Ixazomib Triplet Fails to Meet Primary End Point of PFS in Myeloma, Despite Improvement

Although the addition of ixazomib (Ninlaro) to lenalidomide (Revlimid) and dexamethasone showed an improvement in progression-free survival in patients with newly diagnosed multiple myeloma who are not candidates for autologous stem cell transplant, it was not determined to be of statistical significance, according to additional data from the phase 3 TOURMALINE-MM2 trial (NCT01850524).1

Results presented during the 2020 Society of Hematology Oncology Virtual Scientific Meeting and in a previous update from the trial showed that the ixazomib triplet led to a median PFS of 35.3 months versus 21.8 months with lenalidomide plus dexamethasone, which translated to a 13.5-month improvement (HR, 0.830; P =.073). However, this did not cross the threshold for statistical significance.

Additional results revealed at the meeting showed that in the subgroup of patients with high-risk cytogenetics, the median PFS was 23.8 months with the addition of ixazomib to lenalidomide/dexamethasone versus 18.0 months with lenalidomide/dexamethasone alone (HR, 0.690).

Other key data highlighted at the meeting included the following:

• The complete response (CR) rate was 26% versus 14% with the triplet and the doublet, respectively.
• At a median follow-up of 57.8 months in the ixazomib arm and 58.6 months in the placebo arm, the median overall survival had not yet been reached in either treatment arm (HR, 0.998).
• The median time-to-progression (TTP) was reported to have been longer with the triplet compared with placebo, at 45.8 months versus 26.8 months, respectively (HR, 0.738).

“Newly diagnosed multiple myeloma patients do not currently have an approved proteasome inhibitor-based, all-oral treatment option," Thierry Facon, MD, principal investigator and lead author of the trial and professor of Hematology in the Department of Hematology at Lille University Hospital told OncLive.

"Insights from trials such as TOURMALINE-MM2 are important, especially to clinicians whose patients may benefit from the convenience of treatment options that can be taken at home," Facon added. "We hope these findings will help inform colleagues as they work toward further progress for the multiple myeloma community."

In the randomized, double-blind, multicenter trial, investigators set out to examine the safety and efficacy of ixazomib combined with lenalidomide and dexamethasone versus lenalidomide and dexamethasone alone in patients with newly diagnosed multiple myeloma who were ineligible to undergo stem cell transplant.

To be eligible to participate, patients had to be 18 years of age or older, have had measurable disease as specified in the study protocol, an ECOG performance status of 0 to 2, have suitable venous access for the study-required blood sampling, have had the ability to take concurrent aspirin at 70 mg to 325 mg daily, and be willing and able to adhere to the study visit schedule.²

If patients received previous treatment for their disease with either a standard-of-care or investigational regimen, if they were diagnosed and treated for another malignancy within 5 years prior to the randomization, or if they were previously diagnosed with another malignancy and showed evidence of residual disease, they were not permitted for inclusion. Moreover, patients could not have undergone major surgery or radiotherapy within 14 days prior to randomization and they could not have central nervous system involvement nor evidence of current uncontrolled cardiovascular conditions.

The primary end point of the trial was PFS, while secondary end points included CR, pain response, OS, and median TTP.

Participants who were randomized to the triplet arm received a single 4.0-mg dose of oral ixazomib on days 1, 8, and 15, a single 25-mg dose of oral lenalidomide on days 1-21, and a single 40-mg dose of oral dexamethasone on days 1, 8, 15, and 22 every 28 days for the first 18 cycles or until disease progression or intolerable toxicity, whichever was experienced first. After cycle 18, patients received a reduced dose of ixazomib plus lenalidomide and dexamethasone was discontinued. Patients on the doublet arm received the same schedule of lenalidomide plus dexamethasone as the experimental arm, without ixazomib.

The toxicity profile of ixazomib in the trial proved to be comparable to what has previously been reported with the agent. Treatment-emergent adverse effects (TEAEs) were reported in 96.6% of those who received the triplet versus 92.6% of those who were given the doublet. The most commonly reported TEAEs determined to be of clinical significance in the investigational arm included diarrhea, rash, peripheral edema, constipation, and nausea. Toxicities that were grade 3 or higher in severity were reported in 88.1% of patients who received the ixazomib triplet versus 81.4% of those who were given placebo.

The majority of these TEAEs were found to be manageable without requiring treatment discontinuation. Thirty-five percent of participants on the ixazomib arm reported TEAEs that resulted in discontinuation of treatment versus 26.9% of those on the lenalidomide/dexamethasone arm. Moreover, the rates of on-study deaths were 7.6% versus 6.3% in the triplet and doublet arms, respectively.

In November 2015, ixazomib was the first oral proteasome inhibitor to received regulatory approval from the FDA for use in combination with lenalidomide and dexamethasone in patients with multiple myeloma who had received at least 1 previous therapy. The agent is approved for use in over 65 countries, according to Takeda Pharmaceutical Company Limited, the drug developer.

References

1. Takeda announces results from phase 3 clinical trial evaluating Ninlaro (ixazomib) in newly diagnosed multiple myeloma. News release. Takeda Pharmaceutical Company Limited. September 9, 2020. Accessed September 11, 2020. https://bwnews.pr/33lbXHh.
2. Ixazomib plus lenalidomide and dexamethasone versus placebo plus lenalidomide and dexamethasone in adult patients with newly diagnosed multiple myeloma. ClinicalTrials.gov. Updated December 6, 2019. Accessed September 11, 2020. https://clinicaltrials.gov/ct2/show/NCT01850524.