The European Commission has granted a conditional approval to ixazomib (Ninlaro) in combination with lenalidomide and dexamethasone for adult patients with multiple myeloma.
Philippe Moreau, MD
The European Commission has granted a conditional approval to ixazomib (Ninlaro) in combination with lenalidomide and dexamethasone for adult patients with multiple myeloma following at least 1 prior therapy, based on a near 6-month improvement in progression-free survival (PFS) in the phase III TOURMALINE-MM1 study.
In the pivotal study, the median PFS with the ixazomib triplet was 20.6 months compared with 14.7 months with lenalidomide and dexamethasone alone (HR, 0.74; 95% CI, 0.59-0.94;P= .01), according to findings published inThe New England Journal of Medicine. A very good partial response or better was achieved by 48% of those treated with ixazomib versus 39% in the control arm (P= .01).
The conditional approval follows a positive opinion from the Committee for Medicinal Products for Human Use (CHMP), which was granted in September. Under the conditional program, the developer of the oral proteasome inhibitor, Takeda, will be required to submit additional data from ongoing studies to support continued authorization.
"With the approval of Ninlaro by the European Commission, physicians across the region will have the option to prescribe an all-oral triplet regimen to treat patients with multiple myeloma who have received at least one prior therapy," TOURMALINE-MM1 lead investigator Philippe Moreau, MD, head of the Hematology Department at the University Hospital of Nantes, France, said in a statement.
The phase III study randomized 722 patients in a 1:1 ratio to receive lenalidomide and dexamethasone with placebo (n = 362) or ixazomib (n = 360). Ixazomib was given orally at 4 mg on days 1, 8, and 15 of a 28-day cycle. Patients received oral lenalidomide at 25 mg on days 1 to 21 and dexamethasone was administered orally at 40 mg on days 1, 8, 15, and 22.
The median age of patients was 66 years, and 12% had ISS stage III disease at baseline. The ECOG PS was primarily 1 or 2 (94%). The median creatinine clearance was 78.4 ml/min (range, 20-233) and 19% of patients had high-risk cytogenetics, including 10% with del17p.
Most patients had received 1 prior therapy (61%), with 10% having received 3. Overall, 57% of patients had received prior stem cell transplantation, 77% had relapsed multiple myeloma, and 12% were both relapsed and refractory. Prior therapies included bortezomib (69%), thalidomide (45%), and lenalidomide (12%). Twenty-three percent of patients had disease that was refractory to prior immunomodulatory agents.
The overall response rate was 78.3% with the ixazomib triplet versus 71.5% in the control arm (P= .04). The complete response rate with the proteasome inhibitor was 12% versus 7% with placebo (P= .02). The median duration of response was 20.5 months with ixazomib versus 15.0 months in the control arm.
In patients specifically treated with just 1 prior therapy, the median PFS in the ixazomib arm was 20.6 versus 15.9 months with the doublet alone (HR, 0.83). The median PFS in those treated with 2 prior therapies was 17.5 months with ixazomib versus 14.1 months with placebo (HR, 0.75).
"In the TOURMALINE-MM1 study, we saw a clinically meaningful 6-month improvement in progression-free survival with NINLARO, evidence that has supported its approval in Europe," said Moreau. "As a hematologist, I welcome the availability of this treatment to address a devastating disease like multiple myeloma."
At an analysis conducted after 23 months, the most frequently reported all-grade adverse events (AEs) for the ixazomib arm versus the control group, respectively, were diarrhea (45% vs 39%), rash (36% vs 23%), constipation (35% vs 26%), neutropenia (33% vs 31%), thrombocytopenia (31% vs 16%), anemia (29% vs 27%), nausea (29% vs 22%), and back pain (24% vs 17%), vomiting (23% vs 12%).
AEs traditionally associated with proteasome inhibition were generally mild. Peripheral neuropathy occurred in 27% of patients treated with ixazomib versus 22% with placebo; however, the rates of grade 3 AEs were similar in both arms, at 2%. Similar findings were seen for peripheral edema, with an all-grade rate of 28% and 20% and a grade 3 rate of 2% and 1%, with and without ixazomib, respectively.
Fewer cases of acute renal failure were seen with ixazomib (9% vs 11%). Cardiac events were similar between the arms, with heart failure experienced by 4% of patients in both arms. Thromboembolism was less common with ixazomib (8% vs 11%).
"When developing Ninlaro, Takeda Oncology's scientists sought to formulate an efficacious and unique oral proteasome inhibitor with a manageable safety profile," Christophe Bianchi, MD, president, Takeda Oncology, noted in a statement. "Ninlaro delivers the proven efficacy of a proteasome inhibitor in a convenient once-weekly pill that can be taken at home."
In addition to the MM1 study, the TOURMALINE clinical trial program contains 4 other phase III studies that are exploring ixazomib. In the MM2 trial, the combination of ixazomib, lenalidomide, and dexamethasone is being explored in newly diagnosed patients with multiple myeloma. The MM3 and MM4 studies are investigating maintenance therapy with ixazomib in patients who have or have not undergone an autologous stem cell transplant.
"Following the European Commission's approval, we will continue to study Ninlaro in a variety of settings in the hopes that we can bring this medicine to as many of the patients who may benefit from it as possible," said Bianchi.
The primary completion date for the MM3 study is February 2018 (NCT02181413) and the primary completion date for MM2 is June 2018 (NCT01850524). The MM4 study is still recruiting participants, with an enrollment goal of 761. The primary completion date for this study is December 2018 (NCT02312258).
Moreau P, Masszi T, Grzasko N, et al. Oral ixazomib, lenalidomide, and dexamethasone for multiple myeloma.N Engl J Med. 2016;374:1621-1634.
Patients with high-risk cytogenetics had a median PFS with ixazomib of 21.4 months versus 9.7 months in the control arm (HR, 0.54; 95% CI, 0.32-0.92;P= .02). Specifically, for those with del17p (n = 69), the median PFS was 21.4 versus 9.7 months, with and without ixazomib, respectively (HR, 0.60; 95% CI, 0.29-1.24). In patients with t(4;14) without del17p or t(14;16), the median PFS with ixazomib was 18.5 versus 12.0 months in the control (HR, 0.65; 95% CI, 0.25-1.66).