Despite the recent development of new therapies, multiple myeloma (MM) remains an incurable disease. Thus, new, effective treatments are urgently needed, particularly for relapsed or refractory MM (RRMM). In an earlier phase I study, a novel form of recombinant human Apo2L/tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) that is currently in clinical development for the treatment of hematologic malignancies, i.e., circularly permuted TRAIL (CPT), was well tolerated at a dose of 2.5 mg/kg per day and showed promising preliminary activity in patients with RRMM. This phase II, open-label, multicenter study further investigated the efficacy and safety of 2.5-mg/kg per day CPT as single-agent therapy for patients with RRMM. Patients with RRMM were treated once daily with CPT (2.5 mg/kg, intravenously) for 14 consecutive days for each 21-day cycle. Clinical response and toxicity were assessed after each treatment cycle. Twenty-seven patients received CPT. Using the European Group for Blood and Marrow Transplantation criteria, we calculated the overall response rate of 33.3% with 1 near-complete response (nCR) and 8 partial responses (PRs). The clinical benefit rate (48.1%) included 1 nCR, 8 PRs, and 4 minimal responses. The most common treatment-related adverse events (TRAEs) were fever, aspartate aminotransferase elevation, alanine aminotransferase elevation, leucopenia, rash, neutropenia, and thrombocytopenia. We graded toxicity using the Common Toxicity Criteria for Adverse Events, version 3.0, and determined that 37.0% of patients had at least 1 grade 3-4 TRAE. CPT as a single agent can elicit a response in patients with RRMM and is well tolerated. Further clinical investigation is warranted. Trial Registration ChiCTR-ONC-12002065 http://www.chictr.org/cn.