Results of a phase 1/2 multicenter trial showed that twice-weekly ixazomib added to pomalidomide and dexamethasone treatment was a well-tolerated and promising treatment option for patients with relapsed and refractory multiple myeloma (RRMM); these data were presented at the 63rd American Society of Hematology (ASH) Annual Meeting and Exposition.

According to Omar Nadeem, MD, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, and colleagues, ixazomib is currently approved to be administered once weekly in combination with lenalidomide and dexamethasone. However, most patients are lenalidomide refractory at their first relapse, so pomalidomide-based regimens are more common. 

“We hypothesized that twice weekly dosing of ixazomib may be more efficacious as this has been previously studied as monotherapy (Blood 2014;124(7):1038-46) and in combination with LEN demonstrating promising activity and safety (Br J Haematol.;182(2):231-244),” explained Dr Nadeem et al. 

With this in mind, researchers conducted a single-arm, open-label study to evaluate the combination of twice-weekly ixazomib with pomalidomide and dexamethasone in patients with RRMM.

Patients who received two prior lines of therapy were included; however, one line was allowed if the first-line treatment included a PI and an immunomodulatory agent and disease relapse occurred within 60 days of last therapy.

The primary objective for phase 1 was to determine the safety and maximum tolerated dose (MTD) using a standard 3+3 dose-escalation design; phase 2 primary objective included overall response rate (ORR) with secondary outcomes including progression-free survival (PFS) and clinical benefit rate (CBR).

Researchers study ixazomib at doses of 3mg or 4mg on days 1, 4, 8, 11; pomalidomide at 2mg, 3mg, and 4mg on days 1-14 and dexamethasone administered at a dose of 12mg on days 1, 2, 4, 5, 8, 9, 11, 12 (8mg for patients > 75 years old) on a 21-day cycle.

A total of 22 patients were enrolled at the time of data cutoff, and the median age was 68 years old, with 14% being stage I at the time of diagnosis, 32% stage II, and 23% stage III. The median prior lines of therapy was two (range one-four), with all patients having recieved prior treatment with lenalidomide and 95% with bortezomib. Additionally, two DLTs were noted during the dose-escalation phase (upper respiratory infection and neutropenia), establishing the recommended phase 2 dose (RP2D) of 4mg ixazomib and 4mg pomalidomide. 

The ORR in all cohorts was 45%, 9% of whom achieved stringent complete response (sCR), 9% very good partial response (VGPR), and 86% achieving stable disease or better. At RP2D, the ORR was 50%, 30% of patients achieved VGPR or better. At the median follow-up of 10 months, the median PFS was 13 months (95% CI: 11-NR), and the median overall survival was not reached.

Most treatment-related adverse events (AEs) were grade 1-2, the most common included neutropenia (45%), lower extremity edema (41%), insomnia (36%), dyspnea (32%) and weight gain (32%). Furthermore, 36% of patients noted AEs grade 3 or higher, which includedneutropenia (18%), thrombocytopenia (5%), anemia (5%), atrial fibrillation (5%), dehydration (5%), diarrhea (5%), fall (5%), lung infection (5%), and pneumonitis (5%).

Dose reductions occurred in 13 patients, most of which involved dexamethasone due to weight gain, insomnia, atrial fibrillation, and fatigue. There were no discontinuations due to toxicity, nor were there any treatment-related deaths at the time of cutoff. 

“Twice weekly ixazomib in combination with pomalidomide and dexamethasone is a generally well-tolerated regimen with promising activity. The recommended phase II dose has been established at 4mg of ixazomib and 4mg of pomalidomide demonstrating efficacy in a high-risk cohort of RRMM patients. The all-oral nature of this regimen has allowed for robust accrual during the COVID 19 pandemic,” concluded Dr Nadeem and colleagues.—Alexandra Graziano

Nadeem O, Redd R, Barth P, et al.A Phase I/II Study of Twice Weekly Ixazomib Plus Pomalidomide and Dexamethasone in Relapsed and Refractory Multiple Myeloma. Presented at: the 63rd ASH Annual Meeting and Exposition; December 11-14, 2021; Atlanta, GA. Abstract 1650