Multiple myeloma (MM) is a malignancy marked by uncontrolled plasma cell proliferation, immune evasion, and drug resistance. Despite advances in treatment, the disease remains incurable due to relapses and drug resistance. This study aims to investigate the molecular and cellular interactions within the myeloma microenvironment using single-cell RNA sequencing (scRNA-seq), Mendelian randomization (MR), and pathway analysis to uncover therapeutic targets.We used scRNA-seq to analyze tumor, immune, and stromal cell interactions in MM. Data were processed using Seurat for clustering, dimensionality reduction, and cell-type annotation. Gene Set Variation Analysis (GSVA) and cell-cell interaction analysis were performed to identify signaling pathways involved in disease progression. Two-sample MR was applied to explore causal relationships between genetic variants and gene expression. Finally, molecular docking simulations were used to identify potential small molecule modulators of key proteins involved in MM.We identified significant immune-related signaling pathways, including PI3K-AKT-mTOR, WNT-β-catenin, and TGF-β, upregulated in immune cells within the MM microenvironment. Genes such as HLA-C, CTSS, and LRRFIP1 showed positive causal relationships with MM, while SHISA5 and ISG15 exhibited protective roles. Cell communication analysis revealed key ligand-receptor interactions between immune and tumor cells. Molecular docking identified promising small molecules like actein and aflatoxin B1 targeting ISG15 and TAGLN2.This study reveals key genetic drivers and immune modulation mechanisms in MM. Targeting immune-related pathways, such as PI3K-AKT-mTOR and WNT-β-catenin, and small molecules targeting ISG15 and TAGLN2 could offer new therapeutic strategies.Copyright © 2025 The Author(s). Published by Wolters Kluwer Health, Inc.