Objectives: Circularly permuted tumor necrosis factor-related apoptosis-inducing ligand (CPT), or CPT, is a novel antitumor drug candidate. This phase 1b study evaluated the safety, tolerability, pharmacokinetics (PK), and efficacy of single-agent CPT in patients with relapsed or refractory multiple myeloma (RRMM), and aimed to identify the recommended dose for the phase 2 study. Materials and Methods: Patients received single or multiple doses (once daily for 5 consecutive days per 21-d cycle) of CPT intravenous infusion at doses of 5, 6.5, 8, 10, and 15 mg/kg, to determine the maximum tolerated dose, dose-limiting toxicities, safety, and tolerability. PK were evaluated. Preliminary efficacy was assessed after each treatment cycle. Results: Twenty-nine RRMM patients received CPT. Neither the dose-limiting toxicity nor the maximum tolerated dose were identified. The most common treatment-related adverse events were liver enzyme elevations (eg, elevation of aspartate aminotransferase and alanine aminotransferase), hematological abnormalities (eg, leukopenia and neutropenia), fever, fatigue, and vomiting. CPT had a terminal half-life of 0.90 to 1.27 hours at the 5 dose levels, and no accumulation was observed with repeated doses. Safety and PK profiles were similar across the 5 dose cohorts. The overall response rate (complete and partial response) was 18.5%. The clinical benefit rate (complete, partial, and minimal response) was 33.3%. Sixteen patients did not respond to CPT (no change and progressive disease). Patients treated with higher doses of CPT appeared to have better responses. Conclusions: CPT was safe and well tolerated by RRMM patients, and doses between 8 and 15 mg/kg were recommended for the phase 2 study.