Efficacy of Bispecific Antibodies Vs CAR-T in the Treatment of Extramedullary Disease and High-Risk Cytogenetics in Relapsed Multiple Myeloma: A Systematic Review and Meta-Analysis
Authors: Vegivinti Charan Thej Reddy , Lawrence Alexander Santhi Jaison , Liu Lawrence , Keesari Praneeth Reddy , Thakur Rahul , Hammami M Bakri , Kapu Venkatesh , Pericherla Sindhu , Gopireddy Murali Mohan reddy , Poojary Nagarathna , Ghimire Ananta , Shah Nishi , Janakiram Murali 
Published: December 2023

Background:
Bispecific antibodies (BsAb) and Chimeric antigen receptor T-cell therapy (CAR-T) have emerged as a promising treatment option for patients with relapsed, refractory multiple myeloma (RRMM) for greater than four previous lines of therapy. The efficacy of these novel drugs in extramedullary disease (EMD) and high-risk cytogenetic abnormalities (HRCA) is relatively less reported. The purpose of this systematic review and meta-analysis is to compare the efficacy of BsAbs vs CAR-T in the treatment of EMD and HRCAs in RRMM.
Methods: A systematic literature search was conducted to identify clinical trials that investigated BsAbs and CAR-T therapies in treating RRMM patients using the PubMed, Cochrane, ASH 2022 and ASCO 2023 abstracts using search terms (bispecific antibodies) AND (multiple myeloma), (CAR T cell therapy) AND (multiple myeloma). For BsAbs, our search on PubMed yielded 263 studies. 7 were clinical trials and 5 of these were included. 6 ASH abstracts and one ASCO abstract were also included resulting in a total of 12 studies considered for this meta-analysis.
For CAR-T, our search on PubMed and COCHRANE yielded 84 and 20 studies respectively. After screening, we have included 21 studies and 6 ASCO abstracts in final analysis. RStudio Desktop Version 2023.03.0+ 386 was used for statistical analysis. Cochrane-Q test and I² statistic were used to assess the statistical heterogenicity. Fixed effect model was used for low statistical heterogeneity (P &gt; 0.05 in Cochrane-Q test and I² &lt; 50%), while a random effect model was used for high statistical heterogeneity (P &lt; 0.05 in Cochrane-Q test and I² &gt; 50%). Categorical outcomes were summarized by pooled proportion with 95% CI. Subgroup analysis was performed wherever required. P &lt;0.05 was considered statistically significant.
Results
Bispecific antibodies
Overall response rates (ORR) were reported in a study population of 823 patients across 12 studies. The ORR was reported in 4 studies (n=106) for EMD and 4 studies (n=100) for HRCA respectively. The pooled ORR was 0.67 [95% CI; 0.59; 0.76) for the whole group. The pooled ORR was 0.48 (95% CI of 0.31 to 0.65) for EMD and 0.60 (95% CI of 0.51 to 0.70) for HRCA respectively. Subgroup analysis showed that there was a statistically significant difference in overall response rate according to different targets. However, there was no statistically significant difference in the ORR between the drugs with respect to EMD and HRCA. Combination therapy of Teclistamab and Talquetamab has highest ORR and RR in EMD disease compared to other BsABs in a study by Cohen et al. Funnel plot is symmetrical and showed no probability of publication bias for overall response rate for bispecific antibodies with a p-value of 0.676.
CAR T cell therapy
ORR with CAR-T cell therapy was reported across 27 studies with pooled sample size of 1469. The ORR was reported in 14 studies (n=172) for EMD and 11 studies (n=268) for HRCAs, respectively. The pooled ORR was 0.86 (95% CI of 0.82 to 0.90). The pooled proportion of RR among MM patients with EMD and HRCAs was 0.77 (95% CI of 0.68 to 0.87) and 0.77 (95% CI of 0.69 to 0.86), respectively. Funnel plot asymmetry showed possible publication bias for overall response rate for CAR T cell therapy with p-value of 0.021.
Bispecific antibodies vs CAR-T.
ORR in the whole cohort (P &lt;0.001), EMD cohort (P &lt;0.001), and HRCA cohort (P &lt;0.046) were found to be significantly higher in CAR-T cell therapy as compared to bispecific antibodies.
Conclusion: BsABs and CAR-T cell therapy are effective treatment options for relapsed MM patients.ORR in the whole cohort, EMD cohort, and HRCA cohort were found to be superior with CAR T cell therapy. However, it is difficult to make direct comparisons of pooled estimates of two different therapies. There was no significant difference in EMD and HRCA between the different types of BsAb therapy. Better reporting of EMD responses is urgently needed in published clinical data to know the true effect size and develop strategies to overcome this.