ASH 2015: TOURMALINE: Professor Philippe Moreau (University Hospital, Nantes, France) discusses the Tourmaline study – ixazomib, lenalidomide, dexamethasone (iRd) in R/R myeloma, with opinions on the data from Professor Graham Jackson (NCCC, Newcastle Hospitals Trust, UK), Professor Gordon Cook (Leeds Teaching Hospitals, UK), Erik Low (Chief Executive Myeloma UK) and Dr Shaji Kumar (Mayo Clinic, Rochester, USA)

Ixazomib improves progression-free survival across subgroups

by Thomas R. Collins: The oral proteasome inhibitor (PI) ixazomib with lenalidomide and dexamethasone (IRd) performed well versus placebo plus lenalidomide and dexamethasone (Rd) in relapsed or refractory multiple myeloma (MM) patients, according to the results of the phase 3 TOURMALINE study presented at the 57th Annual Meeting of the American Society of Haematology.

Proteasome inhibitors — which block the action of proteasomes that cause the build-up of proteins in cancer cells, leading to cell death — have become an important part of the treatment regimen in MM. With ixazomib, patients now have their first option for a completely oral regimen, rather than just an injection option. Ixazomib’s safety profile is also highly encouraging, said Philippe Moreau, MD, Head of Haematology at University Hospital in Nantes, France, and lead investigator on the study.

“The feasibility of long-term treatment with current proteasome inhibitors can be limited due to toxicities or to the need for regular and frequent clinic attendance,” he said. “We have a treatment (with an) all-oral regimen that is effective, safe, convenient, simple.”

The drug was approved by the U.S. Food and Drug Administration in November, for use with lenalidomide and dexamethasone for patients who have failed at least one prior therapy.

In TOURMALINE, 722 relapsed/refractory MM patients were randomized to get ixazomib plus lenalidomide and dexamethasone (IRd) or to get a placebo plus lenalidomide and dexamethasone (placebo-Rd). To be enrolled, patients must have received 1 to 3 prior lines of therapy. The study included patients who were primary refractory, meaning they were refractory to all of their prior lines of therapy. Those who were refractory to a PI- or lenalidomide-based therapy were not eligible.

The study was performed across 147 centers and 26 countries.

Those in the IRd group showed a 35% improvement in progression-free survival (PFS), the primary endpoint. The median PFS for the IRd group was 20.6 months, compared to 14.7 months for the placebo-Rd group (p=.012).

Those with high-risk cytogenetics (del[17p] and t[4;14]) showed about the same improvement in PFS as the standard-risk patients. The hazard ratio for the standard-risk patients for PFS was 0.64; for del(17p) patients, 0.596; or t(4;14), 0.645.

Improvements were seen across all other subgroups as well, including both younger patients and those over 75 and patients with prior exposure to a PI and those without.

There were also significant differences, in favour of IRd, in overall response (78.3% vs. 71.5%; p=.035); complete response (11.7% vs. 6.6%; p=.019); and median time to progression (21.4 months vs. 15.7 months; p=.007).

The IRd and placebo-Rd groups had similar rates of adverse events, with 74 AEs Grade 3 or worse in the IRd group and 69 in the Rd group. Seventeen patients in the IRd group discontinued treatment because of AEs, compared to 14 in the placebo-Rd group.

Five new primary malignancies were seen in the IRd group, compared to 4 in the placebo-Rd group.

“This triplet combination,” Dr. Moreau said, “is a very safe one.”

Reference

1. Moreau P, Masszi T, Grzasko N, et al. Ixazomib, an Investigational Oral Proteasome Inhibitor (PI), in Combination with Lenalidomide and Dexamethasone (IRd), Significantly Extends Progression-Free Survival (PFS) for Patients (Pts) with Relapsed and/or Refractory Multiple Myeloma (RRMM): The Phase 3 Tourmaline-MM1 Study (NCT01564537). Presented at the 57th Annual Meeting of the American Society of Hematology. 2015 Dec 5-8. Orlando FL. Abstract 727.