Phase I/II dose-escalation study of daratumumab in patients with relapsed or refractory multiple myeloma.

Abstract

8512^ Background: Daratumumab (DARA) is a human CD38 monoclonal antibody (mAb) with broad-spectrum killing activity. Preliminary safety and efficacy data from this first-in-human dose-escalation study of DARA in pts with relapsed or refractory (RR) multiple myeloma (MM) have previously been published. Here, we present safety and efficacy data from the finalized part 1 and preliminary safety data from the ongoing part 2 of the study. Methods: Pts ≥18 years requiring systemic therapy and considered RR to at least 2 prior lines of therapy and ineligible for ASCT were enrolled. In part 1, a 3+3 dose-escalation design was applied and DARA was administered over a 9-week period as 2 pre- and 7 full doses. The phase II dose was determined to 8mg/kg and these pts receive DARA weekly for 8 weeks followed by dosing every 2nd week for 16 weeks and every 4th week until disease progression, toxicity or for max. 24 months. Results: Data from 32 pts included in part 1 are presented. In part 2, 7/16 pts have been recruited: all available data will be presented at the meeting. In part 1, the median number of prior treatment lines was 6. PK analysis showed plasma peak levels as expected but relatively rapid clearance at low dose levels. At doses ≥4mg/kg, observed PK values approximated model-predicted values. Efficacy evaluation from part 1 was based on IMWG guidelines. In the ≥4mg/kg groups (n=12), 5 PRs and 3 MRs were observed. 7 of these pts had a 50-100% concomitant reduction in bone marrow plasma cells. Median PFS in the ≥4mg/kg dose groups was not reached (median follow-up at data cut-off was 3.8mths (range: 0-9.6mths). No ADA responses were detected. In part 1, the most common adverse events reported were infusion related (IRE) which occurred predominantly during the first full infusion. 44% of subjects across all dose groups had IREs grade 1-3, of which 2 were grade 3. Six related SAEs (1 anemia, 1 thrombocytopenia, 2 bronchospasm, 1 cytokine release, 1 AST increase) were reported. Conclusions: DARA induced a marked reduction in paraprotein and bone marrow plasma cells at doses ≥4mg/kg in heavily pretreated RR MM pts. In addition, high response rates and encouraging PFS data were observed. This is unprecedented for single-agent mAb treatment of MM. Clinical trial information: NCT00574288.