# Preemptive Immunoglobulin Prophylaxis Reduces Infections in Patients Treated With Anti-BCMA Bispecific Antibodies

Bénédicte Piron, Laura Rodrigo, Benoît Tessoulin, Thomas Gastinne, Viviane Dubruille, Valentin Letailleur, Chloé Antier, Anne Lok, Estelle Leroy, Philippe Moreau, et al.

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Bénédicte Piron, Laura Rodrigo, Benoît Tessoulin, Thomas Gastinne, Viviane Dubruille, et al. Preemptive Immunoglobulin Prophylaxis Reduces Infections in Patients Treated With Anti-BCMA Bispecific Antibodies. Clinical Lymphoma Myeloma and Leukemia, 2025, 10.1016/j.clml.2025.10.024. hal-05488790

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Original Study

# Preemptive Immunoglobulin Prophylaxis Reduces Infections in Patients Treated With Anti-BCMA Bispecific Antibodies

Bénédicte Piron,<fnref n="1" /> Laura Rodrigo,<fnref n="2" /> Benoît Tessouin,<fnref n="1" />,<fnref n="3" />,<fnref n="4" /> Thomas Gastinne,<fnref n="1" />
Viviane Dubruille,<fnref n="1" /> Valentin Letailleur,<fnref n="1" /> Chloé Antier,<fnref n="1" /> Anne Lok,<fnref n="1" />,<fnref n="3" /> Estelle Leroy,<fnref n="2" />
Philippe Moreau,<fnref n="1" />,<fnref n="3" />,<fnref n="4" /> Clémentine Fronteau,<fnref n="2" /> Cyrille Touzeau<fnref n="1" />,<fnref n="3" />,<fnref n="4" />

## Abstract

Bispecific antibodies (BsAbs) targeting BCMA are now a standard of care for the treatment of triple-class exposed relapsed multiple myeloma (MM) patients but are associated with high rate of infections. International guidelines now recommend the use of systematic preemptive immunoglobulin (IG) supplementation for patients with IgG level less than 400 mg/dL. We present here the results of a single center retrospective study evaluating the impact of preemptive IG prophylaxy (versus seocndary prophylaxy) in patients treated with BCMA bispecific antibodies (n = 68). Over an equivalent 9-months observation period, patients in the preemptive IG group experienced a significant 66% reduction in all-grade infections (HR 0.34; 95% CI, 0.19-0.60; p = 0.0002) and a 76% reduction in severe infections (HR 0.24; 95% CI, 0.08-0.69; p = 0.0084). This study therefore supports the benefit of early and preemptive IG supplementation in reducing both severe and non-severe infections in MM patients treated with anti-BCMA BsAbs.

**Background:** Bispecific antibodies (BsAbs) targeting B-cell maturation antigen (BCMA) have improved outcomes for patients with relapsed/refractory multiple myeloma (MM). However, hypogammaglobulinemia driven by normal plasma cell depletion expose patients to high risk of infections. Immunoglobulin (IG) prophylaxis is recommended in patients receiving BsAbs and IgG level < 400 mg/dL. Real world evidence of the impact of preemptive IG prophylaxis remains limited. **Methods:** We conducted a retrospective, single-center study including all consecutive MM patients receiving anti-BCMA BsAbs between December 2020 and May 2024. Patients started treatment before June 1, 2023, received IG as secondary prophylaxis. In contrast, patients treated after this date received preemptive IG prophylaxis if IgG level < 400 mg/dL in alignment with international recommendations. **Results:** From Dec 2020 to June 2023, 42 patients received secondary IG prophylaxis with a median initiation time of 7.8 months from first anti-BCMA BsAb injection. From July 2023 to May 2024, 24 received preemptive IG prophylaxis with a median time to initiation of 1.6 months. During a 9-months observation period, patients in the preemptive IG group experienced a significant 66% reduction in all-grade infections (HR 0.34; 95% CI, 0.19-0.60; *P* = .0002) and 76% reduction in severe infections (HR 0.24; 95% CI, 0.08-0.69; *P* = .0084). Infections also occurred earlier without preemptive supplementation. **Conclusion:** This study supports the benefit of early and preemptive IG supplementation in reducing severe and non-severe infections in patients treated with anti-BCMA BsAbs. Prospective studies are needed to confirm these findings, assess cost-effectiveness, and define optimal IG duration and route administration.

*Clinical Lymphoma, Myeloma and Leukemia*, Vol. 000, No. xxx, 1–8 © 2025 The Author(s). Published by Elsevier Inc.
This is an open access article under the CC BY license ([http://creativecommons.org/licenses/by/4.0/](http://creativecommons.org/licenses/by/4.0/))
**Keywords:** Hypogammaglobulinemia, Multiple myeloma, Infectious risk, Elranatamab, Teclistamab

<footnote n="1">¹Department of Hematology, University Hospital, Nantes, France</footnote>

<footnote n="2">²Clinical Pharmacy Unit, Nantes University Hospital, Nantes, France</footnote>

<footnote n="3">³CRCINA, INSERM, CNRS, University of Angers, University of Nantes, Nantes, France</footnote>

<footnote n="4">⁴Site de Recherche Intégrée sur le Cancer (SIRIC) « ILIAD», INCA-DGOS-Inserm_12558, Nantes, France</footnote>

<footnote>Submitted: Sep 12, 2025; Revised: Oct 27, 2025; Accepted: Oct 29, 2025; Epub: xxx</footnote>

<footnote>Address for correspondence: Bénédicte PIRON, MD, Department of Hematology, University Hospital, 1 place Alexis Ricordeau, Cedex 01, Nantes, 44093, France
E-mail contact: benedicte.piron@chu-nantes.fr</footnote>
# Preemptive Immunoglobulin Prophylaxis Reduces Infections

## Introduction

Bispecific antibodies (BsAbs) targeting B-cell maturation antigen (BCMA) and CD3 have become a new standard of care for the treatment of triple class exposed patients with relapsed and refractory myeloma.¹⁻⁴ Although these BsAbs generally have a favorable safety profile, infectious events occur frequently,⁵,⁶ and can be life-threatening,⁷⁻¹⁰ as notably observed in phase II studies.¹,² Profound hypogammaglobulinemia,¹¹⁻¹³ plays a central role in these infections, in addition with concomitant neutropenia and immune effector cell exhaustion.⁴,⁸,¹⁴ Since 2023, International guidelines recommend preemptive administration of immunoglobulin (IG) for patients with low IgG concentrations (< 400 mg/dL).¹²,¹⁵,¹⁶

However, real-world evidence supporting these strategies remains limited, especially regarding the timing for IG initiation. In this retrospective single-center study, we compared preemptive versus reactive IG prophylaxis in patients treated with anti-BCMA BsAbs, aiming to evaluate their impact on infection rates.

## Methods

We conducted a single-center, retrospective observational study including all consecutive patients who received BCMA-targeted BsAb (teclistamab or elranatamab) in the Hematology Department of the University Hospital of Nantes between December 2020 and May 2024. Patients were divided into 2 groups according to the prophylactic strategy used. The secondary prophylaxis group included patients who received IG supplementation only in response to infectious events and hypogammaglobulinemia. The preemptive IG supplementation group included patients who received IG systematically, particularly when IgG levels were below 400 mg/dL, regardless of their infectious clinical history. The cut-off date of June 1, 2023 marked the implementation of preemptive prophylaxis in our center, in alignment with the consensus recommendations published in the same period by the European Myeloma Network (EMN)¹⁵ and from an expert panel.¹⁷ Gammaglobulinemia was assessed every 3 months up to 9 months after initial anti-BCMA injection, by subtracting the monoclonal immunoglobulin (Ig) and defined as an IgG level < 400 mg/dL.¹⁶ To ensure data comparability between groups, we restricted the analysis of infectious events to a 9-month follow-up period after initiation of BsAb. This approach was chosen to avoid bias related to a longer median follow-up in the non-preemptive IG supplementation group.

Because cytokine release syndrome (eg chills) presents with signs and symptoms like those of infection, any infection was confirmed by clinical, imaging, microbiological and/or histopathological tests, and was recorded from the first day of the first cycle up to 9 months after the first anti-BCMA BsAb injection. All patients have been brought up to date with pneumococcal and COVID vaccinations and all also received prophylaxis for herpes zoster (valaciclovir) and pneumocystis jirovecii pneumonia prophylaxis (cotrimoxazole, or pentamidine in case of cotrimoxazole allergy). Infections were classified as bacterial, viral, or fungal based on microbiological confirmation only. Grading of infections was performed using the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 of the National Cancer Institute (NCI). Cytokine release syndrome (CRS) and immune effector cell associated neurotoxicity syndrome (ICANS) were defined according to the American Society for Trans-

plantation and Cellular Therapy consensus (ASTCT) and managed according to institutional guidelines.¹⁸

Neutropenia was defined as an absolute neutrophil count (ANC) of less than 1.0 × 10³/µL, while lymphopenia was defined as an absolute lymphocyte count (ALC) of less than 1.0 × 10³/µL.

High-risk cytogenetic characteristics, defined by fluorescence in situ hybridization (FISH) or next-generation sequencing (NGS) when available, has included (4;14), (14;16) translocations, 1q21 amplification, 1p32 deletion, 17p deletion or TP53 mutation. Triple-class exposed/refractory patients were defined as exposed/refractory to ≥ 1 immunomodulatory drug (IMiDs), ≥ 1 proteasome inhibitor (PI), and ≥ 1 anti-CD38 monoclonal antibody (mAb).

The date of the last update of patient data for this study was March 10, 2025. After this date, no changes or events were considered.

The patients provided their written informed consent to participate in this study (MYRACLE study; NCT03807128).¹⁹

## Statistical Analysis

Demographic and disease characteristics of the study population were summarized using counts with percentages for categorical variables and medians with interquartile range (IQR). Categorical variables are compared with the Chi-squared test or Fisher's exact test, continuous variables with Wilcoxon rank-sum test. Kaplan-Meier methods were used to estimate infection-free survival (IFS), defined as the time to first infection, with 95% confidence intervals and comparisons based on the log-rank test. To model recurrent BsAb related infections, the Prentice-Williams-Peterson (PWP) model²⁰ as an extended Cox proportional hazards model was used. The PWP model is stratified by the number of previous events, meaning each event has a distinct risk and is conditional on the occurrence of the preceding event. Sensitivity analysis consisted of an Andersen-Gill (AG) model,²¹ assuming that the risk of an event is unaffected by prior events and using a common baseline hazard function for all occurrences. Because patients were followed for infections up to 9 months after BsAb initiation irrespective of treatment discontinuation, models were adjusted for time on anti-BCMA BsAb. To mitigate potential inflation of type I errors due to multiple observations per individual, the analysis used robust variance estimates. Performance was evaluated by C-index. Results were presented as hazard ratios (HRs) with 95% CIs, with statistically significant factors having a P-value < .05.

All statistical analyses and graphical representations were performed using RStudio (version 2025.05.0 + 496) and StatAid (version 1.3.1).²²

## Results

Between December 2020 and May 2024, 66 patients were identified. Of these, 42 (63.6%) did not receive preemptive primary IG prophylaxis, whereas the remaining 24 patients (36.4%) did. Baseline characteristics are shown in Table 1.

No significant differences between the 2 groups were observed for most baseline characteristics. The median age was slightly lower in the group that didn't receive IG prophylaxis preemptively (67 years vs. 73 years, *P* = .002). High-risk cytogenetic abnormal-
<table><caption>**Table 1** Baseline Characteristics of Patients Treated With Anti-BCMA BsAbs without IG Preemptive Supplementation and With IG Preemptive Supplementation</caption><thead><tr><th>Age (y), median (IQR)</th><th>Non-Preemptive IG (n = 42)<sup>a</sup></th><th>Preemptive IG (n = 24)<sup>a</sup></th><th>P-Value<sup>b</sup></th></tr></thead><tbody><tr><td></td><td>67 (61.3-73.8)</td><td>73 (70.0-76.0)</td><td>.002<sup>f</sup></td></tr><tr><td>Male sex, n (%)</td><td>25 (59.5)</td><td>10 (41.7)</td><td>.254</td></tr><tr><td>M-protein, n (%)</td><td></td><td></td><td>.073</td></tr><tr><td>IgG</td><td>25 (59.5)</td><td>8 (33.3)</td><td></td></tr><tr><td>Non IgG</td><td>17 (40.5)</td><td>16 (66.7)</td><td></td></tr><tr><td>Time since diagnosis (mo), median (IQR)</td><td>53 (21.3-86.5)</td><td>44 (8.0-89.2)</td><td>.703</td></tr><tr><td>Number of prior lines of treatment, median (IQR)</td><td>5 (1-4)</td><td>2 (0.75-3)</td><td>.250</td></tr><tr><td>Triple-class exposed<sup>d</sup>, n (%)</td><td>34 (81.0)</td><td>19 (79.2)</td><td>1</td></tr><tr><td>Triple-class refractory<sup>d</sup>, n (%)</td><td>32 (76.2)</td><td>19 (79.2)</td><td>1</td></tr><tr><td>High-risk cytogenetics<sup>e</sup>, n (%)</td><td>14 (33.3)</td><td>9 (37.5)</td><td>.634</td></tr><tr><td>Presence of extramedullary disease, n (%)</td><td>5 (11.9)</td><td>1 (4.2)</td><td>.404</td></tr><tr><td>Baseline neutrophil and lymphocyte counts</td><td></td><td></td><td></td></tr><tr><td>Absolute neutrophil count ie ANC × 10<sup>3</sup>/µL, median</td><td>2.82 (2.09-3.77)</td><td>3.04 (1.86-4.39)</td><td>.958</td></tr><tr><td>Absolute lymphocyte count ie ALC × 10<sup>3</sup>/µL, median</td><td>1.00 (0.64-1.57)</td><td>0.96 (0.40-1.34)</td><td>.331</td></tr><tr><td>BCMA BsAb<sup>c</sup></td><td></td><td></td><td></td></tr><tr><td>Teclistamab, n (%)</td><td>30 (71.4)</td><td>12 (50.0)</td><td>.140</td></tr><tr><td>Elranatamab, n (%)</td><td>9 (21.4)</td><td>8 (33.3)</td><td>.441</td></tr><tr><td>Other, n (%)</td><td>3 (7.1)</td><td>4 (16.7)</td><td>.246</td></tr><tr><td>Combination</td><td></td><td></td><td></td></tr><tr><td>BsAb with anti-CD38, n (%)</td><td>17 (40.5)</td><td>4 (16.7)</td><td>.058</td></tr><tr><td>BsAb with -IMiD<sup>c</sup>, n (%)</td><td>14 (33.3)</td><td>4 (16.7)</td><td>.165</td></tr><tr><td>Duration of BsAb on 9 months, median (95% CI)</td><td>NA (NA-NA)</td><td>NA (8-NA)</td><td>.160</td></tr><tr><td>Number of doses of BsAb on 9 months, median (IQR)</td><td>24.5 (19.3-32.0)</td><td>17.5 (11.0-28.0)</td><td>.018<sup>f</sup></td></tr><tr><td>Incidence of CRS<sup>c</sup>, n (%)</td><td>27 (64.3)</td><td>10 (41.7)</td><td>.121</td></tr><tr><td>Use of tocilizumab, n (%)</td><td>9 (21.4)</td><td>3 (12.5)</td><td>.512</td></tr><tr><td>Monthly dose of IG administered, median (IQR) (g/kg)</td><td>0.34 (0.00-0.40)</td><td>0.40 (0.30-0.46)</td><td>.122</td></tr><tr><td>Any SCIG administered, n (%)</td><td>17 (40.5)</td><td>6 (25.0)</td><td>.317</td></tr></tbody></table>

ities (presence of t(4;14), t(14;16), gain(1q), del(1p), del(17p) or TP53 mutation) were observed in 34.8% of patients, with a balanced distribution between groups (33.3% vs. 37.5%, respectively). Extramedullary disease was present in only 9.0% of patients (11.9% in the non-preemptive IG group vs. 4.2% in the preemptive IG group). The median number of prior lines of therapy was similar. Similarly, the median time from diagnosis to treatment initiation was comparable between groups (53 vs. 44 months). A large majority of patients had been exposed to triple-class and were triple-class refractory, with similar distribution between the groups (81.0% vs. 79.2% and 76.2% vs. 79.2%, respectively; both P = 1). Baseline neutropenia or lymphopenia were common, with median neutrophil and lymphocyte counts of 2.82 × 10³/µL (IQR: 2.04-4.24) and 0.98 × 10³/µL (IQR: 0.61-1.49), respectively. Patients also had a comparable treatment duration (P = .160), based on the 9-month observation period during which infections were recorded. Median number of administered BsAb doses were on median at 17.5

in patients who received preemptive IG supplementation versus 24.5 for patients who didn't.

CRS occurred in 64.3% of patients in the not preemptive IG supplementation group versus 41.7% in the preemptive IG supplementation group, and tocilizumab was used in 21.4% and 12.5% of cases, respectively. No cases of ICANS were reported, and the use of systemic corticosteroids was either minimal or not consistently documented.

All patients received anti-BCMA BsAbs, either as monotherapy or in combination in clinical trials (MajesTEC-2 NCT05572515, MajesTEC-3 NCT04722146, MajesTEC-7 NCT05552222, MagnetisMM-5 NCT05020236, MagnetisMM-6 NCT05623020). Teclistamab was the most frequently used anti-BCMA BsAb overall (n = 42, 63.6%), representing more than half of treatments in both groups (71.4% and 50.0%, respectively). Elranatamab, the second BCMA-targeting BsAb developed and approved by regulatory authorities, was the next most frequently

<footnote>a n (%) ; Median (IQR: interquartile range).</footnote>

<footnote>b Wilcoxon rank sum test; Pearson's Chi-squared test; Fisher's exact test.</footnote>

<footnote>c BsAb: bispecific antibody; CRS: cytokine release syndrome, IMiD: immunomodulatory drug</footnote>

<footnote>d Triple-class exposed/refractory means exposed/refractory to an IMiD, a proteasome inhibitor and a CD38- targeting antibody.</footnote>

<footnote>e High-risk cytogenetics defined as presence of t(4;14), t(14;16), gain(1q), del(1p), del(17p) or TP53 mutation.</footnote>

<footnote>f Covariates with non-identical distribution between groups (P < .05): age and the number of anti-BCMA BsAb doses administered over 9 months.</footnote>
# Preemptive Immunoglobulin Prophylaxis Reduces Infections

used (n = 17, 25.8%), with higher representation in the preemptive IG supplementation group compared to the non-preemptive IG group (33.3% vs. 21.4%). A higher not significant proportion of patients in the non-preemptive group received combination therapy, including anti-CD38 monoclonal antibodies (40.5% vs. 16.7% in the preemptive group, P = .058) and/or IMiDs (33.3% vs. 16.7% in the preemptive group, P = .165).

In our study, the median used dosing IG schedule was 370 mg/kg administered every 4 weeks. The median dose was 340 mg/kg in the non-preemptive IG supplementation group and 400 mg/kg in the preemptive group, with no statistically significant difference.

As a broad spectrum of infections occurs in patients receiving anti-BCMA BsAb, we next investigated the incidence and nature of infections in our cohort (Table 2). A total of 129 infections were recorded, with 97 in the non-preemptive IG prophylaxis group and 32 in the preemptive group. Respiratory tract infections were the most common, with upper respiratory infections occurring in 44.3% and 37.5% (P = .637) of patients, and lower respiratory infections observed in 22.7% and 34.4% (P = .280) of patients, respectively.

Bacterial infections were documented in 17.5% of patients in the non-preemptive IG group and 34.4% (P = .079) in the preemptive IG group. Among these, Enterobacteriaceae were the most frequently isolated pathogens, accounting for 47.1% and 72.7% (P = .029) of bacterial isolates, respectively. Other isolated bacteria included *Pseudomonas aeruginosa*, anaerobic species and *Haemophilus influenzae*.

Viral infections were identified in 27.8% and 40.6% (P = .256) of patients in the non-preemptive and preemptive IG groups, respectively. COVID-19 accounted for 11.1% of viral infections in the non-preemptive IG group and 30.8% in the preemptive group. Other viral pathogens included rhinovirus, coronavirus NL63, parainfluenza virus, respiratory syncytial virus, cytomegalovirus, parvovirus B19, herpes simplex virus, human herpesvirus 6, varicella zoster virus, adenovirus, hepatitis B virus, Epstein-Barr virus. Only 1 fungal infection (*Aspergillus* spp.) was reported, occurring in the non-preemptive IG group.

Many infections were of mild to moderate severity, with grade 1 to 2 infections representing 77.3% and 65.6% of cases in the non-preemptive and preemptive IG groups, respectively. However, grade 3 or higher infections occurred in 22.7% and 34.4% of cases, respectively. There were 5 grade 5 events (fatal infections), 3 in the non-preemptive IG group (3.1%) and 2 in the preemptive group (6.3%).

In our center, the timing of IG initiation differed markedly between groups, further supporting the effective implementation of the consensus recommendations.¹⁵,²³ Patients in the preemptive IG group received IG supplementation significantly earlier, with a median time of 1.6 months after the first BsAb injection (95% CI, 0.6-3.3), compared to 7.8 months in the non-preemptive group (95% CI, 5.8-9.4; P < .0001).

Across the cohort, over a 9-month period from the first anti-BCMA BsAb injection, 56 patients experienced at least one infectious episode, of whom 40 (71.4%) were in the non-preemptive IG group and 16 (28.6%) in the preemptive IG group. The median time to the first infection was 2.9 months (95% CI, 1.8-4.4)

(Supplemental Figure 1A), and to second infection, 7.5 months (95% CI, 5.3-NA) (Supplemental Figure 1B).

The median time to onset of a first infection of any grade was significantly shorter in the non-preemptive IG group (1.8 months, 95% CI, 1.2-3.8) compared to the preemptively supplemented group (5.2 months, 95% CI, 2.8-NA) (P = .0012) (Figure 1A). The median time to onset of the most severe all-grade infection per patient was shorter in the non-preemptive IG group (3.2 months, 95% CI, 2.4-4.6) compared to the preemptive IG group (5.4 months, 95% CI, 2.8-NA), with a statistically significant difference (P = .0087) (Figure 1B). When examining the probability of first grade ≥ 3 infection, the median time to event was not reached and the difference between groups was not statistically significant (Figure 1C). Deaths as competing events were not considered in these analyses, as all occurred after these infectious events.

In a multivariate Cox model accounting for recurrent infectious events and patient clustering, the preemptive IG group was significantly associated with a reduced risk of infection (Figure 2). Compared with the non-preemptive group, patients had a 66% reduced risk of all-grade infection (HR 0.34, 95% CI 0.19-0.60, P = .0002) and 76% reduced risk of grade ≥ 3 infection (HR 0.24; 95% CI 0.08-0.69; P = .008). This effect remained significant after adjusting for time on anti-BCMA treatment, included as a time-dependent covariate. Age and number of injections differed significantly at baseline between the 2 groups but were not incorporated as time-dependent covariates in the model, given their intrinsic increase with follow-up and limited interpretative value in this context. The model stratified by episode and grouped by patient correctly predicted which patient would experience an infection earlier (C-index > 0.8). Robust score tests confirmed the overall significance of the model (P ≤ .001), indicating that the observed associations were not due to intra-patient correlation (Supplemental Table 1). Results were consistent across Andersen-Gill model (Supplemental Table 2), supporting the robustness of the observed associations (Supplemental Figure 2). These findings may suggest a clinically relevant protective effect of earlier and preemptive IG prophylaxis.

## Discussion

This study confirms recent literature highlighting a high incidence of infections in patients treated with anti-BCMA BsAbs. The most likely explanation is probably the defect in humoral immunity driven by reduced immunoglobulin levels.¹¹,¹³,²³ This immune defect is more commonly explained by the expression of BCMA on both malignant and normal plasma cells as well as mature B cells associated with advanced disease as well leading to profound humoral immune suppression.²⁴

Based on international recommendations,¹⁵,²³ the preemptive introduction of IG after June 2023 was associated with a significant reduction in the incidence of grade ≥ 3 infections per patient, consistent with previous reports suggesting a protective effect of IG against severe infections.²⁵ Although the absolute rate of grade ≥ 3 infections tends to be higher in the preventive IG group, our model, which takes recurrent events into account, allows us to demonstrate a benefit in terms of reducing the risk of infec-
<figure><img src="image_2.png" /><figcaption>**Figure 2** Forest plot of hazard ratios (HRs) for infection risk according to IG supplementation strategy, adjusted for time on anti-BCMA exposure, calculated by Prentice-Williams-Peterson model. HRs and 95% confidence intervals were derived from a multivariate Cox model adjusted for the time on anti-BCMA BsAbs, as time-dependent covariate. An HR < 1 indicates a lower infection rate in the preemptive IG group. Statistical significance was defined as *P* < .05. The model considers recurrent infectious events and patient clustering by robust variance estimates. Performance was evaluated by C-index (Supplemental Table 1).</figcaption></figure>

<table><thead><tr><th>Variables</th><th>HRs (95% CI)</th><th>p</th></tr></thead><tbody><tr><td>All grades 1–5 infections</td><td>0.34 [0.19; 0.60]</td><td>0.0002</td></tr><tr><td>Grades ≥3 infections</td><td>0.24 [0.08; 0.69]</td><td>0.0084</td></tr></tbody></table>

<figure><img src="image_3.png" /></figure>
# Preemptive Immunoglobulin Prophylaxis Reduces Infections

<table><caption>**Table 2** Infection Characteristics</caption><thead><tr><th>Site of infection. n (%)</th><th>Non-Preemptive IG (n = 97)<sup>a</sup></th><th>Preemptive IG (n = 32)<sup>a</sup></th><th>P-Value<sup>b</sup></th></tr></thead><tbody><tr><td>Upper respiratory tract</td><td>43 (44.3%)</td><td>12 (37.5%)</td><td>.637</td></tr><tr><td>Lower respiratory tract</td><td>22 (22.7%)</td><td>11 (34.4%)</td><td>.280</td></tr><tr><td>Skin/soft tissue</td><td>5 (5.2%)</td><td>1 (3.1%)</td><td>1</td></tr><tr><td>Bloodstream</td><td>12 (12.4%)</td><td>4 (12.5%)</td><td>1</td></tr><tr><td>Catheter-related</td><td>2 (2.1%)</td><td>0 (0.0%)</td><td>1</td></tr><tr><td>Genitourinary tract</td><td>2 (2.1%)</td><td>3 (9.4%)</td><td>.097</td></tr><tr><td>Gastrointestinal tract</td><td>11 (11.3%)</td><td>0 (0.0%)</td><td>.064</td></tr><tr><td>Bacterial. n (%)</td><td>17 (17.5%)</td><td>11 (34.4%)</td><td>.079</td></tr><tr><td>Enterobacteriaceae</td><td>8 (47.1%)</td><td>8 (72.7%)</td><td>.029</td></tr><tr><td>Pseudomonas aeruginosa and other non-fermentative gram-negative bacteria</td><td>1 (5.9%)</td><td>1 (9.1%)</td><td>.436</td></tr><tr><td>Anaerobic bacteria</td><td>3 (17.7%)</td><td>0 (0.0%)</td><td>.574</td></tr><tr><td>Haemophilus influenzae</td><td>1 (5.9%)</td><td>2 (18.2%)</td><td>.152</td></tr><tr><td>Neisseria</td><td>1 (5.9%)</td><td>0 (0.0%)</td><td>1</td></tr><tr><td>Gram-negative spiral-shaped</td><td>1 (5.9%)</td><td>0 (0.0%)</td><td>1</td></tr><tr><td>Staphylococci</td><td>1 (5.9%)</td><td>0 (0.0%)</td><td>1</td></tr><tr><td>Streptococcib</td><td>1 (5.9%)</td><td>0 (0.0%)</td><td>1</td></tr><tr><td>Viral. n (%)</td><td>27 (27.8%)</td><td>13 (40.6%)</td><td>.256</td></tr><tr><td>Rhinovirus</td><td>3 (11.1%)</td><td>4 (30.8%)</td><td>.063</td></tr><tr><td>COVID 19</td><td>3 (11.1%)</td><td>4 (30.8%)</td><td>.063</td></tr><tr><td>Coronavirus NL63</td><td>1 (3.7%)</td><td>1 (7.7%)</td><td>.436</td></tr><tr><td>Parainfluenza virus</td><td>1 (3.7%)</td><td>0 (0.0%)</td><td>1</td></tr><tr><td>RSV</td><td>1 (3.9%)</td><td>0 (0.0%)</td><td>1</td></tr><tr><td>CMV</td><td>4 (14.5%)</td><td>1 (7.7%)</td><td>1</td></tr><tr><td>Parvovirus B19</td><td>2 (7.4%)</td><td>2 (15.4%)</td><td>.257</td></tr><tr><td>HSV</td><td>2 (7.4%)</td><td>0 (0.0%)</td><td>1</td></tr><tr><td>HHV-6</td><td>2 (7.4%)</td><td>0 (0.0%)</td><td>1</td></tr><tr><td>VZV</td><td>1 (3.7%)</td><td>0 (0.0%)</td><td>1</td></tr><tr><td>Adenovirus</td><td>1 (3.7%)</td><td>0 (0.0%)</td><td>1</td></tr><tr><td>HBV</td><td>1 (3.7%)</td><td>0 (0.0%)</td><td>1</td></tr><tr><td>EBV</td><td>0 (0.0%)</td><td>1 (7.7%)</td><td>.248</td></tr><tr><td>Fungi. n (%)</td><td>1 (1.0%)</td><td>0 (0.0%)</td><td>1</td></tr><tr><td>Aspergillus spp</td><td>1 (100.0%)</td><td>0 (0.0%)</td><td>1</td></tr><tr><td>Grade of infection. n (%)</td><td></td><td></td><td></td></tr><tr><td>1</td><td>30 (30.1%)</td><td>7 (21.9%)</td><td>.449</td></tr><tr><td>2</td><td>45 (46.4%)</td><td>14 (43.8%)</td><td>.956</td></tr><tr><td>3</td><td>17 (17.5%)</td><td>9 (28.1%)</td><td>.297</td></tr><tr><td>4</td><td>2 (2.1%)</td><td>0 (0.0%)</td><td>1</td></tr><tr><td>5</td><td>3 (3.1%)</td><td>2 (6.3%)</td><td>.597</td></tr><tr><td>≥ 3</td><td>22 (22.7%)</td><td>11 (34.4%)</td><td>.280</td></tr></tbody></table>

Abbreviations: CMV = cytomegalovirus; EBV = Epstein-Barr virus; HBV = hepatitis B virus; HHV-6 = human herpesvirus 6;

HSV = herpes simplex virus; RSV = respiratory syncytial virus; VZV = varicella zoster virus.

a n (%).

b Pearson's Chi-squared test; Fisher's exact test.

tion with preventive IG while also capturing that patients who experience 1 infection remain at increased risk for subsequent episodes.

Our data also support the concept of preemptive IG use, even before the first infectious episode, particularly considering the early onset of infections observed. These findings echo those of studies²⁶,²⁷ which showed that most infections occur at the begin-

ning of treatment, and that IG dramatically reduces the risk of grade 3 to 5 infections. Thus, our data support a preemptive approach, with early and preemptive supplementation, during the first treatment cycles (median time: 1.6 months), associated with a reduction in the rate of all-grade and grade ≥ 3 infectious events per patient.

While other factors such as prior lines of therapy, cytopenias, and immune exhaustion may also contribute to infection vulnerabil-
ity, continuation of therapy in a profoundly immunocompromised population remained possible when IG supplementation was done. Our limited number of patients on a short follow-up did not allow us to demonstrate a benefit in progression free survival (PFS), overall survival (OS) or non-relapse mortality (NRM) as medians were not reached (Supplemental Figures 3-4). However several studies²⁸,²⁹ have shown trends or improvements in both PFS and OS, likely driven by prolonged infection-free survival enabled by IG prophylaxis.

Over a comparable 9-month observation period, patients treated according to recommendations tended to receive lower cumulative BsAb doses (17.5 vs. 24.5; *P* = .018), despite having a similar treatment duration. This observation supports expert guidance advocating for dose-spacing strategies to reduce infectious toxicity and the implementation of strategies following regulatory approval.³⁰,³¹ However, in our models adjusted for the number of BsAb doses (Supplemental Tables 3-4 and Supplemental Figures 5-6), a lower number of BsAb doses had no lead to decrease the risk of infections obtained in the preemptive group. This lack of association should be interpreted with caution as it contrasts with recent data.³²

CRS occurred more frequently in patients from the preemptive IG group, with greater use of tocilizumab. Although these differences were not statistically significant, they may reflect improved management of these adverse events over time.

Monitoring of gammaglobulin levels is also essential for patients who discontinue anti-BCMA BsAbs, to detect and address ongoing immune vulnerability. These findings should encourage further prospective trials and collaborative consensus efforts to identify the optimal dosing and duration of IG prophylaxis in the context of treatment by anti-BCMA BsAbs.

Altogether, this highlights the need for a tailored approach to infection monitoring and prophylactic strategies.

Limitations of our study include its retrospective, single-center design, the limited follow-up duration post-implementation of preemptive IG, and the lack of immunological characterization (eg vaccine response, B-cell recovery).²⁷ Nevertheless, the data strongly suggest clinical benefits of IG supplementation and underline the necessity for broader guideline implementation in real-world settings. Although the short follow-up period limited immortality bias and highlighted the early benefits of preventive IG, longer-term follow-up analyses are needed to confirm the persistence of this protective effect over time.

More patients in the non-preemptive group tend to receive combination therapy, including anti-CD38 antibodies, which could be a major limitation due to the increased risk of infections in this group. However, although previous trials evaluating these combinations (MajesTEC-2/TRIMM-2³³ and MagnetisMM-6³⁴) reported high infection rates (93% and 70.3% for all grades; 63% and 18.9% for grade ≥ 3, respectively), no influence on association by anti-CD38 was found in our adjusted models (Supplemental Tables 3-4 and Supplemental Figures 5-S6).

## Conclusions

In conclusion, our study highlights the significant infectious burden associated with anti-BCMA BsAbs in multiple myeloma, driven by profound hypogammaglobulinemia. Early (< 2 months)

and preemptive IG significantly reduces all-grade infections and shows a significant 76% reduction grade ≥ 3 infection. Early and preemptive IG supplementation should be considered standard practice in this context, while recognizing the ongoing need to balance clinical benefit with drug availability and economic impact.³⁵ Gammaglobulin levels should also be monitored after treatment discontinuation. Future research should include prospective trials and medico-economic evaluations to better define the role of IG prophylaxis in the evolving landscape of anti-BCMA BsAbs.

## Clinical Practice Points

* Anti-BCMA BsAbs induce severe immunosuppression, particularly impairing humoral immunity through reduced immunoglobulin levels.

* Early and preemptive IG supplementation, initiated during the 2 first treatment cycles (median: 1.6 months), significantly reduces the rate of all-grade and the rate of severe (grade ≥ 3) infections per patient.

* Infections occur earlier without preemptive supplementation.

* Patients who discontinue anti-BCMA therapy should have their gammaglobulin levels monitored. Optimal duration of supplementation remains to be determined.

## Disclosure

The authors declare no conflict of interest.

## CRediT authorship contribution statement

**Bénédicte Piron:** Writing – review & editing, Writing – original draft, Visualization, Validation, Resources, Project administration, Methodology, Investigation, Formal analysis, Data curation, Conceptualization. **Laura Rodrigo:** Writing – review & editing, Writing – original draft, Visualization, Validation, Resources, Project administration, Methodology, Investigation, Formal analysis, Data curation, Conceptualization. **Benoît Tessouin:** Writing – review & editing, Writing – original draft, Visualization, Validation, Supervision, Resources, Project administration, Methodology, Investigation, Formal analysis, Data curation, Conceptualization. **Thomas Gastinne:** Writing – review & editing, Validation. **Viviane Dubruille:** Writing – review & editing, Validation. **Valentin Letailleur:** Writing – review & editing, Validation. **Chloé Antier:** Writing – review & editing, Validation. **Anne Lok:** Writing – review & editing, Validation. **Estelle Leroy:** Writing – review & editing, Writing – original draft, Visualization, Validation, Supervision, Resources, Project administration, Methodology, Investigation, Formal analysis, Data curation, Conceptualization. **Philippe Moreau:** Writing – review & editing, Validation. **Clémentine Fronteau:** Writing – review & editing, Writing – original draft, Visualization, Validation, Supervision, Resources, Project administration, Methodology, Investigation, Formal analysis, Data curation, Conceptualization. **Cyrille Touzeau:** Writing – review & editing, Writing – original draft, Visualization, Validation, Supervision, Resources, Project administration, Methodology, Investigation, Formal analysis, Data curation, Conceptualization.
# Preemptive Immunoglobulin Prophylaxis Reduces Infections

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Supplementary material

Table S1, Table S2, Table S3, Table S4, Figure S1, Figure S2, Figure S3, Figure S4, Figure S5, Figure S6

<table><caption>Supplemental Table 1 Analysis of Infection Risk Using Prentice-Williams-Peterson Model Adjusted for the Time on Anti-BCMA BsAbs</caption><thead><tr><th>PWP Model</th><th>HR</th><th>Lower 95%</th><th>Upper 95%</th><th>Robust SE</th><th>z-score</th><th>P-Value</th><th>C-Index</th><th>Robust Score Tests</th></tr></thead><tbody><tr><td>Predictor of all-grade infections</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Preemptive IG supplementation</td><td><strong>0.3370</strong></td><td>0.1896</td><td>0.5992</td><td>0.2935</td><td>-3.705</td><td>.0002***</td><td>0.865<br>(SE = 0.018)</td><td>40.54<br>(P &lt; .001)</td></tr><tr><td>Time on anti-BCMA BsAb</td><td>0.9752</td><td>0.9736</td><td>0.9826</td><td>0.0023</td><td>-9.407</td><td>&lt; 2e-16***</td><td></td><td></td></tr><tr><td>Predictor of ≥ 3 grade infections</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Preemptive IG supplementation</td><td><strong>0.2385</strong></td><td>0.0821</td><td>0.6925</td><td>0.5439</td><td>-2.635</td><td>.0084**</td><td>0.943<br>(SE = 0.018)</td><td>18.01<br>(P = .001)</td></tr><tr><td>Time on anti-BCMA BsAb</td><td>0.9752</td><td>0.9665</td><td>0.9840</td><td>0.0045</td><td>-5.475</td><td>4.39e-08***</td><td></td><td></td></tr></tbody></table>

Note: Significance levels were reported as: ** for $P \le .01$ and *** for $P \le .001$. SE stands for standard error.

<table><caption>Supplemental Table 2 Analysis of Infection Risk Using Andersen-Gill Model Adjusted for the Time on Anti-BCMA BsAbs</caption><thead><tr><th>AG Model</th><th>HR</th><th>Lower 95%</th><th>Upper 95%</th><th>Robust SE</th><th>z-score</th><th>P-Value</th><th>C-Index</th><th>Robust Score Tests</th></tr></thead><tbody><tr><td>Predictor of all-grade infections</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Preemptive IG supplementation</td><td><strong>0.4557</strong></td><td>0.2765</td><td>0.7512</td><td>0.2545</td><td>-3.082</td><td>.0021**</td><td>0.807<br>(SE = 0.02)</td><td>35.91<br>(P &lt; .001)</td></tr><tr><td>Time on anti-BCMA BsAb</td><td>0.9804</td><td>0.9764</td><td>0.9844</td><td>0.0021</td><td>-9.493</td><td>&lt; 2e-16***</td><td></td><td></td></tr><tr><td>Predictor of ≥ 3 grade infections</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Preemptive IG supplementation</td><td><strong>0.2237</strong></td><td>0.0967</td><td>0.5179</td><td>0.4282</td><td>-3.497</td><td>.0005***</td><td>0.924<br>(SE = 0.021)</td><td>14.54<br>(P &lt; .001)</td></tr><tr><td>Time on anti-BCMA BsAb</td><td>0.9748</td><td>0.9673</td><td>0.9824</td><td>0.0040</td><td>-6.442</td><td>1.18e-10***</td><td></td><td></td></tr></tbody></table>

Note: Significance levels were reported as: ** for $P \le .01$ and *** for $P \le .001$. SE stands for standard error.

<table><caption>Supplemental Table 3 Analysis of Infection Risk Using Prentice-Williams-Peterson Model Adjusted for the Time on Anti-BCMA BsAbs, Number of Anti-BCMA BsAb doses by Time Interval and Anti-CD38 Association</caption><thead><tr><th>PWP Model</th><th>HR</th><th>Lower 95%</th><th>Upper 95%</th><th>Robust SE</th><th>z-score</th><th>P-Value</th><th>C-Index</th><th>Robust Score Tests</th></tr></thead><tbody><tr><td>Predictor of all-grade infections</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Preemptive IG supplementation</td><td><strong>0.3435</strong></td><td>0.2143</td><td>0.5505</td><td>0.2407</td><td>-4.440</td><td>8.99e-06***</td><td>0.87<br>(SE = 0.016)</td><td>42.02<br>(P &lt; .001)</td></tr><tr><td>Time on anti-BCMA BsAb</td><td>0.9853</td><td>0.9783</td><td>0.9924</td><td>0.0037</td><td>-4.055</td><td>5.01e-05***</td><td></td><td></td></tr><tr><td>Number of anti-BCMA BsAb doses by time interval</td><td>0.8928</td><td>0.8320</td><td>0.9581</td><td>0.0360</td><td>-3.150</td><td>.00163**</td><td></td><td></td></tr><tr><td>Association with anti-CD38</td><td>0.8679</td><td>0.6059</td><td>1.2433</td><td>0.1834</td><td>-0.772</td><td>.43982</td><td></td><td></td></tr><tr><td>Predictor of ≥ 3 grade infections</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Preemptive IG supplementation</td><td><strong>0.1799</strong></td><td>0.0830</td><td>0.3903</td><td>0.3950</td><td>-4.342</td><td>1.41e-05***</td><td>0.964<br>(SE = 0.014)</td><td>18.43<br>(P = .001)</td></tr><tr><td>Time on anti-BCMA BsAb</td><td>0.9900</td><td>0.9782</td><td>1.0019</td><td>0.0061</td><td>-1.643</td><td>.10028</td><td></td><td></td></tr><tr><td>Number of anti-BCMA BsAb doses by time interval</td><td>0.6890</td><td>0.5416</td><td>0.8766</td><td>0.1228</td><td>-3.032</td><td>.00243**</td><td></td><td></td></tr><tr><td>Association with anti-CD38</td><td>0.5640</td><td>0.2421</td><td>1.3140</td><td>0.4315</td><td>-1.327</td><td>.18449</td><td></td><td></td></tr></tbody></table>

Note: Significance levels were reported as: ** for $P \le .01$ and *** for $P \le .001$. SE stands for standard error.
# Preemptive Immunoglobulin Prophylaxis Reduces Infections

<caption>Supplemental Table 4</caption>

Analysis of Infection Risk Using Andersen-Gill Model Adjusted for the Time on Anti-BCMA BsAbs, Number of Anti-BCMA BsAb doses by Time Interval and Anti-CD38 Association

<table><thead><tr><th>AG Model</th><th>HR</th><th>Lower 95%</th><th>Upper 95%</th><th>Robust SE</th><th>z-score</th><th>P-Value</th><th>C-Index</th><th>Robust Score Tests</th></tr></thead><tbody><tr><td>Predictor of all-grade infections</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Preemptive IG supplementation</td><td><strong>0.4574</strong></td><td>0.2995</td><td>0.6958</td><td>0.2160</td><td>-3.621</td><td>.000293***</td><td>0.809<br>(SE = 0.019)</td><td>36.6<br>(P &lt; .001)</td></tr><tr><td>Time on anti-BCMA BsAb</td><td>0.9870</td><td>0.9805</td><td>0.9936</td><td>0.0034</td><td>-3.839</td><td>.000123***</td><td></td><td></td></tr><tr><td>Number of anti-BCMA BsAb doses by time interval</td><td>0.9212</td><td>0.8629</td><td>0.9834</td><td>0.0333</td><td>-2.462</td><td>.013806**</td><td></td><td></td></tr><tr><td>Association with anti-CD38</td><td>0.9779</td><td>0.7721</td><td>1.2385</td><td>0.1205</td><td>-0.186</td><td>.852817</td><td></td><td></td></tr><tr><td>Predictor of ≥ 3 grade infections</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Preemptive IG supplementation</td><td><strong>0.1995</strong></td><td>0.1031</td><td>0.3863</td><td>0.3370</td><td>-4.782</td><td>1.73e-06***</td><td>0.942<br>(SE = 0.018)</td><td>16.11<br>(P = .003)</td></tr><tr><td>Time on anti-BCMA BsAb</td><td>0.9973</td><td>0.9873</td><td>1.0074</td><td>0.0052</td><td>-0.528</td><td>.597153</td><td></td><td></td></tr><tr><td>Number of anti-BCMA BsAb doses by time interval</td><td>0.7020</td><td>0.5782</td><td>0.8524</td><td>0.0990</td><td>-3.573</td><td>.000352***</td><td></td><td></td></tr><tr><td>Association with anti-CD38</td><td>0.8056</td><td>0.3828</td><td>1.6952</td><td>0.3796</td><td>-0.570</td><td>.568949</td><td></td><td></td></tr></tbody></table>

Note: Significance levels were reported as: ** for $P \le .01$ and *** for $P \le .001$. SE stands for standard error.

<caption>Supplemental Figure 1</caption>

Time to first onset infection per patient from whole cohort. (A) Time to first onset all-grade 1-5 (CTCAE) infectious event. (B) Time to second onset all-grade 1-5 (CTCAE) infectious event.

<figure><img src="image_4.png" /></figure>

<figure><img src="image_5.png" /></figure>
Supplemental Figure 2

Forest plot of hazard ratios (HRs) for infection risk according to IG supplementation strategy, adjusted for time on anti-BCMA exposure, calculated by Andersen-Gill model. HRs and 95% confidence intervals were derived from a multivariate Cox model adjusted for the time on anti-BCMA BsAbs, as time-dependent covariate. An HR < 1 indicates a lower infection rate in the preemptive IG group. Statistical significance was defined as *P* < .05. The model doesn't consider recurrent infectious events but only patient clustering by robust variance estimates. Performance was evaluated by C-index (Supplemental Table 2).

<figure><img src="image_6.png" /></figure>

Supplemental Figure 3

Overall survival, progression-free survival and non-relapse mortality among whole cohort (data cut-off: 9 months). (A) Overall survival. At 6 months, estimated OS was 93.9% (95% CI, 84.7-97.7). B) Progression-free survival. At 6 months, estimated PFS was 90.9% (95% CI, 80.9-95.8). C) Non-relapsed mortality. At 6 months, estimated NRM was 7.6% (95% CI, 3.2-17.2).

<figure><img src="image_7.png" /></figure>

<figure><img src="image_8.png" /></figure>

<figure><img src="image_9.png" /></figure>
Preemptive Immunoglobulin Prophylaxis Reduces Infections

Supplemental Figure 4

Overall survival, progression-free survival and non-relapse mortality by treatment group (preemptive vs. non-preemptive IG) (data cut-off: 9 months). (A) Overall survival. At 6 months, estimated OS was 92.9% (95% CI, 85.4-100) versus 87.5% (95% CI, 75.2-100) in the non-preemptive and preemptive IG groups, respectively (P = .65). (B) Progression-free survival. At 6 months, estimated PFS was 92.9% (95% CI, 85.4-100) versus 95.8% (95% CI, 88.2-100) in the non-preemptive and preemptive IG groups, respectively (P = .48). (C) Non-relapsed mortality. At 6 months, estimated NRM was 7.1% (95% CI, 0-14.6) vs 8.3% (95% CI, 0-18.7) in the non-preemptive and preemptive IG groups, respectively (P = .83).

A

Groups Non-preemptive Preemptive

<figure><img src="image_10.png" /></figure>

<table><thead><tr><th></th><th>Number at risk</th><th>Number at risk</th><th>Number at risk</th></tr></thead><tbody><tr><th scope="row">Non-preemptive</th><td>42</td><td>42</td><td>39</td></tr><tr><th scope="row">Preemptive</th><td>24</td><td>23</td><td>21</td></tr></tbody></table>

B

<figure><img src="image_11.png" /></figure>

<table><thead><tr><th></th><th>Number at risk</th><th>Number at risk</th><th>Number at risk</th></tr></thead><tbody><tr><th scope="row">Non-preemptive</th><td>42</td><td>41</td><td>39</td></tr><tr><th scope="row">Preemptive</th><td>24</td><td>23</td><td>23</td></tr></tbody></table>

C

<figure><img src="image_12.png" /></figure>
Supplemental Figure 5

Forest plot of hazard ratios (HRs) for infection risk adjusted for IG supplementation strategy, time on anti-BCMA exposure, number of anti-BCMA BsAb doses by time interval and anti-CD38 association. HRs and 95% confidence intervals were derived from a multivariate Prentice-Williams-Peterson model adjusted. An HR < 1 indicates a lower infection rate. Statistical significance was defined as *P* < .05. The model doesn't consider recurrent infectious events but only patient clustering by robust variance estimates. Performance was evaluated by C-index (Supplemental Table 2). (A): All grade infections HRs. (B): ≥ 3 grade infections HRs. **stands for *P* ≤ .01, ***for *P* ≤ .001, NS stands for non-significant.

A

<table><thead><tr><th>Variables</th><th>HRs (95% CI)</th><th>p</th></tr></thead><tbody><tr><td>Preemptive IG supplementation</td><td>0.34 [0.21; 0.55]</td><td>***</td></tr><tr><td>Time on anti-BCMA BsAb</td><td>0.99 [0.98; 0.99]</td><td>***</td></tr><tr><td>Number of anti-BCMA BsAb doses by time interval</td><td>0.89 [0.83; 0.96]</td><td>**</td></tr><tr><td>Association with anti-CD38</td><td>0.87 [0.61; 1.24]</td><td>NS</td></tr></tbody></table>

<figure><img src="image_13.png" /></figure>

B

<table><thead><tr><th>Variables</th><th>HRs (95% CI)</th><th>p</th></tr></thead><tbody><tr><td>Preemptive IG supplementation</td><td>0.18 [0.08; 0.39]</td><td>***</td></tr><tr><td>Time on anti-BCMA BsAb</td><td>0.99 [0.98; 1.00]</td><td>NS</td></tr><tr><td>Number of anti-BCMA BsAb doses by time interval</td><td>0.69 [0.54; 0.88]</td><td>**</td></tr><tr><td>Association with anti-CD38</td><td>0.56 [0.24; 1.31]</td><td>NS</td></tr></tbody></table>

<figure><img src="image_14.png" /></figure>
Preemptive Immunoglobulin Prophylaxis Reduces Infections

**Supplemental Figure 6** Forest plot of hazard ratios (HRs) for infection risk adjusted for IG supplementation strategy, time on anti-BCMA exposure, number of anti-BCMA BsAb doses by time interval and anti-CD38 association. HRs and 95% confidence intervals were derived from a multivariate Andersen-Gill model adjusted. An HR < 1 indicates a lower infection rate. Statistical significance was defined as *P* < .05. The model doesn't consider recurrent infectious events but only patient clustering by robust variance estimates. Performance was evaluated by C-index (Supplemental Table 2). (A): All grade infections HRs. (B): ≥ 3 grade infections HRs. **stands for *P* ≤ .01, ***for *P* ≤ .001, NS stands for non-significant.

<figure><img src="image_15.png" /></figure>

<figure><img src="image_16.png" /></figure>