Novel SRRM2-Targeted CAR-T Therapy Induces Rapid Remission in a Relapsed/Refractory Multiple Myeloma Patient
Authors: Wang Zhitao , Gao Zhimai , Wu Fan , Wang Huiping , Guo Jinjing , Li Yingwei , Li Zijian , Gärtner Kathrin , Li Lietao , Li Cong , Liang Xue , Xiao Hao , Zhai Zhimin 
Published: December 2024

Chimeric antigen receptor (CAR) T-cell therapy targeting B-cell maturation antigen (BCMA) has shown promising therapeutic effects in relapsed/refractory multiple myeloma (R/R MM). However, relapses still occur. Our previous research revealed that the nuclear speckle protein SRRM2 is exposed on the surface of abnormal malignant plasma cells, making it an appealing target molecule and biomarker for immunotherapeutic approaches in MM patients.

Here we report a 62 years old patient with relapsed/refractory IgD-λ multiple myeloma (MM) who was successfully treated with autologous SRRM2-targeted chimeric antigen receptor (CAR)-T cells. The patient was hospitalized due to unexplained retrosternal pain and diagnosed with MM through a series of examinations in 2011. After 6 cycles of VTD regimen chemotherapy (Bortezomib, thalidomide, and dexamethasone), the patient achieved complete response (CR) and underwent autologous stem cell transplantation in 2013, followed by thalidomide maintenance. However, the disease relapsed in August 2020. The patient then received 9 cycles of the VRD regimen chemotherapy (Bortezomib, lenalidomide, and dexamethasone), again achieving CR, and was maintained mainly using lenalidomide. Unfortunately, the disease relapsed again in July 2021, and subsequent treatment with 6 cycles of daratumumab regimen chemotherapy failed to control the disease.

Given the patient's refractory status, treatment with autologous SRRM2 CAR-T cells was considered because flow cytometry analysis revealed that over 97% of the patient's bone marrow plasma cells expressed surface SRRM2. Prior to the infusion of 1.06×106 SRRM2 CAR-T cells/kg, the patient received a lymphodepleting preconditioning regimen consisting of fludarabine (30 mg/m2/day on days -5 to -3) and cyclophosphamide (300 mg/m2/day on days -5 and -3).

After infusion, the SRRM2 CAR-T cells rapidly recognized and eliminated the patient's malignant plasma cells. The percentage of CAR-positive T cells in the peripheral blood peaked at 23.26% on day 21 and gradually declined to 17.38% at day 28 and 7.39% at 2 months. Consistent with the expansion of CAR-positive cells, the proportion of plasma cells in the bone marrow significantly decreased by day 21, accompanied by a substantial reduction in the patient's bone pain score. On day 3 after CAR T-cell infusion, the patient transiently developed fever above 38°C, with elevated ferritin, IL-6, and IL-8 levels, indicating grade 1 cytokine release syndrome without other serious complications. Alongside the depletion of plasma cells, the patient's serum and urine λ-light chain levels markedly decreased, and the λ/κ ratio normalized within 1 month after CAR T- infusion. Correspondingly, the levels of IgG, IgA, and IgM also significantly recovered within 1 month.

This case represents the first reported use of a SRRM2-targeted CAR T-cell therapy in a patient with relapsed/refractory MM. The rapid and profound depletion of malignant plasma cells, accompanied by rapid serological and clinical improvement, highlights the potent anti-myeloma activity of this approach. Importantly, the patient tolerated the treatment well, experiencing only a transient, manageable cytokine release syndrome episode without other significant toxicities.

The protocol of this research was approved by the Ethics Committee of the Second Affiliated Hospital of Anhui Medical University (NO. YJ-YX2021-139) and registered as clinical trial on http://www.chictr.org.cn/index.aspx. (No. ChiCTR2000040368).Zhitao wang and Zhimai Gao contributed equally to this work and share first authorship.