- Drug class: Second-generation proteasome inhibitor.
- Mechanism of action:
- Irreversibly binds to the 20S proteasome (chymotrypsin-like activity).
- Inhibits degradation of ubiquitinated proteins → protein accumulation → apoptosis of malignant plasma cells.
Indications (FDA/EMA approved):
- Relapsed/refractory multiple myeloma:
- Monotherapy or in combination with dexamethasone.
- In combination with lenalidomide + dexamethasone (KRd).
- In combination with daratumumab or isatuximab + dexamethasone (Dara-Kd / Isa-Kd).
Dosing (IV only):
- Dose depends on regimen:
- Once weekly dosing: 70 mg/m² IV over 30 min, Days 1, 8, 15 of 28-day cycle.
- Twice weekly dosing: 20 mg/m² IV Day 1, then escalate to 27–56 mg/m² IV over 10–30 min on Days 1, 2, 8, 9, 15, 16 of 28-day cycle.
- Pre- and post-hydration recommended to reduce risk of renal/cardiac toxicity.
- Dexamethasone premedication (to reduce infusion reaction).
Key adverse effects:
- Cardiac toxicity: Heart failure, ischemia, arrhythmias, hypertension.
- Pulmonary: Dyspnea, pulmonary hypertension.
- Hematologic: Thrombocytopenia, anemia, neutropenia.
- Renal toxicity: AKI (especially early cycles).
- Infusion-related reactions.
- Other: Fatigue, diarrhea, fever.
Pharmacist notes / Monitoring:
- Cardiac monitoring: Assess baseline cardiac history, monitor BP, EF if high risk.
- Renal function: Check before each cycle, adjust dose for toxicity (not strictly for baseline CrCl).
- CBC: Monitor for cytopenias.
- Hydration: 250–500 mL IV before dose (caution in CHF).
- Antiviral prophylaxis (e.g., acyclovir) recommended for herpes zoster prevention.
Exam/clinical highlights:
- Target: 20S proteasome (irreversible inhibitor).
- Use: Relapsed/refractory MM in multiple combinations.
- Toxicities: Cardiac (HF, HTN), renal, cytopenias → distinguish from bortezomib (neuropathy).
- Supportive care: Hydration, dex premedication, antiviral prophylaxis.