Ixazomib Benefit Sustained Across Myeloma Subgroups

Maria-Victoria Mateos, MD, PhD

Triplet combinations are well on their way to becoming a standard approach for the treatment of patients with multiple myeloma, according to Maria-Victoria Mateos, MD, PhD, an associate professor of Hematology at the Hospital Universitario de Salamanca and Centro de Investigación del Cáncer in Spain.

The triplet combination of ixazomib (Ninlaro) plus lenalidomide (Revlimid) and dexamethasone is one that has shown significant promise. In November 2015, the FDA approved ixazomib in combination with lenalidomide and dexamethasone as a treatment for patients with multiple myeloma who have received at least 1 prior therapy, based on the phase III TOURMALINE-MM1 trial.

In the study, the median progression-free survival (PFS) was 20.6 months with the ixazomib triplet compared with 14.7 months with lenalidomide and dexamethasone alone.

OncLive: Can you provide an overview of the TOURMALINE-MM1 study and your subanalysis?

In her discussion with OncLive, Mateos provided insight on a subanalysis of the TOURMALINE-MM1 trial, the impact of ixazomib’s approval, and the future of triplet combinations in the treatment multiple myeloma.Mateos: The TOURMALINE-MM1 study is a phase III randomized trial conducted in relapsed and refractory patients with multiple myeloma after 1 to 3 prior lines of therapy. In the study, ixazomib, the first oral proteasome inhibitor, was added to lenalidomide/dexamethasone, and compared with a placebo in combination with lenalidomide/dexamethasone.

There were 722 patients included in this trial, and the primary endpoint was PFS. The triplet combination of ixazomib/lenalidomide/dexamethasone resulted in significantly superior PFS in comparison with placebo plus lenalidomide/dexamethasone.

At the 2016 ASCO Annual Meeting, we presented a subanalysis according to the prior lines of therapy. Most patients were bortezomib (Velcade) exposed and thalidomide exposed, while a few patients were lenalidomide exposed. There was a subset of patients who were even refractory to thalidomide.

What should community oncologists take away from these findings?

What kind of impact has the TOURMALINE-MM1 study had on the treatment paradigm for multiple myeloma?

Are there any advantages to 1 of these 3-drug combinations over the others?

The results of this subanalysis showed that the benefit of ixazomib with lenalidomide/dexamethasone was sustained across the different subgroups of patients, regardless of the prior lines of therapy.The main message is that when a patient has been previously exposed to bortezomib or thalidomide, or even refractory to thalidomide, they can safely receive ixazomib with lenalidomide/dexamethasone because the benefit is going to be sustained.Ixazomib/lenalidomide/dexamethasone represents a new 3-drug—based combination that we can use in patients relapsing or progressing on 1 to 3 prior lines of therapy. In the past, lenalidomide/dexamethasone was the standard of care for patients experiencing first, second, or even third relapse. Now, we have different 3-drug–based combinations—lenalidomide/dexamethasone plus something else. Some examples are carfilzomib (Kyprolis) plus lenalidomide/dexamethasone, inotuzumab ozogamicin plus lenalidomide/dexamethasone, and now ixazomib in combination with lenalidomide/dexamethasone. Patients can receive these mainly at first relapse.The results are similar for all of these 3-drug combinations. The main advantage for ixazomib in combination with lenalidomide/dexamethasone is that it is an all-oral combination, so the number of visits to the hospital is significantly lower in comparison to the other 3-drug combinations, in which the third drug is given intravenously.

Should any additional analyses of the TOURMALINE-MM1 study be conducted?

Another important advantage is the benefit that has been observed in the TOURMALINE-MM1 study in patients with high rates of cytogenetic abnormalities and in patients with advanced stage of the disease—International Staging System III. For this patient population, we don’t have many options and this subset of patients can obtain a great benefit with the ixazomib triplet regimen.A subanalysis according to the cytogenetic status has been done and was presented at the 2016 ASCO Annual Meeting. This was interesting, because it confirmed the efficacy of ixazomib/lenalidomide/dexamethasone in patients with high-risk cytogenetic abnormalities. Additionally, a subsequent analysis can be done according to the quality of life. Another subanalysis can be done according to the number of prior lines of therapy, in order to find more information about the subset of patients who really are going to obtain the greatest benefit of this combination.

Mateos MV, Masszi T, Grzasko N, et al. Impact of prior therapy on efficacy and safety of oral ixazomib-lenalidomide-dexamethasone (IRd) vs placebo-Rd in patients (pts) with relapsed/refractory multiple myeloma (RRMM) in TOURMALINE-MM1. J Clin Oncol. 2016;34 (suppl; abstr 8039).

“The triplet is superior to the doublet; in the near future, all patients are going to receive triplets in the upfront setting and also receive 3-drug regimens at the moment of relapse,” Mateos said in an interview with OncLive.