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Summary: The tumour microenvironment (TME) plays a critical role in disease progression in multiple myeloma (MM). This study aimed to present an atlas of MM‐TME in disease progression and explore TME‐directed therapeutic strategies. We performed single‐cell RNA sequencing (scRNAseq) in samples from different disease stages. We validated the findings by bulk RNAseq, flow cytometry (FCM) and in vitro and in vivo functional experiments. We delineated a compromised TME during disease progression, characterized by enrichment of exhausted NK cells and CD8+ T cells and reprogramming of macrophages (MPs). The reprogrammed tumour‐associated MPs (TAMs) displayed a mixed phenotype showing both M1 and M2 features, with two TAM clusters exclusively present in the MM stage showing higher M2 scores. We validated the mixed M1/M2 phenotype in TAMs in a clinical cohort and verified phagocytic dysfunction in reprogrammed TAMs. Cellular interaction analysis identified two enriched ligand–receptor pairs between MPs and malignant plasma cells (PCs), including the SIRPA‐CD47 pathway suppressing phagocytosis and the CD74–MIF (macrophage inhibitory factor) reshaping the phenotype of MPs. The expression of CD47 and MIF correlated with disease progression and adverse outcomes. We designed a dual‐MP‐targeted strategy by combining an anti‐CD47 antibody and MIF inhibitor to activate phagocytosis and repolarize MP to a functional phenotype and proved its potent antitumour effect in vitro and in vivo. We drafted alterations in MM‐TME during disease progression and unravelled TAM's reprogramming. The dual MP‐targeted approach blocking both CD47 and MIF showed potent antitumour effects. [ABSTRACT FROM AUTHOR]