BACKGROUND: Multiple myeloma (MM) is a hematological malignancy characterized by profound immunosuppression resulting from both disease-related mechanisms and treatment-induced immune dysfunction. This compromised immune status markedly increases susceptibility to infections, a leading cause of morbidity and mortality in MM patients. While vaccination represents a cornerstone of infection prevention, standard immunization strategies often yield suboptimal responses in this population. OBJECTIVES: This review synthesizes current evidence on the immunological barriers and clinical effectiveness of vaccination in MM. We evaluate vaccines targeting influenza, Streptococcus pneumoniae, SARS-CoV-2, and other relevant pathogens, and explore determinants influencing vaccine efficacy, including optimal timing, formulation, and patient-specific immune parameters. METHODS: A comprehensive literature review was conducted, encompassing clinical trials, retrospective cohort studies, expert consensus guidelines, and population-based data. Extracted outcomes included serological responses, infection-related events, and vaccine safety in MM patients. RESULTS: Patients with MM exhibit impaired vaccine responses due to hypogammaglobulinemia, T- and B-cell dysfunction, and therapy-induced lymphodepletion. Despite modest immunogenicity, influenza and pneumococcal vaccines reduce respiratory infections and hospitalizations. Sequential administration of PCV13 followed by PPSV23, as well as post-autologous stem cell transplantation (ASCT) three-dose regimens, is associated with reduced pneumonia incidence. COVID-19 vaccines elicit variable responses, particularly in patients on anti-CD38 or BCMA-targeted therapies, highlighting the need for booster doses and, in selected cases, prophylactic monoclonal antibodies. Vaccines against herpes zoster, hepatitis B, and Haemophilus influenzae type B are also recommended, particularly around ASCT. Immunophenotypic markers such as CD19+ B-cell and CD4+ T-cell counts are predictive of vaccine responsiveness, supporting immune profiling as a tool for individualized vaccination planning. CONCLUSIONS: Vaccination remains a critical component of infection prevention in MM. Although immunogenicity may be attenuated, clinical benefits-namely, reduced infection burden and healthcare utilization-support broad vaccine implementation. A personalized approach, considering the treatment phase, disease control, and immune status, is essential to optimize vaccine effectiveness. Ongoing research into high-dose, adjuvanted, and next-generation vaccines is critical to enhance protection in this vulnerable population.