FDA Approval Sought for Ixazomib in Relapsed/Refractory Myeloma

Paul G. Richardson, MD

A new drug application has been submitted for the oral proteasome inhibitor ixazomib (MLN9708) in combination with lenalidomide and dexamethasone as a treatment for patients with relapsed and/or refractory multiple myeloma, according to a statement from the drug's developer, Takeda. The FDA is scheduled to review the application within 60 days, at which point the agency will assign a decision deadline under the Prescription Drug User Fee Act.

The application for ixazomib was based on findings from the 722-patient phase III TOURMALINE-MM1 trial, which demonstrated an extension in progression-free survival (PFS) with the oral triplet therapy compared with lenalidomide and dexamethasone alone. With these findings, ixazomib became the first oral proteasome inhibitor to demonstrate efficacy in a phase III trial.

“Proteasome inhibition has become an essential component of treatment, but there are logistical challenges for patients with both intravenous and subcutaneous approaches, and especially in the absence of an effective oral option,” Paul Richardson, MD, clinical program leader and Director of Clinical Research, Jerome Lipper Multiple Myeloma Center at Dana-Farber Cancer Institute, said in a statement. “If approved, ixazomib, with the convenience of once-a-week oral administration as well as promising efficacy, should provide a very meaningful advance for our patients.”

In the phase III study, patients were treated with 25 mg of oral lenalidomide on days 1-21 and 40 mg of oral dexamethasone on days 1, 8, 15, and 22 in combination with ixazomib at 4 mg on days 1, 8, and 15 or placebo. Treatment was administered until disease progression. The study enrolled patients who had received 1 to 3 prior therapies with an ECOG PS of 0, 1, or 2. Patients who were refractory to lenalidomide or a proteasome inhibitor were excluded from the study.

Outside of an announcement that the study had met its primary endpoint of extension in PFS, Takeda has not yet made data from the TOURMALINE-MM1 trial available. Secondary endpoints of the study included overall survival, objective response rate (ORR), and safety along with several other outcome measures.

In a preceding phase II study, induction therapy with the triplet of ixazomib, lenalidomide, and dexamethasone was followed by maintenance therapy with ixazomib in 50 untreated patients with multiple myeloma. After more than 2 years of follow-up, the ORR was 90%, including a 59% very good partial response or better.

The most frequently reported grade 1/2 ixazomib-related adverse events were diarrhea (38%), nausea (14%), extremity pain (14%), anemia (10%), and headache (10%). Peripheral neuropathy was not reported.

“Continuous treatment is emerging as a standard of care in multiple myeloma with demonstrable improvement in long-term outcomes," Richardson added.

The TOURMALINE clinical trial program contains 4 other phase III studies in addition to MM1. In the MM2 study, the combination of ixazomib, lenalidomide, and dexamethasone is being explored in newly diagnosed patients with multiple myeloma. In earlier settings, the MM3 and MM4 studies are investigating maintenance therapy with ixazomib in patients who have and have not undergone an autologous stem cell transplant.

“This submission marks an important step in Takeda’s ongoing commitment to innovation for patients living with multiple myeloma,” Andrew Plump, MD, PhD, Takeda’s chief medical and scientific officer, said in a statement. “The TOURMALINE-MM1 study is the first in a series of five phase III trials within our ixazomib program, which is designed to evaluate whether sustained therapy with a proteasome inhibitor, delivered orally, improves the clinical outcomes of patients living with multiple myeloma or with systemic light-chain amyloidosis.”

In addition to multiple myeloma, ixazomib is being evaluated in combination with dexamethasone for patients with relapsed/refractory systemic light-chain (AL) amyloidosis in the phase III TOURMALINE-AL1 trial. In early December 2014, ixazomib was granted a breakthrough therapy designation as a treatment for patients with AL amyloidosis.

“We thank the patients and their families for placing their trust in us and in ixazomib as they continue to participate in the TOURMALINE program,” Plump added.

Kumar S, Berdeja JG, Niesvizky R, et al. Long-Term Ixazomib Maintenance Is Tolerable and Improves Depth of Response Following Ixazomib-Lenalidomide-Dexamethasone Induction in Patients (Pts) with Previously Untreated Multiple Myeloma (MM): Phase 2 Study Results. Presented at: the 56th Annual Meeting of the American Society of Hematology; December 6-9, 2014; San Francisco, California. Abstract 82.