Oncology Products, said, “As we learn more about the underlying biology of multiple myeloma, we are encouraged to see the development of new ways to treat this disease. Today’s approvalprovides patients with a new oral treatment that slows disease progression when other therapy has failed.”
Mechanism of Action
Ixazomib is a reversible proteasome inhibitor that preferentially binds to the beta subunit of the S proteasome and inhibits its chymotrypsin-like activity.Based on in vitro studies, ixazomib induces apoptosis of multiple myeloma cell lines.
It was also cytotoxic against myeloma cells from patients whose disease relapsed after previous therapies, including bortezomib, lenalidomide, and dexamethasone.
Dosing and Administration
The recommended starting doses of each component of the 28-day regimen are ixazomib 4 mg once weekly on days and ; lenalidomide 25 mg once daily on days through ; and dexamethasone 40 mg once weekly on days 1, 8, 15, and 22.
The recommended starting dose of ixazomib in patients with moderate or severe hepatic impairment, severe renal impairment, or end-stage renal disease requiring dialysis is 3 mg.
Ixazomib should be taken on the same day of the week and at approximately the same hour of the day. Ixazomib should be taken at least hour before or at least hours after eating. The capsule should be swallowed with water and should not be crushed, chewed, or opened.
If a dose of ixazomib is delayed or missed, the dose should be taken only if the next scheduled dose is ≥72 hours away. The patient should not take a double dose of ixazomib to account for the missed dose. Overall, capsule strengths are available for ixazomib—4mg, 3mg, and 2.3mg.
Clinical Trials
TOURMALINE-MM1
TOURMALINE-MM1, a multinational, randomized, double-blind study, compared ixazomib plus lenalidomide and dexamethasone versus placebo plus lenalidomide and dexamethasone in patients with multiple myeloma whose disease progressed during or after to previous therapies.Overall, 722 patients were randomized in a ratio to the active triple-drug regimen or to placebo plus lenalidomide and dexamethasone until disease progression or until unacceptable toxicity.
The treatment cycles were repeated every 28 days in both study arms. Randomization was stratified according to the number of previous lines of therapy (1 vs 2 or 3), myeloma International Staging System (stage I or II vs stage III), and previous therapy status with a proteasome inhibitor (exposed vs not exposed).
The primary efficacy end point in TOURMALINE-MM1 was PFS according to the 2011 International Myeloma Working Group Consensus Uniform Response Criteria.The response assessments were conducted every weeks until disease progression.
Demographic and baseline characteristics were similar between the treatment arms. The patients’ median age was 66 years.
The majority (87%) of patients who received ixazomib plus lenalidomide and dexamethasone had stage I or II disease and 62% had received previous therapy for multiple myeloma. Overall, 59% of the patients receiving ixazomib plus lenalidomide and dexamethasone had undergone stem-cell transplantation for multiple myeloma.
The PFS was significantly improved in the active combination arm compared with the placebo arm (Table).The median PFS was 20.6 months among patients receiving the ixazomib-based combination compared with 14.7 months in the placebo a |
