The treatment landscape of heavily pretreated relapsed/refractory MM has changed considerably in recent years with the introduction of novel BCMA- and GPRC5D-directed immunotherapies, including CAR T-cell therapy, bispecific antibodies (BsAbs), and antibody-drug conjugates (ADCs). Treatment selection and sequencing become increasingly complex with the broad range of therapeutic options. In this review, the European Myeloma Network provides recommendations on how to best incorporate these novel therapies into the present treatment landscape using current evidence. The optimal treatment sequence depends on various patient- and tumor-related features, but also reimbursement and availability issues. In addition, mechanisms underlying relapse (e.g., antigen loss, reduced T-cell fitness, or outgrowth of T-cell resistant clones) dictate the efficacy of sequential BCMA- or GPRC5D-directed immunotherapy. BCMA-targeting BsAbs and ADCs should preferably be avoided prior to CAR T-cell therapy, as some studies have shown that these agents negatively influence clinical outcomes after CAR T-cell therapy. Therefore, we recommend the selection of CAR T-cell therapy first, and BsAbs and/or belamaf later in the disease course, if patients are eligible for CAR T-cell therapy and in case CAR T-cell therapy is available within a short time frame. However, bridging therapy with GPRC5D-directed BsAbs (initiation after apheresis) can be considered to significantly reduce tumor burden, because this was shown to improve the efficacy of consecutive BCMA-directed CAR T-cell therapy. Sequential treatment with agents targeting the same antigen, but with different modes of action, is feasible, but several studies have demonstrated that target switch is a more effective strategy. In addition, there is increasing evidence indicating that the efficacy of sequential use of BsAbs can be improved by creating a BsAb-free interval.

Alfred Health Monash University Melbourne Victoria Australia

Ankara Liv Hospital Istinye University Ankara Turkey

Cancer Center Amsterdam Cancer Biology and Immunology Amsterdam The Netherlands

Cancer Center Clinica Universidad de Navarra CIMA IDISNA CIBERONC Pamplona Spain

Cancer Research Center University Hospital of Salamanca IBSAL Salamanca Spain

Clinic of Hematology University Clinical Center of Serbia Medical Faculty University of Belgrade Belgrade Serbia

Department of Clinical Therapeutics School of Medicine National and Kapodistrian University of Athens Athens Greece

Department of Haematology University College London Hospitals NHS Foundation Trust London United Kingdom

Department of Hemato Oncology Faculty of Medicine University of Ostrava Ostrava Czech Republic

Department of Hemato Oncology University Hospital Ostrava Ostrava Czech Republic

Department of Hematology Amsterdam UMC Vrije Universiteit Amsterdam Amsterdam The Netherlands

Department of Hematology and Oncology Interdisciplinary Cancer Center and Comprehensive Cancer Center Freiburg University of Freiburg Faculty of Freiburg Freiburg Germany

Department of Hematology Ankara University Faculty of Medicine Ankara Turkey

Department of Hematology Erasmus MC Cancer Institute Rotterdam The Netherlands

Department of Hematology Lille University Hospital and INSERM UMR S1277 and CNRS UMR9020 Lille France

Department of Hematology The Royal Marsden Hospital and Division of Genetics and Epidemiology The Institute of Cancer Research London United Kingdom

Department of Hematology University Hospital Hôtel Dieu Nantes France

Department of Hematology University Hospital Leuven Leuven Belgium

Department of Internal Medicine 2 University Hospital of Würzburg Würzburg Germany

Department of Medical Oncology and Hematology HOCH Health Ostschweiz Cantonal Hospital St Gallen St Gallen Switzerland

Department of Medicine Haematology University of Galway Galway Republic of Ireland

Department of Medicine Korea University Seoul South Korea

Department of Molecular Biotechnology and Health Sciences University of Torino Torino Italy

Department of Precision and Regenerative Medicine and Ionian Area Aldo Moro University School of Medicine Bari Italy

Dipartimento di Scienze Mediche e Chirurgiche Università di Bologna Bologna Italy

European Myeloma Network Torino Italy

Heidelberg Myeloma Center Department of Internal Medicine 5 Heidelberg University Hospital and Medical Faculty Heidelberg Germany

Hematology and Stem Cell Transplantation Unit AOU Consorziale Policlinico Bari Italy

Hospital Clínic de Barcelona IDIBAPS University of Barcelona Barcelona Spain

IRCCS Azienda Ospedaliero Universitaria di Bologna Istituto di Ematologia Seràgnoli Bologna Italy

Oslo Myeloma Center Department of Hematology Oslo University Hospital Oslo Norway

Université de Toulouse Centre Hospital Universitaire Institut Universitaire du Cancer Toulouse Oncopole Toulouse France

University Division of Hematology AOU Città della Salute e della Scienza di Torino Torino Italy and Department of Biotechnology and Health Sciences University of Torino Italy

Wilhelminen Cancer Research Institute 1st Department of Medicine Center for Oncology Hematology and Palliative Care Clinic Ottakring Vienna Austria

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