Inappropriate Expression of PD-1 and CTLA-4 Checkpoints in Myeloma Patients Is More Pronounced at Diagnosis: Implications for Time to Progression and Response to Therapeutic Checkpoint Inhibitors

Multiple myeloma (MM) is a hematologic malignancy characterized by severely profound immune dysfunction. Therefore, the efficacy of drugs targeting the immune environments, such as immune checkpoint inhibitors (ICIs), is of high clinical importance. However, several clinical trials evaluating ICIs in MM in different therapeutic combinations revealed underwhelming results showing a lack of clinical efficacy and excessive side effects. The underlying mechanisms of resistance to ICIs observed in the majority of MM patients are still under investigation. Recently, we demonstrated that inappropriate expression of PD-1 and CTLA-4 on CD4 T cells in active MM is associated with adverse clinical outcomes and treatment status. The aim of the current study was to determine the usefulness of immune checkpoint expression assessment as a predictive biomarker of the response to therapeutic inhibitors. For this purpose, along with checkpoint expression estimated by flow cytometry, we evaluated the time to progression (TTP) of MM patients at different clinical stages (disease diagnosis and relapse) depending on the checkpoint expression level; the cut-off point (dividing patients into low and high expressors) was selected based on the median value. Herein, we confirmed the defective levels of regulatory PD-1, CTLA-4 receptors, and the CD69 marker activation in newly diagnosed (ND) patients, whereas relapsed/refractory patients (RR) exhibited their recovered values and reactivity. Additionally, substantially higher populations of senescent CD4(+)CD28(−) T cells were found in MM, primarily in NDMM subjects. These observations suggest the existence of two dysfunctional states in MM CD4 T cells with the predominance of immunosenescence at disease diagnosis and exhaustion at relapse, thus implying different responsiveness to the external receptor blockade depending on the disease stage. Furthermore, we found that lower CTLA-4 levels in NDMM patients or higher PD-1 expression in RRMM patients may predict early relapse. In conclusion, our study clearly showed that the checkpoint level in CD4 T cells may significantly affect the time to MM progression concerning the treatment status. Therefore, when considering novel therapies and potent combinations, it should be taken into account that blocking PD-1 rather than CTLA-4 might be a beneficial form of immunotherapy for only a proportion of RRMM patients.