Leukemias, lymphomas, and other hematologic cancers:
Indications for: NINLARO
In combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received at least 1 prior therapy.
Limitations of Use:
Not recommended for use in the maintenance setting or in newly diagnosed multiple myeloma in combination with lenalidomide and dexamethasone outside of controlled clinical trials.
The efficacy and safety of Ninlaro in combination with lenalidomide and dexamethasone was evaluated in a randomized, double-blind, placebo-controlled, multicenter study in patients with relapsed and/or refractory multiple myeloma who had received at least one prior line of therapy. Patients who were refractory to lenalidomide or proteasome inhibitors were excluded from the study.
A total of 722 patients were randomized in a 1:1 ratio to receive either the combination of Ninlaro, lenalidomide and dexamethasone (n=360; Ninlaro regimen) or the combination of placebo, lenalidomide and dexamethasone (n=362; placebo regimen) until disease progression or unacceptable toxicity. Randomization was stratified according to the number of prior lines of therapy (1 versus 2 or 3), myeloma International Staging System (ISS) (stage I or II versus III), and previous therapy with a proteasome inhibitor (exposed or naïve).
Patients received Ninlaro 4 mg or placebo 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 a 28-day cycle. Patients with renal impairment received a starting dose of lenalidomide according to its prescribing information. Treatment continued until disease progression or unacceptable toxicities.
The efficacy of Ninlaro was evaluated by progression-free survival (PFS) according to the 2011 International Myeloma Working Group (IMWG) Consensus Uniform Response Criteria as assessed by a blinded independent review committee (IRC) based on central lab results.
At study endpoint, patients treated with the Ninlaro regimen demonstrated statistically significant improvement in PFS vs the placebo regimen (HR 0.74, [95% CI: 0.59, 0.94]; P=0.012). The median PFS for the Ninlaro regimen was 20.6 months vs the placebo regimen at 14.7 months. The median time to response and median duration of response were 1.1 months and 20.5 months in the Ninlaro regimen vs 1.9 months and 15 months in the placebo regimen, respectively.
Swallow whole. Take ≥1hr before or ≥2hrs after food. Initially 4mg once weekly on Days 1, 8, and 15 of a 28-day cycle (give with lenalidomide 25mg daily on Days 1–21 and dexamethasone 40mg on Days 1, 8, 15, and 22). Continue until disease progression or unacceptable toxicity. Moderate or severe hepatic impairment, severe renal impairment, or ESRD on dialysis: initially 3mg. Prior to new cycle, ensure ANC ≥1,000/mm3, platelets ≥75,000/mm3, recovery of non-hematologic toxicities to baseline or Grade ≤1. Consider antiviral prophylaxis to decrease risk of herpes zoster reactivation. Dose modifications: see full labeling.
Thrombocytopenia: monitor platelets at least monthly during treatment; consider more frequently for first 3 cycles. Adjust dose for Grade 3/4 GI symptoms or Grade ≥2 rash. Monitor for peripheral neuropathy; adjust dose if worsens. Adjust dosing of dexamethasone or ixazomib if Grade 3/4 peripheral edema symptoms occur. Discontinue if cutaneous reactions occur (eg, Stevens-Johnson syndrome). Thrombotic microangiopathy (including TTP/HUS). Hepatic impairment; monitor enzymes regularly and adjust for Grade 3/4 symptoms. Severe renal impairment or ESRD. Embryo-fetal toxicity. Advise to use effective non-hormonal contraception (females of reproductive potential) or effective contraception (males w. female partners) during and for 90 days after the last dose. Pregnancy: exclude status prior to initiation. Nursing mothers: not recommended (during and for 90 days after the last dose).
Avoid concomitant strong CYP3A inducers (eg, rifampin, phenytoin, carbamazepine, St. John's Wort). Risk of reduced hormonal contraceptives efficacy with concomitant dexamethasone.
Diarrhea, constipation, thrombocytopenia, peripheral neuropathy, nausea, peripheral edema, vomiting, back pain; rash, hepatotoxicity, herpes zoster, eye disorders.
After administration of a single oral dose of 14C-ixazomib to 5 patients with advanced cancer, 62% of the administered radioactivity was excreted in urine and 22% in the feces. Unchanged ixazomib accounted for <3.5% of the administered dose recovered in urine.
The terminal half-life (t1/2) of ixazomib was 9.5 days.
Generic Drug Availability: