The screening results and characteristics of the included studies
The electronic literature search retrieved a total of 184 articles from PubMed, Embase, Medline, Web of Science, Cochrane Library and Chinese Bio-medical Database. The flowchart of the study selection process was presented in Fig.1. Preliminary screening after reading title and abstract, excluding review articles, fundamental researches and so on, there were remaining 41 studies. Then reading full text screens again and excluding single arm and phase1 studies, subgroup-analysis studies, study-design, cohorts study, and no-data-available studies, we obtained 15 articles totally, which includes 11 RCTs and 4 update-analysis studies[14-17]. Eventually, 11 RCTs with 5367 patients were included in quantitative synthesis. Six RCTs[18-23] explored the efficacy and safety of the MAbs targeting CD38 (daratumumab, isatuximab) group, three RCTs[24-26] explored the efficacy and safety of the MAbs targeting SLAMF7 (elotuzumab) group and two RCTs[27, 28] explored the efficacy and safety of MAbs targeting PD-1/PD-L1 (pembrolizumab) group. Characteristics of the included studies was presented in Table 1 and characteristics of the patients at baseline was presented in Supplementary material.
According to “Cochrane collaboration’s tool for assessing risk of bias”, we roughly assessed the quality of included trials, which was considered to be high quality. The details of study quality assessment was presented in Table 2.
Progression-Free Survival
All of the 11 RCTs provided PFS and hazard ratio[12]. Firstly, we synthesized the pooled HR of the MAbs targeting CD38, SLAMF7 and PD-1/PD-L1 groups versus their corresponding control group respectively by stataMP14 software, as shown in Fig.2a, 2b. The pooled HR for PFS of the MAbs targeting CD38, SLAMF7 and PD-1/PD-L1 groups vs their corresponding control groups were 0.45(95CI0.40-0.50), 0.68(95CI0.57-0.79) and 1.42(95CI0.95-1.88) respectively. Secondly, we indirectly calculated HR for PFS of the MAbs targeting CD38 group vs SLAMF7 group, CD38 group vs PD-1/PD-L1 group and SLAMF7 group vs PD-1/PD-L1group respectively by ITC software, the HR for PFS of them were 0.662(95CI0.543-0.806), 0.317(95CI0.221-0.454) and 0.479(95CI0.328-0.699) respectively. The MAbs targeting CD38 group and SLAMF7 group prolonged PFS compared with their corresponding control groups, and the MAbs targeting CD38 group had a longer PFS than the SLAMF7 group by indirect-comparison. In contrast, the MAbs targeting PD-1/PD-L1 group was the worst among the three group. In subgroup-analysis of the MAbs targeting CD38 group, the HR for PFS of the daratumumab group vs the control group was 0.40(95CI0.32-0.48), as compared with 0.60(95CI0.41-0.78) in the isatuximab group, the daratumumab group may result in longer PFS than the isatuximab group in patients with relapsed or refractory MM.
Overall Survival
Two RCTs about the MAbs targeting CD38 and three RCTs about the MAbs targeting SLAMF7 provided OS and HR, the pooled HR were 0.56(95CI0.41-0.70) and 0.69(95CI0.56-0.82) respectively, as shown in Fig.3. The HR for OS of the MAbs targeting CD38 group vs the MAbs targeting SLAMF7 group was 0.812(95CI0.584-1.127) by indirect-comparison. There was no significant difference in overall survival between the two groups.
ORR, CR or better, VGPR or better, VGPR, PR, SD
We used the same method as above-mentioned, the pooled RR for ORR, CR or better, VGPR or better, VGPR, PR and SD in the MAbs targeting CD38 group versus the control group were 1.21(95CI1.10-1.33), 1.78(95CI1.61-1.98), 1.63(95CI1.29-2.05), 1.39(95CI1.02-1.89), 0.70(95CI0.56- 0.87) and 0.42(95CI 0.27-0.66) respectively, as shown in Fig.4a, 4b. According to primary or recurrent treatment and classification of antibodies, we conducted subgroup analysis, and found that there were no significant relations between heterogeneity and the two factors. The pooled RR for ORR, CR or better, VGPR or better, VGPR, PR and SD in the MAbs targeting SLAMF7 group versus the control group were 1.24(95CI0.99-1.56), 0.79(95CI0.45-1.36), 1.25(95CI1.02-1.54), 1.40(95CI1.10-1.78), 0.46(95CI0.28-0.77) and 0.66(95CI0.48-0.90) respectively, as shown in Fig.5a, 5b. The pooled RR for ORR in the MAbs targeting PD-1/PD-L1 group versus the control group was 0.97(95CI0.82-1.13). The RR for ORR, CR or better, VGPR or better, VGPR, PR and SD in the MAbs targeting CD38 group versus the SLAMF7 group were 0.976(95CI0.763-1.248), 2.253(95CI1.284-3.955), 1.304(95CI0.956- 1.778), 0.993(95CI0.671-1.468), 1.522(95CI0.876-2.642) and 0.636(95CI0.368-1.099) respectively by indirect comparison. The RR for ORR in the MAbs targeting CD38 group vs the PD-1/PD-L1 group and in the SLAMF7 group vs the PD-1/PD-L1 group were 1.247(95CI1.035-1.503) and 1.278 (95CI0.968-1.688) respectively. As for treatment response, the MAbs targeting CD38 group was better than the SLAMF7 group in term of CR or better. The MAbs targeting PD-1/PD-L1 group had a worse treatment response than the MAbs targeting CD38 group and SLAMF7 group.
Grade 3 or higher hematological and non-hematological adverse events
The pooled RR for neutropenia, anemia, thrombocytopenia, lymphopenia, pneumonia, diarrhea and fatigue in the MAbs targeting CD38 group versus the control group were 1.40(95CI1.17-1.67), 0.82(95CI0.66-1.01), 1.15(95CI0.92-1.43), 1.70(95CI1.26-2.29), 1.51(95CI1.21-1.89), 1.33(95CI0.92- 1.91) and 2.00(95CI1.33-3.02) respectively, as shown in Fig.6a, 6b. The pooled RR for neutropenia, anemia, thrombocytopenia, lymphopenia, pneumonia, diarrhea and fatigue in the MAbs targeting SLAMF7 group versus the control group were 0.77(95CI0.64-0.92), 0.88(95CI0.67-1.17), 0.97(95CI 0.73-1.28), 1.63(95CI1.43-1.85), 1.32(95CI0.88-1.98), 1.33(95CI0.73-2.41) and 1.19 (95CI 0.75-1.91) respectively, as shown in Fig.7. The pooled RR for neutropenia, anemia, pneumonia, diarrhea and fatigue in the MAbs targeting PD-1/PD-L1 group versus control group were 1.16(95CI0.97-1.38), 1.45(95CI0.89-2.36), 1.14(95CI0.65-1.99), 2.98(95CI0.71-12.44) and 0.40(95CI0.15-1.08) respectively, as shown in Fig.8. The RR for neutropenia, anemia, thrombocytopenia, lymphopenia, pneumonia, diarrhea and fatigue in the MAbs targeting CD38 group versus the SLAMF7 group were 1.818(95CI1.41-2.344), 0.932(95CI0.656-1.323), 1.186(95CI0.83-1.694), 1.043(95CI0.753-1.444), 1.144(95CI0.72-1.817), 1.00(95CI0.497-2.014) and 1.681(95CI 0.903-3.13) respectively by indirect comparison. The RR for neutropenia, anemia, pneumonia, diarrhea and fatigue in the MAbs targeting CD38 group versus the PD-1/PD-L1 group by indirect comparison were 1.207(95CI0.94-1.55), 0.566(95CI 0.332-0.963), 1.325(95CI0.725-2.419), 0.446(95CI0.102-1.956) and 5.00 (95CI1.717 -14.56) respectively. The RR for neutropenia, anemia, pneumonia, diarrhea and fatigue in the MAbs targeting SLAMF7 group versus the PD-1/PD-L1 group were 0.664(95CI0.515-0.855), 0.607(95CI0.346-1.064), 1.158(95CI0.58-2.311), 0.446(95 CI0.095-2.105) and 2.975(95CI0.998-8.867) respectively by indirect comparison. As for the incidence of the adverse events, the MAbs targeting CD38 group had a lower risk of anemia while a higher risk of fatigue than the PD-1/PD-L1 group. The MAbs targeting SLAMF7 group had a lower risk of neutropenia than the PD-1/ PD-L1and CD38 group.
The indirect-comparison results of efficacy and safety among the three groups were summarized in Table 3.