lenalidomide#Multiple myeloma

Lenalidomide is used to treat multiple myeloma.{{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 }} It is a more potent molecular analog of thalidomide, which inhibits tumor angiogenesis, tumor-secreted cytokines, and tumor proliferation through induction of apoptosis.{{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 }}{{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 }}{{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 }}

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.{{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 }} The risk of second primary hematological malignancies does not outweigh the benefit of using lenalidomide in relapsed or refractory multiple myeloma.{{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 }} It may be more difficult to mobilize stem cells for autograft in people who have received lenalidomide.

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.{{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}} In 2017, the FDA approved lenalidomide as standalone maintenance therapy (without dexamethasone) for people with multiple myeloma following autologous stem cell transplant.{{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 }}

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.{{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}}

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.{{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 }}

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.{{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 }}{{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 }}{{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 }} 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.{{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 }}

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").

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.

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.{{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 }}

In addition to embryo-fetal toxicity, lenalidomide carries black box warnings for hematologic toxicity (including neutropenia and thrombocytopenia) and thromboembolism.{{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 }} 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.{{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 }}

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.

Lenalidomide is related to thalidomide, which is known to be teratogenic. Tests in monkeys suggest that lenalidomide is likewise teratogenic.{{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}} It cannot be prescribed for people who are pregnant or who are likely to become pregnant during therapy. For this reason, the drug is only available in the United States through a restricted distribution system in conjunction with a 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.{{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 }}

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.{{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 }}

{{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.{{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 }}

{{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,{{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 }} though it did not advise patients to discontinue treatment with lenalidomide.{{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 }}

{{see also|Cereblon_E3_ligase_modulator#Mechanism_of_action}}

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

IKZF1 and IKZF3 are essential transcription factors for malignant plasma cells.{{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 }} 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.

The first synthesis of lenalidomide was disclosed in patents filed by Celgene.{{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}}

:File:Lenalidomide synthesis US5635517.svg

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.{{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 }}

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

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

Lenalidomide cost {{US$|235,920}} per year before insurance in the United States as of 2024, with the generic version costing {{US$|208,188}}.David Armstrong. "[https://www.propublica.org/article/revlimid-price-cancer-celgene-drugs-fda-multiple-myeloma The Price of Remission]". Pro Publica, May 8, 2025. Lenalidomide made almost $9.7bn for Celgene in 2018.{{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 }}

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.{{cite web |last=Allen |first=Arthur |title=How a Drug's High Cost Is Hidden in Plain Sight |url=https://www.propublica.org/article/revlimid-price-cancer-celgene-drugs-fda-multiple-myeloma |website=ProPublica |date=October 31, 2023 |access-date=May 13, 2025}}

According to a deposition by a Celgene executive, marked as highly confidential, the manufacturing cost of each Revlimid pill has remained approximately $0.25 throughout this period.

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)".{{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 }}

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.{{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 }}

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