Ixazomib/Rituximab/Dexamethasone for Relapsed or Refractory Waldenström’s Macroglobulinemia

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In a phase I/II trial (HOVON124/ECWM-R2) reported in the Journal of Clinical Oncology, Kersten et al found that the combination of oral ixazomib with subcutaneous rituximab and dexamethasone showed efficacy in patients with relapsed or refractory Waldenström’s macroglobulinemia, with a manageable toxicity profile.

As stated by the investigators, “Proteasome inhibitors are effective in Waldenström’s macroglobulinemia but require parenteral administration and are associated with polyneuropathy. We investigated [the] efficacy and toxicity of the less neurotoxic oral proteasome inhibitor ixazomib combined with rituximab in patients with relapsed Waldenström’s macroglobulinemia.”

Study Details

The phase I portion of the trial established the feasibility of an ixazomib dose of 4 mg. In the phase II portion, 59 patients enrolled between January 2015 and January 2019 from sites in the Netherlands, Belgium, and Greece received induction with eight 28-day cycles of ixazomib at 4 mg on days 1, 8, and 15, and oral dexamethasone at 20 mg on days 1, 8, 15, and 22, with rituximab started at cycle three; the first rituximab dose was given intravenously at 375 mg/m2 on day 1, with all subsequent doses given at 1,400 mg subcutaneously on day 1.

After cycle four, patients with progressive disease went off-study. After cycle eight, patients with at least a minor response started rituximab maintenance at 1,400 mg subcutaneously every 3 months for 2 years. The primary endpoint was overall response rate (≥ minimal response) after induction.


After eight cycles, a response was observed in 42 (71%) of 59 patients, with very good partial response in 14%, partial response in 37%, and minor response in 20%. Responses continued to improve with therapy through month 12, with response observed in 50 patients (85%), including very good partial response in 15%, partial response in 46%, and minor response in 24%.

Median time to first response was 4 months, and median duration of response was 36 months. Among 14 patients who did not complete eight cycles, 1 had a very good partial response, 4 had a partial response, 2 had a minor response, 3 had stable disease, and 4 had disease progression.


  • The overall response rate was 71% after eight cycles and 85% at 12 months.
  • Median response duration was 36 months.

Average hematocrit level increased from 0.33 L/L at baseline to 0.37 L/L after four cycles (P < .001) and to 0.38 L/L after eight cycles (P < .001), Median IgM levels decreased significantly from 3,700 mg/dL to 2,700 mg/dL after the first two cycles of ixazomib (P < .0001) and to 1,200 mg/dL after eight cycles (P <.001).

Median progression-free and overall survival were not reached. After a median follow-up of 24 months, rates of progression-free and overall survival were 56% and 88%, respectively.

Adverse Events

Toxicity consisted primarily of grade 2 or 3 cytopenias, grade 1 or 2 neurotoxicity, and grade 2 or 3 infections. No patients experienced IgM flare during induction. Cycles of treatment were interrupted due to adverse events in 58% of patients, with the most common causes being hematologic toxicity (10%) and neurotoxicity (8%). The most common serious adverse event was infection (14%).

The investigators concluded: “[The] combination of ixazomib, rituximab, and dexamethasone shows promising efficacy with manageable toxicity in patients with relapsed or refractory Waldenström’s macroglobulinemia.”

Marie José Kersten, MD, PhD, of the Department of Hematology, Amsterdam UMC, University of Amsterdam, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported by the Dutch Cancer Society, Takeda, and Roche. For full disclosures of the study authors, visit

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