Immunoglobulin prophylaxis reduces severe infections in multiple myeloma: a systematic review and meta-analysis

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Multiple myeloma (MM) is associated with profound immune dysfunction, predisposing patients to severe infections. Immunoglobulin replacement therapy (IgRT) may reduce infection risk, but evidence is heterogeneous and mainly limited to intravenous administration. Its impact, particularly in patients receiving modern therapies such as bispecific T-cell engagers (BiTEs), remains unclear. Methods. We performed a systematic review and meta-analysis of studies comparing MM patients receiving IgRT as preemptive or primary prophylaxis versus those receiving secondary or no IgRT. MEDLINE and LILACS were searched up to December 30, 2025. Both intravenous (IVIg) and subcutaneous (SCIg) routes were included. Comparative studies reporting hazard ratios (HRs) for severe infections or sufficient data to derive them were included, with HRs pooled using random-effects models. Results. Eight studies (358 IgRT-treated, 430 controls) were included, predominantly using IVIg; one study exclusively used SCIg and one included both IVIg and SCIg. IgRT prophylaxis was associated with a 75% reduction in severe infections (pooled HR 0.25, 95% CI 0.13–0.49, p < 0.0001). In BiTEs-treated patients, HR was 0.32 (95% CI 0.18–0.56, p < 0.0001). Results were robust across study designs and sensitivity analyses, with low heterogeneity after leave-one-out analysis. Conclusions. IgRT prophylaxis substantially reduces severe infections in MM, including high-risk BiTEs-treated patients. The benefit is clinically meaningful and mainly reflects IVIg use, though limited evidence suggests SCIg is also effective. These findings support systematic consideration of IgRT in high-risk MM populations, with prospective studies needed to optimize timing, patient selection, and administration. Hematology Immunology multiple myeloma immunoglobulin replacement therapy IgRT IVIg SCIg infections Figures Figure 1 Figure 2 1.Introduction Multiple myeloma (MM) is a plasma cell malignancy characterized by profound immune dysfunction resulting from both disease-related immunoparesis and cumulative treatment-related immunosuppression. 1 Infectious complications remain a leading cause of morbidity and mortality throughout the disease course, particularly in patients with relapsed or refractory disease. 2 Secondary antibody deficiency, driven by impaired B-cell function and suppression of normal polyclonal immunoglobulin production, represents a major determinant of infection susceptibility in this population. 3 Hypogammaglobulinemia is highly prevalent in MM and may affect up to 90% of patients, depending on disease characteristics and treatment exposure. According to recent European consensus recommendations, serum IgG concentrations < 4 g/L (or < 400 mg/dL) define severe hypogammaglobulinemia, whereas values between 4 and 6 g/L are considered mild hypogammaglobulinemia, both associated with an increased risk of severe and recurrent infections. 4 Despite its clinical relevance, routine immunologic assessment is not always systematically incorporated into MM management, and thresholds for preventive interventions vary widely across institutions. The introduction of novel therapies, including monoclonal antibodies and T-cell–redirecting immunotherapies such as bispecific T-cell engagers (BiTEs) and BCMA-directed chimeric antigen receptor T (CAR-T) cells, has markedly improved outcomes in MM but has also been accompanied by a substantial burden of infectious toxicity. 5 In particular, BiTEs are frequently associated with prolonged hypogammaglobulinemia and high rates of severe infections (grade 3–4), a concern that is expected to increase as these agents are moved into earlier lines of therapy and used in more fragile patients. 6 , 7 Immunoglobulin replacement therapy (IgRT) represents a potential preventive strategy in patients with secondary hypogammaglobulinemia. 8 Current expert recommendations suggest considering IgRT in patients with severe hypogammaglobulinemia and prior serious infections, as well as in selected patients with recurrent infections or poor vaccine responses. 4 , 6 However, in routine clinical practice, the use of IgRT remains highly heterogeneous, and there is no clear evidence-based guidance regarding its prophylactic use in frail patients or in those initiating highly immunosuppressive therapies such as BiTEs. 6 Although several retrospective studies suggest that IgRT may reduce infection rates in MM, available data are heterogeneous and derived from studies with different designs, patient populations, and treatment settings. Moreover, no quantitative synthesis has systematically evaluated the impact of IgRT on the incidence of severe infections using time-to-event measures. To address this unmet need, we conducted a systematic review and meta-analysis of published studies comparing patients with MM receiving IgRT as preemptive or primary prophylaxis with those either not receiving IgRT or receiving IgRT only as secondary prophylaxis, with the aim of quantifying the effect of IgRT prophylaxis on the incidence of severe infections. 2. Methods 2.1 Search strategy and selection criteria This systematic review and meta-analysis was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. 9 The study protocol was prospectively registered in the PROSPERO database (registration ID: CRD420261277656). A comprehensive literature search was performed in the MEDLINE and LILACS databases from their inception with no temporal limitations, up to the cutoff date of 30 December 2025, aiming to identify studies reporting infectious outcomes in patients with multiple myeloma receiving IgRT (S-Figure 1). The search strategy combined controlled vocabulary and free-text terms related to MM, IgRT (intravenous or subcutaneous), and infections (full strategy in the Supplementary Materials). No restrictions were applied regarding language, publication year, or geographic origin. Eligible studies included patients with MM receiving IgRT as primary or preemptive prophylaxis compared with patients receiving IgRT as secondary prophylaxis or no IgRT. Preemptive IgRT was defined as administration based on hypogammaglobulinemia, primary IgRT as prophylactic administration irrespective of IgG levels, and secondary IgRT as initiation after a documented infection. Hypogammaglobulinemia was primarily defined as serum polyclonal IgG < 4 g/L (400 mg/dL), with studies using alternative thresholds (including < 700 mg/dL) also considered eligible. No distinction was made between intravenous IgRT (IVIg) and subcutaneous IgRT (SCIg) routes of administration in the inclusion criteria. Both prospective and retrospective comparative studies were eligible, including randomized and non-randomized designs; case reports and single-patient series were excluded. Only studies reporting hazard ratios (HRs) for severe infections or providing sufficient data to estimate HRs with 95% confidence intervals were included. Reference lists of included studies and relevant reviews were manually screened to identify additional eligible publications. 2.2 Data collection process Titles and abstracts identified through the literature search were independently screened by two reviewers (F.S. and A.G.S.). Full-text articles were subsequently assessed for eligibility. Data extraction was performed independently by the same reviewers using a standardized data collection form Rayyan. 10 Any discrepancies were resolved through discussion until consensus was reached. For each included study, information was systematically extracted on study design, length of follow-up, clinical setting, and patient population. Data collection included the number of patients receiving IgRT as preemptive or primary prophylaxis (“cases”) and those not receiving IgRT or receiving IgRT as secondary prophylaxis (“controls”), along with the criteria used for initiating IgRT, the route of immunoglobulin administration, the anti-myeloma treatment regimens, and key baseline patient characteristics. Outcome data extraction focused on measures of severe infection risk, including reported hazard ratios and their corresponding 95% confidence intervals (Cis). 2.3 Outcomes The primary outcome of this meta-analysis was the occurrence of severe infections, defined as grade 3–4 infectious events according to the criteria used in the original studies. 7 The effect of IgRT on the risk of severe infections was evaluated using hazard ratios (HRs), comparing “cases” with “controls”. HRs were selected as the preferred summary measure as they account for variable follow-up duration and allow comparison of time-to-event data across studies with heterogeneous observation periods. 2.4 Data analysis and risk of bias assessment All statistical analyses were performed using the MetanalysisOnline software. 11 Pooled HRs with corresponding 95% CIs were calculated using random-effects models to account for between-study variability. Statistical heterogeneity was assessed using the chi-square test and quantified using the I 2 statistic. 12 A two-sided p-value of less than 0.05 was considered statistically significant. The methodological quality of included studies was assessed using the Quality Appraisal of Case Series Studies Checklist developed by the Institute of Health Economics (IHE). 13 Each study was evaluated across all domains of the checklist, and overall study quality was considered acceptable when at least 70% of the criteria were fulfilled. The certainty of the evidence for the primary outcome was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework. 14 In the presence of substantial heterogeneity, additional analyses were planned to explore potential sources of between-study variability. When sufficient study-level data were available and consistently reported across all included studies, meta-regression analyses were performed to evaluate the association between prespecified moderators and the risk of severe infections. Potential moderators included demographic, clinical, and treatment-related variables reported uniformly across studies. But, in situations where meta-regression was not feasible due to limited availability or inconsistency of study-level covariates, a leave-one-out sensitivity analysis was conducted by sequentially excluding individual studies to assess their influence on the pooled effect estimate and on heterogeneity. Between-study heterogeneity was additionally examined using the chi-square (χ²) test and summarized using the I 2 statistic. 15 Publication bias was evaluated by visual inspection of funnel plots and formally assessed using Egger’s regression test. 16 3.Results 3.1 Study selection The literature search identified a total of 48 records. After screening titles and abstracts and performing full-text assessment, eight studies met the predefined inclusion criteria and were included in the quantitative synthesis. One out of eight of these studies was retrieved by citation searching. The study selection process is summarized in 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 eight 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 (S-Table 2). 3.3 Studies’ and patients’ characteristics The main characteristics of the included studies are summarized in Table 1. Overall, the analysis included eight studies with a total of 358 MM patients receiving IgRT (“cases”) and 430 not receiving IgRT (“controls”). 17–24 Two studies employed a prospective design, including one randomized controlled trial, while the remaining studies were retrospective. Three studies were multicenter, and five were conducted at a single center. In studies where cases and controls consisted of the same patients, data were extracted according to “on-IgRT” and “off-IgRT” observation periods. Based on study design, the included studies were therefore classified into two subgroups: “independent cohort” studies and “within-patient comparison” studies. In two studies the treatment regimens were heterogeneous, while in the remaining studies patients were treated with BiTEs (four out six used teclistamab). The median duration of follow-up across studies ranged from 6 to 18.6 months, with a weighted mean follow-up of 10.6 months. In the case group, IgRT was administered as preemptive prophylaxis in seven studies, whereas primary prophylaxis was adopted in only one study. In the control group, IgRT was administered as secondary prophylaxis in four studies, while no IgRT was given in the remaining studies. IgRT was administered predominantly via the intravenous route: six studies used exclusively IVIg, one study evaluated only subcutaneous IgRT, and one study included both IVIg and SCIg-treated patients. Baseline patient characteristics are reported in Table 2. Across studies, the mean age for case group was 68.3, while for the control group was 67.1. The proportion of female patients was 50.5 for the cases group and 48.6 for the control one. Mean baseline polyclonal IgG levels, when reported, were consistently low (3.8 g/L) and comparable between cases and controls. In three studies, cases and controls consisted of the same patients observed during “on-IgRT” and “off-IgRT” periods, whereas the remaining studies compared independent patient cohorts. 3.4 Severe infection rate All included studies reported the incidence of severe infections in patients receiving preemptive/primary IgRT prophylaxis compared with controls. Individual study estimates are summarized in S-Table 3. In the overall meta-analysis, IgRT prophylaxis was associated with a significantly reduced incidence of severe infections, with a pooled HR of 0.25 (95% CI, 0.13–0.49; p < 0.0001), as shown in Fig. 1 A. Substantial heterogeneity was observed across studies (τ 2 = 0.6688; χ 2 = 57.21, df = 7, p < 0.0001; I 2 = 87.8%). In subgroup analyses according to study design, studies comparing “independent cohorts” yielded a pooled HR of 0.20 (95% CI, 0.07–0.55), with high heterogeneity (τ 2 = 1.0487; χ 2 = 37.75, df = 4, p < 0.0001; I 2 = 89.4%). Studies based on “within-patient comparisons” between “on-IgRT” and “off-IgRT” periods showed a pooled HR of 0.44 (95% CI, 0.23–0.85), with moderate heterogeneity (τ 2 = 0.1577; χ 2 = 3.31, df = 2, p = 0.1907; I 2 = 39.6%). Figure 1 B shows the funnel plot, which did not suggest the presence of publication bias. This was supported by Egger’s regression test, which did not indicate significant funnel plot asymmetry (intercept: -2.41; 95% CI: -5.45 to 0.63; t=-1.551; p = 0.172). Due to the limited availability of study-level moderators consistently reported across all included studies, meta-regression analysis could only be performed for the duration of the observation period; this analysis did not reveal a statistically significant association with the effect size. Therefore, a leave-one-out sensitivity analysis was conducted (S-Figure 2). This analysis yielded a pooled HR of 0.46 (95% CI, 0.34–0.63), with reduced heterogeneity (τ 2 = 0.0483; χ 2 = 7.69, df = 5, p = 0.1739; I 2 = 35%). The overall effect remained statistically significant (Z=-4.85; p < 0.0001). A predefined subgroup meta-analysis restricted to studies including only patients treated with BiTEs showed a pooled HR of 0.32 (95% CI, 0.18–0.56; p < 0.0001), with moderate heterogeneity (τ 2 = 0.2173; χ 2 = 10.11, df = 5, p = 0.0722; I 2 = 50.5%), as illustrated in Fig. 2 A. Within this subgroup, studies with “independent cohorts” yielded a pooled HR of 0.33 (95% CI, 0.16–0.66), whereas “within-patient comparison” studies showed a pooled HR of 0.26 (95% CI, 0.08–0.85). For the BiTEs subgroup, visual inspection of the funnel plot suggested potential asymmetry, which was supported by Egger’s regression test (intercept: -2.38; 95% CI: -3.20 to -1.56; p = 0.005), as showed in Fig. 2 B. As in the overall analysis, meta-regression could not be meaningfully performed for this subgroup because no study-level moderators were consistently available across all included BiTEs studies. Therefore, a leave-one-out sensitivity analysis was conducted (S-Figure 3). This analysis yielded a pooled HR of 0.26 (95% CI, 0.15–0.45), with low residual heterogeneity (τ 2 = 0.0625; χ 2 = 4.69, df = 4, p = 0.3206; I 2 = 14.7%). The overall effect remained statistically significant (Z=-4.78; p < 0.0001). Finally, an additional subgroup analysis within the BiTEs cohort was performed according to target and agent. In studies evaluating BCMA-directed BiTEs, IgRT prophylaxis was associated with a pooled HR of 0.19 (95% CI, 0.07–0.51), whereas in studies specifically including teclistamab the pooled HR was 0.37 (95% CI, 0.20–0.71), as shown in S-Figure 4. 4.Discussion This meta-analysis provides quantitative evidence that IgRT prophylaxis is associated with a marked reduction in the risk of severe infections in patients with MM. Overall, IgRT was associated with an approximately 75% relative reduction in the incidence of grade 3–4 infections compared with no prophylaxis or secondary prophylaxis. This effect remained consistent across sensitivity analyses and study designs, supporting the robustness of the association despite substantial baseline heterogeneity. Importantly, the available evidence is largely based on intravenous administration, as IVIg represented the predominant route in almost all included studies, indicating that the observed benefit mainly reflects the efficacy of IVIg. These findings are clinically relevant, as severe infections represent a major cause of morbidity, treatment interruption, and mortality in MM. 25 The magnitude of benefit observed in this analysis is substantial and supports the biological rationale that correction of secondary antibody deficiency can translate into meaningful clinical protection in highly immunocompromised patients. Importantly, our predefined subgroup analysis focusing on patients treated with BiTEs provides timely and novel evidence. In this population, IgRT prophylaxis was associated with an approximately 68% reduction in the risk of severe infections. However, the protective effect appeared attenuated compared with the overall population, reflecting the exceptionally high baseline infectious risk associated with BiTEs therapy. 26 These results highlight that, although IgRT is beneficial, BiTEs-treated patients remain intrinsically vulnerable to infectious complications. Notably, a further exploratory subgroup analysis within the BiTEs cohort suggested heterogeneity according to target and agent, with a greater relative risk reduction observed in studies evaluating BCMA-directed BiTEs (approximately 81% reduction in severe infections) compared with those specifically including teclistamab (approximately 63% reduction). Although limited by the small number of studies, this finding may reflect differences in patient populations, treatment exposure, or depth and duration of immune suppression, and warrants confirmation in prospective analyses. These findings are highly consistent with recent expert recommendations advocating for routine IgRT prophylaxis in patients receiving BiTEs. 6 In a recent international viewpoint, Banerjee et al. reported that patients receiving BiTEs face a persistent monthly risk of severe infections of about 3%, with cumulative rates exceeding 70%, and advocated for primary IgRT prophylaxis regardless of IgG levels. 27 They also showed that primary prophylaxis can reduce high-grade infections by up to 90% and noted that IgG thresholds alone are insufficient to identify high-risk patients. Additional real-world evidence supports the efficacy of IgRT also when administered subcutaneously in patients with MM. In the SIGNS prospective registry, IgRT markedly reduced infection rates in patients with secondary immunodeficiency, with the proportion of newly treated patients experiencing infections decreasing from 82% before treatment to 21% after one year, and a parallel reduction in severe infections, irrespective of the route of administration. 28 Similarly, in a large French prospective study including patients with MM, initiation of IgRT was associated with a significant increase in serum IgG levels and a concomitant reduction in both frequency and severity of infections, confirming the clinical benefit of IgRT in this setting. 29 Taken together, our findings strongly support systematic consideration of IgRT prophylaxis in patients receiving BiTEs, particularly as these agents are increasingly used earlier in the disease course and in frail patients. 30 This work also addresses an important gap in current clinical practice, where the use of IgRT remains highly heterogeneous and no clear evidence-based guidance exists regarding its preventive use in high-risk settings. By providing a quantitative synthesis based on time-to-event measures, our analysis offers clinically interpretable estimates that may inform future guidelines and prospective studies. Several limitations should be acknowledged. The included studies were heterogeneous in design and were predominantly retrospective, with only one randomized trial available, limiting causal inference and increasing the risk of residual confounding. Definitions of hypogammaglobulinemia and criteria for IgRT initiation varied, and immunologic parameters were inconsistently reported. Moreover, the evidence mainly reflects the use of IVIg, as only one study exclusively evaluated SCIg, precluding robust conclusions on alternative routes. Finally, the limited availability of consistently reported covariates restricted the feasibility of meta-regression analyses. Despite these limitations, the consistency of the effect across analyses supports the reliability of our findings. In conclusion, this meta-analysis demonstrates that IgRT prophylaxis confers a clinically meaningful reduction in severe infections in patients with MM, with the strongest and most consistent evidence observed in those treated with BiTEs, who represented the majority of the analyzed population. In this particularly vulnerable group, characterized by profound and prolonged immune suppression, IgRT prophylaxis was associated with a substantial attenuation of infectious risk and may represent a key component of supportive care. These findings support the systematic consideration of IgRT in patients receiving BiTEs-based therapies. Prospective, controlled studies are now needed to refine patient selection, define optimal timing, dosing, and route of administration, and to integrate IgRT into standardized infection prevention strategies in the era of T-cell-redirecting immunotherapies. 5.Conclusion This meta-analysis shows that IgRT prophylaxis markedly reduces the risk of severe infections in patients with MM, with the most compelling benefit observed in those treated with BiTEs, who account for the majority of available evidence. In this high-risk population, IgRT represents an effective and clinically relevant preventive strategy that should be systematically considered as part of supportive care. Given the profound infectious burden associated with T-cell-redirecting therapies and the limitations of IgG-guided approaches, prospective studies are now needed to optimize patient selection, timing, and route of administration. Declarations Competing interests : Authors declare no competing interests. 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 R.R. conceived the project; F.S., A.G.S. and R.R. designed the analyses; F.S., and V.D. acquired data; F.S. and A.G.S. verified the raw data before analyses and performed pre-processing informatic analysis; F.S. and R.R. performed the informatic analysis and interpreted data; F.S., A.G.S., A.V. and R.R. contributed with scientific discussions; F.S. and R.R. wrote the manuscript, which has been revised and approved by all the authors. Acknowledgement and funding : this study was funded by the Italian network of excellence for advanced diagnosis -INNOVA-, “Ministero della Salute” (code PNC-E3-2022-23683266 PNC-HLS-DA, to VD and AGS) and by European Union—Next Generation EU—PNRR M6C2— “Investimento 2.1 Potenziamento e rafforzamento della ricerca biomedica nel SSN” (project n. PNRR-POC-2022-12375862 FUSION-TARGET) to AGS. Moreover, this study was funded by “Fondo per il Programma Nazionale di Ricerca e Progetti di Rilevante Interesse Nazionale - PRIN” (code 2022ZKKWLW to AGS) and from the “Società Italiana di Medicina Interna-SIMI” 2023 Research Award (Camel to AGS). Data availability statement: Data will be provided by the author upon reasonable request. References Kyle RA, Rajkumar SV (2008) Multiple myeloma. Blood 111:2962–2972 Raje NS, Anaissie E, Kumar SK et al (2022) Consensus guidelines and recommendations for infection prevention in multiple myeloma: a report from the International Myeloma Working Group. Lancet Haematol 9:e143–e161 Jolles S, Michallet M, Agostini C, Albert MH, Edgar D, Ria R, Trentin L, Lévy V (2021) Treating secondary antibody deficiency in patients with haematological malignancy: European expert consensus. 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Studies’ characteristics. study, year study type duration, months (median) cases, n° IgRT prophylaxis criteria controls, n° IgRT prophylaxis criteria treatment IgRT route Vacca, 2018 P, RCT, SC 18 24 preemptive; severe HGG 22 no IgRT heterogeneous regimens SCIg Lancman, 2023 R, SC 18.6 37 preemptive; HGG, at physician’s discretion 37 * no IgRT BCMA BiTEs IVIg Sheu, 2023 R, SC 14 108 preemptive; HGG, at physician’s discretion 108 * no IgRT heterogeneous regimens IVIg Cheruvalath, 2024 R, MC 8.5 71 primary; physician’s discretion 97 secondary teclistamab IVIg Frerichs, 2024 P, NRS, MC 6 20 preemptive; severe HGG 32 secondary teclistamab IVIg Mohan, 2024 R, MC 6 46 preemptive; severe HGG 64 secondary teclistamab IVIg Piron, 2025 R, SC 9 24 preemptive; severe HGG 42 secondary BCMA BiTEs IVIg, SCIg Sheu, 2025 R, SC 6 28 preemptive; HGG 28 * no IgRT teclistamab IVIg total 10.6 Y 358 430 Preemptive immunoglobulin replacement therapy was defined as administration based on the presence of hypogammaglobulinemia. Primary IgRT was defined as prophylactic administration in the absence of documented hypogammaglobulinemia, at the clinician’s discretion. Secondary IgRT was defined as immunoglobulin administration initiated after a documented infectious event. BCMA BiTEs, Bispecific T-cell Engagers targeting B-cell Maturation Antigen ; HGG, hypogammaglobulinemia ; IgRT, immunoglobulin replacement therapy; IVIg, intravenous immunoglobulin ; MC, multi center; NRS, non-randomised study; P, prospective; R, retrospective; RCT, randomised controlled trial; SC, single center; SCIg, subcutaneous immunoglobulin. * Cases and controls consisted of the same patients observed during “on-IgRT” and “off-IgRT” periods. Y Value represents the weighted mean of the medians reported in individual studies, weighted by the number of patients in each trial. Table 2. Patients’ characteristics at baseline. study, year cases, n° female, % age, mean polyclonal IgG level, mean (g/L) controls, n° female, % age, mean polyclonal IgG level, mean (g/L) Vacca, 2018 24 46 71 3.2 22 45 69 3.2 Lancman, 2023 37 62 65.4 5.65 37 * 62 * 65.4 * 5.65 * Sheu, 2023 108 50.9 67.5 n.a. 108* 50.9* 67.5* n.a.* Cheruvalath, 2024 63 n.a. 69.2 Y n.a. 97 n.a. 69.2 Y n.a. Frerichs, 2024 20 45 63.8 1.39 Y 32 44 64 1.39 Y Mohan, 2024 46 49 Y 67.5 Y 5.1 Y 64 49 Y 67.5 Y 5.1 Y Piron, 2025 24 58.3 73 n.a. 42 40.5 67.4 n.a. Sheu, 2025 28 n.a. n.a. n.a. 28 n.a. n.a. n.a. total 358 50.5 § 68.3 § 3.8 § 430 48.6 §* 67.1 §* 3.8 §* *Cases and controls consisted of the same patients observed during “on-IgRT” and “off-IgRT” periods. Y The mean refers to the whole cohort of patients, given by the sum of cases and controls. § The calculation does not include studies that were not assessed for that domain. Additional Declarations The authors declare no competing interests. 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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-9187176","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Systematic Review","associatedPublications":[],"authors":[{"id":609935656,"identity":"82208abe-1116-4fc9-9484-077e43a5cfd8","order_by":0,"name":"Federico Spataro","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABDklEQVRIiWNgGAWjYBAC9gYGAwYQggN+ID4MxDy4tPAcQNZyAIglG6BacOmBaIEBkBYDIMHMgMcaHvbmjY8rCuzkGPjPHvz8oeaenPGN3IOHC2oYZOxxaeE5Vmx4xiDZmEEiL1niwLFiY7MbeQmHZxzD7TB7iRwzyQaDA4kNEjwGEgfYEhK33cgxOMzDhscv8m/Mf4K18J8x/nHgX0Li5hkgLf/waJHgMWMEa2HIMZM42JaQuEECqIW3DY8WnrRioMOSjdkk8tIszvYlGEuceWNweGafBA8wMHGE2OGNHxv+2Mnx8589fKPiW4Icf3uO8eeCbzb2wFjGD9jQ4kGCgHqIhcQoGgWjYBSMgpEIALblVEzMulflAAAAAElFTkSuQmCC","orcid":"","institution":"University of Bari Aldo Moro","correspondingAuthor":true,"prefix":"","firstName":"Federico","middleName":"","lastName":"Spataro","suffix":""},{"id":609935657,"identity":"89e5eee1-5263-4255-874e-b5df558f6bd9","order_by":1,"name":"Antonio Giovanni Solimando","email":"","orcid":"","institution":"University of Bari Aldo Moro","correspondingAuthor":false,"prefix":"","firstName":"Antonio","middleName":"Giovanni","lastName":"Solimando","suffix":""},{"id":609935658,"identity":"55f652ac-73a4-4b93-9b5c-44b2d149de58","order_by":2,"name":"Vanessa Desantis","email":"","orcid":"","institution":"University of Bari Aldo Moro","correspondingAuthor":false,"prefix":"","firstName":"Vanessa","middleName":"","lastName":"Desantis","suffix":""},{"id":609935659,"identity":"6962293d-a4dc-4499-a828-23ade7f70d05","order_by":3,"name":"Angelo Vacca","email":"","orcid":"","institution":"University of Bari Aldo Moro","correspondingAuthor":false,"prefix":"","firstName":"Angelo","middleName":"","lastName":"Vacca","suffix":""},{"id":609935660,"identity":"876f3e5f-3e34-4af9-a107-ee7ee4472c11","order_by":4,"name":"Roberto Ria","email":"","orcid":"","institution":"University of Bari Aldo Moro","correspondingAuthor":false,"prefix":"","firstName":"Roberto","middleName":"","lastName":"Ria","suffix":""}],"badges":[],"createdAt":"2026-03-21 16:45:22","currentVersionCode":1,"declarations":{"humanSubjects":true,"vertebrateSubjects":false,"conflictsOfInterestStatement":false,"humanSubjectEthicalGuidelines":true,"humanSubjectConsent":true,"humanSubjectClinicalTrial":false,"humanSubjectCaseReport":false,"vertebrateSubjectEthicalGuidelines":false},"doi":"10.21203/rs.3.rs-9187176/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9187176/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":105309067,"identity":"3f5b9385-4f6a-473b-b6fe-666753a2e9de","added_by":"auto","created_at":"2026-03-24 15:02:18","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":193149,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eEffect of immunoglobulin replacement therapy on severe infections in multiple myeloma.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eForest plot of the overall meta-analysis (A) and funnel plot for publication bias assessment (B) evaluating the association between IgRT prophylaxis and the risk of grade 3-4 infections in patients with multiple myeloma.\u003c/p\u003e\n\u003cp\u003eCI, confidence interval; IV, inverse variance; logHR, natural logarithm of the hazard ratio; SE, standard error.\u003c/p\u003e","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-9187176/v1/68a158ac30caaf5e22628d2c.jpg"},{"id":105309064,"identity":"a2f773ee-f67e-4fab-a269-3024f1bf1003","added_by":"auto","created_at":"2026-03-24 15:02:17","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":194451,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eEffect of immunoglobulin replacement therapy on severe infections in patients treated with bispecific antibodies.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eForest plot of the BiTEs subgroup meta-analysis (A) and corresponding funnel plot (B) evaluating the association between IgRT prophylaxis and the risk of grade 3-4 infections in multiple myeloma patients treated with BiTEs.\u003c/p\u003e\n\u003cp\u003eCI, confidence interval; IV, inverse variance; logHR, natural logarithm of the hazard ratio; SE, standard error.\u003c/p\u003e","description":"","filename":"Figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-9187176/v1/f524cb0baabea53037df387d.jpg"},{"id":105564546,"identity":"6e81e466-95dc-43a5-8c67-8e1cfd5d85a9","added_by":"auto","created_at":"2026-03-27 12:49:57","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1354198,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9187176/v1/005c633c-cc92-49af-8990-5e4ca310314a.pdf"},{"id":105309070,"identity":"7fe93f6f-aea6-42f7-af06-0a041ce66a33","added_by":"auto","created_at":"2026-03-24 15:02:18","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":7306804,"visible":true,"origin":"","legend":"\u003cp\u003eSupplementary\u003c/p\u003e","description":"","filename":"Supplementary.docx","url":"https://assets-eu.researchsquare.com/files/rs-9187176/v1/b3a4fc1eb582170838123463.docx"}],"financialInterests":"The authors declare no competing interests.","formattedTitle":"\u003cp\u003eImmunoglobulin prophylaxis reduces severe infections in multiple myeloma: a systematic review and meta-analysis\u003c/p\u003e","fulltext":[{"header":"1.Introduction","content":"\u003cp\u003eMultiple myeloma (MM) is a plasma cell malignancy characterized by profound immune dysfunction resulting from both disease-related immunoparesis and cumulative treatment-related immunosuppression.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e Infectious complications remain a leading cause of morbidity and mortality throughout the disease course, particularly in patients with relapsed or refractory disease.\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e Secondary antibody deficiency, driven by impaired B-cell function and suppression of normal polyclonal immunoglobulin production, represents a major determinant of infection susceptibility in this population.\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eHypogammaglobulinemia is highly prevalent in MM and may affect up to 90% of patients, depending on disease characteristics and treatment exposure. According to recent European consensus recommendations, serum IgG concentrations\u0026thinsp;\u0026lt;\u0026thinsp;4 g/L (or \u0026lt;\u0026thinsp;400 mg/dL) define severe hypogammaglobulinemia, whereas values between 4 and 6 g/L are considered mild hypogammaglobulinemia, both associated with an increased risk of severe and recurrent infections.\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e Despite its clinical relevance, routine immunologic assessment is not always systematically incorporated into MM management, and thresholds for preventive interventions vary widely across institutions.\u003c/p\u003e \u003cp\u003eThe introduction of novel therapies, including monoclonal antibodies and T-cell\u0026ndash;redirecting immunotherapies such as bispecific T-cell engagers (BiTEs) and BCMA-directed chimeric antigen receptor T (CAR-T) cells, has markedly improved outcomes in MM but has also been accompanied by a substantial burden of infectious toxicity.\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e In particular, BiTEs are frequently associated with prolonged hypogammaglobulinemia and high rates of severe infections (grade 3\u0026ndash;4), a concern that is expected to increase as these agents are moved into earlier lines of therapy and used in more fragile patients.\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e,\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eImmunoglobulin replacement therapy (IgRT) represents a potential preventive strategy in patients with secondary hypogammaglobulinemia.\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e Current expert recommendations suggest considering IgRT in patients with severe hypogammaglobulinemia and prior serious infections, as well as in selected patients with recurrent infections or poor vaccine responses.\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e,\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e However, in routine clinical practice, the use of IgRT remains highly heterogeneous, and there is no clear evidence-based guidance regarding its prophylactic use in frail patients or in those initiating highly immunosuppressive therapies such as BiTEs.\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eAlthough several retrospective studies suggest that IgRT may reduce infection rates in MM, available data are heterogeneous and derived from studies with different designs, patient populations, and treatment settings. Moreover, no quantitative synthesis has systematically evaluated the impact of IgRT on the incidence of severe infections using time-to-event measures.\u003c/p\u003e \u003cp\u003eTo address this unmet need, we conducted a systematic review and meta-analysis of published studies comparing patients with MM receiving IgRT as preemptive or primary prophylaxis with those either not receiving IgRT or receiving IgRT only as secondary prophylaxis, with the aim of quantifying the effect of IgRT prophylaxis on the incidence of severe infections.\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 was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e The study protocol was prospectively registered in the PROSPERO database (registration ID: CRD420261277656). A comprehensive literature search was performed in the MEDLINE and LILACS databases from their inception with no temporal limitations, up to the cutoff date of 30 December 2025, aiming to identify studies reporting infectious outcomes in patients with multiple myeloma receiving IgRT (S-Figure 1).\u003c/p\u003e \u003cp\u003eThe search strategy combined controlled vocabulary and free-text terms related to MM, IgRT (intravenous or subcutaneous), and infections (full strategy in the Supplementary Materials). No restrictions were applied regarding language, publication year, or geographic origin.\u003c/p\u003e \u003cp\u003eEligible studies included patients with MM receiving IgRT as primary or preemptive prophylaxis compared with patients receiving IgRT as secondary prophylaxis or no IgRT. Preemptive IgRT was defined as administration based on hypogammaglobulinemia, primary IgRT as prophylactic administration irrespective of IgG levels, and secondary IgRT as initiation after a documented infection. Hypogammaglobulinemia was primarily defined as serum polyclonal IgG\u0026thinsp;\u0026lt;\u0026thinsp;4 g/L (400 mg/dL), with studies using alternative thresholds (including\u0026thinsp;\u0026lt;\u0026thinsp;700 mg/dL) also considered eligible. No distinction was made between intravenous IgRT (IVIg) and subcutaneous IgRT (SCIg) routes of administration in the inclusion criteria.\u003c/p\u003e \u003cp\u003eBoth prospective and retrospective comparative studies were eligible, including randomized and non-randomized designs; case reports and single-patient series were excluded. Only studies reporting hazard ratios (HRs) for severe infections or providing sufficient data to estimate HRs with 95% confidence intervals were included. Reference lists of included studies and relevant reviews were manually screened to identify additional eligible publications.\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 identified through the literature search were independently screened by two reviewers (F.S. and A.G.S.). Full-text articles were subsequently assessed for eligibility. Data extraction was performed independently by the same reviewers using a standardized data collection form Rayyan.\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e Any discrepancies were resolved through discussion until consensus was reached.\u003c/p\u003e \u003cp\u003eFor each included study, information was systematically extracted on study design, length of follow-up, clinical setting, and patient population. Data collection included the number of patients receiving IgRT as preemptive or primary prophylaxis (\u0026ldquo;cases\u0026rdquo;) and those not receiving IgRT or receiving IgRT as secondary prophylaxis (\u0026ldquo;controls\u0026rdquo;), along with the criteria used for initiating IgRT, the route of immunoglobulin administration, the anti-myeloma treatment regimens, and key baseline patient characteristics. Outcome data extraction focused on measures of severe infection risk, including reported hazard ratios and their corresponding 95% confidence intervals (Cis).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e2.3 Outcomes\u003c/h2\u003e \u003cp\u003eThe primary outcome of this meta-analysis was the occurrence of severe infections, defined as grade 3\u0026ndash;4 infectious events according to the criteria used in the original studies.\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e The effect of IgRT on the risk of severe infections was evaluated using hazard ratios (HRs), comparing \u0026ldquo;cases\u0026rdquo; with \u0026ldquo;controls\u0026rdquo;. HRs were selected as the preferred summary measure as they account for variable follow-up duration and allow comparison of time-to-event data across studies with heterogeneous observation periods.\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=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e Pooled HRs with corresponding 95% CIs were calculated using random-effects models to account for between-study variability. Statistical heterogeneity was assessed using the chi-square test and quantified using the \u003cem\u003eI\u003c/em\u003e\u003csup\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sup\u003e statistic.\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e A two-sided p-value of less than 0.05 was considered statistically significant.\u003c/p\u003e \u003cp\u003eThe methodological quality of included studies was assessed using the Quality Appraisal of Case Series Studies Checklist developed by the Institute of Health Economics (IHE).\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e Each study was evaluated across all domains of the checklist, and overall study quality was considered acceptable when at least 70% of the criteria were fulfilled. The certainty of the evidence for the primary outcome was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework.\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eIn the presence of substantial heterogeneity, additional analyses were planned to explore potential sources of between-study variability. When sufficient study-level data were available and consistently reported across all included studies, meta-regression analyses were performed to evaluate the association between prespecified moderators and the risk of severe infections. Potential moderators included demographic, clinical, and treatment-related variables reported uniformly across studies. But, in situations where meta-regression was not feasible due to limited availability or inconsistency of study-level covariates, a leave-one-out sensitivity analysis was conducted by sequentially excluding individual studies to assess their influence on the pooled effect estimate and on heterogeneity. 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=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003ePublication bias was evaluated by visual inspection of funnel plots and formally assessed using Egger\u0026rsquo;s regression test.\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\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 literature search identified a total of 48 records. After screening titles and abstracts and performing full-text assessment, eight studies met the predefined inclusion criteria and were included in the quantitative synthesis. One out of eight of these studies was retrieved by citation searching. The study selection process is summarized in 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 eight 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 (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\u003eThe main characteristics of the included studies are summarized in Table\u0026nbsp;1. Overall, the analysis included eight studies with a total of 358 MM patients receiving IgRT (\u0026ldquo;cases\u0026rdquo;) and 430 not receiving IgRT (\u0026ldquo;controls\u0026rdquo;).\u003csup\u003e17\u0026ndash;24\u003c/sup\u003e Two studies employed a prospective design, including one randomized controlled trial, while the remaining studies were retrospective. Three studies were multicenter, and five were conducted at a single center. In studies where cases and controls consisted of the same patients, data were extracted according to \u0026ldquo;on-IgRT\u0026rdquo; and \u0026ldquo;off-IgRT\u0026rdquo; observation periods. Based on study design, the included studies were therefore classified into two subgroups: \u0026ldquo;independent cohort\u0026rdquo; studies and \u0026ldquo;within-patient comparison\u0026rdquo; studies. In two studies the treatment regimens were heterogeneous, while in the remaining studies patients were treated with BiTEs (four out six used teclistamab).\u003c/p\u003e \u003cp\u003eThe median duration of follow-up across studies ranged from 6 to 18.6 months, with a weighted mean follow-up of 10.6 months. In the case group, IgRT was administered as preemptive prophylaxis in seven studies, whereas primary prophylaxis was adopted in only one study. In the control group, IgRT was administered as secondary prophylaxis in four studies, while no IgRT was given in the remaining studies. IgRT was administered predominantly via the intravenous route: six studies used exclusively IVIg, one study evaluated only subcutaneous IgRT, and one study included both IVIg and SCIg-treated patients. Baseline patient characteristics are reported in Table\u0026nbsp;2. Across studies, the mean age for case group was 68.3, while for the control group was 67.1. The proportion of female patients was 50.5 for the cases group and 48.6 for the control one. Mean baseline polyclonal IgG levels, when reported, were consistently low (3.8 g/L) and comparable between cases and controls. In three studies, cases and controls consisted of the same patients observed during \u0026ldquo;on-IgRT\u0026rdquo; and \u0026ldquo;off-IgRT\u0026rdquo; periods, whereas the remaining studies compared independent patient cohorts.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003e3.4 Severe infection rate\u003c/h2\u003e \u003cp\u003eAll included studies reported the incidence of severe infections in patients receiving preemptive/primary IgRT prophylaxis compared with controls. Individual study estimates are summarized in S-Table\u0026nbsp;3.\u003c/p\u003e \u003cp\u003eIn the overall meta-analysis, IgRT prophylaxis was associated with a significantly reduced incidence of severe infections, with a pooled HR of 0.25 (95% CI, 0.13\u0026ndash;0.49; p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001), as shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eA. Substantial heterogeneity was observed across studies (τ\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0.6688; χ\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;57.21, df\u0026thinsp;=\u0026thinsp;7, p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001; \u003cem\u003eI\u003c/em\u003e\u003csup\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;87.8%). In subgroup analyses according to study design, studies comparing \u0026ldquo;independent cohorts\u0026rdquo; yielded a pooled HR of 0.20 (95% CI, 0.07\u0026ndash;0.55), with high heterogeneity (τ\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;1.0487; χ\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;37.75, df\u0026thinsp;=\u0026thinsp;4, p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001; \u003cem\u003eI\u003c/em\u003e\u003csup\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;89.4%). Studies based on \u0026ldquo;within-patient comparisons\u0026rdquo; between \u0026ldquo;on-IgRT\u0026rdquo; and \u0026ldquo;off-IgRT\u0026rdquo; periods showed a pooled HR of 0.44 (95% CI, 0.23\u0026ndash;0.85), with moderate heterogeneity (τ\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0.1577; χ\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;3.31, df\u0026thinsp;=\u0026thinsp;2, p\u0026thinsp;=\u0026thinsp;0.1907; \u003cem\u003eI\u003c/em\u003e\u003csup\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;39.6%). Figure\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eB shows the funnel plot, which did not suggest the presence of publication bias. This was supported by Egger\u0026rsquo;s regression test, which did not indicate significant funnel plot asymmetry (intercept: -2.41; 95% CI: -5.45 to 0.63; t=-1.551; p\u0026thinsp;=\u0026thinsp;0.172). Due to the limited availability of study-level moderators consistently reported across all included studies, meta-regression analysis could only be performed for the duration of the observation period; this analysis did not reveal a statistically significant association with the effect size. Therefore, a leave-one-out sensitivity analysis was conducted (S-Figure 2). This analysis yielded a pooled HR of 0.46 (95% CI, 0.34\u0026ndash;0.63), with reduced heterogeneity (τ\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0.0483; χ\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;7.69, df\u0026thinsp;=\u0026thinsp;5, p\u0026thinsp;=\u0026thinsp;0.1739; \u003cem\u003eI\u003c/em\u003e\u003csup\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;35%). The overall effect remained statistically significant (Z=-4.85; p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eA predefined subgroup meta-analysis restricted to studies including only patients treated with BiTEs showed a pooled HR of 0.32 (95% CI, 0.18\u0026ndash;0.56; p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001), with moderate heterogeneity (τ\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0.2173; χ\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;10.11, df\u0026thinsp;=\u0026thinsp;5, p\u0026thinsp;=\u0026thinsp;0.0722; \u003cem\u003eI\u003c/em\u003e\u003csup\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;50.5%), as illustrated in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA. Within this subgroup, studies with \u0026ldquo;independent cohorts\u0026rdquo; yielded a pooled HR of 0.33 (95% CI, 0.16\u0026ndash;0.66), whereas \u0026ldquo;within-patient comparison\u0026rdquo; studies showed a pooled HR of 0.26 (95% CI, 0.08\u0026ndash;0.85). For the BiTEs subgroup, visual inspection of the funnel plot suggested potential asymmetry, which was supported by Egger\u0026rsquo;s regression test (intercept: -2.38; 95% CI: -3.20 to -1.56; p\u0026thinsp;=\u0026thinsp;0.005), as showed in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eB. As in the overall analysis, meta-regression could not be meaningfully performed for this subgroup because no study-level moderators were consistently available across all included BiTEs studies. Therefore, a leave-one-out sensitivity analysis was conducted (S-Figure 3). This analysis yielded a pooled HR of 0.26 (95% CI, 0.15\u0026ndash;0.45), with low residual heterogeneity (τ\u003csup\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0.0625; χ\u003csup\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;4.69, df\u0026thinsp;=\u0026thinsp;4, p\u0026thinsp;=\u0026thinsp;0.3206; \u003cem\u003eI\u003c/em\u003e\u003csup\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;14.7%). The overall effect remained statistically significant (Z=-4.78; p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001). Finally, an additional subgroup analysis within the BiTEs cohort was performed according to target and agent. In studies evaluating BCMA-directed BiTEs, IgRT prophylaxis was associated with a pooled HR of 0.19 (95% CI, 0.07\u0026ndash;0.51), whereas in studies specifically including teclistamab the pooled HR was 0.37 (95% CI, 0.20\u0026ndash;0.71), as shown in S-Figure 4.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"4.Discussion","content":"\u003cp\u003eThis meta-analysis provides quantitative evidence that IgRT prophylaxis is associated with a marked reduction in the risk of severe infections in patients with MM. Overall, IgRT was associated with an approximately 75% relative reduction in the incidence of grade 3\u0026ndash;4 infections compared with no prophylaxis or secondary prophylaxis. This effect remained consistent across sensitivity analyses and study designs, supporting the robustness of the association despite substantial baseline heterogeneity. Importantly, the available evidence is largely based on intravenous administration, as IVIg represented the predominant route in almost all included studies, indicating that the observed benefit mainly reflects the efficacy of IVIg.\u003c/p\u003e \u003cp\u003eThese findings are clinically relevant, as severe infections represent a major cause of morbidity, treatment interruption, and mortality in MM.\u003csup\u003e25\u003c/sup\u003e The magnitude of benefit observed in this analysis is substantial and supports the biological rationale that correction of secondary antibody deficiency can translate into meaningful clinical protection in highly immunocompromised patients.\u003c/p\u003e \u003cp\u003eImportantly, our predefined subgroup analysis focusing on patients treated with BiTEs provides timely and novel evidence. In this population, IgRT prophylaxis was associated with an approximately 68% reduction in the risk of severe infections. However, the protective effect appeared attenuated compared with the overall population, reflecting the exceptionally high baseline infectious risk associated with BiTEs therapy.\u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e These results highlight that, although IgRT is beneficial, BiTEs-treated patients remain intrinsically vulnerable to infectious complications.\u003c/p\u003e \u003cp\u003eNotably, a further exploratory subgroup analysis within the BiTEs cohort suggested heterogeneity according to target and agent, with a greater relative risk reduction observed in studies evaluating BCMA-directed BiTEs (approximately 81% reduction in severe infections) compared with those specifically including teclistamab (approximately 63% reduction). Although limited by the small number of studies, this finding may reflect differences in patient populations, treatment exposure, or depth and duration of immune suppression, and warrants confirmation in prospective analyses.\u003c/p\u003e \u003cp\u003eThese findings are highly consistent with recent expert recommendations advocating for routine IgRT prophylaxis in patients receiving BiTEs.\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e In a recent international viewpoint, Banerjee et al. reported that patients receiving BiTEs face a persistent monthly risk of severe infections of about 3%, with cumulative rates exceeding 70%, and advocated for primary IgRT prophylaxis regardless of IgG levels.\u003csup\u003e\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e They also showed that primary prophylaxis can reduce high-grade infections by up to 90% and noted that IgG thresholds alone are insufficient to identify high-risk patients.\u003c/p\u003e \u003cp\u003eAdditional real-world evidence supports the efficacy of IgRT also when administered subcutaneously in patients with MM. In the SIGNS prospective registry, IgRT markedly reduced infection rates in patients with secondary immunodeficiency, with the proportion of newly treated patients experiencing infections decreasing from 82% before treatment to 21% after one year, and a parallel reduction in severe infections, irrespective of the route of administration.\u003csup\u003e\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e Similarly, in a large French prospective study including patients with MM, initiation of IgRT was associated with a significant increase in serum IgG levels and a concomitant reduction in both frequency and severity of infections, confirming the clinical benefit of IgRT in this setting.\u003csup\u003e\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eTaken together, our findings strongly support systematic consideration of IgRT prophylaxis in patients receiving BiTEs, particularly as these agents are increasingly used earlier in the disease course and in frail patients.\u003csup\u003e\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThis work also addresses an important gap in current clinical practice, where the use of IgRT remains highly heterogeneous and no clear evidence-based guidance exists regarding its preventive use in high-risk settings. By providing a quantitative synthesis based on time-to-event measures, our analysis offers clinically interpretable estimates that may inform future guidelines and prospective studies.\u003c/p\u003e \u003cp\u003eSeveral limitations should be acknowledged. The included studies were heterogeneous in design and were predominantly retrospective, with only one randomized trial available, limiting causal inference and increasing the risk of residual confounding. Definitions of hypogammaglobulinemia and criteria for IgRT initiation varied, and immunologic parameters were inconsistently reported. Moreover, the evidence mainly reflects the use of IVIg, as only one study exclusively evaluated SCIg, precluding robust conclusions on alternative routes. Finally, the limited availability of consistently reported covariates restricted the feasibility of meta-regression analyses. Despite these limitations, the consistency of the effect across analyses supports the reliability of our findings.\u003c/p\u003e \u003cp\u003eIn conclusion, this meta-analysis demonstrates that IgRT prophylaxis confers a clinically meaningful reduction in severe infections in patients with MM, with the strongest and most consistent evidence observed in those treated with BiTEs, who represented the majority of the analyzed population. In this particularly vulnerable group, characterized by profound and prolonged immune suppression, IgRT prophylaxis was associated with a substantial attenuation of infectious risk and may represent a key component of supportive care. These findings support the systematic consideration of IgRT in patients receiving BiTEs-based therapies. Prospective, controlled studies are now needed to refine patient selection, define optimal timing, dosing, and route of administration, and to integrate IgRT into standardized infection prevention strategies in the era of T-cell-redirecting immunotherapies.\u003c/p\u003e"},{"header":"5.Conclusion","content":"\u003cp\u003eThis meta-analysis shows that IgRT prophylaxis markedly reduces the risk of severe infections in patients with MM, with the most compelling benefit observed in those treated with BiTEs, who account for the majority of available evidence. In this high-risk population, IgRT represents an effective and clinically relevant preventive strategy that should be systematically considered as part of supportive care. Given the profound infectious burden associated with T-cell-redirecting therapies and the limitations of IgG-guided approaches, prospective studies are now needed to optimize patient selection, timing, and route of administration.\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 \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 R.R. conceived the project; F.S., A.G.S. and R.R. designed the analyses; F.S., and V.D. acquired data; F.S. and A.G.S. verified the raw data before analyses and performed pre-processing informatic analysis; F.S. and R.R. performed the informatic analysis and interpreted data; F.S., A.G.S., A.V. and R.R. contributed with scientific discussions; F.S. and R.R. 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: this study was funded by the Italian network of excellence for advanced diagnosis -INNOVA-, \u0026ldquo;Ministero della Salute\u0026rdquo; (code PNC-E3-2022-23683266 PNC-HLS-DA, to VD and AGS) and by European Union\u0026mdash;Next Generation EU\u0026mdash;PNRR M6C2\u0026mdash; \u0026ldquo;Investimento 2.1 Potenziamento e rafforzamento della ricerca biomedica nel SSN\u0026rdquo; (project n. PNRR-POC-2022-12375862 FUSION-TARGET) to AGS. Moreover, this study was funded by \u0026ldquo;Fondo per il Programma Nazionale di Ricerca e Progetti di Rilevante Interesse Nazionale - PRIN\u0026rdquo; (code 2022ZKKWLW to AGS) and from the \u0026ldquo;Societ\u0026agrave; Italiana di Medicina Interna-SIMI\u0026rdquo; 2023 Research Award (Camel to AGS).\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. Blood 111:2962\u0026ndash;2972\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRaje NS, Anaissie E, Kumar SK et al (2022) Consensus guidelines and recommendations for infection prevention in multiple myeloma: a report from the International Myeloma Working Group. 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Stat Methods Med Res 33:745\u0026ndash;764\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMoga 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\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSchunemann H, Brożek J, Guyatt G et al (2013) GRADE Handbook. Grading of Recommendations Assessment, Development and Evaluation. GRADE Working Group\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBetween-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\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEgger M, Davey Smith G, Schneider M et al (1997) Bias in meta-analysis detected by a simple, graphical test. BMJ 315(7109):629\u0026ndash;634\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVacca A, Melaccio A, Sportelli A et al (2018) Subcutaneous immunoglobulins in patients with multiple myeloma and secondary hypogammaglobulinemia: a randomized trial. Clin Immunol 191:110\u0026ndash;115\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLancman G, Parsa K, Kotlarz K et al (2023) IVIg Use Associated with Ten-Fold Reduction of Serious Infections in Multiple Myeloma Patients Treated with Anti-BCMA Bispecific Antibodies. Blood Cancer Discov 4:440\u0026ndash;451\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSheu M, Molina Garcia S, Patel M et al (2023) Intravenous immunoglobulin prophylaxis is associated with decreased rate of infection-related hospitalizations in multiple myeloma patients. Hematol Oncol 41:718\u0026ndash;724\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCheruvalath H, Clennon A, Shresth A et al (2024) Effects of Intravenous Immunoglobulin Supplementation (IVIG) on Infections in Recipients of Teclistamab Therapy for Multiple Myeloma (MM): A Multi-Institutional Study. Blood 144(Supplement 1):256\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFrerichs KA, Verkleij CPM, Mateos MV et al (2024) Teclistamab impairs humoral immunity in patients with heavily pretreated myeloma: importance of immunoglobulin supplementation. Blood Adv 8:194\u0026ndash;206\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\u003ePiron B, Rodrigo L, Tessoulin B, Gastinne T, Dubruille V, Letailleur V, Antier C, Lok A, Leroy E, Moreau P, Fronteau C, Touzeau C (2025) Preemptive Immunoglobulin Prophylaxis Reduces Infections in Patients Treated With Anti-BCMA Bispecific Antibodies. Clin Lymphoma Myeloma Leuk. Oct 31:S2152-2650(25)04264-8.\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\u003eJolles S, Giralt S, Kerre T et al (2023) Agents contributing to secondary immunodeficiency development in patients with multiple myeloma, chronic lymphocytic leukemia and non-Hodgkin lymphoma: A systematic literature review. Front Oncol 13:1098326\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\u003eBanerjee R, Mohan M, Rejeski K et al (2025) Immunoglobulin prophylaxis should be initiated after bispecific antibody therapy in multiple myeloma, regardless of IgG levels. Blood Adv 9:4720\u0026ndash;4726\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eReiser M, Borte M, Huscher D et al (2017) Management of patients with malignancies and secondary immunodeficiencies treated with immunoglobulins in clinical practice: Long-term data of the SIGNS study. Eur J Haematol 99:169\u0026ndash;177\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBenbrahim O, Viallard JF, Choquet S et al (2019) The use of octagam and gammanorm in immunodeficiency associated with hematological malignancies: a prospective study from 21 French hematology departments. Hematology 24:173\u0026ndash;182\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"},{"header":"Tables","content":"\u003cp\u003eTable 1. Studies\u0026rsquo; characteristics.\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"1011\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 10.2767%;\"\u003e\n \u003cp\u003e\u003cstrong\u003estudy, year\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.39921%;\"\u003e\n \u003cp\u003e\u003cstrong\u003estudy type\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13.0435%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eduration, months (median)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 7.50988%;\"\u003e\n \u003cp\u003e\u003cstrong\u003ecases, n\u0026deg;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.7866%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eIgRT prophylaxis\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003ecriteria\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 7.50988%;\"\u003e\n \u003cp\u003e\u003cstrong\u003econtrols, n\u0026deg;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.9091%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eIgRT prophylaxis criteria\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.166%;\"\u003e\n \u003cp\u003e\u003cstrong\u003etreatment\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.39921%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eIgRT route\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 10.2767%;\"\u003e\n \u003cp\u003eVacca, 2018\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.39921%;\"\u003e\n \u003cp\u003eP, RCT, SC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13.0435%;\"\u003e\n \u003cp\u003e18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 7.50988%;\"\u003e\n \u003cp\u003e24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.7866%;\"\u003e\n \u003cp\u003epreemptive; severe HGG\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 7.50988%;\"\u003e\n \u003cp\u003e22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.9091%;\"\u003e\n \u003cp\u003eno IgRT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.166%;\"\u003e\n \u003cp\u003eheterogeneous regimens\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.39921%;\"\u003e\n \u003cp\u003eSCIg\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 10.2767%;\"\u003e\n \u003cp\u003eLancman, 2023\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.39921%;\"\u003e\n \u003cp\u003eR, SC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13.0435%;\"\u003e\n \u003cp\u003e18.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 7.50988%;\"\u003e\n \u003cp\u003e37\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.7866%;\"\u003e\n \u003cp\u003epreemptive; HGG, at physician\u0026rsquo;s discretion\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 7.50988%;\"\u003e\n \u003cp\u003e37\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.9091%;\"\u003e\n \u003cp\u003eno IgRT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.166%;\"\u003e\n \u003cp\u003eBCMA BiTEs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.39921%;\"\u003e\n \u003cp\u003eIVIg\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 10.2767%;\"\u003e\n \u003cp\u003eSheu, 2023\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.39921%;\"\u003e\n \u003cp\u003eR, SC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13.0435%;\"\u003e\n \u003cp\u003e14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 7.50988%;\"\u003e\n \u003cp\u003e108\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.7866%;\"\u003e\n \u003cp\u003epreemptive; HGG, at physician\u0026rsquo;s discretion\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 7.50988%;\"\u003e\n \u003cp\u003e108\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.9091%;\"\u003e\n \u003cp\u003eno IgRT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.166%;\"\u003e\n \u003cp\u003eheterogeneous regimens\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.39921%;\"\u003e\n \u003cp\u003eIVIg\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 10.2767%;\"\u003e\n \u003cp\u003eCheruvalath, 2024\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.39921%;\"\u003e\n \u003cp\u003eR, MC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13.0435%;\"\u003e\n \u003cp\u003e8.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 7.50988%;\"\u003e\n \u003cp\u003e71\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.7866%;\"\u003e\n \u003cp\u003eprimary; physician\u0026rsquo;s discretion\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 7.50988%;\"\u003e\n \u003cp\u003e97\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.9091%;\"\u003e\n \u003cp\u003esecondary\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.166%;\"\u003e\n \u003cp\u003eteclistamab\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.39921%;\"\u003e\n \u003cp\u003eIVIg\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 10.2767%;\"\u003e\n \u003cp\u003eFrerichs, 2024\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.39921%;\"\u003e\n \u003cp\u003eP, NRS, MC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13.0435%;\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 7.50988%;\"\u003e\n \u003cp\u003e20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.7866%;\"\u003e\n \u003cp\u003epreemptive; severe HGG\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 7.50988%;\"\u003e\n \u003cp\u003e32\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.9091%;\"\u003e\n \u003cp\u003esecondary\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.166%;\"\u003e\n \u003cp\u003eteclistamab\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.39921%;\"\u003e\n \u003cp\u003eIVIg\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 10.2767%;\"\u003e\n \u003cp\u003eMohan, 2024\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.39921%;\"\u003e\n \u003cp\u003eR, MC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13.0435%;\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 7.50988%;\"\u003e\n \u003cp\u003e46\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.7866%;\"\u003e\n \u003cp\u003epreemptive; severe HGG\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 7.50988%;\"\u003e\n \u003cp\u003e64\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.9091%;\"\u003e\n \u003cp\u003esecondary\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.166%;\"\u003e\n \u003cp\u003eteclistamab\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.39921%;\"\u003e\n \u003cp\u003eIVIg\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 10.2767%;\"\u003e\n \u003cp\u003ePiron, 2025\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.39921%;\"\u003e\n \u003cp\u003eR, SC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13.0435%;\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 7.50988%;\"\u003e\n \u003cp\u003e24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.7866%;\"\u003e\n \u003cp\u003epreemptive; severe HGG\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 7.50988%;\"\u003e\n \u003cp\u003e42\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.9091%;\"\u003e\n \u003cp\u003esecondary\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.166%;\"\u003e\n \u003cp\u003eBCMA BiTEs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.39921%;\"\u003e\n \u003cp\u003eIVIg, SCIg\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 10.2767%;\"\u003e\n \u003cp\u003eSheu, 2025\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.39921%;\"\u003e\n \u003cp\u003eR, SC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13.0435%;\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 7.50988%;\"\u003e\n \u003cp\u003e28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.7866%;\"\u003e\n \u003cp\u003epreemptive; HGG\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 7.50988%;\"\u003e\n \u003cp\u003e28\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.9091%;\"\u003e\n \u003cp\u003eno IgRT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.166%;\"\u003e\n \u003cp\u003eteclistamab\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.39921%;\"\u003e\n \u003cp\u003eIVIg\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 10.2767%;\"\u003e\n \u003cp\u003e\u003cstrong\u003etotal\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.39921%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 13.0435%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e10.6\u003c/strong\u003e\u003cstrong\u003e\u003csup\u003eY\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 7.50988%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e358\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 17.7866%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 7.50988%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e430\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15.9091%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11.166%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.39921%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003ePreemptive immunoglobulin replacement therapy was defined as administration based on the presence of hypogammaglobulinemia. Primary IgRT was defined as prophylactic administration in the absence of documented hypogammaglobulinemia, at the clinician\u0026rsquo;s discretion. Secondary IgRT was defined as immunoglobulin administration initiated after a documented infectious event.\u003c/p\u003e\n\u003cp\u003eBCMA BiTEs, Bispecific T-cell Engagers targeting B-cell Maturation Antigen\u003cstrong\u003e;\u0026nbsp;\u003c/strong\u003eHGG, hypogammaglobulinemia\u003cstrong\u003e;\u0026nbsp;\u003c/strong\u003eIgRT,\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eimmunoglobulin replacement therapy;\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eIVIg, intravenous immunoglobulin\u003cstrong\u003e;\u003c/strong\u003e MC, multi center; NRS, non-randomised study; P, prospective; R, retrospective; RCT, randomised controlled trial; SC, single center; SCIg, subcutaneous immunoglobulin.\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e*\u003c/sup\u003eCases and controls consisted of the same patients observed during \u0026ldquo;on-IgRT\u0026rdquo; and \u0026ldquo;off-IgRT\u0026rdquo; periods.\u003c/p\u003e\n\u003cp\u003e\u003csup\u003eY\u003c/sup\u003eValue represents the weighted mean of the medians reported in individual studies, weighted by the number of patients in each trial.\u003cbr clear=\"all\"\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTable 2. Patients\u0026rsquo; characteristics at baseline.\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"916\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 15.2838%;\"\u003e\n \u003cp\u003e\u003cstrong\u003estudy, year\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.0786%;\"\u003e\n \u003cp\u003e\u003cstrong\u003ecases, n\u0026deg;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.38865%;\"\u003e\n \u003cp\u003e\u003cstrong\u003efemale, %\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.27948%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eage, mean\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.4105%;\"\u003e\n \u003cp\u003e\u003cstrong\u003epolyclonal IgG level, mean (g/L)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.262%;\"\u003e\n \u003cp\u003e\u003cstrong\u003econtrols, n\u0026deg;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.60699%;\"\u003e\n \u003cp\u003e\u003cstrong\u003efemale, %\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.27948%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eage, mean\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.4105%;\"\u003e\n \u003cp\u003e\u003cstrong\u003epolyclonal IgG level, mean (g/L)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 15.2838%;\"\u003e\n \u003cp\u003eVacca, 2018\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.0786%;\"\u003e\n \u003cp\u003e24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.38865%;\"\u003e\n \u003cp\u003e46\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.27948%;\"\u003e\n \u003cp\u003e71\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.4105%;\"\u003e\n \u003cp\u003e3.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.262%;\"\u003e\n \u003cp\u003e22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.60699%;\"\u003e\n \u003cp\u003e45\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.27948%;\"\u003e\n \u003cp\u003e69\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.4105%;\"\u003e\n \u003cp\u003e3.2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 15.2838%;\"\u003e\n \u003cp\u003eLancman, 2023\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.0786%;\"\u003e\n \u003cp\u003e37\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.38865%;\"\u003e\n \u003cp\u003e62\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.27948%;\"\u003e\n \u003cp\u003e65.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.4105%;\"\u003e\n \u003cp\u003e5.65\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.262%;\"\u003e\n \u003cp\u003e37\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.60699%;\"\u003e\n \u003cp\u003e62\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.27948%;\"\u003e\n \u003cp\u003e65.4\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.4105%;\"\u003e\n \u003cp\u003e5.65\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 15.2838%;\"\u003e\n \u003cp\u003eSheu, 2023\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.0786%;\"\u003e\n \u003cp\u003e108\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.38865%;\"\u003e\n \u003cp\u003e50.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.27948%;\"\u003e\n \u003cp\u003e67.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.4105%;\"\u003e\n \u003cp\u003en.a.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.262%;\"\u003e\n \u003cp\u003e108*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.60699%;\"\u003e\n \u003cp\u003e50.9*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.27948%;\"\u003e\n \u003cp\u003e67.5*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.4105%;\"\u003e\n \u003cp\u003en.a.*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 15.2838%;\"\u003e\n \u003cp\u003eCheruvalath, 2024\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.0786%;\"\u003e\n \u003cp\u003e63\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.38865%;\"\u003e\n \u003cp\u003en.a.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.27948%;\"\u003e\n \u003cp\u003e69.2\u003csup\u003eY\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.4105%;\"\u003e\n \u003cp\u003en.a.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.262%;\"\u003e\n \u003cp\u003e97\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.60699%;\"\u003e\n \u003cp\u003en.a.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.27948%;\"\u003e\n \u003cp\u003e69.2\u003csup\u003eY\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.4105%;\"\u003e\n \u003cp\u003en.a.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 15.2838%;\"\u003e\n \u003cp\u003eFrerichs, 2024\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.0786%;\"\u003e\n \u003cp\u003e20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.38865%;\"\u003e\n \u003cp\u003e45\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.27948%;\"\u003e\n \u003cp\u003e63.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.4105%;\"\u003e\n \u003cp\u003e1.39\u003csup\u003eY\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.262%;\"\u003e\n \u003cp\u003e32\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.60699%;\"\u003e\n \u003cp\u003e44\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.27948%;\"\u003e\n \u003cp\u003e64\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.4105%;\"\u003e\n \u003cp\u003e1.39\u003csup\u003eY\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 15.2838%;\"\u003e\n \u003cp\u003eMohan, 2024\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.0786%;\"\u003e\n \u003cp\u003e46\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.38865%;\"\u003e\n \u003cp\u003e49\u003csup\u003eY\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.27948%;\"\u003e\n \u003cp\u003e67.5\u003csup\u003eY\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.4105%;\"\u003e\n \u003cp\u003e5.1\u003csup\u003eY\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.262%;\"\u003e\n \u003cp\u003e64\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.60699%;\"\u003e\n \u003cp\u003e49\u003csup\u003eY\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.27948%;\"\u003e\n \u003cp\u003e67.5\u003csup\u003eY\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.4105%;\"\u003e\n \u003cp\u003e5.1\u003csup\u003eY\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 15.2838%;\"\u003e\n \u003cp\u003ePiron, 2025\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.0786%;\"\u003e\n \u003cp\u003e24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.38865%;\"\u003e\n \u003cp\u003e58.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.27948%;\"\u003e\n \u003cp\u003e73\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.4105%;\"\u003e\n \u003cp\u003en.a.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.262%;\"\u003e\n \u003cp\u003e42\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.60699%;\"\u003e\n \u003cp\u003e40.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.27948%;\"\u003e\n \u003cp\u003e67.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.4105%;\"\u003e\n \u003cp\u003en.a.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 15.2838%;\"\u003e\n \u003cp\u003eSheu, 2025\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.0786%;\"\u003e\n \u003cp\u003e28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.38865%;\"\u003e\n \u003cp\u003en.a.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.27948%;\"\u003e\n \u003cp\u003en.a.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.4105%;\"\u003e\n \u003cp\u003en.a.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.262%;\"\u003e\n \u003cp\u003e28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.60699%;\"\u003e\n \u003cp\u003en.a.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.27948%;\"\u003e\n \u003cp\u003en.a.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.4105%;\"\u003e\n \u003cp\u003en.a.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 15.2838%;\"\u003e\n \u003cp\u003e\u003cstrong\u003etotal\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 8.0786%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e358\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.38865%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e50.5\u003c/strong\u003e\u003cstrong\u003e\u003csup\u003e\u0026sect;\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.27948%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e68.3\u003c/strong\u003e\u003cstrong\u003e\u003csup\u003e\u0026sect;\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.4105%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e3.8\u003c/strong\u003e\u003cstrong\u003e\u003csup\u003e\u0026sect;\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10.262%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e430\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.60699%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e48.6\u003c/strong\u003e\u003cstrong\u003e\u003csup\u003e\u0026sect;*\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9.27948%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e67.1\u003c/strong\u003e\u003cstrong\u003e\u003csup\u003e\u0026sect;*\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 14.4105%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e3.8\u003c/strong\u003e\u003cstrong\u003e\u003csup\u003e\u0026sect;*\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e*Cases and controls consisted of the same patients observed during \u0026ldquo;on-IgRT\u0026rdquo; and \u0026ldquo;off-IgRT\u0026rdquo; periods.\u003c/p\u003e\n\u003cp\u003e\u003csup\u003eY\u003c/sup\u003eThe mean refers to the whole cohort of patients, given by the sum of cases and controls.\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e\u0026sect;\u003c/sup\u003eThe calculation does not include studies that were not assessed for that domain.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"University of Bari Aldo Moro","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, immunoglobulin replacement therapy, IgRT, IVIg, SCIg, infections","lastPublishedDoi":"10.21203/rs.3.rs-9187176/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9187176/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground.\u003c/h2\u003e \u003cp\u003eMultiple myeloma (MM) is associated with profound immune dysfunction, predisposing patients to severe infections. Immunoglobulin replacement therapy (IgRT) may reduce infection risk, but evidence is heterogeneous and mainly limited to intravenous administration. Its impact, particularly in patients receiving modern therapies such as bispecific T-cell engagers (BiTEs), remains unclear.\u003c/p\u003e\u003ch2\u003eMethods.\u003c/h2\u003e \u003cp\u003eWe performed a systematic review and meta-analysis of studies comparing MM patients receiving IgRT as preemptive or primary prophylaxis versus those receiving secondary or no IgRT. MEDLINE and LILACS were searched up to December 30, 2025. Both intravenous (IVIg) and subcutaneous (SCIg) routes were included. Comparative studies reporting hazard ratios (HRs) for severe infections or sufficient data to derive them were included, with HRs pooled using random-effects models.\u003c/p\u003e\u003ch2\u003eResults.\u003c/h2\u003e \u003cp\u003eEight studies (358 IgRT-treated, 430 controls) were included, predominantly using IVIg; one study exclusively used SCIg and one included both IVIg and SCIg. IgRT prophylaxis was associated with a 75% reduction in severe infections (pooled HR 0.25, 95% CI 0.13\u0026ndash;0.49, p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001). In BiTEs-treated patients, HR was 0.32 (95% CI 0.18\u0026ndash;0.56, p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001). Results were robust across study designs and sensitivity analyses, with low heterogeneity after leave-one-out analysis.\u003c/p\u003e\u003ch2\u003eConclusions.\u003c/h2\u003e \u003cp\u003eIgRT prophylaxis substantially reduces severe infections in MM, including high-risk BiTEs-treated patients. The benefit is clinically meaningful and mainly reflects IVIg use, though limited evidence suggests SCIg is also effective. These findings support systematic consideration of IgRT in high-risk MM populations, with prospective studies needed to optimize timing, patient selection, and administration.\u003c/p\u003e","manuscriptTitle":"Immunoglobulin prophylaxis reduces severe infections in multiple myeloma: a systematic review and meta-analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-03-24 15:02:07","doi":"10.21203/rs.3.rs-9187176/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":"March 24th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":64904341,"name":"Hematology"},{"id":64904342,"name":"Immunology"}],"tags":[],"updatedAt":"2026-03-24T15:02:07+00:00","versionOfRecord":[],"versionCreatedAt":"2026-03-24 15:02:07","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9187176","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9187176","identity":"rs-9187176","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}