An all orally administered treatment regimen containing ixazomib, lenalidomide, and dexamethasone showed a 5.9-month improvement in progression-free survival compared with lenalidomide and dexamethasone alone for patients with relapsed/refractory multiple myeloma.
Philippe Moreau, MD
An all orally administered regimen containing ixazomib (Ninlaro), lenalidomide (Revlimid), and dexamethasone showed a 5.9-month improvement in progression-free survival (PFS) compared with lenalidomide and dexamethasone alone for patients with relapsed/refractory multiple myeloma, according to data presented at the 2015 ASH Annual Meeting.
In the phase III trial, labeled TOURMALINE-MM1, median PFS was 20.6 months with the ixazomib triplet compared with 14.7 months with lenalidomide and dexamethasone. The objective response rate (ORR) was 78.3% with ixazomib versus 71.5% for the doublet therapy (P = .035).
“Ixazomib, when combined with len/dex in patients with refractory myeloma, was associated with a significant and meaningful improvement in progression-free survival, improved time to progression, and response rate, as well,” lead investigator Philippe Moreau, MD, head of the Hematology Department, University of Nantes, France, said at the ASH meeting. “This all-oral treatment regimen may become one of the new standards of care in the relapsed setting, as a very effective combination that is safe and convenient.”
On November 20, 2015, the FDA approved the ixazomib triplet regimen based on data from the TOURMALINE-MM1 trial, which was halted in February 2015 after showing early improvements in the primary endpoint of PFS. Secondary endpoints of the study included ORR, safety, and overall survival, which was not yet mature at the time of the analysis. The ASH talk represents the first presentation of the pivotal data.
In the study, 722 patients were randomized to receive lenalidomide and dexamethasone alone (n = 362) or with ixazomib (n = 360). Ixazomib was given orally at 4 mg on days 1, 8, and 15. Lenalidomide was dosed orally 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 all had a creatinine clearance of ≥30 mL/min. Overall, 88% of patients were ISS stage I/II and 19% had high-risk cytogenetics by FISH. A majority of patients (59%) had received 1 prior therapy, with 77% having relapsed multiple myeloma. Prior therapies included bortezomib (69%), thalidomide (45%), and lenalidomide (12%).
After a median follow-up in the ixazomib arm of 14.8 months, there was a 35% reduction in the risk of progression or death with ixazomib (HR, 0.742; 95% CI, 0.587—0.939; P = .012). At 15 months post randomization, 26.4% of patients remained alive and progression-free in the ixazomib arm versus 19.6% in the control group. The median time to progression was 21.4 versus 15.7 months, with and without ixazomib, respectively (HR, 0.712; P = .007).
For those with high-risk cytogenetics, the benefit with ixazomib was more pronounced, with a 46% improvement in PFS (HR, 0.54). Median PFS was similar in those with high-risk cytogenetics compared with the full population.
“Patients with poor cytogenetics had an identical benefit,” said Moreau. “The groups of patients with high-risk cytogenetics are enjoying exactly the same PFS as those with standard cytogenetics. This is an important point to keep in mind.”
The odds ratio (OR) for the improvement in ORR seen with ixazomib was 1.44 (P = .035). The rate of very good partial response or better was 48.1% versus 39.0%, with and without ixazomib, respectively (OR, 1.45; P = .014). The complete response rate with ixazomib was 11.7% versus 6.6% with the doublet (OR, 1.87; P = .019).
The median time to response was quicker with ixazomib (1.1 vs 1.9 months). Additionally, the duration of response was nearly 5 months longer with the proteasome inhibitor (20.5 vs 15.0 months). At the time of the analysis, half of patients remained on treatment (55% vs 52%).
“Responses were very quick with the triplet combination,” said Moreau. “The median duration of response and the median treatment duration were significantly increased.”
The analysis for safety was conducted after a median follow-up of 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%), thrombocytopenia (13% vs 16%), nausea (29% vs 22%), vomiting (23% vs 12%), and back pain (24% vs 17%).
AEs traditionally associated with proteasome inhibition were generally mild. Peripheral neuropathies 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 1%, with and without ixazomib, respectively.
“When looking at the toxicity of the triplet combination, we immediately notice that versus placebo there were very few grade 3/4 toxicities,” said Moreau. “Rash was not an issue with ixazomib. We had some concerns in phase I, but in combination with dexamethasone we have only 5% of grade 3 and no grade 4 rash.”
Fewer cases of renal failure were seen with ixazomib (4% vs 6%). Cardiac events were similar between the arms. Heart failure was seen in 4% of patients treated with ixazomib versus 3% without the agent. Grade ≥3 cardiac failure was the same between each arm (2%). Rates of thromboembolism and neutropenia were similar between each arm.
“There's a higher number of thrombocytopenia in the ixazomib arm but this did not impact the number of transfusions and did not impact the number of severe bleedings, as well,” said Moreau. “There was no peripheral neuropathy with this oral proteasome inhibitor and no increase in deep vein thrombosis. It is a very safe profile for the triplet combination.”
In addition to the MM1 study, the TOURMALINE clinical trial program contains four other phase III studies. 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.
Moreau P, Masszi T, Grzasko N, et al. Ixazomib, an Investigational Oral Proteasome Inhibitor (PI), in Combination with Lenalidomide and Dexamethasone (IRd), Significantly Extends Progression-Free Survival (PFS) for Patients (Pts) with Relapsed and/or Refractory Multiple Myeloma (RRMM): The Phase 3 Tourmaline-MM1 Study (NCT01564537). Presented at: 57th American Society of Hematology Annual Meeting; Orlando, Florida; December 5-8, 2015. Abstract 727.