Ixazomib Delays Myeloma Progression in Phase 3 Trial

Ixazomib, also known as MLN9708, met its primary endpoint of improving progression-free survival at an interim analysis of a phase 3 trial of relapsed or refractory multiple myeloma.

The investigational agent, ixazomib, may well become another treatment option for patients with relapsed multiple myeloma, after a late-stage trial showed success in delaying disease progression.

Ixazomib, also known as MLN9708, met its primary endpoint of improving progression-free survival (PFS) at an interim analysis of a phase 3 trial of relapsed or refractory multiple myeloma, according to Takeda, the company developing the agent. Ixazomib is the first oral proteasome inhibitor to enter a phase 3 trial. Other proteasome inhibitors include Velcade (bortezomib) and Kyprolis (carfilzomib).

In the study, 722 adult patients with relapsed or refractory multiple myeloma were randomized to receive Revlimid (lenalidomide) and dexamethasone with ixazomib or placebo.

Patients must have received between one and three prior therapies to be included on the trial, but were excluded if they were refractory to Revlimid 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, a professor of medicine at the Mayo Clinic, presented early data for the ixazomib combination in 2012.1 In this 65-patient phase 1/2 trial, the overall response rate was 92 percent with ixazomib, Revlimid and dexamethasone. Overall, 55 percent of patients reached a very good partial response or better, including 23 percent who experienced complete remission.

Last year, at the annual American Society of Hematology annual meeting, Kumar presented data from a 50-patient phase 2 study looking at ixazomib as maintenance therapy following the triplet regimen of ixazomib, Revlimid and dexamethasone, for patients with previously untreated multiple myeloma.

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

Adverse events during maintenance included diarrhea, nausea, extremity pain and anemia. Investigators concluded that maintenance therapy with ixazomib for a year and a half is feasible and well tolerated.

Kumar says 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 says. “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 1 study in Blood showing promising results for single-agent ixazomib in patients with relapsed or refractory multiple myeloma. In total, 60 patients received ixazomib weekly for three of four weeks, with 18 percent achieving a partial response or better. Patients who received the maximum tolerated dose of experienced a majority of these responses (89 percent).

Ixazomib is currently being investigated in a collection of clinical trials called TOURMALINE. TOURMALINE-MM1 is comparing ixazomib with placebo in combination with Revlimid and dexamethasone in relapsed or refractory disease. TOURMALINE-MM2 is evaluating ixazomib versus placebo in combination with Revlimid 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 or 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, 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."