Ixazomib-Based Regimen Induces Responses in Heavily Pretreated Waldenström Macroglobulinemia

Treatment with proteasome inhibitor ixazomib plus subcutaneous rituximab and dexamethasone (IRD) was associated with high rates of response and manageable toxicity in patients with relapsed or refractory Waldenström macroglobulinemia (WM), according to a study led by Marie José Kersten, MD, PhD, of the University of Amsterdam in the Netherlands.

Patients with WM are primarily treated with anti-CD20 monoclonal antibody–based combinations, yet significant challenges in managing relapsed or refractory disease remain. According to Dr. Kersten, previous results suggest IRD may be associated with high response rates and prolonged progression-free survival (PFS) in treatment-naïve patients with WM. However, the data regarding the clinical activity and safety of IRD in relapsed/refractory WM are sparse.

The international phase I/II HOVON124 study was conducted at 18 centers: 14 in the Netherlands, three in Belgium, and one in Greece. During phase I, six patients with relapsed or refractory WM were enrolled, followed by 54 patients in the phase II portion of the study. Phase II included a total of eight 28-day treatment cycles of ixazomib at the recommended dose level (4 mg orally on days 1, 8, and 15) and dexamethasone (20 mg orally on days 1, 8, 15, and 22).

One patient was ineligible for inclusion in the phase II analysis by Dr. Kersten and colleagues from the HOVON Lymphoma Group, the Greek Myeloma Study Group, and the European Consortium for WM, because of disease that was refractory to rituximab. The phase II analysis included 59 patients with progressive or relapsed WM and measurable disease following prior systemic treatment. To reduce the risk of immunoglobin M (IgM) flare, rituximab was added to the treatment regimen from cycle three onward, with the first dose given intravenously at 375 mg/m2 and the subsequent doses administered subcutaneously at a dose of 1,400 mg.

Patients with progressive disease after cycle four went off study. After eight cycles, patients with at least minor response (MR) continued rituximab maintenance at 400 mg subcutaneously every three months for two years.

The investigators examined the overall response rate (ORR) following induction, based on the IgM level. Additional endpoints included rates of complete response, very good partial response (VGPR), partial response (PR), and MR, time to first and best responses, duration of response (DOR), PFS, and overall survival (OS).

At baseline, the median age of the population was 69 years (range = 46-91). Patients had undergone a median of two prior treatments (range = 1-7). Approximately 70% of patients had an intermediate or high International Prognostic Scoring System score for WM.

At the end of eight treatment cycles, the ORR was 71%, including 14% with VGPR, 37% with PR, and 20% with MR. There was an improvement in depth of response until month 12, with a best ORR of 85% (15% VGPR, 46% PR, and 24% MR). The median DOR was 36 months.

Mean hematocrit level significantly increased from 33% at baseline to 38% following eight treatment cycles (p<0.001). Levels of IgM significantly decreased after two cycles of ixazomib, from a median of 3,700 to 2,700 mg/dL (p<0.0001) and further to 1,200 mg/dL following eight cycles (p<0.001).

The median time to first response was four months. The median PFS and OS were not reached during the study; however, PFS was 56% and OS was 88% after a median 24-month follow-up period.

Six patients died during the study as a result of disease progression (n=2), progressive multifocal leukoencephalopathy (n=1), graft-versus-host disease following allogeneic hematopoietic cell transplantation after disease progression (n=1), and cardiac comorbidities (n=2).

In terms of toxicity, most events included grade 2 or 3 cytopenias, grade 1 or 2 neurotoxicity, and grade 2 or 3 infections. There were no infusion-related reactions or IgM flares with subcutaneous rituximab. Patients reported significant improvements in quality of life after induction.

These findings are limited by the study’s small sample size and lack of a control group. “Larger randomized trials need to compare the efficacy of IRD to other regimens for relapsed or refractory WM,” Dr. Kersten wrote.


Kersten MJ, Amaador K, Minnema MC, et al. Combining ixazomib with subcutaneous rituximab and dexamethasone in relapsed or refractory Waldenström’s macroglobulinemia: Final analysis of the phase I/II HOVON124/ECWM-R2 study [published online ahead of print, 2021 Aug 13]. J Clin Oncol. doi: 10.1200/JCO.21.00105.