Novel biological strategies for cancer therapy have recently been able to generate improved anti-tumor effects in the clinic. Of these new advancements, oncolytic virotherapy is a promising strategy through a dual mechanism of oncolysis and stimulation of tumor immunogenicity against the target cancer cells. Myxoma virus (MYXV) is an oncolytic poxvirus that has a natural tropism for Leporids, being nonpathogenic in humans and all other known vertebrates. MYXV is able to infect cancer cells due to mutations and defects in many innate signaling pathways, such as those involved in anti-viral responses. While MYXV alone infects and kills many classes of human cancer cells, recombinant techniques allow for the implementation of therapeutic transgenes, which have the potential of ‘arming’ the virus to enhance its potential as an oncolytic virus. The implementation of certain transgenes allows improved cancer cell killing and/or promotion of more robust anti-tumor immune responses. To investigate the potential of immune-inducing transgenes in MYXV, in vitro screening experiments were performed with several single transgene-armed recombinant MYXVs. As recent studies have shown the ability of MYXV to uniquely target malignant human hematopoietic stem cells, the potential of oncolytic MYXV armed with individual immune-enhancing transgenes was investigated through in vitro killing analysis using human acute myeloid leukemia (AML) and multiple myeloma (MM) cell lines. Additionally, in vitro experiments were performed using primary bone marrow (BM) cells obtained from human patients diagnosed with MM. Furthermore, the action of an engineered bispecific killer engager (huBIKE) was investigated through co-culture studies between the CD138 surface marker of target MM cells and the CD16 surface marker of primary effector peripheral blood mononuclear cells (PBMCs), particularly NK cells and neutrophils. In this study, several of the test armed MYXV-infected human AML and MM cell lines resulted in increased cell death compared to unarmed MYXV-infected cells. Additionally, increased killing of CD138+ MM cells from primary human BM samples was observed following infection with huBIKE-armed MYXV relative to infection with unarmed MYXV. Furthermore, analysis of co-culture studies performed suggests enhanced killing of target MM cells via engagement of NK cells with U266 MM cells by huBIKE.