Dexamethasone, Rituximab and Cyclophosphamide with Bortezomib is a rapidly acting and highly efficient first-line treatment in Waldenström's Macroglobulinemia: Final analysis of ECWM-1 trial of the European Consortium for Waldenström's Macroglobuline

Abstract Beside Rituximab-Bendamustine, the Dexamethasone, Rituximab and Cyclophospamide (DRC) regimen is still one of the most frequently used first-line treatments for patients with Waldenström's Macroglobulinemia (WM). It was originally reported to induce a 2-years PFS of 65 % (Dimopoulos et al., JCO, 2007, 25; 3344) when given in three weeks intervals for 6 cycles. The academic prospective randomized multicenter ECWM-1 trial of the European Consortium for Waldenström's Macroglobulinemia (ECWM) aimed at improving the outcome of treatment naive WM by the addition of Bortezomib (B) to DRC, given in 4-weeks cycles for 6 cycles. We reported previously that B-DRC induced deep and fast remission with no significant difference in the 2-year PFS compared to DRC alone after a median follow-up of 27.5 months (Buske et al., JCO, 2023, 41; 2607). This final analysis reports on the treatment outcome and long-term safety of this study after a median follow-up of 68.8 months. From 2012 to 2018, 204 patients were registered with 2 patients being excluded due to incorrect randomization. One hundred patients were randomized into the DRC arm and 102 patients into the B-DRC arm. Median age was 68 years (Interquartile range: 60;74). One hundred and three progressions and 30 deaths (11 without progression [3 grade 5 adverse events and 8 WM unrelated deaths] and 19 after progression [9 WM related deaths and 10 deaths from WM unrelated or unknown cause]) occurred. The median PFS was 56.7 months (95% confidence interval [95CI]: 46; n.a.) versus 50.1 months (95CI: 39.2; 69.4) for B-DRC versus DRC, respectively (p=0.64, 2-year PFS 79% [95CI: 73; 85] for the total patient population). The 4-months cumulative incidence of first response occurrence was 73% for B-DRC (95CI: 64; 81) versus 61% for DRC (95CI: 52; 70), Fine and Gray test: p=0.83). The CR/VGPR rate at the time of best response was 35.4% (95CI: 26.6; 45.4) for B-DRC compared to 22.2% (95CI: 14.9; 31.8) for DRC (p=0.32). There was no numerical difference in the median time to next treatment (68.8 months for B-DRC [95CI: 59.2 ; n.a.] and 67.5 months for DRC [95CI: 57.8; n.a.]). The median overall survival (OS) was not achieved in both arms, with a 5-year OS at 90% (95CI : 86; 95) for the total patient population (89% for B-DRC and 91% for DRC). The mutational status was available in 106 patients (53 in each arm); 92.5% of patients had MYD88(L265P) mutation and 30% a CXCR4 mutation (all associated with mutation of MYD88(L265P). CXCR4 mutational status was missing in 11 patients. PFS was not influenced by the mutational status of the two genes. The IPSSWM, originally designed for predicting OS with age as covariate, remained discriminant (p<0.001) in 173 evaluable patients, with a 5-year OS of high-risk patients of 83%, in accordance with the low number of deaths. Grade ≥3 adverse events were recorded in 101 patients (B-DRC: 52 and DRC: 49). Grade≥3 toxicities were mainly hematological. Seventy-two SAEs have been recorded in 41 patients (B-DRC: 14, DRC: 27). Seventy-one drug-related sensory peripheral neuropathies were observed. They were 2.5 times more frequent in the B-DRC arm (51 vs 20), however, with only four grade 3 neuropathies, all caused by B-DRC. Second malignancies have been recorded in 15 patients (B-DRC: 5 patients, DRC: 10 patients).In conclusion, this final analysis of one of the largest prospective randomized trials in WM demonstrated excellent activity, tolerability and, importantly, long-term safety of B-DRC and DRC delivered every 4 weeks, independently of the MYD88 and CXCR4 mutational status of the patients. Addition of Bortezomib to DRC induced numerically, but non-significant higher rate of deep remissions with a shorter time to response. Thus, with an estimated five-year overall survival of 90%, these data justify the recommendation of fixed duration immunochemotherapy such as DRC as one of the standard first-line treatments for WM in the era of BTK inhibitors. The currently running prospectively randomized VIWA-1 trial (NCT05099471) of the ECWM compares 6 cycles of DRC to Venetoclax/Ritxuximab given for 12 months in treatment naive WM. It will help to understand to which extent first-line targeted treatments can outcompete Rituximab/chemotherapy when applied as fixed-duration treatment in WM.