New horizons in our understanding of precursor multiple myeloma and early interception.

Multiple myeloma is an incurable plasma cell malignancy that evolves over decades through the selection and malignant transformation of monoclonal plasma cells. The evolution from precursor states to symptomatic disease is characterized by an increasing complexity of genomic alterations within the plasma cells and a remodelling of the microenvironment towards an immunosuppressive state. Notably, in patients with advanced disease, similar mechanisms of tumour escape and immune dysfunction mediate resistance to modern T cell-based therapies, such as T cell-engaging bispecific antibodies and chimeric antigen receptor (CAR)-T cells. Thus, an increasing number of clinical trials are assessing the efficiency and safety of these therapies in individuals with newly diagnosed multiple myeloma and high-risk smoldering multiple myeloma. In this Review, we summarize the current knowledge about tumour intrinsic and extrinsic processes underlying progression from precursor states to symptomatic myeloma and discuss the rationale for early interception including the use of T cell-redirecting therapies.