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Efficacy and Safety of CAR-Modified T Cell Therapy in Patients with Relapsed or Refractory Multiple Myeloma: A Meta-Analysis of Prospective Clinical Trials.

ABSTRACT: Background: In recent years, chimeric antigen receptor-modified T (CAR-T) cell therapy for B-cell leukemia and lymphoma has shown high clinical efficacy. Similar CAR-T clinical trials have also been carried out in patients with refractory/relapsed multiple myeloma (RRMM). However, no systematic review has evaluated the efficacy and safety of CAR-T cell therapy in RRMM. The purpose of this study was to fill this literature gap. Methods: Eligible studies were searched in PUBMED, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL), CNKI, and WanFang from data inception to December 2019. For efficacy assessment, the overall response rate (ORR), minimal residual disease (MRD) negativity rate, strict complete response (sCR), complete response (CR), very good partial response (VGPR), and partial response (PR) were calculated. The incidence of any grade cytokine release syndrome (CRS) and grade ?3 adverse events (AEs) were calculated for safety analysis. The effect estimates were then pooled using an inverse variance method. Results: Overall, 27 studies involving 497 patients were included in this meta-analysis. The pooled ORR and MRD negativity rate were 89% (95% Cl: 83-94%) and 81% (95% Cl: 67-91%), respectively. The pooled sCR, CR, VGPR, and PR were 14% (95% Cl: 5-27%), 13% (95% Cl: 4-26%), 23% (95% Cl: 14-33%), and 15% (95% Cl: 10-21%), respectively. Subgroup analyses of ORR by age, proportion of previous autologous stem cell transplantation (ASCT), and target selection of CAR-T cells revealed that age ? 55 years (?55 years vs. > 55 years, p = 0.0081), prior ASCT ?70% (?70% vs. > 70%, p = 0.035), and bispecific CAR-T cells (dual B-cell maturation antigen (BCMA)/BCMA + CD19 vs specific BCMA, p = 0.0329) associated with higher ORR in patients. Subgroup analyses of remission depth by target selection suggested that more patients achieved a better response than VGPR with dual BCMA/BCMA + CD19 CAR-T cells compared to specific BCMA targeting (p = 0.0061). In terms of safety, the pooled incidence of any grade and grade ? 3 CRS was 76% (95% CL: 63-87%) and 11% (95% CL: 6-17%). The most common grade ? 3 AEs were hematologic toxic effects. Conclusion: In heavily treated patients, CAR-T therapy associates with promising responses and tolerable AEs, as well as CRS in RRMM. However, additional information regarding the durability of CAR-T cell therapy, as well as further randomized controlled trials, is needed.

SUBMITTER: Xiang X

PROVIDER: S-EPMC7744881 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Efficacy and Safety of CAR-Modified T Cell Therapy in Patients with Relapsed or Refractory Multiple Myeloma: A Meta-Analysis of Prospective Clinical Trials.

Xiang Xinrong X He Qiao Q Ou Yang Y Wang Wen W Wu Yu Y

Frontiers in pharmacology 20201203

<b>Background</b>: In recent years, chimeric antigen receptor-modified T (CAR-T) cell therapy for B-cell leukemia and lymphoma has shown high clinical efficacy. Similar CAR-T clinical trials have also been carried out in patients with refractory/relapsed multiple myeloma (RRMM). However, no systematic review has evaluated the efficacy and safety of CAR-T cell therapy in RRMM. The purpose of this study was to fill this literature gap. <b>Methods</b>: Eligible studies were searched in PUBMED, EMBA ...[more]

PMID: 33343342

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Project description:BackgroundB-cell maturation antigen (BCMA) chimeric antigen receptor T (CAR-T) cell therapy has obtained promising results in relapsed or refractory multiple myeloma (R/R MM), while some patients do not response, or relapse in short term after treatment. Combining with anti-CD38 might solve the problem of targeting BCMA alone. We aimed to assess the efficacy and safety of BCMA and CD38 (BCMA-CD38) bispecific CAR-T cells in R/R MM patients.MethodsWe did a single-center, single-arm clinical study at the Second Affiliated Hospital of Yangtze University in China. Patients meeting with the inclusion criteria were administered with fludarabine and cyclophosphamide before CAR-T cells infusion. Response and adverse events were assessed after infusion. This study was registered with the Chinese Clinical Trial Registration Center (ChiCTR1900026286).ResultsFirst, we found BCMA-CD38 CAR-T cells exhibited enhanced killing effect on BCMA+CD38+ cells in vitro, compared to BCMA CAR-T and CD38 CAR-T cells. We further demonstrated its anti-tumor activity in vivo. Then, we enrolled 16 R/R MM patients for safety and efficacy analyses. Of the 16 evaluable patients, 14 (87.5%) respond to the treatment, including 13 stringent complete response (sCR) and one partial response (PR), while two patients did not respond. At a median follow-up of 11.5 months, of the 13 patients who achieved sCR, 76.9% (10/13) did not relapse or progress during follow-up. Relapse occurred in 3 patients (Patient 2, 3 and 4) after achieving sCR. In sum, four patients died, of which one died of hemophagocytic lymphohistiocytosis syndrome secondary to severe cytokine release syndrome (CRS) and three died of disease progression or relapse. The 1-year progression-free survival rates was 68.8%. The 1-year overall survival rate was 75.0%. Extramedullary lesions were eliminated in 62.5% (5/8) patients. The most common symptoms after CAR-T infusion were cytopenia (16, 100%), fever (10, 62.5%), fatigue (8, 50.0%) and myalgias (8, 50.0%). Twelve patients (75.0%) were observed with various grades of CRS, of which five patients (31.3%) got serious CRS (Grade ≥ 3). The CAR+ cell expansion levels were associated with the severity of CRS. Transient clonal isotype switch was observed after CAR-T infusion.ConclusionOur results confirm that BCMA-CD38 CAR-T cells therapy is feasible in treating R/R MM patients, with high response rate, low recurrence rate and manageable CRS, which will be a promising treatment option for R/R MM.Trial registrationChiCTR1900026286, registered on September 29, 2019, retrospectively registered, URL: https://www.chictr.org.cn/showproj.aspx?proj=43805.

Project description:The present study aimed to study the efficacy and adverse effects of anti-B-cell maturation antigen (BCMA) chimeric antigen receptor T (CAR-T) cell therapy in relapsed or refractory multiple myeloma. Patients were divided into three dose groups based on cell therapy concentration. After CAR-T cell therapy for 10 patients with recurrent or refractory multiple myeloma, the patients were monitored and evaluated regularly to observe the efficacy and adverse reactions of CAR-T cell therapy. At a median follow-up of 337 (253-504) days, one patient succumbed 24 days due to rapidly progressing disease. The overall response rate of nine patients was 88.9%, including 77.8% (7/9) with minimal residual disease negative complete remission (CR) and 11.1% (1/9) with partial remission. A total of three patients were maintained in remission state for more than a year and eight were maintained for more than six months. Among the three patients with extramedullary invasion, two extramedullary lesions disappeared and one was stable. The highest copy number of CAR-T cells in seven patients with CR was >1x105 copies/µl gDNA, and the best therapeutic effect can be achieved within 30 (7-30) days after the copy number of CAR-T cells reached 1x105 copies/µl genomic DNA. The median onset time in the nine patients was 43 (22-169) days, and the median progression-free survival was 337 (253-504). Among the 10 patients, nine (90%) had cytokine release syndrome, all of which were below grade II. There were nine (90%) patients with hematological adverse reactions, six (60%) patients with severe anemia, five (50%) patients with grade III and above leukopenia, five (50%) patients with granulocytopenia, four (40%) patients with grade III and above thrombocytopenia, and three (30%) patients with grade III and above pancytopenia. It was concluded that anti-BCMA CAR-T cell therapy is a promising treatment method for relapsed or refractory multiple myeloma and extramedullary invasion, with stable efficacy and controllable adverse effects.

Dataset Information

Efficacy and Safety of CAR-Modified T Cell Therapy in Patients with Relapsed or Refractory Multiple Myeloma: A Meta-Analysis of Prospective Clinical Trials.

Publications

Efficacy and Safety of CAR-Modified T Cell Therapy in Patients with Relapsed or Refractory Multiple Myeloma: A Meta-Analysis of Prospective Clinical Trials.

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