Real-World Evidence on Infection Risk in Multiple Myeloma Treated with BiTEs and CAR-T cells: A Meta-Analysis

Real-World Evidence on Infection Risk in Multiple Myeloma Treated with BiTEs and CAR-T cells: A Meta-Analysis | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Systematic Review Real-World Evidence on Infection Risk in Multiple Myeloma Treated with BiTEs and CAR-T cells: A Meta-Analysis Federico Spataro, Vanessa Desantis, Giuseppe Dicuonzo, Angelo Vacca, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8549937/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background T-cell-redirecting therapies, including bispecific T-cell engagers (BiTEs) and chimeric antigen receptor T-cell (CAR-T) therapies, have substantially improved outcomes in relapsed or refractory multiple myeloma (RRMM). However, infectious complications remain a major safety concern, particularly in real-world settings, where patients are more heterogeneous than those enrolled in clinical trials. Methods We conducted a systematic review and meta-analysis of real-world retrospective studies evaluating severe (grade 3–4) infections in adult patients with RRMM treated with approved BiTEs or CAR-T cell therapies. Pooled event rates were estimated using random-effects models. Heterogeneity was explored through subgroup analyses, meta-regression, and sensitivity analyses. Results Sixteen studies encompassing 2,097 patients were included. Overall, 24.2% of patients developed grade 3–4 infections (pooled event rate 0.24; 95% CI, 0.21–0.28). Among BiTEs-treated patients (n = 1,602), the pooled severe infection rate was 0.26 (95% CI, 0.23–0.30), with higher rates observed for BCMA-directed BiTEs (0.27) compared with GPRC5D-directed BiTEs (0.25). CAR-T cell therapies (n = 495) were associated with a lower pooled infection rate (0.19; 95% CI, 0.12–0.27). Conclusions In real-world practice, severe infections affect approximately one in four patients receiving T-cell-redirecting therapies for RRMM. Observed differences in infection rates across platforms and targets should be interpreted with caution, as they derive from indirect comparisons in non-randomized, heterogeneous cohorts. Nevertheless, these data support incorporating patient frailty and prior infection history into therapeutic decision-making. CAR-T therapy, or GPRC5D-directed BiTEs when CAR-T is not feasible, may represent reasonable options in patients at higher infectious risk, within an individualized and context-dependent treatment strategy. Hematology multiple myeloma bispecific CAR-T infections Figures Figure 1 Figure 2 Figure 3 1. Introduction Multiple myeloma (MM) is a malignant plasma cell disorder characterized by clonal proliferation within the bone marrow, resulting in end-organ damage and profound immune dysregulation. 1 Infections remain a leading cause of morbidity and mortality in patients with MM, both at diagnosis and throughout the disease course, reflecting disease-related humoral and cellular immune impairment as well as cumulative treatment-related immunosuppression. 2 Although major therapeutic advances, including proteasome inhibitors, immunomodulatory drugs, and monoclonal antibodies, have substantially improved survival, MM remains incurable, and most patients ultimately relapse after multiple lines of therapy. For patients with relapsed or refractory MM (RRMM), T-cell-redirecting immunotherapies have reshaped the therapeutic landscape. In particular, Bi-specific T-cell engager or bispecific antibodies (BiTEs) and chimeric antigen receptor T-cell (CAR-T) therapies have emerged as highly effective approaches capable of inducing deep and durable responses in heavily pretreated populations. 3 , 4 Both platforms harness cytotoxic T-cell activity against malignant plasma cells, most commonly through targeting B-cell maturation antigen (BCMA), although BiTEs may also exploit alternative antigens such as G protein–coupled receptor family C group 5 member D (GPRC5D). Currently, three BiTEs are approved for clinical use in RRMM: teclistamab and elranatamab, both targeting BCMA, and talquetamab, targeting GPRC5D. In parallel, two BCMA-directed CAR-T cell products, idecabtagene vicleucel (idecel) and ciltacabtagene autoleucel (ciltacel), have received regulatory approval and are increasingly incorporated into routine clinical practice. Notably, both BiTEs and CAR-T cells are approved for the same therapeutic indication, namely the treatment of heavily pretreated RRMM, and are therefore used in patients at a comparable stage of disease. At present, no clear evidence-based guidance exists to preferentially select one T-cell–redirecting platform over the other in routine clinical practice, making them functionally alternative strategies within the same therapeutic setting. Pivotal clinical trials have consistently demonstrated high response rates with both BiTEs and CAR-T cell therapies in heavily pretreated RRMM, but at the cost of a clinically meaningful burden of infectious complications. Across registration studies, grade 3–4 infections were reported in approximately 20–45% of patients treated with BCMA-directed BiTEs, 18–26% with GPRC5D-directed BiTEs, and around 20–22% with BCMA-directed CAR-T cell products. 5 – 9 However, these estimates derive from highly selected trial populations with heterogeneous follow-up durations and supportive care strategies, limiting their generalizability to routine clinical practice. The mechanisms underlying infectious susceptibility associated with T-cell-redirecting therapies are multifactorial and largely shared between BiTEs and CAR-T cells, including prolonged hypogammaglobulinemia, B-cell aplasia, T-cell dysfunction, and cumulative immunosuppression from prior treatments. 10 Although BiTEs are administered as continuous therapy and CAR-T cells as a single infusion, both strategies can induce sustained immune perturbations, leading to prolonged vulnerability to infections and limiting direct cross-study comparisons. While infectious complications are well described in prospective clinical trials, these studies enroll highly selected populations and differ substantially in follow-up duration, monitoring intensity, and supportive care strategies. As a result, the true burden of infections in routine clinical practice may not be accurately captured. Although real-world evidence studies on BiTEs and CAR-T therapies are increasingly reported, available data remain heterogeneous and fragmented. Therefore, a robust quantitative synthesis of real-world severe infection rates across T-cell–redirecting therapies in MM is still lacking. To address this unmet need, we conducted a systematic review and meta-analysis of real-world retrospective studies in patients with MM treated with BiTEs and CAR-T cells, aiming to estimate the pooled incidence of grade 3–4 infections and to explore potential sources of heterogeneity among studies. 2. Methods 2.1 Search strategy and selection criteria This systematic review and meta-analysis were performed and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. 11 The study protocol was prospectively registered in the PROSPERO database (registration ID: CRD420251163450). A comprehensive literature search was performed in the MEDLINE and LILACS databases from their inception through November 30th, 2025, to identify studies reporting severe infection outcomes in patients with RRMM treated with BiTEs or CAR-T cell therapies. The detailed search strategy is provided in S-Figure 1. Eligible studies were required to meet the following criteria: (1) retrospective study design; (2) inclusion of adult patients diagnosed with MM who received BiTEs or CAR-T cell therapy; (3) use of BiTEs or CAR-T products approved for clinical use at the time of the search; and (4) availability of data on the incidence of grade 3–4 infections. Studies evaluating investigational or non-approved products, as well as those without sufficient data for outcome extraction, were excluded. No limitations were imposed with respect to language or year of publication. Additionally, reference lists of included articles, their citing publications, and relevant review articles were manually reviewed to identify further eligible studies. Only retrospective studies were considered to enhance methodological consistency and comparability across datasets. At present, the majority of real-world evidence concerning BiTEs and CAR-T cell therapies in MM originates from retrospective analyses; therefore, restricting inclusion to this study design reduced heterogeneity related to study conduct and outcome assessment. 2.2 Data collection process Titles and abstracts were first screened, after which potentially relevant articles underwent full-text evaluation. Data extraction, along with independent appraisal of study quality and risk of bias, was performed by two reviewers (FS and AGS) using the web-based platform Rayyan. 12 Disagreements were resolved through discussion until consensus was reached. For each study meeting the inclusion criteria, information was collected on study design, methodological characteristics, clinical context, eligibility criteria, patient demographics, type of intervention, and reported outcomes. 2.3 Outcomes The main outcome evaluated was the proportion of patients with RRMM who experienced grade 3–4 infectious events (severe infections) while receiving BiTEs or CAR-T cell therapy. 13 As all included studies reported infection occurrences in relation to the total number of treated patients, results were summarized using pooled event rates rather than comparative effect estimates. 2.4 Data analysis and risk of bias assessment All statistical analyses were performed using the MetanalysisOnline software. 14 Statistical significance was defined by a two-sided p-value of less than 0.05. Between-study variability was quantified using the I 2 statistic, which estimates the proportion of total variance attributable to heterogeneity rather than random error. 15 A random-effects model was employed to calculate the pooled incidence of events along with corresponding 95% confidence intervals (CIs). Summary of findings tables were generated using the GRADEpro GDT platform (available at gradepro.org). Study quality was evaluated with the Quality Appraisal of Case Series Studies Checklist developed by the Institute of Health Economics (IHE). Each item was classified as “yes,” “unclear/partial,” or “no,” and studies were considered to have acceptable methodological quality (low to moderate risk of bias) when at least 70% of the criteria were met. 16 Potential publication bias was assessed by visual inspection of funnel plots. 17 The overall certainty of the evidence was rated using the GRADE framework. 18 Meta-regression analyses were undertaken to investigate potential sources of heterogeneity and to assess whether study-level factors were associated with the incidence of severe (grade 3–4) infections. Prespecified moderators included median treatment duration, patient age, sex distribution, prior autologous stem cell transplantation (ASCT), prevalence of extramedullary disease (EMD), high-risk cytogenetic features, International Staging System (ISS) stage I and III, previous exposure to BCMA-directed therapies, and pentarefractory disease status. To preserve statistical robustness and minimize bias related to sparse data, only covariates reported in a sufficient number of studies were included in the meta-regression models. To evaluate the stability of the pooled estimates, a leave-one-out sensitivity analysis was performed by sequentially excluding each study. Between-study heterogeneity was additionally examined using the chi-square (χ²) test and summarized using the I 2 statistic. 19 3. Results 3.1 Study selection The bibliographic searches yielded 182 records. After the initial screening and triage process, 16 articles met the inclusion criteria and were included in the meta-analysis (S-Figure 1). 3.2 Quality assessment and risk of bias The overall quality for all outcomes was deemed acceptable (low risk of bias) in most studies. All 16 studies (100%) reported ≥ 70% “yes” responses according to the critical appraisal tool adopted (S-Table 1). The overall certainty of the evidence for the severe infection rate outcome was judged to be low both for BiTEs and CAR-T (S-Table 2). 3.3 Studies’ and patients’ characteristics Table 1 summarizes the 16 studies’ characteristics included in the analysis. All studies had a retrospective design, and 13 were multicenter. Table 1 Studies’ characteristics at baseline. study, year study type treatment patients at baseline, n° treatment duration, months (median) Mohan, 2024 R, MC teclistamab 110 3.5 Riedhammer, 2024 R, MC teclistamab 123 6 Al Hadidi, 2025 R, MC talquetamab 114 6 Cani, 2025 R, SC BiTEs 158 5.5 Frenking, 2025 R, MC talquetamab 138 7.8 Mian, 2025 R, MC teclistamab 81 13.1 Razzo, 2025 R, MC teclistamab 509 10.1 Sheu, 2025 R, SC teclistamab 44 6.7 Stork, 2025 R, MC teclistamab 73 4.9 Tan, 2025 R, MC teclistamab 210 5.3 Yi, 2025 R, MC teclistamab 42 16.4 Logue, 2022 R, MC ide-cel 52 3 Rejeski, 2023 R, MC BCMA directed CAR-T 113 7.9 Dima, 2024 R, MC idecel 69 10 Trando, 2024 R, SC idecel 25 6 Sidana, 2025 R, MC ciltacel 236 13 total 2,097 8.3 * MC, multicenter; R, retrospective; SC, single center, * Value represents the weighted mean of the medians reported in individual studies, weighted by the number of patients in each trial. As concerns BiTEs treatment, 8 studies reported data on patients treated with teclistamab, and two focused on talquetamab. 20 – 29 No retrospective studies evaluating elranatamab were identified. The study by Cani et al., 30 provided separate outcomes for patients treated with BCMA-targeting BiTEs (teclistamab and elranatamab; hereafter referred to as “Cani BCMA”) and for those receiving GPRC5D-targeting BiTEs (hereafter referred to as “Cani GPRC5D”). This stratification allowed inclusion of both cohorts in the subsequent subgroup analyses. For CAR-T therapy, three studies reported data on patients treated with idecel, one study on ciltacel and one study with BCMA directed CAR-T not providing the specific data on single medications. 31 – 35 The duration of treatment varied across the studies, ranging from a median of 3 to 16.4 months, with a weighted median duration of 8.3 months. Overall, the baseline patient population included 2,097 individuals (females, 44.2%), with a mean age of 66.3 years (Table 2 ). The sample size of the studies varied, ranging from 25 patients to 509 patients. Table 2 Patient’s characteristics at baseline. study, year n° patients age, mean female, n° (%) n° previous line of treatment, mean previous ASCT, % EMD, % high cytogenetic risk, % ISS III, % ISS I, % BCMA exposed, % pentarefractory, % Mohan, 2024 110 67.5 54 (49) 6.2 87 44 62* n.a. n.a. 35 76 Riedhammer, 2024 123 66.4 53 (43.1) 6.2 n.a. 36.1* 36.8* 33.7* 27.1* 37.4 60.2 Al Hadidi, 2025 114 66.5 50 (44) 6.3 81.6 34* 70* n.a. n.a. 64.9 78.9 Cani, 2025 158 65.5 n.a. 5.8 81 n.a. n.a. n.a. n.a. 41 n.a. Frenking, 2025 138 63.1 42 (30) 6.2 86 48* 48* 43* 30* 51 47* Mian, 2025 81 76.6 33 (40.7) 6.7 n.a. 38.7* 56.9* 32* 28* 38.3 46* Razzo, 2025 509 67.8 234 (46) 6.1 65.5* # 44.7* 54 n.a. n.a. 46.4 38* Sheu, 2025 44 67.8 20 (45.5) 6.9 6.8 n.a. 50 n.a. n.a. 45.5 n.a. Stork, 2025 73 66.1 37 (50.7) 5.3 n.a. 24.7 44* 26 30.1 12.3 68.5 Tan, 2025 210 66.7 93 (44.3) 6.3 n.a. 29.4* 50* 30.6* 37.9* 43.8 44.1* Yi, 2025 42 66.8 15 (35.7) 6.1 86 28.6 42.9 40.5 21.4 7.1 19 Logue, 2022 52 65.0 29 (56) 6.4 81 62 40 n.a. n.a. 10 44 Rejeski, 2023 113 64.2 48 (42) 5.9 88 45.1 29.5* n.a. n.a. 13* 42.5 Dima, 2024 69 63.4 35 (51) 6.5 n.a. 52 40* n.a. n.a. 26 48 Trando, 2024 25 64.9 13 (52) 6.5 100 40 48 n.a. n.a. 16 88 Sidana, 2025 236 63.0 102 (43) 6.0 85 25.5* 40.7* n.a. n.a. 14 30 total 2,097 66.3 858 (44.2) 6.1 77.4 § 39.2 § 48.8 § 34.3 § 30.5 § 37.0 § 47.1 § ​​n.a., not available. # This value includes both autologous SCT and allogeneic STC. * Percentage is calculated based on the total of patients assessed for that clinical manifestation. § The denominator does not include patients that were not assessed for that clinical manifestation. The overall mean number of prior lines of therapy across studies was 6.1. The pooled proportion of patients who had previously undergone autologous stem cell transplantation was 77.4%, while 39.2% presented with extramedullary disease. The prevalence of high-risk cytogenetic abnormalities was 48.8%, and 34.3% of patients were classified as ISS stage III (30.5% of patients were ISS stage I). Prior exposure to BCMA-directed therapy was observed in 37% of patients, and 47.1% were classified as pentarefractory (Table 2 ). 3.4 Severe infection rate A total of 505 patients (24.2%) experienced grade 3–4 infections after a weighted median follow-up of 8.3 months, corresponding to a pooled event rate of 0.24 (95% CI, 0.21–0.28) as shown in Fig. 1 , meaning that 24% of patients developed severe infections during treatment. HIgh heterogeneity was observed (Tau²=0.0042; Chi²=46.26, df = 15, p < 0.0001; I ²=67.6%). BiTEs group included a total of 1,602 patients, with a pooled event rate of 0.26 (95% CI, 0.23–0.30). Heterogeneity was moderate (Tau²=0.0019; Chi²= 20.26; df = 10; p = 0.0269; I ²=50.6%). Given the moderate heterogeneity across the included studies, a meta-regression analysis was conducted. It revealed a counterintuitive and significant association between the rate of severe infections and the mean number of the proportion of patients previously exposed to BCMA-targeted therapy (p = 0.047), as shown in S-Figure 2. Studies including patients with a greater number of patients exposed to prior BCMA therapy reported lower rates of severe infections. Indeed, when outlier studies were excluded from the pooled analysis, heterogeneity markedly decreased to 12.5%, with a pooled event rate of 0.24 (95% CI, 0.22–0.26) as shown in S-Figure 3. Within the BiTEs cohort, a predefined subgroup analysis was performed according to the targeted antigen, distinguishing between BCMA-directed BiTEs and GPRC5D-directed BiTEs (Fig. 2 ). In the subgroup of patients treated with BCMA BiTEs, comprising 1,293 patients, the pooled proportion of grade 3–4 infections was 0.27 (95% CI, 0.23–0.31). Moderate heterogeneity was observed across studies (Tau²=0.0027; Chi²=18.83, df = 8; p = 0.0158; I² =57.5%). In contrast, the subgroup of patients treated with GPRC5D BiTEs included 309 patients and showed a pooled event rate of 0.25 (95% CI, 0.20–0.30). No significant heterogeneity was detected in this subgroup (Tau²=0; Chi²=1.28, df = 2; p = 0.5274; I² =0%). Studies assessing CAR-T comprised 495 patients, showing a pooled event rate of 0.19 (95% CI, 0.12–0.27) with high heterogeneity (Tau²=0.0071; Chi²=13.75, df = 4, p = 0.0081; I ²=70.9%). Given the substantial heterogeneity observed among studies evaluating CAR-T cell therapies, meta-regression analyses were performed to explore potential sources of between-study variability using the predefined moderators. However, none of the evaluated study-level covariates showed a statistically significant association with the proportion of severe infections. Subsequently, a leave-one-out sensitivity analysis was conducted to assess the robustness of the pooled estimate and to identify influential studies. This analysis revealed that exclusion of a single outlier study (Sidana 2025) markedly reduced heterogeneity, with the I² statistic decreasing to 26.9%, indicating low residual heterogeneity. Under this condition, the pooled event rate increased to 0.22 (95% CI, 0.16–0.29), as shown in S-Figure 3. 3.5 Other BiTEs-related adverse events Across all the included studies, the overall incidence of cytokine release syndrome (CRS) of any grade was 57.5%, while immune effector cell-associated neurotoxicity syndrome (ICANS) occurred in 11.6% of patients. The pooled overall response rate (ORR) was 67.8%, and immunoglobulin supplementation was reported in 48.4% of cases. Unfortunately, not all studies reported data for every variable (S-Table 3). 4. Discussion T-cell-redirecting immunotherapies represent one of the most transformative advances in the management of RRMM. Both BiTEs and CAR-T therapies have demonstrated unprecedented efficacy in heavily pretreated patients and are currently approved for the same therapeutic indication, namely advanced RRMM. As their use increasingly extends beyond clinical trials into routine clinical practice, a comprehensive understanding of their safety profile, particularly the risk of severe infections, has become critically important. Infectious complications remain a major determinant of morbidity, treatment discontinuation, and mortality in MM, arising from a complex interplay between disease-related immune dysfunction, cumulative treatment exposure, and therapy-induced immunosuppression. In this context, the present systematic review and meta-analysis provides the first quantitative synthesis focused exclusively on real-world retrospective studies evaluating severe infections across both approved BiTEs and CAR-T cell therapies in MM. By deliberately including both platforms, this analysis reflects contemporary clinical practice, where BiTEs and CAR-T cells are used in patients at a comparable stage of disease and currently represent alternative therapeutic strategies rather than sequentially mandated options. Across 16 retrospective cohorts including 2,097 patients, approximately one in four individuals (24%) experienced a severe infection during treatment, confirming that infectious toxicity remains a clinically meaningful and shared complication of T-cell-redirecting therapies in real-world settings. When stratified by therapeutic platform, patients treated with BiTEs showed a pooled severe infection rate of 26%, whereas those receiving CAR-T cell therapy exhibited a lower pooled rate of 19%, which further decreased to 22% after exclusion of a single influential outlier study. These findings suggest that, although both platforms confer substantial infectious risk, CAR-T therapy may be associated with a comparatively more favorable infectious safety profile in routine practice. Within the BiTEs cohort, subgroup analyses revealed important antigen-specific differences. BCMA-directed BiTEs were associated with a slightly higher pooled rate of severe infections (27%) compared with GPRC5D-directed BiTEs (25%), with the latter showing no detectable between-study heterogeneity. Although these differences are numerically modest, their consistency across analyses and alignment with published literature suggest that target antigen selection may contribute to differential immune perturbation and infectious vulnerability. The higher infection burden observed with BCMA-directed strategies may reflect deeper and more sustained plasma cell depletion, prolonged hypogammaglobulinemia, and cumulative immune exhaustion, particularly in patients previously exposed to BCMA-targeted therapies. Importantly, the heterogeneity observed in the BiTEs analysis was partially explained by meta-regression, which revealed a counterintuitive inverse association between severe infection rates and both prior BCMA exposure and number of previous treatment lines. This counterintuitive finding is most plausibly explained by clinical selection bias inherent to real-world practice and should not be interpreted as evidence of a biologically protective effect of prior BCMA exposure. In retrospective settings, clinicians may preferentially select fitter patients with preserved immune reserve for BiTEs therapy in later lines, resulting in cohorts that are more resilient despite heavier pretreatment. In contrast to clinical trials, clinicians may preferentially select fitter patients with preserved immune reserve for BiTE therapy, especially in later lines of treatment. As a result, cohorts with heavier pretreatment may paradoxically represent more resilient patients, leading to lower observed infection rates. A similar phenomenon has been reported in retrospective analyses of CAR-T therapies and underscores the challenges of interpreting observational safety data in the absence of randomized allocation. For CAR-T therapies, high heterogeneity was initially observed, but no predefined study-level moderators were significantly associated with infection risk. Sensitivity analysis identified a single outlier study whose exclusion substantially reduced heterogeneity and yielded a pooled infection rate comparable to, yet still lower than, that observed with BiTEs. These findings support the robustness of the CAR-T estimate and suggest that, despite differences in manufacturing, delivery, and kinetics, CAR-T cell therapy may induce a more temporally confined period of immunosuppression compared with the continuous immune engagement associated with BiTEs. To contextualize these results within the existing literature, we systematically compared our findings with all previously published meta-analyses addressing severe infections in patients treated with BiTEs and/or CAR-T cells (Table 3 ). 36 – 41 Notably, most prior analyses included clinical trials, investigational products, or mixed study designs, whereas the present study exclusively focused on approved therapies in real-world settings. Across studies, reported severe infection rates for BiTEs ranged from 21% to 39%, while CAR-T-associated rates ranged from 17% to 25%. Our estimates fall within this spectrum and reinforce the notion that, among approved therapies, BCMA BiTEs are associated with slightly higher rates of severe infections compared with GPRC5D BiTEs, and CAR-T therapies appear overall safer with respect to infectious toxicity. In all scenarios, appropriate vaccination strategies are recommended, while immunoglobulin replacement treatment (IgRT) could be taken in consideration for the frailest group. Table 3 Comparison between meta-analysis on severe infection rate. current study Reynolds et al. Wang et al. Li et al. Bakogeorgou et al Techaapornkun et al. Vandenboom et al. type of studies included real-life trials trials trials, real-life trials real-life trials also includes investigational BiTEs or CAR-T, Y/N N Y Y N Y Y Y BCMA BiTEs severe infection rate 27% n.a. 25% 50%*; 24% Ψ n.a. n.a. n.a. non-BCMA BiTEs severe infection rate 25% n.a. 20% n.a. n.a. n.a. n.a. GPR5CD BiTEs severe infection rate 25% n.a. n.a. n.a. n.a. n.a. n.a. overall BiTEs severe infection rate 26% 21% 22% 50%*; 24% Ψ 29% 39% 30% CAR-T severe infection rate 17% n.a. n.a. n.a. n.a. 25% 17% N, not; Y, yes. *clinical trials. Ψ real-life studies. Taken together, both our real-world data and the broader meta-analytic literature support a clinically meaningful gradient of infectious risk across T-cell-redirecting strategies. However, these observations arise from indirect comparisons across heterogeneous retrospective cohorts and should therefore be interpreted with appropriate caution. On this basis, and in the absence of definitive comparative efficacy or safety data favoring one platform over another, we propose a pragmatic, infection-oriented conceptual framework to support therapeutic decision-making in routine clinical practice (Fig. 3 ). In patients who are clinically fit and have no significant history of severe or recurrent infections, either BiTEs or CAR-T therapy may represent reasonable treatment options, with the final choice guided by availability, logistical considerations, and physician experience. Conversely, in patients who are frail, immunologically vulnerable, or have a documented history of severe or recurrent infections, CAR-T therapy may be preferentially considered when feasible, given its numerically lower pooled rate of severe infections observed in real-world settings. When CAR-T therapy is not available or contraindicated, GPRC5D-directed BiTEs may represent a potentially safer alternative compared with BCMA-directed BiTEs, although this distinction should not be interpreted as evidence of superiority. Importantly, the decision framework proposed in this study should be interpreted as a conceptual and pragmatic aid rather than as a prescriptive or hierarchical algorithm. The comparisons presented herein are inherently indirect and derive from heterogeneous real-world retrospective cohorts, characterized by variable follow-up durations, non-randomized patient selection, and differences in supportive care practices. Consequently, the observed differences in severe infection rates across BiTEs and CAR-T therapies should not be construed as definitive comparative safety signals. Rather, this framework is intended to support, rather than replace, clinical judgment, existing guidelines, and individualized patient assessment. Several limitations of this meta-analysis warrant consideration. All included studies were retrospective, introducing inherent risks of selection bias, incomplete reporting, and heterogeneity in infection definitions, monitoring intensity, and supportive care strategies. Data on antimicrobial prophylaxis, vaccination status, and immunoglobulin replacement were inconsistently reported, despite their known impact on infection risk. Moreover, real-world data on elranatamab were not available at the time of analysis, limiting generalizability to all approved BiTEs. Finally, the overall certainty of evidence was graded as low, reflecting the observational nature of the available data. Despite these limitations, this study provides the most comprehensive real-world assessment to date of severe infections associated with approved T-cell-redirecting therapies in MM. The findings emphasize that severe infections remain frequent, affecting approximately one quarter of patients, and that meaningful differences exist across therapeutic platforms and targets. These results underscore the need for structured infection prevention strategies, including immunoglobulin replacement, antimicrobial prophylaxis, and optimized vaccination programs, particularly for high-risk patients. 43 Future prospective registries and harmonized real-world pharmacovigilance initiatives are urgently needed to refine risk stratification, validate comparative safety signals, and optimize patient selection. Ultimately, integrating efficacy, safety, patient frailty, and infection history into therapeutic decision-making will be essential to maximize the benefits of T-cell-redirecting immunotherapies while minimizing their infectious burden in RRMM. 5. Conclusion This real-world meta-analysis demonstrates that severe infections remain a frequent and clinically relevant complication of T-cell-redirecting therapies in RRMM, affecting approximately one in four treated patients. Both BiTEs and CAR-T cell therapies are associated with a substantial infectious burden, highlighting the need for careful risk assessment in routine clinical practice. Although differences in pooled infection rates were observed across therapeutic platforms and targets, these findings derive from indirect comparisons and should be interpreted with caution. BCMA-directed BiTEs were associated with numerically higher rates of severe infections compared with GPRC5D-directed BiTEs, while CAR-T therapies showed lower pooled infection rates in this real-world analysis, without implying formal superiority. In the absence of randomized comparative data, infectious risk should be considered alongside efficacy, patient frailty, prior treatment exposure, and logistical feasibility when selecting T-cell-redirecting therapies. Tailored preventive strategies and prospective real-world surveillance are essential to optimize the safety and long-term benefit of these treatments in MM. Declarations Competing interests : Authors declare no competing interests. Data Sharing Statement For original data, please contact [email protected] Competing interest: authors declare no competing interests. Ethics approval and consent to participate: not applicable. Consent for publication: not applicable. Author contributions: F.S. and A.G.S. conceived the project; F.S. and A.G.S. designed the analyses; F.S., V.D. and G.D. acquired data; F.S. and G.D. verified the raw data before analyses and performed pre-processing informatic analysis; F.S. and A.G.S. performed the informatic analysis and interpreted data; F.S., V.D., A.G.S. contributed with scientific discussions; F.S. and A.G.S. wrote the manuscript, which has been revised and approved by all the authors. Acknowledgement and funding : “Fondo per il Programma Nazionale di Ricerca e Progetti di Rilevante Interesse Nazionale—PRIN” (project n. 2022ZKKWLW) to A.G.S.; by the Italian network of excellence for advanced diagnosis (INNOVA), Ministero della Salute (code PNC-E3-2022-23683266 PNC-HLS-DA) to V.D. and A.G.S.; Complementary National Plan PNC-I.1 "Research initiatives for innovative technologies and pathways in the health and welfare sector” D.D. 931 of 06/06/2022, DARE - DigitAl lifelong pRevEntion initiative (code PNC0000002) to A.V. and R.R.; PNRR-MCNT1-2023-12377893 DEMMO- “Deciphering multiple myeloma using multiomic approaches for immunotherapy modeling“ (CUP: H93C23001080006) to V.D. and A.G.S. Data availability statement: Data will be provided by the author upon reasonable request. References Kyle RA, Rajkumar SV (2008) Multiple myeloma. 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Front Oncol 13:1098326 Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD et al (2021) The PRISMA 2020 statement: an updated guideline for reporting systematic reviews BMJ Ouzzani M, Hammady H, Fedorowicz Z et al (2016) Rayyan—a web and mobile app for systematic reviews. Syst Rev 5:210 Freites-Martinez A, Santana N, Arias-Santiago S, Viera A (2021) Using the Common Terminology Criteria for Adverse Events (CTCAE - Version 5.0) to Evaluate the Severity of Adverse Events of Anticancer Therapies. Actas Dermosifiliogr (Engl Ed) 112:90–92 Fekete JT, Gyorffy B (2025) MetaAnalysisOnline.com: an Online Tool for the Rapid Meta-Analysis of Clinical and Epidemiological Studies. J Med Internet Res Wang Y, DelRocco N, Lin L (2024) Comparisons of various estimates of the I2 statistic for quantifying between-study heterogeneity in meta-analysis. Stat Methods Med Res 33:745–764 Moga C, Guo B, Schopflocher D et al (2012) Development of a Quality Appraisal Tool for Case Series Studies Using a Modified Delphi Technique. Institute of Health Economics Egger M, Davey Smith G, Schneider M et al (1997) Bias in meta-analysis detected by a simple, graphical test. BMJ 315(7109):629–634 Schunemann H, Brożek J, Guyatt G et al (2013) GRADE Handbook. Grading of Recommendations Assessment, Development and Evaluation. GRADE Working Group Higgins JPT, Thompson SG (2002) Quantifying heterogeneity in a meta-analysis. Stat Med 21:1539–1558 Mohan M, Monge J, Shah N et al (2024) Teclistamab in relapsed refractory multiple myeloma: multi-institutional real-world study. Blood Cancer J 14:35 Riedhammer C, Bassermann F, Besemer B, Bewarder M, Brunner F, Carpinteiro A, Einsele H, Faltin J, Frenking J, Gezer D, Goldman-Mazur S et al (2024) Real-world analysis of teclistamab in 123 RRMM patients from Germany. Leukemia 38:365–371 Al Hadidi S, Szabo A, Mohan Lal B et al (2025) Talquetamab in relapsed refractory multiple myeloma: multi-institutional real-world study. Blood Cancer J 15:196 Frenking JH, Riedhammer C, Teipel R et al (2025) A German multicenter real-world analysis of talquetamab in 138 patients with relapsed/refractory multiple myeloma. Hemasphere 9:e70114 Mian H, Martin TG, Pond GR et al (2025) Outcomes of frailty subgroups of older adults (age ≥ 70) treated with teclistamab: an International Myeloma Foundation immunotherapy database real-world analysis. Leukemia 39:1252–1255 Razzo BM, Midha S, Portuguese AJ et al (2025) Real-World Experience with Teclistamab for Relapsed/ Refractory Multiple Myeloma from the U.S. Myeloma Immunotherapy Consortium. Blood Cancer Discov. Jul 9 Sheu M, Molina Garcia S, Patel M et al (2025 Oct) Infection Prophylaxis with Intravenous Immunoglobulin in Multiple Myeloma Patients Treated with Teclistamab. Oncology 23:1–5 Stork M, Radocha J, Mihalyova J et al (2025) De-escalated Teclistamab dosing in relapsed/refractory multiple myeloma: Czech myeloma group real-world evidence analysis. Ann Hematol 104:4141–4147 Tan CR, Asoori S, Huang CY et al (2025) Real-world evaluation of teclistamab for the treatment of relapsed/refractory multiple myeloma (RRMM): an International Myeloma Working Group Study. Blood Cancer J 15:53 Yi JH, Lee JH, Jung SH et al (2025) Real-World Efficacy and Safety of Teclistamab for Patients with Relapsed or Refractory Multiple Myeloma: Nationwide Retrospective Analysis of the Named Patient Program in Korea. Cancer Res Treat. Jul 30 Cani L, Scott SA, Roberts D et al (2025) Infection risk in 158 patients with relapsed/refractory multiple myeloma treated with bispecific antibodies: a single-center experience. Haematologica. Sep 4 Logue JM, Peres LC, Hashmi H, Colin-Leitzinger CM et al (2022) Early cytopenias and infections after standard of care idecabtagene vicleucel in relapsed or refractory multiple myeloma. Blood Adv 6:6109–6119 Rejeski K, Hansen DK, Bansal R et al (2023) The CAR-HEMATOTOX score as a prognostic model of toxicity and response in patients receiving BCMA-directed CAR-T for relapsed/refractory multiple myeloma. J Hematol Oncol 16:88 Dima D, Rashid A, Davis JA et al (2024) Efficacy and safety of idecabtagene vicleucel in patients with relapsed-refractory multiple myeloma not meeting the KarMMa-1 trial eligibility criteria: A real-world multicentre study. Br J Haematol 204(4):1293–1299 Trando A, Ghamsari F, Yeung P, Costello C, Saunders I, Jeong AR (2024) Outcomes of Idecabtagene Vicleucel Therapy in Patients with Relapsed/Refractory Multiple Myeloma: A Single-Institution Experience. Biomedicines 13:36 Sidana S, Patel KK, Peres LC et al (2025) Safety and efficacy of standard-of-care ciltacabtagene autoleucel for relapsed/refractory multiple myeloma. Blood 145:85–97 Reynolds G, Cliff ERS, Mohyuddin GR et al (2023) Infections following bispecific antibodies in myeloma: a systematic review and meta-analysis. Blood Adv 7:5898–5903 Wang X, Zhao A, Zhu J et al (2024) Efficacy and safety of bispecific antibodies therapy for relapsed or refractory multiple myeloma: a systematic review and meta-analysis of prospective clinical trials. Front Immunol 15:1348955 Li W, Zhao D, Jiao Y et al (2025) Effectiveness and safety of teclistamab for relapsed or refractory multiple myeloma: a systematic review and meta-analysis. Front Immunol 16:1565407 Bakogeorgou S, Filippatos C, Malandrakis P et al (2025) Safety and Efficacy of Bispecific Antibody Treatment in Relapsed/Refractory Multiple Myeloma: A Systematic Review and Meta-Analysis of Proportions from Clinical Trials. Cancers (Basel) 17:2727 Techaapornkun P, Rojpalakorn W, Mejun N et al (2025) 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. Ann Hematol 104:4791–4809 Vandenboom H, Akhtar O, Szabo A et al (2025) Safety and efficacy of BCMA CAR-T vs. bispecific antibodies in patients with relapsed multiple myeloma: a systematic review and meta-analysis. Haematologica. Aug 14 Palumbo A, Bringhen S, Mateos MV et al (2015) Geriatric assessment predicts survival and toxicities in elderly myeloma patients: an International Myeloma Working Group report. Blood 125:2068–2074 Desantis V, Borrelli P, Panebianco T et al (2024) Comprehensive analysis of clinical outcomes, infectious complications and microbiological data in newly diagnosed multiple myeloma patients: a retrospective observational study of 92 subjects. Clin Exp Med 24:137 Additional Declarations The authors declare no competing interests. Supplementary Files Supplementary.docx Supplementary Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8549937","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Systematic Review","associatedPublications":[],"authors":[{"id":571389254,"identity":"dc05235d-ebc7-4808-b207-10818fd67255","order_by":0,"name":"Federico Spataro","email":"","orcid":"","institution":"University of Bari Aldo Moro","correspondingAuthor":false,"prefix":"","firstName":"Federico","middleName":"","lastName":"Spataro","suffix":""},{"id":571390332,"identity":"59192c17-c6a1-4342-bbba-cb4923ae27e3","order_by":1,"name":"Vanessa Desantis","email":"","orcid":"","institution":"University of Bari Aldo 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07:12:45","extension":"xml","order_by":2,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":130995,"visible":true,"origin":"","legend":"","description":"","filename":"rs85499370enriched.xml","url":"https://assets-eu.researchsquare.com/files/rs-8549937/v1/7d012aad8c9b9c8f143f0822.xml"},{"id":100017855,"identity":"ffb39297-6973-47cf-bc0d-322d94cb0af4","added_by":"auto","created_at":"2026-01-12 07:12:45","extension":"xml","order_by":3,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":128194,"visible":true,"origin":"","legend":"","description":"","filename":"rs85499370structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-8549937/v1/9ca24b84ba9734a1562899ea.xml"},{"id":100017850,"identity":"df3af140-87cc-4188-90a5-81898c0ae66e","added_by":"auto","created_at":"2026-01-12 07:12:45","extension":"html","order_by":4,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":139283,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-8549937/v1/30db74f0b5e16a63e6f794c2.html"},{"id":100017851,"identity":"6d20043a-c959-4843-a585-c7b1547953de","added_by":"auto","created_at":"2026-01-12 07:12:45","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":167336,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ePooled incidence of grade 3-4 infections in patients with multiple myeloma treated with T-cell-redirecting therapies.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eForest plot of pooled event rates of grade 3-4 infections across included real-world studies in patients with multiple myeloma treated with BiTEs and CAR-T cell therapies. Effect estimates are expressed as pooled proportions with corresponding 95% confidence intervals (CIs) using a random-effects model.\u003c/p\u003e","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8549937/v1/3a2b6eb1d5a167602988a33d.jpg"},{"id":100362618,"identity":"02116a6e-ed88-420d-a574-cc0d2f301216","added_by":"auto","created_at":"2026-01-16 07:47:39","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":162793,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSubgroup meta-analysis of grade 3-4 infections according to target antigen in BiTEs-treated multiple myeloma patients.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eForest plot showing pooled event rates of grade 3-4 infections in patients with multiple myeloma treated with BiTEs, stratified by target antigen (BCMA-directed \u003cem\u003evs\u003c/em\u003e GPRC5D-directed). Effect estimates are expressed as pooled proportions with corresponding 95% confidence intervals (CIs) using a random-effects model.\u003c/p\u003e","description":"","filename":"Figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8549937/v1/34a0d31681c93c16e2793bea.jpg"},{"id":100362311,"identity":"39b158c2-3144-436b-a619-3027bf363b76","added_by":"auto","created_at":"2026-01-16 07:46:33","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":68009,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eProposed conceptual framework for interpreting infectious risk across T-cell-redirecting therapies in relapsed or refractory multiple myeloma.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis figure illustrates a pragmatic and conceptual framework integrating real-world infection risk to support treatment selection between BiTEs and CAR-T cell therapies in patients with relapsed or refractory multiple myeloma (R/R MM). Assessment of patient frailty and prior history of severe or recurrent infections represents the first step in the decision-making process. In patients who are clinically fit and without a history of significant infectious complications, either T-cell-redirecting strategy may be considered appropriate, based on availability and clinical judgment. Conversely, in frail patients or in those with a documented history of severe or recurrent infections, CAR-T cell therapy may be preferentially considered when feasible. When CAR-T therapy is not available or not suitable, GPRC5D-directed BiTEs may represent a potentially safer alternative compared with BCMA-directed BiTEs. In all scenarios, appropriate vaccination strategies are recommended, while immunoglobulin replacement treatment (IgRT) could be taken in consideration for the frailest group.\u003c/p\u003e\n\u003cp\u003eR/R MM, relapsed or refractory multiple myeloma.\u003c/p\u003e\n\u003cp\u003eIgRT, immunoglobulin replacement treatment.\u003c/p\u003e","description":"","filename":"Figure3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8549937/v1/c7bee89e80cbac22c44385e2.jpg"},{"id":100381349,"identity":"0a737b60-0f5e-42bc-86cc-9b848745f646","added_by":"auto","created_at":"2026-01-16 10:38:28","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1700226,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8549937/v1/6559d4c9-ea1d-473a-82d6-27bd07cb626e.pdf"},{"id":100017854,"identity":"4b6bcdce-6e0e-4b76-b628-b488c8240138","added_by":"auto","created_at":"2026-01-12 07:12:45","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":6130266,"visible":true,"origin":"","legend":"\u003cp\u003eSupplementary\u003c/p\u003e","description":"","filename":"Supplementary.docx","url":"https://assets-eu.researchsquare.com/files/rs-8549937/v1/ad76a149ed8c111298583533.docx"}],"financialInterests":"The authors declare no competing interests.","formattedTitle":"\u003cp\u003eReal-World Evidence on Infection Risk in Multiple Myeloma Treated with BiTEs and CAR-T cells: A Meta-Analysis\u003c/p\u003e","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eMultiple myeloma (MM) is a malignant plasma cell disorder characterized by clonal proliferation within the bone marrow, resulting in end-organ damage and profound immune dysregulation.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e Infections remain a leading cause of morbidity and mortality in patients with MM, both at diagnosis and throughout the disease course, reflecting disease-related humoral and cellular immune impairment as well as cumulative treatment-related immunosuppression.\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e Although major therapeutic advances, including proteasome inhibitors, immunomodulatory drugs, and monoclonal antibodies, have substantially improved survival, MM remains incurable, and most patients ultimately relapse after multiple lines of therapy.\u003c/p\u003e \u003cp\u003eFor patients with relapsed or refractory MM (RRMM), T-cell-redirecting immunotherapies have reshaped the therapeutic landscape. In particular, Bi-specific T-cell engager or bispecific antibodies (BiTEs) and chimeric antigen receptor T-cell (CAR-T) therapies have emerged as highly effective approaches capable of inducing deep and durable responses in heavily pretreated populations.\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e,\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e Both platforms harness cytotoxic T-cell activity against malignant plasma cells, most commonly through targeting B-cell maturation antigen (BCMA), although BiTEs may also exploit alternative antigens such as G protein\u0026ndash;coupled receptor family C group 5 member D (GPRC5D).\u003c/p\u003e \u003cp\u003eCurrently, three BiTEs are approved for clinical use in RRMM: teclistamab and elranatamab, both targeting BCMA, and talquetamab, targeting GPRC5D. In parallel, two BCMA-directed CAR-T cell products, idecabtagene vicleucel (idecel) and ciltacabtagene autoleucel (ciltacel), have received regulatory approval and are increasingly incorporated into routine clinical practice. Notably, both BiTEs and CAR-T cells are approved for the same therapeutic indication, namely the treatment of heavily pretreated RRMM, and are therefore used in patients at a comparable stage of disease. At present, no clear evidence-based guidance exists to preferentially select one T-cell\u0026ndash;redirecting platform over the other in routine clinical practice, making them functionally alternative strategies within the same therapeutic setting.\u003c/p\u003e \u003cp\u003ePivotal clinical trials have consistently demonstrated high response rates with both BiTEs and CAR-T cell therapies in heavily pretreated RRMM, but at the cost of a clinically meaningful burden of infectious complications. Across registration studies, grade 3\u0026ndash;4 infections were reported in approximately 20\u0026ndash;45% of patients treated with BCMA-directed BiTEs, 18\u0026ndash;26% with GPRC5D-directed BiTEs, and around 20\u0026ndash;22% with BCMA-directed CAR-T cell products.\u003csup\u003e\u003cspan additionalcitationids=\"CR6 CR7 CR8\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e However, these estimates derive from highly selected trial populations with heterogeneous follow-up durations and supportive care strategies, limiting their generalizability to routine clinical practice.\u003c/p\u003e \u003cp\u003eThe mechanisms underlying infectious susceptibility associated with T-cell-redirecting therapies are multifactorial and largely shared between BiTEs and CAR-T cells, including prolonged hypogammaglobulinemia, B-cell aplasia, T-cell dysfunction, and cumulative immunosuppression from prior treatments.\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e Although BiTEs are administered as continuous therapy and CAR-T cells as a single infusion, both strategies can induce sustained immune perturbations, leading to prolonged vulnerability to infections and limiting direct cross-study comparisons.\u003c/p\u003e \u003cp\u003eWhile infectious complications are well described in prospective clinical trials, these studies enroll highly selected populations and differ substantially in follow-up duration, monitoring intensity, and supportive care strategies. As a result, the true burden of infections in routine clinical practice may not be accurately captured. Although real-world evidence studies on BiTEs and CAR-T therapies are increasingly reported, available data remain heterogeneous and fragmented.\u003c/p\u003e \u003cp\u003eTherefore, a robust quantitative synthesis of real-world severe infection rates across T-cell\u0026ndash;redirecting therapies in MM is still lacking. To address this unmet need, we conducted a systematic review and meta-analysis of real-world retrospective studies in patients with MM treated with BiTEs and CAR-T cells, aiming to estimate the pooled incidence of grade 3\u0026ndash;4 infections and to explore potential sources of heterogeneity among studies.\u003c/p\u003e"},{"header":"2. Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1 Search strategy and selection criteria\u003c/h2\u003e \u003cp\u003eThis systematic review and meta-analysis were performed and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e The study protocol was prospectively registered in the PROSPERO database (registration ID: CRD420251163450). A comprehensive literature search was performed in the MEDLINE and LILACS databases from their inception through November 30th, 2025, to identify studies reporting severe infection outcomes in patients with RRMM treated with BiTEs or CAR-T cell therapies. The detailed search strategy is provided in S-Figure 1.\u003c/p\u003e \u003cp\u003eEligible studies were required to meet the following criteria: (1) retrospective study design; (2) inclusion of adult patients diagnosed with MM who received BiTEs or CAR-T cell therapy; (3) use of BiTEs or CAR-T products approved for clinical use at the time of the search; and (4) availability of data on the incidence of grade 3\u0026ndash;4 infections. Studies evaluating investigational or non-approved products, as well as those without sufficient data for outcome extraction, were excluded.\u003c/p\u003e \u003cp\u003eNo limitations were imposed with respect to language or year of publication. Additionally, reference lists of included articles, their citing publications, and relevant review articles were manually reviewed to identify further eligible studies. Only retrospective studies were considered to enhance methodological consistency and comparability across datasets. At present, the majority of real-world evidence concerning BiTEs and CAR-T cell therapies in MM originates from retrospective analyses; therefore, restricting inclusion to this study design reduced heterogeneity related to study conduct and outcome assessment.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.2 Data collection process\u003c/h2\u003e \u003cp\u003eTitles and abstracts were first screened, after which potentially relevant articles underwent full-text evaluation. Data extraction, along with independent appraisal of study quality and risk of bias, was performed by two reviewers (FS and AGS) using the web-based platform Rayyan.\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e Disagreements were resolved through discussion until consensus was reached. For each study meeting the inclusion criteria, information was collected on study design, methodological characteristics, clinical context, eligibility criteria, patient demographics, type of intervention, and reported outcomes.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e2.3 Outcomes\u003c/h2\u003e \u003cp\u003eThe main outcome evaluated was the proportion of patients with RRMM who experienced grade 3\u0026ndash;4 infectious events (severe infections) while receiving BiTEs or CAR-T cell therapy.\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e As all included studies reported infection occurrences in relation to the total number of treated patients, results were summarized using pooled event rates rather than comparative effect estimates.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003e2.4 Data analysis and risk of bias assessment\u003c/h2\u003e \u003cp\u003eAll statistical analyses were performed using the MetanalysisOnline software.\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e Statistical significance was defined by a two-sided p-value of less than 0.05. Between-study variability was quantified using the \u003cem\u003eI\u003c/em\u003e\u003csup\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sup\u003e statistic, which estimates the proportion of total variance attributable to heterogeneity rather than random error.\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e A random-effects model was employed to calculate the pooled incidence of events along with corresponding 95% confidence intervals (CIs).\u003c/p\u003e \u003cp\u003eSummary of findings tables were generated using the GRADEpro GDT platform (available at gradepro.org). Study quality was evaluated with the Quality Appraisal of Case Series Studies Checklist developed by the Institute of Health Economics (IHE). Each item was classified as \u0026ldquo;yes,\u0026rdquo; \u0026ldquo;unclear/partial,\u0026rdquo; or \u0026ldquo;no,\u0026rdquo; and studies were considered to have acceptable methodological quality (low to moderate risk of bias) when at least 70% of the criteria were met.\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003ePotential publication bias was assessed by visual inspection of funnel plots.\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e The overall certainty of the evidence was rated using the GRADE framework.\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eMeta-regression analyses were undertaken to investigate potential sources of heterogeneity and to assess whether study-level factors were associated with the incidence of severe (grade 3\u0026ndash;4) infections. Prespecified moderators included median treatment duration, patient age, sex distribution, prior autologous stem cell transplantation (ASCT), prevalence of extramedullary disease (EMD), high-risk cytogenetic features, International Staging System (ISS) stage I and III, previous exposure to BCMA-directed therapies, and pentarefractory disease status. To preserve statistical robustness and minimize bias related to sparse data, only covariates reported in a sufficient number of studies were included in the meta-regression models.\u003c/p\u003e \u003cp\u003eTo evaluate the stability of the pooled estimates, a leave-one-out sensitivity analysis was performed by sequentially excluding each study. Between-study heterogeneity was additionally examined using the chi-square (χ\u0026sup2;) test and summarized using the \u003cem\u003eI\u003c/em\u003e\u003csup\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sup\u003e statistic.\u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/div\u003e"},{"header":"3. Results","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003e3.1 Study selection\u003c/h2\u003e \u003cp\u003eThe bibliographic searches yielded 182 records. After the initial screening and triage process, 16 articles met the inclusion criteria and were included in the meta-analysis (S-Figure 1).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003e3.2 Quality assessment and risk of bias\u003c/h2\u003e \u003cp\u003eThe overall quality for all outcomes was deemed acceptable (low risk of bias) in most studies. All 16 studies (100%) reported\u0026thinsp;\u0026ge;\u0026thinsp;70% \u0026ldquo;yes\u0026rdquo; responses according to the critical appraisal tool adopted (S-Table\u0026nbsp;1). The overall certainty of the evidence for the severe infection rate outcome was judged to be low both for BiTEs and CAR-T (S-Table\u0026nbsp;2).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003e3.3 Studies\u0026rsquo; and patients\u0026rsquo; characteristics\u003c/h2\u003e \u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e summarizes the 16 studies\u0026rsquo; characteristics included in the analysis. All studies had a retrospective design, and 13 were multicenter.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eStudies\u0026rsquo; characteristics at baseline.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003estudy,\u003c/p\u003e \u003cp\u003e\u003cem\u003eyear\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003estudy\u003c/p\u003e \u003cp\u003etype\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003etreatment\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003epatients at baseline, \u003cem\u003en\u0026deg;\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003etreatment duration, months (median)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMohan, 2024\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eR, MC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eteclistamab\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e110\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3.5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRiedhammer, 2024\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eR, MC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eteclistamab\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e123\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAl Hadidi, 2025\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eR, MC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003etalquetamab\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e114\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCani, 2025\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eR, SC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eBiTEs\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e158\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e5.5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFrenking, 2025\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eR, MC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003etalquetamab\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e138\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e7.8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMian, 2025\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eR, MC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eteclistamab\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e81\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e13.1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRazzo, 2025\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eR, MC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eteclistamab\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e509\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e10.1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSheu, 2025\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eR, SC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eteclistamab\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e44\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6.7\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStork, 2025\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eR, MC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eteclistamab\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e73\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4.9\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTan, 2025\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eR, MC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eteclistamab\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e210\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e5.3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYi, 2025\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eR, MC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eteclistamab\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e16.4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLogue, 2022\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eR, MC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eide-cel\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e52\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRejeski, 2023\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eR, MC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eBCMA directed CAR-T\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e113\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e7.9\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDima, 2024\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eR, MC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eidecel\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e69\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTrando, 2024\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eR, SC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eidecel\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSidana, 2025\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eR, MC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eciltacel\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e236\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003etotal\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e2,097\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e8.3\u003c/b\u003e\u003csup\u003e\u003cb\u003e*\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eMC, multicenter; R, retrospective; SC, single center,\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e\u003csup\u003e*\u003c/sup\u003eValue represents the weighted mean of the medians reported in individual studies, weighted by the number of patients in each trial.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eAs concerns BiTEs treatment, 8 studies reported data on patients treated with teclistamab, and two focused on talquetamab.\u003csup\u003e\u003cspan additionalcitationids=\"CR21 CR22 CR23 CR24 CR25 CR26 CR27 CR28\" citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e No retrospective studies evaluating elranatamab were identified. The study by Cani et al.,\u003csup\u003e30\u003c/sup\u003e provided separate outcomes for patients treated with BCMA-targeting BiTEs (teclistamab and elranatamab; hereafter referred to as \u0026ldquo;Cani BCMA\u0026rdquo;) and for those receiving GPRC5D-targeting BiTEs (hereafter referred to as \u0026ldquo;Cani GPRC5D\u0026rdquo;). This stratification allowed inclusion of both cohorts in the subsequent subgroup analyses.\u003c/p\u003e \u003cp\u003eFor CAR-T therapy, three studies reported data on patients treated with idecel, one study on ciltacel and one study with BCMA directed CAR-T not providing the specific data on single medications.\u003csup\u003e\u003cspan additionalcitationids=\"CR32 CR33 CR34\" citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThe duration of treatment varied across the studies, ranging from a median of 3 to 16.4 months, with a weighted median duration of 8.3 months.\u003c/p\u003e \u003cp\u003eOverall, the baseline patient population included 2,097 individuals (females, 44.2%), with a mean age of 66.3 years (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). The sample size of the studies varied, ranging from 25 patients to 509 patients.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePatient\u0026rsquo;s characteristics at baseline.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"12\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c11\" colnum=\"11\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c12\" colnum=\"12\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003estudy,\u003c/p\u003e \u003cp\u003e\u003cem\u003eyear\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003en\u0026deg; patients\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eage,\u003c/p\u003e \u003cp\u003e\u003cem\u003emean\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003efemale,\u003c/p\u003e \u003cp\u003e\u003cem\u003en\u0026deg;\u003c/em\u003e (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003en\u0026deg; previous line of treatment, mean\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eprevious ASCT, %\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eEMD, %\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003ehigh cytogenetic risk, %\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003eISS III, %\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c10\"\u003e \u003cp\u003eISS I, %\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c11\"\u003e \u003cp\u003eBCMA exposed, %\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c12\"\u003e \u003cp\u003epentarefractory, %\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMohan, 2024\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e110\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e67.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e54 (49)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e6.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e87\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e44\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e62*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003en.a.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003en.a.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e76\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRiedhammer, 2024\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e123\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e66.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e53 (43.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e6.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003en.a.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e36.1*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e36.8*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e33.7*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e27.1*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e37.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e60.2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAl Hadidi, 2025\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e114\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e66.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e50 (44)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e6.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e81.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e34*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e70*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003en.a.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003en.a.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e64.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e78.9\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCani, 2025\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e158\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e65.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003en.a.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e5.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e81\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003en.a.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003en.a.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003en.a.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003en.a.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e41\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003en.a.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFrenking, 2025\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e138\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e63.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e42 (30)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e6.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e86\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e48*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e48*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e43*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e30*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e51\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e47*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMian, 2025\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e81\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e76.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e33 (40.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e6.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003en.a.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e38.7*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e56.9*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e32*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e28*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e38.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e46*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRazzo, 2025\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e509\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e67.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e234 (46)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e6.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e65.5*\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e44.7*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e54\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003en.a.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003en.a.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e46.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e38*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSheu, 2025\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e44\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e67.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e20 (45.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e6.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e6.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003en.a.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003en.a.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003en.a.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e45.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003en.a.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStork, 2025\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e73\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e66.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e37 (50.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e5.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003en.a.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e24.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e44*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e30.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e12.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e68.5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTan, 2025\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e210\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e66.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e93 (44.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e6.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003en.a.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e29.4*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e50*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e30.6*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e37.9*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e43.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e44.1*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYi, 2025\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e66.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e15 (35.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e6.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e86\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e28.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e42.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e40.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e21.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e7.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e19\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLogue, 2022\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e52\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e65.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e29 (56)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e6.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e81\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e62\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003en.a.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003en.a.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e44\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRejeski, 2023\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e113\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e64.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e48 (42)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e5.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e88\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e45.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e29.5*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003en.a.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003en.a.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e13*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e42.5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDima, 2024\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e69\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e63.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e35 (51)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e6.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003en.a.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e52\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e40*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003en.a.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003en.a.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e48\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTrando, 2024\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e64.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e13 (52)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e6.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e100\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e48\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003en.a.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003en.a.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e88\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSidana, 2025\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e236\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e63.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e102 (43)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e6.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e85\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e25.5*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e40.7*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003en.a.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003en.a.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e30\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003etotal\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e2,097\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e66.3\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e858 (44.2)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e6.1\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e77.4\u003c/b\u003e\u003csup\u003e\u003cb\u003e\u0026sect;\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e39.2\u003c/b\u003e\u003csup\u003e\u003cb\u003e\u0026sect;\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u003cb\u003e48.8\u003c/b\u003e\u003csup\u003e\u003cb\u003e\u0026sect;\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e\u003cb\u003e34.3\u003c/b\u003e\u003csup\u003e\u003cb\u003e\u0026sect;\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e\u003cb\u003e30.5\u003c/b\u003e\u003csup\u003e\u003cb\u003e\u0026sect;\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e\u003cb\u003e37.0\u003c/b\u003e\u003csup\u003e\u003cb\u003e\u0026sect;\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e\u003cb\u003e47.1\u003c/b\u003e\u003csup\u003e\u003cb\u003e\u0026sect;\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"12\"\u003e​​n.a., not available.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"12\"\u003e\u003csup\u003e#\u003c/sup\u003eThis value includes both autologous SCT and allogeneic STC.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"12\"\u003e\u003csup\u003e*\u003c/sup\u003ePercentage is calculated based on the total of patients assessed for that clinical manifestation.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"12\"\u003e\u003csup\u003e\u0026sect;\u003c/sup\u003eThe denominator does not include patients that were not assessed for that clinical manifestation.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThe overall mean number of prior lines of therapy across studies was 6.1. The pooled proportion of patients who had previously undergone autologous stem cell transplantation was 77.4%, while 39.2% presented with extramedullary disease. The prevalence of high-risk cytogenetic abnormalities was 48.8%, and 34.3% of patients were classified as ISS stage III (30.5% of patients were ISS stage I). Prior exposure to BCMA-directed therapy was observed in 37% of patients, and 47.1% were classified as pentarefractory (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003e3.4 Severe infection rate\u003c/h2\u003e \u003cp\u003eA total of 505 patients (24.2%) experienced grade 3\u0026ndash;4 infections after a weighted median follow-up of 8.3 months, corresponding to a pooled event rate of 0.24 (95% CI, 0.21\u0026ndash;0.28) as shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, meaning that 24% of patients developed severe infections during treatment. HIgh heterogeneity was observed (Tau\u0026sup2;=0.0042; Chi\u0026sup2;=46.26, df\u0026thinsp;=\u0026thinsp;15, p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001; \u003cem\u003eI\u003c/em\u003e\u0026sup2;=67.6%).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eBiTEs group included a total of 1,602 patients, with a pooled event rate of 0.26 (95% CI, 0.23\u0026ndash;0.30). Heterogeneity was moderate (Tau\u0026sup2;=0.0019; Chi\u0026sup2;= 20.26; df\u0026thinsp;=\u0026thinsp;10; p\u0026thinsp;=\u0026thinsp;0.0269; \u003cem\u003eI\u003c/em\u003e\u0026sup2;=50.6%).\u003c/p\u003e \u003cp\u003eGiven the moderate heterogeneity across the included studies, a meta-regression analysis was conducted. It revealed a counterintuitive and significant association between the rate of severe infections and the mean number of the proportion of patients previously exposed to BCMA-targeted therapy (p\u0026thinsp;=\u0026thinsp;0.047), as shown in S-Figure 2. Studies including patients with a greater number of patients exposed to prior BCMA therapy reported lower rates of severe infections. Indeed, when outlier studies were excluded from the pooled analysis, heterogeneity markedly decreased to 12.5%, with a pooled event rate of 0.24 (95% CI, 0.22\u0026ndash;0.26) as shown in S-Figure 3.\u003c/p\u003e \u003cp\u003eWithin the BiTEs cohort, a predefined subgroup analysis was performed according to the targeted antigen, distinguishing between BCMA-directed BiTEs and GPRC5D-directed BiTEs (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). In the subgroup of patients treated with BCMA BiTEs, comprising 1,293 patients, the pooled proportion of grade 3\u0026ndash;4 infections was 0.27 (95% CI, 0.23\u0026ndash;0.31). Moderate heterogeneity was observed across studies (Tau\u0026sup2;=0.0027; Chi\u0026sup2;=18.83, df\u0026thinsp;=\u0026thinsp;8; p\u0026thinsp;=\u0026thinsp;0.0158; \u003cem\u003eI\u0026sup2;\u003c/em\u003e=57.5%). In contrast, the subgroup of patients treated with GPRC5D BiTEs included 309 patients and showed a pooled event rate of 0.25 (95% CI, 0.20\u0026ndash;0.30). No significant heterogeneity was detected in this subgroup (Tau\u0026sup2;=0; Chi\u0026sup2;=1.28, df\u0026thinsp;=\u0026thinsp;2; p\u0026thinsp;=\u0026thinsp;0.5274; \u003cem\u003eI\u0026sup2;\u003c/em\u003e=0%).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eStudies assessing CAR-T comprised 495 patients, showing a pooled event rate of 0.19 (95% CI, 0.12\u0026ndash;0.27) with high heterogeneity (Tau\u0026sup2;=0.0071; Chi\u0026sup2;=13.75, df\u0026thinsp;=\u0026thinsp;4, p\u0026thinsp;=\u0026thinsp;0.0081; \u003cem\u003eI\u003c/em\u003e\u0026sup2;=70.9%). Given the substantial heterogeneity observed among studies evaluating CAR-T cell therapies, meta-regression analyses were performed to explore potential sources of between-study variability using the predefined moderators. However, none of the evaluated study-level covariates showed a statistically significant association with the proportion of severe infections.\u003c/p\u003e \u003cp\u003eSubsequently, a leave-one-out sensitivity analysis was conducted to assess the robustness of the pooled estimate and to identify influential studies. This analysis revealed that exclusion of a single outlier study (Sidana 2025) markedly reduced heterogeneity, with the \u003cem\u003eI\u0026sup2;\u003c/em\u003e statistic decreasing to 26.9%, indicating low residual heterogeneity. Under this condition, the pooled event rate increased to 0.22 (95% CI, 0.16\u0026ndash;0.29), as shown in S-Figure 3.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003e3.5 Other BiTEs-related adverse events\u003c/h2\u003e \u003cp\u003eAcross all the included studies, the overall incidence of cytokine release syndrome (CRS) of any grade was 57.5%, while immune effector cell-associated neurotoxicity syndrome (ICANS) occurred in 11.6% of patients. The pooled overall response rate (ORR) was 67.8%, and immunoglobulin supplementation was reported in 48.4% of cases. Unfortunately, not all studies reported data for every variable (S-Table\u0026nbsp;3).\u003c/p\u003e \u003c/div\u003e"},{"header":"4. Discussion","content":"\u003cp\u003eT-cell-redirecting immunotherapies represent one of the most transformative advances in the management of RRMM. Both BiTEs and CAR-T therapies have demonstrated unprecedented efficacy in heavily pretreated patients and are currently approved for the same therapeutic indication, namely advanced RRMM. As their use increasingly extends beyond clinical trials into routine clinical practice, a comprehensive understanding of their safety profile, particularly the risk of severe infections, has become critically important. Infectious complications remain a major determinant of morbidity, treatment discontinuation, and mortality in MM, arising from a complex interplay between disease-related immune dysfunction, cumulative treatment exposure, and therapy-induced immunosuppression.\u003c/p\u003e \u003cp\u003e In this context, the present systematic review and meta-analysis provides the first quantitative synthesis focused exclusively on real-world retrospective studies evaluating severe infections across both approved BiTEs and CAR-T cell therapies in MM. By deliberately including both platforms, this analysis reflects contemporary clinical practice, where BiTEs and CAR-T cells are used in patients at a comparable stage of disease and currently represent alternative therapeutic strategies rather than sequentially mandated options.\u003c/p\u003e \u003cp\u003eAcross 16 retrospective cohorts including 2,097 patients, approximately one in four individuals (24%) experienced a severe infection during treatment, confirming that infectious toxicity remains a clinically meaningful and shared complication of T-cell-redirecting therapies in real-world settings. When stratified by therapeutic platform, patients treated with BiTEs showed a pooled severe infection rate of 26%, whereas those receiving CAR-T cell therapy exhibited a lower pooled rate of 19%, which further decreased to 22% after exclusion of a single influential outlier study. These findings suggest that, although both platforms confer substantial infectious risk, CAR-T therapy may be associated with a comparatively more favorable infectious safety profile in routine practice.\u003c/p\u003e \u003cp\u003eWithin the BiTEs cohort, subgroup analyses revealed important antigen-specific differences. BCMA-directed BiTEs were associated with a slightly higher pooled rate of severe infections (27%) compared with GPRC5D-directed BiTEs (25%), with the latter showing no detectable between-study heterogeneity. Although these differences are numerically modest, their consistency across analyses and alignment with published literature suggest that target antigen selection may contribute to differential immune perturbation and infectious vulnerability. The higher infection burden observed with BCMA-directed strategies may reflect deeper and more sustained plasma cell depletion, prolonged hypogammaglobulinemia, and cumulative immune exhaustion, particularly in patients previously exposed to BCMA-targeted therapies.\u003c/p\u003e \u003cp\u003eImportantly, the heterogeneity observed in the BiTEs analysis was partially explained by meta-regression, which revealed a counterintuitive inverse association between severe infection rates and both prior BCMA exposure and number of previous treatment lines. This counterintuitive finding is most plausibly explained by clinical selection bias inherent to real-world practice and should not be interpreted as evidence of a biologically protective effect of prior BCMA exposure. In retrospective settings, clinicians may preferentially select fitter patients with preserved immune reserve for BiTEs therapy in later lines, resulting in cohorts that are more resilient despite heavier pretreatment. In contrast to clinical trials, clinicians may preferentially select fitter patients with preserved immune reserve for BiTE therapy, especially in later lines of treatment. As a result, cohorts with heavier pretreatment may paradoxically represent more resilient patients, leading to lower observed infection rates. A similar phenomenon has been reported in retrospective analyses of CAR-T therapies and underscores the challenges of interpreting observational safety data in the absence of randomized allocation.\u003c/p\u003e \u003cp\u003eFor CAR-T therapies, high heterogeneity was initially observed, but no predefined study-level moderators were significantly associated with infection risk. Sensitivity analysis identified a single outlier study whose exclusion substantially reduced heterogeneity and yielded a pooled infection rate comparable to, yet still lower than, that observed with BiTEs. These findings support the robustness of the CAR-T estimate and suggest that, despite differences in manufacturing, delivery, and kinetics, CAR-T cell therapy may induce a more temporally confined period of immunosuppression compared with the continuous immune engagement associated with BiTEs.\u003c/p\u003e \u003cp\u003eTo contextualize these results within the existing literature, we systematically compared our findings with all previously published meta-analyses addressing severe infections in patients treated with BiTEs and/or CAR-T cells (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003csup\u003e\u003cspan additionalcitationids=\"CR37 CR38 CR39 CR40\" citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e\u003c/sup\u003e Notably, most prior analyses included clinical trials, investigational products, or mixed study designs, whereas the present study exclusively focused on approved therapies in real-world settings. Across studies, reported severe infection rates for BiTEs ranged from 21% to 39%, while CAR-T-associated rates ranged from 17% to 25%. Our estimates fall within this spectrum and reinforce the notion that, among approved therapies, BCMA BiTEs are associated with slightly higher rates of severe infections compared with GPRC5D BiTEs, and CAR-T therapies appear overall safer with respect to infectious toxicity. In all scenarios, appropriate vaccination strategies are recommended, while immunoglobulin replacement treatment (IgRT) could be taken in consideration for the frailest group.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eComparison between meta-analysis on severe infection rate.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"8\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003ecurrent study\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eReynolds et al.\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eWang et al.\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eLi et al.\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eBakogeorgou et al\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eTechaapornkun et al.\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eVandenboom et al.\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003etype of studies included\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ereal-life\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003etrials\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003etrials\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003etrials, real-life\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003etrials\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003ereal-life\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003etrials\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ealso includes investigational BiTEs or CAR-T, Y/N\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eN\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eY\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eY\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eN\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eY\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eY\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eY\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eBCMA BiTEs severe infection rate\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e27%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003en.a.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e25%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e50%*; 24%\u003csup\u003eΨ\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003en.a.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003en.a.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003en.a.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003enon-BCMA BiTEs severe infection rate\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e25%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003en.a.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e20%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003en.a.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003en.a.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003en.a.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003en.a.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eGPR5CD BiTEs severe infection rate\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e25%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003en.a.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003en.a.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003en.a.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003en.a.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003en.a.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003en.a.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eoverall BiTEs severe infection rate\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e26%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e21%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e22%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e50%*; 24%\u003csup\u003eΨ\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e29%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e39%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e30%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCAR-T severe infection rate\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e17%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003en.a.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003en.a.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003en.a.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003en.a.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e25%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e17%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"8\"\u003eN, not; Y, yes.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"8\"\u003e*clinical trials.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"8\"\u003e\u003csup\u003eΨ\u003c/sup\u003ereal-life studies.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eTaken together, both our real-world data and the broader meta-analytic literature support a clinically meaningful gradient of infectious risk across T-cell-redirecting strategies. However, these observations arise from indirect comparisons across heterogeneous retrospective cohorts and should therefore be interpreted with appropriate caution. On this basis, and in the absence of definitive comparative efficacy or safety data favoring one platform over another, we propose a pragmatic, infection-oriented conceptual framework to support therapeutic decision-making in routine clinical practice (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eIn patients who are clinically fit and have no significant history of severe or recurrent infections, either BiTEs or CAR-T therapy may represent reasonable treatment options, with the final choice guided by availability, logistical considerations, and physician experience. Conversely, in patients who are frail, immunologically vulnerable, or have a documented history of severe or recurrent infections, CAR-T therapy may be preferentially considered when feasible, given its numerically lower pooled rate of severe infections observed in real-world settings. When CAR-T therapy is not available or contraindicated, GPRC5D-directed BiTEs may represent a potentially safer alternative compared with BCMA-directed BiTEs, although this distinction should not be interpreted as evidence of superiority.\u003c/p\u003e \u003cp\u003eImportantly, the decision framework proposed in this study should be interpreted as a conceptual and pragmatic aid rather than as a prescriptive or hierarchical algorithm. The comparisons presented herein are inherently indirect and derive from heterogeneous real-world retrospective cohorts, characterized by variable follow-up durations, non-randomized patient selection, and differences in supportive care practices. Consequently, the observed differences in severe infection rates across BiTEs and CAR-T therapies should not be construed as definitive comparative safety signals. Rather, this framework is intended to support, rather than replace, clinical judgment, existing guidelines, and individualized patient assessment.\u003c/p\u003e \u003cp\u003eSeveral limitations of this meta-analysis warrant consideration. All included studies were retrospective, introducing inherent risks of selection bias, incomplete reporting, and heterogeneity in infection definitions, monitoring intensity, and supportive care strategies. Data on antimicrobial prophylaxis, vaccination status, and immunoglobulin replacement were inconsistently reported, despite their known impact on infection risk. Moreover, real-world data on elranatamab were not available at the time of analysis, limiting generalizability to all approved BiTEs. Finally, the overall certainty of evidence was graded as low, reflecting the observational nature of the available data.\u003c/p\u003e \u003cp\u003eDespite these limitations, this study provides the most comprehensive real-world assessment to date of severe infections associated with approved T-cell-redirecting therapies in MM. The findings emphasize that severe infections remain frequent, affecting approximately one quarter of patients, and that meaningful differences exist across therapeutic platforms and targets. These results underscore the need for structured infection prevention strategies, including immunoglobulin replacement, antimicrobial prophylaxis, and optimized vaccination programs, particularly for high-risk patients.\u003csup\u003e\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eFuture prospective registries and harmonized real-world pharmacovigilance initiatives are urgently needed to refine risk stratification, validate comparative safety signals, and optimize patient selection. Ultimately, integrating efficacy, safety, patient frailty, and infection history into therapeutic decision-making will be essential to maximize the benefits of T-cell-redirecting immunotherapies while minimizing their infectious burden in RRMM.\u003c/p\u003e"},{"header":"5. Conclusion","content":"\u003cp\u003eThis real-world meta-analysis demonstrates that severe infections remain a frequent and clinically relevant complication of T-cell-redirecting therapies in RRMM, affecting approximately one in four treated patients. Both BiTEs and CAR-T cell therapies are associated with a substantial infectious burden, highlighting the need for careful risk assessment in routine clinical practice.\u003c/p\u003e \u003cp\u003eAlthough differences in pooled infection rates were observed across therapeutic platforms and targets, these findings derive from indirect comparisons and should be interpreted with caution. BCMA-directed BiTEs were associated with numerically higher rates of severe infections compared with GPRC5D-directed BiTEs, while CAR-T therapies showed lower pooled infection rates in this real-world analysis, without implying formal superiority.\u003c/p\u003e \u003cp\u003eIn the absence of randomized comparative data, infectious risk should be considered alongside efficacy, patient frailty, prior treatment exposure, and logistical feasibility when selecting T-cell-redirecting therapies. Tailored preventive strategies and prospective real-world surveillance are essential to optimize the safety and long-term benefit of these treatments in MM.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e \u003ch2\u003e \u003cb\u003eCompeting interests\u003c/b\u003e:\u003c/h2\u003e \u003cp\u003eAuthors declare no competing interests.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eData Sharing Statement\u003c/strong\u003e \u003cp\u003eFor original data, please contact [email protected]\u003c/p\u003e \u003c/p\u003e\u003cp\u003e \u003ch2\u003eCompeting interest:\u003c/h2\u003e \u003cp\u003eauthors declare no competing interests.\u003c/p\u003e \u003c/p\u003e\u003cp\u003e \u003ch2\u003eEthics approval and consent to participate:\u003c/h2\u003e \u003cp\u003enot applicable.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eConsent for publication:\u003c/strong\u003e \u003cp\u003enot applicable.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eAuthor contributions:\u003c/h2\u003e \u003cp\u003eF.S. and A.G.S. conceived the project; F.S. and A.G.S. designed the analyses; F.S., V.D. and G.D. acquired data; F.S. and G.D. verified the raw data before analyses and performed pre-processing informatic analysis; F.S. and A.G.S. performed the informatic analysis and interpreted data; F.S., V.D., A.G.S. contributed with scientific discussions; F.S. and A.G.S. wrote the manuscript, which has been revised and approved by all the authors.\u003c/p\u003e\u003ch2\u003eAcknowledgement\u003c/h2\u003e \u003cp\u003e \u003cb\u003eand funding\u003c/b\u003e: \u0026ldquo;Fondo per il Programma Nazionale di Ricerca e Progetti di Rilevante Interesse Nazionale\u0026mdash;PRIN\u0026rdquo; (project n. 2022ZKKWLW) to A.G.S.; by the Italian network of excellence for advanced diagnosis (INNOVA), Ministero della Salute (code PNC-E3-2022-23683266 PNC-HLS-DA) to V.D. and A.G.S.; Complementary National Plan PNC-I.1 \"Research initiatives for innovative technologies and pathways in the health and welfare sector\u0026rdquo; D.D. 931 of 06/06/2022, DARE - DigitAl lifelong pRevEntion initiative (code PNC0000002) to A.V. and R.R.; PNRR-MCNT1-2023-12377893 DEMMO- \u0026ldquo;Deciphering multiple myeloma using multiomic approaches for immunotherapy modeling\u0026ldquo; (CUP: H93C23001080006) to V.D. and A.G.S.\u003c/p\u003e\u003ch2\u003eData availability statement:\u003c/h2\u003e \u003cp\u003eData will be provided by the author upon reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eKyle RA, Rajkumar SV (2008) Multiple myeloma. 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GRADE Working Group\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHiggins JPT, Thompson SG (2002) Quantifying heterogeneity in a meta-analysis. Stat Med 21:1539\u0026ndash;1558\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMohan M, Monge J, Shah N et al (2024) Teclistamab in relapsed refractory multiple myeloma: multi-institutional real-world study. Blood Cancer J 14:35\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRiedhammer C, Bassermann F, Besemer B, Bewarder M, Brunner F, Carpinteiro A, Einsele H, Faltin J, Frenking J, Gezer D, Goldman-Mazur S et al (2024) Real-world analysis of teclistamab in 123 RRMM patients from Germany. Leukemia 38:365\u0026ndash;371\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAl Hadidi S, Szabo A, Mohan Lal B et al (2025) Talquetamab in relapsed refractory multiple myeloma: multi-institutional real-world study. 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Jul 9\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSheu M, Molina Garcia S, Patel M et al (2025 Oct) Infection Prophylaxis with Intravenous Immunoglobulin in Multiple Myeloma Patients Treated with Teclistamab. Oncology 23:1\u0026ndash;5\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eStork M, Radocha J, Mihalyova J et al (2025) De-escalated Teclistamab dosing in relapsed/refractory multiple myeloma: Czech myeloma group real-world evidence analysis. Ann Hematol 104:4141\u0026ndash;4147\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTan CR, Asoori S, Huang CY et al (2025) Real-world evaluation of teclistamab for the treatment of relapsed/refractory multiple myeloma (RRMM): an International Myeloma Working Group Study. Blood Cancer J 15:53\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYi JH, Lee JH, Jung SH et al (2025) Real-World Efficacy and Safety of Teclistamab for Patients with Relapsed or Refractory Multiple Myeloma: Nationwide Retrospective Analysis of the Named Patient Program in Korea. Cancer Res Treat. Jul 30\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCani L, Scott SA, Roberts D et al (2025) Infection risk in 158 patients with relapsed/refractory multiple myeloma treated with bispecific antibodies: a single-center experience. Haematologica. Sep 4\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLogue JM, Peres LC, Hashmi H, Colin-Leitzinger CM et al (2022) Early cytopenias and infections after standard of care idecabtagene vicleucel in relapsed or refractory multiple myeloma. Blood Adv 6:6109\u0026ndash;6119\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRejeski K, Hansen DK, Bansal R et al (2023) The CAR-HEMATOTOX score as a prognostic model of toxicity and response in patients receiving BCMA-directed CAR-T for relapsed/refractory multiple myeloma. J Hematol Oncol 16:88\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDima D, Rashid A, Davis JA et al (2024) Efficacy and safety of idecabtagene vicleucel in patients with relapsed-refractory multiple myeloma not meeting the KarMMa-1 trial eligibility criteria: A real-world multicentre study. Br J Haematol 204(4):1293\u0026ndash;1299\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTrando A, Ghamsari F, Yeung P, Costello C, Saunders I, Jeong AR (2024) Outcomes of Idecabtagene Vicleucel Therapy in Patients with Relapsed/Refractory Multiple Myeloma: A Single-Institution Experience. Biomedicines 13:36\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSidana S, Patel KK, Peres LC et al (2025) Safety and efficacy of standard-of-care ciltacabtagene autoleucel for relapsed/refractory multiple myeloma. Blood 145:85\u0026ndash;97\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eReynolds G, Cliff ERS, Mohyuddin GR et al (2023) Infections following bispecific antibodies in myeloma: a systematic review and meta-analysis. Blood Adv 7:5898\u0026ndash;5903\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWang X, Zhao A, Zhu J et al (2024) Efficacy and safety of bispecific antibodies therapy for relapsed or refractory multiple myeloma: a systematic review and meta-analysis of prospective clinical trials. Front Immunol 15:1348955\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLi W, Zhao D, Jiao Y et al (2025) Effectiveness and safety of teclistamab for relapsed or refractory multiple myeloma: a systematic review and meta-analysis. Front Immunol 16:1565407\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBakogeorgou S, Filippatos C, Malandrakis P et al (2025) Safety and Efficacy of Bispecific Antibody Treatment in Relapsed/Refractory Multiple Myeloma: A Systematic Review and Meta-Analysis of Proportions from Clinical Trials. Cancers (Basel) 17:2727\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTechaapornkun P, Rojpalakorn W, Mejun N et al (2025) 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. Ann Hematol 104:4791\u0026ndash;4809\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVandenboom H, Akhtar O, Szabo A et al (2025) Safety and efficacy of BCMA CAR-T \u003cem\u003evs.\u003c/em\u003e bispecific antibodies in patients with relapsed multiple myeloma: a systematic review and meta-analysis. Haematologica. Aug 14\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePalumbo A, Bringhen S, Mateos MV et al (2015) Geriatric assessment predicts survival and toxicities in elderly myeloma patients: an International Myeloma Working Group report. Blood 125:2068\u0026ndash;2074\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDesantis V, Borrelli P, Panebianco T et al (2024) Comprehensive analysis of clinical outcomes, infectious complications and microbiological data in newly diagnosed multiple myeloma patients: a retrospective observational study of 92 subjects. Clin Exp Med 24:137\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"multiple myeloma, bispecific, CAR-T, infections","lastPublishedDoi":"10.21203/rs.3.rs-8549937/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8549937/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eT-cell-redirecting therapies, including bispecific T-cell engagers (BiTEs) and chimeric antigen receptor T-cell (CAR-T) therapies, have substantially improved outcomes in relapsed or refractory multiple myeloma (RRMM). However, infectious complications remain a major safety concern, particularly in real-world settings, where patients are more heterogeneous than those enrolled in clinical trials.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003e We conducted a systematic review and meta-analysis of real-world retrospective studies evaluating severe (grade 3\u0026ndash;4) infections in adult patients with RRMM treated with approved BiTEs or CAR-T cell therapies. Pooled event rates were estimated using random-effects models. Heterogeneity was explored through subgroup analyses, meta-regression, and sensitivity analyses.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eSixteen studies encompassing 2,097 patients were included. Overall, 24.2% of patients developed grade 3\u0026ndash;4 infections (pooled event rate 0.24; 95% CI, 0.21\u0026ndash;0.28). Among BiTEs-treated patients (n\u0026thinsp;=\u0026thinsp;1,602), the pooled severe infection rate was 0.26 (95% CI, 0.23\u0026ndash;0.30), with higher rates observed for BCMA-directed BiTEs (0.27) compared with GPRC5D-directed BiTEs (0.25). CAR-T cell therapies (n\u0026thinsp;=\u0026thinsp;495) were associated with a lower pooled infection rate (0.19; 95% CI, 0.12\u0026ndash;0.27).\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eIn real-world practice, severe infections affect approximately one in four patients receiving T-cell-redirecting therapies for RRMM. Observed differences in infection rates across platforms and targets should be interpreted with caution, as they derive from indirect comparisons in non-randomized, heterogeneous cohorts. Nevertheless, these data support incorporating patient frailty and prior infection history into therapeutic decision-making. CAR-T therapy, or GPRC5D-directed BiTEs when CAR-T is not feasible, may represent reasonable options in patients at higher infectious risk, within an individualized and context-dependent treatment strategy.\u003c/p\u003e","manuscriptTitle":"Real-World Evidence on Infection Risk in Multiple Myeloma Treated with BiTEs and CAR-T cells: A Meta-Analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-01-12 07:12:40","doi":"10.21203/rs.3.rs-8549937/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"d374ed5d-567b-48c7-bac1-4684fc71a23b","owner":[],"postedDate":"January 12th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":60805702,"name":"Hematology"}],"tags":[],"updatedAt":"2026-01-12T07:12:40+00:00","versionOfRecord":[],"versionCreatedAt":"2026-01-12 07:12:40","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8549937","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8549937","identity":"rs-8549937","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}