Patterns of Progression and Outcomes in Multiple Myeloma after Anti-BCMA CAR T-Cell Therapy

Introduction
Anti-BCMA CAR T-cell therapy is effective for patients with heavily pre-treated and refractory multiple myeloma (MM). However, it is not curative therapy, and all patients relapse. Following anti-BCMA CAR-T therapy, relapse can occur in different forms: biochemical progression with asymptomatic disease, symptomatic disease with new bone lesions, and extramedullary disease or paramedullary disease (EMD/PMD). Understanding how patients progress is important to developing optimal disease monitoring strategies and interventions. The detailed knowledge of patterns of progression post anti-BCMA CAR T-cell therapy is lacking in the literature.

Methods
This single-center retrospective study assesses the patterns of progression and the impact of the presence of EMD/PMD on clinical outcomes post-CAR T-cell therapy in patients with MM. The study included MM patients treated at Moffitt Cancer Center with commercial anti-BCMA CAR T-cell therapy (Ide-cel or Cilta-cel) between May 2021 and December 2023 who experienced progression post-CAR T-cell therapy. The clinical, laboratory, imaging, pathology, and genetics data were reviewed prior to CAR T-cell infusion, on day 90 post-CAR T-cell therapy, and at progression.

Results
A total of 251 patients with MM received commercial anti-BCMA CAR T-cell therapy (Ide-cel=176, Cilta-cel=75), with 106 had disease progression (Ide-cel=92, Cilta-cel=14). The median age at the time of CAR T-cell infusion for those who progressed was 66 years, with a majority being men (56%) and white (66%). Most patients had IgG subtype (57%), and kappa light chain involvement (67%). High-risk disease was present in 64%, with chromosome 1 abnormalities in 58%, chromosome 17p deletions in 30%, t(4;14) in 13%, and t(14;16) in 6%. EMD/PMD (either detected on imaging or biopsy) was present in 46% of cases prior to CAR T-cell infusion, most commonly in lymph nodes (18%), skin/soft tissue (13%), and paraspinal masses (12%).

The objective response rate at day 90 post-CAR T-cell infusion was 63%, with a complete response rate of 50%, including stringent complete response. The median time to progression was 7.7 months (IQR: 3.2-11.6). At progression, 59% of patients had bone marrow involvement (≥5% plasma cells), 82% had biochemical progression (an increase in paraprotein that fulfills the International Myeloma Working Group criteria for progression), 50% developed new bone disease, and 52% had EMD/PMD (by imaging or biopsy). Of those who had EMD/PMD at progression, 55% had EMD/PMD at baseline prior to CAR T-cell infusion, and 45% developed new EMD/PMD. The most common sites were skin/soft tissue (19%), lymph nodes (15%), and lungs (11%).

The median overall survival (OS) from the time of progression was 12.5 months (95%CI: 8.6–not achieved). Median OS was significantly longer in patients without EMD/PMD prior to CAR T-cell therapy (21 vs. 7 months, p=0.023) and at progression (21 vs. 7.4 months, p=0.033). The median progression-free survival (PFS) from time of progression was 5.8 months (95%CI: 4.74–not achieved), with a lower median PFS in patients with EMD/PMD prior to CAR T-cell infusion (4 vs. 7.4 months, p=0.012) and at progression (4.8 vs. 8.5 months, p=0.05).

Conclusion

The progression pattern post-CAR T-cell therapy is heterogeneous. Our study showed a significant impact of EMD/PMD on survival outcomes. Patients without EMD/PMD prior to CAR T-cell therapy had significantly longer OS and PFS. These results highlight the need for tailored treatment strategies to improve outcomes for MM patients with EMD/PMD.