Comprehensive meta-analysis of anti-BCMA chimeric antigen receptor T-cell therapy in relapsed or refractory multiple myeloma

Abstract

Background: Chimeric antigen receptor (CAR) T-cell therapy shows impressive results in clinical trials. We conducted a meta-analysis based on the most recent data to systematically describe the efficacy and safety of anti-BCMA CAR T therapy for patients with relapsed or refractory multiple myeloma (R/R MM).

Methods: PubMed, Embase, Web of Science, Cochrane library, ClinicalTrials.gov, China Biology Medicine disc (CBM disc) and Wanfang Data were searched on 8 November 2020. Registration number of PROSPERO was CRD42020219127.

Results: From 763 articles, we identified 22 appropriate studies with 681 patients. The pooled overall response rate (ORR) was 85.2% (95%CI 0.797-0.910), complete response rate (CRR) was 47.0% (95%CI 0.378-0.583), and minimal residual disease (MRD) negativity rate was 97.8% (95%CI 0.935-1.022). The pooled incidence of grade 3-4 cytokine release syndrome was 6.6% (95%CI 0.036-0.096) and neurotoxicity was 2.2% (95%CI 0.006-0.038). The median progression-free survival (PFS) was 14.0 months and median overall survival (OS) was 24.0 months. Subgroup analysis showed dual epitope-binding CAR T cells achieved the best therapy outcomes and humanized CAR T cells had the best safety profile. Patients who were older, heavily pre-treated or received lower dose of CAR T cells had worse ORR. There was no significant difference in ORR, CRR and PFS between patients with and without high-risk cytogenetic features. The PFS and CRR of non-extramedullary disease (EMD) group was superior to those of EMD group.

Conclusion: Anti-BCMA CAR T therapy is effective and safe for patients with R/R MM. It can improve the prognosis of patients with high-risk cytogenetic features while the prognosis of patients with EMD remains poor. Moreover, patients are likely to benefit from an earlier use of CAR T therapy and human-derived CAR T cells have obvious advantages based on the existing data.

Keywords: Chimeric antigen receptor T-cell therapy; efficacy; multiple myeloma; safety.

Conflict of interest statement

No potential conflict of interest was reported by the author(s).

Figures

Figure 1.

Flow chart of literature screening process.

Figure 2.

Pooled rates of ORR, CRR and MRD negativity. (A) The pooled ORR is 85.2%. (B) The pooled CRR is 47.0%. (C) The pooled rate of MRD negativity is 97.8%.

Figure 3.

Subgroup analysis of ORR according to the structures of CAR. 1- murine group; 2- human group; 3- dual epitope-binding group. (A) Dual epitope-binding group shows the highest ORR, followed by human group, while the worst ORR is murine group. (B) The CRR in dual epitope-binding group is highest, followed by human group, and murine group has the lowest.

Figure 4.

Subgroup analysis of ORR in human group. (A) High dose group has a higher ORR compared with low dose group. 1- low dose group; 2-high dose group. (B) Elderly group has lower ORR compared with younger group. 1-younger group; 2-elderly group. (C) Relapsed group has greater ORR than multiply relapsed group. 1-relapsed group; 2-multiply relapsed group.

Figure 5.

The effects of high-risk karyotypes on the efficacy of CAR T therapy. The results show that there is no significant difference in ORR (A) and CRR (B) between high-risk group and low-risk group.

Figure 6.

The effects of extramedullary disease (EMD) on the efficacy of CAR T therapy. (A) The results show that there is no significant difference in ORR between EMD group and non-EMD group. In EMD. (B) In EMD group, less patients can achieve CR than non-EMD group.

Figure 7.

The effects of BCMA expression on the efficacy of CAR T therapy. The results show that there is no significant difference in ORR (A) and CRR (B) between high-expression group and low-expression group.

Figure 8.

Pooled incidence of CRS and neurotoxicity. (A) The pooled incidence of grade 3–4 CRS is 6.6%. (B) The pooled incidence of grade 3–4 neurotoxicity is 2.2%.

Figure 9.

Subgroup analysis of incidence of grade 3–4 CRS. (A) Human group shows significantly reduced incidence of grade 3–4 CRS, followed by murine group and dual epitope-binding group has the highest incidence of grade 3–4 CRS. 1-murine group; 2-human group; 3-dual epitope-binding group. (B) In the studies using humanized CAR T cells, elderly group has a lower incidence of grade 3–4 CRS compared with younger group. 1-younger group; 2-elderly group. (C) In the studies using humanised CAR T cells, high dose group shows a trend to have higher incidence of grade 3–4 CRS than low dose group without reaching a statistical significance. 1-low dose group; 2-high dose group.

Figure 10.

Survival analysis of CAR T therapy. (A) The median PFS is 14.5 months for R/R MM patients who receive CAR T therapy. One-year PFS is 54.5% and two-year PFS is 36.9%. (B) The median OS is 24 months, and the estimated 1-year OS is 81.2% and two-year OS is 39.1%. (C) The longest PFS is observed in dual epitope-binding group, followed by human group and murine group has the shortest PFS. (D) No significant difference in PFS is identified between the high-risk and low-risk group. (E) The PFS of non-EMD group is superior to the PFS of EMD group.

Figure 11.

Sensitivity analysis and publication bias assessment. (A) Sensitivity analysis is performed by the “leave-one-out” approach to assess the stability of our results. (B) No significant publication bias is noted on funnel plots. (C) The results of Egger’s test reveal no evidence of publication bias.