Ablation of CD38 in Multiple Myeloma Cells Leads to an Aggressive Phenotype in a Mouse Xenograft Model.

Abstract

Multiple myeloma (MM) is a plasma cell malignancy characterized by bone pain and organ failure. A major challenge in treating MM is therapeutic resistance. CD38-targeted immunotherapies, such as daratumumab, have significantly improved outcomes, however, variable responses, resistance, and relapse remain challenges. We hypothesized that loss of CD38 drives a more aggressive phenotype and resistance to therapy. To test this, we developed a CD38 knockout (KO) clone of a human MM cell line and evaluated it in immunodeficient mice. Mice with CD38 KO tumors exhibited an increased tumor burden and reduced survival compared to those with CD38 WT tumors. Imaging and histology revealed increased osteolytic lesions caused by CD38 KO tumors, while FDG PET demonstrated elevated metabolic activity and tracer uptake in KO tumors. Mice with CD38 KO tumors also developed bilateral kidney metastases, whereas none occurred in WT tumors. Blood analysis showed elevated markers of disease progression and renal dysfunction, and cytokine profiling identified increased pro-inflammatory cytokines within the bone microenvironment. RNA-seq identified marked transcriptional changes, with enrichment of pathways involving cell adhesion, cytokine signaling, and migration. Daratumumab-resistant MM.1S cells mirrored CD38 KO cells with reduced cell cycle progression and dexamethasone sensitivity, underscoring the microenvironment's role in driving aggressiveness and implicating CD38 loss as a possible mediator of cross-resistance. Overall, these findings demonstrate that CD38 loss drives an aggressive MM phenotype characterized by bone degradation, renal metastasis, and reduced survival, highlighting the need to develop strategies to target CD38-deficient clones and offering RNA signatures as candidate regulators of this phenotype.