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Ixazomib Plus Rituximab and Dexamethasone Safe, Effective for WM

Ixazomib in combination with subcutaneous rituximab and dexamethasone (IRD) is feasible and shows promising efficacy and manageable toxicity in patients with relapsed Waldenström macroglobulinemia (WM), according to results from a phase 1/2 study presented at the virtual 2020 EHA Annual Congress.

“There is rationale for proteasome inhibition in WM. The MYD88 mutation, which is present in more than 90% of patients, is responsible for the high NFκB activity and the NFκB is activated via the proteasome. Therefore, proteasome inhibitors like bortezomib have shown promising responses in WM,” explained Karima Amaador, MD, Amsterdam University Medical Center, Netherlands, during her presentation.

“The downside is that they are also associated with high rates of polyneurothapy. Therefore ixazomib, which is an oral proteasome inhibitor, is ideal because it is well-tolerated and it has shown to have low rates of polyneuropathy in multiple myeloma,” she continued.

The aim of the study was to evaluate the efficacy and safety IRD in relapsed WM. Patients underwent a total of 8 cycles of therapy.

The primary end point of the trial was overall response rate (ORR) after induction, based on IgM levels. Secondary end points included safety, durability of response (DOR), progression-free survival (PFS), and overall survival (OS).

A total of 60 patients (median age, 69 years; 68% male) with relapsed WM were enrolled in the trial, 59 of whom were eligible for treatment. Median number of prior treatments was 2, median hemoglobin level was 10.1 g/dl, and median IgM level was 3.28 g/dl.

Overall, 45 (76%) of 59 patients completed all 8 cycles of induction therapy. The ORR was 71% (19% ≥VGPR, 52% ≥PR, 71% ≥MR). At 24 months follow-up, the DOR was 60%, PFS was 60%, and OS was 88%. Median DOR, PFS, and OS were not reached.

Additionally, a rapid and statistically significant decrease in IgM levels was seen after 2 cycles of ixazomib alone before the start of subcutaneous rituximab (IgM 3.28 to 2.66 g/dl, P <.0001). This was accompanied by a rapid increase in hemoglobin (10.5 to 11.2 g/dl, P <.001). DOR continued to increase until 12 months.

Grade 3 adverse events (AEs) were reported 31% of patients and grade 4 AEs were seen in 8%. The most common AEs were cytopenias, laboratory abnormalities, and infections. New onset polyneuropathy occurred in 13 patients, but no increase in neuropathy-related symptom burden were noted.

“This trial demonstrated that the IRD regimen is feasible in WM. It is easy to administer, there had been no IgM flares, and with the subcutaneous administration of rituximab, none of the patients developed hypersensitivity,” said Dr Amaador.

“Further improvements could be that in the future we can use this as a backbone for a combination treatment and ixazomib could be used as consolidation or maintenance treatment,” she concluded.—Janelle Bradley

Kersten MJ, Minnema M, Amaador K, et al. Ixazomib, Rituximab and Dexamethasone (IRD) in Patients With Relapsed or Progressive Waldenström’s Macroglobulinemia: Final Analysis of the HOVON124/ECWM-R2 Trial. Presented at: the Virtual 2020 EHA Annual Congress; June 11-21, 2020. Abstract S226.

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