Ixazomib, Rituximab, and Dexamethasone Combo Demonstrates Promising Efficacy in R/R Waldenströms Macroglobulinemia


Patients with relapsed/refractory Waldenströms macroglobulinemia benefited from treatment with ixazomib, rituximab, and dexamethasone and maintained a tolerable safety profile.

The combination of ixazomib, rituximab (Rituxan), and dexamethasone (IRD) exhibited promising efficacy data with a manageable toxicity profile when used to treat patients with relapsed or refractory Waldenströms macroglobulinemia (WM), according to data from the phase 1/2 HOVON124/ECWM-R2 study, which was published in the Journal of Clinical Oncology.

At the interim analysis, 83% patients treated in the phase 2 portion of the study achieved a response. In the intention-to-treat population, the overall response rate (ORR), the primary end point of the study, after 8 treatment cycles was 71% (95% CI, 60%-79%). The responses included a very good partial response (VGPR) in 14% of patients, a partial response (PR) in 37% of patients, and a minor response (MR) in 20% of patients.

“The IRD regimen with oral ixazomib and subcutaneous rituximab provides a patient-friendly and efficient treatment in patients with heavily pretreated [Waldenströms macroglobulinemia], inducing high rates of response and respectable [progression-free survival (PFS)] with very good [overall survival] and, thus, could be an additional treatment option for patients with [relapsed/refractory Waldenströms macroglobulinemia],” the investigators wrote.

A total of 59 patients with relapsed/refractory Waldenströms macroglobulinemia were enrolled on the study with a median age of 69 years (range, 46-91). Additionally, 68% of patients were male and 36% of patients were high risk based on International Prognostic Scoring System for Waldenströms macroglobulinemia. Eligible patients who enrolled were treated with 8 28-day cycles of oral ixazomib at 4 mg on days 1, 8, and 15, and oral dexamethasone at 20 mg on days 1, 8, 15, and 22. Rituximab was given during cycle 3 and onward, with the first dose given intravenously at 375 mg/m2 and all subsequent doses given at 1400 mg subcutaneously.

Eligibility criteria for the HOVON124 study required patients to have progressive or relapsed Waldenströms macroglobulinemia following prior systemic therapy.

Of the analysis population, 81% completed at least 6 cycles of treatment with IRD. Reasons for discontinuation included progression (n = 6), toxicity (n = 3), unrelated intercurrent death (n = 2), incompliance (n = 1), and other reasons (n = 2).

The median duration of response among these patients was 36 months. In terms of survival, median PFS and OS were not reached. Additionally, after a median follow-up of 24 months (range, 7.4-54.3), investigators reported a PFS rate of 56% (95% CI, 40%-67%) and an OS of 88% (95% CI, 75%-95%).

One cycle of IRD was delayed for 34 patients due to hematologic toxicity (n = 6), infusion-related reactions (IRRs) to intravenous rituximab (n = 2), neurotoxicity (n = 5), or other toxicity (n = 21). Some common adverse effects (AEs) included grade 1 neurotoxicity and grade 2 infections, gastrointestinal disorders, and local reactions. Grade 3 anemia (n = 4), thrombocytopenia (grade 2, n = 11; grade 3, n = 4; grade 4, n = 3), and neutropenia (grade 3, n = 7; grade 4, n = 4) were also observed. Serious AEs included infections (n = 8) and other conditions (n = 7) such as dehydration, subarachnoid bleeding, and secondary malignancy.

The research team suggests introducing larger randomized trials to compare the efficacy of treatment with IRD with other existing regimens for relapsed/refractory Waldenströms macroglobulinemia.


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 J Clin Oncol. Published online ahead of print, August 13, 2021. doi:10.1200/JCO.21.00105

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