Treatment of Patients With R/R WM With Ixazomib Appears Safe and Effective

Treatment of patients with relapsed or refractory (R/R) Waldenström's macroglobulinemia (WM) with the oral proteasome inhibitor ixazomib combined with subcutaneous rituximab was associated with a median duration of response of 36 months, according to a final analysis of the results from a multicenter phase 1/2 trial.

“Proteasome inhibitors are effective in WM, but require parenteral administration and are associated with polyneuropathy. We investigated efficacy and toxicity of the less neurotoxic oral proteasome inhibitor ixazomib,” wrote lead author Marie Kersten, MD, PhD, University of Amsterdam, and co-authors.

In HOVON124/ECWM-R2, 59 patients (median age 69 years; range, 46-91 years) were enrolled and treated with ixazomib, rituximab, and dexamethasone (IRD). The median number of prior treatments was 2 (range 1-7); 70% of participants had an intermediate or high WM score on the International Prognostic Scoring System.

Phase 1 showed the feasibility of a 4 mg dose of ixazomib. Induction consisted of 8 cycles of IRD; rituximab was started in cycle 3, followed by rituximab maintenance. Of the patients, 81% completed at least 6 cycles of IRD.

After 8 cycles, the overall response rate (ORR), which was the primary endpoint, was 71%. Of the entire cohort, 14% had a very good partial response (VGPR), 37% a PR, and 20% a minor response. The depth of response improved until month 12 (ORR 85%). The median time to the first response was 4 months.

Median progression-free survival (PFS) and overall survival (OS) were not reached, but at a median follow-up of 24 months (range 7.4 - 54.3 months), PFS was 56% and OS was 88%.

No infusion-related reactions or immunoglobulin M flare occurred with use of subcutaneous rituximab. However, in more than half of the patients (n = 34), a cycle of IRD was delayed because of toxicity, including grade 2 or 3 cytopenia, grade 1 or 2 neurotoxicity, and grade 2 or 3 infections.

Nervous system disorders occurred in 22% of subjects, including syncope, Bing-Neel Syndrome, vasovagal reaction, neurological absence, depressed level of consciousness, and peripheral motoric neuropathy.

Other serious adverse events (AEs) which occurred in 4% or more of patients included secondary malignancy (breast cancer), subarachnoid bleeding due to trauma, infections, and dehydration.

Source:
Kersten M, Amaador K, Minnema M, 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.