AUTHORS
Paula Rodriguez Otero, MD, PhD, Binod Dhakal, MD, MS2, Jin Lu, MD3, Yael C. Cohen, MD4, Shahzad Raza, MD5, Chang-Ki Min, MD, PhD6, Meral Beksac, MD7, Francesca Gay, MD, PhD8, Georgia McCaughan9, Hang Quach10, Daniel O'Leary, MD11, Vania Hungria, MD, PhD12, Elena Zamagni, MD, PhD13, Weijun Fu, MD, PhD14, Sameer Melinkeri, MD, DM15, Meletios-Athanasios (Thanos) C. Dimopoulos, MD16, Salomon Manier17, Edvan de Queiroz Crusoé, MD, PhD, MSc18, Guldane Cengiz Seval, MD, PhD19, Marc-Steffen Steffen Raab, MD20, Tanya Wildes, MD,MSc21, Roberto Ovilla-Martínez, MD22, Guillermina Remaggi, MD23, Carmine Liberatore, MD24, Hira Mian, MD25, Satoshi Yoshihara, MD, PhD26, Angelo Maiolino, MD, PhD27, Maria Clavijo, MD28, Ceri Bygrave, MBBCh29, Senem Maral30, Ignacio Casas-Avilés31, Tomasz Wrobel, MD, PhD32, Jacek Krzanowski, MD33, Marten Nijziel, MD, PhD34, Inger Nijhof, MD PhD35, Silvia Mangiacavalli, MD36, Aurore Perrot Sr, MD37, Cyrille Hulin, MD38, Cyrille Touzeau Sr, MD, PhD39, Thomas Chalopin Jr, MD40, Jean Marc Schiano De Colella, MD41, Lionel Karlin, MD42, Suzanne Trudel, MD43, Hannah Hunter, FRCPath, MB, MRCP44, Esther González García45, Matthew J. Pianko, MD46, Kenneth H. Shain, MD, PhD47, Roman Hajek, MD, PhD48, Thomas Melchardt, MD49, Junya Kuroda, MD, PhD50, Iuliana Vaxman51, Bas D. Koster, MD, PhD52, Ankit Kansagra, MD53, Christoph Heuck54, Michele Kosh55, Lorena Lopez-Masi, MPH56, Annick Bessems, PharmD57, Tara Masterson, MS58, Jiangxiu Zhou59, Deeksha Vishwamitra, PhD60, Nizar Bahlis, MD61
AFFILIATIONS
1 Cancer Center Clínica Universidad de Navarra, Pamplona, Spain
2 Medical College of Wisconsin, Milwaukee, United States
3 Collaborative Innovation Center of Hematology, Beijing, China, National Clinical Research Center for Hematologic Disease, Beijing, China, Peking University Institute of Hematology, Beijing, China, Peking University People’s Hospital, Beijing, China
4 Tel Aviv Sourasky (Ichilov) Medical Center, Gray Faculty of Medical & Health Sciences, Tel Aviv University, Tel Aviv, Israel
5 Taussig Cancer Institute, Cleveland Clinic, Cleveland, United States
6 Seoul St. Mary’s Hospital, The Catholic University of Korea, Seoul, Korea, Rep. of South
7 Istinye University, Ankara, Turkey
8 Myeloma Unit, Division of Hematology, University of Torino, Azienda Ospedaliero-Universitaria Città della Salute e della Scienza, Torino, Italy
9 St Vincent’s Hospital, Sydney, Australia, Sydney, Australia
10 University of Melbourne, St. Vincent’s Hospital, Melbourne, VIC, Australia
11 University of Minnesota, Minneapolis, United States
12 Clinica São Germano, Sao Paulo, Brazil
13 University of Bologna, Bologna, Italy
14 Department of Hematology, Shanghai Fourth People’s Hospital, School of Medicine, Tongji University, Shanghai, China
15 Deenanath Mangeshkar Hospital & Research Center, Pune, Maharashtra, India
16 Department of Clinical Therapeutics, National and Kapodistrian University of Athens, Athens, Greece
17 University of Lille, CHU Lille, Lille, France
18 D’Or Institute for Research and Education, Salvador, Brazil, Department of Internal Medicine, Federal University of Bahia, Salvador, Brazil
19 Ankara University Faculty of Medicine, Ankara, Turkey
20 Heidelberg Myeloma Center, Department of Medicine V, University Hospital and Medical Faculty, Heidelberg, Germany
21 University of Nebraska Medical Center, Omaha, United States
22 Hematológica Alta Especialidad S.C., Huixquilucan, Estado de Mexico, Mexico
23 Fundaleu, Buenos Aires, Argentina
24 Department of Medicine and Aging Sciences, University G. d'Annunzio of Chieti-Pescara, Chieti, Italy
25 Juravinski Cancer Center, Hamilton, Canada
26 Department of Hematology, Hyogo Medical University Hospital, Nishinomiya, Japan
27 Instituto Americas de Ensino, Pesquisa e Inovação, Rio de Janeiro, Brazil
28 Hospital Alemán, Buenos Aires, Argentina
29 University Hospital of Wales, Cardiff, United Kingdom
30 Medipol University Hospital, Istanbul, Turkey
31 Hospital San Pedro de Alcántara, Cáceres, Extremadura, Spain
32 Wroclaw Medical University, Wroclaw, Poland
33 Specialist Hospital in Brzozów, Brzozów, Poland
34 Catharina Hospital, Eindhoven, Netherlands
35 St. Antonius Hospital, Nieuwegein, Netherlands
36 Fondazione IRCCS Policlinico San Matteo, Lombardy, Italy
37 Université de Toulouse, Centre Hospitalier Universitaire de Toulouse, Service Hématologie, IUCT Oncopole, Toulouse, France
38 Hôpital Haut Leveque, University Hospital, Pessac, France
39 Centre Hospitalier Universitaire (CHU) Hotel Dieu, Nantes, France
40 Centre Hospitalier Universitaire de Tours, Tours, France
41 Institut Paoli-Calmettes, Marseille, Provence-Alpes-Côte d’Azur, France
42 Centre Hospitalier Lyon Sud, Pierre-Bénite, France
43 Princess Margaret Cancer Centre, Toronto, Canada
44 University Hospitals Plymouth NHS Trust, Plymouth, United Kingdom
45 University Hospital Cabueñes, Gijón, Spain
46 University of Michigan Health, Ann Arbor, United States
47 H. Lee Moffitt Cancer Center and Research Institute, Tampa, United States
48 University Hospital Ostrava, Ostrava, Czech Republic
49 Cancer Research Laboratory of the Department of Internal Medicine III, Paracelsus Medical University, Salzburg, Austria
50 University Hospital, Kyoto Prefectural University of Medicine, Kyoto, Japan
51 Gray Faculty of Medical & Health Sciences, Tel Aviv University, Tel Aviv, Israel, Institute of Hematology, Davidoff Cancer Center, Rabin Medical Center, Petah Tikva, Israel, Tel Aviv Sourasky (Ichilov) Medical Center; Gray Faculty of Medical & Health Sciences, Tel Aviv University, Tel Aviv, Israel
52 Johnson & Johnson, Leiden, Netherlands
53 Formerly of Johnson & Johnson, Raritan, United States
54 Johnson & Johnson, Spring House, United States
55 Johnson & Johnson, Spring House, United States
56 Johnson & Johnson, Raritan, United States
57 Johnson & Johnson, Beerse, Belgium
58 Johnson & Johnson, Spring House, United States
59 Johnson & Johnson, Spring House, United States
60 Johnson & Johnson, Spring House, United States
61 Arnie Charbonneau Cancer Research Institute, University of Calgary, Calgary, United States
ABSTRACT
Introduction: Tec (anti-BCMA×CD3) and Tal (anti-GPRC5D×CD3) are the only bispecific antibodies with proven progression-free and overall survival (PFS, OS) benefit in RRMM as monotherapy or combined with daratumumab (Dara) as early as second line (2L). As Dara-based triplets/quadruplets are first-line standards of care (SOC), anti-CD38 monoclonal antibody (mAb) exposure and refractoriness are important clinical considerations for subsequent treatment (tx). Dual myeloma antigen targeting with Tec+Tal may broaden activity across heterogenous disease by enhancing T-cell redirection and tumor cell lysis while mitigating antigen escape; Pom activates adaptive and innate immunity and may enhance the anti-tumor effects of Tal. We report efficacy and safety of Tec+Tal and Tal+Pom vs investigator’s choice of EPd/PVd in RRMM with 1–4 prior LOT from the preplanned interim analysis of MonumenTAL-6 (NCT06208150).
Methods: Phase 3 study randomizing pts with RRMM aged ≥18 y and 1–4 prior LOT, including anti-CD38 mAb and lenalidomide (Len) exposure, 1:1:1 to Tec+Tal (26 cycles [C] total), Tal+Pom (Tal for 26C, with Pom continued until progression), or EPd/PVd. Tec+Tal and Tal+Pom tx C were 28 days (D). Following step-up-dosing, Tec and Tal were given on D1 of each subsequent C: Tec 3 mg/kg Q4W and Tal 0.8 mg/kg Q2W from C2, with switch to Tal Q4W at C7 with ≥PR (pts in early ≥VGPR could switch to Q4W at C5–6). In Tal+Pom, Pom 2 mg was dosed D1–21 of each C from C2 (up to 4 mg permitted from C3). EPd/PVd were administered per established schedules. Primary endpoint was PFS by independent review committee. Secondary endpoints included overall response, ≥CR, OS, and safety.
Results: 838 pts were randomized (Tec+Tal, n=278; Tal+Pom, n=282; EPd/PVd, n=278). Baseline characteristics were balanced across tx arms (median age, 67 y; median prior LOT, 2; ISS stage III, 13.6%; high-risk cytogenetics, 31.6%; true extramedullary disease, 12.6%; refractoriness: anti-CD38 mAbs [80.2%], Len [79.8%], triple-class [40.7%], last LOT [90.5%]).
At 13.4-mo median follow-up, Tec+Tal and Tal+Pom significantly improved PFS vs EPd/PVd (HRs [95% CI]: 0.11 [0.08–0.16], P<0.0001 and 0.27 [0.20–0.35], P<0.0001, respectively). 12-mo PFS rates (95% CI) were 88.6% (83.8–92.0) for Tec+Tal, 73.1% (66.6–78.5) for Tal+Pom, and 30.4% (24.1–37.0) for EPd/PVd. PFS benefit was consistent across all prespecified clinically relevant subgroups. ORRs (86.3%, 83.0%, and 45.3%) and ≥CR rates (65.1%, 55.3%, and 4.3%) were significantly higher with Tec+Tal and Tal+Pom vs EPd/PVd, respectively. Tec+Tal and Tal+Pom significantly improved OS vs EPd/PVd (HRs [95% CI]: 0.38 [0.23–0.60], P<0.0001 and 0.55 [0.36–0.83], P=0.0044, respectively). 12-mo OS rates (95% CI) were 91.3% (87.0–94.2) for Tec+Tal, 88.8% (83.8–92.3) for Tal+Pom, and 79.6% (73.8–84.2) for EPd/PVd.
Tx-emergent adverse events (TEAEs) were consistent with the known profiles of each agent (TEAE rates [grade (gr) 3/4, gr 5]: Tec+Tal [84.9%, 3.3%], Tal+Pom [85.0%, 2.9%], and EPd/PVd [77.4%, 2.3%]) Discontinuation (d/c) of all study tx due to AEs occurred in 5.9% (Tec+Tal), 6.4% (Tal+Pom), and 3.8% (EPd/PVd). Infection rates (gr 3/4, gr 5) were: Tec+Tal (31.7%, 1.1%), Tal+Pom (25.4%, 1.4%), and EPd/PVd (24.8%, 1.1%) Rates of hypogammaglobulinemia and ≥1 dose of immunoglobulin replacement therapy use were: Tec+Tal (59.8%, 92.3%), Tal+Pom (46.8%, 79.6%), and EPd/PVd (30.8%, 31.6%). CRS (any gr, gr 1, gr 2) in Tec+Tal (65.3%, 53.9%, 10.0%) and Tal+Pom (63.9%, 47.9%, 13.9%) was predominantly gr 1 and ICANS was mostly gr 1/2 (any gr: 6.3% [Tec+Tal] and 5.0% [Tal+Pom]). Taste changes with Tec+Tal, Tal+Pom, and EPd/PVd were reported in 76.0%, 73.9%, and 4.5% of pts and weight loss was reported in 40.6%, 38.9%, and 5.3%; most events were gr 1/2 and infrequently led to Tal d/c. Ataxia/balance disorders (any gr, gr 3) with Tec+Tal (3.3%, no gr 3) and Tal+Pom (5.7%, 0.7%) were mostly gr 1/2 (no gr ≥4), and led to Tal d/c in 0.7% and 1.1% of pts, respectively.
Conclusions: Tec+Tal demonstrated profound, significant improvements in PFS and OS vs EPd/PVd in early line RRMM, with gr ≥3 infection rates similar to EPd/PVd and low rates of tx d/c due to AEs. These data underscore the benefits of dual-antigen targeting of BCMA and GPRC5D as early as 2L and support Tec+Tal as a new SOC in anti-CD38 mAb- and Len-refractory disease. Tal+Pom also outperformed EPd/PVd and may provide a promising sequencing option post BCMA-directed tx.
DISCLOSURES
Paula Rodriguez Otero, MD, PhD: Bristol Myers Squibb - Honoraria; Pfizer - Honoraria; Johnson & Johnson - Honoraria; Kite Pharma - Honoraria; Sanofi - Honoraria; AstraZeneca - Honoraria; Johnson & Johnson Innovative - Honoraria; Menarini Stemline - Honoraria; AbbVie - Honoraria; GSK - Honoraria; Pfizer - Research Funding; Johnson & Johnson - Consultancy (Includes expert testimony); AstraZeneca - Consultancy (Includes expert testimony); AbbVie - Consultancy (Includes expert testimony); Menarini Stemline - Consultancy (Includes expert testimony); Roche - Consultancy (Includes expert testimony); Pfizer - Consultancy (Includes expert testimony); Bristol Myers Squibb - Consultancy (Includes expert testimony); Regeneron Pharmaceuticals, Inc. - Consultancy (Includes expert testimony); Sanofi - Consultancy (Includes expert testimony); GSK - Consultancy (Includes expert testimony); Oncopeptides - Consultancy (Includes expert testimony)