IL-37 and IL-38 act as endogenous regulators of CAR-T-associated hyperinflammation in multiple myelomaNew Proteins May Help Control Inflammation in Multiple Myeloma Treatment

Multiple myeloma remains largely incurable despite advances in proteasome inhibitors and monoclonal antibodies. Chimeric antigen receptor (CAR)-T-cell therapy targeting B-cell maturation antigen (BCMA) has achieved deep responses in relapsed/refractory multiple myeloma; however, its clinical utility is constrained by cytokine release syndrome (CRS). CRS is a multicellular hyperinflammatory process driven by CAR-T-derived cytokines, monocyte/macrophage activation, and amplification of the IL-1β–IL-6 axis, leading to endothelial dysfunction and metabolic reprogramming. While IL-6 blockade is the standard of care, severe CRS often persists due to redundant upstream inflammatory signalling. This mini-review evaluates the emerging roles of IL-37 and IL-38, anti-inflammatory members of the IL-1 superfamily, as endogenous regulators of CAR-T-associated hyperinflammation. IL-37 functions primarily as a systemic mediator that suppresses NF-κB/MAPK signalling, inflammasome activity, and endothelial injury. In contrast, IL-38 acts as a tissue-resident regulator that restrains early innate immune priming and modulates macrophage-dendritic cell interactions within the bone marrow microenvironment. We propose a phase-dependent regulatory axis wherein IL-38 limits inflammatory initiation while IL-37 suppresses systemic amplification during peak CRS. These pathways represent promising immunoregulatory checkpoints with translational potential as biomarkers and therapeutic targets. Leveraging these cytokines through recombinant proteins or “armoured” CAR-T-cells equipped with inducible regulatory circuits may improve the safety and efficacy of cellular immunotherapies in multiple myeloma.