Ninlaro Maintenance Therapy Improves Survival in Patients Not Given ASCT, Trial Shows

First-line maintenance therapy with Ninlaro (ixazomib) significantly delays disease progression or death in adults with multiple myeloma who had not been initially treated with an autologous stem cell transplant (ASCT), according to data from a Phase 3 trial.

“There is a strong need for additional maintenance treatments for multiple myeloma, where currently approved options are limited,” Meletios Dimopoulos, MD, the trial’s principal investigator, and a professor and chairman of the department of clinical therapeutics at the University of Athens School of Medicine, said in a press release.

“These data could be highly impactful for those who currently have limited options, which is often the case with patients not eligible for a stem cell transplant,” he added.

The results were recently revealed in an oral presentation, “Ixazomib vs placebo as post-induction maintenance therapy in newly diagnosed multiple myeloma (NDMM) patients (pts) Not undergoing autologous stem cell transplant (ASCT): Phase 3 TOURMALINE-MM4 trial,” at the 25th European Hematology Association Annual Congress, held virtually due to the COVID-19 pandemic.

Ninlaro, an oral proteasome inhibitor marketed by Takeda, works by blocking the activity of proteasomes, cellular complexes that break down unnecessary or faulty proteins inside cells.

Myeloma cells are more dependent on proteasomes than normal cells, which help them clear out the toxic products of their overactive metabolism. By preventing the clearance of this toxic buildup of proteins in cancer cells, Ninlaro is thought to lead to the death of these cells.

Ninlaro is currently approved to be used in combination with Revlimid (lenalidomide) and dexamethasone in previously treated multiple myeloma patients.

The global TOURMALINE-MM4 Phase 3 trial (NCT02312258) is evaluating the safety and effectiveness of Ninlaro as a first-line maintenance therapy in 706 adults newly diagnosed with multiple myeloma who were ineligible for or did not want to undergo ASCT.

Participants, who had to have achieved at least a partial response to first-line induction therapy, were randomly assigned to receive either a 3 or 4 mg capsule of Ninlaro (425 patients) or a placebo (281 patients) on days 1, 8, and 15 of each 28-day cycle, for up to two years.

Patients in both groups were of similar median age (72 vs. 73 years old in the control group) and other clinical features, including proportion of patients with advanced disease (35% vs. 36%), and those receiving a proteasome inhibitor (83% vs. 82%) or an immunomodulatory therapy (32% vs. 33%) during induction therapy.

The trial’s primary goal was to assess patients’ progression-free survival (PFS), or the time they lived until disease worsening or death from any cause. Key secondary goals included overall survival and safety.

At a median follow-up of 21.1 months, results showed that Ninlaro-treated patients lived significantly longer without disease worsening (17.4 months) than those receiving a placebo (9.4 months), meeting the study’s main goal. This corresponded to a 34% lower risk of progression or death in patients treated with Ninlaro, compared with those in the placebo group.

This PFS benefit was observed across all predefined subgroups, stratified by induction therapy response, disease stage at enrollment, age, and prior treatment with or without a proteasome inhibitor or immunomodulatory therapy.

In particular, Ninlaro significantly lowered the risk of disease progression or death by 60% among patients not previously treated with a proteasome inhibitor (median 24.1 vs 7.7 months in the placebo group) and by 41% among those achieving complete or very good partial responses to induction therapy (median 25.6 vs 12.9 months in the placebo group).

Median overall survival had not been reached in either group, meaning that more than half of the patients were still alive; follow-up is ongoing.

Ninlaro’s safety profile was consistent with that reported in previous studies, with no new safety concerns. The therapy was generally well-tolerated, with most adverse events being mild to moderate in severity.

The most common adverse events occurring more frequently in the Ninlaro group compared with the placebo group included nausea (27% vs. 8%), vomiting (24% vs. 4%), and diarrhea (23% vs. 12%).

Treatment discontinuation due to adverse events was considered low — 12.9% among Ninlaro-treated patients and 8% in the placebo group — and the rate of new malignancies was 5.2% vs. 6.2% in the placebo group. Deaths during the study were observed in 2.6% of patients receiving Ninlaro and 2.2% of those on a placebo.

“Data from this Phase 3 clinical trial reinforce the role of proteasome inhibition as a maintenance therapy and suggest that longer duration of therapy can improve a response, in addition to extending it,” Dimopoulos said.

At the annual the meeting, Takeda also presented positive data from the U.S.-based, real-world US MM-6 Phase 4 trial (NCT03173092), showing that transitioning from Velcade (bortezomib)-based therapy to an all oral Ninlaro-based regimen increased the overall response rate in newly diagnosed multiple myeloma patients not eligible for ASCT. Velcade is a proteasome inhibitor given directly into the bloodstream.

Altogether, these data add to the body of evidence suggesting that Ninlaro “could be an effective, tolerable and convenient medicine for patients with multiple myeloma that allows for an increased duration of treatment with proteasome inhibitors resulting in better outcomes,” said Christopher Arendt, PhD, Takeda’s head of the oncology therapeutic area unit.