BACKGROUND: New treatment options are needed for patients with multiple myeloma 
that is refractory to proteasome inhibitors and immunomodulatory drugs. We 
assessed daratumumab, a novel CD38-targeted monoclonal antibody, in patients 
with refractory multiple myeloma.
METHODS: In this open-label, multicentre, phase 2 trial done in Canada, Spain, 
and the USA, patients (age ≥18 years) with multiple myeloma who were previously 
treated with at least three lines of therapy (including proteasome inhibitors 
and immunomodulatory drugs), or were refractory to both proteasome inhibitors 
and immunomodulatory drugs, were randomly allocated in a 1:1 ratio to receive 
intravenous daratumumab 8 mg/kg or 16 mg/kg in part 1 stage 1 of the study, to 
decide the dose for further assessment in part 2. Patients received 8 mg/kg 
every 4 weeks, or 16 mg/kg per week for 8 weeks (cycles 1 and 2), then every 2 
weeks for 16 weeks (cycles 3-6), and then every 4 weeks thereafter (cycle 7 and 
higher). The allocation schedule was computer-generated and randomisation, with 
permuted blocks, was done centrally with an interactive web response system. In 
part 1 stage 2 and part 2, patients received 16 mg/kg dosed as in part 1 stage 
1. The primary endpoint was overall response rate (partial response [PR] + very 
good PR + complete response [CR] + stringent CR). All patients who received at 
least one dose of daratumumab were included in the analysis. The trial is 
registered with ClinicalTrials.gov, number NCT01985126.
FINDINGS: The study is ongoing. In part 1 stage 1 of the study, 18 patients were 
randomly allocated to the 8 mg/kg group and 16 to the 16 mg/kg group. Findings 
are reported for the 106 patients who received daratumumab 16 mg/kg in parts 1 
and 2. Patients received a median of five previous lines of therapy (range 
2-14). 85 (80%) patients had previously received autologous stem cell 
transplantation, 101 (95%) were refractory to the most recent proteasome 
inhibitors and immunomodulatory drugs used, and 103 (97%) were refractory to the 
last line of therapy. Overall responses were noted in 31 patients (29.2%, 95% CI 
20.8-38.9)-three (2.8%, 0.6-8.0) had a stringent CR, ten (9.4%, 4.6-16.7) had a 
very good PR, and 18 (17.0%, 10.4-25.5) had a PR. The median time to first 
response was 1.0 month (range 0.9-5.6). Median duration of response was 7.4 
months (95% CI 5.5-not estimable) and progression-free survival was 3.7 months 
(95% CI 2.8-4.6). The 12-month overall survival was 64.8% (95% CI 51.2-75.5) 
and, at a subsequent cutoff, median overall survival was 17.5 months (95% CI 
13.7-not estimable). Daratumumab was well tolerated; fatigue (42 [40%] patients) 
and anaemia (35 [33%]) of any grade were the most common adverse events. No 
drug-related adverse events led to treatment discontinuation.
INTERPRETATION: Daratumumab monotherapy showed encouraging efficacy in heavily 
pretreated and refractory patients with multiple myeloma, with a favourable 
safety profile in this population of patients.
FUNDING: Janssen Research & Development.