Background: Multiple myeloma (MM) is an incurable disease characterized by immune dysregulation and exhaustion, whereby proliferation of malignant plasma cells is not checked by the native immune system. Allogeneic natural killer (NK) cells are active in various hematologic malignancies and may have a role against MM. We have recently completed a phase I, first-in-human trial of NK cells derived from umbilical cord blood (CB-NK cells) in conjunction with high dose chemotherapy and autologous stem cell transplant (SCT). In this high-risk patient group, there was no GVHD or infusion reaction and 10/12 patients achieved VGPR or better. We are now conducting a phase II trial of this novel adoptive cell therapy at the MTD of 1 e8 CB-NK cells/kg. Methods: This is a single-arm, phase II trial of CB-NK cells for MM patients undergoing SCT. A total of 33 patients will be enrolled. Patients with symptomatic MM who are candidates for autologous SCT are eligible. CB units with at least 4/6 match at HLA-A, B and DR are chosen. When possible, CB units with potential NK alloreactivity (as determined by KIR typing) are prioritized. On day (-19) CB units are thawed and mononuclear cells (MNCs) are cultured in a gas permeable bioreactor with irradiated (100 Gy) K562-based aAPCs expressing membrane bound IL-21 “Clone 9.mbIL21” (2:1 feeder cell:MNC ratio) and IL-2 (100 IU/mL) . On day 7, cells are CD3-depleted and remaining cells are re-stimulated with aAPC feeder cells and cultured for an additional 7 days. Patients receive lenalidomide (10 mg orally daily) from days (-8) to day (-2). Melphalan 200 mg/ m2 is given IV on day (-7). CB-NK cells are infused on day (-5) with autologous SCT on day (0). Peripheral blood is drawn for correlative analyses (in vivo CB- NK persistence and phenotype) at day (-4), day (0) and weekly thereafter. Responses at day 90 are determined by international Myeloma Working Group criteria. The primary endpoint is rate of complete response (CR) at 90 days after SCT. Secondary endpoints include in vivo persistence of CB-NK cells, in vivo CB-NK phenotype, PFS and OS. Modified Bayesian analysis is being utilized for ongoing toxicity and efficacy monitoring. Study was initiated in December 2014. Clinical trial information: NCT01729091