 />
| legal_EU = Rx-only
| legal_EU_comment = <ref name="Revlimid EPAR">{{cite web | title=Revlimid EPAR | website=European Medicines Agency | date=14 June 2007 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/revlimid | access-date=2 July 2024}}</ref>
| legal_UN = <!-- N I, II, III, IV / P I, II, III, IV -->
| legal_UN_comment = 
| legal_status = <!-- For countries not listed above -->

<!-- Pharmacokinetic data -->
| bioavailability = Undetermined
| protein_bound = 30%
| metabolism = Undetermined
| metabolites = 
| onset = 
| elimination_half-life = 3 hours
| duration_of_action = 
| excretion = [[Kidney]] (67% unchanged)

<!-- Identifiers -->
| CAS_number_Ref = {{cascite|correct}}
| CAS_number = 191732-72-6
| CAS_supplemental = 
| PubChem = 216326
| IUPHAR_ligand = 7331
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB00480
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 187515
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = F0P408N6V4
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D04687
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 848
| NIAID_ChemDB = 
| PDB_ligand = 
| synonyms =

<!-- Chemical and physical data -->
| IUPAC_name = (3''RS'')-3-(4-Amino-1-oxo-1,3-dihydro-2''H''-isoindol-2-yl)piperidine-2,6-dione
| C=13 | H=13 | N=3 | O=3
| SMILES = O=C1NC(=O)CCC1N3C(=O)c2cccc(c2C3)N
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C13H13N3O3/c14-9-3-1-2-7-8(9)6-16(13(7)19)10-4-5-11(17)15-12(10)18/h1-3,10H,4-6,14H2,(H,15,17,18)
| StdInChI_comment = 
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = GOTYRUGSSMKFNF-UHFFFAOYSA-N
| density = 
| density_notes = 
| melting_point = 
| melting_high = 
| melting_notes = 
| boiling_point = 
| boiling_notes = 
| solubility = 
| sol_units = 
| specific_rotation = 
}}

<!-- Definition and medical uses -->
'''Lenalidomide''', sold under the brand name '''Revlimid''' among others, is a medication used to treat [[multiple myeloma]], [[smoldering myeloma]], and [[myelodysplastic syndrome]]s (MDS).<ref name=AHFS2019/> For multiple myeloma, it is a first line treatment, and is given with [[dexamethasone]].<ref name=AHFS2019/> It is taken [[Oral administration|by mouth]].<ref name=AHFS2019/>

<!-- Side effects and mechanism -->
Common side effects include diarrhea, itchiness, joint pain, fever, headache, and trouble sleeping.<ref name=AHFS2019/> Severe side effects include [[low blood platelets]], [[low white blood cells]], and [[blood clots]].<ref name=AHFS2019/> The dose may need to be adjusted in people with [[kidney problems]].<ref name=AHFS2019/>  Lenalidomide is closely related to [[thalidomide]], which is known to cause severe birth defects, so its use during pregnancy is very likely to harm the fetus.<ref name=AHFS2019>{{cite web |title=Lenalidomide Monograph for Professionals |url=https://www.drugs.com/monograph/lenalidomide.html |website=Drugs.com |access-date=27 October 2019 |archive-date=4 March 2016 |archive-url=https://web.archive.org/web/20160304094340/http://www.drugs.com/monograph/Lenalidomide.html |url-status=live }}</ref> 

Lenalidomide belongs to a class of drugs known as immunomodulatory imide drugs (IMiDs) or [[Cereblon E3 ligase modulator|Cereblon E3 ligase modulators]], which includes [[thalidomide]] and its analogs.<ref name=Fink2015 /> In [[lymphocytes]], these drugs target an [[E3 ubiquitin ligase]] and change its specificity to include new targets.<ref name="Fink2015">{{cite journal | vauthors = Fink EC, Ebert BL | title = The novel mechanism of lenalidomide activity | journal = Blood | volume = 126 | issue = 21 | pages = 2366–2369 | date = November 2015 | pmid = 26438514 | doi = 10.1182/blood-2015-07-567958 | pmc = 4653765 }}</ref> This results in the rapid degradation of several disease-related proteins including [[IKZF1]], [[IKZF3]], and [[CSNK1A1]].<ref name=Fink2015 />

<!-- History and culture -->
Lenalidomide was approved for medical use in the United States in 2005.<ref name=AHFS2019/> It is on the [[WHO Model List of Essential Medicines|World Health Organization's List of Essential Medicines]].<ref name="WHO23rd">{{cite book | vauthors = ((World Health Organization)) | title = The selection and use of essential medicines 2023: web annex A: World Health Organization model list of essential medicines: 23rd list (2023) | year = 2023 | hdl = 10665/371090 | author-link = World Health Organization | publisher = World Health Organization | location = Geneva | id = WHO/MHP/HPS/EML/2023.02 | hdl-access=free }}</ref>

==Medical uses==

===Multiple myeloma===
Lenalidomide is used to treat [[multiple myeloma]].<ref>{{cite journal | vauthors = Armoiry X, Aulagner G, Facon T | title = Lenalidomide in the treatment of multiple myeloma: a review | journal = Journal of Clinical Pharmacy and Therapeutics | volume = 33 | issue = 3 | pages = 219–26 | date = June 2008 | pmid = 18452408 | doi = 10.1111/j.1365-2710.2008.00920.x | s2cid = 1228171 | doi-access = free | title-link = doi }}</ref> It is a more potent molecular analog of thalidomide, which inhibits tumor [[angiogenesis]], tumor-secreted [[cytokine]]s, and tumor [[cell proliferation|proliferation]] through induction of [[apoptosis]].<ref name="pmid20689431">{{cite journal | vauthors = Li S, Gill N, Lentzsch S | title = Recent advances of IMiDs in cancer therapy | journal = Current Opinion in Oncology | volume = 22 | issue = 6 | pages = 579–85 | date = November 2010 | pmid = 20689431 | doi = 10.1097/CCO.0b013e32833d752c | s2cid = 205547603 }}</ref><ref>{{cite journal | vauthors = Tageja N | title = Lenalidomide - current understanding of mechanistic properties | journal = Anti-Cancer Agents in Medicinal Chemistry | volume = 11 | issue = 3 | pages = 315–26 | date = March 2011 | pmid = 21426296 | doi = 10.2174/187152011795347487 }}</ref><ref>{{cite journal | vauthors = Kotla V, Goel S, Nischal S, Heuck C, Vivek K, Das B, Verma A | title = Mechanism of action of lenalidomide in hematological malignancies | journal = Journal of Hematology & Oncology | volume = 2 | pages = 36 | date = August 2009 | pmid = 19674465 | pmc = 2736171 | doi = 10.1186/1756-8722-2-36 | doi-access = free }}</ref>

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]], [[infection]]s, and an increased risk of other [[hematological malignancy|hematological malignancies]].<ref>{{cite journal | vauthors = Yang B, Yu RL, Chi XH, Lu XC | title = Lenalidomide treatment for multiple myeloma: systematic review and meta-analysis of randomized controlled trials | journal = PLOS ONE | volume = 8 | issue = 5 | pages = e64354 | year = 2013 | pmid = 23691202 | pmc = 3653900 | doi = 10.1371/journal.pone.0064354 | bibcode = 2013PLoSO...864354Y | doi-access = free | title-link = doi }}</ref> The risk of second primary hematological malignancies does not outweigh the benefit of using lenalidomide in relapsed or refractory multiple myeloma.<ref>{{cite journal | vauthors = Dimopoulos MA, Richardson PG, Brandenburg N, Yu Z, Weber DM, Niesvizky R, Morgan GJ | title = A review of second primary malignancy in patients with relapsed or refractory multiple myeloma treated with lenalidomide | journal = Blood | volume = 119 | issue = 12 | pages = 2764–7 | date = March 2012 | pmid = 22323483 | doi = 10.1182/blood-2011-08-373514 | doi-access = free | title-link = doi }}</ref> It may be more difficult to mobilize [[stem cell]]s for [[autograft]] in people who have received lenalidomide.<ref name="pmid20689431" />

In 2006, lenalidomide received US [[Food and Drug Administration]] (FDA) approval for use in combination with [[dexamethasone]] in people with multiple myeloma who have received at least one prior therapy.<ref>{{cite web|url=https://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/ucm095626.htm|archive-url=https://web.archive.org/web/20111125071541/http://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/ucm095626.htm|url-status=dead|archive-date=25 November 2011|title=FDA approves lenalidomide oral capsules (Revlimid) for use in combination with dexamethasone in patients with multiple myeloma|date=29 June 2006|publisher=U.S. [[Food and Drug Administration]] (FDA)|access-date=15 October 2015}}</ref> In 2017, the FDA approved lenalidomide as standalone [[maintenance therapy]] (without dexamethasone) for people with multiple myeloma following autologous stem cell transplant.<ref>{{cite web | url=https://www.fda.gov/drugs/resources-information-approved-drugs/lenalidomide-revlimid | title=Lenalidomide (Revlimid) | publisher=U.S. [[Food and Drug Administration]] (FDA) | date=22 February 2017 | access-date=13 August 2020 | archive-date=13 August 2020 | archive-url=https://web.archive.org/web/20200813030443/https://www.fda.gov/drugs/resources-information-approved-drugs/lenalidomide-revlimid | url-status=live }}</ref>

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.<ref>{{cite news | title = 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 | work = Reuters | date = 23 April 2009 | url = https://www.reuters.com/article/pressRelease/idUS83290+23-Apr-2009+BW20090423| archive-url = https://web.archive.org/web/20090624013337/http://www.reuters.com/article/pressRelease/idUS83290+23-Apr-2009+BW20090423| url-status = dead| archive-date = 24 June 2009}}</ref>

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 result in an increase of the overall survival.<ref>{{cite journal | vauthors = Piechotta V, Jakob T, Langer P, Monsef I, Scheid C, Estcourt LJ, Ocheni S, Theurich S, Kuhr K, Scheckel B, Adams A, Skoetz N | title = Multiple drug combinations of bortezomib, lenalidomide, and thalidomide for first-line treatment in adults with transplant-ineligible multiple myeloma: a network meta-analysis | journal = The Cochrane Database of Systematic Reviews | volume = 2019 | issue = 11 | date = November 2019 | pmid = 31765002 | doi = 10.1002/14651858.CD013487 | pmc = 6876545 | collaboration = Cochrane Haematology Group }}</ref>

===Myelodysplastic syndromes ===
Lenalidomide was approved by the FDA in December 2005, for people with low- or intermediate-1-risk [[myelodysplastic syndrome]]s who have [[chromosome 5q deletion syndrome]] (5q- syndrome) with or without additional [[cytogenetic abnormalities]].<ref name=List>{{cite journal | vauthors = List A, Kurtin S, Roe DJ, Buresh A, Mahadevan D, Fuchs D, Rimsza L, Heaton R, Knight R, Zeldis JB | title = Efficacy of lenalidomide in myelodysplastic syndromes | journal = The New England Journal of Medicine | volume = 352 | issue = 6 | pages = 549–57 | date = February 2005 | pmid = 15703420 | doi = 10.1056/NEJMoa041668 | doi-access = free | title-link = doi }}</ref><ref>{{cite journal | vauthors = List AF | title = Emerging data on IMiDs in the treatment of myelodysplastic syndromes (MDS) | journal = Seminars in Oncology | volume = 32 | issue = 4 Suppl 5 | pages = S31-5 | date = August 2005 | pmid = 16085015 | doi = 10.1053/j.seminoncol.2005.06.020 }}</ref><ref>{{cite journal | vauthors = List A, Dewald G, Bennett J, Giagounidis A, Raza A, Feldman E, Powell B, Greenberg P, Thomas D, Stone R, Reeder C, Wride K, Patin J, Schmidt M, Zeldis J, Knight R | title = Lenalidomide in the myelodysplastic syndrome with chromosome 5q deletion | journal = The New England Journal of Medicine | volume = 355 | issue = 14 | pages = 1456–65 | date = October 2006 | pmid = 17021321 | doi = 10.1056/NEJMoa061292 | doi-access = free | title-link = doi }}</ref> 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]] [[Blood transfusion|transfusion]]s, for whom other treatment options have been found to be insufficient or inadequate.<ref>{{cite web | title=Revlimid Approved In Europe For Use In Myelodysplastic Syndromes | url=http://www.mdsbeacon.com/news/2013/06/17/revlimid-lenalidomide-european-approval-mds/ | publisher=The MDS Beacon | access-date=17 June 2013 | archive-date=21 September 2015 | archive-url=https://web.archive.org/web/20150921191433/http://www.mdsbeacon.com/news/2013/06/17/revlimid-lenalidomide-european-approval-mds/ | url-status=dead }}</ref>

=== Mantle cell lymphoma ===
Lenalidomide is approved by FDA 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]].<ref name=PI2019/>

=== AL amyloidosis ===
Although not specifically approved by the FDA for use in treating [[AL amyloidosis]], lenalidomide is sometimes used in the treatment of that condition, often in combination with [[dexamethasone]].<ref>{{cite web | title=Revlimid and Amyloidosis AL | url=https://www.myeloma.org.uk/wp-content/uploads/2018/03/Myeloma-UK-AL-amyloidosis-Revlimid.pdf | publisher=MyelomaUK | access-date=3 October 2020 | archive-date=27 September 2021 | archive-url=https://web.archive.org/web/20210927080501/https://www.myeloma.org.uk/wp-content/uploads/2018/03/Myeloma-UK-AL-amyloidosis-Revlimid.pdf | url-status=dead }}</ref>

==Adverse effects==
In addition to [[teratogenicity|embryo-fetal toxicity]], lenalidomide carries [[black box warnings]] for [[hematotoxicity|hematologic toxicity]] (including [[neutropenia]] and [[thrombocytopenia]]) and [[thromboembolism]].<ref name=PI2019>{{cite web |title=DailyMed - Revlimid- lenalidomide capsule |url=https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=5fa97bf5-28a2-48f1-8955-f56012d296be |website=dailymed.nlm.nih.gov |access-date=27 October 2019 |archive-date=16 February 2020 |archive-url=https://web.archive.org/web/20200216112557/https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=5fa97bf5-28a2-48f1-8955-f56012d296be |url-status=live }}</ref> Serious side effects include [[thrombosis]], [[pulmonary embolus]], [[hepatotoxicity]], and [[myelotoxicity|bone marrow toxicity]] resulting in neutropenia and thrombocytopenia. [[Myelosuppression]] is the major dose-limiting toxicity, which is not the case with thalidomide.<ref>{{cite journal | vauthors = Rao KV | title = Lenalidomide in the treatment of multiple myeloma | journal = American Journal of Health-System Pharmacy | volume = 64 | issue = 17 | pages = 1799–807 | date = September 2007 | pmid = 17724360 | doi = 10.2146/ajhp070029 }}</ref>

Lenalidomide may be associated with adverse effects as second primary [[malignancy]], severe [[cutaneous]] reactions, [[hypersensitivity reaction]]s, [[tumor lysis syndrome]], tumor flare reaction, [[hypothyroidism]], and [[hyperthyroidism]].<ref name=PI2019/>

===Teratogenicity===
Lenalidomide is related to [[thalidomide]], which is known to be [[teratogen]]ic. Tests in monkeys suggest that lenalidomide is likewise teratogenic.<ref>{{cite web|title=Revlimid Summary of Product Characteristics. Annex I|year=2012|publisher=[[European Medicines Agency]]|page=6|url=http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000717/WC500056018.pdf|access-date=16 April 2014|archive-date=1 March 2014|archive-url=https://web.archive.org/web/20140301075507/http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000717/WC500056018.pdf|url-status=live}}</ref> It cannot be prescribed for people who are pregnant or who are likely to become pregnant during therapy.<ref name="Drugs.com pregnancy" /> For this reason, the drug is only available in the United States through a [[specialty pharmacy|restricted distribution system]] in conjunction with a [[Specialty drugs#Risk evaluation and mitigation strategies (REMS)|risk evaluation and mitigation strategy]]. People 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.<ref name=PI2019/><ref name="pharmacytimes_2014">{{cite journal | url=http://www.pharmacytimes.com/publications/issue/2014/march2014/new-specialty-drugs | title=New Specialty Drugs | journal=Pharmacy Times | date=13 March 2014 | access-date=5 November 2015 | vauthors = Ness S | series=March 2014 Mental Health | volume=80 | issue=3 | archive-date=21 September 2015 | archive-url=https://web.archive.org/web/20150921061353/http://www.pharmacytimes.com/publications/issue/2014/march2014/New-Specialty-Drugs | url-status=dead }}</ref>

===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]].<ref>{{cite journal | vauthors = Bennett CL, Angelotta C, Yarnold PR, Evens AM, Zonder JA, Raisch DW, Richardson P | title = Thalidomide- and lenalidomide-associated thromboembolism among patients with cancer | journal = JAMA | volume = 296 | issue = 21 | pages = 2558–60 | date = December 2006 | pmid = 17148721 | doi = 10.1001/jama.296.21.2558-c }}</ref>

===Stevens-Johnson syndrome===
{{Update|section|date=April 2020}}
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.<ref>{{cite web |title = Potential Signals of Serious Risks/New Safety Information Identified from the Adverse Event Reporting System (AERS) between January - March 2008 |url = https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Surveillance/AdverseDrugEffects/ucm085914.htm |publisher = U.S. [[Food and Drug Administration]] |date = March 2008 |access-date = 16 December 2019 |archive-date = 19 April 2014 |archive-url = https://web.archive.org/web/20140419025736/https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Surveillance/AdverseDrugEffects/ucm085914.htm |url-status = dead }}</ref>

===FDA ongoing safety review===
{{Update|section|date=April 2020}}
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]],<ref name="Badros">{{cite journal | vauthors = Badros AZ | title = Lenalidomide in myeloma--a high-maintenance friend | journal = The New England Journal of Medicine | volume = 366 | issue = 19 | pages = 1836–8 | date = May 2012 | pmid = 22571206 | doi = 10.1056/NEJMe1202819 }}</ref> though it did not advise patients to discontinue treatment with lenalidomide.<ref>{{cite web |title = FDA Drug Safety Communication: Ongoing safety review of Revlimid (lenalidomide) and possible increased risk of developing new malignancies |url = https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-ongoing-safety-review-revlimid-lenalidomide-and-possible-increased |publisher = U.S. [[Food and Drug Administration]] (FDA) |date = April 2011 |access-date = 13 August 2020 |archive-date = 13 August 2020 |archive-url = https://web.archive.org/web/20200813030016/https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-ongoing-safety-review-revlimid-lenalidomide-and-possible-increased |url-status = live }}</ref>

==Mechanism of action==
{{see also|Cereblon_E3_ligase_modulator#Mechanism_of_action}}

Lenalidomide changes the substrate specificity of the CRL4<sup>CRBN</sup> E3 ubiquitin ligase, a complex consisting of DNA-binding protein 1 ([[DDB1]]), cullin 4a ([[CUL4A]]), regulator of cullins 1 (ROC1), and cereblon (CRBN).<ref name=Fink2015 /> [[Cereblon]] is the substrate adapter for the complex and is the primary molecular target of the drug.<ref name=Fink2015 /> Treatment with lenalidomide changes the targets of the ligase complex.<ref name=Fink2015 /> Subsequently, proteins [[IKZF1]], [[IKZF3]], and [[CSNK1A1|CK1α]] are recruited to the complex, [[Ubiquitin|ubiquinated]], and then degraded by the [[proteasome]].<ref name=Fink2015 />

IKZF1 and IKZF3 are essential [[transcription factors]] for malignant plasma cells.<ref name="Kulig2023">{{cite journal | vauthors = Kulig P, Milczarek S, Bakinowska E, Szalewska L, Baumert B, Machalinski B | title = Lenalidomide in Multiple Myeloma: Review of Resistance Mechanisms, Current Treatment Strategies and Future Perspectives  | journal = Cancers | volume = 15 | issue = 3 | pages = 963 | date = February 2023 | pmid =  36765919 | doi = 10.3390/cancers15030963 | doi-access = free | pmc = 9913106 }}</ref> In particular, loss of IKZF3 then decreases the expression of interferon regulatory factor 4 ([[IRF4]]).<ref name=Fink2015 /> IRF4 is a master regulator of a number of cancer-promoting genes and is required for the survival of multiple myeloma.<ref name=Fink2015 />

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]].<ref name=Kulig2023 />

==Synthesis==
The first synthesis of lenalidomide was disclosed in patents filed by [[Celgene]].<ref>{{cite patent |country=US |number=5635517 |inventor=George W Muller, David I Stirling, Roger S-C Chen |title=Method of reducing TNFalpha levels with amino substituted 2-(2,6-dioxopiperidin-3-YL)-1-oxo-and 1,3-dioxoisoindolines |status=patent |gdate=1997-06-03 |fdate=1996-07-24 |assign1=Celgene Corp}}</ref>
:[[File:Lenalidomide synthesis US5635517.svg|upright=2]]
Methyl 2-methyl-3-nitrobenzoate is [[Free-radical halogenation|brominated]] using [[N-Bromosuccinimide|''N''-bromosuccinimide]] and the product is treated with 3-amino-piperidine-2,6-dione, a cyclic derivative of [[glutamine]] to form a [[2-Pyrrolidone|lactam]]. [[Catalytic hydrogenation]] then gives lenalidomide.<ref>{{cite journal |doi=10.1007/s10593-015-1670-0 |title=Scalable and green process for the synthesis of anticancer drug lenalidomide |date=2015 | vauthors = Ponomaryov Y, Krasikova V, Lebedev A, Chernyak D, Varacheva L, Chernobroviy A |journal=Chemistry of Heterocyclic Compounds |volume=51 |issue=2 |pages=133–138 }}</ref>

==History==
{{see also|Development of analogs of thalidomide}}

== Society and culture ==
=== Legal status ===
Lenalidomide was approved for medical use in the United States in 2005.<ref name=AHFS2019/>

=== Economics ===
Lenalidomide costs {{US$|163,381}} per year for the average person in the United States as of 2012.{{update inline|date=October 2022}}<ref name="Badros"/> Lenalidomide made almost $9.7bn for [[Celgene]] in 2018.<ref name="genengnews_2019">{{cite web | url=https://www.genengnews.com/a-lists/top-10-best-selling-cancer-drugs-of-2018/ | title=Top 10 Best-Selling Cancer Drugs of 2018 | publisher=Genetic Engineering and Biotechnology News | date=22 April 2019 | access-date=25 April 2019 | archive-date=23 April 2019 | archive-url=https://web.archive.org/web/20190423062615/https://www.genengnews.com/a-lists/top-10-best-selling-cancer-drugs-of-2018/ | url-status=live }}</ref>

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 {{GBP|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)".<ref name="pmlive.com">{{cite web | url=http://www.pmlive.com/pharma_news/revlimid_faces_nice_rejection_for_use_in_rare_blood_cancer_488554 | title=Revlimid faces NICE rejection for use in rare blood cancer Watchdog's draft guidance does not recommend Celgene's drug for NHS use in England and Wales | publisher=Pharma News | date=11 July 2013 | access-date=5 November 2015 | archive-date=13 February 2016 | archive-url=https://web.archive.org/web/20160213202101/http://www.pmlive.com/pharma_news/revlimid_faces_nice_rejection_for_use_in_rare_blood_cancer_488554 | url-status=live }}</ref>

In Australia, a 21-day course of 25&nbsp;mg lenalidomide tablets costs [[Medicare (Australia)|Medicare]] A$2397, however the patient only pays $30 due to the [[Pharmaceutical Benefits Scheme]].<ref>{{Citation |last=Care |first=Australian Government Department of Health and Aged |title=Pharmaceutical Benefits Scheme (PBS) {{!}} |url=https://www.pbs.gov.au/medicine/item/11041D-11055W-12036L-12037M-12059Q-12068E-12979D-12993W-5786M-9645P |access-date=31 March 2023 |publisher=Australian Government Department of Health and Aged Care |archive-date=31 March 2023 |archive-url=https://web.archive.org/web/20230331012232/https://www.pbs.gov.au/medicine/item/11041D-11055W-12036L-12037M-12059Q-12068E-12979D-12993W-5786M-9645P |url-status=live }}</ref>

== References ==
{{reflist}}

{{Immunosuppressants}}
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[[Category:Antineoplastic drugs]]
[[Category:Aromatic amines]]
[[Category:Drugs developed by Bristol Myers Squibb]]
[[Category:Drugs with unknown mechanisms of action]]
[[Category:Glutarimides]]
[[Category:Immunosuppressants]]
[[Category:Isoindolines]]
[[Category:World Health Organization essential medicines]]
[[Category:Wikipedia medicine articles ready to translate]]
[[Category:Cereblon E3 ligase modulators]]