Revlimid
Revlimid
Generic Name
Revlimid
Mechanism
- CRBN binding: Lenalidomide binds to the cereblon (CRBN) subunit of the CRL4^CRBN E3 ubiquitin‑ligase complex.
- Targeted protein degradation: This induces ubiquitination and proteasomal degradation of the transcription factors Ikaros (IKZF1) and Aiolos (IKZF3), leading to:
- Suppressed proliferation of malignant plasma cells.
- Induction of apoptosis.
- Immunomodulation:
- Enhances T‑cell and natural killer (NK)‑cell cytotoxicity.
- Down‑regulates pro‑inflammatory cytokines (TNF‑α, IL‑6).
- Angiogenesis inhibition: Decreases VEGF and other pro‑angiogenic mediators.
Pharmacokinetics
- Absorption: Rapid, peak plasma concentration (T_max) ~1–2 h; ~100 % oral bioavailability.
- Distribution: Volume of distribution ~0.5 L/kg; protein binding ~30 % (moderate).
- Metabolism: Primarily non‑catalytic; low CYP involvement (minimal drug‑drug interaction with CYP3A4).
- Elimination: Renal excretion (~70 %) as unchanged drug; half‑life ≈3–6 h (adjusted in renal impairment).
- Food effect: No clinically significant influence.
Indications
| Indication | Typical Regimen |
| Relapsed or refractory multiple myeloma | 25 mg PO daily (days 1‑21) of a 28‑day cycle, ± dexamethasone |
| Front‑line myeloma | 25 mg PO daily (days 1‑21) ± dexamethasone; often combined with lenalidomide‑dexamethasone‑PIs |
| Multiple myeloma with renal impairment | Dose‑adjusted (15 mg, 10 mg, 5 mg) based on CrCl |
| Smoldering myeloma (high‑risk) | 25 mg PO daily (days 1‑21) |
| AL amyloidosis | 25 mg PO daily (days 1‑21) |
| Myelodysplastic syndromes (MDS) with 5‑q deletion | 10 mg PO daily (days 1‑21) |
| Primary plasma cell leukemia | 25 mg PO daily (days 1‑21) |
Contraindications
- Pregnancy: Category D; teratogenic (fetal bone marrow suppression).
- Severe renal impairment: CrCl <15 mL/min (no dose recommendation).
- Hepatic failure: Contraindicated if cirrhotic (Child‑Pugh C).
- Concurrent use: Strong CYP3A4 inducers (e.g., rifampin) or inhibitors (ketoconazole) → dose adjustment.
- Active infection: May worsen sepsis or viral reactivations.
- Thrombosis risk: Prothrombotic state → requires thromboprophylaxis (low‑dose aspirin or LMWH).
- Bone marrow suppression: Pre‑existing cytopenias → dose delay or reduction.
Dosing
| Population | Renal Function | Dose (mg) | Schedule |
| Adults, CrCl ≥60 mL/min | 60 mL/min–≥80 mL/min | 25 | Days 1–21 of 28‑day cycle |
| CrCl 30–59 mL/min | 30–59 mL/min | 15 | Days 1–21 |
| CrCl 15–29 mL/min | 15–29 mL/min | 10 | Days 1–21 |
| CrCl <15 mL/min | <15 mL/min | Not recommended | – |
| Pediatrics (≤18 y) | Adjusted by BSA | 1 mg/kg (max 25 mg) | Days 1–21 |
| Special | |||
| Pregnancy/Breastfeeding | Contraindicated | – | – |
• Administration: Oral capsule; can be taken with or without food.
• Cycling: Typical 28‑day cycle; consider a 1‑week break to mitigate cumulative toxicity.
Adverse Effects
Common (≥10 %)
• Myelosuppression: neutropenia, thrombocytopenia, anemia
• GI upset: nausea, vomiting, diarrhea
• Skin rash (maculopapular)
• Peripheral sensory neuropathy (early onset)
• Fatigue, insomnia
Serious (≥1 %)
• Thromboembolic events (deep‑vein thrombosis, pulmonary embolism)
• Progressive multifocal leukoencephalopathy (rare)
• Severe infections (sepsis, viral reactivation)
• Hemorrhagic cystitis (rare)
• Secondary malignancies (rare; monitor long‑term)
• Severe cutaneous adverse reactions (SJS/TEN)
Monitoring
| Parameter | Frequency | Rationale |
| CBC with differential | Every 2 weeks, then monthly | Detect cytopenias |
| CMP, liver enzymes | Every 2 weeks, then monthly | Hepatotoxicity |
| Renal function (CrCl) | Every 2 weeks, then monthly | Dose adjustment |
| Neuropathy assessment | Baseline, then every cycle | Early intervention |
| Blood pressure | Baseline, then monthly | Hypertension risk |
| Thromboembolism signs | Continuous | Prompt anticoagulation |
| Fasting glucose | Every 6 months | Potential hyperglycemia |
| Pregnancy test | Baseline, then periodic | Teratogenic risk |
Clinical Pearls
- Teratogenic vigilance: Use dual contraception (oral + barrier) for at least 90 days after last dose; pregnancy test prior to initiation and during therapy.
- Thromboprophylaxis: Even low‑dose aspirin may suffice; consider LMWH in high‑risk patients (obesity, immobility, prior thrombus).
- Dose adjustment logic: Use the most recent CrCl; do not exceed max daily dose of 25 mg; consider a 2‑week drug holiday if ANC < 1.5 × 10⁹/L or platelets < 50 × 10⁹/L.
- Drug interactions: Avoid concomitant use with strong CYP3A4 inducers (rifampin, phenytoin) and inhibitors (ketoconazole, itraconazole); monitor for altered plasma drug levels.
- Neuropathy monitoring: Use the Total Neuropathy Score‐Clinical (TNS‑C) at baseline and every cycle; consider dose reduction if grade ≥ 2 symptoms appear.
- Bone marrow suppression recovery: If neutropenia or thrombocytopenia persists beyond 5 days, consider granulocyte‑stimulating factor or thrombopoietin‑mimetic agents.
- Secondary malignancy surveillance: Long‑term survivors benefit from biennial dermatologic exam and screening for colorectal cancer per standard guidelines.
- Patient education: Emphasize the importance of reporting fever, chills, or signs of infection promptly; reinforce adherence to dosing schedule and follow‑up labs.
Key Takeaway: Revlimid is a potent, orally‑administered IMiD that exerts anti‑malignant effects via CRBN‑dependent ubiquitination, immune modulation, and anti‑angiogenesis. Its use demands meticulous renal dosing, vigilant monitoring for cytopenias and thrombosis, and strict teratogenic precautions.