Comparative efficacy and safety of BCMA-targeted CAR T cells and BiTEs in relapsed/refractory multiple myeloma: a meta-analysis of interventional and real-world studies.

Introduction

Multiple myeloma (MM) is a clonal plasma cell neoplasm characterized by the uncontrolled proliferation of monoclonal plasma cells in bone marrow, resulting in the excessive production of monoclonal immunoglobulins. This abnormal plasma cell expansion can lead to significant end-organ damage [ 1 ]. This can result in substantial end-organ damage, including bone lesions, renal impairment, anemia, and hypercalcemia [ 2 , 3 ].MM accounts for 1% of all cancers and is the second most common hematologic malignancy, accounting for 13% of hematologic malignancies, with increasing incidence among the elderly [ 2 , 4 , 5 ]. The median age at diagnosis is approximately 69 years, and while survival has improved, the disease remains incurable [ 4 , 5 ].

Over the past two decades, treatment outcomes have improved with the introduction of autologous stem cell transplantation (ASCT), proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), and monoclonal antibodies [ 6 , 7 ]. These therapies have significantly prolonged survival, particularly among younger and transplant-eligible patients. Although OS rates have improved recently, MM is still an incurable disease [ 8 , 9 ]. Relapsed/refractory multiple myeloma (R/R MM) remains a major clinical challenge. Triple-class exposed (TCE) and penta-drug exposed (PE) patients often face limited therapeutic options and have poor prognoses, with real-world data showing median overall survival under one year [ 10 ].

Among the most promising targets for novel therapies is B-cell maturation antigen (BCMA), a member of the tumor necrosis factor receptor superfamily (TNFRSF17), which is expressed almost exclusively on mature B cells and plasma cells, and highly overexpressed on myeloma cells [ 11 – 13 ]. It is absent on naïve B cells and other hematopoietic cells, making it an ideal tumor-associated antigen (TAA) for targeted therapy in MM [ 14 , 15 ].

Two classes of BCMA-targeted immunotherapies have emerged as powerful options in the R/R MM setting: chimeric antigen receptor T-cell (CAR-T) therapies and bispecific T-cell engagers (BiTEs) [ 16 ]. CAR-T cells are engineered ex vivo to express synthetic receptors that recognize BCMA on tumor cells, enabling MHC-independent T cell activation and potent cytotoxicity [ 17 ]. BiTEs are recombinant antibodies that simultaneously bind BCMA on myeloma cells and CD3 on T cells, facilitating immune synapse formation and targeted cell lysis [ 18 ].

CAR-T products such as idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel) have demonstrated high response rates and durable remissions in heavily pre-treated patients [ 19 , 20 ]. However, they require autologous T-cell collection, manufacturing time, lymphodepletion chemotherapy, and inpatient monitoring [ 21 ]. In contrast, BiTEs such as teclistamab and elranatamab are administered off-the-shelf and continuously, offering immediate availability and greater feasibility for patients with aggressive disease or comorbidities. However, durability of response and immune-related toxicity remain important considerations [ 22 – 25 ]. Furthermore, BCMA downregulation is a known resistance mechanism, and dual-target CAR-T therapies (e.g., BCMA/CD19) have shown promising results in early-phase studies, potentially improving response durability [ 26 – 28 ].

Although both therapies have been approved and incorporated into treatment algorithms, there remains no consensus on the optimal sequencing of these agents [ 24 , 25 , 29 ]. Numerous studies have investigated the efficacy and safety of CAR-T and BiTEs therapies that target BCMA; however, the study populations vary in terms of age, ethnicity, prior treatment exposure, comorbidities, and other variables. Head-to-head comparisons are lacking, and previous meta-analyses have not included data from real-world settings or dual-target CAR-T constructs, which may overcome resistance mechanisms such as BCMA downregulation [ 30 ]. Additionally, construct-level differences in CAR-T design—such as scFv origin, costimulatory domains, and transduction method—may influence both efficacy and toxicity, yet remain underexplored in comparative studies.

The introduction of CAR-T and BiTEs brought inevitable toxicities linked to Cytokine Release Syndrome (CRS) and Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS). CRS is an inflammatory reaction caused by sustained elevation of reactive cytokines and heightened vascular permeability, which can vary in severity from a mild fever to a severe, shock-like condition. ICANS can manifest as headaches, confusion, challenges with word retrieval and speech, or, in more serious cases, as encephalopathy and reduced consciousness [ 9 ]. The CRS and ICAN severity grading were according to the consensus of the American Society for Transplantation and Cellular Therapy [ 31 ].

In this context, we conducted a comprehensive systematic review and meta-analysis to compare the efficacy and safety of BCMA-targeted CAR-T therapies and BiTEs in patients with R/R MM. Our study integrates both interventional and observational data, includes emerging dual-target CAR-T constructs, and provides detailed comparisons across product types to inform personalized treatment strategies.

Materials and methods

Protocol and registration

The systematic literature review and meta-analysis were conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement [ 32 ]. It was prospectively registered on PROSPERO ( http://www.crd.york.ac.uk/PROSPERO ) under the registration number CRD42023435174.

Literature search and study selection

The PICO/PECOs framework served as the foundation for defining the inclusion and exclusion criteria for this study [ 33 , 34 ]. Articles were systematically gathered from three major databases: PubMed, Embase, and the Cochrane Library, with data extraction conducted up to October 2nd, 2024. The search strategy was shown in the eMethod in the supplementary file. Study selection (title/abstract screening and subsequent full-text review) was managed in Covidence© to streamline duplicate removal, blinded screening, and consensus tracking [ 35 ]. Two authors independently assessed the selection process using the established criteria, resolving any discrepancies through group discussion at each stage.

The search was limited to English-language publications and studies, focusing on the outcomes of BCMA-targeted CAR-T and BiTEs therapies in patients with relapsed or refractory multiple myeloma.

Inclusion and exclusion criteria

The following inclusion criteria were established for this meta-analysis. Both interventional and observational studies investigating BCMA-targeted CAR-T therapies (including but not limited to single-target constructs) and BCMA-targeted BiTEs therapies in patients with relapsed or refractory multiple myeloma were considered eligible. For interventional studies, comparator arms could include historical controls or standard-of-care treatments. Exclusion criteria encompassed animal studies, in vitro research, phase 1 studies, review articles, non-peer-reviewed publications (e.g. meeting abstracts, case reports), procedural reports, letters, editorials, commentaries, recommendations, and guidelines. Notably, phase 1 trials were excluded due to their exploratory nature and limited sample sizes. However, studies with a combined Phase 1/2 design were included, provided they reported relevant efficacy and/or safety outcomes in a format suitable for meta-analysis. At each stage of the screening process, any disagreements between reviewers were resolved through consensus.

Data extraction

Two authors performed the data extraction independently by utilizing a custom-designed extraction form. In cases of disagreement, a third author intervened to resolve the issues. If data was insufficient, authors were contacted via email and given two weeks to respond. If there was no reply, decisions were made based on the available information, and any issues were addressed through discussion.

The study’s characteristics encompassed several key details, including the author(s), publication information, study period, study design, corresponding author, country of execution, and trial identification number. Important characteristics of the study participants were meticulously extracted, distinguishing between those who received CAR-T cell therapy and BiTEs. For both groups, data included sample size, age range of participants, gender, median follow-up duration, median time since diagnosis, ECOG performance status, cut-off for bone marrow plasma cells, and the presence of plasmacytoma. Additionally, the study assessed the number of high-risk patients based on cytogenetic factors such as t(4;14), t(14;16), del(17p), and gain1q, alongside staging classifications according to the International Staging System (ISS) and the Revised International Staging System (R-ISS). Information on prior lines of treatment, including transplant status, triple-class refractory status, and penta-drug refractory status, was also documented.

The interventional characteristics of CAR-T and BiTEs encompass various crucial data points. For CAR-T, the extracted information includes the product name, type, and origin of the monoclonal antibody, along with details on the co-stimulatory domain, expansion protocol, transduction process, dosing regimens, and lymphodepletion protocols. In contrast, the characteristics of BiTEs comprise the product name, type and origin of the monoclonal antibody, the linker used, expansion protocol, and dosing information.

The efficacy outcomes of the study included detailed information on various endpoints, such as overall response rate (ORR), progression-free survival (PFS), overall survival (OS), duration of response (DOR), stringent complete response (sCR), complete response (CR), very good partial response (VGPR), partial response (PR), minimal response, stable disease (SD), progressive disease (PD), and minimal residual disease (MRD). Additionally, data on safety outcomes reported in the studies were meticulously extracted, encompassing important metrics such as 30-day mortality rates, instances of all and severe hematotoxicity, and occurrences of cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), neurotoxicity, and infection.

While our PROSPERO registration included quality-of-life (QoL) as a secondary outcomes, unfortunately, none of the studies eligible for meta-analysis reported QoL outcomes in an extractable format.

Risk of bias

Two independent authors assessed the risk of bias (ROB) in the retrieved intervention studies. For the randomized control trial studies, we used the Cochrane Risk of Bias tool 2.0 (ROB2), and for evaluating ROB in non-randomized control trials and observational cohort studies, we used the methodological index for non-randomized studies (MINORS). Concerning the MINORS, which the global score closer to 16 reflects high-quality non-comparative non-randomized studies, and the global score closer to 24 for comparative studies [ 36 ]. Equally, more than 12 total scores for non-comparative studies and ≥ 20 total scores for comparative studies were considered low risk of bias by MINORS [ 37 ].

Statistical analysis

A random-effects meta-analysis, following the DerSimonian and Laird method [ 38 ], was performed to account for potential statistical heterogeneity across studies. Effect sizes were reported with 95% confidence interval (CI) to estimate the precision of the estimates. A random forest plot was used to visually represent the pooled effect sizes and the distribution of individual study results. Heterogeneity was assessed using I² statistic, with values categorized as low (0–25%), moderate (26–50%), and high (> 50%).

To assess the relationship between various study-level factors and overall response rate (ORR), mixed-effect meta-regression analysis was conducted using Restricted Maximum Likelihood (REML), which provides a more robust estimation of heterogeneity in multivariate analysis. All six variables included in our univariate screening were selected before analysis based on clinical relevance and consistency with prior BCMA-targeted therapy studies. Based on the univariate findings and to maintain model parsimony given the number of included studies (k = 15), we retained treatment type and three clinically relevant covariates in the final multivariable model.

Robustness of the pooled ORR was tested with a leave-one-out influence analysis. Each study was removed in turn, the random-effects model refitted, and changes in the pooled ORR, 95% CI and τ² recorded. Publication bias was assessed using a Doi plot and the LFK index, which are recommended for single-arm proportional meta-analyses. The mean and SD values of total methodological index were analysed for non-randomized studies (MINORS). All statistical analyses were conducted in R Studio (version 4.3.1) using the packages (meta version 8.1-0 and metasens version 1.5-3) with statistical significance set at p < 0.05.

Results

Study selection

A total of 6,685 articles were initially identified, comprising 4,290 from Embase, 2,300 from PubMed, and 95 from CENTRAL. After removing duplicates, 2,798 papers were subjected to screening. Of these, 280 articles were assessed for eligibility, 254 were excluded primarily due to the lack of peer review, and 3 were excluded secondary to the pooled analysis of clinical trials fashion. Ultimately, 26 papers were included in this systematic review and meta-analysis. Study selection is shown in Fig. 1 . Among the twenty-six studies included, fifteen were interventional, and the others were observational/retrospective. Interventional studies were included in the meta-analysis, and the others were reported by qualitative data analysis. Fig. 1 Flow diagram of the study selection in the systematic literature review. Abbreviation: n = Number

Study characteristics

Of the total of 2,246 patients, 1,357 were from fifteen interventional studies and 889 from eleven observational/retrospective studies. Only the interventional studies were assembled for the meta-analysis, while the observational/retrospective studies were systematically reviewed as qualitative data. All interventional studies were published between 2021 and 2024. There are two randomized controlled Phase III studies [ 19 , 20 ] and seven Phase II studies [ 25 , 39 – 44 ], while the remaining studies are Phase I/II [ 45 , 46 ]. Ten studies focused on BCMA-targeting CAR-T [ 19 , 20 , 39 – 48 ], and three concentrated on BCMA-targeting bispecific T-cell engagers [ 24 , 25 , 49 ]. Two studies predominantly centered on the dual-targeted (anti-BCMA and anti-CD38/CD19) CAR-T. Thirteen are single-arm studies, and two of them are sub-analyses of the Japanese cohorts. The Japanese cohorts reported by Ri et al. [ 39 ] and Minakata et al. [ 41 ] were conducted under the same protocol framework as the original global cohorts of CARTITUDE-1 and KarMMa, respectively, but were independently enrolled and reported separately. The main baseline characteristics of 15 interventional studies are presented in Table 1 . Other baseline characteristics can be found in Table S1 of the supplementary file. Table 1 Baseline characteristics of the included interventional studies Trial name Identifier Author, Year Phase Bispecific antibody/CAR-T Sample Size (intervention arm) Median age (range) Median prior lines of therapy, no, (range) High risk cytogenetic, no, (%) Definition of high-risk cytogenetics Presense of extramedullary plasmacytoma, n (%) Tripple-class refractory, no, (%) CARTITUDE-1 NCT03548207 Berdeja et al. 2021 [ 45 ] 1b/2 Cilta-cell 97 61.0 (56–68) 6 (4–8) 23 (24) t(4;14), t(14;16) and del(17p) 13 (13) 85 (88) CARTITUDE-1 NCT03548207 (Japan) Ri et al. 2022 [ 39 ] 2 Cilta-cell 9 61.0 (56–68) 5 (3–7) 5 (55.6) t(4;14), t(14;16),del(17p) 3 (33.3) 8 (88.9) CARTITUDE-4 NCT04181827 San-Miguel et al. 2023 [ 19 ] 3 Cilta-cell 208 61.5 (27–78) 2 (1–3) 123 (59.4) del17p, t(4;14), t(14;16), gain/amp(1q) 44 (21.2) for Cilta-cel, 35 (16.6) for standard of care 30 (14.4) KarMMa NCT03361748 Munshi et al. 2021 [ 40 ] 2 Ide-cell 128 61.0 (33–78) 6 (3–16) 45 (35) del(17p), t(4;14), or t(14;16). 50 (39) 108 (84) KarMMa NCT03361748 (Japan) Minakata et al. 2023 [ 41 ] 2 Ide-cell 9 61.0 (33–78) 4 (3–15) 2 (22) del(17p) and t(4;14) 5 (56) 3 (33) KarMMa-3 NCT03651128 Rodriguez-Otero et al. 2023 [ 20 ] 3 Ide-cell 254 63.0 (30–81) 3 (3–4) 107 (42) t(4;14), t(14;16),del(17p) 61 (24) for Ide-cel, 32 (24) for standard of care 164 (65) - ChiCTR1800017051 Zhang et al. 2022 [ 42 ] 2 anti-BCMA & anti-CD38 22 56.0 (47–68) 8 (4–12) 19 (86.4) t(4;14), t(14;16),del(17p) 3 (13.6) NA - ChiCTR-OIC-17,011,272 Wang et al. 2022 [ 43 ] 2 anti-BCMA & anti-CD19 62 58.0 (30–69) 4 (2–17) 18 (29) NA 15 (24) NA HDS269B NCT03093168 Du et al. 2022 [ 46 ] 1/2 HDS269B 49 57.0 (37–75) 4 (2–12) 21 (42.8) NA 11 (22.45) NA CARTIFAN-1 NCT03758417 Mi et al. 2022 [ 44 ] 2 Cilta-cell 48 61.0 (30–72) 4 (3–9) 21 (43.8) t(4;14),del(17p) 5 (10.4) 9 (18.8) CS1-BCMA CAR-T NCT04662099 Li et al. 2024 [ 47 ] 1b/2 CS1-BCMA CAR-T 16 60.0 (42–73) 4 (2–8) 9 (56) amp(1q21), del(17p), t(4;14), t(14;16), t(11;14). 9 (38) NA HBI0101 NCT04720313 Kfir-Erenfeld et al. 2024 [ 48 ] 1b/2 HBI0101 50 65.0 (40–84) 4 (3–13) 12 (24) t(4:14), t(14:16), or del(17p) 16 (32) 47 (94) MagnetisMM-3 NCT04649359 Lesokhin et al. 2023 [ 25 ] 2 Elranatamab 123 68.0 (36–89) 5 (2–22) 31 (25.2) t(4;14), t(14;16) and del(17p) 39 (31.7) 119 (96.7) LINKER-MM1 NCT03761108 Bumma et al. 2024 [ 49 ] 1/2 Linvoseltamab 117 70.0 (37–91) 5 (2–16) 46 (39.4) t(4:14), t(14:16), or del(17p) 19 (16.2) 96 (82.1) MajesTEC-1 NCT03145181 , NCT04557098 Moreau et al. 2022 [ 24 ] 1/2 Teclistamab 165 64.0 (33–84) 5 (2–14) 38 (25.7) t(4:14), t(14:16), or del(17p) 28 (17) 128 (77.6) Abbreviation: ASCT Autologous stem cell transplantation; BCMA B−cell maturation antigen; CAR−T Chimeric antigen receptors T−cell; Cilta−cell Ciltacabtagene autoleucel; Ide−cell Idecabtagene vicleucel; ISS International Staging System; R−ISS Revised International Staging System; no. Number

As mentioned, the total number of patients who received CAR-T or BiTEs in all 15 studies was 1,357. Nine hundred and fifty-two patients were included in CAR-T cell studies. Male patients who received CAR-T therapy were 553 (58%), and female patients were 399 (42%). We collected data from 405 patients from BiTEs studies, of which 228 (56%) were male and 177 (44%) were female. The median age of patients from CAR-T studies ranged from 56 to 65 years old, while the median age of patients from BiTEs was 64 to 70. The median age of patients in BiTEs studies was a little higher than that of CAR-T studies. The median prior lines of therapy for all studies were a minimum of two lines up to six prior lines of therapy. The number of patients classified as high-risk by cytogenetics varied between 22% and 86.4%, and the definitions of high-risk cytogenetics differed in each study. The number of patients with extramedullary plasmacytoma was hugely different between studies. From as low as 13% in the Berdeja et al. study [ 45 ] to as many as 56% in Minakata et al. study [ 41 ]. Aside from CARTIFAN-1 by Mi et al. [ 44 ] and CARTITUDE-4 by San-Miguel et al. [ 19 ], the percentage of patients with triple-class refractory status was quite elevated, ranging from 80 to 95% in the other studies. The characteristics of CAR-T in this meta-analysis, including structures, product manufacturing, lymphodepletion regimen, and median CAR-T dose, are demonstrated in Table 2 . Moreover, the details of BiTEs are shown in Table 3 . Table 2 Characteristics of CAR-T Identifier Author, Year CAR-T name Type of monoclonal antibody Origin of monoclonal antibody Co-stimulatory signal Transduction Median CAR-T cell doses Lymphodepletion regimen/Conditioning NCT03548207 Berdeja et al. 2021 [ 45 ] Ciltacell scFv Chimeric (Llama + Murine) 4-1BB Lentiviral 0.75*10 6 /kg 300 mg/m 2 cyclophosphamide + 30 mg/m 2 fludarabine NCT03548207 (Japan) Ri et al. 2022 [ 39 ] Ciltacell scFv Chimeric (Llama + Murine) 4-1BB Lentiviral 0.624 × 10 6 CAR-positive viable T cells/kg (range, 0.41 × 10 6 to 0.72 × 10 6 ) Cyclophosphamide (300 mg/m 2 ) and fludarabine (30 mg/m 2 ) daily for 3 days NCT04181827 San-Miguel et al. 2023 [ 19 ] Ciltacell scFv Chimeric 4-1BB Lentiviral 0.75 × 10 6 CAR + viable T cells/kg Cyclophosphamide + fludarabine NCT03361748 Munshi et al. 2021 [ 40 ] Idecel scFv Chimeric 4-1BB Lentiviral (150–450)*10 6 /kg 300 mg/m 2 cyclophosphamide + 30 mg/m2 fludarabine NCT03361748 (Japan) Minakata et al. 2023 [ 41 ] Idecel scFv Chimeric 4-1BB Lentiviral 450 × 10 6 CAR + T cells/kg Cyclophosphamide 300 mg/m 2 /day and fludarabine 30 mg/m 2 /day for 3 days NCT03651128 Rodriguez-Otero et al. 2023 [ 20 ] Idecel scFv Chimeric 4-1BB Lentiviral (150–450)*10 6 300 mg/m 2 cyclophosphamide + 30 mg/m 2 fludarabine ChiCTR1800017051 Zhang et al. 2022 [ 42 ] Humanized anti-BCMA CAR-T and murine anti-CD38 CAR-T scFv Humanized (BCMA), Murine (CD38) 4-1BB Lentiviral 2.0 × 10 6 /kg Fludarabine 30 mg/m 2 and cyclophosphamide 300 mg/m 2 ChiCTR-OIC-17,011,272 Wang et al. 2022 [ 43 ] Combined anti-BCMA and anti-CD19 CAR (ChiCTR) scFv Chimeric 4-1BB Lentiviral 1*10 6 /kg 750 mg/m 2 cyclophosphamide + 30 mg/m 2 fludarabine NCT03093168 Du et al. 2022 [ 46 ] HDS269B scFv Chimeric 4-1BB Retroviral 9*10 6 /kg 300 mg/m 2 cyclophosphamide + 30 mg/m 2 fludarabine NCT03758417 Mi et al. 2022 [ 44 ] Ciltacell scFv Chimeric (Llama + Murine) 4-1BB Lentiviral 0.67*10 6 /kg 300 mg/m 2 cyclophosphamide + 30 mg/m 2 fludarabine NCT04662099 Li et al. 2024 [ 47 ] Bispecific CS1-BCMA CAR Murine anti-CS1 scFv + murine anti-BCMA scFv Murine 4-1BB Lentiviral 0.75 × 10 6 , 1.5 × 10 6 , and 3.0 × 10 6 CAR + T cells/kg cyclophosphamide (250 mg/m2, d-5 to d-3) and fludarabine (30 mg/m 2 , d-5 to d-3) NCT04720313 Kfir-Erenfeld et al. 2024 [ 48 ] HBI0101 C11D5.3 BCMA scFv humanized 4-1BB MSGV1 retroviral 150–800 × 10 6 CAR-T cells cyclophosphamide 300 mg/m 2 and fludarabine renally-dose adjusted per institutional guidelines. Abbreviation: BCMA B−cell maturation antigen; CAR−T Chimeric antigen receptors T−cell; scFv single−chain variable fragment Table 3 Characteristic of BiTEs Identifier Author, Year BiTEs name Target antigen Type of mAb (Fv-based, IgG-based) Origin of mAb (Recombinant or humanized) Linker BiTEs doses NCT04649359 Lesokhin et al. 2023 [ 25 ] Elranatamab BCMA and CD3 Anti-BCMA scFv-Anti-CD3 scFv Humanized NA Two-step priming dose of 12 mg and 32 mg in the first week followed by 76 mg weekly NCT03761108 Bumma et al. 2024 [ 49 ] Linvoseltamab BCMA and CD3 Anti-BCMA scFv-Anti-CD3 scFv Humanized NA 200 mg NCT03145181 , NCT04557098 Moreau et al. 2022 [ 24 ] Teclistamab BCMA and CD3 Anti-BCMA scFv-Anti-CD3 scFv Humanized NA 1.5 mg per kilogram of body weight weekly, after step-up doses of 0.06 mg and 0.3 mg per kilogram Abbreviation: BCMA B−cell maturation antigen; scFv single−chain variable fragment

The data from eleven observation studies were extracted as qualitative data and demonstrated in Table S2 . Most of them were studies about BCMA-targeting CAR-T, two were CAR-T and BiTEs, and two were focused on only BiTEs.

Assessment of risk of bias

The risk of bias (ROB) for randomized-controlled studies was shown online in Supplement Figure S2 , revealing a low ROB in two studies [ 20 , 45 ]. For non-randomized interventional studies, the risk of bias was shown in Table S3 . The majority of these studies were rated as having a low risk of bias, with a mean global score of 13.46 ± 2.02 (95% CI: 12.24–14.69). For observational retrospective studies, the average MINORS score was 12.36 ± 0.92 (95% CI: 11.74–12.98), as presented in Table S4 . These scores indicate an overall low risk of bias across both non-randomized interventional and retrospective studies.

Sensitivity analysis

The Doi plot showed major asymmetry (LFK = 4.53; Figure S1 ). Removing the two smallest studies reduced the LFK index to 4.15 (data not shown). Leave-one-out sensitivity analysis showed that the pooled ORR estimate remained consistent (0.79–0.83), indicating robustness of the primary result despite evidence of small-study effects (Table S5 ).

Efficacy

In our pooled analysis of BCMA-targeting CAR-T cell therapies ( n = 952 patients), the overall response rate (ORR) reached an impressive rate of 84% (95% CI: 0.77–0.90; I² = 74.5%, p < 0.0001). The high heterogeneity suggests that true response rates differ substantially between studies likely reflecting differences in patient selection, disease characteristics, and manufacturing or dosing protocols. By contrast, two studies evaluating dual-targeting CAR-T therapies (anti-BCMA + anti-CD38 and anti-BCMA + anti-CD19) showed the pooled ORR of 92% (95% CI: 0.84–0.96; I² = 0%, p = 0.8811), suggesting a consistent benefit across studies. Meanwhile, three studies investigating BCMA-targeting bispecific T-cell engagers (BiTEs) showed a moderate ORR of 65% (95% CI: 0.59–0.70; I² = 31.6%, p = 0.2317). Overall, the pooled ORR across all modalities was 82% (95% CI: 0.74–0.87; I² = 81.4%, p < 0.0001), as illustrated in Fig. 2 a. Notably, the prediction interval in our forest plots was meant to reflect between-study variability and provided a range within which future study effects may fall but was not the primary inference for the research question. The wide prediction interval observed in the pooled ORR for CAR-T and BiTEs suggests substantial variability among different settings and patient populations. Fig. 2 Meta-analysis of the efficacy of BCMA-targeted CAR T-cell therapy, Bispecific T-cell engagers (BiTEs) and dual-targeted therapy on ( a ) Overall response rate (ORR); b Complete response (CR)/stringent CR (sCR); c Very good partial response (VGPR); d MRD negativity rate

When assessing deep responses (CR/sCR), the pooled CR/sCR rate in BCMA CAR-T studies was 55% (95% CI: 0.41–0.68; I² = 92.2%, p < 0.0001), showing a high heterogeneity. Dual-targeting CAR-T therapies achieved a slightly higher CR/sCR rate of 58% (95% CI: 0.48–0.68; I² = 0%, p = 0.6751). In contrast, BiTEs reached a pooled CR/sCR of 41% (95% CI: 0.33–0.50; I² = 63.9%, p = 0.0627). The overall pooled CR/sCR stood at 52% (95% CI: 0.43–0.62; I² = 89.9%, p < 0.0001), as shown in Fig. 2 b.

The numbers for very good partial response (VGPR) rates were remarkably consistent. BCMA-targeting CAR-T studies reported a pooled VGPR of 18% (95% CI: 0.13–0.24; I² = 66.6%, p < 0.0001). Dual-targeting CAR-T showed 20% VGPR (95% CI: 0.13–0.30; I² = 0%, p = 0.7354), and BiTEs matched CAR-T at 18% (95% CI: 0.15–0.23; I² = 18.1%, p = 0.2951). Across all studies, the overall pooled VGPR was 18% (95% CI: 0.15–0.22; I² = 53.1%, p = 0.0008), as seen in Fig. 2 c.

As for minimal residual disease (MRD) negativity among patients achieved ≥ CR, the pooled rate among BCMA CAR-T studies was 73% (95% CI: 0.53–0.87; I² = 94.6%, p < 0.0001). Dual-target CAR-T therapies had a pooled MRD negativity rate of 63% (95% CI: 0.31–0.87; I² = 81.5%, p = 0.0096). BiTEs yielded a higher MRD negativity rate of 79% (95% CI: 0.42–0.95; I² = 89.7%, p < 0.0001). The overall pooled MRD negativity was 73% (95% CI: 0.58–0.84; I² = 93.1%, p < 0.0001) (Fig. 2 d). Most studies used next-generation sequencing for MRD assessment, with a minority employing flow cytometry.

Safety

In the safety analysis, we separated the hematotoxicity analysis into severe anemia, neutropenia, and thrombocytopenia. The pooled analysis of severe anemia in BCMA-targeting CAR-T studies was 53% (95% CI: 0.44–0.61; I² = 79.9%, p < 0.0001). For the dual-targeted CAR-T, the pooled analysis for severe anemia was unexpectedly lower than that of BCMA-targeting CAR-T with a rate of 43% (95% CI: 0.18–0.71; I² = 80.8%, p = 0.0223). While in the BiTEs study, the pooled analysis of severe anemia was 35% (95% CI: 0.31–0.40; I² = 0%, p = 0.4758) with a lack of heterogeneity. The pooled rates of severe neutropenia were 90% (95% CI: 0.81–0.95; I² = 83.9%, p < 0.0001), 74% (95% CI: 0.11–0.99; I² = 95.6%, p < 0.0001), 52% (95% CI: 0.39–0.65; I² = 86.5%, p = 0.0006) for BCMA-targeting CAR-T, dual-targeted CAR-T, and BiTEs respectively. The pooled rates of severe neutropenia were reported in Fig. 3 a. All ten BCMA-targeted CAR-T studies pooled severe thrombocytopenia rate was 49% (95% CI: 0.44–0.55; I² = 56.9%, p = 0.0131). For two dual-targeted CAR-T studies, the pooled severe thrombocytopenia rate was 19% (95% CI: 0.00-0.93; I² = 88%, p = 0.0039) with a marked heterogeneity. In three BCMA-targeted BiTEs studies, the pooled thrombocytopenia rate was 22% (95% CI: 0.18–0.27; I² = 0%, p = 0.6331). Fig. 3 Meta-analysis on the adverse effects, a Severe neutropenia; b Severe infection; c Cytokine release syndrome (CRS), d Immune Effector Cell-Associated Neurotoxicity Syndrome (ICAN)

The infection rate of pooled BCMA-targeted CAR-T was 59% (95% CI: 0.54–0.65; I² = 57.1%, p = 0.0299) with high heterogeneity. In addition, the pooled severe infection rate was 25% (95% CI: 0.21–0.29; I² = 45.5%, p = 0.759). For dual-targeted CAR-T, the infection rate was only 15% (95% CI: 0.01–0.85; I² = 83.8%) with a pooled severe infection rate was 11% (95% CI: 0.01–0.66; I² = 73.5%) with a marked heterogeneity. While in patients who received BiTEs, the pooled rate of infection was elevated to 72% (95% CI: 0.67–0.76; I² = 0%, p = 0.7457). Furthermore, the severe infection rate was 39% (95% CI: 0.31–0.47; I² = 0%, p = 0.3953). Overall, the pooled rate of infection was 60% (95% CI: 0.52–0.67; I² = 77.4%, p = 0.2117) with high heterogeneity. Severe infection can be seen in Fig. 3 b. with the total pooled rate for all cohort of 28% (95% CI: 0.22–0.34; I² = 74.6%, p < 0.0001).

The pooled CRS rate was 84% (95% CI: 0.68–0.93; I² = 90.4%, p < 0.0001) for BCMA-targeting CAR-T, 96% (95% CI: 0.88–0.98; I² = 0%, p = 0.5927) for the dual-targeted CAR-T, and 59% (95% CI: 0.44–0.73; I² = 89.6%, p = 0.2761) for the BiTEs, shown in Fig. 3 c. In addition, CAR-T BCMA studies pooled severe CRS rate was 7% (95% CI: 0.04–0.13; I² = 82.6%, p < 0.001) with a pronounced heterogeneity. For two dual-targeted CAR-T studies, the pooled severe CRS rate was 16% (95% CI: 0.05–0.40; I² = 73.6%, p = 0.0514). In three BiTEs BCMA studies, the pooled CRS rate was 1% (95% CI: 0.00-0.02; I² = 0%, p = 0.9073). The pooled ICAN rate for BCMA-targeting CAR-T was only 6% (95% CI: 0.02–0.15; I² = 81.7%, p = 0.0009) with the heterogeneity. As low as that of BiTEs, which were 5% (95% CI: 0.02–0.09; I² = 47.9%, p = 0. 1467). The pooled rate of ICAN is shown in Fig. 3 d. In addition, the pooled severe ICAN rate of 2% (95% CI: 0.01–0.04; I² = 0%, p = 0.4136).

To conduct a more detailed evaluation, we performed a meta-regression analysis using a mixed-effects model to assess the relationship between various study-level factors and ORR. BiTEs were designated as the reference category for comparison. CAR-T therapies were categorized into three groups: cilta-cel, ide-cel, and other CAR-T products. The results, summarized in Table 4 , the univariate meta-regression identified that all CAR-T subtypes—cilta-cel, ide-cel, dual-targeted CAR-T, and other CAR-T products—were associated with higher ORR compared to BiTEs, with cilta-cel and dual-targeted CAR-T showing the strongest associations ( p < 0.001). Median age was inversely associated with ORR in univariate analysis ( p = 0.035), but this association lost significance in the multivariate model. In the multivariate model adjusting for clinically relevant covariates, dual-targeted CAR-T therapies had the highest odds of response (OR = 15.31, p < 0.001), followed by cilta-cel (OR = 8.88, p < 0.001), other CAR-Ts (OR = 5.38, p = 0.001), and ide-cel (OR = 2.64, p = 0.016). Patient-level factors such as high-risk cytogenetics, extramedullary plasmacytoma, and median age did not significantly influence ORR after adjustment. Notably, high-risk cytogenetics showed a borderline inverse association ( p = 0.075), suggesting a potential trend toward reduced efficacy in this subgroup. These results highlighted that product type, particularly dual-targeting constructs and cilta-cel, was a stronger predictor of treatment response.

Table 4 Univariate and multivariate analysis to evaluate study-level factors that affect the overall response rate Univariate analysis Multivariate analysis Variable Coefficient (95% CI) SE P Coefficient (95% CI) SE P OR (multivar) CAR-T vs. BiTEs • Ciltacel* 1.37 (0.87–1.86) 0.25 < 0.001 2.18 (1.26–3.10) 0.46 < 0.001 8.88 • Idecel* 0.37 (–0.05–0.79) 0.21 0.087 0.96 (0.17–1.76) 0.40 0.0162 2.64 • Dual-targeted CAR-T* 1.78 (0.93–2.64) 0.44 < 0.001 2.72 (1.38–4.07) 0.68 < 0.001 15.31 • Other CAR-T* 0.96 (0.35–1.56) 0.31 0.002 1.68 (0.68–2.68) 0.51 0.001 5.38 Median age (per year) –0.11 (–0.21 – − 0.01) 0.05 0.035 0.06 (–0.02–0.16) 0.05 0.170 1.07 High risk cytogenetics 0.01 (–0.02–0.03) 0.01 0.654 –0.01 (–0.03 to 0.00) 0.01 0.075 0.98 Extramedullary plasmacytoma –0.01 (–0.06–0.03) 0.02 0.521 –0.01 (–0.03–0.02) 0.01 0.467 0.99 Median prior therapies 0.05 (–0.28–0.40) 0.18 0.743 NA NA NA NA Triple-classes refractory –0.01 (–0.03–0.01) 0.01 0.483 NA NA NA NA *Compared to bispecific antibody CAR−T Chimeric antigen receptor T−cell 95% CI 95% confidence interval; OR Odd ratio; SE Standard error

Qualitative data analysis

There has been a lot of interesting data that we could summarize from observational studies in Table S2 . of the supplementary file. Overall, both CAR-T cell therapies and bispecific T-cell engagers (BiTEs) demonstrate promising efficacy across diverse patient populations. The ORR of CAR-T ranged between 69 and 100%, with most studies between 84% − 93%. The ORR percentage of BiTEs ranged between 44% and 66%. Consistent with the number of patients who achieved at least a complete response (CR), which was 42–70% in CAR-T group and 29–44% in BiTEs group. Consistently, CAR-T therapies showed higher and deeper response rates than BiTEs, as reflected in higher ORR and more frequent achievement of complete responses (CRs) in studies directly comparing the two modalities [ 50 , 51 ]. However, these improved outcomes come with a trade-off in toxicity. CRS and ICAN seem to occur more frequently in CAR-T compared to BiTEs. The CRS rate in CAR-T was around 81–96%, while in BiTEs, it was a lower rate of 64–78%. The same trend could be seen for ICAN. The rate of ICAN in BiTEs was around 0–14%, consistently lower than 6–28% in CAR-T. Infection rate from these observational studies showed similarly wide variability in both CAR-T and BiTEs cohorts. As such, BiTEs may represent a more appropriate therapeutic option for patients deemed unfit for CAR-T, particularly due to age or comorbidities. No novel safety signals emerged in real-world settings.

In addition, the ORR of patients with prior BCMA-targeted treatment (e.g. such as CAR-T, BiTEs, antibody-drug conjugated (ADC)) was behind that of patients who were naive to BCMA-targeted treatment. As well as the PFS and OS which were significantly shorter [ 52 , 53 ]. According to Ferreri et al. [ 53 ]., the ORR of the prior BCMA-targeted therapy was 74% compared to 88% ( p = 0.021) in no prior BCMA-targeted therapy. The PFS was only 3.2 months compared to 9 months ( p = 0.0002). Suggested other targeted treatments for a better response. The elderly group did not significantly impact ORR or survival in cohorts focused on the correlation between age and response rate [ 54 , 55 ]. CRS and ICAN are uniformly higher in the elderly group from the study by Kalariya et al. [ 54 ]. Furthermore, patients with prior allogeneic stem cell transplant (all-HCT) who later received CAR-T or BiTEs showed inferior ORR from both treatment modalities compared to the data in patients in clinical studies without a history of allo-HCT.

Discussion

Despite advancements in treatment for relapsed or refractory multiple myeloma during the past decades, multiple myeloma remains incurable [ 56 ]. The majority of multiple myeloma patients eventually faces relapsed or refractory disease due to the development of drug resistance [ 10 ]. This underscores the urgent need for novel therapies that provide deeper and more durable responses. BCMA is identified on the surface of almost all myeloma cells and is more abundantly present in malignant myeloma cells than in normal plasma cells [ 12 ]. Importantly, it is not expressed on naive B cells or other hematopoietic cells, including T cells, macrophages, neutrophils, or other normal tissues [ 12 , 13 ]. This makes BCMA an ideal target antigen for multiple myeloma treatments [ 14 , 15 ]. With the recent approval of several BCMA-targeted therapies, treatment sequencing will be an important consideration [ 20 ]. In this systematic review and meta-analysis, we focused on the efficacy and safety of BCMA-targeted CAR-T and BiTEs due to their high efficacy and were approval as monotherapy for relapsed or refractory multiple myeloma [ 24 , 25 , 57 , 58 ].

Our meta-analysis of 15 interventional studies and 11 real-world observational studies comprising 2,246 patients offered a comprehensive assessment of the efficacy and safety of these BCMA-targeted therapies. The pooled ORR for CAR-T-cell therapies was 84%, with a complete/stringent complete response (CR/sCR) rate of 55%. BiTEs, while offering the benefit of immediate administration and reduced logistical complexity, demonstrated a lower ORR of 65% and a CR/sCR rate of 41%. Building on the strong performance of BCMA-directed CAR-T therapies, dual-target constructs such as those combining BCMA with CD19 or CD38 targets yielded the highest ORR at 92%. These findings suggest a potential advantage in reducing BCMA escape-related relapse and enhancing the durability of response. Although prediction intervals were provided to illustrate between-study heterogeneity and expected variability in future studies, they were not the primary basis for our comparative inferences. Instead, our conclusions were derived from subgroup analyses and meta-regression comparing CAR-T subtypes with BiTEs directly. Our study is among the first to systematically include dual-target CAR-T therapies in a meta-analysis, highlighting their emerging clinical significance.

Studies have shown that achieving MRD (minimal residual disease) negativity is associated with improved progression-free survival (PFS) and overall survival (OS) [ 59 , 60 ]. Among patients who achieved a complete response (CR) or better, the pooled MRD negativity rate was 73%, highlighting the deep responses attainable with both CAR T-cell and BiTEs therapies. All included studies employed standard MRD assessment techniques for multiple myeloma [ 61 ]. However, the specific MRD testing methods and the timing of assessments varied across studies. Future research is needed to determine which treatment modality yields the highest rates of MRD negativity and to establish the optimal timing for MRD evaluation.

Although dual-targeted CAR-T therapies showed excellent efficacy, they came with the highest rate of CRS, followed by BCMA-targeted CAR-T. BiTEs, although, yielded a lower response rate, conveyed the lowest rate of CRS. In contrast to the ICAN rate, which was consistently low in all treatments. Beyond cytokine and neurologic toxicity, infectious complications also emerged as a key differentiating safety feature. Our analysis found a higher incidence of severe infections in patients treated with BiTEs (39%) compared to CAR-T therapies (25% for single-target, 11% for dual-target). This finding aligns with observations from Memorial Sloan Kettering Cancer Center and is likely attributable to the continuous T-cell stimulation and persistent B-cell depletion associated with BiTEs therapy, leading to prolonged hypogammaglobulinemia [ 62 , 63 ]. In contrast, CAR-T-cell therapies are administered as a single infusion, with immune recovery typically occurring within 6 to 12 months [ 64 ]. Moreover, T cell exhaustion by continuously stimulating T cells through these agents can also reduce the ability of T cell-mediated immune response [ 65 ]. The highest chance of infection was BCMA-targeted BiTEs, since BCMA is also expressed on normal mature B-cell and plasma cells, and they lost their capability to generate humoral immunity during treatment with BiTEs. Prophylactic administration of intravenous or subcutaneous immunoglobulin can help correct humoral immune deficiencies and has been linked to a significant reduction in severe infections during anti-BCMA therapy [ 66 – 68 ]. Severe neutropenia and thrombocytopenia were more common among CAR-T recipients (90% and 49%, respectively) compared to BiTEs (52% and 22%).

Both RCTs included in our meta-analysis were determined to be at low risk of bias. The non-randomized interventional studies yielded a mean MINORS score of 13.46 ± 2.02, indicating high methodological quality and a low risk of bias. Similarly, the retrospective observational studies had a mean score of 12.36 ± 0.92, suggesting moderate to high quality.

The meta-regression analysis using a mixed-effect model confirms that Cilta-cel, Dual-targeted CAR-T, Ide-cel, and Other CAR-T products were independently associated with higher odds of response in ORR compared to BiTEs. High-risk cytogenetics showed a borderline association with lower ORR ( p = 0.075), emerging only after adjustment. Age, while significant univariately, lost significance after adjusting for treatment product. Extramedullary plasmacytoma was non-significant in both models. These covariates we analysed in our meta-regression analysis were prespecified due to their degree of association with response rate reported from previous studies, as well as prior meta-analysis related to the field [ 25 , 30 , 46 ]. For instance, baseline extramedullary disease and R-ISS stage III were associated with poor response in more than one studies [ 25 , 40 ]. The depth of remission was associated with the number of prior lines of therapy in Du et al. [ 46 ]. Furthermore, resistance to many prior-exposed drugs in triple-class or penta-drug exposed patients was correlated with poor response in the historical treatment study mentioned [ 10 ].

The inclusion of real-world evidence in our analysis enhanced the generalizability of our findings by capturing a broader patient population, including older individuals and those with comorbidities who are often excluded from clinical trials. The retrospective observational cohorts qualitatively confirmed the efficacy of both CAR-T and BiTEs therapies, with consistently high ORR and CR/sCR rates. Notably, CAR-T therapies continued to demonstrate higher ORR even in real-world settings, mirroring results from interventional trials. However, direct comparisons between real-world studies are limited due to differences in study design, patient characteristics, and response assessment timepoints. Although CAR-T therapies tended to show superior response rates, they were also associated with a higher incidence of cytokine release syndrome (CRS) compared to BiTEs. Importantly, prior exposure to BCMA-targeted agents was associated with reduced ORR and survival outcomes in subsequent therapies, underscoring the need for careful treatment sequencing and patient selection strategies. In particular, patients who previously received antibody-drug conjugates (ADC) exhibited slightly better ORR and longer PFS and OS when treated with BiTEs than those previously treated with CAR-T. While some real-world studies reported subgroup outcomes in elderly patients and those with prior allo-HCT, the small sample sizes and retrospective design limit the ability to draw definitive conclusions. This aligns with the meta-regression findings, where age was inversely associated with ORR in univariate analysis but not in the multivariate model. Further prospective studies are warranted to better evaluate treatment outcomes in these special populations.

While this study offers a comprehensive and timely comparison of BCMA-targeted CAR-T and BiTEs therapies by integrating both interventional and real-world evidence, several limitations should be acknowledged. First, although only interventional studies were included in the meta-analytic synthesis, the inclusion of real-world data significantly enhanced the generalizability of our findings by incorporating broader patient populations, such as older adults and those with comorbidities, often excluded from clinical trials. However, the observational nature and small sample sizes in some real-world cohorts limited the ability to conduct robust subgroup analyses or adjust for potential confounders. Second, we observed substantial heterogeneity across studies, particularly in efficacy and safety outcomes. This heterogeneity was likely multifactorial, arising from variations in study design, population characteristics, CAR-T/BiTEs constructs, and response assessment methods (e.g., timing and MRD techniques). To address this, we used a random-effects model, which was well-suited for accounting for such between-study variability and generating more conservative estimates. Furthermore, we performed sensitivity and subgroup analyses and meta-regression to explore potential sources of heterogeneity. Despite the presence of heterogeneity, the direction and magnitude of treatment effects remained consistent, as confirmed by stability in leave-one-out sensitivity analyses. Therefore, we believe that conducting a meta-analysis was justified and informative for evaluating overall trends while acknowledging inherent variability. Importantly, our meta-regression analyses, while informative in identifying product-level trends (e.g., superior ORR with cilta-cel compared to BiTEs), were based on aggregated study-level data. This approach could not fully account for the complex interplay between patient-specific factors (e.g., comorbidities, disease burden, prior lines of therapy) and the biological heterogeneity inherent to different CAR-T or BiTEs constructs. As a result, potential interaction effects might be masked, and findings should be interpreted with caution when applied to individualized clinical decision-making. The presence of major asymmetry on the Doi plot likely reflected a combination of small-study effects and early-phase cohorts with high response rates. While such studies were clinically meaningful, particularly for establishing safety and early efficacy—the potential for publication or selective reporting bias could not be ruled out. Nonetheless, the pooled ORR remained stable across multiple sensitivity analyses, supporting the reliability of our main conclusion. Third, while our PROSPERO registration included these outcomes, unfortunately, none of the studies eligible for meta-analysis reported QoL outcomes in an extractable format. Similarly, survival outcomes such as OS and PFS were inconsistently reported across studies and were often immature or limited to Kaplan-Meier plots, precluding quantitative synthesis. As a result, we focused our meta-analysis on response rates and safety outcomes, which were consistently available and reportable across studies. Lastly, while this meta-analysis captures the most up-to-date evidence to date, the rapidly evolving nature of BCMA-targeted immunotherapies, along with the emergence of novel constructs and ongoing trials, underscores the need for continuous updates and further head-to-head prospective studies. Despite these limitations, our findings provide valuable insights into the comparative efficacy and safety of current BCMA-directed therapies and serve as a foundation for optimizing treatment sequencing and patient selection in relapsed/refractory multiple myeloma.

This systematic review and meta-analysis provided high-level comparative evidence on the efficacy and safety of BCMA-targeted therapies in relapsed/refractory multiple myeloma. Our quantitative synthesis of interventional trials demonstrated that CAR-T cell therapies, particularly cilta-cel, consistently achieved significantly higher ORR and CR/sCR rates compared to BiTEs. These results remained robust across multiple subgroups and sensitivity analyses, and meta-regression further highlighted product-level differences that might inform treatment selection. BiTEs, in contrast, represented a safer and more accessible alternative due to their off-the-shelf availability, making them especially suitable for patients ineligible for apheresis or prolonged manufacturing timelines. Notably, BiTEs comes with slightly lower efficacy and a higher reported risk of infection. Prior exposure to BCMA-targeted therapies was associated with diminished efficacy of subsequent treatments, underscoring the importance of optimal sequencing strategies. While some real-world studies support these findings in broader patient populations, their retrospective design and small sample sizes limit definitive conclusions. As BCMA-directed immunotherapy continues to evolve, our findings offer a strong evidence base for guiding clinical decisions and prioritizing future research, particularly in the context of head-to-head trials and treatment optimization.

Supplementary Information

Below is the link to the electronic supplementary material. Supplementary Material 1 (DOCX 139 KB)

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Acknowledgements

Thailand Hub of Talents in Cancer Immunotherapy (TTCI).

Author contributions

PT contributed to the study on the conceptualization, data curation, and methodology while also providing key resources and drafting the original manuscript. WR and NM played essential roles in data curation, investigation, and methodology, and AK further supported these efforts by contributing to data curation, investigation, and writing the original draft. AT gave his contribution in data curation. MST contributed to data curation, formal analysis, methodology, software development, resource management, visualization, as well as reviewing and editing the manuscript. NH enhanced the project through contributions to conceptualization, data curation, methodology, project administration, and supervision, along with reviewing and editing the manuscript. PP, serving as the guarantor of the review, contributed to conceptualization, data curation, investigation, methodology, supervision, validation, and the review and editing process. All authors read and approved the final manuscript.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

Funding .

This project is funded by the National Research Council of Thailand (NRCT): High-Potential Research Team Grant Program (N42A680423).

The academic endeavours of Thailand Hub of Talents in Cancer Immunotherapy (TTCI) receive support from the National Research Council of Thailand (N34E670096).

NH and MST were supported by the Second Century Fund (C2F), Chulalongkorn University, Bangkok, Thailand.

Abbreviations

Cochrane Central Register of Controlled Trials

Confidence intervals

Preferred Reporting Items for Systematic review and Meta-analysis Protocols

Randomized controlled trials

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