Ixazomib, rituximab, and dexamethasone in patients with relapsed or progressive Waldenström’s macroglobulinemia: Final analysis of the HOVON124/ECWM-R2 study

Waldenström’s macroglobulinemia (WM) is a rare condition in which abnormal numbers of lymphoplasmacytic cells accumulate in the bone marrow. These cells produce high levels of immunoglobulin M (IgM), which can result in thickening of the blood and lead to multiple symptoms in affected patients. At the Virtual Edition of the 25th European Hematology Association (EHA) Annual Congress, Karima Amadoor presented the final results of the HOVON124/ECWM-R2 study, a multicenter phase I/II trial investigating the use of the triplet combination of ixazomib, rituximab, and dexamethasone (IRd) in relapsed and progressive patients with WM.

MYD88 is a common mutation in WM, present in > 90% of patients, and is responsible for the high NFκB activity. NFκB is activated via the proteasome, therefore the use of a proteasome inhibitor, such as bortezomib or ixazomib, is justified. Bortezomib is associated with a high degree of polyneuropathy so the present study selected ixazomib for further analysis.

Patients and methods

Key inclusion criteria for the study included patients with relapsed/progressed WM who needed treatment and who had measurable disease (IgM > 1 g/dL). Prior bortezomib and/or rituximab was allowed unless the patient was refractory.

Six patients were included in the phase I section of the trial, which investigated ixazomib doses between 1−4 mg. As the toxicity was within acceptable limits, 4 mg was established as the recommended phase II dose.

In the phase II section of the trial, a further 54 patients were eligible. Patient baseline characteristics are shown in Table 1 (N = 59 because one patient was refractory to rituximab). The primary endpoint was overall response rate (ORR) based on IgM levels. Secondary endpoints were safety, durability of response, and improvement of response during maintenance.

Treatment schedule:

• Induction: Eight cycles, every 28 days
  • Ixazomib: 4 mg on Days 1, 8, and 15
  • Rituximab: 1,400 mg subcutaneously on Day 1 of Cycles 3–8
  • Dexamethasone: 20 mg on Days 1, 8, 15, and 22
• Rituximab maintenance for 2 years, every 3 months: 1,400 mg subcutaneously on Day 1

Table 1. Baseline patient characteristics¹

Out of the 59 eligible patients, 53 patients completed Cycles 1–4, 45 patients completed Cycles 5–8, and 41 patients continued to maintenance. The most common reasons for patients coming off treatment were disease progression, death, and toxicity.

Key findings

The primary endpoint was met: ORR, 71%. The best responses were obtained during induction:

• ORR, 85%
• Very good partial response, 15%
• Partial response, 46%
• Minor response, 24%

At 24 months, progression-free survival was 56%, duration of response was 60%, and overall survival was 88%; the median of each was not reached.

A rapid and significant decrease in IgM levels was seen after two cycles of ixazomib alone (prior to the addition of rituximab; baseline to Cycle 2 IgM: 3.66–2.66 g/dL; p < 0.0001) accompanied by a fast increase in hemoglobin levels (baseline to Cycle 2: 10.52–11.15 g/dL; p = 0.0004).

Of the patients included, n = 32 (88%) had a MYD88 mutation. The MYD88 mutational load decreased during the study, as measured by next-generation sequencing.

In total, 23 serious adverse events occurred in 16 patients, mainly due to infections (Table 2). During induction, six patients died:

• 2 patients died of disease progression
• 2 patients died of sudden deaths associated with cardiac issues
• 1 patient died of promyelocytic leukemia, unrelated to treatment
• 1 patient died of graft-versus-host disease after allogeneic stem cell transplantation, considered to be unrelated to treatment

No treatment-related mortality was seen.

Table 2. Summary of serious adverse events¹

In terms of neuropathy, 16 patients experienced new onset or worsening peripheral neuropathy, though this was reversible in 63% of patients. Overall quality of life was also assessed, and patients reported a significant increase after eight cycles (p = 0.03), which was mainly due to a decrease in fatigue.

Conclusion

Since there are no curative treatments for WM, there is an ongoing need for trials assessing therapeutic options. The present study demonstrates that the IRd regimen is a feasible and effective treatment for WM and increased the overall quality of life of the patients included. The authors speculate that IRd could be used a backbone for combination treatment in the future.