Therapeutic Target Discovery for Multiple Myeloma: Identifying Druggable Genes via Mendelian Randomization.

: Multiple myeloma (MM) is a hematological malignancy originating from the plasma cells present in the bone marrow. Despite significant therapeutic advancements, relapse and drug resistance remain major clinical challenges, highlighting the urgent need for novel therapeutic targets. : To identify potential druggable genes associated with MM, we performed Mendelian randomization (MR) analysis. Causal candidates were further validated using a single-tissue transcriptome-wide association study (TWAS), and colocalization analysis was conducted to assess shared genetic signals between gene expression and disease risk. Potential off-target effects were assessed through an MR phenome-wide association study (MR-PheWAS). Additionally, molecular docking and functional assays were used to evaluate candidate drug efficacy. : The MR analysis identified nine druggable genes (FDR < 0.05), among which Orosomucoid 1 () and Oviductal Glycoprotein 1 () were supported by both TWAS and colocalization evidence (PPH4 > 0.75). Experimental validation demonstrated the significant downregulation of ORM1 and OVGP1 in MM cells ( < 0.05). Pregnenolone and irinotecan, identified as agonists of ORM1 and OVGP1, respectively, significantly inhibited MM cell viability, while upregulating their expression ( < 0.05). : Our study highlights ORM1 and OVGP1 as novel therapeutic targets for MM. The efficacy of pregnenolone and irinotecan in suppressing MM cell growth suggests their potential for clinical application. These findings provide insights into MM pathogenesis and offer a promising strategy for overcoming drug resistance.