A new meta-analysis finds high rates of efficacy and high rates of toxicity in multiple myeloma patients treated with B-cell maturation agent (BCMA)-targeted chimeric antigen receptor (CAR)- T cells.
B-cell maturation agent (BCMA)-targeted chimeric antigen receptor (CAR) T-cell therapy is highly effective in treating multiple myeloma (MM), though it does come with significant toxicity, according to a new analysis.
CAR T cell therapy has become one of the most important innovations in cancer therapy in recent years, and BCMA has become one of the most promising myeloma target antigens under investigation, according to corresponding author Sébastien Anguille, MD, PhD, of the University of the University of Antwerp, and colleagues. However, the existing literature examining the use of BCMA-targeted CAR T-cell therapy in MM generally involves small-scale studies that make it difficult to extrapolate broad conclusions about efficacy.
Anguille and colleagues decided to address the problem by performing a meta-analysis of published literature, published this month in the Journal of Hematology & Oncology. They conducted searches of Web of Science and the PubMed/MEDLINE seeking studies involving BCMA and CAR T cells for MM. The studies captured in the searches were published between 2015 and 2020. Twenty-seven studies were located that met inclusion criteria. These studies comprised 640 unique patients, who received a total of 23 different CAR T-cell products.
The authors found a pooled overall response rate (ORR) of 80.5%, with 44.8% of patients achieving a complete response (CR). The pooled CR rate was much higher (71.9%) in studies that used alpaca/llama-based constructs; in studies that used retroviral vectors for CAR transduction, the CR rate was just 18.0%. The median progression-free survival (PFS) was 12.2 months, significantly higher than the 1.9-month PFS of the control groups in the studies, Anguille and colleagues said.
“The low PFS in the control group is congruent with previous literature and illustrates the grim prognosis of the patients included so far in BCMA CAR T-cell studies,” Anguille and colleagues wrote.
The investigators cautioned that while the therapy had high response rates, those responses were generally temporary and relapses were common.
Anguille and colleagues added that the improvement, albeit temporary, sparked by CAR T-cell therapy also came with significant toxicities.
Four out of 5 patients (80.3%) experienced cytokine release syndrome, and 1 in 10 (10.5%) had neurotoxicity. The authors said neurotoxicity was highest in more heavily pretreated patients compared with those who were not (19.1% versus 2.8%).
The rate of CRS was lower in studies that used murine single-chain variable fragment (scFv)-based CAR constructs, there was still a clear pattern between dosage and toxicity, the investigators said.
“For example, with the bb2121 CAR-T product, which contains a murine anti-BCMA scFv, a CRS rate of 96.3% was noted at the recommended phase II dose of 450 × 106 cells, whereas it was only 75.7% and 50.0% at the 300 × 106 and 150 × 106 dose levels, respectively,” they said.
In their conclusion, the authors said the data clearly show that BCMA-targeted CAR T-cell therapy is effective, even in cases of advanced MM, but also comes with toxicity concerns. They said the heterogeneity of the data suggest that it might be possible to identify individual factors that can affect safety and efficacy. Such factors would need to be studied in more detail in order to optimize the results of BCMA-based CAR T-cell therapy.
Roex, G., Timmers, M., Wouters, K. et al. Safety and clinical efficacy of BCMA CAR-T-cell therapy in multiple myeloma. J Hematol Oncol. Published December 2, 2020. doi: 10.1186/s13045-020-01001-1