Ixazomib Frontline Triplet Misses PFS Endpoint in Transplant-Ineligible Myeloma

Christopher Arendt, head of the Oncology Therapeutic Area Unit, Takeda

Christopher Arendt

The triplet therapy of ixazomib (Ninlaro), lenalidomide (Revlimid), and dexamethasone showed an improvement in progression-free survival (PFS), but it was not statistically significant, compared with lenalidomide/dexamethasone alone for patients with newly diagnosed multiple myeloma who were ineligible for stem cell transplant, missing the primary endpoint of the phase III TOURMALINE-MM2 trial (NCT01850524).¹

The median PFS with the addition of ixazomib to lenalidomide/dexamethasone was 35.3 months compared with 21.8 months for lenalidomide/dexamethasone alone (HR, 0.83; P = .073), which did not meet the threshold for statistical significance.

The safety profile for ixazomib was found to be consistent with prior studies of the oral proteasome inhibitor. Full findings will be presented at an upcoming medical meeting, Takeda Pharmaceutical Company Limited, the developer of ixazomib, stated in a press release.

“There is a need for treatment options in transplant ineligible patients. We remain committed to advancing the field of multiple myeloma and continue to drive innovation through ongoing research and development,” Christopher Arendt, head of the Oncology Therapeutic Area Unit, Takeda, stated in the press release. “We are confident there will be numerous learnings from this trial and look forward to sharing these data with the community. We want to thank the patients and investigators for their participation in this important program.”

Takeda added that study investigators have been informed of the results and will discuss the potential impact with enrolled patients. It will be up to physician discretion on whether they will continue on the current study treatment.

In the international, randomized, double-blind, multicenter, placebo-controlled, phase III TOURMALINE-MM2 trial, investigators evaluated ixazomib plus lenalidomide/dexamethasone compared with placebo plus lenalidomide/dexamethasone in 705 adult patients with newly diagnosed myeloma who are ineligible for transplant.

For the first 18 cycles, placebo or ixazomib was administered at a single oral dose at 4.0 mg on days 1, 8, 15; lenalidomide was given orally at 25 mg on days 1 to 21, and dexamethasone at 40 mg on days 1, 8, 15, and 22 every 28 days until disease progression or unacceptable toxicity, whichever comes first. After 18 cycles, the doses for ixazomib and lenalidomide will be reduced and dexamethasone will be discontinued.

To be eligible for enrollment, patients must have had newly diagnosed multiple myeloma and did not receive prior treatment, were not eligible for high-dose therapy followed by stem cell transplant, had measurable disease, and had an ECOG performance status of 0 to 2. Those who were diagnosed and had received treatment for another malignancy within 5 years of study treatment or had evidence of residual disease, received anti-thrombotic therapy, or had central nervous system involvement could not enroll on the trial. Additionally, patients could not have had a diagnosis of the following: Waldenström macroglobulinemia, POEMS syndrome, plasma cell leukemia, primary amyloidosis, myelodysplastic syndrome, or myeloproliferative syndrome.

The primary endpoint is PFS; key secondary endpoints include rate of complete response (CR), pain response, and overall survival.

In 2015, the FDA approved ixazomib in combination with lenalidomide and dexamethasone as a treatment for patients with multiple myeloma who have received ≥1 prior therapy. The approval was based on findings from the phase III TOURMALINE-MM1 trial, which showed a median PFS of 20.6 months with ixazomib plus lenalidomide/dexamethasone compared with 14.7 months with lenalidomide/dexamethasone alone (HR, 0.74; P = .01).²

Moreover, the objective response rates were 78% in the ixazomib group and 72% in the placebo group, and the CR plus very good partial response rates were 48% and 39%, respectively. The median time to response on the ixazomib arm was 1.1 months and was 1.9 months on the placebo group; the median duration of response was 20.5 months and 15.0 months, respectively.

Additionally, in the phase III TOURMALINE-MM4 trial, investigators evaluated switch maintenance therapy with ixazomib or placebo, and enrolled patients with multiple myeloma who had completed 6 to 12 months of initial therapy and achieved a partial response or better. Topline results showed that ixazomib demonstrated a significant improvement in PFS as a frontline maintenance treatment compared with placebo in patients with myeloma who had not undergone stem cell transplant.³

References

1. Takeda provides update on TOURMALINE-MM2 phase 3 rrial [news release]: Cambridge, MA, and Osaka, Japan. Takeda Pharmaceutical Company. Published March 10, 2020. https://bwnews.pr/3aJCXlI. Accessed March 10, 2020.
2. Moreau P, Masszi T, Grzasko N, et al. Oral ixazomib, lenalidomide, and dexamethasone for multiple myeloma. N Eng J Med. 2016;374(17):1621-1634. doi: 10.1056/NEJMoa1516282
3. Phase 3 trial of Ninlaro (ixazomib) as first line maintenance therapy met primary endpoint in multiple myeloma patients not treated with stem cell transplantation. Takeda Pharmaceutical Company Limited. Published November 7, 2019. https://bwnews.pr/2JZRdMn. Accessed November 7, 2019.