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.