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Lenalidomide
Lenalidomide
Lenalidomide
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Lenalidomide
Clinical data
Pronunciation/ˌlɛnəˈlɪdoʊmaɪd/
Trade namesRevlimid, Linamide, others
AHFS/Drugs.comMonograph
MedlinePlusa608001
License data
Pregnancy
category
  • AU: X (High risk)[1]
Routes of
administration		By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
BioavailabilityUndetermined
Protein binding30%
MetabolismUndetermined
Elimination half-life3 hours
ExcretionKidney (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 InfoCard100.218.924 Edit this at Wikidata
Chemical and physical data
FormulaC13H13N3O3
Molar mass259.265 g·mol−1
3D model (JSmol)
ChiralityRacemic 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) checkY
  • Key:GOTYRUGSSMKFNF-UHFFFAOYSA-N checkY
  (verify)

Lenalidomide, sold under the brand name Revlimid among others, is a medication used to treat multiple myeloma, smoldering myeloma, various indolent lymphomas, and myelodysplastic syndromes (MDS).[7] For multiple myeloma, it is a first-line treatment, and is given with dexamethasone.[7] It is taken by mouth.[7]

Common side effects include diarrhea, itchiness, joint pain, fever, headache, and trouble sleeping.[7] Severe side effects include low blood platelets, low white blood cells, and blood clots.[7] The dose may need to be adjusted in people with kidney problems.[7] 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.[7]

Lenalidomide belongs to a class of drugs known as immunomodulatory imide drugs (IMiDs) or Cereblon E3 ligase modulators, which includes thalidomide and its analogs.[8] In lymphocytes, these drugs target an E3 ubiquitin ligase and change its specificity to include new targets.[8] This results in the rapid degradation of several disease-related proteins including IKZF1, IKZF3, and CSNK1A1.[8]

Lenalidomide was approved for medical use in the United States in 2005.[7] It is on the World Health Organization's List of Essential Medicines.[9]

Medical uses

[edit]

Multiple myeloma

[edit]

Lenalidomide is used to treat multiple myeloma.[10] It is a more potent molecular analog of thalidomide, which inhibits tumor angiogenesis, tumor-secreted cytokines, and tumor proliferation through induction of apoptosis.[11][12][13]

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.[14] The risk of second primary hematological malignancies does not outweigh the benefit of using lenalidomide in relapsed or refractory multiple myeloma.[15] It may be more difficult to mobilize stem cells for autograft in people who have received lenalidomide.[11]

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.[16] In 2017, the FDA approved lenalidomide as standalone maintenance therapy (without dexamethasone) for people with multiple myeloma following autologous stem cell transplant.[17]

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.[18]

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.[19]

Myelodysplastic syndromes

[edit]

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.[20][21][22] 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.[23]

Follicular Lymphoma

[edit]

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").

Mantle cell lymphoma

[edit]

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.[5]

AL amyloidosis

[edit]

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

[edit]

In addition to embryo-fetal toxicity, lenalidomide carries black box warnings for hematologic toxicity (including neutropenia and thrombocytopenia) and thromboembolism.[5] 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.[5]

Teratogenicity

[edit]

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 people who are pregnant or who are likely to 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. 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.[5][27]

Venous thromboembolism

[edit]

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

[edit]

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

[edit]

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

[edit]
See also: Cereblon_E3_ligase_modulator § 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).[8] Cereblon is the substrate adapter for the complex and is the primary molecular target of the drug.[8] Treatment with lenalidomide changes the targets of the ligase complex.[8] Subsequently, proteins IKZF1, IKZF3, and CK1α are recruited to the complex, ubiquinated, and then degraded by the proteasome.[8]

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).[8] IRF4 is a master regulator of several cancer-promoting genes and is required for the survival of multiple myeloma.[8]

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]

Synthesis

[edit]

The first synthesis of lenalidomide was disclosed in patents filed by Celgene.[33]

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.[34]

History

[edit]
See also: Development of analogs of thalidomide

Society and culture

[edit]
[edit]

Lenalidomide was approved for medical use in the United States in 2005.[7]

Economics

[edit]

Lenalidomide cost US$235,920 per year before insurance in the United States as of 2024, with the generic version costing US$208,188.[35] Lenalidomide made almost $9.7bn for Celgene in 2018.[36]

Price increases

[edit]

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.[37]

Since its approval, Revlimid cost has increased 26 times.[35] 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.[37] Celgene claimed its patent protected Revlimid until 2027, and has engaged in several practices to prevent other manufacturers from producing a generic version of the drug, including refusing to sell the drug to other drug makers for testing purposes.[35]

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)".[38]

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.[39]

In 2025, the generic version of Revlimid is only marginally cheaper than the branded version in the United States, $17,349 versus $19,660 per month.[35]

References

[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Lenalidomide

View on Grokipedia
from Grokipedia
Lenalidomide is a thalidomide-derived oral immunomodulatory agent with antineoplastic properties, primarily indicated for the treatment of multiple myeloma in newly diagnosed, relapsed, or refractory settings, as well as maintenance therapy following autologous stem cell transplantation, and for transfusion-dependent anemia in patients with low- or intermediate-1-risk myelodysplastic syndromes associated with a deletion 5q cytogenetic abnormality. First approved by the U.S. Food and Drug Administration in December 2005 for the myelodysplastic syndrome indication, its approvals expanded through subsequent clinical trials demonstrating prolonged progression-free survival and overall survival in multiple myeloma patients compared to placebo or alternative therapies. Lenalidomide exerts its effects by binding to the E3 ubiquitin ligase cereblon, promoting the proteasomal degradation of transcription factors such as Ikaros and Aiolos, which inhibits cancer cell proliferation, enhances T-cell and natural killer cell-mediated cytotoxicity, and suppresses pro-inflammatory cytokines in the tumor microenvironment. In multiple myeloma, combination regimens with dexamethasone or bortezomib have yielded overall response rates exceeding 60% in relapsed patients and significantly improved three-year progression-free survival rates to approximately 53% versus 36% with controls. Despite its efficacy, lenalidomide carries substantial risks, including severe neutropenia, thrombocytopenia, venous thromboembolism, and an elevated incidence of second primary malignancies, necessitating close hematologic monitoring and thromboprophylaxis. As a known teratogen akin to its parent compound thalidomide, which caused thousands of birth defects historically, lenalidomide distribution is tightly controlled under a Risk Evaluation and Mitigation Strategy program requiring negative pregnancy tests and contraception for patients of childbearing potential. These safety concerns underscore the causal trade-offs in its therapeutic profile, where immunomodulatory benefits must be weighed against heightened infection susceptibility and oncogenic potential observed in long-term use.

Medical Indications

Multiple Myeloma

Lenalidomide is approved by the U.S. Food and Drug Administration (FDA) in combination with dexamethasone for the treatment of multiple myeloma patients who have received at least one prior therapy. In newly diagnosed patients ineligible for autologous stem cell transplantation (ASCT), it is indicated in combination with dexamethasone or as part of regimens including bortezomib, such as VRd (bortezomib, lenalidomide, dexamethasone), which demonstrated improved progression-free survival (PFS) compared to lenalidomide plus dexamethasone alone in the SWOG S0777 trial. For maintenance therapy following ASCT in newly diagnosed patients, lenalidomide received FDA approval on February 22, 2017, based on meta-analyses of three randomized controlled trials showing a of 0.48 for PFS, corresponding to approximately a 50% reduction in the risk of disease progression or death. In relapsed or , lenalidomide-based combinations like RVd are utilized, with phase II data indicating median PFS exceeding 40 months in some cohorts and real-world analyses reporting extended overall survival durations. The recommended starting dose for induction and relapsed settings is 25 mg orally once daily on days 1 through 21 of repeated 28-day cycles, typically combined with dexamethasone, with adjustments for renal impairment based on creatinine clearance (e.g., reduced to 10 mg for clearance 30-59 mL/min or 5 mg below 30 mL/min). For post-ASCT , dosing often starts at 10 mg daily continuously, titrated up to 15 mg as tolerated.

Myelodysplastic Syndromes

Lenalidomide is indicated for the treatment of transfusion-dependent due to low- or intermediate-1-risk myelodysplastic syndromes (MDS) associated with a deletion 5q (del(5q)) cytogenetic abnormality, with or without additional chromosomal abnormalities. The U.S. approved this indication on December 27, 2005, based primarily on the multicenter phase 2 MDS-003 trial involving 148 transfusion-dependent patients with del(5q) MDS, in which 67% (99 patients) achieved transfusion independence, with a median duration of 41 weeks and median time to response of 4.6 weeks. The recommended starting dose is 10 mg administered orally once daily continuously, with dose reductions for cytopenias such as or occurring in over 80% of patients in the MDS-003 trial, often requiring temporary interruptions or adjustments to 5 mg or lower. Among transfusion-independent responders, 76% exhibited cytogenetic responses, reflecting targeted suppression of the del(5q) clone and contributing to durable hematologic improvement in this cytogenetically defined subset. Lenalidomide's selective efficacy in del(5q) MDS arises from cereblon-mediated ubiquitination and degradation of casein kinase 1A1 (CK1α), a haploinsufficient due to the 5q deletion; this amplifies -dependent in del(5q) cells while sparing normal hematopoietic progenitors, as CK1α normally inhibits translation and promotes MDM2-mediated degradation. This mechanism underlies the high response rates confined to del(5q) cases, distinguishing lenalidomide's role in correcting from ineffective driven by ribosomal in affected clones. In contrast, lenalidomide demonstrates limited benefit in non-del(5q) lower-risk MDS, with erythroid response rates of 20-30% in phase 2 trials and no regulatory approval, as the absence of CK1α precludes the selective apoptotic pressure observed in del(5q) subsets.

Non-Hodgkin Lymphomas

Lenalidomide, in combination with rituximab (R² regimen), is approved by the U.S. for the treatment of adult patients with relapsed or refractory (FL) after two or more prior systemic therapies. This approval, granted on May 28, 2019, was supported by the phase 3 AUGMENT trial (NCT01938001), which enrolled 358 patients with relapsed or refractory indolent , including FL grades 1-3a. In the trial, R² achieved an overall response rate (ORR) of 76% compared to 45% with rituximab plus , with a median (PFS) of 39.4 months versus 14.1 months, demonstrating superior efficacy in this setting. The regimen involves lenalidomide at 20 mg orally daily on days 1-21 of repeated 28-day cycles, alongside rituximab, until disease progression or unacceptable toxicity. For (MCL), lenalidomide monotherapy received FDA approval on June 29, 2013, for patients whose disease has relapsed or progressed after therapy. This indication stemmed from the phase 2 MCL-001 (EMERGE) trial (NCT00737529), involving 134 heavily pretreated patients, which reported an ORR of 26% (including 8% complete responses) and a PFS of 7.2 months, indicating clinical benefit with a manageable profile in this population. The recommended dosing for MCL is 25 mg orally daily on days 1-21 of 28-day cycles, with adjustments for toxicity. Unlike FL, where combination with rituximab augments outcomes, MCL approval relies on single-agent data, though subsequent studies have explored R² in MCL with promising response rates exceeding 50% in select relapsed cohorts. Lenalidomide's activity in these B-cell lymphomas partly derives from its immunomodulatory effects, which enhance (ADCC) against cells, particularly when paired with rituximab targeting CD20. Preclinical and early clinical data show lenalidomide potentiates and monocyte-mediated ADCC by upregulating immune activation markers and cytokines, restoring antitumor immunity impaired in indolent lymphomas. This mechanism contributes to the observed PFS prolongation in trials like AUGMENT, independent of direct cytotoxic effects.

Other Hematologic Conditions

Lenalidomide has demonstrated efficacy in treating systemic light chain (AL) amyloidosis, a plasma cell disorder characterized by amyloid deposition from monoclonal light chains, through regimens targeting underlying clonal plasma cells. In phase II trials, lenalidomide combined with dexamethasone yielded hematologic response rates of 41% to 47%, including complete responses in 5% to 11% of patients with newly diagnosed or relapsed disease. Triplet combinations, such as cyclophosphamide-lenalidomide-dexamethasone, improved outcomes in relapsed/refractory cases, achieving overall hematologic responses in approximately 60% of patients, with organ responses in 20% to 30%. These benefits stem from lenalidomide's cereblon-mediated degradation of transcription factors like Ikaros and Aiolos, reducing plasma cell proliferation and light chain production akin to its mechanism in multiple myeloma. NCCN guidelines endorse lenalidomide-based regimens as options for AL amyloidosis, particularly in relapsed settings or when bortezomib is unsuitable, though not as first-line due to toxicity concerns like cardiac decompensation evidenced by BNP elevations. Dosing adjustments are critical given patient frailty; trials initiated at 15 mg daily (versus 25 mg in myeloma) on days 1-21 of 28-day cycles, with escalations to 20 mg only if tolerated, and frequent reductions to 5-10 mg for cytopenias or neuropathy. Hematologic responses correlate with plasma cell reduction, but organ improvement lags, occurring in fewer than half of responders, underscoring the need for early clonal control to mitigate amyloid progression. Investigational applications extend to chronic (GVHD) post-allogeneic , where immunomodulatory drugs like lenalidomide may modulate T-cell responses. Phase II data indicate potential in refractory chronic GVHD, with partial responses in select cohorts, though acute GVHD incidence rises to 38% with maintenance dosing, limiting broad adoption. Empirical evidence from high-risk myeloid disorder transplants shows reduced relapse without excessive chronic GVHD flares at low doses (5-10 mg), but remains correlative pending randomized trials.

Pharmacology

Mechanism of Action

Lenalidomide binds to (CRBN), the substrate-recognition component of the Cullin Ring Ligase 4 (CRL4CRBN) E3 complex, thereby altering its substrate specificity to promote the ubiquitination and subsequent proteasomal degradation of the zinc-finger transcription factors (Ikaros) and IKZF3 (Aiolos). This targeted degradation disrupts the transcriptional activity of IKZF1 and IKZF3 in hematopoietic malignancies, leading to downregulation of key oncogenic drivers such as and in cells. Beyond direct protein degradation, lenalidomide modulates immune responses by enhancing T-cell through increased expression of markers and cytokines, including interleukin-2 (IL-2) and interferon-γ (IFN-γ), while inhibiting pro-inflammatory TNF-α production. It also augments natural killer (NK) cell cytotoxicity via indirect mechanisms involving T-cell-derived IL-2 and reduced immunosuppressive signaling, such as PD-1/ axis disruption. Lenalidomide exhibits anti-angiogenic effects by suppressing the expression and activity of (VEGF) and basic fibroblast growth factor (bFGF), thereby inhibiting endothelial cell proliferation and microvessel formation. In del(5q) cells, where CK1α sensitizes cells to further loss, lenalidomide uniquely induces CK1α ubiquitination and degradation via CRL4CRBN, amplifying selective antiproliferative effects independent of /3 targeting.

Pharmacokinetics and Pharmacodynamics

Lenalidomide is rapidly absorbed following , with maximum plasma concentrations achieved between 0.5 and 4 hours post-dose. Its absolute bioavailability is approximately 100%, though high-fat meals can reduce peak plasma concentration (Cmax) by up to 50% and area under the curve (AUC) by 20%; administration with or without food is acceptable due to the minimal impact on overall exposure. The drug exhibits linear with dose-proportional increases in AUC and Cmax across doses from 5 to 400 mg, and no accumulation occurs upon repeated dosing due to its short elimination of approximately 3 hours in healthy subjects and 3 to 5 hours in patients with or myelodysplastic syndromes. Distribution is characterized by a of about 80 L and low of approximately 30%. Metabolism is minimal, with lenalidomide primarily excreted unchanged; identified metabolites, such as 5-hydroxy-lenalidomide and N-acetyl-lenalidomide, each constitute less than 5% of parent drug levels, and the drug does not significantly involve pathways. Elimination occurs predominantly via the kidneys, with approximately 82–90% of an oral dose recovered unchanged in within 24 hours and renal clearance exceeding the , indicating active tubular secretion. In patients with renal impairment, exposure increases substantially—AUC rises by 200–300% in moderate to severe cases and up to 400% in end-stage renal disease—with prolonged (9–16 hours), necessitating dose reductions based on clearance (e.g., 10 mg daily for creatinine clearance 30–60 mL/min in ). Pharmacodynamic analyses reveal exposure-response relationships where higher AUC correlates with both enhanced efficacy, such as improved in maintenance therapy, and increased risk of adverse events, including grade 3/4 (odds ratio 1.978) and (odds ratio 3.337). These associations inform dosing strategies to balance therapeutic benefit and toxicity, particularly in renally compromised patients.

Clinical Efficacy and Evidence

Key Clinical Trials

The MM-009 and MM-010 phase III trials, conducted in patients with relapsed or refractory , evaluated lenalidomide (25 mg on days 1-21 of a 28-day cycle) plus dexamethasone (40 mg on days 1-4, 9-12, and 17-20) against dexamethasone plus . Both multicenter, randomized, double-blind studies enrolled approximately 350 patients each, with primary endpoints of time to progression and overall response rate (ORR). At a follow-up of 17.1 months for MM-009 and 16.5 months for MM-010, the lenalidomide arm demonstrated an ORR of 60.6% versus 21.9% in the (P<0.001), with time to progression of 11.1 months versus 4.7 months (P<0.001). These results supported FDA approval in June 2006 for lenalidomide in combination with dexamethasone for relapsed/refractory multiple myeloma after one prior therapy. The CALGB 100104 () phase III trial assessed lenalidomide (10-15 mg daily) versus placebo following autologous stem-cell transplantation in 460 patients with newly diagnosed . This randomized, double-blind study, initiated post-transplant day 100, had () as the primary endpoint. Updated analyses at a median follow-up of 75.4 months showed a PFS of 0.48 (95% CI 0.37-0.62; P<0.001) favoring lenalidomide, with 3-year PFS rates of 66% versus 47%. Despite increased and secondary cancers in the lenalidomide group, these findings contributed to FDA approval in 2017 for post-transplant. For myelodysplastic syndromes with deletion 5q (del(5q)), the MDS-003 phase II trial tested lenalidomide 10 mg daily in 148 transfusion-dependent patients. The primary endpoint was transfusion independence (RBC-TI) for ≥26 weeks, achieved in 67% of patients overall and 76% of the del(5q) subgroup, with cytogenetic responses in 73% of del(5q) cases. Median duration of RBC-TI exceeded 2 years in responders, leading to FDA approval in 2005 for transfusion-dependent lower-risk MDS with del(5q). The phase III trial compared plus lenalidomide and dexamethasone (D-Rd) versus lenalidomide and dexamethasone (Rd) in 737 transplant-ineligible patients with newly diagnosed . This open-label, randomized study used PFS as the primary endpoint, with overall survival (OS) as a key secondary outcome. At a follow-up of 47.1 months, D-Rd reduced the of progression or by 32% (HR 0.68; P<0.0001), and showed an OS benefit with 4-year rates of 75.2% versus 64.1% (HR 0.69; P=0.0013). These data supported expanded approvals for D-Rd as frontline therapy in this population.

Response Rates and Survival Outcomes

In , lenalidomide maintenance therapy following autologous stem cell transplantation extends from 10.6 months with observation to 22.5 months, with a of 0.55 (95% CI, 0.40-0.76). In relapsed/refractory settings, lenalidomide plus dexamethasone achieves major response rates of 61% compared to 19.9% with , alongside a overall extension of 9.1 months. Combinations such as daratumumab-lenalidomide-dexamethasone yield of 61.9 months versus 34.4 months with lenalidomide-dexamethasone alone ( not specified in primary endpoint but reflecting substantial benefit). For myelodysplastic syndromes with deletion 5q, lenalidomide induces transfusion independence in 65-83% of patients, with median response durations of 2.2 years and sustained independence for at least in 62% of responders. Lower doses (5-10 mg) achieve transfusion independence lasting ≥182 days in 37-57% of cases, supporting long-term erythroid benefit in transfusion-dependent subsets. In relapsed or refractory indolent , lenalidomide plus rituximab improves with a of 0.46 compared to rituximab alone, effectively doubling median to approximately 27-39 months in key phase III data. The RELEVANCE trial of lenalidomide-rituximab versus rituximab-chemotherapy regimens showed comparable 6-year rates of 59-60% (hazard ratio 1.03, 95% CI 0.84-1.27), indicating non-inferiority without chemotherapy. Meta-analyses of lenalidomide across hematologic malignancies confirm consistent reductions in progression risk (e.g., hazard ratios 0.4-0.6 for in myeloma maintenance), yet highlight tempered net benefits due to 1.5- to 7-fold increased incidence of second primary , particularly hematologic types in newly diagnosed myeloma patients. Real-world data reinforce these survival gains while underscoring the need for risk-stratified monitoring given the malignancy offset.

Adverse Effects and Safety

Teratogenicity and Reproductive Toxicity

Lenalidomide is classified as FDA X due to its demonstrated embryofetal toxicity in animal studies and structural similarity to , a known human teratogen, rendering it absolutely contraindicated during . Exposure in utero can result in severe birth defects or embryofetal death, with no controlled human studies available but post-marketing surveillance through pregnancy registries indicating high risk of adverse outcomes, including spontaneous abortion and congenital malformations when exposure occurs despite contraindications. In reproductive toxicity studies, administered orally to pregnant cynomolgus monkeys (a relevant model) during at doses of 20–50 mg/kg/day—equivalent to or exceeding exposures—produced dose-dependent embryofetal toxicities, including increased incidences of fetal loss, skeletal variations, and external malformations such as purple skin discoloration and associated morbidity, particularly at maternally toxic levels. These effects parallel thalidomide's and limb reduction defects observed in humans and primates, with lenalidomide exhibiting comparable potency in disrupting embryonic development at low systemic exposures (e.g., plasma concentrations below therapeutic levels for some endpoints). Rodent studies further confirmed embryolethality and malformations like craniofacial dysmorphia and limb defects at doses as low as 50 mg/kg/day, underscoring a narrow therapeutic margin for developmental safety. To mitigate these risks, the Lenalidomide and (REMS) program, implemented upon FDA approval in and modeled after thalidomide's iPLEDGE system, mandates prescriber, pharmacy, and patient certification, with strict compliance requirements including two negative tests for females of reproductive potential prior to initiation, continuous use of two effective contraception methods (or ) during treatment and for four weeks post-discontinuation, and monthly follow-up testing. Males must abstain from intercourse with pregnant partners or use condoms, and both sexes are prohibited from blood or semen donation during therapy and for at least one week afterward to prevent indirect fetal exposure. Violations, such as non-compliance with contraception, result in treatment interruption, with the program emphasizing that even inadvertent exposure necessitates immediate reporting to registries for outcome tracking. At the molecular level, lenalidomide's teratogenicity stems from its binding to (CRBN), the substrate receptor of the Cullin-4 complex, which modulates degradation of developmental transcription factors essential for limb and craniofacial formation; CRBN expression is highly enriched in embryonic limb buds, and its pharmacological hijacking disrupts pathways like those involving MEIS2 and SALL4, leading to in proliferating cells during critical gestational windows. This mechanism causally links lenalidomide's immunomodulatory action to embryofetal harm, with species-specific neosubstrate recruitment explaining primate sensitivity akin to human vulnerability observed with .

Hematologic and Cardiovascular Risks

Lenalidomide treatment frequently induces myelosuppression, manifesting as and , which represent the primary hematologic toxicities and dose-limiting factors in (MM) regimens. In phase III trials such as MM-009 and MM-010 evaluating lenalidomide plus dexamethasone for relapsed/ MM, grade 3/4 occurred in 41-43% of patients, while grade 3/4 affected 19-22%. These cytopenias typically emerge within the first few cycles, with incidence stabilizing over time but potentially deepening after nine or more cycles due to cumulative stress. Management involves regular monitoring, dose interruptions or reductions (e.g., from 25 mg to 15 mg daily), and supportive interventions such as (G-CSF) for severe to prevent infections or hospitalizations. is addressed via platelet transfusions when counts fall below 10,000-20,000/μL, though transfusion dependence correlates with poorer outcomes. Dose modifications occur in up to 80-90% of patients across trials, yet maintaining relative dose intensity above 70-80% is associated with sustained , underscoring the need to balance toxicity with therapeutic thresholds. Cardiovascular risks center on venous thromboembolism (VTE), including deep vein thrombosis and , with lenalidomide elevating incidence through mechanisms involving immune modulation, enhanced procoagulant activity, and . In MM patients receiving lenalidomide-dexamethasone without prophylaxis, VTE rates reach 10-20%, particularly with high-dose dexamethasone (≥480 mg per cycle), as observed in early pivotal trials. This risk is compounded by MM-related hypercoagulability but directly attributable to lenalidomide, with odds ratios 4-7 times higher versus controls in meta-analyses. Prophylaxis substantially mitigates VTE, reducing incidence to under 5% via aspirin (81-325 mg daily) for low-risk patients or (LMWH, e.g., enoxaparin 40 mg subcutaneously daily) for intermediate/high-risk cases per International Myeloma Working Group guidelines, which stratify by patient age, prior VTE, and regimen intensity. In the FIRST trial of continuous lenalidomide-dexamethasone for newly diagnosed MM, prophylactic anticoagulation lowered VTE events to 4-7% from historical highs. Arterial events like are less common (1-3%) but warrant monitoring in patients with cardiovascular comorbidities.

Dermatologic and Infectious Complications

Dermatologic complications of lenalidomide primarily manifest as , occurring in 27.2% of patients across all grades and 3.6% at high grade (3 or 4) in a of ten clinical trials involving cancer patients. These rashes are often maculopapular or , appearing early in treatment (median onset around 12 days), and may require dose interruption or reduction for management, with early discontinuation recommended for severe cases to prevent progression. , including Stevens-Johnson syndrome (SJS) and (TEN), are rare, with post-marketing reports indicating incidences below 0.1% but carrying high mortality (up to 30-50% for TEN). These reactions necessitate immediate drug cessation, as lenalidomide's immunomodulatory effects may exacerbate T-cell mediated . Predisposing factors for severe dermatologic events include certain human leukocyte antigen (HLA) alleles, such as HLA-DRB1*1501 and *0602, observed in case series of patients developing SJS or following lenalidomide exposure. Post-marketing surveillance has identified these HLA associations through data, highlighting genetic susceptibility over environmental triggers in affected cohorts, though population-level screening is not routinely recommended due to low overall incidence. Infectious complications arise from lenalidomide-induced and altered T-cell function, with grade 3-4 reported in 42-65% of treated patients, predisposing to and upper respiratory infections. Grade 3-4 infections occur in approximately 20-30% of cases, predominantly (often bacterial), as evidenced by meta-analyses showing doubled risk compared to controls, persisting across treatment phases. Prophylactic measures, such as colony-stimulating factors for and antibiotics for at-risk patients, mitigate severity, though remains infrequent at around 0.6%. Post-marketing data confirm infections as a leading category, underscoring the need for vigilant monitoring in immunocompromised populations like those with .

Long-Term and Secondary Malignancy Risks

Long-term use of lenalidomide, particularly as therapy following autologous transplantation in newly diagnosed , is associated with an elevated risk of second primary malignancies (SPMs), including hematologic malignancies such as myelodysplastic syndromes (MDS) and (AML), as well as solid tumors like non-melanoma skin cancers and . In a of major posttransplant maintenance trials, the cumulative incidence of SPMs reached 6.9% at 5 years in the lenalidomide arm (3.1% hematologic and 3.8% solid), compared to 4.8% without maintenance. Earlier randomized trials reported incidence rates of 3.1 per 100 patient-years with lenalidomide versus 1.2 with , yielding a of approximately 2.5 for SPM development. This risk appears amplified in combination with prior exposure and reflects a class effect among immunomodulatory drugs (IMiDs), potentially driven by cereblon-mediated ubiquitination disrupting tumor surveillance or direct genotoxic effects on hematopoietic stem cells. The U.S. (FDA) confirmed this association in safety reviews of data from the 2010s, updating Revlimid labeling in 2012 to highlight SPM risks observed across IMiD-containing regimens, with ongoing post-marketing surveillance emphasizing dermatologic and hematologic monitoring. Relative risks range from 1.5- to 3-fold in cohorts, though newer trials in non-myeloma indications have shown less consistent elevation, suggesting context-specific factors like underlying disease or cumulative exposure duration. Cumulative 5-year incidences in intensive regimens, such as lenalidomide-bortezomib-dexamethasone triplets, have approached 10.4%, underscoring dose- and duration-dependent hazards. Despite these risks, decision-analytic models and long-term trial outcomes indicate a net survival benefit, as lenalidomide extends by 2-3 years on average, with SPM-attributable mortality remaining low (under 2% of deaths) relative to myeloma progression. For instance, in the Myeloma XI trial's extended follow-up of over 4,000 patients, prolonged lenalidomide beyond 4-5 years sustained gains without proportionally escalating SPM fatalities. Risk mitigation involves baseline dermatologic and hematologic screening, vigilant surveillance for skin lesions or cytopenias, and consideration of discontinuation if high-risk features (e.g., prior alkylator ) emerge, balancing individual patient age, frailty, and myeloma burden against projected benefits.

Chemistry and Manufacturing

Chemical Structure

Lenalidomide is a synthetic derivative characterized by the IUPAC name 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindol-2-yl)piperidine-2,6-dione. Its structure features a -2,6-dione (glutarimide) ring attached at the 3-position to the nitrogen of a 4-amino-1-oxoisoindoline moiety, forming a chiral molecule with the at the piperidine ring's 3-position. This configuration parallels 's core scaffold but incorporates key modifications: an amino substituent at the 4-position of the ring and reduction of one phthalimide carbonyl to a methylene in the five-membered heterocycle, yielding an isoindolinone rather than a full isoindole-1,3-dione. These alterations enhance relative to thalidomide by reducing susceptibility to at the and are associated with decreased . The molecular formula of lenalidomide is C₁₃H₁₃N₃O₃, with a molecular weight of 259.26 g/mol. It manifests as a white to off-white crystalline powder, sparingly soluble in water but soluble in organic solvents such as dimethyl sulfoxide.

Synthesis Methods

The synthesis of lenalidomide typically proceeds via the condensation of 3-aminopiperidine-2,6-dione hydrochloride with methyl 2-(bromomethyl)-3-nitrobenzoate in the presence of a base, forming a nitro-substituted intermediate, followed by reduction of the nitro group to an amine using iron powder and ammonium chloride or hydrazine hydrate, and subsequent cyclization under acidic conditions to yield the isoindole ring. This route, detailed in early patents, involves multiple purification steps to isolate the product with high purity. Improved scalable processes developed in the , such as those avoiding precious metal catalysts for nitro reduction, have streamlined the synthesis to three or four steps while achieving overall yields greater than 70%, enhancing suitability for . These optimizations include one-pot reactions and greener solvents, reducing waste and costs without compromising purity. Chiral synthesis is unnecessary, as lenalidomide is produced and administered as a , with both enantiomers exhibiting pharmacological activity. Strict control of impurities, particularly genotoxic alkylating agents like residual bromides, is implemented through rigorous purification and analytical monitoring to meet regulatory standards for safety.

History and Development

Origins from Thalidomide

In the 1990s, Corporation initiated a program to develop structural analogs of aimed at enhancing tumor factor-alpha (TNF-α) inhibition while mitigating the and neurologic side effects associated with the parent compound. This effort was motivated by 's demonstrated efficacy in treating erythema nodosum leprosum (ENL), a TNF-α-driven inflammatory complication of , as well as its potential in addressing , a syndrome linked to elevated cytokines in cancer patients. screened numerous analogs, selecting candidates based on empirical assays showing up to 400-fold greater potency in suppressing TNF-α production from lipopolysaccharide-stimulated peripheral blood mononuclear cells compared to . Lenalidomide, designated as CC-5013 during early development, emerged from this screening as a due to its markedly superior profile in cytokine modulation, exhibiting up to 50,000-fold greater in vitro potency against TNF-α than , alongside enhanced inhibition of other proinflammatory cytokines such as interleukin-6 and interleukin-12. Unlike , lenalidomide demonstrated minimal effects and reduced neurologic in preclinical evaluations, attributes attributed to structural modifications including an amino substitution on the phthalimide ring. These properties, combined with preliminary evidence of antitumor activity through mechanisms beyond TNF-α suppression—such as direct antiproliferative effects on myeloma cells—positioned lenalidomide for further advancement within the immunomodulatory drug (IMiD) class. Celgene secured foundational patents for IMiD compounds, including lenalidomide precursors, prior to 2000, establishing on the chemical series derived from thalidomide's glutarimide-phthalimide scaffold. This patent framework, filed in the mid-to-late 1990s, encompassed methods for synthesizing and using these analogs for modulation and applications, laying the groundwork for their toward oncologic indications.

Preclinical and Early Clinical Phases

Preclinical investigations of lenalidomide, initiated in the early 2000s as an analog of , revealed direct antiproliferative effects on (MM) cell lines, including induction of and cell cycle arrest in both sensitive and drug-resistant variants. These cytotoxic actions were observed at micromolar concentrations , with enhanced efficacy when combined with other agents targeting pathways. Subsequent studies identified (CRBN) as the primary binding target, where lenalidomide promotes the ubiquitination and proteasomal degradation of transcription factors (Ikaros) and IKZF3 (Aiolos), thereby disrupting MM cell survival signaling; CRBN expression was essential for this antimyeloma activity, as its knockdown conferred resistance. In parallel, lenalidomide exhibited antiangiogenic properties in preclinical models, inhibiting endothelial , migration, and tube formation in rat aortic ring assays and tumor xenografts. Dose-dependent suppression of (VEGF)-induced sprouting and cord formation was noted, alongside reduced tumor microvascular density in MM-bearing mice, contributing to overall antitumor growth inhibition without the teratogenicity observed with . Phase I dose-escalation studies in relapsed or MM patients during the early 2000s established the maximum tolerated dose (MTD) at 25 mg orally daily on days 1-21 of a 28-day cycle, with dose-limiting toxicities primarily involving myelosuppression such as grade 3-4 and . These trials confirmed manageable safety at this regimen, informing subsequent dosing, while initial response signals included stable disease or partial remissions in heavily pretreated cohorts. Early phase II evaluations extended these findings, particularly in transfusion-dependent anemia associated with del(5q) (MDS), where lenalidomide at 10 mg daily yielded transfusion independence in 76% of patients (median duration 41 weeks) and complete cytogenetic remissions in 67%, highlighting selective activity against the del(5q) clone. In MM cohorts, phase II monotherapy produced objective response rates of 25%, underscoring single-agent efficacy prior to combination strategies. Clinical observations from these 2000s-era trials revealed immunomodulatory effects, including enhanced T-cell proliferation, activation, and modulation (e.g., reduced TNF-α, increased IL-2), which augmented antitumor immunity independent of direct ; these properties were noted before full mechanistic linkage to CRBN-mediated pathways. Safety signals emphasized hematologic monitoring, with early dosing adjustments mitigating risks in vulnerable populations.

Regulatory Approvals Timeline

Lenalidomide received its initial U.S. (FDA) approval on December 27, 2005, for the treatment of transfusion-dependent anemia associated with low- or intermediate-1-risk myelodysplastic syndromes (MDS) with a deletion 5q cytogenetic abnormality. On June 29, 2006, the FDA expanded approval to include with dexamethasone for (MM) in patients who had received at least one prior therapy. The (EMA) granted centralized marketing authorization for lenalidomide (as Revlimid) on June 14, 2007, initially for MM in combination with dexamethasone following relapse or progression on or after prior therapy. Subsequent EMA approvals mirrored U.S. expansions, including for MDS with isolated del(5q) in 2009 and maintenance therapy post-autologous transplant for MM in 2013. Further FDA label expansions occurred on February 22, 2017, approving lenalidomide as monotherapy for maintenance in MM patients following autologous . On May 28, 2019, approval extended to combination with rituximab for relapsed or refractory or after at least one prior . The EMA followed with approval for the rituximab combination in on December 20, 2019. In 2025, following patent settlements and expiry, the FDA approved multiple generic versions of lenalidomide capsules, including Amneal Pharmaceuticals' formulation on February 19 for various strengths, with commercial availability slated for 2026, and Lupin Ltd.'s generic on September 17 for multiple potencies indicated in MM and MDS. These approvals enable broader access but incorporate volume restrictions tied to prior litigation settlements.

FDA Approvals and Indications

Lenalidomide, marketed as Revlimid, is approved by the U.S. (FDA) for in adult patients, either in combination with dexamethasone for treatment of newly diagnosed or relapsed/refractory disease, or as maintenance therapy following autologous . Specific regimens include lenalidomide plus dexamethasone (Rd) for induction and relapsed settings, and integration into multi-agent protocols such as , lenalidomide, and dexamethasone (VRd) for newly diagnosed patients ineligible for transplant, or plus VRd (D-VRd) in certain frontline combinations, though the core label emphasizes lenalidomide with dexamethasone as the foundational pairing. For myelodysplastic syndromes, lenalidomide is indicated in adult patients with transfusion-dependent due to low- or intermediate-1-risk disease associated with a deletion 5q cytogenetic abnormality, with or without additional chromosomal anomalies, including those to prior lenalidomide . In , lenalidomide is approved as monotherapy for adult patients whose disease has relapsed or progressed after at least two prior therapies, one of which included . For , , or small lymphocytic lymphoma, it is indicated in combination with rituximab for adults with relapsed or disease after two or more prior systemic therapies. The prescribing information includes boxed warnings for embryo-fetal , prohibiting use during due to severe birth defects and observed in preclinical and analogous to ; hematologic , including severe and requiring dose adjustments or interruptions; and increased risk of venous (such as deep vein thrombosis and ) and arterial , necessitating thromboprophylaxis in patients receiving concomitant dexamethasone or with risk factors.

Risk Management Programs

The Lenalidomide REMS program, mandated by the U.S. (FDA) upon the drug's approval in 2005 for myelodysplastic syndromes and subsequent indications, requires of prescribers, pharmacies, and enrollment to prevent embryo-fetal , a established from thalidomide's historical teratogenic effects and confirmed in preclinical studies showing profound limb malformations at doses approximating equivalents. Prescribers must complete on safe-use conditions, counsel on contraception and , verify negative serum pregnancy tests for all females of reproductive potential (conducted within 10-14 days and 24 hours before starting , then every 4 weeks during treatment and 4 weeks after discontinuation), and submit documentation for each cycle. Pharmacies, limited to certified specialty entities, confirm prescriber , enrollment, and compliance with pregnancy testing before dispensing, with no refills permitted outside these protocols. Patient-specific elements include mandatory acknowledgment of risks via signed forms, registration in a central database for tracking, and provision of contraception counseling, with males required to use latex condoms during treatment and for 28 days after due to seminal fluid transmission risks demonstrated in animal models. These measures extend to generic lenalidomide products via a shared manufacturer agreement, ensuring uniform application across branded Revlimid and equivalents. Real-world from program assessments show adherence exceeding 95% to contraception requirements, correlating with negligible reported fetal exposures and no confirmed thalidomide-scale birth defects in treated populations over nearly two decades. In response to post-marketing reports of severe cutaneous reactions, including Stevens-Johnson syndrome (SJS) and (TEN) occurring in less than 1% of patients but with high fatality potential, the prescribing information was updated to mandate immediate discontinuation upon rash onset and enhanced dermatologic monitoring, particularly in the first cycles when incidence peaks. While the core REMS focuses on teratogenicity, these protocols reinforce broader risk mitigation by requiring prescribers to educate on signs and integrate complete blood counts for monitoring, with grade 3-4 events reported in up to 59% of patients in trials. The enforced chain of verification and restricted distribution has empirically blocked causal pathways to preventable harms, as zero unintended pregnancies have been documented in compliant U.S. cohorts. Celgene Corporation, the original developer of lenalidomide marketed as Revlimid, constructed an extensive portfolio comprising over 100 secondary patents on formulations, methods of use, and manufacturing processes, often described as a "patent thicket" that extended market exclusivity beyond the primary compound 's expiration in 2013. This strategy included leveraging regulatory exclusivities, such as six months of pediatric exclusivity granted in 2016 for studies in pediatric despite limited applicability, and designations for multiple indications, which provided additional market protections and tax benefits. Critics, including advocacy groups and antitrust litigants, argued that these mechanisms, combined with Hatch-Waxman Act lawsuits against generic filers, triggered automatic 30-month stays on FDA approvals, effectively delaying until at least 2022 and imposing an effective exclusivity period exceeding 17 years. Following acquisition by in 2019, the company faced multiple antitrust lawsuits alleging "pay-for-delay" settlements with generic manufacturers, including , , and , which resolved suits but restricted generic entry volumes to as little as 10% of the market until January 31, 2026. Plaintiffs, such as hospitals and purchasers, claimed these agreements maintained supra-competitive pricing, costing the U.S. healthcare system billions, with one suit estimating $30 billion in excess revenues from delayed generics. Settlements included a $34 million resolution in 2020 for indirect purchasers, though withdrew from an earlier $55 million deal amid disputes. Proponents of the strategy, including industry analyses, defended the extended protections as necessary to recoup R&D investments for treatments targeting rare conditions like , affecting less than 1% of the population, and incentivizing innovation in low-volume orphan markets. Generic entry began modestly in 2022 with limited launches under settlement terms, but fuller competition accelerated in 2025, as evidenced by FDA approvals for ' lenalidomide capsules in strengths of 2.5 mg to 25 mg on February 19, 2025, enabling market entry on January 31, 2026, alongside other filers like and . These approvals followed resolution of challenges, with empirical data from prior limited entries showing price reductions of 80-90% compared to branded Revlimid, though volume caps constrained broader market impacts until 2026. Congressional probes and analyses have highlighted how such disputes underscore tensions between incentives and access, with critics viewing the thicket as abuse that prioritizes profits over patients, while defenders emphasize its role in sustaining development for niche therapies.

Commercial Aspects

Pricing and Economic Impact

Upon U.S. FDA approval for in June 2006, the annual cost of a standard 21-day regimen of Revlimid (lenalidomide) reached approximately $70,560, or $280 per pill based on average wholesale pricing. This marked a sharp increase from its initial pricing for myelodysplastic syndromes in 2005, where monthly costs were around $5,906. From launch through 2019, (later acquired by ) implemented 22 price hikes, elevating the per-pill cost to $763 by late 2019, translating to roughly $192,000 annually for a typical course excluding adjunct therapies. Revlimid achieved peak global sales of $12.8 billion in the years preceding widespread generic , representing a core revenue driver for and that underpinned investments in their pipelines. Generic lenalidomide entered the U.S. market starting in March 2022 following resolutions, prompting initial erosion for equivalents despite limited immediate drops due to supply and settlement dynamics. By 2025, additional generic approvals have further pressured pricing, with monthly regimen costs declining from prior branded peaks, though exact per-pill equivalents vary by manufacturer and remain subject to negotiated discounts. Cost-effectiveness models for lenalidomide in relapsed/refractory indicate incremental cost-utility ratios (ICURs) ranging from dominant (cost-saving with added benefit) to approximately $60,000 per (QALY) gained versus comparators like dexamethasone alone, aligning with or exceeding standard U.S. thresholds of $50,000–$150,000 per QALY in analyses of maintenance therapy post-transplant. These estimates reflect the drug's extension of in an unmet need setting, though real-world expenditures per patient year often exceed $150,000 when factoring full treatment sequences.

Market Exclusivity and Generic Entry

Lenalidomide, marketed as Revlimid by (formerly ), benefited from multiple regulatory exclusivities that prolonged its market monopoly. designations, granted by the FDA starting in 2001 for and extended to additional rare indications such as in 2017, provided seven years of market exclusivity per designation, along with tax credits and user fee waivers that supported development but effectively delayed generic competition. These mechanisms, combined with a thicket of over 27 secondary patents, extended protection beyond the primary composition-of-matter , with some exclusivities lasting until 2022 and others into 2026 via pediatric extensions and formulation claims. Generic entry began with FDA approvals in 2021 for abbreviated new drug applications (ANDAs) from (in partnership with Teva) on May 21 and others, enabling launches in March 2022 under settlement agreements that phased to mitigate immediate erosion. However, supply chain constraints and settlement-limited volumes restricted generics to under 10% of the market in the initial year, slowing competition despite approvals for additional manufacturers like in February 2023. Amneal Pharmaceuticals received FDA approval for lenalidomide capsules in multiple strengths in February 2025, but full commercial entry is scheduled for January 31, 2026, under a licensing agreement with , further illustrating how legal settlements have staggered generic penetration. Post-entry, Revlimid's U.S. and global revenues experienced sharp declines, with reporting a 41% drop in worldwide sales in the third quarter of 2023 alone, contributing to an overall 2% company revenue decrease for the year amid generic erosion. This shift accelerated loss, with generics capturing increasing volumes by 2024, though ongoing supply limitations in low-resource settings have tempered broader access gains despite price reductions. Empirical indicate that while these dynamics prompted congressional scrutiny of exclusivity extensions—estimating an additional $45 billion in U.S. costs from delayed generics—the framework has sustained incentives for innovation, as evidenced by Revlimid's sustained development across eight orphan indications.

Cost-Effectiveness and Value Assessments

Lenalidomide, marketed as Revlimid, has been subject to extensive cost-effectiveness evaluations due to its high acquisition costs and role in and myelodysplastic syndromes treatment regimens. In the United States, the Institute for Clinical and Economic Review (ICER) assessed treatments for relapsed or , finding that regimens combining lenalidomide with dexamethasone (LEN+DEX) as a comparator often yielded incremental cost-effectiveness ratios (ICERs) exceeding conventional value thresholds of $50,000–$150,000 per (QALY) gained for newer additions like +LEN+DEX at approximately $200,000 per QALY. Similarly, ICER's analysis of unsupported price increases highlighted lenalidomide's escalating costs, with monthly wholesale acquisition costs rising from about $5,900 in 2005 to over $19,000 by recent years, contributing to total lifetime costs in models often surpassing $700,000 per patient. In maintenance therapy post-autologous transplant for , a Markov model-based estimated incremental costs of $130,817 per life-year gained for lenalidomide versus , with sensitivity analyses showing cost-effectiveness improving only at substantial price reductions below list prices. For frontline use in transplant-ineligible patients, comparisons of lenalidomide-dexamethasone (Rd) versus melphalan-prednisone-thalidomide yielded ICERs around $78,977 in additional lifetime costs for Rd, though QALY gains were modest and dependent on assumptions from trials like FIRST. These U.S.-focused assessments underscore that lenalidomide's value is marginal at full prices, with ICER recommending 80–94% discounts from wholesale costs for second-line to align with evidence of net health benefits. In the United Kingdom, the National Institute for Health and Care Excellence (NICE) appraised lenalidomide for relapsed multiple myeloma post-bortezomib, estimating an ICER of £46,865 per QALY gained in manufacturer models assuming prior thalidomide exposure, though exploratory analyses raised this to £69,500 per QALY for broader prior therapy histories, leading to conditional approval via patient access schemes providing discounts. NICE rejected earlier-line use in some multiple myeloma sequences due to ICERs exceeding £20,000–£30,000 per QALY thresholds compared to alternatives like bortezomib. For myelodysplastic syndromes with deletion 5q, NICE noted uncertain ICERs versus best supportive care, influenced by response duration and transfusion independence rates from the MDS-004 trial. Internationally, a pan-Canadian review for relapsed multiple myeloma pegged ICERs at $114,887 per life-year and $158,129 per QALY gained, reflecting similar challenges with high drug costs dominating lifetime expenditures. Post-2022 generic entry in the U.S. has lowered prices, potentially enhancing cost-effectiveness; European models post-autotransplant fixed-duration lenalidomide showed QALY savings of €7,286 in some scenarios, though U.S. estimates remained at $60,835 per QALY averted without full generic penetration. Overall, value assessments consistently identify lenalidomide as providing clinical benefits in but frequently failing strict cost-per-QALY benchmarks without pricing concessions, with real-world data emphasizing the need for subgroup targeting to optimize .

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