Ablation of CD38 in multiple myeloma cells leads to an aggressive phenotype in a mouse xenograft model

Multiple myeloma (MM) is a plasma cell malignancy characterized by bone pain and end-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 vital 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 with those with CD38 wild-type (WT) tumors. Multimodal imaging and histologic analyses revealed increased osteolytic lesions caused by CD38 KO tumors, while [18F]-fluorodeoxyglucose positron emission tomography demonstrated elevated metabolic activity and tracer uptake. Mice with CD38 KO tumors also developed bilateral renal metastases, whereas none were observed in WT tumors. Blood analysis showed elevated markers of disease progression and renal dysfunction, and cytokine profiling identified increased proinflammatory cytokines within the bone microenvironment. RNA sequencing 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 identifying RNA signatures as potential regulators of this phenotype.