Lenalidomide

Last updated

Lenalidomide
Lenalidomide enantiomers.svg
Clinical data
Pronunciation /ˌlɛnəˈlɪdoʊmaɪd/
Trade names Revlimid, Linamide, others
AHFS/Drugs.com Monograph
MedlinePlus a608001
License data
Pregnancy
category
  • AU:X (High risk) [1]
Routes of
administration 		By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability Undetermined
Protein binding 30%
Metabolism Undetermined
Elimination half-life 3 hours
Excretion Kidney (67% unchanged)
Identifiers
  • (3RS)-3-(4-Amino-1-oxo-1,3-dihydro-2H-isoindol-2-yl)piperidine-2,6-dione
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.218.924 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C13H13N3O3
Molar mass 259.265 g·mol−1
3D model (JSmol)
Chirality Racemic mixture
  • O=C1NC(=O)CCC1N3C(=O)c2cccc(c2C3)N
  • 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) Yes check.svgY
  • Key:GOTYRUGSSMKFNF-UHFFFAOYSA-N Yes check.svgY
   (verify)

Lenalidomide, sold under the brand name Revlimid among others, is a medication used to treat multiple myeloma, smoldering myeloma, and myelodysplastic syndromes (MDS). [6] For multiple myeloma, it is a first line treatment, and is given with dexamethasone. [6] It is taken by mouth. [6]

Contents

Common side effects include diarrhea, itchiness, joint pain, fever, headache, and trouble sleeping. [6] Severe side effects include low blood platelets, low white blood cells, and blood clots. [6] Use during pregnancy may harm the fetus. [6] The dose may need to be adjusted in people with kidney problems. [6]

Lenalidomide belongs to a class of drugs known as immunomodulatory imide drugs (IMiDs) or Cereblon E3 ligase modulators, which include thalidomide and its analogs. [7] In lymphocytes, these drugs target an E3 ubiquitin ligase and change its specificity to include new targets. [7] This results in the rapid degradation of several disease-related proteins including IKZF1, IKZF3, and CSNK1A1. [7]

Lenalidomide was approved for medical use in the United States in 2005. [6] It is on the World Health Organization's List of Essential Medicines. [8]

Medical uses

Multiple myeloma

Lenalidomide is used to treat multiple myeloma. [9] It is a more potent molecular analog of thalidomide, which inhibits tumor angiogenesis, tumor-secreted cytokines, and tumor proliferation through induction of apoptosis. [10] [11] [12]

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. [13] The risk of second primary hematological malignancies does not outweigh the benefit of using lenalidomide in relapsed or refractory multiple myeloma. [14] It may be more difficult to mobilize stem cells for autograft in people who have received lenalidomide. [10]

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. [15] In 2017, the FDA approved lenalidomide as standalone maintenance therapy (without dexamethasone) for people with multiple myeloma following autologous stem cell transplant. [16]

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. [17]

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. [18]

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. [19] [20] [21] 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. [22]

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. [23]

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. [24]

Adverse effects

In addition to embryo-fetal toxicity, lenalidomide carries black box warnings for hematologic toxicity (including neutropenia and thrombocytopenia) and thromboembolism. [23] 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. [25]

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. [23]

Teratogenicity

Lenalidomide is related to thalidomide, which is known to be teratogenic. Tests in monkeys suggest that lenalidomide is likewise teratogenic. [26] It cannot be prescribed for women who are pregnant or who may become pregnant during therapy. [1] 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. 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. [23] [27]

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. [28]

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. [29]

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, [30] though it did not advise patients to discontinue treatment with lenalidomide. [31]

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). [7] Cereblon is the substrate adapter for the complex and is the primary molecular target of the drug. [7] Treatment with lenalidomide changes the targets of the ligase complex. [7] Subsequently, proteins IKZF1, IKZF3, and CK1α are recruited to the complex, ubiquinated, and then degraded by the proteasome. [7]

IKZF1 and IKZF3 are essential transcription factors for malignant plasma cells. [32] In particular, loss of IKZF3 then decreases the expression of interferon regulatory factor 4 (IRF4). [7] IRF4 is a master regulator of a number of cancer-promoting genes and is required for the survival of multiple myeloma. [7]

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. [32]

History

Lenalidomide was approved for medical use in the United States in 2005. [6]

Economics

Lenalidomide costs US$163,381 per year for the average person in the United States as of 2012.[ needs update ] [30] Lenalidomide made almost $9.7bn for Celgene in 2018. [33]

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$5,746.73) price-tag of lenalidomide for use in the treatment of people with a specific type of the bone marrow disorder myelodysplastic syndrome (MDS)". [34]

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. [35]

Related Research Articles

<span class="mw-page-title-main">Thalidomide</span> Immunomodulatory drug known for its ability to cause birth defects

Thalidomide, sold under the brand names Contergan and Thalomid among others, is an oral medication used to treat a number of cancers, graft-versus-host disease, and many skin disorders. While thalidomide has been used in a number of HIV-associated conditions, such use is associated with increased levels of the virus.

<span class="mw-page-title-main">Myelodysplastic syndrome</span> Diverse collection of blood-related cancers

A myelodysplastic syndrome (MDS) is one of a group of cancers in which immature blood cells in the bone marrow do not mature, and as a result, do not develop into healthy blood cells. Early on, no symptoms typically are seen. Later, symptoms may include fatigue, shortness of breath, bleeding disorders, anemia, or frequent infections. Some types may develop into acute myeloid leukemia.

<span class="mw-page-title-main">Multiple myeloma</span> Cancer of plasma cells

Multiple myeloma (MM), also known as plasma cell myeloma and simply myeloma, is a cancer of plasma cells, a type of white blood cell that normally produces antibodies. Often, no symptoms are noticed initially. As it progresses, bone pain, anemia, kidney dysfunction, and infections may occur. Complications may include hypercalcemia and amyloidosis.

<span class="mw-page-title-main">Chromosome 5q deletion syndrome</span> Human disease

Chromosome 5q deletion syndrome is an acquired, hematological disorder characterized by loss of part of the long arm of human chromosome 5 in bone marrow myelocyte cells. This chromosome abnormality is most commonly associated with the myelodysplastic syndrome.

Primary myelofibrosis (PMF) is a rare bone marrow blood cancer. It is classified by the World Health Organization (WHO) as a type of myeloproliferative neoplasm, a group of cancers in which there is activation and growth of mutated cells in the bone marrow. This is most often associated with a somatic mutation in the JAK2, CALR, or MPL genes. In PMF, the bony aspects of bone marrow are remodeled in a process called osteosclerosis; in addition, fibroblast secrete collagen and reticulin proteins that are collectively referred to as (fibrosis). These two pathological processes compromise the normal function of bone marrow resulting in decreased production of blood cells such as erythrocytes, granulocytes and megakaryocytes, the latter cells responsible for the production of platelets.

<span class="mw-page-title-main">Bortezomib</span> Chemical compound

Bortezomib, sold under the brand name Velcade among others, is an anti-cancer medication used to treat multiple myeloma and mantle cell lymphoma. This includes multiple myeloma in those who have and have not previously received treatment. It is generally used together with other medications. It is given by injection.

<span class="mw-page-title-main">Celgene</span> American biopharmaceutical company

Celgene Corporation is a pharmaceutical company that makes cancer and immunology drugs. Its major product is Revlimid (lenalidomide), which is used in the treatment of multiple myeloma, and also in certain anemias. The company is incorporated in Delaware, headquartered in Summit, New Jersey, and a subsidiary of Bristol Myers Squibb (BMS).

<span class="mw-page-title-main">Chronic myelomonocytic leukemia</span> Medical condition

Chronic myelomonocytic leukemia (CMML) is a type of leukemia, which are cancers of the blood-forming cells of the bone marrow. In adults, blood cells are formed in the bone marrow, by a process that is known as haematopoiesis. In CMML, there are increased numbers of monocytes and immature blood cells (blasts) in the peripheral blood and bone marrow, as well as abnormal looking cells (dysplasia) in at least one type of blood cell.

Elotuzumab, sold under the brand name Empliciti, is a humanized IgG1 monoclonal antibody medication used in combination with lenalidomide and dexamethasone, for adults that have received 1 to 3 prior therapies for the treatment of multiple myeloma. It is also indicated for adult patients in combination with pomalidomide and dexamethasone, who have received 2 prior therapies including lenalidomide and a protease inhibitor. Administration of elotuzumab is done intravenously. Each intravenous injection of elotuzumab should be premedicated with dexamethasone, diphenhydramine, ranitidine and acetaminophen. It is being developed by Bristol Myers Squibb and AbbVie.

<span class="mw-page-title-main">Pomalidomide</span> Chemical compound

Pomalidomide, sold under the brand names Pomalyst and Imnovid, is an anti-cancer medication used for the treatment of multiple myeloma and AIDS-related Kaposi sarcoma.

<span class="mw-page-title-main">Carfilzomib</span> Chemical compound

Carfilzomib, sold under the brand name Kyprolis, is an anti-cancer medication acting as a selective proteasome inhibitor. Chemically, it is a tetrapeptide epoxyketone and an analog of epoxomicin. It was developed by Onyx Pharmaceuticals.

<span class="mw-page-title-main">Daratumumab</span> Monoclonal antibody

Daratumumab, sold under the brand name Darzalex, is an anti-cancer monoclonal antibody medication. It binds to CD38, which is overexpressed in multiple myeloma cells. Daratumumab was originally developed by Genmab, but it is now being jointly developed by Genmab along with the Johnson & Johnson subsidiary Janssen Biotech, which acquired worldwide commercialization rights to the drug from Genmab.

<span class="mw-page-title-main">Cereblon E3 ligase modulator</span> Class of immunomodulatory drugs

Cereblon E3 ligase modulators, also known as immunomodulatory imide drugs (IMiDs), are a class of immunomodulatory drugs containing an imide group. The IMiD class includes thalidomide and its analogues. These drugs may also be referred to as 'Cereblon modulators'. Cereblon (CRBN) is the protein targeted by this class of drugs.

<span class="mw-page-title-main">Isatuximab</span> Monoclonal antibody

Isatuximab, sold under the brand name Sarclisa, is a monoclonal antibody (mAb) medication for the treatment of multiple myeloma.

<span class="mw-page-title-main">Ixazomib</span> Chemical compound

Ixazomib is a drug for the treatment of multiple myeloma, a type of white blood cell cancer, in combination with other drugs. It is taken by mouth in the form of capsules.

<span class="mw-page-title-main">Melphalan flufenamide</span> Alkylating type cancer drug

Melphalan flufenamide, sold under the brand names Pepaxto and Pepaxti, is an anticancer medication used to treat multiple myeloma.

Luspatercept, sold under the brand name Reblozyl, is a medication used for the treatment of anemia in beta thalassemia and myelodysplastic syndromes.

<span class="mw-page-title-main">Selinexor</span> Anti-cancer drug

Selinexor sold under the brand name Xpovio among others, is a selective inhibitor of nuclear export used as an anti-cancer medication. It works by blocking the action of exportin 1 and thus blocking the transport of several proteins involved in cancer-cell growth from the cell nucleus to the cytoplasm, which ultimately arrests the cell cycle and leads to apoptosis. It is the first drug with this mechanism of action.

Idecabtagene vicleucel, sold under the brand name Abecma, is a cell-based gene therapy to treat multiple myeloma.

Benjamin Levine Ebert is the Chair of Medical Oncology at the Dana–Farber Cancer Institute and the George P. Canellos, MD and Jean S. Canellos Professor of Medicine at Harvard Medical School.

References

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  2. ↑ "LENALIDOMIDE VIATRIS (Alphapharm Pty Ltd)". Department of Health and Ages Care. Archived from the original on 13 November 2022. Retrieved 1 April 2023.
  3. ↑ "Lenalidomide Sun/Lenalidomide Rbx/Lenalidomide Ran (Sun Pharma ANZ Pty Ltd)". Department of Health and Ages Care. Archived from the original on 18 March 2023. Retrieved 1 April 2023.
  4. ↑ Anvisa (31 March 2023). "RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial" [Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control] (in Brazilian Portuguese). Diário Oficial da União (published 4 April 2023). Archived from the original on 3 August 2023. Retrieved 15 August 2023.
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  8. ↑ World Health Organization (2023). The selection and use of essential medicines 2023: web annex A: World Health Organization model list of essential medicines: 23rd list (2023). Geneva: World Health Organization. hdl: 10665/371090 . WHO/MHP/HPS/EML/2023.02.
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  10. 1 2 Li S, Gill N, Lentzsch S (November 2010). "Recent advances of IMiDs in cancer therapy". Current Opinion in Oncology. 22 (6): 579–85. doi:10.1097/CCO.0b013e32833d752c. PMID   20689431. S2CID   205547603.
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  13. ↑ Yang B, Yu RL, Chi XH, Lu XC (2013). "Lenalidomide treatment for multiple myeloma: systematic review and meta-analysis of randomized controlled trials". PLOS ONE. 8 (5): e64354. Bibcode:2013PLoSO...864354Y. doi: 10.1371/journal.pone.0064354 . PMC   3653900 . PMID   23691202.
  14. ↑ Dimopoulos MA, Richardson PG, Brandenburg N, Yu Z, Weber DM, Niesvizky R, et al. (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.
  15. ↑ "FDA approves lenalidomide oral capsules (Revlimid) for use in combination with dexamethasone in patients with multiple myeloma". U.S. Food and Drug Administration (FDA). 29 June 2006. Archived from the original on 25 November 2011. Retrieved 15 October 2015.
  16. ↑ "Lenalidomide (Revlimid)". U.S. Food and Drug Administration (FDA). 22 February 2017. Archived from the original on 13 August 2020. Retrieved 13 August 2020.
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  19. ↑ List A, Kurtin S, Roe DJ, Buresh A, Mahadevan D, Fuchs D, 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.
  20. ↑ List AF (August 2005). "Emerging data on IMiDs in the treatment of myelodysplastic syndromes (MDS)". Seminars in Oncology. 32 (4 Suppl 5): S31-5. doi:10.1053/j.seminoncol.2005.06.020. PMID   16085015.
  21. ↑ List A, Dewald G, Bennett J, Giagounidis A, Raza A, Feldman E, et al. (October 2006). "Lenalidomide in the myelodysplastic syndrome with chromosome 5q deletion". The New England Journal of Medicine. 355 (14): 1456–65. doi: 10.1056/NEJMoa061292 . PMID   17021321.
  22. ↑ "Revlimid Approved In Europe For Use In Myelodysplastic Syndromes". The MDS Beacon. Archived from the original on 21 September 2015. Retrieved 17 June 2013.
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  30. 1 2 Badros AZ (May 2012). "Lenalidomide in myeloma--a high-maintenance friend". The New England Journal of Medicine. 366 (19): 1836–8. doi:10.1056/NEJMe1202819. PMID   22571206.
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  32. 1 2 Kulig P, Milczarek S, Bakinowska E, Szalewska L, Baumert B, Machalinski B (February 2023). "Lenalidomide in Multiple Myeloma: Review of Resistance Mechanisms, Current Treatment Strategies and Future Perspectives". Cancers. 15 (3): 963. doi: 10.3390/cancers15030963 . PMID   36765919.
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