Bortezomib in Combination with Dexamethasone, Rituximab and Cyclophosphamide (B-DRC) As First - Line Treatment of Waldenstrom's Macroglobulinemia: Results of a Prospectively Randomized Multicenter European Phase II Trial

Background: Rituximab/chemotherapy is still one of the cornerstones of treatment for patients with Waldenström's macroglobulinemia (WM) despite the emergence of BTK inhibitors. Beside Rituximab-Bendamustine the combination Dexamethasone, Rituximab and Cyclophospamide (DRC) is the most widely recommended immunochemotherapy in national and international guidelines based on its low myelotoxicity and anti-lymphoma activity in WM. In addition, the proteasome inhibitor Bortezomib (B) has shown significant activity in WM as single agent or combined with Rituximab and/or Dexamethasone. This study aimed at evaluating the efficacy and toxicity of Bortezomib-DRC (B-DRC) as first line treatment in WM.

Methods: In this prospective randomized multicenter European phase II study, patients with the diagnosis of WM confirmed by reference pathology and in need of treatment were randomized 1:1 to DRC (Dexamethasone 20 mg orally d1, Rituximab 375 mg/m² IV d1 cycle 1 and 1400 mg SC d1 cycle 2-6, Cyclophosphamide 100 mg/m² x 2 orally d1-5) or to B-DRC (DRC plus Bortezomib SC 1,6mg/m² day 1, 8, 15) for 6 cycles (28d interval). Primary endpoint was progression free survival (PFS). Secondary endpoints included response rates, overall survival (OS), and toxicity.

Results: Of 204 registered patients, 2 patients were excluded due to incorrect randomization. Median follow-up was 27.5 months at the time of the data cut. Median age was 68 years (range 34-89) in both arms. According to the ISSWM prognostic score 14 % of patients were at low, 73 % at intermediate and 13 % at high risk in both treatment arms. Median baseline hemoglobin for B-DRC and DRC was 10.0 and 9.8 g/dl and median baseline IgM 31.7 and 31.9 g/dl, respectively. Mutational status was available for 72 patients: in the B-DCR vs DRC treatment arm 26 and 16 patients were MYD88 mutated (MYD88^MT) and CXCR4 wildtype (CXCR4^WT), 8 and 12 patients were MYD88^MT/CXCR4^MT and 5 and 5 patients MYD88^WT/CXCR4^WT, respectively. Median PFS has not been reached in the B-DRC arm (95% CI: 33.5; --) compared to 50.1 months in the DRC arm (95% CI: 31.1; --) with an estimated PFS at 24 months of 80.6 % (95% CI: 69.5; 88.0) and 72.8 % (95% CI: 61.3; 81.3), respectively (p=0.32). Median OS has not been reached in either treatment arm with 5 deaths and 6 deaths in the B-DRC and DRC arm, respectively. At the end of treatment B-DRC induced major responses (at least PR) in 79.1 % of patients (vs 68.9% for DRC) and a CR/VGPR in 18.7 % of patients (vs 11.1 % for DRC) with an overall response of 91.2 compared to 86.7 % for DRC. Compared to baseline IgM decreased by 79 % and 73 % and Hb increased by 28 % and 32 % in the B-DRC and DRC arm, respectively. Responses and PFS were independent of the mutational status in both treatment arms. B-DRC and DRC were well tolerated: grade ≥3 AEs occurred in 48% of all patients (B-DRC 48%, DRC 47%). Most common grade ≥3 AEs included neutropenia (25%), anemia (6%), and thrombocytopenia (5%). Overall, 16 pts (8%) developed infections (1% grade ≥3). Serious AEs occurred in 40 pts (20%) (DRC: 26 (26%), B-DRC: 14 (14%)). Peripheral sensory neuropathy occurred in 18 patients treated with B-DRC (2 patients with grade 3, 16 patients grade 1-2) and in 3 patients treated with DRC (all grade 1 and 2).

Conclusions: This is the first and largest prospective randomized trial to evaluate bortezomib in combination with standard immunochemotherapy, demonstrating that B-DRC is a well-tolerated regimen which induces a high rate of major responses including deep remissions after 6 months of treatment with a 2-year PFS of 81%, independently of the mutational status of MYD88 and CXCR4. At this time point of analysis, adding Bortezomib to DRC did not induce significant differences in PFS compared to DRC alone. Future trials will have to compare chemotherapy-free approaches such as continuous treatment with BTK inhibitors with fixed duration treatments exemplified by B-DRC to understand which of the two treatment approaches offers the highest long - term sustained clinical benefit to WM patients.