The combination of ixazomib, rituximab, and dexamethasone (IRD) showed “promising efficacy with manageable toxicity” in patients with relapsed or refractory Waldenstrom macroglobulinemia (WM), researchers reported in the Journal of Clinical Oncology. 

In the phase 1/2 HOVON124/ECWM-R2 trial, researchers evaluated the efficacy and safety of IRD in 59 patients with relapsed or refractory WM. 

The patients’ median age was 69 years (range, 46-91 years), 68% were men, and they had received a median of 2 prior treatments (range, 1-7). Most patients had intermediate-risk (34%) or high-risk (36%) disease.  

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Patients were treated with 8 cycles of ixazomib (4 mg orally on days 1, 8, and 15) and dexamethasone (20 mg orally on days 1, 8, 15, and 22). Rituximab was added from cycle 3 onward. The first dose was given intravenously (375 mg/m2 on day 1), and all subsequent doses were given subcutaneously (1400 mg). 

After cycle 4, patients who had progressive disease were taken off study. After cycle 8, patients who had at least a minor response (MR) went on to receive rituximab maintenance (400 mg every 3 months for 2 years).

In all, 48 patients completed at least 6 cycles of treatment, and 41 proceeded to maintenance. 

After 8 cycles, the overall response rate (ORR) was 71%, with 14% of patients achieving a very good partial response (VGPR), 37% having a partial response (PR), and 20% having an MR. 

Responses continued to improve until month 12. The best ORR was 85%, with a VGPR seen in 15% of patients, a PR in 46%, and an MR in 24%. 

The median time to first response was 4 months, the median time to best response was 5 months, and the median duration of response was 36 months. 

At a median follow-up of 24 months, the progression-free survival (PFS) rate was 56%, and the overall survival (OS) rate was 88%. The median PFS and OS were not reached.  

The most common grade 3 adverse events (AEs) were blood and lymphatic system disorders (10%), nervous system disorders (8%), blood investigation abnormalities (7%), and infections and infestations (5%). 

Grade 4 AEs included blood investigation abnormalities (5%), blood and lymphatic system disorders (2%), and malignant or benign neoplasms (2%).

None of the patients experienced immunoglobulin M flare during induction, and there was no significant increase in neuropathy-associated symptoms during treatment. 

The researchers concluded that IRD “provides a patient-friendly and efficient treatment in patients with heavily pretreated WM, inducing high rates of response and respectable PFS with very good OS and, thus, could be an additional treatment option for patients with RR [relapsed/refractory] WM.”

Disclosures: This research was partially supported by Takeda and Roche. Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.


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 August 13, 2021. doi:10.1200/JCO.21.00105