Prospective Phase II Study of Ixazomib, Dexamethasone and Rituximab in Previously Untreated Patients with Waldenström Macroglobulinemia

Introduction: Waldenström macroglobulinemia (WM) is an incurable B-cell lymphoma characterized by the accumulation of IgM-secreting lymphoplasmacytic cells in the bone marrow and other organs. Bortezomib in combination with rituximab and dexamethasone (BDR) is highly active as primary therapy in WM, though treatment-related neuropathy is common with BDR in WM, and often leads to premature treatment discontinuation (Treon et al. J Clin Oncol 2009). Ixazomib is an orally administered proteasome inhibitor with limited neuropathy that is active in myeloma, but has not been previously evaluated in WM

Methods: Symptomatic, previously untreated patients with a clinicopathological diagnosis of WM were included in this prospective, single-arm phase II study evaluating ixazomib 4 mg PO on days 1, 8 and 15 + dexamethasone 20 mg PO on days 1, 8 and 15 + rituximab 375 mg/m2 IV on day 1 (IDR) were administered for six 4-week cycles (induction) followed by six 8-week cycles (maintenance) for a total of 12 cycles. Rituximab was held for the first two cycles of therapy to minimize risk of an IgM flare. Zoster prophylaxis and proton pump inhibitors were administered throughout IDR therapy. The study was approved by the institutional review board at the Dana-Farber Cancer Institute, and registered under Clinicaltrials.gov ID NCT02400437.

Results: Twenty-six WM patients were enrolled, and received protocol therapy. The median age at WM diagnosis was 63 years (range 46-81 years) and the median age at initiation of therapy was 65 years (range 46-82 years). Baseline median hemoglobin was 10.2 g/dl (range 6.9-13.2 g/dL), median serum IgM level was 4,528 mg/dl (range 653-7,650 mg/dL), 46% of patients had lymphadenopathy and 12% had splenomegaly. The median bone marrow involvement was 55% (range 5-95%). The MYD88 L265P gene mutation was identified in all cases. CXCR4 WHIM mutations were identified in 15 patients (58%), of whom 10 (67%) had nonsense, and 5 (33%) frameshift mutations. All patients have completed induction and maintenance therapy at this time. The median number of cycles received was 12 (range 4-12). Following induction therapy, the median serum IgM level decreased to 2,279 mg/dl (range 287-5,820 mg/dL), the median hemoglobin increased to 12.7 mg/dl (range 10.4-14.6 g/dL), and the median bone marrow involvement decreased to 15% (range 0-76%). P-value <0.001 for all comparisons against baseline. At end of study, the median serum IgM decreased to 871 mg/dl (range 76-5,715), the median hemoglobin increased to 13.6 g/dl (range 9.2-15.7 g/dl), and the median bone marrow involvement decreased to 5% (range 0-70%). P-value <0.001 for all comparisons against baseline. Using consensus response criteria, the overall response rate (ORR) was 96% (VGPR 15%, PR 62%, MR 19%) with a major response rate (VGPR + PR) of 77%. Major responses were observed in 69% of patients with CXCR4 mutations versus 82% in those who were wild-type CXCR4 (p>0.05). The median time to response was 8 weeks. The median time to response in CXCR4 mutant patients was 12 weeks versus 8 weeks in wild-type CXCR4 patients (log-rank p=0.03). After a median follow-up of 18 months, the median progression-free survival (PFS) was not reached. The 18-month PFS rate was 90% (95% CI 65-97%). Most common adverse events (grade 1 and 2) included infusion reactions (n=10), nausea (n=9), insomnia (n=7), rash (n=7), neuropathy (n=5), edema (n=5), diarrhea (n=5) and hyperglycemia (n=5). Grade 3 adverse events included neuropathy (n=1), pneumonia (n=1) and sepsis (n=1). The median IgG level decreased from 609 mg/dl (range 160-4,677 mg/dl) to 409 mg/dl (range 113-822 mg/dl) (p=0.02). The median IgA level decreased from 62 mg/dl (range 8-140 mg/dl) to 33 mg/dl (range 7-109 mg/dl) (p<0.001). No deaths have occurred.

Conclusion: The results of this study showed that the combination of IDR is highly effective in symptomatic untreated WM patients with an ORR of 95% and 18-month PFS rate of 90%. IDR was well-tolerated, and represents a novel, neuropathy-sparing proteasome inhibitor regimen for the treatment of WM. CXCR4 mutations impact the time to response but not the depth of response to IDR.

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