Ninlaro Combo Fails to Halt Progression of Newly Diagnosed Multiple Myeloma, Trial Data Show

Adding Takeda’s Ninlaro (ixazomib) to Revlimid (lenalidomide) and dexamethasone failed to significantly extend life without disease progression in people newly diagnosed with multiple myeloma who are ineligible for autologous stem cell transplant, top-line data from a Phase 3 clinical trial show.

Still, Ninlaro’s triple combination was significantly superior to the Revlimid-dexamethasone combo at promoting profound treatment responses, delaying time to progression, and extending progression-free survival in patients with high-risk cytogenetics (chromosomal abnormalities).

The findings, “Ixazomib Plus Lenalidomide-Dexamethasone (IRd) vs. Placebo-Rd for Newly Diagnosed Multiple Myeloma (NDMM) Patients Not Eligible for Autologous Stem Cell Transplant: The Double-Blind, Placebo-Controlled, Phase 3 TOURMALINE-MM2 Trial,” were presented by Shaji Kumar, MD, a trial investigator with Mayo Clinic, at the Society of Hematologic Oncology (SOHO) 2020 annual meeting, held virtually Sept. 9–12.

“There is a specific need in newly diagnosed multiple myeloma, given there are currently no approved all-oral, proteasome inhibitor-based treatment options,” Thierry Facon, MD, said in a press release. Facon is the trial’s principal investigator and lead author, based at Lille University Hospital in France.

“Findings from the TOURMALINE-MM2 trial are important overall for this patient population as well as across multiple subgroups including patients with high-risk cytogenetics. We hope these data will help inform future research and further progress for the multiple myeloma community,” said Facon.

Ninlaro, an oral proteasome inhibitor, 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, as they need to clear out the toxic products of their overactive metabolism.

As such, by preventing the clearance of this toxic buildup of proteins in cancer cells, Ninlaro is thought to lead to their death. The therapy is currently approved to be used in combination with Revlimid and dexamethasone in previously treated multiple myeloma patients.

The international TOURMALINE-MM2 Phase 3 trial (NCT01850524) evaluated whether such a Ninlaro triple combo was superior to Revlimid and dexamethasone alone in 705 adults newly diagnosed with myeloma.

Participants were assigned randomly to receive either 4 mg of Ninlaro (351 patients) or a placebo (354 patients) once a week, in addition to daily oral Revlimid and once-weekly oral dexamethasone.

Patients’ median age was 73 years in the Ninlaro group and 74 in the placebo group, and chromosomal abnormalities were detected in 38% and 41%, respectively.

The trial’s main goal was to assess patients’ progression-free survival (PFS), or the time until disease worsening or death from any cause. Secondary goals included the proportion of patients achieving a complete response, pain response and use of analgesics, and overall survival.

Results showed that patients on Ninlaro lived a median of 13.5 months longer without disease progression than those given a placebo (35.3 months vs. 21.8 months). However, this 17% reduction in the risk of disease progression or death did not reach statistical significance, meaning the trial failed to meet its primary goal.

However, the Ninlaro triple combo was significantly better than the double combo at extending PFS among patients with high-risk cytogenetics (23.8 months vs. 18.0 months). The triple combo also significantly extended time to progression, compared with the double combo (45.8 months vs. 26.8 months).

Compared with the placebo group, patients on Ninlaro showed significantly stronger responses to treatment, including complete responses (26% vs. 14%) and very good partial responses or better (63% vs. 48%).

Overall survival had not been reached for either group after a median of four-and-a-half years, meaning that more than half of the patients were still alive at that time.

The safety of the triple combo was generally consistent with its well-known safety profile; diarrhea, rash, swelling in lower legs or hands, constipation, and nausea as the most common adverse events (side effects).

Compared with those given the double combo, a slightly higher proportion of patients on the triple combo reported adverse events (96.6% vs. 92.6%) and severe adverse events (88.1% vs. 81.4%).

Treatment discontinuation due to adverse events occurred in 35% of patients in the Ninlaro group and in 26.9% of those in the placebo group. A total of 7.6% patients given the triple combo died during the study, compared with 6.3% of patients treated with the double combo.

The Ninlaro combo “demonstrated a strongly positive trend in PFS, improved [time to progression] and [complete response] rate, and improved the poor PFS associated with high-risk cytogenetics, as seen in the TOURMALINE-MM1 study … in relapsed/refractory [multiple myeloma],” the researchers wrote in the abstract.

Adding Ninlaro to Revlimid and dexamethasone “is a feasible treatment option for certain transplant-ineligible patients who could benefit from an all-oral triplet combination,” the team concluded.

Paul Giusti, president and CEO of the Multiple Myeloma Research Foundation, said that “insights from studies like TOURMALINE-MM2 are important, especially to those patients who may benefit from the convenience of treatment options that can be taken at home.”

“We hope the findings from the TOURMALINE-MM2 trial will encourage constructive conversations and help progress future research efforts, particularly for patients who could benefit from an all-oral, proteasome inhibitor-based combination that helps preserve quality of life,” said Christopher Arendt, PhD, head of Takeda’s oncology therapeutic area unit.

“As a company, we remain committed to the multiple myeloma community and look forward to sharing mature data from our ongoing Phase 3 multiple myeloma maintenance studies in the future,” Arendt said.

To date, results from the ongoing TOURMALINE-MM3 (NCT02181413) and TOURMALINE-MM4 (NCT02312258) Phase 3 trials showed that first-line maintenance therapy with Ninlaro significantly delayed disease progression in patients either undergoing or not autologous stem cell transplant as part of their initial therapy.