Lenalidomide

Synthetic Routes and Reaction Conditions: The synthesis of lenalidomide typically involves the cyclization of methyl 2-(bromomethyl)-3-nitrobenzoate with 3-aminopiperidine-2,6-dione hydrochloride to form the nitro precursor. This precursor is then subjected to hydrogenation using palladium on charcoal as a catalyst to yield this compound . The reaction conditions include maintaining a hydrogen pressure of 0.3-0.8 Mpa and a temperature of 80°C .

Industrial Production Methods: Industrial production of this compound follows similar synthetic routes but on a larger scale. The process involves stringent quality control measures to ensure the purity and efficacy of the final product. Advanced chromatographic techniques, such as high-performance liquid chromatography, are employed to separate and purify this compound from related substances .

Types of Reactions: Lenalidomide undergoes various chemical reactions, including:

Oxidation: this compound can be oxidized to form 5-hydroxythis compound.

Reduction: The nitro precursor of this compound is reduced to form the final product.

Substitution: this compound can undergo substitution reactions, particularly at the amino group.

Common Reagents and Conditions:

Oxidation: Reagents such as hydrogen peroxide or potassium permanganate can be used under controlled conditions.

Reduction: Palladium on charcoal is commonly used as a catalyst in hydrogenation reactions.

Substitution: Various nucleophiles can be employed depending on the desired substitution product.

Major Products:

Oxidation: 5-hydroxythis compound

Reduction: this compound from its nitro precursor

Substitution: Various substituted derivatives of this compound

Treatment of Multiple Myeloma

Overview : Lenalidomide is primarily utilized in treating multiple myeloma, a cancer of plasma cells. It received FDA approval in March 2006 and has since been a cornerstone in multiple myeloma therapy.

Clinical Efficacy :

• Single-Agent Therapy : In a randomized phase 2 study, this compound alone achieved an overall response rate of 25%, with complete responses observed in 6% of patients . The median duration of response was reported as 19 months .
• Combination Therapy : The combination of this compound with dexamethasone has shown improved outcomes. A pivotal phase III study indicated that this regimen significantly enhanced progression-free survival compared to dexamethasone alone .

Myelodysplastic Syndromes

This compound has also been effective in treating patients with myelodysplastic syndromes, particularly those with del(5q) chromosomal abnormalities. Clinical trials have demonstrated that this compound can improve hematologic responses and decrease transfusion dependence in these patients .

Case Studies and Adverse Effects

While this compound is generally well-tolerated, certain adverse effects have been documented:

• Hepatotoxicity : A case study reported a patient developing acute liver injury associated with this compound treatment, which resolved upon discontinuation of the drug . This highlights the need for monitoring liver function during treatment.

Emerging Applications

Research is ongoing to explore the efficacy of this compound in other hematological malignancies:

• Acute Lymphoblastic Leukemia : Recent studies indicate that this compound may increase the risk of developing acute lymphoblastic leukemia in patients previously treated for other malignancies .

Lenalidomide exerts its effects through multiple mechanisms:

Molecular Targets: It binds to the protein cereblon, a component of the E3 ubiquitin ligase complex.

Pathways Involved: this compound modulates the activity of the E3 ubiquitin ligase, leading to the degradation of specific proteins such as IKZF1 and IKZF3.

Structural Features

Lenalidomide, thalidomide, and pomalidomide share a glutarimide core but differ in substitutions on the phthalimide ring (Table 1):

• Thalidomide : Contains two keto groups on the phthalimide ring, rendering it prone to hydrolysis into glutarimide and phthalimide metabolites .
• This compound: Replaces one keto group with an amino group, enhancing metabolic stability and reducing hydrolysis .
• Pomalidomide: Features an additional amino group on the phthalimide ring, increasing oxidative metabolism but retaining CRBN-binding efficacy .

Mechanism of Action and CRBN Binding

All three drugs bind CRBN but differ in affinity and downstream effects:

• This compound and pomalidomide exhibit higher CRBN-binding affinity than thalidomide in vitro, correlating with superior degradation of IKZF1/3 and antimyeloma activity . Structural modifications in this compound and pomalidomide enhance target specificity, reducing off-teratogenic effects compared to thalidomide .

Pharmacokinetic Profiles

Clinical Efficacy

• This compound : Superior to thalidomide in MM, with higher response rates (61% vs. historical ~30% for thalidomide) and survival benefits .
• Pomalidomide : Used in this compound-refractory MM, with response rates of ~30–35% in late-line therapy .
• Thalidomide : Largely replaced by this compound due to inferior efficacy and tolerability .

Lenalidomide is an immunomodulatory drug (IMiD) primarily used in the treatment of multiple myeloma and certain types of lymphoma. Its biological activity is characterized by a unique mechanism involving the modulation of the E3 ubiquitin ligase cereblon (CRBN), leading to the degradation of specific transcription factors and subsequent immune modulation. This article explores the biological activity of this compound, supported by case studies, research findings, and data tables.

Ubiquitin-Proteasome Pathway

This compound acts by altering the substrate specificity of the CRL4 CRBN E3 ubiquitin ligase. It induces the ubiquitination and degradation of key transcription factors such as Ikaros (IKZF1) and Aiolos (IKZF3), which are critical for lymphocyte function. This mechanism leads to enhanced T-cell activation and proliferation, particularly through increased production of interleukin-2 (IL-2) .

Key Molecular Interactions

Multiple Myeloma

This compound has shown significant efficacy in multiple myeloma (MM). Studies indicate that it enhances the effectiveness of other treatments, particularly proteasome inhibitors. The drug's ability to degrade IKZF1 and IKZF3 is crucial for its antitumor activity, as these proteins typically repress IL-2 expression, thereby inhibiting T-cell activation .

Non-Hodgkin Lymphoma (NHL)

In non-Hodgkin lymphoma, this compound demonstrates a direct tumoricidal effect, particularly in diffuse large B-cell lymphoma (DLBCL). The drug's activity is more pronounced in non-germinal center DLBCLs due to their dependence on IRF4 and NF-κB signaling pathways .

Case Study: Efficacy in DLBCL

A clinical study involving patients with MYD88-mutated DLBCL showed that this compound treatment led to significant tumor regression when combined with other agents targeting IRAK4. This combination therapy exploits the synergistic effects of IMiDs with targeted therapies, resulting in improved outcomes for patients .

Immunomodulatory Effects

This compound's immunomodulatory properties extend beyond direct antitumor effects. It enhances the immune response by:

• Increasing T-cell proliferation.
• Augmenting natural killer (NK) cell activity.
• Promoting a favorable cytokine environment through elevated IL-2 levels.

These effects contribute to its therapeutic efficacy in hematological malignancies .

Summary of Clinical Trials

A review of clinical trials indicates that this compound significantly improves progression-free survival (PFS) and overall survival (OS) in patients with multiple myeloma and certain lymphomas. The following table summarizes key findings from recent studies:

Future Directions

Research continues to explore the potential of this compound in combination therapies and its role in targeting previously "undruggable" proteins through innovative mechanisms involving E3 ligase modulation. Ongoing trials aim to further elucidate its efficacy across various malignancies .

Basic Research Questions

Q. What are the standard dosing regimens for lenalidomide in clinical trials for multiple myeloma, and how do they impact trial design?

Answer: this compound is typically administered orally at 25 mg/day on days 1–21 of a 28-day cycle, combined with dexamethasone (40 mg weekly or pulsed). This regimen was established in pivotal phase III trials (e.g., NCCN guidelines) and validated in studies comparing continuous vs. fixed-duration therapy . Key considerations for trial design include:

• Dose adjustments for adverse events (e.g., neutropenia, thrombocytopenia), requiring frequent hematologic monitoring .
• Dexamethasone scheduling : High-dose pulsed dexamethasone (days 1–4, 9–12, 17–20) was associated with higher toxicity vs. low-dose weekly regimens, influencing survival outcomes in E4A03 .
• Continuous vs. fixed-duration therapy : Prolonged this compound maintenance post-transplant improved progression-free survival (PFS) but increased secondary malignancies, necessitating risk-benefit analysis in trial protocols .

Q. What are the most common adverse events (AEs) associated with this compound, and how are they managed in clinical research?

Answer: Grade 3/4 AEs include neutropenia (29.5%), thrombocytopenia (11.4%), and venous thromboembolism (VTE; 11.4%) . Mitigation strategies in trials involve:

• Prophylactic anticoagulation : Low-molecular-weight heparin or aspirin for VTE prevention, mandated in protocols after early trial findings .
• Dose interruptions/reductions : For hematologic toxicity, with predefined criteria (e.g., ANC <500/mm³) .
• Monitoring schedules : Weekly CBCs during initial cycles and biweekly thereafter .

Q. How is this compound combined with dexamethasone in relapsed/refractory myeloma, and what are key efficacy endpoints?

Answer: The combination improves PFS and overall survival (OS) vs. dexamethasone alone, with median PFS of 11.3 months vs. 4.7 months . Methodological considerations include:

• Response criteria : IMWG uniform response criteria (complete response, partial response) for endpoint standardization .
• Crossover design : Placebo-controlled trials (e.g., MM-009/010) allowed crossover upon progression, requiring stratified survival analysis .
• OS confounders : Long-term follow-up accounts for subsequent therapies, requiring adjusted Cox models .

Advanced Research Questions

Q. What molecular mechanisms underlie this compound's immunomodulatory effects in non-myeloma malignancies?

Answer: this compound binds cereblon (CRBN), a substrate receptor of the E3 ubiquitin ligase complex, promoting degradation of IKZF1/3 in lymphoid malignancies . Key findings include:

• Gene expression profiling : Downregulation of MYC, IRF4, and upregulation of CDKN1A in NSCLC cells, inducing apoptosis .
• Immune modulation : Increased CD8+ T and NK cells in mantle cell lymphoma correlating with response duration .
• CRBN polymorphisms : A/A genotype in non-del(5q) MDS predicts resistance, necessitating pre-treatment genotyping in biomarker-driven trials .

Q. How can researchers address contradictions in survival benefits vs. secondary primary malignancy (SPM) risks in this compound maintenance therapy?

Answer: Pooled analyses show SPM incidence of 3.62 events/100 patient-years, primarily non-melanoma skin cancers . Strategies include:

• Risk stratification : Exclude high-risk populations (e.g., prior alkylator exposure) in trial eligibility .
• Long-term monitoring : Protocol-mandated dermatologic exams and blood counts .
• Benefit-risk frameworks : OS improvement (29.6 vs. 20.2 months in relapsed myeloma) justifies SPM risks in most scenarios .

Q. What biomarkers predict response to this compound in non-del(5q) myelodysplastic syndromes (MDS)?

Answer:

• NPM1 expression : Low levels correlate with treatment failure (HR = 3.2, p < 0.01) .
• CRBN polymorphisms : A/A genotype at rs1714327 reduces drug binding efficiency .
• Validation methods : Retrospective analysis of phase II trials using qRT-PCR and next-gen sequencing .

Q. How do pharmacokinetic (PK) challenges influence this compound dosing in renal-impaired populations?

Answer:

• Dose adjustments : Reduce by 50% for CrCl 30–60 mL/min and 75% for CrCl <30 mL/min, based on LC-MS/MS plasma quantification studies .
• PK modeling : Box-Behnken experimental designs optimize LC-MS/MS methods for this compound quantitation, ensuring accuracy in renal impairment trials .

Q. What experimental designs are optimal for studying this compound resistance mechanisms?

Answer:

• In vitro models : CRISPR-Cas9 knockout of CRBN in myeloma cell lines to validate target engagement .
• Transcriptomic profiling : RNA-seq of paired pre/post-treatment samples to identify resistance pathways (e.g., Wnt/β-catenin) .
• Correlative clinical trials : Embedding biopsies in phase II studies to assess clonal evolution .