ORLANDO, Fla. — The addition of the oral proteasome inhibitor ixazomib to lenalidomide and dexamethasone significantly prolonged PFS without increasing toxicity among patients with relapsed and/or refractory multiple myeloma, according to phase 3 study results presented at the ASH Annual Meeting and Exposition.
Further, the triplet regimen may confer favorable outcomes even among high-risk patients with genetic alterations, according to the researchers.
“This all-oral regimen may become one of the new standards of care in the relapse setting of multiple myeloma,” Philippe Moreau, MD, head of hematology at University of Nantes in France, said during a press conference. “It has a very safe profile. It is a very effective combination, and it is simple and convenient.”
Ixazomib (Ninlaro, Takeda Pharmaceuticals) is the first orally administered proteasome inhibitor studied in a clinical setting. A previous phase 1/2 study that evaluated the safety and efficacy of triplet therapy with ixazomib, lenalidomide (Revlimid, Celgene) and dexamethasone yielded a 90% overall response rate in 65 patients with newly diagnosed multiple myeloma.
Thus, Moreau and colleagues conducted a randomized, controlled, double blind phase 3 study to evaluate the oral triplet’s efficacy in patients with relapsed and/or refractory disease.
The study enrolled 722 patients (median age, 66 years; range, 30-91) with relapsed and/or refractory multiple myeloma who had one to three prior lines of therapy, who were not refractory to lenalidomide or proteasome inhibitor-based therapy.
Seventy percent of patients had previous treatment with a proteasome inhibitor and 59% of patients received one prior line of therapy. Prior therapies included bortezomib (Velcade, Millennium/Takeda; 69%), thalidomide (Thalomid, Celgene; 45%) and lenalidomide (12%).
Further, 19% of patients had high-risk cytogenetics confirmed by fluorescent in situ hybridization.
The researchers randomly assigned patients to a 28-day treatment cycle of lenalidomide (25 mg, days 1 through 21) and dexamethasone (40 mg, days 1, 8, 15 and 22) with 4 mg ixazomib (n = 360) or placebo (n = 362) on days 1, 8 and 15. Patients repeated treatment cycles until disease progression or unacceptable toxicity.
PFS served as the primary endpoint. OS in the entire cohort and OS in high-risk patients served as secondary endpoints.
The overall response rate appeared significantly higher in the ixazomib arm (78.3% vs. 71.5%; P = .035). More patients on the ixazomib arm achieved a complete response (11.7% vs. 6.6%; OR = 1.87; P = .019) and a very good partial response (48.1% vs. 39%; OR = 1.45; P = .014).
Median time to first response was 1.1 months in the ixazomib arm and 1.9 months on the placebo arm.
Patients assigned ixazomib achieved significantly longer PFS than patients assigned placebo (20.6 months vs. 14.7 months; HR = 0.74; 95% CI, 0.58-0.93).
Patients with high-risk cytogenetics assigned ixazomib achieved a similar HR for PFS as the overall active agent arm (HR = 0.543), indicating that ixazomib may overcome certain negative implications of cytogenetic alterations.
OS data were not mature at time of presentation.
Patients in both arms received a similar median number of treatment cycles (ixazomib, n = 13; placebo, n = 12). Fifty-five percent of patients assigned ixazomib and 52% of patients assigned placebo remained on treatment at time of reporting.
Sixty-eight percent of patients assigned ixazomib and 61% of patients assigned placebo experienced grade 3 or worse adverse events, which were primarily driven by thrombocytopenia. Similar rates of serious adverse events (40% vs. 44%), study discontinuation due to adverse events (13% vs. 11%) and death while on treatment (3% vs. 5%) occurred between the two groups.
Adverse events observed in patients assigned ixazomib were consistent with the drug’s reported safety profile. Common grade 3 or higher adverse events that occurred on the ixazomib and placebo arms included neutropenia (19% vs. 16%), anemia (9% vs. 13%), thrombocytopenia (13% vs. 5%) and pneumonia (6% vs. 8%).
Reported gastrointestinal adverse events included diarrhea (42% vs. 36%; ≥ grade 3, 6% vs. 2%), nausea (26% vs. 21%; ≥ grade 3, 2% vs. 0%) and vomiting (22% vs. 11%; ≥ grade 3, 1% vs. > 1%).
Other observed adverse events included peripheral neuropathy (28% vs. 21%; ≥ grade 3, 2% vs. 2%), rash events (35% vs. 21%; ≥ grade 3, 4% vs. 1%), renal failure (4% vs. 6%; ≥ grade 3, 2% vs. 3%) and heart failure (4% vs. 3%; ≥ grade 3, 2% vs. 2%).
“Ixazomib was approved by the FDA on November 20, 2015, under the trade name Ninlaro,” Moreau said. – by Cameron Kelsall
Moreau P, et al. Abstract 727. Presented at: ASH Annual Meeting and Exposition; Dec. 5-8, 2015; Orlando, Fla.
Disclosure: Moreau reports honoraria from and advisory roles with Bristol-Myers Squibb, Celgene, Janssen-Cilag, Millennium Pharmaceuticals and Novartis. Please see the abstract for a list of all other researchers’ relevant financial disclosures.