Long-Term Efficacy Observation of Anti-BCMA CAR-T Cell Therapy Combined with Autologous Hematopoietic Stem Cell Transplantation in Relapsed/Refractory Multiple Myeloma with Extramedullary Disease

Background:

Although the objective response rate (ORR) was significant, more than half of the relapsed/refractory (R/R) multiple myeloma (MM) patients received anti-BCMA CAR-T cell therapy relapsed within one year. The presence of R/R MM with extramedullary disease (EMD) associated with significantly worse survival outcomes following CAR-T cell infusion. Autologous hematopoietic stem cell transplantation (Auto-HSCT) is the cornerstone of MM treatment. Anti-BCMA CAR-T cell therapy combined with auto-HSCT could combine the advantages of the two therapies, reducing the recurrence rate. This combination therapy could expand the scope of auto-HSCT.

Methods: Eighteen R/R MM patients had collected peripheral blood stem cells and peripheral blood mononuclear cells to prepare anti-BCMA CAR-T cells. However, only 8 patients had collected enough CD34+ cells (>1.0×10⁶/kg, 1.5-6.6×10⁶/kg), and other 10 patients had not collected enough CD34+ cells (less than 1.0×10⁶/kg, 0-0.5×10⁶/kg). All the eight patients received anti-BCMA CAR-T cell therapy combined with auto-HSCT (C-T group), while the other ten patients received anti-BCMA CAR-T cell therapy only (C group). We observed the clinical responses and ORR, the overall survival (OS) and progression-free survival (PFS), the cytokine release syndrome (CRS) and immune-effector cell-associated neurotoxicity syndrome (ICANS), expression of CAR-T cells, hematologic toxicities and other adverse events.

Results: In our study, all the 18 patients with R/R MM had at least one EMD prior to enrolling in our clinical trial. There were no differences in age, sex, high-risk cytogenetics, ISS stage III, median prior lines of therapy between the two groups. Seven patients (7/8, 87.5%) obtained stringent complete response (sCR)/ complete response (CR), and one patient (1/8, 12.5%) obtained very good partial response (VGPR) in C-T group. The EMD of all the eight patients disappeared after combination therapy. The ORR was 100.0% in C-T group. While, four patients (4/10, 40.0%) obtained CR, two patients (2/10, 20.0%) obtained VGPR, two patients (2/10, 20.0%) obtained PR, and two patients (2/10, 20.0%) obtained stable disease (SD)/progressive disease (PD) only in C group. The EMD of eight patients in all the ten patients disappeared after anti-BCMA CAR-T cell therapy. The ORR was 80.0% (8/10) in C group. In C-T group, only two patients relapsed at 6 and 19 months after combination therapy. The other six patients (6/8, 75.0%) survived at CR state to cutoff date. Of the eight patients in C group who obtained ORR, five patients had disease progression again at three to ten months after anti-BCMA CAR-T cell therapy. All these five patients had recurrent EMD or new EMD. And only four patients (4/10, 40.0%) survived at CR/VGPR state to the cutoff date in C group (including one patient who received allogeneic hematopoietic stem cell transplantation as salvage treatment). There were no differences of the PFS and OS between C-T group and C group at six months after therapy (P_C-T=0.305 and P_C=0.305). The PFS and OS were higher in C-T group than that of in C group at twelve months (P_C-T=0.015 and P_C=0.030). The peaks of CAR-T cells were higher in C-T group than that of in C group (P=0.022). The ≥ grade 3 of CRS was found in three patients (4/8, 50.0%) in C-T group, and four patients (4/10, 40.0%) in C group. The results were similar for ICANS in the two groups. The ≥ grade 3 of neutropenia, anemia and thrombocytopenia were found in eight patients (8/8, 100.0%), five patients (5/8, 62.5%) and seven patients (7/8, 87.5%) in C-T group, and three patients (3/10, 30.0%), four patients (4/10, 40.0%) and two patients (2/10, 20.0%) in C group. None of the patients died of bacterial infections or invasive fungal diseases in these two groups in the course of their combination therapy or CAR-T therapy.

Conclusion: Anti-BCMA CAR-T cell therapy combined with auto-HSCT in R/R MM patient with EMD is associated with higher ORR and longer term of survival. But it is also associated with higher level of hematological toxicity. The results were similar for CRS and ICANS in the two groups. However, there were no serious adverse results due to hematological toxicity. Anti-BCMA CAR-T cell therapy combined with auto-HSCT in R/R MM patient with EMD could combine the advantages of both, reducing the recurrence rate after anti-BCMA CAR-T cell therapy, and the combination of the two could expand the scope of auto-HSCT.