Bortezomib, Dexamethasone and Rituximab in Newly Diagnosed Patients with WaldenströM's Macroglobulinemia: Final Analysis of a Phase 2 Study after a Minimum Follow up of 6 Years

Waldenström macroglobulinemia (WM) is a rare low grade lymphoma, with a prolonged course. With a median survival exceeding 7 years, prolonged follow up is needed in order to evaluate the outcomes of patients with WM after a specific primary therapy. Anti-CD20 monoclonal antibodies, such as rituximab, remain cornerstones of WM therapy, usually in combination with alkylating agents. Bortezomib is a proteasome inhibitor which has shown activity in myeloma but also has shown significant activity, especially in terms of rapid IgM reduction, in patients with relapsed/refractory or treatment naïve WM. Clinical and preclinical data have indicated potential synergistic activity for the combination of bortezomib and rituximab. Thus, in a large phase 2 trial we evaluated the activity of the chemotherapy free combination of bortezomib with dexamethasone and rituximab (BDR) in 59 newly diagnosed patients with WM fulfilling the contemporary criteria for diagnosis and treatment initiation. Here we present the results from the long term follow up of this study, focusing on long term outcomes and long term toxicity, after a minimum follow up of 6 years.

A total of 5 cycles of therapy with BDR were planned. In order to manage complications that are associated with high IgM levels, reduce the need for plasmapheresis and the risk and severity of rituximab-associated "IgM flare", single-agent intravenous (iv) bortezomib at a dose of 1.3 mg/m² was administered on days 1, 4, 8, and 11 of the first 21-day cycle. On cycles 2 to 5, bortezomib was administered IV weekly at a dose of 1.6 mg/m² on days 1, 8, 15, and 22 in four 35-day consecutive cycles. On cycles 2 and 5, IV dexamethasone 40 mg and IV rituximab at a dose of 375 mg/m² were given on days 1, 8, 15, and 22 (total of 8 infusions of rituximab).

Fifty-nine patients were treated with BDR from March 2007 until June 2010. The characteristics of the patients, response rates and toxicity have been published previously (Dimopoulos MA, et al Blood. 2013 Nov 7;122(19):3276-82). Briefly, most patients had advanced age (61% were >65 years) and advanced disease with adverse prognostic factors such as, anemia (hemoglobin <11.5 g/dL in 82%) and elevated β2-microglobulin (≥3 mg/dL in 64%), so that 45.5% and 40% were rated as high and intermediate risk per the International Prognostic Scoring System for WM. On intent to treat, 85% of the patients responded [3% complete response (CR), 7% very good partial response (VGPR), 58% partial response (PR), 17% minor response (MR)] for a major response rate (≥PR) of 68%.

Median follow up is86 months (range 0.6- 112). At 7 years 40 patients (68%) had disease progression or died due to WM, while 9 patients (15%) died due to unrelated causes without progression. Median progression-free survival (PFS) was 43 months (95% CI 23-63) and 10 patients (17%) still remain in remission after a median of 90 months (range 73.5-112). As per ISSWM stage PFS at 7-years was 62.5%, 42% and 15% for patients with low, intermediate and high risk disease respectively. Median duration of response for patients who achieved at least PR was 64.5 months. Among the 40 (68%) patients with disease progression or relapse, 21 (35.5%) received second line treatment.

Up to the date of data cutoff (June 2016), 20 patients (34%) have died and accounting for WM-unrelated death as a competing event, WM-related death rate at 7 years was 18.5% and unrelated death rate was 15.5%. Overall survival (OS) rate at 7-years was 66% and OS rate was 87.5% for low, 68.2% for intermediate and 48% for high risk patients per ISSWM. No patient has developed secondary MDS and transformation to DLBCL occurred in 2 (3.3%) patients, who had received chemo-immunotherapy after BDR.

In conclusion, BDR is a very active regimen, well tolerated and, importantly, with favorable long term toxicity profile. Primary therapy with this chemotherapy- free regimen, which was completed in 23 weeks, induced durable responses in newly diagnosed symptomatic WM patients with approximately 17% of patients still remaining in response after 7 years. Our data support the use of BDR as one of the recommended regimens for the treatment of this disease WM.