Three-Drug Combinations May Soon Become Standard in Myeloma Care

Treatment of multiple myeloma may soon be shifting into a three-drug approach says Maria-Victoria Mateos, M.D., Ph.D., an associate professor of Hematology at the Hospital Universitario de Salamanca and Centro de Investigación del Cáncer in Spain.

“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 three-drug regimens at the moment of relapse,” Mateos said in an interview with CURE.

The triplet combination of Ninlaro (ixazomib) plus Revlimid (lenalidomide) and dexamethasone is one that has shown significant promise. In November 2015, the FDA approved Ninlaro in combination with Revlimid and dexamethasone as a treatment for patients with multiple myeloma who have received at least one prior therapy, based on the phase 3 TOURMALINE-MM1 trial.

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

In her discussion with CURE, Mateos provided insight on a subanalysis of the TOURMALINE-MM1 trial, the impact of Ninlaro’s approval, and the future of triplet combinations in the treatment multiple myeloma.

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

The TOURMALINE-MM1 study is a phase 3 randomized trial conducted in relapsed and refractory patients with multiple myeloma after one to three prior lines of therapy. In the study, Ninlaro, the first oral proteasome inhibitor, was added to Revlimid/dexamethasone, and compared with a placebo in combination with Revlimid/dexamethasone.

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

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

What is the main takeaway from these findings?

The results of this subanalysis showed that the benefit of Ninlaro with Revlimid/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 Velcade or thalidomide, or even refractory to thalidomide, they can safely receive Ninlaro with Revlimid/dexamethasone because the benefit is going to be sustained.

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

Ninlaro/Revlimid/dexamethasone represents a new three-drug—based combination that we can use in patients relapsing or progressing on one to three prior lines of therapy. In the past, Revlimid/dexamethasone was the standard of care for patients experiencing first, second, or even third relapse. Now, we have different three -drug–based combinations — Revlimid/dexamethasone plus something else. Some examples are Kyprolis (carfilzomib) plus Revlimid/dexamethasone, inotuzumab ozogamicin plus Revlimid/dexamethasone, and now Ninlaro in combination with Revlimid/dexamethasone. Patients can receive these mainly at first relapse.

Are there any advantages to one of these three-drug combinations over the others?

The results are similar for all of these three-drug combinations. The main advantage for Ninlaro in combination with Revlimid/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 three-drug combinations, in which the third drug is given intravenously.

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 3. For this patient population, we don’t have many options and this subset of patients can obtain a great benefit with the Ninlaro triplet regimen.

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

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 Ninlaro/Revlimid/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.