Daratumumab, a human CD38 IgG1κ monoclonal antibody, has activity as monotherapy in multiple myeloma (MM). This phase 1/2 study investigated daratumumab plus lenalidomide/dexamethasone in refractory and relapsed/refractory MM. Part 1 (dose-escalation) evaluated 4 daratumumab doses plus lenalidomide (25 mg/day p.o. on Days 1 21 of each cycle) and dexamethasone (40 mg/week). Part 2 (dose-expansion) evaluated daratumumab at the recommended phase 2 dose (RP2D) plus lenalidomide/dexamethasone. Safety, efficacy, pharmacokinetics, immunogenicity and accelerated daratumumab infusions were studied. In Part 1 (13 patients), no dose-limiting toxicities were observed; 16 mg/kg was selected as the R2PD. In Part 2 (32 patients), median time since diagnosis was 3.2 years, with a median (range) of two (one-three) prior therapies, including proteasome inhibitors (91%), alkylating agents (91%), autologous stem cell transplant (78%), thalidomide (44%), and lenalidomide (34%); 22% were refractory to last line of therapy. Grade 3/4 adverse events (≥5%) included neutropenia, thrombocytopenia, and anemia. In Part 2, infusion-related reactions (IRRs) occurred in 18 patients (56%); most were grade ≤2 (grade 3, 6.3%). IRRs predominantly occurred during first infusions and were more common during accelerated infusions. In Part 2 (median follow-up of 15.6 months), overall response rate was 81% with 8 (25%) stringent complete responses, 3 (9%) complete responses, and 9 (28%) very good partial responses. Eighteen-month progression-free and overall survival rates were 72% (95% CI, 51.7-85.0) and 90% (95% CI, 73.1-96.8), respectively. Daratumumab plus lenalidomide/dexamethasone resulted in rapid, deep, durable responses. The combination was well-tolerated and consistent with the safety profiles observed with lenalidomide/dexamethasone or daratumumab monotherapy.