Patients with relapsed/refractory multiple myeloma showed a 26 percent reduced risk of disease progression and even death with the addition of Ninlaro (ixazomib) to Revlimid (lenalidomide) and dexamethasone, according to findings from a phase 3 study published in The New England Journal of Medicine (NEJM).
Findings from the trial, known as TOURMALINE-MM1, were pivotal in the FDA approval of the oral proteasome inhibitor Ninlaro in November 2015 for patients with relapsed multiple myeloma. In the trial, median progression-free survival (PFS) with the Ninlaro triplet was 20.6 months compared with 14.7 months with Revlimid and dexamethasone alone.
“NEJM has published the results of the first phase 3 study supporting an all-oral triplet regimen containing a proteasome inhibitor in multiple myeloma,” lead investigator Philippe Moreau, 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 Revlimid and dexamethasone with placebo (362 patients) or Ninlaro (360 patients). Ninlaro was given orally at four mg on days one, eight, and 15 of a 28-day cycle. Patients received oral Revlimid at 25 mg on days one to 21 and dexamethasone was administered orally at 40 mg on days one, eight, 15 and 22.
The median age of patients was 66 years, and 12 percent had ISS stage 3 disease at baseline. The ECOG PS was primarily one or two (94 percent). The median creatinine clearance was 78.4 ml/min and 19 percent of patients had high-risk cytogenetics, including 10 percent with del17p.
A majority of patients had received one prior therapy (61 percent), with 10 percent having received three. Overall, 57 percent of patients had received prior stem cell transplantation, 77 percent had relapsed multiple myeloma, and 12 percent were both relapsed and refractory. Prior therapies included Velcade (bortezomib) (69 percent), thalidomide (45 percent), and Revlimid (12 percent). Twenty-three percent of patients had disease that was refractory to prior immunomodulatory agents.
The overall response rate was 78.3 percent with the Ninlaro triplet versus 71.5 percent in the control arm. A very good partial response or better was achieved for 48 percent of those in the Ninlaro arm versus 39 percent in the control. The complete response rate with the proteasome inhibitor was 12 percent versus 7 percent with placebo. The median duration of response was 20.5 months with Ninlaro versus 15.0 months in the control arm. The median time to progression was 21.4 months with Ninlaro versus 15.7 months in the control arm.
In those with high-risk cytogenetics, the median PFS with Ninlaro was 21.4 months versus 9.7 months in the control arm. Specifically for those with del17p (69 patients), the median PFS was 21.4 versus 9.7 months, with and without Ninlaro, respectively. In patients with t(4;14) without del17p or t(14;16), the median PFS with Ninlaro was 18.5 versus 12.0 months in the control.
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 Ninlaro arm versus the control group, respectively, were diarrhea (45 percent vs 39 percent), rash (36 percent vs 23 percent), constipation (35 percent vs 26 percent), neutropenia (33 percent vs 31 percent), thrombocytopenia (31 percent vs 16 percent), anemia (29 percent vs 27 percent), nausea (29 percent vs 22 percent) and back pain (24 percent vs 17 percent), vomiting (23 percent vs 12 percent).
AEs traditionally associated with proteasome inhibition were generally mild. Peripheral neuropathy occurred in 27 percent of patients treated with Ninlaro versus 22 percent with placebo; however, the rates of grade 3 AEs were similar in both arms, at 2 percent. Similar findings were seen for peripheral edema, with an all-grade rate of 28 percent and 20 percent and a grade 3 rate of 2 percent and 1 percent, with and without Ninlaro, respectively.
Fewer cases of acute renal failure were seen with Ninlaro (9 percent vs 11 percent). Cardiac events were similar between the arms, with heart failure experienced by 4 percent of patients in both arms. Thromboembolism was less common with Ninlaro (8 percent vs 11 percent).
“The TOURMALINE-MM1 results demonstrated that Ninlaro in combination with Revlimid 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 3 studies that are exploring Ninlaro. In the MM2 trial, the combination of Ninlaro, Revlimid, and dexamethasone is being explored in newly diagnosed patients with multiple myeloma. The MM3 and MM4 studies are investigating maintenance therapy with Ninlaro in patients who have or have not undergone an autologous stem cell transplant.
“The publication concluded that the addition of Ninlaro to Revlimid 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 Ninlaro data from our ongoing TOURMALINE studies over the next few years,” Dixie-Lee Esseltine, vice president, Oncology Clinical Research, Takeda, the developer of Ninlaro, said in a statement.