Chimeric antigen receptor (CAR) -T cell immunotherapy has achieved good therapeutic effect in multiple myeloma (MM) , and the most common target is B cell maturation antigen (BCMA) . The disadvantage of single target CAR-T cell immunotherapy is that it can lead to disease resistance and recurrence, which may be related to antigen escape. Therefore, the dual-targeted CAR-T cell therapy for refractory-relapsed multiple myeloma (RRMM) has been improved and developed, but there is still a lack of systematic clinical analysis in this field.

A meta-analysis was conducted on the efficacy and safety of dual-targeted CAR-T cell therapy for RRMM patients.

PubMed, Embase, Cochrane Library, Web of Science, CNKI, Wanfang Data, and VIP were searched for single-group rate studies on dual-targeted CAR-T cell therapy in patients with RRMM from inception to 2023-02-06. The data were extracted for collection by 2 investigators using a self-designed form and the quality of literature was evaluated using the methodological index for non-randomized studies (MINORS) . The data analysis was conducted using RStudio software.

A total of 9 clinical studies, involving 200 RRMM patients who had previously received multi-line therapy were included in the study. Dual-targeted CAR-T cell therapy can be mainly divided into four categories based on different targets of BCMA/CD₁₉, BCMA/CD₃₈, BCMA/TACI, and BCMA/CS1, of which the BCMA+CD₁₉ target is more studied. Dual-targeted CAR-T cell therapy also can be divided into four categories of bispecific categories, combined/sequential infusion of two different CAR-T cells, bicistronic or cotransduction according to the different forms of infusion. Meta-analysis showed that the overall response rate (ORR) of dual-targeted CAR-T cells for RRMM was 90.0% (95%CI=0.849-0.943) , and the complete response rate (CRR) was 54.6% (95%CI=0.416-0.673) , the negative rate of minimal residual disease (MRD) was 75.6% (95%CI=0.489-0.952) , the ORR of extramedullary diseases (EMD) was 55.1% (95%CI=0.234-0.851) , the recurrence rate at the last follow-up was 29.7% (95%CI=0.141-0.454) , and the survival rate was 75.6% (95%CI=0.554-0.915) . The incidence of grade 3 to 4 cytokine release syndrome (CRS) was 16.4% (95%CI=0.094-0.245) , and the incidence of immune effector cell-associated neurotoxicity syndrome (ICANS) was 4.0% (95%CI=0-0.120) . Sensitivity analysis suggested stable results. The results of Egger's test indicated a potential bias risk for ORR (P=0.03) and overall response rate of EMD (P=0.02) . Meanwhile, no publication bias was suggested for CRR (P=0.53) , MRD negative rate (P=0.79) , recurrence rate at the last follow-up (P=0.71) , survival rate (P=0.98) , incidence of grade 3-4 CRS (P=0.90) , and incidence of ICANS (P=0.30) .

Dual-targeted CAR-T cell therapy for RRMM has shown favorable efficacy and safety, and multicenter, large-sample, and longer follow-up studies are needed to further evaluate its efficacy and safety.

嵌合抗原受体（CAR）-T细胞免疫疗法已在多发性骨髓瘤（MM）中取得较好的疗效，最常见的靶点为B细胞成熟抗原（BCMA）。单靶点CAR-T细胞免疫疗法的缺点是会导致疾病抵抗和复发，可能与抗原逃逸有关。为此，改进开发了双靶点CAR-T细胞治疗复发难治多发性骨髓瘤（RRMM），此方面尚缺乏系统的临床分析。

对RRMM患者应用双靶点CAR-T细胞免疫疗法治疗的有效性及安全性进行Meta分析。

计算机检索PubMed、Embase、Cochrane Library、Web of Science、中国知网、万方数据知识服务平台、维普网7个数据库中有关双靶点CAR-T细胞治疗RRMM的单组率研究，检索时限为建库至2023-02-06。由2名研究人员使用自制的数据表单来提取收集数据，并采用非随机对照试验方法学评价指标进行文献质量评价。采用R Studio软件进行数据分析。

共纳入9篇文献，包括200例既往接受过多线治疗的RRMM患者。双靶点CAR-T细胞疗法根据不同靶点可分为4类：BCMA+CD₁₉、BCMA+CD₃₈，BCMA+跨膜剂与钙调节亲环素配体的相互作用者（TACI）、BCMA+人信号淋巴细胞激活分子家族成员7（CS1），其中BCMA+CD₁₉靶点的研究较多。根据输注形式不同CAR-T细胞疗法可分为4类：双特异性CAR-T细胞、联合或序贯输注两种不同CAR-T细胞、双顺反子结构、共转导。Meta分析显示，双靶点CAR-T细胞治疗RRMM的总缓解率（ORR）为90.0%（95%CI=0.849~0.943），完全缓解率（CRR）为54.6%（95%CI=0.416~0.673），微小残留病（MRD）阴性率为75.6%（95%CI=0.489~0.952），髓外病变（EMD）总缓解率为55.1%（95%CI=0.234~0.851），最后一次随访时的复发率为29.7%（95%CI=0.141~0.454），最后一次随访时的生存率为75.6%（95%CI=0.554~0.915），3~4级细胞释放因子综合征（CRS）发生率为16.4%（95%CI=0.094~0.245），神经毒性（ICANS）发生率为4.0%（95%CI=0~0.120）。敏感性分析提示结果稳定。Egger's检验结果显示，ORR（P=0.03）及EMD总缓解率（P=0.02）提示存在一定的偏倚风险；CRR（P=0.53）、MRD阴性率（P=0.79）、最后一次随访时的复发率（P=0.71）、生存率（P=0.98）、3~4级CRS发生率（P=0.90）、ICANS发生率（P=0.30）提示不存在发表偏倚。

双靶点CAR-T细胞免疫治疗RRMM显示出良好的疗效和安全性，未来需要多中心、大样本、更长随访期的研究来进一步评估其疗效和安全性。