Talquetamab–Daratumumab in Relapsed or Refractory Myeloma

Author(s): Roberto Mina, M.D.^1,2; Meral Beksac, M.D.³; Paula Rodríguez-Otero, M.D., Ph.D.⁴; Wenming Chen, M.D., Ph.D.⁵; María-Victoria Mateos, M.D., Ph.D.⁶; Jian Li, M.D.⁷; Philippe Moreau, M.D.⁸; Yael C. Cohen, M.D.^9,10; Chang-Ki Min, M.D., Ph.D.¹¹; Tomas Jelinek, M.D., Ph.D.¹²; Jing Christine Ye, M.D.¹³; Hila Magen, M.D.^14,15; Samuel M. Rubinstein, M.D.¹⁶; Weijun Fu, M.D., Ph.D.¹⁷; Vania Hungria, M.D., Ph.D.¹⁸; Guldane Cengiz Seval, M.D.¹⁹; Joao Samuel Farias, M.D.²⁰; Jakub Radocha, M.D.²¹; Senem Maral, M.D.²²; Mehmet Turgut, M.D., Ph.D.²³; Youngil Koh, M.D., Ph.D.²⁴; Daniel O’Leary, M.D.²⁵; Jayr Schmidt Filho, M.D.²⁶; Raymond Thertulien, M.D., Ph.D.²⁷; Gang An, M.D., Ph.D.²⁸; Shang-Yi Huang, M.D., Ph.D.²⁹; Sebastian Grosicki, M.D.³⁰; Agata Tyczyńska, M.D., Ph.D.³¹; Rahul Banerjee, M.D.³²; Matthew J. Pianko, M.D.³³; Joaquín Martínez-López, M.D., Ph.D.³⁴; Pawel Steckiewicz, M.D., Ph.D.³⁵; Dai Maruyama, M.D., Ph.D.³⁶; Kentaro Fukushima, M.D., Ph.D.³⁷; Albert Oriol, M.D., Ph.D.³⁸; Jordi Lopez Pardo, M.D.³⁹; Hartmut Goldschmidt, M.D.⁴⁰; Charlotte Pawlyn, M.D., Ph.D.^41,42; Aurore Perrot, M.D., Ph.D.⁴³; Elena Zamagni, M.D., Ph.D.⁴⁴; Meletios A. Dimopoulos, M.D.^45,46; Leo Rasche, M.D.⁴⁷; Jaszianne Tolbert, M.D.⁴⁸; William Terry, M.D.⁴⁸; Christelle Courtoux, M.Eng.⁴⁸; Xiao Liu, M.D.⁴⁹; Sandra Y. Vasey, M.S.⁴⁸; Kaitlyn Connors, B.S.⁵⁰; Mariacristina Festa, M.S.⁵¹; Christoph Heuck, M.D.⁴⁸; Angélique Langlois, M.Sc.⁴⁸; Lisa O’Rourke, M.S.⁴⁸; Jiangxiu Zhou, Ph.D.⁴⁸; Xiang Qin, M.S.⁴⁸; Jiashen Lu, Ph.D.⁵²; Joy Gong, Ph.D.⁴⁸; Diego Vieyra, Ph.D.⁴⁸; Peter M. Voorhees, M.D.⁵³; the MonumenTAL-3 Investigators*;

Source: DOI: 10.1056/NEJMoa2604657

Dr. Anjan Patel's Thoughts

Talquetamab plus daratumumab (with or without pomalidomide) delivered a striking progression-free survival (PFS) benefit over daratumumab plus pomalidomide and dexamethasone (DPd) in early-line relapsed/refractory myeloma, 24-month PFS of ~80% versus 51% and MRD-negative CR rates three times higher than the control arm. OS trending favorably but not yet mature. The GPRC5D toxicity profile is manageable but distinct, counsel patients upfront on taste changes, skin/nail effects, weight loss, and watch closely for ataxia/balance issues, which warrant holding the drug and early neurology involvement.

BACKGROUND

Talquetamab, a bispecific antibody targeting GPRC5D and CD3, has led to durable responses in patients with heavily pretreated relapsed or refractory multiple myeloma in phase 1–2 trials, with a limited effect on normal B cells.

METHODS

In a phase 3 trial, we randomly assigned patients with relapsed or refractory multiple myeloma who had previously received least one line of therapy to receive talquetamab plus daratumumab and pomalidomide (Tal-DP), talquetamab plus daratumumab (Tal-D), or daratumumab plus pomalidomide and dexamethasone (DPd). The primary end point was progression-free survival as assessed by an independent review committee. Key secondary end points were overall response, complete response or better (complete or stringent complete response), measurable residual disease–negative complete response, and overall survival.

RESULTS

A total of 287, 287, and 290 patients were assigned to the Tal-DP, Tal-D, and DPd groups, respectively. the interim analysis (median follow-up, 24.6 months), progression-free survival was significantly longer with Tal-DP and Tal-D than with DPd (24-month estimate, 81.3% and 77.6% vs. 51.2%; hazard ratio for disease progression or death, Tal-DP vs. DPd, 0.28 [95% confidence interval {CI}, 0.20 to 0.40], and Tal-D vs. DPd, 0.33 [95% CI, 0.24 to 0.46]; P

CONCLUSIONS

Among patients with relapsed or refractory multiple myeloma who had previously received least one line of therapy, both Tal-DP and Tal-D led to significantly longer progression-free survival than DPd. (Funded by Johnson & Johnson; MonumenTAL-3 ClinicalTrials.gov number, NCT05455320.)

Author Affiliations

¹Division of Hematology, Department of Molecular Biotechnology and Health Sciences, Azienda Ospedaliero-Universitaria Città della Salute e della, Scienza di Torino, University of Turin, Turin, Italy; ²Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta; ³Istinye University, Ankara University, Ankara, Turkey; ⁴Cancer Center Clínica Universidad de Navarra, Cima, Pamplona, Spain; ⁵Beijing Chaoyang Hospital, Capital Medical University, Chaoyang District, Beijing; ⁶Hospital Universitario de Salamanca, Instituto de Investigación Biomédica de Salamanca, Instituto de Biología Molecular y Celular del Cáncer (Universidad de Salamanca-Consejo Superior de Investigaciones Científicas), Centro de Investigación Biomédica en Red de Cáncer, Salamanca, Spain; ⁷Department of Hematology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing; ⁸Hematology Clinic, University Hospital Hôtel-Dieu, Nantes, France; ⁹Tel Aviv Sourasky (Ichilov) Medical Center, Tel Aviv, Israel; ¹⁰Gray Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv, Israel; ¹¹Seoul St. Mary’s Hospital, Catholic University of Korea, Seoul, South Korea; ¹²Department of Hemato-oncology, University Hospital Ostrava, Ostrava, Czech Republic; ¹³M.D. Anderson Cancer Center, University of Texas, Houston; ¹⁴Chaim Sheba Medical Center, Ramat-Gan, Israel; ¹⁵Sackler Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv, Israel; ¹⁶Division of Hematology and Oncology, Department of Medicine, University of North Carolina School of Medicine, Chapel Hill; ¹⁷Department of Hematology, Shanghai Fourth People’s Hospital, School of Medicine, Tongji University, Shanghai; ¹⁸Clinica Médica São Germano, São Paulo; ¹⁹Ankara University Faculty of Medicine, Department of Hematology and Oncology, Ankara University, Ankara, Turkey; ²⁰Liga Paranaense de Combate ao Câncer, Curitiba, Paraná, Brazil; ²¹4th Department of Internal Medicine–Hematology, University Hospital Hradec Kralove, Faculty of Medicine in Hradec Kralove, Charles University, Prague, Czech Republic; ²²Medipol Mega University Hospital, Bağcılar, Istanbul, Turkey; ²³Ondokuz Mayıs University, Samsun, Turkey; ²⁴Seoul National University Hospital, Seoul National University, Jongno-gu, Seoul, South Korea; ²⁵University of Minnesota, Minneapolis; ²⁶A.C.Camargo Cancer Center, São Paulo; ²⁷Novant Health Cancer Institute, Charlotte, NC; ²⁸Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences, Tianjin, China; ²⁹National Taiwan University Hospital, National Taiwan University College of Medicine, Zhongzheng District, Taipei; ³⁰Department of Cancer Prevention, Medical University of Silesia, Katowice, Poland; ³¹Medical University of Gdańsk, Department of Hematology and Transplantology and University Clinical Center Gdańsk, Department of Hematology, Transplantology and Cellular Therapies, Gdańsk, Poland; ³²Fred Hutchinson Cancer Center, Seattle; ³³University of Michigan Health, Ann Arbor; ³⁴Hospital Universitario 12 de Octubre, Instituto de Investigación Sanitaria Hospital 12 de Octubre, Complutense University of Madrid, Centro Nacional de Investigaciones Oncológicas, Madrid Institute of Cancer, Madrid; ³⁵Holy Cross Cancer Center, Department of Hematology and Bone Marrow Transplantation, Kielce, Poland; ³⁶Cancer Institute Hospital, Japanese Foundation for Cancer Research, Koto-ku, Tokyo; ³⁷University of Osaka Graduate School of Medicine, Suita, Japan; ³⁸Institut Català d’Oncologia and Josep Carreras Research Institute, Hospital Germans Trias I Pujol, Badalona, Barcelona; ³⁹l’Hospital de la Santa Creu i Sant Pau, Barcelona; ⁴⁰Internal Medicine V, Hematology, Oncology and Rheumatology, German-Speaking Myeloma Multicenter Group Study Group, Heidelberg University Hospital and National Center for Tumor Diseases, Heidelberg, Germany; ⁴¹Institute of Cancer Research, London; ⁴²Royal Marsden NHS Foundation Trust, London; ⁴³Universite de Toulouse, Centre Hospitalier Universitaire de Toulouse, Service Hematologie, Institut Universitaire du Cancer de Toulouse Oncopole, Toulouse, France; ⁴⁴University of Bologna, Bologna, Italy; ⁴⁵Department of Clinical Therapeutics, National and Kapodistrian University of Athens, School of Medicine, Athens; ⁴⁶Department of Medicine, Korea University, Seoul, South Korea; ⁴⁷University Hospital of Würzburg, Würzburg, Germany; ⁴⁸Johnson & Johnson, Spring House, PA; ⁴⁹Johnson & Johnson, Beijing; ⁵⁰Johnson & Johnson, Raritan, NJ; ⁵¹Johnson & Johnson, Leiden, the Netherlands; ⁵²Johnson & Johnson, Shanghai; ⁵³Atrium Health Levine Cancer Institute, Wake Forest University School of Medicine, Charlotte, NC

Teclistamab plus Daratumumab in Relapsed or Refractory Multiple Myeloma

Dual Targeting of Extramedullary Myeloma with Talquetamab and Teclistamab

This is a very impressive signal in a notoriously difficult population—seeing a 79% response rate and median progression-free survival (PFS) of 15.4 months in true extramedullary, triple-class–exposed myeloma is better than expected. Toxicity is real and management-intensive, but the depth and durability of response make this dual-bispecific approach feel like a meaningful advance.

Measurable Residual Disease–Guided Therapy in Newly Diagnosed Myeloma

Quadruplet induction with isatuximab, carfilzomib, lenalidomide, and dexamethasone (Isa‑KRd) has reset expectations for transplant‑eligible NDMM and enables measurable residual disease (MRD)‑adapted strategies; MRD‑negativity at 10^-5 is strongly prognostic, and the necessity of autologous stem-cell transplantation (ASCT)—particularly tandem ASCT—amid deep responses is being re‑examined. Practically, MRD‑adapted consolidation after Isa‑KRd suggests no added depth from ASCT in MRD patients and no advantage for tandem ASCT over single ASCT + Isa‑KRd in MRD+ patients. So in day‑to‑day practice, this looks like a chance to de‑escalate transplant intensity while awaiting mature progression-free survival (PFS)/overall survival (OS) data.

Prognostic value of minimal residual disease negativity in myeloma: combined analysis of POLLUX, CASTOR, ALCYONE, and MAIA

MRD status in MM has unquestionable prognostic informational value, however many questions remain as how to address positive / negative MRD results. Should we de-escalate or stop Rx? When? Can we escalate Rx if + MRD? Which regimen, how long? It will be another few years till objective data are available. I do see value in at least having identification of clonality established upfront for tracking.