Bortezomib in Combination with Ibrutinib/Rituximab Is a Highly Effective and Well Tolerated First - Line Treatment for Waldenström's Macroglobulinemia: Results of the Multicenter Phase II trial (<i>ECWM-2</i>) of the <i>European Consortium for Waldenström's Macroglobulinemia</i>

Background:Covalent BTK inhibitors are the backbone of treatment for patients with Waldenström's Macroglobulinemia (WM). Addition of rituximab to ibrutinib has shown a remarkable efficacy in WM in the iNNOVATE trial, including patients carrying CXCR4 mutations or MYD88 wildtype (Dimopoulos et al, NEJM 2018, Buske et al. JCO 2022). In addition, the proteasome inhibitor Bortezomib (B) has shown significant activity in WM as single agent or combined with Rituximab, Dexamethasone and Cyclophoshamide (DRC) (Buske et al., JCO 2023). The ECWM-2 trial of the European Consortium for Waldenström's Macroglobulinemia (NCT03620903) aimed at evaluating the efficacy and toxicity of Bortezomib-Ibrutinib/Rituximab (B-IR) as first line treatment in WM. Methods:In this multicenter European single-arm phase II trial, treatment naïve patients with WM requiring therapy received 6 cycles (C) (d=28) of Bortezomib (1.6 mg/ m2 s.c. d1,8,15), Rituximab (375 mg/m2 i.v (C1d1), 1400 mg absolute s.c (C2-6 d1) and Ibrutinib (420 mg p.o. daily) followed by maintenance with Rituximab (1400 mg absolute s.c; D1 every 2nd month) combined with Ibrutinib for 24 months and subsequent ibrutinib treatment until progression or non-tolerated toxicity. Primary endpoint was the 1-year progression free survival (PFS) rate (1YPFS). Secondary endpoints included response rates, PFS, overall survival (OS), and toxicity. Plasma cell-free DNA (cfDNA) and digital droplet PCR (ddPCR) was used for identifying and quantifying MYD88L265P mutational burden in patients at different time points before and during treatment. Results: 53 patients were included and started trial treatment. Median age was 63 years (range 36-84), 62% were male and 70% of patients had intermediate/high risk according to the ISSWM prognostic score. Median baseline hemoglobin was 10.1 g/dl (7.1-14.5) and median baseline IgM 33.9 g/l (3.05-102.87). Mutational status was available for 51 patients with 31 pts (60.8%) showing mutated MYD88 (MYD88MT) and CXCR4 wildtype (CXCR4WT), 18 patients (35.3%) MYD88MT/CXCR4MT and 2 pts (3.9%) MYD88 wildtype (MYD88WT). Of note, no patients showed progression after a median follow-up of 37 months. The primary endpoint 1YPFS was 93% (38/41, p<0.001 in a one-sided exact binomial test to reject 1YPFS ≤ 60%), with 3 deaths. 2YPFS was 0.88 (95% CI: 0.79-0.97). OS probabilities were identical to PFS probabilities due to the fact of lacking progressions. B-IR reduced rapidly deep responses with an overall response rate (ORR) and a major response rate (MRR) of 98% and 70%, respectively, after 3 cycles, with a median reduction of IgM serum levels by 74%. At best response 98% of all patients achieved a MRR with 100% ORR. The proportion of patients with VGPR/CR increased over time with 19% versus 28% versus 38% after 6 cycles, 12 cycles and at best response, respectively. Median time to major response was 2.8 months. Responses were largely independent of CXCR4 mutations with an MRR of 76 and 70 % in the CXCR4WT vs CXCR4MT patients, respectively, at end of induction. In total 104 cfDNA plasma samples from 32/53 patients were analyzed by ddPCR for MYD88L265P mutation: 93% of patients (30/32) showed MYD88L265P at baseline (median AF: 3.8%; range 50%-0.24%) with 41% of samples reaching MRD negativity and an almost 1 log reduction among MRD positive cases (median residual AF: 0.63%; range 5.6%-0.1%) after 3 cycles and a MRD negativity rate of 65% (median residual AF of 0.16% (range 2.34%-0.035%) at end of induction. Grade ≥3 AEs related to treatment occurred in 45% of all patients. Most common grade ≥3 AEs included COVID-19 pneumonia (13.0 %), lower respiratory tract infection (11.1 %), and anemia (7.4%). Overall, 12 pts (22.6 %) developed infections grade ≥3. Peripheral sensory neuropathy occurred in 8 patients (all grade 1 and 2). There have been 8 deaths in the course of the study in total, 5 caused by COVID-19 and three caused by respiratory tract infection. Conclusion: With a 1YPFS of 93%, a major response rate of 98%, 65% MRD negativity after 6 cycles of treatment and no observed progression of disease after a median follow-up of 37 months, B-IR shows impressive efficacy in WM. All deaths were caused by respiratory infections, for which COVID-19 was confirmed as the cause in the majority of cases, reflecting patient recruitment of this trial in the COVID-19 pandemic. These data characterize B-IR as a novel and powerful treatment option for patients with WM.