Ixazomib, Rituximab, and Dexamethasone in Patients with Relapsed or Progressive Waldenström Macroglobulinemia

Conference Correspondent 

Evidence suggests that proteasome inhibitors (PIs) show synergy with rituximab in newly diagnosed and relapsed patients with Waldenström macroglobulinemia (WM). Given that WM is often associated with polyneuropathy (PNP), bortezomib is associated with increased risk for induced PNP or worsening of existing PNP. The current multicenter phase 1/2 trial was undertaken to investigate the efficacy and toxicity of the less neurotoxic PI, ixazomib citrate, in combination with subcutaneous (SC) rituximab and dexamethasone, in patients with relapsed WM.

The phase 1 part of the trial used a standard 3 + 3 design to determine dose-limiting toxicity and to establish the recommended phase 2 dose level (RP2D). The primary end point for phase 2 was overall response rate (ORR; at least minimal response [MR]) after 8 induction cycles.

Eligible patients had relapsed/progressed WM with measurable disease (immunoglobulin M [IgM] >16/dL), and need for treatment (consensus criteria); prior bortezomib and/or rituximab was allowed unless refractory. Treatment consisted of 8 induction cycles every 28 days with ixazomib citrate (4 mg orally on days 1, 8, and 15; de-escalate to 3 mg if too toxic) and dexamethasone (20 mg orally on days 1, 8, 15, and 22). Rituximab (375 mg/m2 intravenously) was added on day 1 of cycle 3, followed by SC administration (1400-mg flat dose on day 1) in cycles 4 through 8. Patients who achieved at least a partial response (PR) received 2 years of rituximab maintenance treatment (1400 mg SC every 3 months).

A total of 60 patients were enrolled. Ixazomib citrate 4 mg was established as the RP2D. Of the 59 patients (1 rituximab-refractory patient was deemed ineligible) treated with the RP2D, the median age was 69 years (range, 46-91), the median number of prior treatments was 2 (range, 1-7), 70% had an intermediate or high WM International Prognostic Scoring System score, median hemoglobin (Hb) level was 10.1 g/dL (range, 6.4-15.9), and median IgM level was 3.28 g/dL (range, 1.0-9.13).

Of the 59 patients, 45 patients completed 8 cycles of induction therapy; 14 discontinued early (6 due to progression, 3 due to toxicity, 2 due to intercurrent death, 1 due to insufficient clinical benefit, 2 due to other reasons). Of the evaluable patients, ORR was 71%, with ≥PR of 51%; the best ORR was 85%, including 15% very good PR, 46% PR, and 24% MR. With a median follow-up of 24 months, the median duration of response (DOR), median progression-free survival (PFS), and overall survival (OS) were not reached. At 24 months, PFS was 56%, DOR was 60%, and OS was 88%. Before the introduction of rituximab (after cycle 2), a rapid and statistically significant decrease in IgM levels was observed (3.66 g/dL-2.66 g/dL; P <.0001), accompanied by a rapid increase in Hb levels (10.5 g/dL-11.5 g/dL; P =.0004). Depth of response continued to increase until month 12.

Grade 3 toxicity was reported in 28% of patients and grade 4 toxicity in 10% of patients. Serious adverse events (n = 23) were reported in 16 patients, mostly infections. Six deaths were reported: 2 due to progressive disease; 1 due to progressive multifocal leukoencephalopathy (symptoms present at study entry); 2 were considered unrelated; and 1 due to graft-versus-host disease after progression and subsequent allogeneic stem-cell transplantation. Twenty-one patients had PNP at baseline, with new onset or worsening of PNP occurring in 16 patients. Significant increase in global health status was observed during induction therapy (cycle 8 vs baseline; P = .03).

The study investigators concluded that the combination of ixazomib citrate, SC rituximab, and dexamethasone was feasible and showed promising efficacy with manageable toxicity in patients with relapsed or progressive WM.

Kersten MJ, et al. ASH Abstract 344. Session 623.

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