Oral Proteasome Inhibitor Shows Promise in Multiple Myeloma

Once-a-week treatment is the first oral proteasome inhibitor to reach late stage clinical development.

Patients with multiple myeloma may soon have a significant new weapon in their battle with the disease.

At the upcoming American Society of Hematology (ASH) Annual Meeting, Takeda Pharmaceutical Company will present data from a phase 3 clinical trial evaluating the experimental drug ixazomib in the treatment of relapsed and/or refractory multiple myeloma (RRMM).

Ixazomib, which is the first oral proteasome inhibitor to reach late stage clinical development, was previously granted Priority Review from the FDA and Accelerated Assessment by the Committee for Medicinal Products for Human Use of the European Medicines Agency.

The phase 3 TOURMALINE-MM1 trial is an international, randomized, double-blind, placebo-controlled study comparing the efficacy of once-per-week oral treatment with ixazomib plus lenalidomide and dexamethasone versus placebo plus lenalidomide and dexamethasone in adult RRMM patients.

The trial randomized 722 adults with RRMM after 1 to 3 previous lines of therapy who were not refractory to prior treatment with lenalidomide or proteasome inhibitor-based therapy. The primary endpoint of the trial was progression free survival.

Of the patients enrolled, 360 were placed in the ixazomib compared with 362 in the placebo group with an overall median age of 66 years.

Among these patients, 70% were previously exposed to treatment with proteasome inhibitors, 59% received 1 prior therapy, and 77%, 11%, and 11% were relapsed, refractory/relapsed, or refractory, respectively, with 6% of those patients primary refractory.

Prior therapies included 69% of patients treated with bortezomib, 45% treated with thalidomide, and 12% treated with lenalidomide.

Patients in the ixazomib group demonstrated a 35% improvement in progression free survival compared with placebo. At this first interim analysis, ixazomib increased median progression free survival from 14.7 months to 20.6 months without a significant increase in overall toxicity.

If approved by the FDA, the all-oral combination therapy could become a new standard of care in the treatment of RRMM, according to Takeda.

In terms of safety, 68% of patients in the ixazomib group had a grade 3 or greater adverse event, compared with 61% of patients in the placebo group, while 40% in the ixazomib had a serious adverse event versus 44% in the placebo group.

Furthermore, 13% of patients in the ixazomib group discontinued all study drugs due to adverse events compared with 11% on placebo, and 3% in the ixazomib group died on treatment compared with 5% on placebo.

Common grade 3 adverse events on ixazomib versus placebo were neutropenia (19% vs 16%), anemia (9% vs 13%), thrombocytopenia (13% vs 5%), and pneumonia (6% vs 8%).

Takeda will present data from this trial, along with 5-year overall survival data from brentuximab vedotin (Adcetris) in the treatment of relapsed/refractory Hodgkin lymphoma, at the 57th annual ASH meeting, held in Orlando, FL from December 5 to 8, 2015.

“This is the first time phase 3 data will be presented for ixazomib, an oral, once-weekly proteasome inhibitor which, if approved, would enable the first all-oral triplet regimen containing a proteasome inhibitor for the treatment of relapsed/refractory multiple myeloma,” said TOURMALINE-MM1 principal investigator Philippe Moreau, MD, University of Nantes, France. “In working with Takeda Oncology on the evolution of proteasome inhibition, we continue to strive towards providing new options to address the unmet needs of patients with multiple myeloma.”