ASH 2019 – Ixazomib with rituximab and dexamethasone effective in Waldenstrom’s macroglobulinemia

  • W. Todd Penberthy, Ph.D.
  • Univadis
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  • Combination treatment with ixazomib citrate, rituximab, and dexamethasone is feasible, shows promising efficacy, and manageable toxicity in patients with relapsed or progressive Waldenstrom’s macroglobulinemia.

Why this matters

  • Proteasome inhibitors like bortezomib have shown considerable efficacy in treating progressive Waldenstrom’s macroglobulinemia, but polyneuropathy is a common problem.
  • Adding dexamethasone with alternative proteosome inhibibitor ixazomib may be effective.

Study design

  • A multicenter phase 1/2 trial of 60 patients with relapsed Waldenstrom’s macroglobulinemia, treated with ixazomib, rituximab, and dexamethasone (IRD). 
  • Patients received 4 mg oral ixazomib citrate and 20 mg dexamethasone every week on a 28-day cycle. 
  • Rituximab was added in cycle 3.
  • Phase 2 primary endpoint: overall response rate after 8 induction cycles.
  • Funding: Takeda Oncology; Roche; and the Dutch Cancer Society.

Key results

  • Phase 1: ixazomib 4 mg was feasible and continued as phase 2 dose.
  • Phase 2: 50 patients were included.
  • 39 patients completed 8 cycles of induction therapy.
  • 11 patients discontinued treatment due to progression (n=5), toxicity (n=3), intercurrent death (n=2), or insufficient clinical benefit (n=1).
  • 74% of patients achieved the primary endpoint (≥very good partial response [VGPR], 16%; ≥partial response [PR], 52%; at least minimal response [MR], 74%).
  • Best overall response rate was 88% (complete response, 2%; VGPR, 22%; PR, 44%; MR, 20%). 
  • Median follow-up was 19.5 (range, 7-49) months.
  • Median duration of response and median PFS were not reached. 
  • IgM levels decreased significantly from 3.93 to 2.37 g/dL by cycle 2 (P<.001>
  • 15 patients experienced a total of 21 serious adverse events.
  • 6 patients died due to:
    • progressive disease, 2;
    • progressive multifocal leukoencephalopathy, 1 (symptoms present already at entry);
    • unrelated deaths in elderly patients with multiple preexisting comorbidities, 2; and
    • graft vs host disease after progression and subsequent allogeneic stem cell transplantation, 1.