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Subcutaneous Delivery of Daratumumab in Relapsed or Refractory Multiple Myeloma

Saad Z. Usmani, Hareth Nahi, Maria-Victoria Mateos, Niels W.C.J. van de Donk, Ajai Chari, Jonathan L. Kaufman, Philippe Moreau, Albert Oriol, Torben Plesner, Lotfi Benboubker, Peter Hellemans, Tara Masterson, Pamela L. Clemens, Man Luo, Kevin Liu and Jesus San Miguel

Key Points

  • Subcutaneously administered daratumumab had similar pharmacokinetics and safety, and a reduced IRR rate, compared with the IV formulation

  • The 1,800 mg subcutaneous dose of daratumumab induced deep, durable responses in patients with heavily pre-treated multiple myeloma

Abstract

Daratumumab, a human monoclonal antibody targeting CD38, is approved as monotherapy and in combination regimens for patients with multiple myeloma (MM). Currently, daratumumab is administered IV. The phase 1b PAVO (MMY1004) study evaluated subcutaneously administered daratumumab in combination with the recombinant human hyaluronidase PH20 enzyme (rHuPH20) in patients with relapsed or refractory MM (RRMM). Part 1 of the study, reported here, evaluated a mix-and-deliver (MD) formulation of daratumumab and rHuPH20 (DARA-MD) administered by subcutaneous infusion. Patients received subcutaneous daratumumab per the approved IV monotherapy dosing schedule at 1,200 mg (n=8) or 1,800 mg (n=45). Primary endpoints were safety and pharmacokinetics. The most common treatment emergent adverse events (TEAEs) with DARA-MD 1,200 mg were thrombocytopenia, upper respiratory tract infection (URTI), insomnia, and decreased appetite (37.5% each). Anemia (33.3%), URTI, pyrexia, and diarrhea (26.7% each) were the most common TEAEs with DARA-MD 1,800 mg. One patient in the 1,200 mg dose group (12.5%) and 11 patients in the 1,800 mg dose group (24.4%) experienced infusion-related reactions, which were generally grade 1-2 and typically occurred at the first infusion. The 1,800 mg dose achieved similar or greater serum concentrations compared to the 16 mg/kg IV dose. Overall response rates of 25.0% and 42.2% were achieved with 1,200 mg and 1,800 mg DARA-MD, respectively. Subcutaneous administration of DARA-MD was well tolerated in patients with RRMM, with the 1,800 mg dose demonstrating pharmacokinetic concentrations and responses consistent with IV daratumumab in a similar patient population. This study was registered at www.clinicaltrials.gov as #NCT02519452.

  • Submitted March 19, 2019.
  • Revision received July 2, 2019.
  • Accepted June 28, 2019.