BACKGROUND: Lenalidomide and bortezomib frontline exposure has raised a growing 
need for novel treatments for patients with relapsed or refractory multiple 
myeloma. Carfilzomib in combination with daratumumab has shown substantial 
efficacy with tolerable safety in relapsed or refractory multiple myeloma in a 
phase 1 study. In this study, we aimed to compare the efficacy and safety of 
carfilzomib, dexamethasone, and daratumumab versus carfilzomib and dexamethasone 
in patients with relapsed or refractory multiple myeloma.
METHODS: In this randomised, multicentre, open-label, phase 3 study, 466 
patients recruited from 102 sites across North America, Europe, Australia, and 
Asia with relapsed or refractory multiple myeloma were randomly assigned 2:1 to 
carfilzomib, dexamethasone, and daratumumab (KdD) or carfilzomib and 
dexamethasone (Kd). All patients received twice per week carfilzomib at 56 mg/m2 
(20 mg/m2; days 1 and 2 during cycle 1). Daratumumab (8 mg/kg) was administered 
intravenously on days 1 and 2 of cycle 1 and at 16 mg/kg weekly for the 
remaining doses of the first two cycles, then every 2 weeks for four cycles 
(cycles 3-6), and every 4 weeks thereafter. Patients received 40 mg 
dexamethasone weekly (20 mg for patients ≥75 years old starting on the second 
week). The primary endpoint was progression-free survival assessed by intention 
to treat. Adverse events were assessed in the safety population. This trial 
(NCT03158688) is registered with ClinicalTrials.gov, and is active but not 
recruiting.
FINDINGS: Between June 13, 2017, and June 25, 2018, 466 patients of 569 assessed 
for eligibility were enrolled. After median follow-up of approximately 17 
months, median progression-free survival was not reached in the KdD group versus 
15·8 months in the Kd group (hazard ratio 0·63; 95% CI 0·46-0·85; p=0·0027). 
Median treatment duration was longer in the KdD versus the Kd group (70·1 vs 
40·3 weeks). Grade 3 or higher adverse events were reported in 253 (82%) 
patients in the KdD group and 113 (74%) patients in the Kd group. The frequency 
of adverse events leading to treatment discontinuation was similar in both 
groups (KdD, 69 [22%]; Kd, 38 [25%]).
INTERPRETATION: KdD significantly prolonged progression-free survival versus Kd 
in patients with relapsed or refractory multiple myeloma and was associated with 
a favourable benefit-risk profile.
FUNDING: Amgen.