Ixazomib in Previously Treated Multiple Myeloma


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Ixazomib for Multiple Myeloma

In the Clinic provides overviews of novel oncology agents, addressing indications, mechanisms, administration recommendations, safety profiles, and other essential information needed for the appropriate clinical use of these drugs.

On November 20, 2015, ixazomib (Ninlaro) was approved by the U.S. Food and Drug Administration (FDA) for use in combination with lenalidomide (Revlimid) and dexamethasone for the treatment of patients with multiple myeloma who have received at least one prior therapy.1,2 Ixazomib is the first FDA-approved oral proteasome inhibitor.

Supporting Efficacy Data

Approval was based on improvement in progression-free survival in a phase III double-blind trial.2 In the trial, 722 patients who had received one to three prior lines of therapy were randomly assigned to receive ixazomib at 4 mg (n = 360) or placebo (n = 362) on days 1, 8, and 15 plus lenalidomide (25 mg) on days 1 through 21 and dexamethasone (40 mg) on days 1, 8, 15, and 22 of 28-day cycles until disease progression or unacceptable toxicity.

Patients had a median age of 66 years, 56% to 58% were male, 83% to 86% were white, 87% to 88% had stage I or II disease, 60% to 62% had one prior line of therapy, 77% had relapsed disease, 23% had light chain disease and 12% had free light chain measurable–only disease, and 17% to 21% had del(17), t(4;14) or t(14;16) and 9% to 10% had del(17). Prior treatments included bortezomib (Velcade, 69%), melphalan (80%–81%), thalidomide (Thalomid, 44%–47%), lenalidomide (12%), and stem cell transplantation (55%–59%).

Median progression-free survival was 20.6 months (95% confidence interval [CI] = 17.0 months to not estimable) in the ixazomib group vs 14.7 months (95% CI = 12.9–17.6 months) in the placebo group (hazard ratio = 0.74, P = .012). The overall response rate was 78% vs 72%, including a complete response in 12% vs 7%.

How It Works

Ixazomib is a reversible proteasome inhibitor that preferentially binds and inhibits the chymotrypsin-like activity of the beta 5 subunit of the 20S proteasome. It induces apoptosis of multiple myeloma cell lines in vitro and exhibits cytotoxicity against myeloma cells from patients relapsing after multiple prior therapies including bortezomib, lenalidomide, and dexamethasone.

The combination of ixazomib and lenalidomide showed synergistic cytotoxic effects in multiple myeloma cell lines. The agent has shown antitumor activity in a mouse multiple myeloma tumor xenograft model.

How It Is Used

The recommended starting dose of ixazomib is 4 mg orally once a week on days 1, 8, and 15 of a 28-day treatment cycle. The recommended starting dose of lenalidomide is 25 mg/d on days 1 to 21 and the recommended starting dose of dexamethasone is 40 mg/d on days 1, 8, 15, and 22.

Prior to initiating a new cycle of therapy, absolute neutrophil count should be ≥ 1,000/mm3, platelet count ≥ 75,000/mm3, and nonhematologic toxicities should, at the physician’s discretion, generally be recovered to baseline condition or grade ≤ 1. Ixazomib dose reduction should be to 3 mg for first reduction and to 2.3 mg for the second reduction, with discontinuation thereafter.

For decrease in platelet count to < 30,000/mm3 or neutrophil count to < 500/mm3, ixazomib and lenalidomide should be withheld until recovery back to these levels, with granulocyte colony-stimulating factor considered for neutropenia. With recovery, lenalidomide should be resumed at its next lowest dose (according to its prescribing information) and ixazomib at its most recent dose.

For first recurrence, both drugs should be withheld until recovery and lenalidomide resumed at its most recent dose and ixazomib at its next lowest dose. For additional recurrences, dose modifications of lenalidomide and ixazomib should be alternated.

For grade 2 or 3 rash, lenalidomide should be withheld until recovery to grade ≤ 1 and then resumed at the next lower dose. For recurrence, ixazomib and lenalidomide should be withheld until recovery to grade ≤ 1, with ixazomib resumed at the next lower dose and lenalidomide at the most recent dose.

For peripheral neuropathy of grade 1 with pain or grade 2, ixazomib should be withheld until recovery to grade ≤1 and resumed at the most recent dose. For peripheral neuropathy of grade 2 with pain or grade 3 and for other nonhematologic grade 3 or 4 reactions, ixazomib should be withheld and toxicities should, at the physician’s discretion, generally be recovered to baseline condition or grade ≤ 1 before resuming ixazomib; ixazomib can be resumed at the next lowest dose.

Treatment should be discontinued for grade 4 rash or peripheral neuropathy.

Concomitant administration with strong CYP3A inducers (eg, rifampin, phenytoin, carbamazepine, and St. John’s Wort) should be avoided. The starting dose of ixazomib should be reduced to 3 mg in patients with moderate or severe hepatic impairment and in patients with severe renal impairment or end-stage renal disease requiring dialysis. Ixazomib is not dialyzable and can be administered without regard to the timing of dialysis.

Safety Profile

In the phase III trial, the most common adverse events of any grade occurring with a frequency ≥ 5% higher in the ixazomib group were diarrhea (42% vs 36%, grade 3 in 6% vs 2%), constipation (34% vs 25%, grade 3 in < 1% vs < 1%), peripheral neuropathy (28% vs 21%, grade 3 in 2% vs 2%), nausea (26% vs 21%, grade 3 in 2% vs 0%), peripheral edema (25% vs 18%, grade 3 in 2% vs 1%), vomiting (22% vs 11%, grade 3 in 1% vs < 1%), back pain (21% vs 16%, grade 3 in < 1% vs 3%), and rash (19% vs 11%, grade 3 in 3% vs 1%). Any grade thrombocytopenia and neutropenia occurred in 78% vs 54% and 67% vs 66% and was of grade 3 or 4 in 26% vs 11% and 26% vs 30%.

The most common serious adverse events in ixazomib patients were thrombocytopenia (2%) and diarrhea (2%). Eye disorders occurred in 26% of the ixazomib group vs 16% of the placebo group (grade 3 in 2% vs 1%), with the most common being blurred vision (6% vs 3%), dry eye (5% vs 1%), and conjunctivitis (6% vs 1%).

Serious adverse reactions reported at a frequency of < 1% in patients receiving ixazomib outside of the phase III trial include acute febrile neutrophilic dermatosis (Sweet’s syndrome), Stevens-Johnson syndrome, transverse myelitis, posterior reversible encephalopathy syndrome, tumor lysis syndrome, and thrombotic thrombocytopenic purpura.

Ixazomib carries warnings/precautions for thrombocytopenia, gastrointestinal toxicity, peripheral neuropathy, peripheral edema, cutaneous reactions, hepatotoxicity, and embryofetal toxicity. Platelet counts should be monitored at least monthly during treatment, and hepatic enzymes should be monitored during treatment. Women of reproductive potential should be advised of the potential risk to a fetus and to use effective contraception. ■

References

1. U.S. Food and Drug Administration: Ixazomib. Available at www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm473804.htm. Accessed December 2, 2015.

2. Ninlaro (ixazomib) capsules prescribing information, Millennium Pharmaceuticals, Inc, November 2015. Available at www.accessdata.fda.gov/drugsatfda_docs/label/2015/208462lbl.pdf. Accessed December 2, 2015.



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