Table of Contents
- Key Points
- Background: Why This Research Matters
- How the Research Was Conducted
- Study Quality and Risk of Bias
- Findings for Teclistamab
- Findings for Elranatamab
- Findings for Talquetamab
- Findings for CAR-T Cell Therapies
- Comparing Infections Across Treatments
- Which Pathogens Cause Infections
- Risk Factors for Infection
- Prevention Strategies
- Extended Dosing Intervals
- What This Means for Patients
- Limitations of the Research
- Recommendations
- Frequently Asked Questions
- Source Information
Key Points
- In a review of 123 studies, any-grade infections occurred in roughly 40–80% of patients receiving CAR-T cell therapy or bispecific antibodies for multiple myeloma.
- Severe infections (grade 3 or higher) exceeded 50% in several bispecific antibody studies and ranged from 4.2% to 34% across CAR-T cell studies.
- Risk was highest early after CAR-T infusion and during the first months of bispecific antibody therapy, with some risk persisting over time.
- Key risk factors included low white blood cell counts, corticosteroid and tocilizumab exposure, and low antibody levels (hypogammaglobulinemia).
- Antiviral, PJP, antibacterial, and antifungal prophylaxis plus immunoglobulin replacement reduced infections, and extended dosing intervals may lower severe infections.
Background: Why This Research Matters
Multiple myeloma (a cancer of plasma cells in the bone marrow) has seen a major shift in treatment. After monoclonal antibodies were introduced, two newer types of immunotherapy became central to treating relapsed or refractory multiple myeloma (RRMM). These two newer types of immunotherapy are bispecific antibodies (BsAbs) and CAR-T cell therapy. RRMM means the cancer has returned or stopped responding to prior treatments.
Both treatment types produce deep responses against the cancer. However, they also cause prolonged immune system disruption. This makes infections a major cause of illness, death, and increased healthcare use.
Several factors contribute to this weakened immune state:
- Persistent low blood cell counts (cytopenias)
- B-cell aplasia (loss of antibody-producing B cells)
- Hypogammaglobulinemia (low levels of protective antibodies)
- Impairment of both innate and adaptive immune compartments
Despite the growing use of these therapies, a systematic, infection-focused summary has been limited. This summary would cover how often infections occur, when infections occur, how severe infections are, what causes infections, and how to prevent infections. This review was designed to fill that gap.
The authors also noted an important practical difference between the two treatment types. CAR-T cell therapy is resource-intensive and requires complex logistics. Bispecific antibodies are given continuously in most current regimens, which may prolong the period of infection risk related to ongoing exposure.
Direct head-to-head comparisons between CAR-T and bispecific antibodies are currently lacking. However, emerging real-world data suggest there may be differences in infection profiles and toxicity severity between the two approaches.
How the Research Was Conducted
This review followed PRISMA 2020 guidelines, which are internationally recognized standards for conducting and reporting systematic reviews.
The researchers searched PubMed/MEDLINE through May 22, 2026. They included randomized trials, cohort studies, and real-world studies that reported infectious outcomes in patients with multiple myeloma treated with CAR-T cells or bispecific antibodies.
Studies were excluded if they involved:
- Cancers other than multiple myeloma
- No reported infectious outcomes
- Treatments other than CAR-T cells or bispecific antibodies
Reviews, meta-analyses, case reports, and editorials were also excluded, as were studies without extractable infection data.
Screening and data extraction were performed independently by two reviewers (MB and NS), with consensus resolution by a third reviewer (TW).
The search strategy combined terms for the disease ("multiple myeloma"), the treatments ("CAR-T," "bispecific antibody," teclistamab, elranatamab, linvoseltamab, talquetamab, cevostamab, cilta-cel, ide-cel), and the outcome ("infection").
The included studies were highly heterogeneous, meaning the studies varied widely in design, patient populations, and reporting methods. Because of this heterogeneity, the researchers decided that a quantitative meta-analysis was not appropriate. A quantitative meta-analysis is a statistical pooling of results. Instead, results are presented narratively by treatment modality and by individual agent.
Language editing was performed using AI tools (DeepL, ChatGPT) and professional editing services. The authors state they are solely responsible for the scientific content.
Study Quality and Risk of Bias
The researchers assessed the methodological quality of each included study using CASP checklists (Critical Appraisal Skills Programme), with separate versions for randomized controlled trials and cohort studies.
Lower CASP scores reflected several common issues:
- Non-comparative study designs
- Small patient cohorts
- Short follow-up periods
- Incomplete reporting of patient dropouts and confounder control
No study met criteria for low completeness (below 33%). Studies were categorized as intermediate (34–66% of criteria fulfilled) or high completeness (67% or more).
Risk of bias was evaluated using RoB 2 for randomized trials and ROBINS-I for non-randomized studies. Overall judgments followed the "worst-domain" principle, meaning the worst rating in any single domain determined the overall rating.
Overall risk of bias was often rated as serious. This was mainly due to confounding and selection bias, which are inherent to early-phase, single-arm studies. Other domains were rated low to moderate, indicating generally robust conduct within those areas.
Findings for Teclistamab
The review included seven early-phase trial reports, one phase III trial, and fifteen real-world cohort studies of teclistamab.
An extended safety analysis of the MajesTEC-1 trial reported infections in 80% of patients. Respiratory tract infections were most common, occurring in 19.4% of patients. The infection-related mortality rate was 12.7%.
The median time to first infection was 1.7 months. Although most infections occurred within the first 30 days, the risk persisted over time.
Specific pathogens reported in the MajesTEC-1 analysis included:
- Herpesviruses: 4.2%
- CMV (cytomegalovirus) reactivation: 1.2%
- PJP (Pneumocystis jirovecii pneumonia): 4.2%
- Fungal infections: 5.5%
The phase III MajesTEC-3 trial confirmed the substantial infectious burden associated with BCMA-directed bispecific antibody therapy when used in earlier treatment lines. In that trial, infections occurred in 96.5% of patients, grade 3–4 infections occurred in 54.1%, and fatal infections occurred in 4.6%.
Most infection-related deaths occurred within the first six months of therapy. The incidence of new severe infections declined after patients transitioned to monthly dosing and reinforced immunoglobulin replacement strategies.
Real-world data confirmed infection rates of 42–60%, with serious infections in 22% to 42.9%. In real-world settings, 13% of patients discontinued treatment due to infection, and 30% required hospitalization.
Infections in real-world cohorts were predominantly viral (50%) and bacterial (45%). Opportunistic infections occurred less frequently, including fungal infections (5%) and CMV reactivation (22%).
Infections remain the leading cause of treatment discontinuation in the real-world setting.
The authors noted that cohorts were consistently heavily pretreated but heterogeneous in recruitment and design. Prospective trials applied CTCAE (Common Terminology Criteria for Adverse Events) reporting standards, whereas real-world studies were retrospective. This contributed to differences in how low-grade events were captured.
Findings for Elranatamab
Across the elranatamab studies included in this review, any-grade infections ranged from 44% to 74.5%. Grade 3 or higher infections ranged from 18.7% to 34.5%.
Hypogammaglobulinemia (low antibody levels) was reported in 47.5% to 94.6% of patients. This is a key risk factor for infection.
Other reported infection types included:
- Viral infections other than CMV and herpesviruses: 5.7% to 10.8%
- CMV reactivation: 3% to 4.9%
- Fungal infections: up to 7%
Findings for Talquetamab
Talquetamab showed lower infection rates compared with BCMA-targeted therapies, with any-grade infections ranging from 47% to 55%. However, it was associated with relevant mucocutaneous toxicity (side effects affecting the skin and mucous membranes).
Grade 3 or higher infections ranged from 16.7% to 48% across the talquetamab studies. Hypogammaglobulinemia was reported in 23% to 49% of patients.
Specific infection types included:
- Viral infections other than CMV and herpesviruses: 1% to 11%
- CMV reactivation: 0%
- Fungal infections: 2% to 2.9%
Findings for CAR-T Cell Therapies
The review included studies of two BCMA-directed CAR-T cell products: ide-cel (idecabtagene vicleucel) and cilta-cel (ciltacabtagene autoleucel).
For ide-cel, any-grade infections ranged from 44% to 78.8%. Grade 3 or higher infections ranged from 8% to 20%. Hypogammaglobulinemia was reported in 12% to 23%.
For cilta-cel, any-grade infections ranged from 58.4% to 100%. Grade 3 or higher infections ranged from 11.1% to 34%. Hypogammaglobulinemia was reported in 20% to 70%.
Across all CAR-T cell studies combined, any-grade infections ranged from 30.6% to 61%. Grade 3 or higher infections ranged from 4.2% to 24%. Hypogammaglobulinemia occurred frequently after BCMA-directed CAR-T therapy (80%).
In randomized CAR-T trials, grade 5 infections (fatal infections) represented a substantial proportion of treatment-related deaths.
One real-world study comparing CAR-T and bispecific antibodies found infection rates of 20% for CAR-T versus 24% for bispecific antibodies. Another study reported 50% for CAR-T versus 44% for bispecific antibodies. A third study reported 60% for CAR-T versus 49% for bispecific antibodies.
Another real-world analysis found grade 3 or higher infection rates of 19% for CAR-T versus 76% for bispecific antibodies. A separate study reported 8% for PGPRD5 bispecific antibodies versus 19% for BCMA bispecific antibodies.
Comparing Infections Across Treatments
The review found that infections were frequent across all BCMA-directed CAR-T products and bispecific antibodies, with any-grade incidence of approximately 40–80%.
The highest risk occurred early after CAR-T infusion and during the first months of bispecific antibody therapy.
Grade 3 or higher infections were common and exceeded 50% in several bispecific antibody cohorts. Fatal infections were less frequent but occurred across both CAR-T and bispecific antibody studies.
Real-world data suggest higher infection-related healthcare use and mortality with bispecific antibodies compared with CAR-T therapy. However, the authors caution that direct comparative data are currently lacking, and these differences may reflect differences in patient populations and treatment settings.
Which Pathogens Cause Infections
Viral and bacterial pathogens predominated across the studies. The most commonly reported pathogens included:
- Viral infections: Herpesviruses (including HSV and VZV), CMV reactivation, and other viral pathogens
- Bacterial infections: Respiratory tract infections were most common
- Fungal infections: Invasive fungal infections were reported, particularly in patients not receiving antifungal prophylaxis
- Pneumocystis jirovecii pneumonia (PJP): Reported particularly in patients without PJP prophylaxis
CMV reactivation was a notable concern, with rates ranging from 0% to 22% depending on the treatment and study population.
Risk Factors for Infection
The review identified several key risk factors that increased the likelihood of infection in patients receiving CAR-T cell therapy or bispecific antibodies:
- Neutropenia (low levels of neutrophils, a type of white blood cell that fights infection)
- Corticosteroid exposure (steroid medications that suppress the immune system)
- Tocilizumab exposure (a medication used to treat cytokine release syndrome, a common side effect of immunotherapy)
- Hypogammaglobulinemia (low levels of protective antibodies)
Persistent cytopenias (low blood cell counts that continue over time) and B-cell aplasia (loss of antibody-producing B cells) also contributed to immunosuppression.
The authors noted that risk is particularly high with BCMA-targeted therapies and continuous bispecific antibody administration.
Prevention Strategies
The review found that several prevention strategies reduced infections, though residual risk persisted.
Antiviral prophylaxis against HSV (herpes simplex virus) and VZV (varicella-zoster virus) became standard alongside PJP prophylaxis. In the dose-finding trial, PJP prophylaxis was initially used in 83% of patients.
Antibacterial and antifungal prophylaxis during periods of neutropenia was also recommended.
Intravenous immunoglobulin (IVIG) use increased from 11% to 62% across studies and was associated with fewer severe infections. At 6 months, grade 3/4 infections occurred in 5.3% of patients receiving IVIG versus a higher rate in those who did not receive it.
In real-world settings, immunoglobulin supplementation was administered to 46% of patients and was associated with improved infection-free survival.
The authors noted that immunoglobulin replacement most notably reduced infections, though the implementations were heterogeneous across clinical trials.
Extended Dosing Intervals
The review found evidence that extended dosing intervals may reduce infections, particularly severe infections, while preserving treatment efficacy.
In the MajesTEC-3 trial, the incidence of new severe infections declined after patients transitioned to monthly dosing and reinforced immunoglobulin replacement strategies.
This finding suggests that response-adapted treatment strategies, including extended dosing intervals, may improve safety and outcomes for patients receiving bispecific antibodies.
What This Means for Patients
Infectious toxicity remains a key limitation of both CAR-T cell therapy and bispecific antibodies for multiple myeloma. Patients considering these treatments should be aware that infections are common and can be serious.
The risk is particularly high with BCMA-targeted therapies and continuous bispecific antibody administration. However, several strategies can reduce this risk:
- Antiviral prophylaxis against HSV and VZV
- PJP prophylaxis
- Antibacterial and antifungal prophylaxis during neutropenia
- Immunoglobulin replacement therapy
- Extended dosing intervals when appropriate
Patients should discuss these prevention strategies with their healthcare team before starting treatment. Early immunoglobulin replacement may be particularly important for patients who develop hypogammaglobulinemia.
The authors emphasize that tailored prophylaxis, early immunoglobulin replacement, and response-adapted treatment strategies may improve safety and outcomes for patients receiving these therapies.
Limitations of the Research
The authors identified several important limitations of this review:
- Heterogeneity: The included studies varied widely in design, patient populations, and reporting methods, making direct comparisons difficult.
- Lack of direct comparative data: No head-to-head randomized trials directly compared infection profiles between CAR-T cell therapy and bispecific antibodies.
- Risk of bias: Overall risk of bias was often rated as serious, mainly due to confounding and selection bias inherent to early-phase, single-arm studies.
- Retrospective real-world data: Real-world studies were retrospective, which may lead to underreporting of low-grade infections compared with prospective trials using CTCAE reporting.
- Short follow-up: Many studies had short follow-up periods, which may not capture late infections.
- Small cohorts: Some studies included small numbers of patients, limiting the precision of infection rate estimates.
- Incomplete reporting: Some studies did not report attrition or confounder control, and some infection data were not extractable.
The authors also noted that the definition of infection outcomes and follow-up duration varied across studies, limiting comparability.
Recommendations
Based on the findings of this systematic review, the authors recommend the following:
- Tailored prophylaxis: Patients should receive antiviral prophylaxis against HSV and VZV, PJP prophylaxis, and antibacterial and antifungal prophylaxis during periods of neutropenia.
- Early immunoglobulin replacement: Immunoglobulin replacement therapy should be considered early, particularly for patients who develop hypogammaglobulinemia.
- Response-adapted treatment strategies: Extended dosing intervals may reduce infections, particularly severe infections, while preserving efficacy.
- Careful patient selection: Given the infection risk, patient selection for CAR-T cell therapy and bispecific antibodies should carefully weigh the benefits against the risks.
- Monitoring: Patients should be monitored closely for infections, especially during the early treatment period (first 30 days after CAR-T infusion and first months of bispecific antibody therapy).
- Further research: Direct comparative studies are needed to better understand differences in infection profiles between CAR-T cell therapy and bispecific antibodies.
The authors conclude that infectious toxicity remains a key limitation of these therapies. Risk is particularly high with BCMA-targeted therapies and continuous bispecific antibody administration. Tailored prophylaxis, early immunoglobulin replacement, and response-adapted treatment strategies, including extended dosing intervals, may improve safety and outcomes.
Frequently Asked Questions
How common are infections with CAR-T cell therapy or bispecific antibodies for multiple myeloma?
In the 123 studies reviewed, any-grade infections occurred in roughly 40–80% of patients receiving either treatment. Severe infections (grade 3 or higher) exceeded 50% in several bispecific antibody studies. Risk was highest early after CAR-T infusion and during the first months of bispecific antibody therapy. Fatal infections were less frequent but occurred with both treatment types.
When is the risk of infection highest after starting these treatments?
The review found that risk was highest early after CAR-T infusion and during the first months of bispecific antibody therapy. For teclistamab, the median time to first infection was 1.7 months, and most infections occurred within the first 30 days, though risk persisted over time. In one phase III trial, most infection-related deaths occurred within the first six months.
What factors increase the risk of infection during these treatments?
Key risk factors identified were low white blood cell counts (neutropenia), corticosteroid exposure, tocilizumab exposure, and low antibody levels (hypogammaglobulinemia). Persistent low blood cell counts and loss of antibody-producing B cells also contributed to a weakened immune state. Risk was particularly high with BCMA-targeted therapies and continuous bispecific antibody administration.
What prevention strategies can reduce infections during these treatments?
The review found that antiviral prophylaxis against HSV and VZV, PJP prophylaxis, and antibacterial and antifungal prophylaxis during neutropenia reduced infections. Immunoglobulin replacement also helped: in one analysis, grade 3/4 infections at 6 months occurred in 5.3% of patients receiving IVIG versus a higher rate in those who did not. Some risk remained despite these measures.
Can extending the time between doses lower the risk of severe infections?
Yes, the review found evidence that extended dosing intervals may reduce infections, particularly severe infections, while preserving treatment efficacy. In the MajesTEC-3 trial, the incidence of new severe infections declined after patients transitioned to monthly dosing and reinforced immunoglobulin replacement strategies. This suggests response-adapted treatment strategies may improve safety and outcomes.
Are infection rates different between CAR-T cell therapy and bispecific antibodies?
Real-world data suggest higher infection-related healthcare use and mortality with bispecific antibodies compared with CAR-T therapy, but direct head-to-head comparisons are lacking. For example, one real-world analysis found grade 3 or higher infection rates of 19% for CAR-T versus 76% for bispecific antibodies. These differences may reflect differences in patient populations and treatment settings.
When should a patient with multiple myeloma considering CAR-T cell therapy or bispecific antibodies seek a second opinion?
Infections occur in roughly 40–80% of patients receiving CAR-T cell therapy or bispecific antibodies, with grade 3 or higher infections exceeding 50% in several bispecific antibody studies. Risk is highest in the first 30 days after CAR-T infusion and during the first months of bispecific antibody therapy. Because prevention strategies such as antiviral and PJP prophylaxis, immunoglobulin replacement, and extended dosing intervals can reduce this risk, a second opinion can help confirm whether the recommended regimen and its supportive care plan are appropriate. Diagnostic Detectives Network provides independent expert second opinions.
Source Information
Original article title: Infectious toxicities associated with bispecific antibodies and CAR-T Cells in multiple myeloma: a systematic review.
Authors: Magdalena Benda, Patrick Reimann, Wolfgang Willenbacher, Eberhard Gunsilius, Katja Weisel, Irene Strassl, Maria Theresa Krauth, Stefan Knop, Thomas Winder, Normann Steiner
Publication: Annals of Hematology (2026) 105:397
DOI: https://doi.org/10.1007/s00277-026-07140-8
Received: 4 May 2026 / Accepted: 15 June 2026 / Published online: 18 June 2026
Affiliated institutions: Department of Internal Medicine II, Feldkirch Academic Teaching Hospital, Feldkirch, Austria; Faculty of Medical Sciences, Private University of the Principality of Liechtenstein, Triesen, Principality of Liechtenstein; Molecular Biology Laboratory, Vorarlberg Institute for Vascular Investigation and Treatment, Dornbirn, Austria; Department of Internal Medicine V, Comprehensive Cancer Center Innsbruck, Medical University of Innsbruck, Innsbruck, Austria; Connect to Cure, Syndena GmbH, Innsbruck, Austria; Department of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, University Cancer Center Hamburg-Eppendorf, Hamburg, Germany; Division of Hematology with Stem Cell Transplantation, Hemostaseology and Medical Oncology, Department of Internal Medicine I, Ordensklinikum Linz, Linz, Austria; Medical Faculty, Johannes Kepler University Linz, Linz, Austria; Department of Internal Medicine I, Division Hematology & Hemostaseology, Medical University of Vienna, Vienna, Austria; Department of Internal Medicine 5, Hematology and Oncology, Nuremberg General Hospital, Paracelsus Medical University, Nuremberg, Germany; University of Zurich, Zurich, Switzerland
This patient-friendly article is based on peer-reviewed research.
