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Plasma Cell Disorders
Subcutaneous daratumumab in patients with relapsed or refractory multiple myeloma: part 2 of the open-label, multicenter, dose-escalation phase Ib study (PAVO)
Ferrata Storti Foundation
Haematologica 2021 Volume 106(6):1725-1732
Jesus San-Miguel,1 Saad Z. Usmani,2 Maria-Victoria Mateos,3 Niels W.C.J. van de Donk,4 Jonathan L. Kaufman,5 Philippe Moreau,6 Albert Oriol,7 Torben Plesner,8 Lotfi Benboubker,9 Kevin Liu,10 Peter Hellemans,11 Tara Masterson,12 Pamela L. Clemens,12 Man Luo,12 Andrew Farnsworth,13 Hareth Nahi14 and Ajai Chari15
1Clínica Universidad de Navarra-CIMA, IDISNA, CIBERONC, Pamplona, Spain; 2Levine Cancer Institute/Atrium Health, Charlotte, NC, USA; 3University Hospital of Salamanca/IBSAL, Salamanca, Spain; 4Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Hematology, Amsterdam, the Netherlands; 5Winship Cancer Institute, Emory University, Atlanta, GA, USA; 6University Hospital of Nantes, Nantes, France; 7Institut Català d’Oncologia, HGTiP, Barcelona, Spain; 8Vejle Hospital and University of Southern Denmark, Vejle, Denmark; 9Service d’Hématologie et Thérapie Cellulaire, Hôpital Bretonneau, Centre Hospitalier Régional Universitaire (CHRU), Tours, France; 10Janssen Research & Development, LLC, Raritan, NJ, USA; 11Janssen Research & Development, Beerse, Belgium; 12Janssen Research & Development, LLC, Spring House, PA, USA; 13Janssen Research & Development, LLC, High Wycombe, UK; 14Karolinska Institute, Department of Medicine, Division of Hematology, Karolinska University Hospital at Huddinge, Stockholm, Sweden and 15Tisch Cancer Institute, Mount Sinai School of Medicine, New York, NY, USA
ABSTRACT
Intravenous daratumumab is approved for the treatment of multiple myeloma. In part 1 of the PAVO study, a mix-and-deliver subcutaneous formulation of daratumumab with recombinant human hyaluronidase PH20 (rHuPH20) was well tolerated, with low rates of infusion-related reac- tions and an efficacy similar to that of intravenous daratumumab. Part 2 of PAVO evaluated a concentrated, pre-mixed co-formulation of daratumum- ab and rHuPH20 (DARA SC). Patients who had received two or more prior lines of therapy, including a proteasome inhibitor and an immunomodula- tory drug, were given daratumumab (1,800 mg) and rHuPH20 (30,000 U) in 15 mL subcutaneously over 3 to 5 minutes as per the approved intra- venous monotherapy dosing schedule. Primary endpoints were daratu- mumab trough concentration at the end of weekly dosing (just prior to the day 1 dose of cycle 3) and safety. Twenty-five patients were enrolled in PAVO part 2. DARA SC achieved daratumumab trough concentrations similar to or greater than those achieved with intravenous daratumumab 16 mg/kg. The adverse event profile of DARA SC was consistent with that of intravenous daratumumab, with no new safety concerns and a lower infusion-related reaction rate. At a median follow-up of 14.2 months, the overall response rate was 52%, the median duration of response was 15.7 months, and the median progression-free survival was 12.0 months. DARA SC 1,800 mg was well tolerated in relapsed/refractory multiple myeloma, with a low infusion-related reaction rate and reduced adminis- tration time. Daratumumab serum concentrations following DARA SC were consistent with those following intravenous dosing, and deep and durable responses were observed. Based on these results, ongoing studies are investigating DARA SC in the treatment of multiple myeloma and other conditions. (ClinicalTrials.gov identifier: NCT02519452).
Introduction
Daratumumab is a human IgGκ monoclonal antibody targeting CD38 with a direct on-tumor1-4 and immunomodulatory5-7 mechanism of action. The direct on- tumor actions of daratumumab are mediated by complement-dependent cytotoxi-
Correspondence:
JESUS SAN-MIGUEL
sanmiguel@unav.es
Received: November26,2019. Accepted: April 29, 2020. Pre-published: April 30, 2020.
https://doi.org/10.3324/haematol.2019.243790
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