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859 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 (ECWM-2) of the European Consortium for Waldenström’s Macroglobulinemia

Program: Oral and Poster Abstracts
Type: Oral
Session: 623. Mantle Cell, Follicular, Waldenstrom’s, and Other Indolent B Cell Lymphomas: Clinical and Epidemiological: Clinical Trials for Marginal Zone Lymphoma, Waldenstrom's Macroglobulinemia and Hairy Cell Leukemia
Hematology Disease Topics & Pathways:
Research, Clinical trials, Adult, Lymphomas, Clinical Research, Diseases, Indolent lymphoma, Lymphoid Malignancies, Study Population, Human, Measurable Residual Disease
Monday, December 9, 2024: 2:45 PM

Christian Buske, MD1, Efstathios Kastritis, MD, PhD2*, Alexander Grunenberg, MD3*, Andreas Viardot, MD, PhD3, Dajana Kaczynski1*, Heike Mund4*, Katja Gutmair5*, Matthias Zingerle6*, Paul Duewel7*, Susanne Saussele, MD8, Björn Schöttker9*, Ullrich Graeven, MD10*, Martin Dreyling, MD11, Andrea Kerkhoff, MD12*, Thomas Weber13*, Holger F. Hebart, MD14, Ralf Ulrich Trappe, MD15*, Lisa Kaiser1*, Elke Runge1*, Jasmin Mark1*, Simone Ferrero, MD16, Daniela Drandi17*, Falko Fend, MD18*, Irina Bonzheim19*, Eva Hoster, PhD, Prof.20*, Jens Dreyhaupt21* and Meletios A. Dimopoulos, MD2

1Institute of Experimental Cancer Research, University Hospital Ulm, Ulm, Germany
2Department of Clinical Therapeutics, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece
3Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany
4University Hospital Ulm, Ulm, Germany
5Institute of Medical Information, University of Munich, Munich, Germany
6Haematology and Oncology, Munich-Pasing MVZ GmbH,, Munich, Germany
7Oncological Specialist Practice, Studiengesellschaft Onkologie Bielefeld, Bielefeld, Germany
8Universitätsmedizin Mannheim, Ilvesheim, Germany
9Joint practice for Haematology and Internal Oncology, Wuerzburg, Germany
10Department of Hematology, Oncology and Gastroenterology, Medical Clinic I, Hospital Maria Hilf GmbH, Mönchengladbach, Germany, Mönchengladbach, DEU
11Department of Internal Medicine 3, Ludwig-Maximilians-Universität (LMU), Munich, Germany
12Department of Medicine A, Hematology, Oncology and Pneumology, University Hospital Muenster, Muenster, Germany
13Department of Internal Medicine IV, Haematology and Oncology, University Hospital Halle (Saale), Martin-Luther-University Halle-Wittenberg, Halle, Germany
14Department of Internal Medicine, Hematology and Oncology, Stauferklinikum, Mutlangen, Mutlangen, Germany
15Department of Internal Medicine III, DIAKO Ev. Diakonie-Krankenhaus, Bremen, Germany
16Department of Molecular Biotechnology and Health Sciences, Hematology Division, University of Torino, Torino, TO, Italy
17Hematology Division I, Department of Molecular Biotechnologies and Health Sciences, University of Turin/University Hospital A.O.U. “Città della Salute e della Scienza”, Torino, Italy, Italy
18University of Tübingen, Department of Pathology and Neuropathology, Tuebingen, Germany
19Institute of Pathology, Tuebingen, DEU
20Institute of Medical Data Processing, Biometrics and Epidemiology (IBE), LMU Munich, Munich, Germany
21Institute of Epidemiology and Medical Biometry, University of Ulm, Ulm, Germany

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.

Disclosures: Buske: Roche/Genentech: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; BeiGene: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Research Funding, Speakers Bureau; Incyte: Consultancy, Honoraria, Speakers Bureau; AbbVie: Consultancy, Honoraria, Research Funding, Speakers Bureau; Gilead Sciences: Consultancy, Honoraria, Speakers Bureau; Celltrion: Consultancy, Honoraria, Research Funding, Speakers Bureau; MorphoSys: Consultancy, Honoraria, Speakers Bureau; Regeneron: Consultancy, Honoraria, Speakers Bureau; Sobi: Consultancy, Honoraria, Speakers Bureau; Lilly: Consultancy, Honoraria, Speakers Bureau; MSD: Research Funding; Amgen: Research Funding. Kastritis: GSK: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Janssen-Cilag: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Sanofi: Honoraria. Viardot: AbbVie, Amgen, Kite, Roche, Astra Zeneca: Membership on an entity's Board of Directors or advisory committees; AbbVie, BMS, Kite, Novartis, Roche, Sobi: Honoraria. Saussele: Novartis, Pfizer, Incyte, Roche: Honoraria; Novartis, BMS, Incyte: Research Funding. Dreyling: AstraZeneca, Beigene, Gilead/Kite, Janssen, Lilly, Novartis, F. Hoffmann-La Roche Ltd.: Honoraria; AbbVie, Bayer, BMS/Celgene, Gilead/Kite, Janssen, Lilly, F. Hoffmann-La Roche Ltd.: Research Funding; AbbVie, AstraZeneca, Beigene, BMS/Celgene, Gilead/Kite, Janssen, Lilly/Loxo, Novartis, F. Hoffmann-La Roche Ltd.: Membership on an entity's Board of Directors or advisory committees. Kerkhoff: Takeda: Honoraria; MSD: Honoraria; Amgen: Honoraria; BMS: Honoraria, Other: Travel- & congress-support; EUSA: Other: Travel- & congress-support; BeiGene: Other: Travel- & congress-support; Abbvie: Honoraria, Other: Travel- & congress-support; AstraZeneca: Honoraria; Sobi: Other: Travel- & congress-support; Roche: Honoraria. Hebart: AbbVie, AstraZeneca, Beigene, Janssen: Consultancy. Ferrero: Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Eli Lilly: Speakers Bureau; Beigene: Research Funding, Speakers Bureau; Sandoz: Consultancy, Speakers Bureau; Gentili: Speakers Bureau; Italfarmaco: Membership on an entity's Board of Directors or advisory committees; EUSA Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees; Gilead: Research Funding, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Dimopoulos: AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; BeiGene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Swixx: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Menarini: Honoraria, Membership on an entity's Board of Directors or advisory committees; Regeneron: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees.

See more of: 623. Mantle Cell, Follicular, Waldenstrom’s, and Other Indolent B Cell Lymphomas: Clinical and Epidemiological: Clinical Trials for Marginal Zone Lymphoma, Waldenstrom's Macroglobulinemia and Hairy Cell Leukemia
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