Interventions and outcomes of patients with multiple myeloma receiving salvage therapy after BCMA-directed CAR T therapy

Abstract

B-cell maturation antigen (BCMA)-directed chimeric antigen receptor T cell therapy (CAR T) has demonstrated remarkable efficacy in patients with relapsed/refractory multiple myeloma, and there are now two FDA-approved BCMA-directed CAR T products. However, despite high initial response rates, most patients eventually relapse. The outcomes of patients with disease recurrence after BCMA-directed CAR T have not been comprehensively studied and such an analysis would help define optimal treatment strategies. We analyzed the salvage treatments and outcomes of 79 patients with multiple myeloma from two academic institutions who had progression of disease after treatment with BCMA-directed CAR T. A total of 237 post-CAR T salvage treatment lines were used, and patients received a median of 2 (range, 1-10) treatment lines. The median overall survival from the date of relapse post-CAR T was 17.9 months (95% confidence interval (CI), 14.0-NE). The overall response rate to the first salvage regimen was 43.4%, with a median progression-free survival of 3.5 months (CI, 2.5-4.6). Thirty-five (44.3%) patients received a T cell-engaging therapy (bispecific antibody or subsequent CAR T) as salvage treatment. The overall survival in patients that received a subsequent T cell-engaging therapy was not reached after a median follow-up of 21.3 months. Patients with multiple myeloma who relapse after BCMA-directed CAR T have a limited prognosis but can be potentially treated with multiple lines of salvage therapy. T cell-engaging therapies appear to maintain pronounced clinical activity in this setting.

CAR-T cell therapy in multiple myeloma: Current limitations and potential strategies

“…At present, relapses occur frequently after anti-BCMA CAR-T cell therapy, especially in high-risk MM patients ( 132 – 134 ). However, currently there is a lack of recommended salvage treatment for R/R MM patients after relapse on CAR-T cell therapy.…”

“…Therefore, there is an urgent need to explore suitable subsequent therapy for R/R MM patients who have been refractory to anti-BCMA CAR-T cell therapy. In addition to treatment with optimized CAR-T therapy and previous chemotherapy regimens, as well as auto-HSCT ( 134 , 135 ), novel anti-myeloma agents provide additional salvage options for R/R MM patients who have relapsed after anti-BCMA CAR-T cell therapy, including selinexor, carfilzomib, pomalidomide, monoclonal antibodies, and T cell redirecting bispecific antibodies ( 132 – 134 , 136 ). Furthermore, several studies showed that the R/R MM patients who had experienced relapse after anti-BCMA CAR-T cell therapy could also benefit from carfilzomib-based therapy, venetoclax-based therapy, and selinexor-based therapy ( 132 – 134 , 136 ).…”

“…In addition to treatment with optimized CAR-T therapy and previous chemotherapy regimens, as well as auto-HSCT (134,135), novel anti-myeloma agents provide additional salvage options for R/R MM patients who have relapsed after anti-BCMA CAR-T cell therapy, including selinexor, carfilzomib, pomalidomide, monoclonal antibodies, and T cell redirecting bispecific antibodies (132)(133)(134)136). Furthermore, several studies showed that the R/R MM patients who had experienced relapse after anti-BCMA CAR-T cell therapy could also benefit from carfilzomib-based therapy, venetoclax-based therapy, and selinexor-based therapy (132)(133)(134)136). In addition, T cell redirecting bispecific antibodies, such as Cevostamab and Talquetamab, have also proved to be feasible salvage treatment after anti-BCMA CAR-T cell therapy and able to induce durable responses (137)(138)(139).…”

CAR T cell therapy in multiple myeloma, where are we now and where are we heading for?

“…Additionally, it was found that the ORR did not significantly decrease with following lines of therapy. 17 However, the optimal strategy to treat relapse from CAR T cell therapies is still unknown. In the future, it will be very important to identify patients at risk for early relapse to implement pre-emptive strategies to avoid treatment failure.…”

“…The ORR was 91.4% for the cohort receiving T‐cell‐engaging therapies after PD from anti‐BCMA CAR T cells. Additionally, it was found that the ORR did not significantly decrease with following lines of therapy 17 . However, the optimal strategy to treat relapse from CAR T cell therapies is still unknown.…”