Interim Phase 2 Trial Results Show Quadruplet Regimen Tolerable, Effective in MM

Interim results of a phase 2 trial show that combination daratumumab, pomalidomide, dexamethasone, and ixazomib (DIPd) is well tolerated and effective in early relapsed or refractory multiple myeloma (MM). The findings were presented at the recent American Society of Clinical Oncology Annual Meeting.

The quadruplet combination sees the addition of ixazomib to the triplet of daratumumab, pomalidomide, and dexamethasone (DPd) that has produced durable responses and high rates of minimal residual disease (MRD) negativity in relapsed or refractory MM. The DIPd regimen aims to improve on those response rates and efficacy.

Main end points of the ongoing prospective, multicenter, single-arm phase 2 trial include the safety, efficacy, and overall response rate (ORR) of DIPd in early relapsed or refractory MM. Progression-free survival (PFS), overall survival (OS), and MRD negativity rate are secondary end points.

Eligibility requirements included no prior exposure to daratumumab or ixazomib and no progression on pomalidomide. Eligible patients received 1 to 3 previous lines of treatment. The study used a Simon’s optimal 2-stage design and included 14 patients in stage 1 and 32 patients in stage 2. Patients with a very good or partial response (VGPR) or with potential complete response (CR) to the regimen were assessed for MRD, and custom panel mass cytometry was used to assess pharmacodynamic changes in the tumor microenvironments.

In the safety run-in, 6 patients received 16 mg/kg of intravenous daratumumab weekly for 8 doses, biweekly for 8 doses, and then monthly. On days 1 to 21 of a 28-day cycle, patients received 4 mg of pomalidomide orally each day and 4 mg of ixazomib on days 1, 8, and 15 of each 28-day cycle. Each week, patients also received 20 to 40 mg of dexamethasone. During the safety run-in, all patients experienced grade 3 or 4 neutropenia, and the Data and Safety Monitoring Board reduced the ixazomib and pomalidomide doses to 3 mg each.

At the time of the interim analysis, 14 participants had been treated in stage 1 and 18 in stage 2. The median patient age was 61 years, half of the patients were female, and 72% of the patients reported White as their racer. The median time on treatment was 4 months, and 11 patients were still on the DIPd regimen at the time of the analysis. Five patients died —4 due to disease progression and 1 from sepsis. All of the patients had previously received lenalidomide, and 47% showed high-risk cytogenic features.

The median OS was 38.9 months, and the median PFS was 9.5 months. The ORR was 84%, with 26% of patients showing stringent CR, 21% achieving VGPR, and 37% experiencing partial response. The immunophenotypic changes that took place were similar to those seen in patients treated with DPd.

Neutropenia, infection, leukopenia, respiratory conditions, psychiatric disturbance, and thrombosis were the most common grade 3 or 4 adverse events (78%, 30%, 11%, 7%, 4%, and 4%, respectively).

Overall, the interim results suggest that DIPd is safe and effective with a favorable ORR in relapsed or refractory MM. It was also well tolerated and showed efficacy, even in patients who had high-risk cytogenic abnormalities.

Reference

Kumar AD, Rosenberg A, Padilla M, et al. Phase II study of the combination of daratumumab, ixazomib, pomalidomide, and dexamethasone as salvage therapy in relapsed/refractory multiple myeloma: Stage 2 interim results. Poster presented at: 2022 American Society of Clinical Oncology Annual Meeting; June 3-7, 2022; Chicago, IL. Accessed June 22, 2022. https://meetings.asco.org/abstracts-presentations/207926