Background: Multiple myeloma (MM) is characterized by the neoplastic proliferation of plasma cells resulting in monoclonal immunoglobulins in the blood, bone marrow, and urine (1). According to a 2019 American Cancer Society (ACS) report, MM is now classified as subtypes of non-Hodgkin lymphoma (NHL). ACS expects there will be ~32,110 new MM cases (18,130 in men and 13,980 in women) and ~12,960 (6,990 in men and 5,970 in women) anticipated deaths in 2019. MM is a heterogenous disease; characterizing its molecular phenotypes is important for effective treatment of MM and predicting relapse. CXCL13-CXCR5 interactions are involved in malignancy cell homing, adhesion, signal transduction, and calcium flux, all of which promote MM progression. Methods: We analyzed RNA-sequence data from matched normal, primary and relapsed MM cases. Patient control mRNA samples matched primary tumor and relapse samples were acquired from dbGap (database of Genotypes and Phenotypes) to evaluate the mRNA expression patterns of CXCL13, CXCR5 and associated genes in MM. A bioinformatics strategy was used to integrate published genomic data from MM patients (n = 480) and identify genes associated with CXCL13-CXCR5 signaling. DESeq analysis was used to determine differentially expressed genes between normal tissues, primary tumor and relapse groups. Weighted gene co-expression network analysis (WGCNA) identified clusters of genes significantly associated with the molecular phenotypes of MM. Results: Notably, gene expression driven by NFAT and JUN, known to be activated by the CXCL13-CXCR5 axis, and plasma cell signaling pathways significantly correlated with select MM molecular phenotypes and patient survival. Ingenuity pathway analysis (IPA) was performed to analyze upstream regulators, gene interaction networks and canonical pathways. Taken together, our data show CXCR5-CXCL13 signaling networks are significantly expressed and associated with MM pathogenesis and plasma clonality. Conclusions: This study provides a better understanding of the heterogeneous nature of MM and the role of the CXCL13-CXCR5 axis in MM.