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Daratumumab plus carfilzomib and dexamethasone in patients with relapsed or refractory multiple myeloma

Ajai Chari, Joaquín Martinez-Lopez, María-Victoria Mateos, Joan Bladé, Lotfi Benboubker, Albert Oriol, Bertrand Arnulf, Paula Rodriguez-Otero, Luis Pineiro, Andrzej Jakubowiak, Carla de Boer, Jianping Wang, Pamela L. Clemens, Jon Ukropec, Jordan Schecter, Sagar Lonial and Philippe Moreau

Key Points

  • Daratumumab plus carfilzomib/dexamethasone induced deep durable responses, regardless of prior treatment with lenalidomide.

  • Splitting the first dose of daratumumab was feasible, and the regimen was well tolerated.

Abstract

Patients with relapsed or refractory multiple myeloma (RRMM) have limited treatment options and poor survival outcomes. The increasing adoption of lenalidomide-based therapy for frontline treatment of multiple myeloma has resulted in a need for effective regimens for lenalidomide-refractory patients. This phase 1b study evaluated daratumumab plus carfilzomib and dexamethasone (D-Kd) in patients with RRMM after 1 to 3 prior lines of therapy, including bortezomib and an immunomodulatory drug; lenalidomide-refractory patients were eligible. Carfilzomib- and daratumumab-naïve patients (n = 85) received carfilzomib weekly on days 1, 8, and 15 of each 28-day cycle (20 mg/m2 initial dose, escalated to 70 mg/m2 thereafter) and dexamethasone (40 mg/wk). Of these, 10 patients received the first daratumumab dose as a single infusion (16 mg/kg, day 1 cycle 1), and 75 patients received a split first dose (8 mg/kg, days 1-2 cycle 1). Subsequent dosing was per the approved schedule for daratumumab. Patients received a median of 2 (range, 1-4) prior lines of therapy; 60% were lenalidomide refractory. The most common grade 3/4 treatment-emergent adverse events were thrombocytopenia (31%), lymphopenia (24%), anemia (21%), and neutropenia (21%). Infusion-related reactions were observed in 60% and 43% of single and split first-dose patients, respectively. Overall response rate was 84% (79% in lenalidomide-refractory patients). Median progression-free survival (PFS) was not reached; 12-month PFS rates were 74% for all treated patients and 65% for lenalidomide-refractory patients. D-Kd was well tolerated with low neutropenia rates, and it demonstrated deep responses and encouraging PFS, including in patients refractory to lenalidomide. The trial was registered at www.clinicaltrials.gov as #NCT01998971.

  • Submitted March 21, 2019.
  • Accepted May 9, 2019.
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