Ixazomib Triplet Combo Effective in R/R Myeloma

A phase II study has established that the combination of ixazomib, pomalidomide, and dexamethasone was effective and well-tolerated in patients with relapsed or refractory multiple myeloma. The study, published in Leukemia, looked at the entirely oral regimen in patients who were refractory to lenalidomide.

“Responses were promising in the context that patients had one to five prior lines of therapy,” wrote Amrita Krishnan, of the department of hematology and hematopoietic cell transplantation at City of Hope, and colleagues. “Less is known about the therapeutic efficacy of ixazomib for patients who are bortezomib-resistant; however, preclinical experiments point toward activity of ixazomib on cells from patients resistant to bortezomib, and several studies have shown activity even in bortezomib refractory patients, although responses may be infrequent.”

In the study, 7 patients were treated at dose level 1 (3 mg ixazomib, 4 mg pomalidomide, 40 mg dexamethasone). One patient was inevaluable for having received less than 75% of the dexamethasone and pomalidomide prescribed. Twenty-five patients were treated at dose level 2 (4 mg ixazomib, 4 mg pomalidomide, 40 mg dexamethasone).

During the phase I portion of the study, 1 of the 3 initial patients enrolled at level 1 had grade 3 fatigue, grade 3 lung infection, grade 4 neutropenia, and grade 4 thrombocytopenia. All of these toxicities were dose-limiting. Among the 3 additional patients enrolled at this dose level, no dose-limiting toxicities occurred.

Among the first 3 patients treated at dose level 2, 1 had grade 4 febrile neutropenia, grade 4 neutropenia, and grade 4 thrombocytopenia; however, when the study was expanded to treat 3 additional patients at level 2, no dose-limiting toxicities occurred. Dose level 2 was recommended for the phase II portion of the study.

“Of note, the dose might be further increased, beyond 4 mg ixazomib (the study’s recommended phase 2 dose) as in a randomized phase 2 trial of ixazomib and dexamethasone, where 5.5 mg ixazomib yielded a superior overall response rate over 4 mg ixazomib (54% vs. 31%),” the researchers wrote. “However, in that two-drug regimen, toxicities were more frequent, and 40% of patients required a dose reduction by the fourth cycle, suggesting that the increase in the ixazomib dose may ultimately affect the ability to achieve dose intensity of pomalidomide without undue toxic effects.”

Thirty-one patients from the phase I and phase II portions of the study were evaluated for response at a median follow-up of 12 months. About half (48%) of patients treated at dose level 2 had a partial response, with 20% of patients achieving very good partial response, and 76% achieving stable disease or better.

The most common adverse events of grade 2 or higher were anemia, neutropenia, thrombocytopenia, and infections.

“Notably, few patients experienced peripheral neuropathy that was at least possibly related to treatment,” the researchers wrote. “On the basis of the promising efficacy and manageable toxicity resulting from the use of the ixazomib-pomalidomide-dexamethasone regimen for lenalidomide-refractory patients, we believe that the findings justify further study of this combination for relapsed patients with myeloma who are refractory to lenalidomide, preferably with randomized comparisons to specifically identify clinical benefit.”