First Oral Proteasome Inhibitor Meets PFS Endpoint in Phase III Myeloma Trial

Shaji K. Kumar, MD

The proteasome inhibitor ixazomib (MLN9708) met its primary endpoint of improving progression-free survival (PFS) at a prespecified interim analysis of a phase III trial of patients with relapsed/refractory multiple myeloma, according to Takeda Pharmaceutical Company Limited, the company developing the agent. Ixazomib is the first oral proteasome inhibitor to enter a phase III trial.

“We are very pleased with the outcome of this interim analysis of the pivotal trial, and are excited about the potential that investigational ixazomib holds for patients with multiple myeloma,” Dixie-Lee Esseltine, MD, vice president, Oncology Clinical Research, Takeda, said in a statement. “We thank the patients and investigators for their engagement and continued participation in this ongoing clinical evaluation of ixazomib.”

Efficacy and safety data were reviewed by an independent data monitoring committee and will be submitted to regulatory health authorities around the world, according to Takeda.

In the study, 722 adult patients with relapsed/refractory multiple myeloma were randomized to receive ixazomib, lenalidomide, and dexamethasone or placebo, lenalidomide, and dexamethasone. Patients received ixazomib at 4 mg or placebo on days 1, 8, and 15 in combination with 25 mg of lenalidomide on days 1-21 and 40 mg of dexamethasone on days 1, 8, 15, and 22, every 28 days until disease progression.

Patients must have received 1-3 prior therapies to be included on the trial, but were excluded if they were refractory to lenalidomide or proteasome-based therapy. The trial’s primary endpoint was PFS. Secondary endpoints focused on overall survival, overall survival among high-risk patients with 17p deletion, and overall response rate, among others.

Shaji K. Kumar, MD, presented early data for the ixazomib combination at the 2012 ASH Annual Meeting.¹ In this 65-patient phase I/II trial, the overall response rate was 92% with ixazomib, lenalidomide, and dexamethasone. Overall, 55% of patients reached a very good partial response or better, including 23% who experienced complete remission.

At the 2014 ASH Annual Meeting, Kumar, a professor of medicine at the Mayo Clinic, presented data from a 50-patient phase II study looking at ixazomib as maintenance therapy following the triplet of ixazomib, lenalidomide, and dexamethasone, for patients with previously untreated multiple myeloma.²

In the induction portion of the study, 29 patients discontinued treatment to undergo either autologous stem cell transplantation (n = 14) or because of adverse events (n = 6) or trial withdrawal (n = 4). Of the 21 patients who received maintenance ixazomib, 52% achieved a complete response and 71% had a very good partial response.

Adverse events during maintenance included diarrhea (43%), nausea (19%), extremity pain (14%), anemia (10%), hypokalemia (10%), and thrombocytopenia (10%). Investigators concluded that maintenance therapy with ixazomib for 1.5 years is feasible and well tolerated.

In an interview with OncLive at the 2014 ASH Annual Meeting, Kumar said the triplet regimen of a proteasome inhibitor, immunomodulatory agent, and a steroid has been proven to be efficacious for the treatment of multiple myeloma.

“One of the problems we have with the current proteasome inhibitors is that they both need to be given either intravenously or have to be given subcutaneously, which means patients have to come into the clinic once or twice a week to get the therapy,” Kumar said. “Since the proteasome inhibitor class is such an integral part of the myeloma therapy, the search has [begun] to develop a drug that can be given as a pill, which then would make for a completely oral regimen for treating multiple myeloma.”

In August 2014, Kumar published data from a phase I study in Blood showing promising results for single-agent ixazomib in patients with relapsed/refractory multiple myeloma.³ In total, 60 patients received ixazomib weekly for 3 of 4 weeks, with 18% (n = 9) achieving a partial response or better. Patients who received the maximum tolerated dose of 2.97 mg/m² (n = 30) experienced a majority of these responses (89%).

Dose-limiting toxicities included grade 3 nausea, vomiting, and diarrhea (3%) and grade 3 rash (1.7%). Other adverse events included thrombocytopenia (43%) and fatigue (37%).

Ixazomib is currently being investigated in a collection of clinical trials called TOURMALINE. TOURMALINE-MM1 is comparing ixazomib with placebo in combination with lenalidomide and dexamethasone in relapsed/refractory disease. TOURMALINE-MM2 is evaluating ixazomib versus placebo in combination with lenalidomide and dexamethasone in patients with newly diagnosed disease and TOURMALINE-MM3 is looking at ixazomib compared with placebo as maintenance therapy in patients with newly diagnosed disease following induction therapy and autologous stem cell transplant.

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

“Patients with AL amyloidosis face a debilitating disease that can affect many of their organs and tissues," Raymond L. Comenzo, MD, the director of the Blood Bank and Stem Cell Processing Laboratory at Tufts University School of Medicine, said when the designation was granted. "The breakthrough therapy designation for ixazomib is a major milestone in the development of new treatment options for patients battling this rare and aggressive disease."

References

1. Kumar SK, Bensinger WI, Zimmerman TM, et al. Phase 1 study of weekly dosing with the investigational oral proteasome inhibitor ixazomib in relapsed/refractory multiple myeloma. Blood. 2014; 124(7):1047-1055.
2. Kumar SK, Berdeja JG, Niesvizky R, et al. A phase 1/2 study of weekly MLN9708, an investigational oral proteasome inhibitor, in combination with lenalidomide and dexamethasone in patients with previously untreated multiple myeloma (MM). Presented at: 54th ASH Annual Meeting; December 8-11, 2012; Atlanta, GA. Abstract 332.
3. Kumar SK, 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: 56th ASH Annual Meeting; December 5-8, 2014; San Francisco, CA. Abstract 82.