Editor’s Note: From April 14 to 17, 2024, the 50th European Society for Blood and Marrow Transplantation (EBMT) Annual Meeting was grandly held in Glasgow, UK, a city renowned for its historical significance. This year marks the 50th anniversary of EBMT, and the event gathered leading figures in the field of hematopoietic stem cell transplantation and over 6,000 hematology experts from around the world. The attendees reviewed the remarkable achievements in the fields of hematology and bone marrow transplantation over the past 50 years and explored forward-looking patient management strategies. At the conference, chimeric antigen receptor T-cell (CAR-T) therapy, a highlight of this meeting, showcased a series of breakthroughs in the treatment of multiple myeloma and lymphoma, attracting significant attention. This issue features a special invitation to Professor Jun Ma from the Harbin Institute of Hematological Oncology to provide an insightful interpretation of five major research studies in the field of CAR-T cell therapy. Here, we present a compilation of these insights for our readers.
Study Background
CAR-T cell therapies targeting B-cell maturation antigen (BCMA) or bispecific antibodies (BsAbs) targeting BCMA×CD3 or GPRC5D×CD3 have been approved for treating patients with relapsed or refractory multiple myeloma who have received ≥4 lines of therapy. However, the side effects of these salvage therapies, including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), still limit their accessibility. Better defining the incidence, timing, severity, and management of these side effects will help safely expand their clinical use and application.
Study Methods
A systematic literature search and pooled analysis of clinical trials of FDA-approved BsAbs and CAR-T cell therapies for patients with relapsed or refractory multiple myeloma were conducted. This analysis included 11 abstracts or full-text articles. Fisher’s exact test and Wilcoxon rank-sum test were used for multivariate analysis.
Study Results
Neurotoxicity included ICANS, headaches, seizures, loss of smell, taste disorders, dizziness, sensory changes, tremors, gear rigidity, decreased level of consciousness, sensory abnormalities, altered mental status, aphasia, encephalopathy, somnolence, confusion, and disorientation. In six studies, 746 patients treated with BsAbs and 1310 patients treated with CAR-T cells reported CRS and neurotoxic events. Among them, 87.7% (range: 80%-95%) of patients treated with CAR-T and 57.6% (range: 13%-76.3%) treated with BsAbs experienced CRS (P=0.003). Grade ≥3 CRS occurred in 5.5% (range: 3%-10%) of CAR-T-treated patients and 1.5% (range: 0-4.9%) of BsAb-treated patients (P=0.006). The median onset time for CAR-T cell-related CRS was 4.5 days compared to 2 days for the BsAb group (P=0.503). The median duration of CRS was 4 days for CAR-T cells and 2 days for BsAbs (P=0.003). Neurotoxicity was reported by 16.4% (range: 5.3%-28%) of CAR-T cell and 8.36% (range: 3%-14.5%) of BsAb-treated patients (P=0.022). Grade ≥3 neurotoxicity occurred in 2.17% (range: 0-5%) of CAR-T and 1.27% (range: 0-3%) of BsAb-treated patients (P=0.507). The median onset time for neurotoxicity was 5.5 days post-CAR-T treatment and 3 days post-BsAb treatment (P=0.429). The median duration of neurotoxicity was 3.5 days for CAR-T cells and 2 days for BsAbs (P=0.427). The use of tocilizumab and steroids for CRS and ICANS did not differ significantly between groups.
Study Conclusion
BsAbs reduce the incidence and severity of CRS and the occurrence of neurotoxicity. Most patients treated with BsAbs experienced CRS during the first
cycle, dose escalation, or after the first full dose. These findings suggest that BsAbs can be safely used in conventional cancer centers and outpatient or day clinics, potentially expanding their coverage to rural and economically disadvantaged patient groups. However, prospective randomized controlled trial data are still needed for further validation.
Expert Commentary
As the treatment of multiple myeloma enters the era of immunotherapy, particularly as BsAbs and CAR-T gradually transition from clinical trials to more widespread clinical use across centers, we must focus on the incidence of adverse events while achieving high-quality therapeutic effects. This study pooled 11 abstracts or full-text articles for statistical analysis, comparing the incidence and severity of CRS and ICANS between BsAbs and CAR-T treatments, providing data that other centers can refer to for treatment choices. We also look forward to further validation from prospective randomized controlled trial data.
