CD38 is a transmembrane glycoprotein that functions both as a receptor and an ectoenzyme, playing key roles in the regulation of calcium signaling and migration of immune cells to tumor microenvironments. High expression on multiple myeloma (MM) cells and limited expression on normal cells makes CD38 an ideal target for the treatment of MM patients. Two monoclonal antibodies directed at CD38, isatuximab and daratumumab, are available for use in patients with relapsed and/or refractory MM (RRMM); daratumumab is also approved in newly diagnosed MM and light-chain amyloidosis. Clinical experience has shown that anti-CD38 antibody therapy is transforming treatment of MM owing to its anti-myeloma efficacy and manageable safety profile. Isatuximab and daratumumab possess similarities and differences in their mechanisms of action, likely imparted by their binding to distinct, non-overlapping epitopes on the CD38 molecule. In this review, we present the mechanistic properties of these two antibodies and outline available evidence on their abilities to induce adaptive immune responses and modulate the bone marrow niche in MM. Further, we discuss differences in regulatory labeling between these two agents and analyze recent key clinical trial results, including evidence in patients with underlying renal impairment and other poor prognostic factors. Finally, we describe the limited existing evidence for the use of isatuximab or daratumumab after disease progression on prior anti-CD38 mono- or combination therapy, highlighting the need for additional clinical evaluations to define optimal anti-CD38 antibody therapy selection and sequencing in RRMM.

Clinical Haematology Service St Vincent's Hospital University of Melbourne Melbourne Australia

Department of Haematology University College Hospitals NHS Foundation Trust London UK

Department of Hematology and Oncology Nagoya City University Nagoya Japan

Department of Hematology CHU Universite de Lille Lille France

Department of Hematology College of Medicine Catholic Hematology Hospital and Leukemia Research Institute Seoul St Mary's Hospital The Catholic University of Korea Seoul Korea

Department of Hematology Institut Universitaire du Cancer de Toulouse Toulouse France

Department of Medical Oncology Dana Farber Cancer Institute Boston MA USA

Department of Medical Sciences University of Torino Medical School Fondazione Ricerca Molinette Turin Italy

Department of Medicine Department of Hematology 1st Faculty of Medicine Charles University and General Hospital Prague Czech Republic

Department of Medicine University of California at San Francisco San Francisco CA USA

Division of Cancer Therapeutics The Institute of Cancer Research London UK

Division of Hematology and Medical Oncology Tisch Cancer Institute Mount Sinai New York NY USA

Hospital Universitario Marqués de Valdecilla Universidad de Cantabria Santander Spain

Oslo Myeloma Center Department of Hematology KG Jebsen Center for B Cell Malignancies Oslo University Hospital University of Oslo Oslo Norway

Service d'Hématologie Et Thérapie Cellulaire CHU and CIC Inserm 1402 Poitiers Cedex France

University Medical Center Hamburg Eppendorf Hamburg Germany

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