Background: Immunomodulatory agent (IMiD)/bortezomib (BTZ) combinations are common frontline therapy in patients with multiple myeloma (MM). Despite high initial objective response rates (ORR) and prolonged progression-free survival (PFS), almost all patients eventually relapse. Treatment for relapsed or refractory disease typically includes regimens that maintain IMiDs and/or proteasome inhibitors (PIs) as a foundation. Filanesib is a highly selective, targeted kinesin spindle protein (KSP) inhibitor that has shown promising preliminary activity and manageable toxicity as a single agent and in combination with dexamethasone, BTZ and carfilzomib (CFZ). Due to a distinct mechanism of action, filanesib demonstrates activity in patients with myeloma that has become resistant to IMiDs and PIs, potentially addressing a significant unmet medical need. Methods: This multicenter, randomized (2:1), open-label Phase 2 study is designed to assess the efficacy, safety and pharmacokinetics (PK) of CFZ ± filanesib in 75 patients with measurable MM who have received at least 2 prior treatment regimens (including BTZ and an IMiD) and have disease refractory to their last myeloma therapy (NCT01989325). Patients at community and academic centers in the United States are stratified by BTZ-refractory disease status and randomized to receive CFZ + filanesib (~50 patients) or single-agent CFZ (~25 patients) in continuous 28-day cycles until disease progression or unacceptable toxicity. CFZ (20/27 mg/m²) is administered intravenously (IV) on Days 1, 2, 8, 9, 15 and 16. Filanesib is administered as 1.25 mg/m²/day IV on Days 1, 2, 15 and 16 with prophylactic filgrastim. Crossover from single-agent CFZ to combination treatment is permitted upon confirmed disease progression. The primary endpoint is PFS; secondary endpoints include PFS rate at 6 months, ORR, duration of response, time to best response, clinical benefit rate, disease control rate, safety, and PK. No formal comparisons will be made between treatment arms. Exploratory measurements of alpha 1-acid glycoprotein (AAG), a potential predictive biomarker for filanesib treatment, will be performed. Clinical trial information: NCT01989325