Adding ixazomib (Ninlaro) to lenalidomide (Revlimid) and dexamethasone reduced the risk of disease progression or death by 26% compared with lenalidomide and dexamethasone alone for patients with relapsed/refractory multiple myeloma, according to findings from a phase III study published in
Findings from the trial, known as TOURMALINE-MM1, were pivotal in the FDA approval of the oral proteasome inhibitor ixazomib in November 2015 for patients with relapsed multiple myeloma. In the trial, median progression-free survival (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;
has published the results of the first phase III study supporting an all-oral triplet regimen containing a proteasome inhibitor in multiple myeloma,” lead investigator Philippe Moreau, MD, University of Nantes, France, said in a statement. “With the emergence of long-term treatment as a preferred approach for multiple myeloma, it is crucial that we investigate more ways to improve treatment sustainability for patients.”
In the study, 722 patients were randomized 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.
A majority of 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). A very good partial response or better was achieved for 48% of those in the ixazomib arm versus 39% in the control (P
= .01). 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. The median time to progression was 21.4 months with ixazomib versus 15.7 months in the control arm (P
In those with high-risk cytogenetics, the median PFS with ixazomib was 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).
At an analysis conducted in July 2015 after a median of 23 months of follow-up, the median overall survival (OS) had not yet been reached in either arm. The primary endpoint of the study was PFS, and the trial was halted upon meeting this endpoint in February 2015. Median OS was not assessed for individual subgroups.
At the 23 month analysis, 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%).
“The TOURMALINE-MM1 results demonstrated that ixazomib in combination with lenalidomide and dexamethasone is an effective and tolerable oral regimen with a manageable safety profile for patients with relapsed and/or refractory multiple myeloma,” said Moreau.
In addition to the MM1 study, the TOURMALINE clinical trial program contains four 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.
“The publication concluded that the addition of ixazomib to lenalidomide and dexamethasone was associated with significantly longer progression-free survival; the additional toxic effects with this all-oral regimen were limited. We look forward to sharing additional ixazomib data from our ongoing TOURMALINE studies over the next few years,” Dixie-Lee Esseltine, MD, vice president, Oncology Clinical Research, Takeda, the developer of ixazomib, said in a statement.
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 (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.