Abstract No: 8533
Background: Daratumumab (DARA) (HuMax-CD38), a human IgG1κ monoclonal antibody effectively mediates destruction of CD38-expressing malignant plasma cells. In the first-in-human dose-escalation study, 42% of heavily pretreated patients with relapsed or relapsed, refractory (RR) multiple myeloma (MM) treated with DARA alone (≥4mg/kg) achieved partial response (PR) and 25% had minimal response (MR) (modified IMWG guidelines). In preclinical studies, DARA + lenalidomide (LEN) enhanced killing of MM cells in vitro.We evaluated safety, pharmacokinetics (PK) and efficacy of DARA + LEN + dexamethasone (DEX) in patients with relapsed or RR MM.
Methods: In this ongoing phase I/II open-label multicenter dose-escalation (part 1) study, patients (≥ 18 years old) with life expectancy ≥3 months and ECOG status 0, 1 or 2 received DARA+LEN+DEX: (DARA [2-16 mg/kg] per week [8 wks], twice a month [16 wks], then, once monthly until disease progression, unmanageable toxicity or ≤24 months; LEN [25 mg]; DEX [40 mg] once weekly). Cohort expansion (part 2) study explores testing of maximum DARA dose determined in part 1.
Results: Data from 12 patients (10 men, 2 women), median age 62 years (48-76) are evaluable to date. Median prior therapies: 4 (2-4); median ECOG status: 0.5 (0-1); median DARA infusions: 14.5 (1-23); median infusion time: 6.6 (5.9-7.3) hours. One patient (2 mg/kg dose) withdrew from study due to recurrent grade 1 QT prolongation and hypokalemia. Most frequent (>40% patients) adverse events were neutropenia and diarrhea; 17 were ≥ grade 3 with 70% hematological (neutropenia, thrombocytopenia, anemia). MTD was not reached. DARA+LEN+DEX PK-profile was similar to DARA alone suggesting LEN and DEX do not affect the DARA PK-profile. Available efficacy data from 11 patients demonstrated marked decrease in M-protein in all patients; 8/11 patients achieved PR or better, 5/11 with VGPR, 2/11 with MR. Median time to response was 4.1 weeks (2.1-4.3).
Conclusions: DARA+LEN+DEX has favorable safety profile with manageable toxicities in relapsed and RR MM. Encouraging early activity is seen with marked reduction in M-protein and 8/11 patients (72%) achieving PR or better. Part 2 data will be presented.
Clinical trial information: 2011-005709-62.
Author(s): Torben Plesner, Hendrik-Tobias Arkenau, Henk M. Lokhorst, Peter Gimsing, Jakub Krejcik, Charlotte Rose Lemech, Monique Minnema, Ulrik Niels Lassen, Tahamtan Ahmadi, Howard Yeh, Mary Guckert, Nikolai C. Brun, Steen Lisby, Linda Basse, Antonio Palumbo, Paul G. Richardson; Vejle Hospital, Vejle, Denmark; Sarah Cannon Research Institute, London, United Kingdom; UMC Utrecht, Utrecht, Netherlands; Copenhagen University Hospital, Copenhagen, Denmark; Department of Oncology, Rigshospitalet, Copenhagen, Denmark; Janssen Research and Development, Raritan, NJ; Genmab A/S, Copenhagen, Denmark; Genmab, Copenhagen, Denmark; Multiple Myeloma Unit, University of Torino, Torino, Italy; Dana-Farber Cancer Institute, Boston, MA