Introduction

Relapsed and refractory multiple myeloma (R/R MM) and B-cell leukemia/lymphoma with extramedullary disease (EMD) represent some of the most formidable challenges in hematology. These conditions often carry a bleak prognosis due to their resistance to conventional therapies and the complex nature of extramedullary disease, where cancer cells spread outside the bone marrow. Chimeric antigen receptor (CAR)-T cell therapy has revolutionized the treatment landscape for these malignancies, offering hope where few options existed. However, even with CAR-T cell therapy, patients with EMD have experienced limited success, highlighting the need for innovative approaches to improve outcomes.

In this light, a study led by Dr. Chunrui Li and colleagues from the Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology , published in Blood Science, explores the potential of combining pomalidomide, an immunomodulatory drug, with CAR-T cell therapy. Pomalidomide, a third-generation derivative of thalidomide, has shown promise in modulating the immune environment, enhancing T-cell function, and crossing the blood-brain barrier—qualities that could be particularly beneficial in treating EMD.

Study Design and Patient Profile

The study reviewed six patients with RRMM or B-cell leukemia/lymphoma at Shanxi Bethune Hospital and Tongji Hospital from December 2020 to September 2023. These patients, aged 16 to 67, had received multiple treatments, including HSCT and CAR-T therapy, but their disease progressed. They were given CAR-T cells targeting BCMA or CD19/CD22, combined with pomalidomide, to explore the efficacy and safety of this combination treatment.

Key Findings

The results were highly encouraging. All six patients responded to the treatment, with an overall response rate (ORR) of 100%. This included four patients achieving complete remission (CR) and two patients achieving partial remission (PR). The median follow-up period was 211.5 days, with no reported treatment-related deaths.

One of the most notable findings was that pomalidomide did not diminish the effectiveness of CAR-T cells. Instead, it appeared to enhance the immune response by significantly increasing the secretion of key cytokines, such as tumor necrosis factor (TNF)-α and interferon (IFN)-γ. These cytokines play a critical role in the anti-tumor activity of CAR-T cells, suggesting that pomalidomide might bolster the efficacy of CAR-T therapy by creating a more favorable tumor microenvironment.

Detailed Case Outcomes

（Blood Science 6(2):p e00184, April 2024. | DOI: 10.1097/BS9.0000000000000184）

The study detailed the outcomes of individual patients, providing a clear picture of the therapy’s impact:

• Patient 1 (RRMM with CNS involvement): This patient, who had extensive brain and cerebellar lesions, achieved complete remission one month after receiving BCMA-CAR-T cells combined with pomalidomide. MRI scans confirmed the disappearance of the lesions, and the patient remained in remission during the follow-up period.
• Patient 2 (RRMM with multiple extramedullary lesions): Despite previous resistance to pomalidomide in chemotherapy, this patient showed a significant slowdown in disease progression after the addition of pomalidomide to the CAR-T therapy. The patient achieved partial remission, with a notable reduction in CAR-T cell copy number decline, suggesting enhanced CAR-T cell persistence and activity.
• Patient 4 (B-ALL with CNS involvement): This patient achieved complete remission after CAR-T therapy, with MRI scans showing the resolution of lesions in the basal ganglia. The patient remained in remission, underscoring the potential for pomalidomide to enhance CAR-T cell efficacy in treating central nervous system malignancies.
• Patient 5 (B-ALL with pericardial involvement): This patient presented with massive pericardial effusion due to extramedullary infiltration of leukemia. After receiving CD19/22-CAR-T cells combined with pomalidomide, the pericardial effusion was completely absorbed within 30 days, and the patient achieved complete remission. Notably, the CAR-T cell copy number, which had decreased to zero, rebounded after pomalidomide was added, suggesting a significant boost in CAR-T cell efficacy.

Significance

The study by Dr. Chunrui Li and colleagues provides compelling evidence that combining pomalidomide with CAR-T cell therapy can significantly improve outcomes in patients with RRMM or B-cell leukemia/lymphoma, particularly those with extramedullary involvement. This research not only highlights a novel therapeutic synergy but also suggests a potential shift in the standard of care for these challenging malignancies.

Conclusion

The integration of pomalidomide into CAR-T cell therapy offers a promising new avenue for treating relapsed and refractory hematological malignancies. By enhancing the tumor-fighting capabilities of CAR-T cells and creating a more favorable immune environment, this combination therapy has the potential to significantly improve patient outcomes. As research continues to build on these findings, pomalidomide combined with CAR-T therapy may soon become a cornerstone in the treatment of high-risk multiple myeloma and B-cell leukemias/lymphomas with extramedullary disease.