Introduction
Ninlaro (ixazomib) is an oral proteasome inhibitor approved for the treatment of multiple myeloma. It represents the first oral proteasome inhibitor available in clinical practice, offering patients a convenient treatment option that can be administered at home rather than requiring clinic visits for intravenous therapy. Ninlaro is typically used in combination with lenalidomide and dexamethasone for patients who have received at least one prior therapy.
Mechanism of Action
Ixazomib is a reversible proteasome inhibitor that primarily targets the 20S proteasome, specifically the chymotrypsin-like activity. The proteasome is a large protein complex that degrades ubiquitinated proteins, playing a critical role in cellular protein homeostasis. By inhibiting proteasome function, ixazomib causes accumulation of polyubiquitinated proteins, leading to endoplasmic reticulum stress, cell cycle arrest, and ultimately apoptosis (programmed cell death) in malignant plasma cells. This mechanism is particularly effective against multiple myeloma cells due to their high protein synthesis rate and dependence on proteasome function for survival.
Indications
Ninlaro is indicated in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received at least one prior therapy. This approval is based on the results of the TOURMALINE-MM1 phase 3 clinical trial, which demonstrated significant improvement in progression-free survival compared to placebo plus lenalidomide and dexamethasone.
Dosage and Administration
The recommended dosage of Ninlaro is 4 mg taken orally once weekly on days 1, 8, and 15 of a 28-day cycle. The drug should be taken at least one hour before or at least two hours after food. Capsules should be swallowed whole with water and not opened, crushed, or chewed.
Dose Modifications:- Renal impairment: No initial dose adjustment needed for mild or moderate impairment (CrCl ≥30 mL/min). For severe impairment (CrCl <30 mL/min), reduce to 3 mg
- Hepatic impairment: Mild impairment (total bilirubin ≤ULN and AST >ULN, or total bilirubin >1-1.5×ULN) - no adjustment; moderate to severe impairment - reduce to 3 mg
- Hematologic toxicity: Based on platelet count and neutrophil count with specific guidelines for dose holds and reductions
Pharmacokinetics
Absorption: Median Tmax is approximately 1 hour. Administration with food reduces AUC by 28% and Cmax by 69%. Distribution: Mean volume of distribution is 543 L. Protein binding is approximately 99%. Metabolism: Primarily metabolized by multiple CYP isoforms (mainly 3A4, and to a lesser extent 1A2, 2B6, 2C8, 2C9, 2C19, 2D6) and non-CYP enzymes. Elimination: Mean elimination half-life is 9.5 days. Approximately 62% of the dose is excreted in urine (<3.5% as unchanged drug) and 22% in feces.Contraindications
- Hypersensitivity to ixazomib or any component of the formulation
- Concomitant use with strong CYP3A inducers (e.g., rifampin, phenytoin, carbamazepine, St. John's wort)
Warnings and Precautions
Thrombocytopenia: Platelet nadirs typically occur between days 14-21 of each 28-day cycle. Monitor platelet counts at least monthly and more frequently during the first three cycles. Gastrointestinal Toxicity: Diarrhea, constipation, nausea, and vomiting occur commonly. Provide antiemetic, antidiarrheal, and laxative medications as needed. Peripheral Neuropathy: Mostly sensory. Monitor patients for symptoms and manage with dose modifications if needed. Peripheral Edema: Monitor for fluid retention, especially in patients with heart failure. Hepatotoxicity: Drug-induced liver injury, hepatocellular injury, and hepatic steatosis have been reported. Monitor liver enzymes regularly. Pregnancy: May cause fetal harm. Advise women of reproductive potential to use effective contraception.Drug Interactions
Strong CYP3A Inducers: Concomitant use may decrease ixazomib exposure. Avoid combination. Strong CYP3A Inhibitors: May increase ixazomib exposure. Monitor closely and consider dose reduction. Gastric Acid Reducing Agents: Proton pump inhibitors may decrease ixazomib absorption. Separate administration by at least 2 hours.Adverse Effects
Most Common (≥20%): Diarrhea, constipation, thrombocytopenia, peripheral neuropathy, nausea, peripheral edema, vomiting, back pain, fatigue, rash, insomnia Serious Adverse Reactions: Thrombocytopenia, gastrointestinal toxicity, hepatotoxicity, peripheral neuropathy, acute renal failure, interstitial lung disease, peripheral edema, cutaneous reactionsMonitoring Parameters
- Complete blood counts (weekly for first 3 cycles, then monthly)
- Liver function tests (regularly)
- Renal function (baseline and periodically)
- Signs and symptoms of peripheral neuropathy
- Gastrointestinal symptoms
- Fluid status and signs of peripheral edema
- Skin reactions
Patient Education
- Take Ninlaro exactly as prescribed, once weekly on the same day each week
- Take on an empty stomach (at least 1 hour before or 2 hours after food)
- Swallow capsules whole with water; do not open, crush, or chew
- Report any signs of bleeding, bruising, fever, or infection
- Report new or worsening numbness, tingling, or pain in hands or feet
- Maintain adequate hydration and report significant diarrhea or vomiting
- Use effective contraception during treatment and for periods after treatment
- Inform all healthcare providers about all medications being taken, including over-the-counter products and herbal supplements
References
1. Moreau P, Masszi T, Grzasko N, et al. Oral Ixazomib, Lenalidomide, and Dexamethasone for Multiple Myeloma. N Engl J Med. 2016;374(17):1621-1634. 2. Ninlaro (ixazomib) [package insert]. Cambridge, MA: Takeda Pharmaceuticals America, Inc.; 2021. 3. Kumar SK, Berdeja JG, Niesvizky R, et al. Safety and tolerability of ixazomib, an oral proteasome inhibitor, in combination with lenalidomide and dexamethasone in patients with previously untreated multiple myeloma: an open-label phase 1/2 study. Lancet Oncol. 2014;15(13):1503-1512. 4. Richardson PG, Baz R, Wang M, et al. Phase 1 study of twice-weekly ixazomib, an oral proteasome inhibitor, in relapsed/refractory multiple myeloma patients. Blood. 2014;124(7):1038-1046. 5. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Multiple Myeloma. Version 4.2023.