Abstract
Background: Drug resistance remains a major challenge in multiple myeloma (MM). This study explores the role of the oncogenic long non-coding RNA (lncRNA) metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) in MM pathogenesis and lenalidomide resistance. Methods: MALAT1 expression and function were examined in MM cell lines and patient-derived samples using antisense oligonucleotide (ASO) knockdown. Single-cell RNA sequencing (scRNA-seq) and bulk RNA sequencing (RNA-seq) profiled transcriptional changes. Mitochondrial membrane potential and reactive oxygen species (ROS) were measured by fluorescence microscopy. Cellular adenosine triphosphate (ATP) and oxidative phosphorylation (OXPHOS) activity were quantified by colorimetric and luminescence assays. Cytokine profiling of patient bone marrow mononuclear cells (BMMCs) was performed with a 48-plex MILLIPLEX assay. Functional assays were performed in primary patient samples and lenalidomide-resistant MM cell lines, and combination therapy experiments were conducted in resistant MM cell lines. Results: MALAT1 was significantly overexpressed in lenalidomide-resistant MM cells and positively correlated with CD38 expression. scRNA-seq analysis revealed elevated CD38 expression and increased OXPHOS activity in relapsed MM plasma cells. Analysis of the MMRF CoMMpass dataset confirmed a positive correlation between CD38 and MALAT1 expression. MALAT1 knockdown reduced CD38 via PRC2-mediated epigenetic repression and impaired mitochondrial function, leading to reduced OXPHOS activity, decreased ATP production, and increased ROS accumulation. These effects were confirmed in patient-derived BMMCs. MALAT1 inhibition reduced viability of drug-resistant MM cells and patient-derived BMMCs, and disrupted the tumor-supportive bone marrow microenvironment by lowering pro-tumorigenic and immunosuppressive cytokine secretion. Combining anti-MALAT1 ASO with lenalidomide, pomalidomide, or carfilzomib synergistically enhanced cytotoxicity in lenalidomide-resistant MM cells. Conclusions: MALAT1 promotes drug resistance in MM through epigenetic regulation, metabolic reprogramming, and microenvironmental remodeling. Targeting MALAT1 with ASOs sensitizes MM cells to standard therapies and disrupts tumor-supportive signaling, highlighting its potential as a therapeutic target to help overcome drug resistance in MM. Supplementary Information: The online version contains supplementary material available at 10.1186/s12967-025-07252-1.