The IL-6 Network in Multiple Myeloma: From Tumor Survival Pathways to Immune Dysfunction and Cytokine Storm in Modern Therapies

Interleukin 6 (IL-6) is a pleiotropic pro-inflammatory cytokine that plays a central role in multiple myeloma (MM) pathogenesis, coordinating tumor survival, immune modulation, and therapy-related toxicity. In the bone marrow microenvironment, IL-6 is produced by stromal cells, osteoblasts, osteoclasts, and malignant plasma cells, creating a supportive niche that promotes proliferation, survival, osteoclastogenesis, and drug resistance. IL 6 activates JAK/STAT3, PI3K/AKT, and MAPK signaling, driving anti-apoptotic programs, metabolic adaptation, and clonal expansion. Beyond tumor-intrinsic effects, IL-6 induces T-cell exhaustion, enhances myeloid-derived suppressor cell activity, and reinforces immunosuppressive networks, facilitating immune evasion. Clinically, elevated serum IL-6 correlates with advanced disease, poor prognosis, and reduced therapeutic responsiveness, and it mediates cytokine release syndrome (CRS) during CAR-T and bispecific T-cell therapies. Therapeutic targeting of IL-6 or its receptor using monoclonal antibodies (Siltuximab, Tocilizumab) or next-generation agents (Clazakizumab, Sari-lumab, sgp130Fc) shows promise in controlling disease progression and mitigating therapy-related toxicity. Overall, IL 6 represents a pivotal nexus linking tumor biology, immune dysfunction, and treatment complications, and its modulation offers a rational strategy to improve outcomes in MM.