JCO (IF=45) Xu Kailin's team from Xuzhou Medical University found that the combination of B cell maturation antigen and CD19 CAR-T cells is safe and effective in the treatment of multiple myeloma

The combination of iNature anti-B cell maturation antigen (BCMA) and anti-CD19 chimeric antigen receptor (CAR) T cells induces high response rates in relapsed or refractory (R/R) multiple myeloma (MM) patients, but Long-term outcomes have not been assessed
.

On March 25, 2022, Xu Kailin's team from Xuzhou Medical University published online in the Journal of Clinical Oncology (IF=45) entitled "Long-Term Follow-Up of Combination of B-Cell Maturation Antigen and CD19 Chimeric Antigen Receptor T Cells in Multiple Myeloma" research paper, in this single-arm phase II trial, patients with R/R MM received cyclophosphamide and fludarabine
.

Overall response, long-term outcomes and safety and their association with clinical and disease characteristics were assessed
.

Of the 69 enrolled patients, 62 received a combined infusion of anti-BCMA and anti-CD19 CAR T cells with a median follow-up of 21.
3 months
.

The overall response rate was 92% (57/62), with 37 patients (60%) seeing complete responses or better
.

Minimal residual disease was confirmed negative and detectable in 77% (43/56) of patients
.

The estimated median duration of response was 20.
3 months (95% CI, 9.
1 to 31.
5)
.

The median progression-free survival was 18.
3 months (95% CI, 9.
9 to 26.
7), and the median overall survival was not reached
.

 Cytokine release syndrome was present in 59 patients (95%), 10% of which were grade 3 or higher
.

Neurotoxic events occurred in 7 patients (11%), 3% of which were grade 3 or higher
.

With the exception of B-cell aplasia, hypogammaglobulinemia, and infection, late adverse effects are rare
.

In conclusion, the combination of anti-BCMA and anti-CD19 CAR T cells elicited durable responses in R/R MM patients with a median progression-free survival of 18.
3 months and a manageable long-term safety profile
.

Adoptive transfer of B-cell maturation antigen (BCMA)-specific chimeric antigen receptor (CAR) T cells has shown unprecedented efficacy in the treatment of relapsed or refractory (R/R) multiple myeloma (MM), overall yields an 80% to 100% response rate (ORR)
.

Cilta-cel achieved a high complete response (CR) rate of 67% in the heavily pretreated population
.

However, after a certain percentage of patients achieve a response, the disease progresses or relapses quickly, and some patients are completely unresponsive to anti-BCMA CAR T cells
.

Therefore, it is necessary to develop more effective CAR T cell regimens for R/R MM, especially to improve long-term prognosis
.

A small subset of MM cell clones may express CD19, which are considered poorly differentiated MM cells or myeloma-like stem cells
.

Therapies targeting this subgroup may be synergistic with traditional myeloma therapies
.

Anti-CD19 CAR T cells combined with autologous stem cell transplantation (ASCT) also showed potential activity in R/R MM patients
.

Furthermore, by applying super-resolution microscopy, CD19 is expressed at ultra-low densities on a small fraction of myeloma cells in most patients, and ultra-low CD19 molecules per myeloma cell can trigger the elimination of anti-CD19 CAR T cells
.

Based on these observations, we hypothesized that anti-CD19 CAR T cells might synergize with anti-BCMA CAR T cells in R/R MM patients
.

Preliminary studies showed that the combination of anti-BCMA and anti-CD19 CAR T cells produced encouraging activity in R/R MM with an ORR of 95%
.

However, long-term efficacy and safety require further evaluation
.

Here, the study reports long-term follow-up results in patients with R/R MM who received a combination of anti-BCMA and anti-CD19 CAR T cells
.

In this single-arm phase II trial, patients with R/R MM were treated with cyclophosphamide and fludarabine
.

Overall response, long-term outcomes and safety and their association with clinical and disease characteristics were assessed
.

Of the 69 enrolled patients, 62 received a combined infusion of anti-BCMA and anti-CD19 CAR T cells with a median follow-up of 21.
3 months
.

Kaplan-Meier analysis of DOR, PFS and OS
.

(A) Kaplan-Meier curve of DOR for 57 patients with partial response or better; (B) Kaplan-Meier curve of PFS for all 62 patients; (C) Kaplan-Meier curve of OS for all 62 patients
.

The tick marks indicate the time of data review at the last follow-up
.

CAR, chimeric antigen receptor; DOR, duration of response; NE, not estimable; NR, not reached; OS, overall survival; PFS, progression-free survival (Figure from Journal of Clinical Oncology) Overall response rate 92 % (57/62), a complete response or better was observed in 37 patients (60%)
.

Minimal residual disease was confirmed negative and detectable in 77% (43/56) of patients
.

The estimated median duration of response was 20.
3 months (95% CI, 9.
1 to 31.
5)
.

The median progression-free survival was 18.
3 months (95% CI, 9.
9 to 26.
7), and the median overall survival was not reached
.

 Cytokine release syndrome was present in 59 patients (95%), 10% of which were grade 3 or higher
.

Neurotoxic events occurred in 7 patients (11%), 3% of which were grade 3 or higher
.

With the exception of B-cell aplasia, hypogammaglobulinemia, and infection, late adverse effects are rare
.

In conclusion, the combination of anti-BCMA and anti-CD19 CAR T cells elicited durable responses in R/R MM patients with a median progression-free survival of 18.
3 months and a manageable long-term safety profile
.

Reference message: https://ascopubs.
org/doi/full/10.
1200/JCO.
21.
01676