Proteasome Inhibitors

Proteasome inhibitors block the 26S proteasome, causing build-up of misfolded proteins, activation of the unfolded protein response, and apoptosis. Myeloma cells make large amounts of immunoglobulin and are especially sensitive. They are central to treatment of multiple myeloma, AL amyloidosis and mantle cell lymphoma.

Classification. Bortezomib (reversible, boronic acid), carfilzomib (irreversible, epoxyketone), ixazomib (oral, reversible).

Pharmacokinetics. Bortezomib is metabolised by CYP3A4, CYP2C19 and CYP1A2; carfilzomib is cleared by peptidases; ixazomib is metabolised by CYP3A4 and others.

• Bortezomib 1.3 mg/m2 subcutaneously (or intravenously) on days 1, 4, 8 and 11 of a 21-day cycle; weekly 1.3 to 1.6 mg/m2 in frailer patients or maintenance.
• Carfilzomib 20 mg/m2 on days 1 and 2 of cycle 1, then 27 mg/m2 twice weekly for 3 weeks of 4 (or 56 mg/m2 with dexamethasone, 70 mg/m2 weekly); intravenous over 10 to 30 minutes.
• Ixazomib 4 mg orally on days 1, 8 and 15 of a 28-day cycle, on an empty stomach, with lenalidomide and dexamethasone.

Differences. Bortezomib causes peripheral neuropathy and herpes zoster; carfilzomib causes cardiovascular events, hypertension and dyspnoea but little neuropathy; ixazomib is convenient with fewer neuropathy and cardiac effects.

• Newly diagnosed myeloma: bortezomib with lenalidomide and dexamethasone (a triplet regimen) or with cyclophosphamide and dexamethasone where lenalidomide is unavailable; with daratumumab if transplant-eligible.
• Relapsed myeloma: carfilzomib or ixazomib-based regimens.
• Mantle cell lymphoma: bortezomib in combination regimens.
• Dexamethasone: 20 mg on the day of and the day after bortezomib (40 mg weekly in older adults).
• Antiviral prophylaxis (mandatory): aciclovir 400 mg twice daily or valaciclovir 500 mg daily throughout and for 3 months after, to prevent herpes zoster.
• Neuropathy dose adjustment (bortezomib): grade 1 with pain or grade 2, reduce to 1.0 mg/m2; grade 2 with pain or grade 3, hold until resolved and restart at 0.7 mg/m2 once weekly; grade 4, stop. Use the subcutaneous route to lower neuropathy risk.
• Carfilzomib safety: hydrate before and after infusion in cycle 1 (250 to 500 mL), control blood pressure, and assess cardiac function in patients with heart disease.
• Regional: generic bortezomib has improved access; ask for funding for full courses.

Selection. Choose by prior neuropathy and cardiac status; tolerance may decide between schedules.

Contraindications. Hypersensitivity to bortezomib, boron or mannitol; intrathecal administration of bortezomib (fatal); pregnancy.

Adverse effects. Peripheral neuropathy, thrombocytopenia (cyclical, recovers before the next cycle), neutropenia, anaemia, nausea, diarrhoea, constipation, fatigue, herpes zoster, orthostatic hypotension, hypertension, heart failure (carfilzomib), pulmonary hypertension, tumour lysis syndrome, and kidney injury (carfilzomib).

Interactions. Strong CYP3A4 inducers (rifampicin, carbamazepine, St John's wort) lower bortezomib exposure; strong inhibitors (ketoconazole, ritonavir) raise it; oral hypoglycaemic agents may need adjustment; antihypertensives need review.

Special groups.

• Pregnancy: contraindicated.
• Breastfeeding: avoid.
• Older adults: use weekly dosing and lower dexamethasone.
• Kidney impairment: no adjustment for bortezomib or carfilzomib; ixazomib 3 mg at creatinine clearance under 30 mL/min.
• Liver impairment: bortezomib starting dose 0.7 mg/m2 in moderate to severe impairment; ixazomib 3 mg.

Monitoring. Full blood count before each dose, neuropathy assessment each visit, blood pressure, liver and renal function, electrolytes, and cardiac assessment with carfilzomib.

Referral and escalation. Grade 3 neuropathy, platelets under 25 x 10^9/L, herpes zoster, heart failure symptoms, and new dyspnoea need urgent review.