Background: B cells are critical to inhibiting tumor progression, as they generate tumor-reactive antibodies; promote anti-tumor killing capacity of NK cells and phagocytosis of macrophages/DCs; and enrich priming of T cells against the tumor. Multiple myeloma (MM) is a B-cell-derived malignancy, and its survival is partly driven by a deficiency in the immune response. Yet, the abnormalities of the B-cell-mediated humoral responses in MM are ill defined. Methods: We investigated B cell composition in bone marrow (BM) from patients with newly diagnosed MM (NDMM, N = 170), relapsed refractory MM (RRMM, N = 140) and healthy donors (HD, N = 21) by multi-color flow cytometry. Results: We observed that B1b cells was significantly reduced by 45% (p = 0.004) in NDMM patients compared to HD. B1b cells are important in generating long-lasting protective antibodies, particularly against vaccines, in a T cell independent fashion. Similarly, B2 cells, which can produce all antibody types, were significantly reduced in the periphery of NDMM and RRMM patients. Within the B2 cell population, germinal center (GC) matured B cells were significantly reduced in both BM and periphery of MM patients, as shown by significantly higher expression of Fas receptor. Because of deficiencies in the GC-maturation of these B cells, their ability to switch from IgM to IgG was also significantly decreased. On the other hand, the population of regulatory B cells (Bregs) were significantly elevated by 2.3-fold (p < 0.05) in the BM and periphery of NDMM and periphery of RRMM patients. However, the ability of Breg cells to produce suppressive cytokines, like IL-10, was significantly reduced (p = 0.03), indicating impaired suppressive functional capacity. We investigated whether this dysregulated B cell homeostasis impacts myeloma patient survival following treatment. We found that a higher proportion of Bregs and a lower percent of B1a in BM and periphery prior to treatment was associated with favorable progression-free survival (PFS) in both NDMM and RRMM patients. We hypothesized that reduction of B2 cells and their inability to have GC-based maturation could impair antibody generation against acute infections and tumor neoantigens. Therefore, we evaluated MM patients’ ability to produce antibodies against hepatitis B surface antigen-based vaccination. We observed that only 31% of MM patients (N = 32) respond to the vaccine compared to 90% of HD. Furthermore, MM patients’ antibody titers were significantly lower ( < 120 IU/L) compared to > 5000IU/L in HD. Conclusions: All together, these results show that in MM patients, vaccine-responsive populations of B cells are reduced, with fewer mature B cells with limited repertoires in GC to fight against acute infections, and with a high number of dysregulated regulatory B cells. These results indicate that compromised B cell functionality in MM patients could impact therapeutic outcome.