Interleukin-1 Receptor-Associated Kinases (IRAKs) and Multiple Myeloma (MM) development Alexandra Ma University of Toronto, Life Sciences, Sun Life Gene Medical Science Institute Cancer Research Program Student, Toronto, Ontario, Canada

Abstract Multiple myeloma (MM) develops within an inflammatory, TLR‑responsive bone‑marrow niche where innate‑immune signaling shapes plasma‑cell behavior and microenvironmental interactions. This review examines the Interleukin‑1 receptor‑associated kinase (IRAK) family, which are serine/threonine kinases and pseudokinases that regulate MyD88‑dependent TLR/IL‑1R pathways, and outlines their emerging relevance to MM biology. We summarize the structural and functional features of IRAK1, IRAK2, IRAK3, and IRAK4; their roles in NF‑κB activation, cytokine production, immune tolerance, and stromal–myeloid communication; and how these pathways differ between mutation‑driven signaling in other B‑cell malignancies and microenvironment‑driven activation in MM. The review highlights how IRAK‑dependent signaling integrates intrinsic plasma‑cell stress responses with extrinsic cues from macrophages, dendritic cells, and stromal cytokine networks. We also evaluate current and emerging therapeutic strategies—including IRAK4 inhibitors, dual IRAK1/4 blockade, IRAK1 degraders, and IRAK3‑modulating approaches—and discuss how targeting IRAK family members may enhance immunotherapy responsiveness and reshape precision‑medicine strategies in MM. Together, these topics provide a framework for understanding IRAK signaling as a central regulator of MM progression, immune evasion, and therapeutic resistance. 

Keywords: bone marrow microenvironment, multiple myeloma, Interleukin‑1 receptor‑associated kinases, therapeutics