Thalidomide is an immunomodulatory and anti-angiogenic agent used today mainly in multiple myeloma and certain dermatological and inflammatory conditions. Originally developed in the 1950s as a sedative and antiemetic in pregnancy, it caused severe limb malformations, leading to one of the most infamous drug disasters in medical history. Its re-introduction under strict regulation has provided major therapeutic benefit in oncology.

⚙️ Mechanism of Action

Thalidomide acts through multiple mechanisms: it inhibits TNF-α production, reduces leukocyte adhesion and angiogenesis, and modulates T-cell and NK-cell function. Its precise molecular target is the cereblon (CRBN) protein, part of an E3 ubiquitin ligase complex. Binding alters substrate specificity, promoting degradation of transcription factors required for myeloma cell survival.

📋 Indications (UK Context)

Multiple myeloma — first-line or relapse treatment in combination with dexamethasone or other agents (e.g. bortezomib or cyclophosphamide).
Erythema nodosum leprosum — anti-inflammatory effect.
Occasionally used for cutaneous lupus erythematosus or refractory Behçet’s disease (specialist supervision).

💉 Administration

Given orally, usually at night (sedative effect).
Dose titrated (typically 50–200 mg daily) depending on tolerance and combination therapy.
Strict pregnancy-prevention and controlled-access programme required due to teratogenicity.

⚠️ Adverse Effects

Teratogenicity — causes severe limb and organ malformations (absolute contraindication in pregnancy).
Peripheral neuropathy — may be irreversible; dose-limiting.
Venous thromboembolism — particularly when combined with steroids or chemotherapy; LMWH prophylaxis often used.
Somnolence, constipation, rash, and bradycardia.
Myelosuppression (less prominent than with cytotoxics).

🧠 Key Clinical Points

Always enrol under the Thalidomide Pregnancy Prevention Programme.
Monitor for neuropathy and stop early if symptoms arise.
Give VTE prophylaxis in combination regimens.
Preferred for older or transplant-ineligible myeloma patients (low-intensity oral regimen).

🔬 Pathophysiological Rationale

Myeloma cells rely on TNF-α–driven microenvironmental support and angiogenesis within the bone marrow. Thalidomide disrupts these survival signals and enhances immune-mediated cytotoxicity. Its evolution from teratogen to targeted therapy illustrates the principle that dose, context, and mechanism define drug toxicity and value.

📚 References & Notes

BNF: Thalidomide
NICE TA228, TA171 — thalidomide use in myeloma (first-line combination therapy).
Palumbo A

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Thalidomide

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