Multiple myeloma (MM) is a terminal cancer of bone marrow plasma cells whose pathophysiological mechanisms remain poorly understood. Similar genetic mutations are shared between MM and its requisite, pre-malignant phase monoclonal gammopathy of undetermined significance (MGUS), suggesting that other factors are required for disease progression. There are two types of mice that are susceptible to the engraftment of malignant plasma cells. KaLwRij, a spontaneous mutant of the control mouse C57BL/6J, has a high rate of the mouse equivalent of human MGUS. Chronic intermittent hypoxia (CIH), a feature of sleep apnea, has been shown to allow malignant plasma cells to engraft in typically disease-resistant C57BL/6J mice. To identify overlapping expressed genes and pathways, bulk RNA-sequencing was used to quantify differential gene expression in KaLwRij vs. C57BL/6J and CIH-exposed C57BL/6J vs. normoxic C57BL/6J. Genes were considered significant if p-adj<0.05 and their differential gene expression value, measured in log2(fold change), was <-1 or >1. A total of 400 significant genes for KaLwRij and 69 significant genes for CIH were identified, with 31 significant overlapping genes between the two datasets and all 31 genes being up-regulated in both experimental mice compared to the control mice. The RNA bulk sequencing dataset was then further analyzed using QIAGEN Ingenuity Pathway Analysis (IPA). 193 and 46 significant enriched signaling pathways were identified in the KaLwRij and CIH datasets, respectively. Each enriched pathway had an associated p-value and z-score, the latter of which predicts activation or inhibition. 14 overlapping pathways with available z-scores were identified. Multiple identified overlapping genes and pathways are directly or indirectly involved in B-cell and macrophage functions. The data suggests that macrophages are important in the microenvironment of both susceptible models and may be a potential therapeutic target for MM. These results provide potential mechanistic targets to prevent the terminal engraftment of malignant plasma cells in the bone marrow.