Lenalidomide

Names
Pronunciation	/ˌlɛnəˈlɪdoʊmaɪd/
Trade names	Revlimid, Linamide, others
IUPAC name (RS)-3-(4-Amino-1-oxo-1,3-dihydro-2H-isoindol-2-yl)piperidine-2,6-dione
Clinical data
Drug class	Thalidomideanalogue[1]
Main uses	Multiple myeloma (MM),myelodysplastic syndromes (MDS)[2]
Side effects	Diarrhea, itchiness, joint pain, fever, headache, trouble sleeping[2]
Pregnancy category	AU: X (High risk) US: X (Contraindicated)
Routes of use	By mouth (capsules)
Defined daily dose	10 Mg[3]
External links
AHFS/Drugs.com	Monograph
MedlinePlus	a608001
Legal
License data	EU EMA: by INN US DailyMed: Lenalidomide
Legal status	AU: S4 (Prescription only) UK: POM (Prescription only) US: ℞-only
Pharmacokinetics
Bioavailability	Undetermined
Protein binding	30%
Metabolism	Undetermined
Eliminationhalf-life	3 hours
Excretion	Kidney (67% unchanged)
Chemical and physical data
Formula	C13H13N3O3
Molar mass	259.265 g·mol−1
3D model (JSmol)	Interactive image
Chirality	Racemic mixture
SMILES O=C1NC(=O)CCC1N3C(=O)c2cccc(c2C3)N
InChI InChI=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) Y Key:GOTYRUGSSMKFNF-UHFFFAOYSA-N Y

Lenalidomide, sold under the trade nameRevlimid among others, is a medication used to treatmultiple myeloma (MM) andmyelodysplastic syndromes (MDS).^[2] For MM it is used after at least one other treatment and generally together withdexamethasone.^[2] It is taken by mouth.^[2]

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

Lenalidomide was approved for medical use in the United States in 2005.^[2] It is on theWorld Health Organization's List of Essential Medicines.^[4] In the United States it costs about US$16,000 to US$21,000 per month as of 2019.^[5] In the United Kingdom this amount costs the NHS about £3,400 to 4,400.^[6] Ageneric version was approved in 2021 in the USA.^[7]

Medical uses

Multiple myeloma

Lenalidomide is used to treatmultiple myeloma.^[8] It is a more potent molecular analog of thalidomide, which inhibits tumorangiogenesis, tumor-secretedcytokines, and tumorproliferation through induction ofapoptosis.^[9][10][11]

Lenalidomide is effective at inducing a complete or "very good partial" response and improvesprogression-free survival. Adverse events more common in people receiving lenalidomide for myeloma includeneutropenia,deep vein thrombosis,infections, and an increased risk of otherhematological malignancies.^[12] The risk of second primary hematological malignancies does not outweigh the benefit of using lenalidomide in relapsed or refractory multiple myeloma.^[13] It may be more difficult to mobilizestem cells forautograft in people who have received lenalidomide.^[9]

In 2006, lenalidomide received U.S.Food and Drug Administration (FDA) clearance for use in combination withdexamethasone in people with multiple myeloma who have received at least one prior therapy.^[14] In 2017, the FDA approved lenalidomide as standalonemaintenance therapy (without dexamethasone) for people with multiple myeloma following autologous stem cell transplant.^[15]

In 2009, TheNational 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.^[16]

As of 2019 continuous bortezomib, lenalidomide, and dexamethasone (VRDc) works well for people with multiple myeloma who are not able to receive a transplant.^[17]

Myelodysplastic syndromes

Lenalidomide was approved by the FDA on 27 December 2005 for patients with low- or intermediate-1-riskmyelodysplastic syndromes who havechromosome 5q deletion syndrome (5q- syndrome) with or without additionalcytogenetic abnormalities.^[18][19][20] It was approved on 17 June 2013 by theEuropean 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 onred blood celltransfusions, for whom other treatment options have been found to be insufficient or inadequate.^[21]

Mantle cell lymphoma

Lenalidomide is approved by FDA as aspecialty drug requiring aspecialty pharmacy distribution formantle cell lymphoma in patients whose disease has relapsed or progressed after at least two prior therapies, one of which must have includedbortezomib.^[1]

Dosage

Thedefined daily dose is 10 mg (by mouth).^[3]

Side effects

In addition toembryo-fetal toxicity, lenalidomide carriesblack box warnings forhematologic toxicity (includingneutropenia andthrombocytopenia) andthromboembolism.^[1] Serious potential side effects includethrombosis,pulmonary embolus,hepatotoxicity, andbone marrow toxicity resulting in neutropenia and thrombocytopenia.Myelosuppression is the major dose-limiting toxicity, which is not the case with thalidomide.^[22]

Lenalidomide may be associated with such adverse effects as second primarymalignancy, severecutaneous reactions,hypersensitivity reactions,tumor lysis syndrome, tumor flare reaction,hypothyroidism, andhyperthyroidism.^[1]

Teratogenicity

Lenalidomide is related tothalidomide, which is known to beteratogenic. Tests in monkeys suggest that lenalidomide is likewise teratogenic.^[23] It falls underpregnancy 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 theUnited States through arestricted distribution system in conjunction with arisk evaluation and mitigation strategy. Females who may become pregnant must use at least two forms of reliablecontraception during treatment and for at least four weeks after discontinuing treatment with lenalidomide.^[1][24]

Venous thromboembolism

Lenalidomide, like its parent compound thalidomide, may causevenous thromboembolism (VTE), a potentially serious complication with their use. High rates of VTE have been found in patients with multiple myeloma who received thalidomide or lenalidomide in conjunction withdexamethasone,melphalan, ordoxorubicin.^[25]

Stevens-Johnson syndrome

In March 2008, the U.S.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 developingStevens–Johnson syndrome, a life-threatening skin condition.^[26]

Mechanism of action

Lenalidomide has been used to successfully treat both inflammatory disorders and cancers in the past ten years.^[when?] There are multiplemechanisms of action, and they can be simplified by organizing them as mechanisms of actionin vitro andin vivo.^[28]

In vitro, lenalidomide has three main activities: directanti-tumor effect, inhibition of angiogenesis, andimmunomodulation.In vivo, lenalidomide induces tumor cellapoptosis directly and indirectly by inhibition of bone marrowstromal cell support, byanti-angiogenic andanti-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 ligasecereblon^[29] and target this enzyme to degrade the Ikaros transcription factorsIKZF1 andIKZF3.^[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.^[2]

Price

Lenalidomide costs $163,381 per year for the average person in the United States in 2012.^{[citation needed]} Lenalidomide made almost $9.7bn forCelgene in 2018.^[31]

In 2013, the UKNational Institute for Health and Care Excellence (NICE) rejected lenalidomide for "use in the treatment of people with a specific type of the bone marrow disordermyelodysplastic 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 forHodgkin's lymphoma,^[33] as well asnon-Hodgkin's lymphoma,chronic lymphocytic leukemia and solid tumor cancers, such ascarcinoma of thepancreas.^[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 withchlorambucil.^[35]

References

External links

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