CHICAGO — Adding daratumumab to bortezomib and dexamethasone was associated with a 61% reduction in risk of disease progression in patients with relapsed or refractory multiple myeloma (RRMM), according to results of the phase 3 CASTOR study presented in a plenary session at the American Society of Clinical Oncology (ASCO) 2016 Annual Meeting.1
“Daratumumab, bortezomib, and dexamethasone can today potentially be considered a new standard of care” for patients who are currently receiving bortezomib/dexamethasone alone, said Antonio Palumbo, MD, associate professor, University of Torino, Torino, Italy, on behalf of the CASTOR investigators.
Compared with bortezomib and dexamethasone alone, the addition of daratumumab significantly improved progression-free survival, time to progression, and overall response rates, with the treatment benefit consistent across subgroups. In fact, “earlier treatment with daratumumab-bortezomib/dexamethasone may be the most beneficial,” Dr. Palumbo said.
Daratumumab is a human CD38 IgGκ monoclonal antibody with direct and indirect antimyeloma activity that depletes CD38+ immunosuppressive regulatory cells while promoting T cell expansion and activation. The US Food and Drug Administration has approved daratumumab as a single agent in RRMM.
The CASTOR study randomly assigned 251 patients to receive daratumumab 16 mg/kg IV every week for cycles 1 to 3; every 3 weeks for cycles 4 to 8; and every 4 weeks for cycle 9 and beyond plus bortezomib 1.3 mg/m2 on days 1, 4, 8, and 11 of cycles 1 to 8 and dexamethasone 20 mg on days 1, 2, 4, 5, 8 ,9 ,11, and 12 of cycles 1 to 8 and 247 patients to the same bortezomib and dexamethasone regimens. Cycles 1to 8 were repeated every 21 days and cycles 9 and beyond, every 28 days.
Baseline demographics and disease characteristics were well balanced between the 2 treatment arms. Patients received a median of 2 prior lines of therapy (range, 1-10), including 66% who had received bortezomib; 76%, ImiD; and 48%, protease inhibitors and ImiD. A total of 33% of patients were ImiD-refractory and 32% were refractory to last line of prior therapy.
At a median follow-up of 7.4 months (range, 0-14.9), daratumumab significantly improved median progression-free survival as well as time to progression compared with bortezomib and dexamethasone.
Median progression-free survival was not reached in the daratumumab arm vs 7.2 months in the control arm (HR, 0.39; 95% CI, 0.28-0.53; P < .0001); rates at 1 year were 60.7% vs 26.9%. In addition, median time to progression was not reached in the daratumumab arm vs 7.3 months in the control arm (HR, 0.30; 95% CI, 0.21, 0.43; P < .0001); rates at 1 year were 65.4% vs 28.8%.
Daratumumab also significantly increased overall response rates (83% vs 63%; P < .0001), and doubled very good partial response (59% vs 29%; P < .0001), and complete response rates (19% vs 9%; P = .0012). Among patients who were MRD-negative, overall response rate was 14% in the daratumumab arm compared with 3% in the control arm.
The most common adverse events were thrombocytopenia (59% in the daratumumab arm vs 44% in the control arm; sensory peripheral neuropathy (47% vs 38%), diarrhea (32% vs 22%) and anemia (26% vs 31%). The most common grade 3/4 adverse events were thrombocytopenia (45% vs 33%), anemia (14% vs 16%), and neutropenia (13% vs 4%).
A total of 7% of patients in the daratumumab arm discontinued due to a treatment-emergent adverse event, as did 9% of patients in the control arm. Daratumumab-associated infusion-related reactions occurred in 45% of patients, primarily during the first infusion. The majority were grade 1/2; 9% were grade 3/4.
1. Palumbo A, Chanan-Khan AA, Weisel K, et al. Phase III randomized controlled study of daratumumab, bortezomib, and dexamethasone (DVd) versus bortezomib and dexamethasone (Vd) in patients (pts) with relapsed or refractory multiple myeloma (RRMM): CASTOR study. Plenary presentation at: ASCO 2016 Annual Meeting; June 3-7, 2016; Chicago, IL.