Multiple myeloma (MM) is a plasma cell malignancy whose incidence is increasing with an ageing population, with a median diagnosis age ≥65 years. Although therapeutic advances have extended survival, MM cells frequently resist treatment owing to supportive interactions with the bone marrow microenvironment, particularly tumour-associated macrophages (TAMs). We recently identified β2-microglobulin (β2m) amyloid aggregation within TAM lysosomes as a trigger of NLRP3 inflammasome activation, leading to secretion of IL-1β and IL-18 and thereby sustaining MM progression. Clinically, β2m levels are integral to disease staging and prognosis, and correlate with IL-1β/IL-18 concentrations, reinforcing the direct link between β2m and inflammation-driven tumour support. Inhibition of this pathway is expected to enhance the susceptibility of MM cells to cytotoxic therapies. Despite its pathological relevance, the molecular mechanisms underlying β2m-mediated inflammation in TAMs remain undefined, and no strategies exist to block this process. This project aims to: (i) delineate the molecular events following β2m uptake in macrophages, including the biochemical species and structural organisation of β2m deposits in lysosomes; and (ii) identify β2m-binding molecules capable of preventing its pro- inflammatory activity, i.e. affibodies. We will characterise β2m internalisation, aggregation, lysosomal damage, inflammasome activation, and cytokine release in TAMs. Lysosomal composition will be profiled by proteomics, while confocal microscopy and FT-IR spectroscopy will assess membrane integrity and provide in situ structural characterisation of β2m aggregates. In parallel, affibodies will be tested for their ability to limit aggregation and suppress IL-1β/ IL-18 secretion. Outcomes will establish a mechanistic framework for novel interventions aimed at weakening microenvironmental support and improving treatment efficacy in MM.