Data Supports Ixazomib for Phase III Myeloma Trial

Data from a phase I/II clinical trial supports further evaluation of the investigational, oral, proteasome inhibitor ixazomib in combination with lenalidomide and dexamethasone for the treatment of newly diagnosed multiple myeloma.

“The results suggest that the combination could be active in this setting, with more than 90% of the patients achieving a disease response,” researchers led by Shaji K. Kumar, MD, of Mayo Clinic, Rochester, Minnesota, wrote in the Lancet Oncology. “Despite the limitation of short follow-up time, and a substantial number receiving transplantation, we showed that the combination was well tolerated in the current study, with more than a third of the enrolled patients proceeding to maintenance phase after completion of 12 cycles of induction therapy.”

According to the study, combination bortezomib, lenalidomide, and dexamethasone has already been established as effective therapy in patients with newly diagnosed multiple myeloma. However, the investigational drug ixazomib has also shown potential in this group with low rates of peripheral neuropathy.

The researchers first conducted a phase I study to established maximum tolerated dose. The study included 65 patients aged 18 years or older with an ECOG status of 0–2 and less than grade 2 peripheral neuropathy. Patients were treated with ixazomib plus lenalidomide 25 mg and dexamethasone 40 mg for up to 12 28-day cycles followed by maintenance therapy with the study drug alone.

During phase I, there were four dose-limiting toxicities; one occurred at a dose of 2.97 mg/m² and three at a dose of 3.95 mg/m². Based on these results, the maximum tolerated dose was set at 2.97 mg/m² and a dose of 2.23 mg/m² was recommended for phase II.

In phase II, the drug dose was converted to a fixed dose of 4 mg. Overall, 63% of patients reported grade 3 or higher adverse events related to the study drug, but grade 3 or higher peripheral neuropathy was only reported in 6% of patients.

“Overall, the regimen was well tolerated with patients receiving a median of 7 cycles and only 8% of patients discontinuing because of adverse events,” the researchers wrote. “Drug-related adverse events, mostly hematological, were reported in most patients but could be managed easily with dose modifications.”

Sixty-four of the patients were evaluable for response, with 37 having a very good partial response or better. Seventeen patients had a complete response. Twenty-five of the patients continued on treatment to the maintenance phase, with 20% experiencing an improvement in the depth of their response to the study drug. To date, durable responses have latest up to 2 years in some patients.

Phase III studies of ixazomib are underway in both newly diagnosed patients and those with relapsed multiple myeloma.