This is a Phase 2 study during which patients with advanced multiple myeloma will receive either carfilzomib alone (single-agent) or carfilzomib in combination with investigational study drug filanesib (ARRY-520). Patients will be followed to determine the effectiveness of both single-agent carfilzomib and carfilzomib + filanesib in treating myeloma. Patients will be allowed to crossover from single-agent carfilzomib to carfilzomib + filanesib if disease progression occurs. Approximately 75 patients from the US will be enrolled in this study.

Key Inclusion Criteria:

• Confirmed multiple myeloma with measurable disease.
• Disease refractory to last myeloma regimen.
• Patients must have received at least 2 prior treatment regimens, including bortezomib and an IMiD (e.g., lenalidomide, thalidomide, pomalidomide). Induction therapy and stem cell transplant ± maintenance are to be considered as a single regimen.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2 within 14 days prior to first dose of study treatment.
• Adequate hematology, liver and renal function laboratory values within 14 days prior to first dose of study treatment.
• Additional criteria exist.

Key Exclusion Criteria:

• Prior treatment with carfilzomib, filanesib, or any other KSP inhibitor.
• Past or current plasma cell leukemia.
• Primary amyloidosis (amyloidosis associated with multiple myeloma is allowed).
• POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein and skin changes).
• Ongoing Grade 3 or Grade 4 peripheral neuropathy, or Grade 2 peripheral neuropathy with pain despite appropriate interventions, within 28 days prior to first dose of study treatment.
• Autologous or allogeneic stem cell or bone marrow transplant within 3 months prior to first dose of study treatment.
• Concomitant malignancies or previous malignancies (other than multiple myeloma) with less than a 2-year disease-free interval at the time of first dose of study treatment. Patients with adequately resected basal or squamous cell carcinoma of the skin, carcinoma in situ of the cervix or breast, or Stage 1 prostate cancer are eligible irrespective of the time of diagnosis.
• Known pulmonary hypertension of any severity.
• Concurrent cardiac disease that, in the judgment of the Investigator, would make the patient inappropriate for study participation.
• Known positive serology for the human immunodeficiency virus (HIV), active hepatitis B and/or hepatitis C.
• Acute active infection requiring treatment.
• Additional criteria exist.

Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical\_trials/trial\_data\_and\_results/data\_requests.