Introduction
T-cell redirecting bispecific antibodies (BsAbs) have high efficacy in heavily pretreated patients with relapsed/refractory multiple myeloma (RRMM). Various BsAbs have been developed, targeting different myeloma-associated antigens, including B-cell maturation antigen (BCMA) [ 1 – 3 ], G protein-coupled receptor GPRC5D [ 4 ], and FcRH5 [ 5 , 6 ]. By simultaneously targeting CD3 on T-cells and a tumor-specific antigen, an immune synapse is formed, leading to T-cell activation and subsequent lysis of myeloma cells. Despite the encouraging results in both clinical trials as well as in real-world data, there is concern about the incidence of severe infections (CTC grade 3 or higher). The increased infection risk is driven by a combination of factors, including hypogammaglobulinemia due to B-cell and plasma cell depletion (most pronounced with BCMA- and FcRH5-targeting BsAbs) [ 7 , 8 ], neutropenia [ 9 ], lymphopenia, and T-cell exhaustion [ 10 – 12 ]. The highest infection rates were reported in patients treated with BCMA-directed BsAbs, whereas infections occur less frequently with BsAbs targeting GPRC5D [ 4 , 5 , 13 ].
In the phase I-II trial with teclistamab (MajesTEC-1)—the first BCMA-directed BsAb to obtain approval by the FDA and EMA in 2022—hypogammaglobulinemia (IgG < 4 g/L) occurred in 75% of patients [ 1 , 14 ]. After a median follow-up of 30.4 months, infections were reported in 79% of patients, with 55% experiencing at least one grade 3-4 infection [ 14 , 15 ]. In retrospective studies, we and others have previously shown that intravenous immunoglobulin (IVIG) supplementation significantly reduces the risk of severe infections [ 7 , 16 – 19 ], with two studies reporting a ten-fold reduction in severe infection risk [ 7 , 16 ]. Consequently, clinical guidelines recommend IVIG prophylaxis for RRMM patients receiving BsAbs when IgG levels fall below 4.0 mg/L [ 20 , 21 ].
Despite the growing body of literature on infection incidence and -management in patients receiving BsAbs, several critical aspects remain underexplored. First, it is unclear whether IVIG therapy reduces the risk of grade 1–2 infections. Additionally, infection incidence is often reported as cumulative incidence, capturing only one infectious event with the highest grade and overlooking multiple infections in the same patient [ 22 ]. This may lead to an underestimation of the infection burden in patients treated with BsAbs. Moreover, whether longer dosing intervals of BsAbs impact the incidence of infections remains unknown.
Here, we report a retrospective study including all patients treated with teclistamab in a single academic research center. We characterized types of infections and estimated infection risk reduction by treatment with IVIG. Furthermore, we assessed potential risk factors for infections despite IVIG prophylaxis and investigated the association between alternative BsAbs dosing strategies and infection risk.
Methods
Study design
In this single-center, retrospective cohort study, all patients with RRMM who initiated teclistamab treatment between January 2019 and December 2024 in Amsterdam University Medical Center in the Netherlands were included. All patients who were either treated in the setting of a clinical trial or in a compassionate use program provided written informed consent. Clinical trials were approved by the medical ethics committee of the Amsterdam University Medical Center. Clinical data were extracted from electronic health records, with a data cut-off on February 2 nd , 2025. Clinical outcomes of part of our patient cohort were previously described, but with a shorter follow-up [ 7 ]. All methods were performed in accordance with relevant guidelines and regulations, including the Declaration of Helsinki.
Infection prophylaxis, including IVIG supplementation
Patients received antimicrobial prophylaxis in accordance with international guidelines, which consisted of cotrimoxazole (or pentamidine in case of cotrimoxazole allergy) and valaciclovir for the entire duration of treatment and at least 6 months after the last BsAb administration. Granulocyte-colony stimulating factor (G-CSF) was used to manage neutropenia. Polyclonal IgG levels were determined at baseline and monitored monthly. In cases of IgG myeloma, the M-spike component was subtracted from the total IgG level to approximate the amount of polyclonal IgG. IVIG (Nanogam; Prothya Biosolutions, Amsterdam, The Netherlands) was prescribed as primary prophylaxis of infections in cases with polyclonal IgG of <4 g/L, or as secondary prophylaxis in patients who developed a severe infection (CTC grade ≥3) with polyclonal IgG <4 g/L (at individual physicians’ discretion). Over time, patients more often received primary prophylaxis due to increasing evidence on the benefit of IVIG. IVIG was administered every 4 weeks (on the same day as teclistamab) with a fixed starting dose (10–20 gram), whereby the dose was subsequently adjusted to achieve IgG levels of >4 g/L. IVIG treatment was continued during teclistamab therapy in all patients, and at least 6 months after last teclistamab administration in those who stopped teclistamab treatment. Patients did not receive other antibacterial or antifungal prophylaxis. On suspicion of infection, patients underwent physical examination, laboratory, and microbiological tests (cultures, PCR) as indicated. Presence of CMV viremia was evaluated in cases of unexplained fever and in patients who previously experienced CMV infection. Empiric broad-spectrum antibiotics were started in cases of febrile neutropenia or systemic symptoms.
Definition of infections
Infections were documented from the start of treatment until disease progression, death, or the date of last follow-up. An infectious episode was recorded if explicitly noted in the health records by the treating physician. When available, microbiological data associated with each infection were collected. Infections were classified by organ system and graded according to the Common Terminology Criteria for Adverse Events (CTC-AE) version 5.0. Persistent or recurrent infections were defined as those in which the same pathogen was cultured again after at least 30 days since the last positive test.
Statistics
Cumulative incidences of all-grade and severe infections were compared between patients who received primary IVIG prophylaxis and those who did not receive IVIG, using Gray’s test. Patients who did not experience all-grade or severe infection were censored at the date of last follow-up. Patients who started teclistamab treatment without IVIG and received delayed IVIG prophylaxis without experiencing a severe infection were censored at the date of IVIG initiation for analysis of cumulative incidence of infections. Annualized infection rates (infections per patient-year) were calculated for each patient by dividing the total number of infections by the total time on treatment (in years) and comparing between periods without IVIG and on IVIG, using Poisson models. Univariate and multivariate analyses were performed using a negative binomial model, which accommodates overdispersion potentially arising from heterogeneity and excess zero events in the data. We incorporated a time-dependent offset variable in these models to adjust for variations in treatment duration. To calculate annualized infection rates for each dosing schedule, the total number of infections per schedule was divided by the total number of patient-years (time on treatment) for that schedule. Doses were categorized into interval groups based on the monthly cumulative dose of teclistamab (weekly, biweekly, monthly, bimonthly). If treatment was discontinued due to infections, infections occurring within the following three months were attributed to the previous dosing schedule. Associations between annualized infection rates and dosing schedules were assessed using negative binomial regression models.
Results
Patient characteristics
Eighty patients with RRMM who received teclistamab treatment were included in the study. Fifty-one patients (64%) participated in a clinical trial, and 29 patients (36%) enrolled in a compassionate use program. Median age was 65 years (range 42–81). High disease stage (International Staging System [ISS] III) was present in 17%, and 40% of patients had one or more high-risk cytogenetic abnormalities (defined as the presence of del(17p), t (4;14), t (14;16), del(1p), and/or amp(1q)). Patients received a median of 5 prior lines of therapy, and 52% were triple class refractory (Table 1 ). Nine out of 28 (32%) patients treated in the compassionate use program did not fulfil eligibility criteria of the MajesTEC-1 trial, most often due to neutropenia or renal impairment (for one patient, this data was not available). Table 1 Baseline characteristics of patients with RRMM who were treated with teclistamab. Total n = 80 Age (range) 65 (42–81) ≥ 70 years 23 (29) ≥ 80 years 4 (5%) Male (%) 42 (53) M-protein IgG 45 (56) IgA 10 (13) Light chain 20 (25) Non-secretor 1 (1) Other 4 (5) Beta-2-microglobulin (IQR) 3.0 (2.4–4.3) ISS stage (%) I 9 (19) II 31 (64) III 8 (17) Unknown 32 Cytogenetics a Normal 46 (61) High risk b 31 (39) Extramedullary disease (%) 18 (23) Prior treatment lines, median (range) 5 (2–11) Triple-class exposed (%) 75 (99) Triple-class refractory (%) 45 (56) WHO performance status (%) 0 60 (78) 1 17 (22) Unknown 3 eGFR below <40 ml/min 7 (9%) Median (IQR) Hemoglobin (mmol/L) 6.7 (6.2–7.6) Thrombocytes (x 10 9 /L) 166 (126–215) Neutrophils (x 10 9 /L) 2.7 (1.9–3.8) Lymphocytes (x 10 9 /L) 0.5 (0.3–1.0) Albumin (g/L) 33 (30–36) Creatinine (μmol/L) 78 (70–101) LDH (U/L) 207 (175–252) a At time of start of treatment with teclistamab. In case cytogenetics at this timepoint were missing, the most recent results were used. b Extended definition: del(17p), t (4;14), t (14;16), del(1p), and/or amp(1q).
Table 1
Baseline characteristics of patients with RRMM who were treated with teclistamab.
a At time of start of treatment with teclistamab. In case cytogenetics at this timepoint were missing, the most recent results were used. b Extended definition: del(17p), t (4;14), t (14;16), del(1p), and/or amp(1q).
| Total n = 80 | |
| Age (range) | 65 (42–81) |
| ≥ 70 years | 23 (29) |
| ≥ 80 years | 4 (5%) |
| Male (%) | 42 (53) |
| M-protein | |
| IgG | 45 (56) |
| IgA | 10 (13) |
| Light chain | 20 (25) |
| Non-secretor | 1 (1) |
| Other | 4 (5) |
| Beta-2-microglobulin (IQR) | 3.0 (2.4–4.3) |
| ISS stage (%) | |
| I | 9 (19) |
| II | 31 (64) |
| III | 8 (17) |
| Unknown | 32 |
| Cytogenetics a | |
| Normal | 46 (61) |
| High risk b | 31 (39) |
| Extramedullary disease (%) | 18 (23) |
| Prior treatment lines, median (range) | 5 (2–11) |
| Triple-class exposed (%) | 75 (99) |
| Triple-class refractory (%) | 45 (56) |
| WHO performance status (%) | |
| 0 | 60 (78) |
| 1 | 17 (22) |
| Unknown | 3 |
| eGFR below <40 ml/min | 7 (9%) |
| Median (IQR) | |
| Hemoglobin (mmol/L) | 6.7 (6.2–7.6) |
| Thrombocytes (x 10 9 /L) | 166 (126–215) |
| Neutrophils (x 10 9 /L) | 2.7 (1.9–3.8) |
| Lymphocytes (x 10 9 /L) | 0.5 (0.3–1.0) |
| Albumin (g/L) | 33 (30–36) |
| Creatinine (μmol/L) | 78 (70–101) |
| LDH (U/L) | 207 (175–252) |
After a median follow-up of 21 months, median progression-free survival was 18.1 months (95% CI 11.8–37.6 months). Median overall survival was 43.5 months (95% CI 24.6–NA). During treatment with teclistamab, 66 patients (83%) received IVIG supplementation, of whom 51 patients (77%) received IVIG as primary prophylaxis, and 15 (23%) received IVIG after a severe infection (secondary prophylaxis). Median time to starting IVIG as primary prophylaxis was 1.11 months, and for secondary prophylaxis, 4.92 months. Fourteen patients (17%) never received IVIG supplementation during treatment with teclistamab. Eleven/14 patients had primary refractory disease, and 3/14 patients died of an infection while in remission without having received IVIG (median time on treatment 3.3 months).
IVIG-associated Infusion-related reactions occurred in 10/66 (15%) patients (30% grade 1, for which infusion was halted and resumed at a lower speed, 70% grade 2, for which patients also received prednisolone and clemastine). Patients who experienced a grade 2 infusion-related reaction received prednisolone 25 mg and clemastine 1–2 mg as prophylaxis, prior to the next IVIG infusions.
Incidence of infections
After a median follow-up of 21 months, 72 of 80 patients (90%) experienced at least one infection (all grades), and 30/80 (38%) experienced at least one severe infection (grade 3 or higher) (Fig. 1 ). Four patients (5%) died due to infection (all pneumosepsis, 3 of these patients did not receive IVIG). The median duration of treatment in the 8 patients who did not develop any infections was 0.92 months (range 0.69–25). Median time to first infection was 1.3 months, and time to first severe infection was 6.5 months. In total, 390 infections occurred, of which 48 (12%) were severe. Considering variable time on treatment, annualized rates of all-grade infections were 3.81 infections per patient-year. For severe infections, this was 0.47 infections per patient-year. Fig. 1 Incidence of infections in 80 patients with RRMM treated with teclistamab. Colors depict duration of teclistamab treatment without IVIG supplementation (blue) and teclistamab treatment with IVIG supplementation (grey).
Cumulative incidence of severe infections was lower in patients who received IVIG as primary prophylaxis ( p < 0.001), whereas the cumulative incidence of all-grade infections did not differ between patients who received primary IVIG-prophylaxis and those who did not receive IVIG as primary prophylaxis ( p = 0.99) (Fig. 2 ). A subgroup analysis excluding the fourteen patients who never received IVIG, showed similar results (Supplementary Fig. 1 ). To account for the possibility of multiple infections occurring in patients with variable time on treatment, we calculated the annualized rates of infections (defined as the number of infections per patient-year) during treatment with or without IVIG. Treatment with IVIG resulted in lower annualized rates of all-grade infections (3.15 vs. 4.41, p = 0.007), and severe infections (0.33 vs. 0.93, p < 0.001) (Table 2 ). IVIG numerically reduced the rate of low-grade infections (2.85 vs. 3.48, p = 0.15), however, this was not statistically significant, probably due to limited patient numbers. With an absolute risk reduction of 1.26 for all-grade infections and 0.60 for severe infections, the number needed to treat (NNT) to prevent one infection with IVIG was 0.79 for all-grade infections and 1.67 for severe infections. Subgroup analysis excluding the 14 patients who never received IVIG showed a similar effect of IVIG in reducing annualized rates of (severe) infections (Supplementary Table S1 ). Fig. 2 Cumulative incidence of all grade infections (left) and severe infections (right), compared between patients who received IVIG as primary prophylaxis ( n = 51) and patients who did not receive IVIG as primary prophylaxis ( n = 29). Table 2 Annualized rates of infections, defined as the total number of infections per patient-year, were compared between periods of no IVIG and during treatment with IVIG using Poisson models. Annualized rate (95% CI) No IVIG IVIG p -value All grade infections 4.41 (3.56–5.45) 3.19 (2.83–3.60) 0.01 Non severe (grade 1–2) 3.48 (2.74–4.12) 2.85 (2.51–3.24) 0.15 Severe infections (grade ≥3) 0.93 (0.59–1.48) 0.34 (0.24–0.50) <0.001
Table 2
Annualized rates of infections, defined as the total number of infections per patient-year, were compared between periods of no IVIG and during treatment with IVIG using Poisson models.
| Annualized rate (95% CI) | No IVIG | IVIG | p -value |
| All grade infections | 4.41 (3.56–5.45) | 3.19 (2.83–3.60) | 0.01 |
| Non severe (grade 1–2) | 3.48 (2.74–4.12) | 2.85 (2.51–3.24) | 0.15 |
| Severe infections (grade ≥3) | 0.93 (0.59–1.48) | 0.34 (0.24–0.50) | <0.001 |
Respiratory infections were the most common type of infection (in total 316 of 390 infections (81%); 55% grade 1, 34% grade 2, 7% grade 3, 3% grade 4 and 1% grade 5), followed by gastro-intestinal infections (total of 43 infections (11%); 63% grade 1, 26% grade 2, 12% grade 3, no grade ≥4 events) (Fig. 3 ). In 235/390 infections (60%) microbiological tests were performed. In 193 (82%) cases, one or more pathogens were identified: this was 79% for low-grade infections and 94% for severe infections (Supplementary Table S2 ). Most commonly cultured pathogens in patients with respiratory infections ( n = 65) were rhinovirus ( n = 101), SARS-CoV-2 ( n = 33), Haemophilus influenzae ( n = 20), and Pseudomonas aeruginosa ( n = 16). Most commonly cultured pathogens in patients with gastro-intestinal infections ( n = 25) were Campylobacter jejuni ( n = 7), norovirus ( n = 7), and Clostridium difficile ( n = 4). Types of infections did not differ between patients who received IVIG and those who did not, with respiratory infections being most common (80% in patients receiving IVIG, and 84% in those not receiving IVIG) (Supplementary Table S3A ). Fig. 3 Frequency of infections occurring in 80 RRMM patients treated with teclistamab, categorized by organ system. Systemic infections were defined as severe infections that caused fever in the presence of positive blood culture or positive PCR (for the detection of pathogens in blood), in the absence of focal signs of infection.
When comparing pathogens in respiratory infections that occurred in patients while receiving IVIG versus no IVIG, Pseudomonas aeruginosa infections occurred more often in patients who did not receive IVIG (14% versus 3%, p = 0.003), while Haemophilus influenzae infections occurred more often in patients receiving IVIG (2% vs. 8%, p = 0.05) (Supplementary Table S3B ).
Opportunistic infections occurred in four patients (one patient with two opportunistic infections) (Supplementary Table S2 ), of which three were respiratory infections ( Pneuomocytis Jirovecii pneumonia (PJP), Aspergillus fumigatus, Aspergillus niger ) and two were systemic infections (cytomegalovirus and Stenotrophomonas maltophilia ). Except for the PJP infection, all opportunistic infections occurred while patients received IVIG.
Recurring or persisting infections
Ten patients (12%) experienced one or more recurring or persisting bacterial infections, defined as infectious episodes in which the same pathogen was cultured at least twice, with a ≥ 30-day interval. Median interval between recurring/persisting infections was 55 days [IQR 37–150]. All 10 patients received IVIG supplementation; however, in 2/10 patients, IVIG was initiated shortly after the first infection (polyclonal IgG at the time of the infection: 2.04 and 1.65 g/L). Among 10 patients infected with Pseudomonas aeruginosa , 4 patients (40%) experienced recurrence after initial resolution of symptoms with antibacterial treatment. In two of these cases, suboptimal antibiotic penetration may have contributed to treatment failure: one patient had a thoracic abscess, and the other had an infected hip prosthesis. In addition, development of ciprofloxacin resistance may have contributed to recurrence in two other Pseudomonas aeruginosa cases. Of the 9 patients with Haemophilus influenzae infections, 4 (44%) experienced recurrence. In one patient development of doxycycline resistance of Haemophilus influenzae may have contributed to recurrence.
Twenty-five patients (31%) experienced one or more recurring or persisting viral infections, with a median interval between infections of 96 days [IQR 60–172]. All 25 patients received IVIG supplementation; however, in 8/25 patients, IVIG was only initiated after the first infection. In these 8 patients, median polyclonal IgG level was 2.36 g/L (range 1.23–3.93) at the time of the first infection prior to initiation of IVIG supplementation. In 21 of 36 patients (58%) who experienced a rhinovirus infection, rhinovirus persisted or recurred. These infections were mostly low-grade and most likely persistent, as symptoms did not completely disappear in the majority of patients before start of the next infectious episode. In seven patients, rhinovirus was cultured at least 5 times, with one patient reaching 10 instances over the course of 16 months (Fig. 4 ). Infections with SARS-CoV-2 recurred in 6/25 patients (24%). In addition, two patients had persisting gastro-intestinal infections: one with Clostridium difficile and one with norovirus. Detailed demographics of sixteen patients who experienced at least 3 recurring/persisting infections with one or more pathogens (Fig. 4 ) are summarized in Supplementary Table S4 . No comorbidities could be identified as risk factors for these recurring or persisting infections. Fig. 4 Recurring or persisting respiratory infections in 16 patients who experienced at least 3 recurring/persistent infections. The figure depicts the recurring infections only caused by the four most common respiratory pathogens. For clarity, infections with other pathogens are not shown.
Breakthrough infections during treatment with IVIG
Although IVIG treatment significantly reduced risk of infections, patients could still develop (severe) infections during teclistamab therapy (breakthrough infections). To characterize these breakthrough infections, we investigated the polyclonal IgG levels at the time of infection. Polyclonal IgG levels at time of infection were available in 265 out of 308 infections that occurred during IVIG treatment. The median polyclonal IgG level at the time of low-grade breakthrough infections was 5.00 g/L (range 1.44–15.50) and for severe infections this was 4.84 g/L (range 2.16–11.30) (Fig. 5A ). However, in 82 out of 265 breakthrough infections (31%) IgG levels were below the target IgG level of 4 g/L; IgG was <4 g/L in 8 of 23 severe infections (34%). Most breakthrough infections with suboptimal IgG levels (IgG <4 g/L) occurred relatively early after start of IVIG (56% in first 3 months, 73% in first 6 months) (Fig. 5B ). Severe breakthrough infections in patients with IgG levels >4 g/L ( n = 15) were both viral and bacterial respiratory infections, gastrointestinal infections, and urinary tract infections. Regarding recurring or persisting bacterial infections occurring during IVIG supplementation, median polyclonal IgG level at the time of infection was 4.88 g/L (range 2.16–7.36). For recurring or persisting viral infections, this number was 5.41 g/L (range 2.15–12.7). Fig. 5 Polyclonal IgG levels at time of breakthrough infection. A Polyclonal IgG levels at time of breakthrough infection (infection occurring during IVIG treatment), categorized by low-grade infections (grade 1 and 2) and severe infections (grade ≥ 3). B Polyclonal IgG levels at time of breakthrough infection (defined as time since IVIG initiation). Regression line represents a linear model fitted to show the overall trend of IgG levels at the time of each breakthrough infection.
To investigate potential risk factors for infections despite IVIG supplementation, we assessed associations between baseline patient- and disease-specific characteristics with the annualized rates of infections occurring in patients receiving IVIG. In univariate analyses, low lymphocyte counts, low thrombocyte counts, high beta-2-microglobulin, and triple class refractoriness were significantly associated with higher risk for infections (all grades) despite receiving IVIG supplementation (Supplementary Table S5 ). In multivariable analysis, lymphocyte count and triple class refractoriness remained significant predictors. For severe infections, older age, high beta-2-microglobulin, and having received 4 or more prior lines of therapy were identified as predictors in univariate analysis (Supplementary Table S6 ). In multivariable analysis, age and beta-2-microglobulin retained significance.
Treatment discontinuation due to infections
Twenty-four (30%) patients temporarily discontinued treatment (for >1 month). In 23/24 patients (96%), this was due to infections, and one patient temporarily discontinued because of neurological symptoms. Seven (9%) patients permanently discontinued teclistamab due to severe infections, while being in complete serological remission. One patient discontinued treatment due to reactivation of cytomegalovirus—which had also occurred during treatment lines prior to teclistamab—and went off protocol to receive different treatment. One patient discontinued treatment due to sepsis with organ failure requiring long-term ICU admission, after which the patient remained progression-free for 43 months. Recently, the patient experienced progression and did not respond to retreatment with teclistamab. The other 5 patients remained in complete remission and were still progression-free at the clinical cut-off date, with duration of ongoing response from the moment of discontinuation ranging from 9.4 to 23.3 months (Supplementary Table S7 ). After discontinuation of therapy, (severe) infections still occurred, with the latest occurring 21 months after definitive discontinuation (Supplementary Fig. 2 ). These infections all occurred while patients still received IVIG.
Impact of dosing schedules on infections
During treatment with teclistamab, 60/80 (75%) of patients switched to different dosing schedules. To investigate a potential association of incidence of infections with therapy de-escalation, we compared annualized rates of infections across different dosing schedules (weekly [QW], biweekly [Q2W], monthly [Q4W], and bimonthly [Q8W]). During weekly dosing, 6.08 all-grade infections occurred per patient-year. Switching to longer intervals, reduced the incidence of infections to 3.54 per patient-year during biweekly dosing ( p < 0.01), 2.93 during monthly ( p < 0.01) and 2.25 during bimonthly dosing schedules ( p < 0.001) (Fig. 6A ). For severe infections, annualized rates of infections decreased from 0.81 during weekly dosing, to 0.39 during biweekly ( p = 0.19), 0.29 during monthly ( p = 0.07) and 0.1 during bimonthly dosing ( p < 0.05) (Fig. 6C ). Fig. 6 Annualized rates of infections (all-grade and severe) by dosing schedule. Seventy-six out of 80 patients started treatment on a weekly schedule, 1 patient started on biweekly, and 3 patients started on monthly schedule. Infections per patient-year were compared between dosing schedules using negative binomial models. For the sensitivity analyses, no statistical testing could be performed due to limited patient numbers. A All-grade infections by dosing schedule corrected for time on treatment (person-years). Number of patients per dosing schedule was: 76 patients weekly schedule, 47 biweekly schedule, 24 monthly schedule, and 11 bimonthly schedule. B Sensitivity analysis for all-grade infections occurring in 66 patients during IVIG supplementation. Numbers of patients per dosing schedule while receiving IVIG supplementation were: 62 patients weekly schedule, 46 biweekly schedule, 24 monthly schedule, and 11 bimonthly schedule. C Severe infections by dosing schedule in 80 patients, corrected for time on treatment. D Sensitivity analysis for severe infections occurring in 66 patients during IVIG supplementation.
During weekly and biweekly dosing schedules, not all patients received IVIG supplementation, while all received IVIG by the time patients received monthly or bimonthly teclistamab. To address the potential confounding of IVIG supplementation on the incidence of infections per dosing schedule, we performed a sensitivity analysis in 66 patients who received IVIG supplementation during treatment with teclistamab, including only the infections during the time-period that patients received IVIG. While receiving IVIG, all-grade infection rates did not differ between different dosing intervals (Fig. 6B ). For severe infections, however, a reduction in infection burden could still be observed when patients switched to longer dosing intervals (0.44 infections per patient-year during weekly dosing, 0.31 during biweekly, 0.32 during monthly, and 0.13 during bimonthly dosing) (Fig. 6D ).
Discussion
Patients with RRMM who are treated with BCMA-directed BsAbs are at an increased risk for infections, which is partly caused by BsAb-induced hypogammaglobulinemia, neutropenia, lymphopenia, and T-cell exhaustion [ 12 , 23 ]. In addition, the exposure to immunosuppressive anti-MM agents in previous lines of therapy may also contribute to infectious risk [ 24 ]. In this retrospective, single-center analysis, we found that IVIG prophylaxis reduced the annualized rate of both all-grade and of severe infections. However, despite IVIG prophylaxis, infections were still common. Multivariable analysis identified low lymphocyte counts and triple class refractoriness as significant risk factors for all grade infections in patients receiving IVIG supplementation. Older age and elevated beta-2-microglobulin were found to be independently associated with risk for severe breakthrough infections. In addition, we show for the first time that switching to longer dosing intervals reduced infection risk, with annualized rates of both all-grade and severe infections declining following de-escalation. Importantly, de-escalation still seemed to impact the risk for severe infections in patients already receiving IVIG supplementation.
The incidence of infections in our cohort is in line with previous literature, reporting severe infections in 22–55% of patients [ 9 , 13 , 25 – 27 ]. A meta-analysis including 16 clinical trials with BCMA-directed BsAbs reported all-grade infections in 56% and grade ≥3 infections in 24% of patients (median follow-up of 7.6 months) [ 28 ]. However, differences in follow-up duration across studies likely contribute to the wide range of reported incidence of infections. In addition, this approach does not account for multiple infections in the same patient.
To more accurately reflect the true infectious burden per patient, we calculated annualized infection rates by incorporating all infections and correcting for observation time. This is in line with the approach recently proposed by Ludwig et al., in which infections per month per 100 patients were reported for RRMM patients receiving various BsAbs [ 22 ]. For the MajesTEC-1 trial, they reported 2.4 grade ≥3 infections per 100 patients per month, translating to 0.28 per patient-year, which is slightly lower than in our cohort (0.47 severe infections per patient-year) [ 22 ]. A potential explanation is our inclusion of recurrent infections, which were counted as new events if symptoms reappeared more than 30 days after a prior infection. In addition, patients who were treated in the compassionate use program often did not fulfill the in- and exclusion criteria of the MajesTEC-1 trial due to the presence of comorbidities and/or cytopenias, which may have contributed to an increased vulnerability to infections [ 29 ]. A different retrospective study in 37 patients treated with BCMA-directed BsAbs reported annualized infection rates of 3.3 per patient-year for all-grade infections and 0.7 severe infections per patient-year [ 16 ], which corresponds with our results. Given that each infectious episode— including grades 1 and 2—may impact the quality of life in RRMM patients receiving BsAbs, our findings reporting a total of 390 infections occurring in 80 patients, underscore the importance of capturing all infectious events to more accurately reflect the true infectious burden associated with these therapies.
Our results align with previous studies demonstrating that adding IVIG to standard prophylaxis with cotrimoxazole and valaciclovir further reduces the risk of severe infections in patients treated with BsAbs [ 7 , 16 ]. Interestingly, a recent study reported that patients who received primary IVIG prophylaxis remained longer on treatment [ 19 ]. There is scarce data on the incidence, severity and type of breakthrough infections in patients who receive IVIG. In a proportion of patients, suboptimal polyclonal IgG levels (< 4 g/L) despite IVIG treatment may have contributed to breakthrough infections, which were most frequent during the first six months after IVIG initiation. Starting with higher IVIG loading doses in patients with severe hypogammaglobulinemia could help achieve protective IgG levels (>4 g/L) more rapidly. Monthly IgG monitoring and rapid dose adaptations are also crucial to minimize infection risk.
IVIG supplementation was generally well-tolerated. Infusion-related reactions occurred in 15% of patients and were effectively managed by temporarily halting the infusion and resuming at a lower speed, or by additional administration of clemastine and prednisolone. Subcutaneous immunoglobulin (SCIG) may be an alternative to IVIG, with fewer systemic adverse events and the option of at-home administration. Moreover, previous studies in patients with primary immunodeficiency demonstrated that hyaluronidase-facilitated SCIG (fSCIG) enables larger absorption volumes, with patients receiving fSCIG typically at 3- or 4-week intervals [ 30 – 32 ].
Breakthrough infections despite adequate IVIG supplementation (IgG >4 g/L) suggest that susceptibility to infections persists due to multiple other mechanisms contributing to immunosuppression, including sustained low levels of IgA, which is important for defending mucosal surfaces against pathogens (IVIG contains only trace amounts of non-IgG antibodies) [ 33 ]. Additionally, T-cell exhaustion due to continuous T-cell stimulation by BsAbs—as well as previous exposure to immunosuppressive anti-MM agents—may contribute to impaired immune responses [ 12 ]. In patients with severe breakthrough infections despite IgG levels of more than 4 g/L, intensification of IVIG therapy can be considered to achieve physiological IgG levels (>7 g/L). In addition, we showed that less frequent BsAb dosing (monthly or bimonthly, instead of weekly) reduced the risk for severe infections, even in patients who were already receiving IVIG supplementation. These results suggest that, in case of recurring infections despite IVIG supplementation, longer dosing intervals may be considered—provided the disease is in deep remission. The beneficial impact of longer dosing intervals on infection rates may be explained by observations from preclinical and clinical studies demonstrating that less frequent BsAb administration decreases BsAb-induced T-cell exhaustion [ 34 , 35 ]. Moreover, given the frequent discontinuation of therapy due to severe infections— and the durable deep responses observed in these patients—maintenance strategies such as longer dosing intervals or fixed duration treatment should be evaluated in prospective, preferentially randomized, clinical studies [ 36 ].
Other strategies to further reduce the infection risk in patients treated with BCMA-directed BsAbs include additional antibacterial prophylaxis, especially in patients at high risk of infections. A phase III trial demonstrated that levofloxacin prophylaxis reduced infections compared with placebo in newly diagnosed MM patients, also in patients using cotrimoxazole [ 37 ]. Older age and elevated beta-2-microglobulin—reflective of high tumor burden—were significant predictors of severe infections despite IVIG treatment in our study, suggesting that patients with these risk factors may benefit from additional prophylaxis, such as levofloxacin, which also has activity against the most frequently cultured bacteria in our study ( Haemophilus influenzae and Pseudomonas aeruginosa) . Importantly, patients who definitively discontinued BsAb therapy remained at high risk for infections, underscoring the need for ongoing infectious prophylaxis (including IVIG) even after therapy discontinuation, given that recovery of IgG and IgA may take many months [ 16 ].
This study has several limitations that should be acknowledged. It is a retrospective cohort study with a limited sample size and no randomized allocation to teclistamab treatment with or without IVIG supplementation. Patients who were treated in earlier phases of the clinical trial may have received a starting dose of teclistamab that was different than the recommended phase 2 dose, which may have introduced heterogeneity in our patient cohort. In addition, switching to different treatment schedules occurred for various reasons, which may influence infection risk on its own. Unmeasured confounding factors—such as differences in immune profiles and broad timelines of study enrollment—may have influenced infection risk. A key strength of the study is the single-center design, which ensures uniformity in antibiotic prophylaxis and extensive microbiological testing, including cultures and PCR, which was performed in many cases. Additionally, the availability of detailed data on each dose or interval adjustment enabled modeling of infection risk across different treatment schedules—a novel approach in the analysis of adverse events.
In conclusion, our study demonstrated the importance of the assessment of annualized infection rates, counting all infectious events that occurred in patients who were treated with anti-BCMA BsAbs. IVIG supplementation reduced the rates of all-grade and severe infections. We provide the first evidence for the benefit of treatment de-escalation for reducing the risk of severe infections, also in patients receiving IVIG supplementation. These findings support future clinical studies investigating longer dosing intervals for patients who achieved and sustained deep remission with BsAb therapy.
Supplementary information
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Supplementary information
The online version contains supplementary material available at 10.1038/s41408-026-01451-9.
Acknowledgements
The MajesTEC-1 study ( NCT04557098 ) and the compassionate use program were supported by Janssen Pharmaceuticals. We acknowledge the International Myeloma Society (IMS) for support of this study by granting travel support to the IMS annual meeting.
Author contributions
FS, KN, SZ, and NvdD conceived, conceptualized and designed the study. KG, CK, SZ, and NvdD included and treated patients in the clinical trial. FS, KN, SZ, and NvdD analyzed and interpreted the data. FS and NvdD wrote the first draft of the manuscript. All authors reviewed and approved the final version.
Data availability
Data are available from the corresponding author, Prof. Dr. N. van de Donk (n.vandedonk@amsterdamumc.nl), upon reasonable request.
Competing interests
KG has received payment/honoraria for presentations from Bristol Myers Squibb and Beigene (no personal funding). KN is employed by CSL Behring as a contractor. SZ has received research funding from Takeda, Celgene, and Janssen. SZ participates in advisory boards of Takeda, Celgene, Janssen, Sanofi, Oncopeptides, and Amgen, all paid to the employer. NWCJvdD has received research support from Janssen Pharmaceuticals, AMGEN, Celgene, Novartis, Cellectis, and Bristol Myers Squibb. He serves on advisory boards for Janssen Pharmaceuticals, AMGEN, Celgene, Bristol Myers Squibb, Takeda, Roche, Novartis, Bayer, Pfizer, Merck, Kite Pharma, AbbVie, Adaptive, and Servier, all paid to the employer. All other authors have no conflicts of interest to disclose.
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