Immunomodulatory Drugs in Myeloma

Immunomodulatory drugs bind cereblon, a component of an E3 ubiquitin ligase, which causes degradation of the transcription factors Ikaros and Aiolos. This is directly toxic to myeloma cells and enhances T-cell and natural killer cell activity. They are given orally and are a backbone of myeloma treatment, alone or combined with a proteasome inhibitor, an anti-CD38 antibody and dexamethasone.

Classification. Thalidomide, lenalidomide, pomalidomide.

Pharmacokinetics. Lenalidomide and pomalidomide are renally cleared (lenalidomide mostly unchanged); thalidomide is cleared by spontaneous hydrolysis. Pomalidomide is also metabolised by CYP1A2.

• Thalidomide 100 to 200 mg orally at night, titrated from 50 mg; usual maximum 200 mg daily.
• Lenalidomide 25 mg orally daily on days 1 to 21 of a 28-day cycle; maintenance 10 mg daily (continuous or days 1 to 21); 10 mg daily for myelodysplastic syndrome with 5q deletion.
• Pomalidomide 4 mg orally daily on days 1 to 21 of a 28-day cycle, with dexamethasone.
• Dexamethasone 40 mg weekly (20 mg in patients over 75 years or frail).

Differences. Thalidomide causes sedation, constipation and neuropathy but little marrow suppression; lenalidomide and pomalidomide cause neutropenia and thrombocytopenia with less neuropathy. Lenalidomide and pomalidomide are more potent.

• Newly diagnosed myeloma: lenalidomide with bortezomib and dexamethasone; or lenalidomide with dexamethasone in transplant-ineligible patients; thalidomide with cyclophosphamide and dexamethasone or melphalan and prednisolone where lenalidomide is unavailable.
• Maintenance after autologous transplant: lenalidomide 10 mg daily until progression or intolerance.
• Relapsed myeloma: pomalidomide with dexamethasone, with or without an anti-CD38 antibody or proteasome inhibitor.
• Other uses: thalidomide 100 to 300 mg at night for erythema nodosum leprosum (specialist use under strict pregnancy prevention); lenalidomide for myelodysplasia with 5q deletion and some lymphomas.
• Prevent venous thromboembolism (mandatory): risk is highest in the first 6 months and with dexamethasone; aspirin 75 to 100 mg daily for low risk; low molecular weight heparin (enoxaparin 40 mg daily) or a direct oral anticoagulant for high risk (prior thrombosis, obesity, immobility, high-dose dexamethasone, combination with an anthracycline).
• Before starting: pregnancy test, full blood count, creatinine clearance, liver function, thyroid function, and hepatitis B and HIV status.
• Prophylaxis: aciclovir for herpes zoster with a proteasome inhibitor; antibacterial cover in neutropenia.

Selection. Choose by renal function, neuropathy, thrombosis risk, funding and access; thalidomide and generic lenalidomide are the more affordable options in East Africa.

Contraindications. Pregnancy and women of childbearing age who cannot comply with contraception (foetal malformation, including phocomelia); hypersensitivity; severe uncontrolled infection.

Adverse effects. Venous and arterial thromboembolism, neutropenia, thrombocytopenia, anaemia, fatigue, diarrhoea, rash, hypothyroidism, peripheral neuropathy, constipation, somnolence and bradycardia (thalidomide), second primary malignancies, tumour flare, and cataract with prolonged dexamethasone.

Interactions. Fluvoxamine and ciprofloxacin (CYP1A2 inhibitors) raise pomalidomide exposure, so reduce the pomalidomide dose by 50 percent; erythropoiesis-stimulating agents and oestrogens increase thrombosis risk; digoxin levels rise with lenalidomide; sedatives add to thalidomide drowsiness.

Special groups.

• Pregnancy: contraindicated. Women of childbearing age need effective contraception 4 weeks before, during and 4 weeks after treatment, and pregnancy tests before each cycle; men need condoms during and for 4 weeks after treatment because the drugs are present in semen.
• Breastfeeding: avoid.
• Children: not used.
• Older adults: use lower doses and dexamethasone 20 mg weekly.
• Kidney impairment: lenalidomide 10 mg daily at creatinine clearance 30 to 60 mL/min; 15 mg on alternate days under 30 mL/min (not on dialysis); 5 mg daily on dialysis (after dialysis on dialysis days); pomalidomide 3 mg daily on dialysis.
• Liver impairment: caution; reduce pomalidomide to 3 mg in mild to moderate impairment.

Monitoring. Full blood count weekly for the first 8 weeks, then monthly; creatinine; thyroid function every 3 months; signs of thrombosis; neuropathy with thalidomide; pregnancy tests; and second malignancy surveillance.

Referral and escalation. Limb swelling, chest pain, dyspnoea, suspected pregnancy (stop immediately and refer), neutropenic fever, and severe rash need urgent care.