Сбалансирую эффективность и безопасность в нескольких пациентах с миеломой, получающих B-камерную антигенную терапию CAR-Cell.

Key Points

Introduction

Multiple myeloma (MM) is a plasma cell malignancy characterized by the accumulation of malignant plasma cells in the bone marrow, leading to lytic bone lesions, cytopenias, hypercalcemia, renal impairment, and immune dysfunction [ 1 ]. Before the introduction of T-cell immunotherapies, patients with triple-class exposed relapsed/refractory MM (RRMM; defined as prior treatment with at least an immunomodulatory drug, a proteasome inhibitor, and an anti-CD38 monoclonal antibody) had a very poor prognosis when treated with standard-of-care regimens (overall response rate: 29.8%; median progression-free survival [PFS]: 4.6 months; median overall survival: 12.4 months [ 2 ]. The introduction of novel T-cell immunotherapies, such as T-cell engaging bispecific antibodies and chimeric antigen receptor (CAR) T-cell therapies, has substantially improved survival of patients with RRMM.

CAR T-cells are autologous T lymphocytes engineered to express chimeric receptors, which recognize a specific antigen on tumor cells, triggering T-cell activation, expansion, and targeted elimination of malignant cells. For MM treatment, B-cell maturation antigen (BCMA) is an attractive target due to its high expression on malignant plasma cells. BCMA-directed CAR T-cell therapies were initially evaluated in heavily pretreated, triple-class exposed MM patients. Impressive results were reported in the KarMMa study with idecabtagene vicleucel (ide-cel; median PFS of 8.8 months) and in the CARTITUDE-1 study with ciltacabtagene autoleucel (cilta-cel; median PFS 34.9 months) [ 3 , 4 ]. Ide-cel has a single-binding BCMA domain, while cilta-cel contains a dual-binding domain using two llama VHH elements (variable heavy domain of heavy-chain) binding two distinct BCMA epitopes and thus has a higher BCMA binding affinity, which may explain its superior efficacy (Fig. 1 ).

Based on the high activity of BCMA-directed CAR T-cells in the late relapse setting, phase III trials were initiated in patients with less heavily pretreated disease. Both the KarMMa-3 study (2–4 prior lines of therapy; median PFS: 13.8 vs 4.4 months) and CARTITUDE-4 study (1–3 prior lines of therapy; 30-month PFS: 59.4% vs 25.7%) showed a PFS advantage of CAR T-cell therapy compared with standard-of-care regimens [ 5 – 7 ]. Importantly, the CARTITUDE-4 study also showed an overall survival benefit of cilta-cel versus standard of care, which was not observed in KarMMa-3, probably due to cross-over of patients from the standard-of-care arm to the CAR T-cell arm upon disease progression [ 5 , 6 ].

While the therapeutic impact of BCMA CAR T-cell therapy is clear, this treatment is also associated with specific toxicities (Fig. 2 ). Common adverse events, including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), are increasingly understood and manageable. These adverse events are related to cytokine release upon T-cell activation and observed with all available CAR T-cell therapies, irrespective of the target. Clinical experience has also brought attention to more uncommon and sometimes delayed toxicities including movement and neurocognitive disorders (parkinsonism), immune effector cell hemophagocytic lymphohistiocytosis-like syndrome (IEC-HS), prolonged cytopenias, secondary malignancies, immune-mediated enterocolitis, and opportunistic infections. Current targets for CAR T-cell therapy are not tumor-exclusive and are also expressed on normal cells, which can result in the development of on-target off-tumor side effects. For example, BCMA is also expressed by a subset of normal B cells and by normal plasma cells, which explains the rapid elimination of these cells after the BCMA-directed CAR T-cell infusion and development of severe hypogammaglobulinemia, which leads to an increased infection risk. The underlying pathogenesis of most immune effector cell (IEC)–associated immune-related adverse events (e.g., enterocolitis, cranial nerve palsies and parkinsonism) is not completely understood and off-target/off-tumor immune interactions may play a role. Risk factors for CAR T-cell immune-related adverse events include greater CAR T-cell expansion and CD4/CD8 ratio >1 at apheresis [ 8 , 9 ]. In addition, immune-related adverse events are more frequently seen with cilta-cel versus ide-cel [ 8 ]. This difference is likely due to its CAR design, as the dual binding capacity of cilta-cel may lead to more robust T-cell activation and proliferation. Patient and disease characteristics are also important. For example, patients without response to bridging therapy, and therefore with a high tumor burden at the time of CAR T-cell infusion, are more likely to develop complications, such as parkinsonism, prolonged thrombocytopenia and neutropenia as well as infections, explaining the higher rate of non-relapse mortality following CAR T-cell infusion [ 10 ]. This review aims to summarize current knowledge on the toxicity profile of approved BCMA-directed CAR T-cell therapies, including a description of timing of different adverse events and their underlying pathophysiologic mechanisms, to increase awareness and provide guidance on their recognition, assessment, and management.

Search Strategy

We searched PubMed and the websites for the major conferences of the American Society of Hematology, European Haematology Association, and American Society of Clinical Oncology for papers published between January 1, 1995, and February 10, 2026, using the search terms ‘CAR T-cell therapy’, ‘CAR T-cell’, ‘cytokine-release syndrome’, ‘neurotoxicity’, ‘Immune effector cell-associated neurotoxicity syndrome’, ‘hemophagocytic lymphohistiocytosis’, ‘secondary malignancies’, ‘infections’, ‘multiple myeloma’, and ‘myeloma’. We searched for papers and abstracts published in English. The literature search was updated on April 1, 2026, during the revision process for this review. The final reference list was generated on the basis of originality and relevance to the broad scope of this review.

Classical Toxicities

Cytokine Release Syndrome

CRS is caused by activated CAR T-cells and other immune cells secreting pro-inflammatory cytokines (e.g., interleukin [IL]-6, interferon [IFN]-γ, and tumor necrosis factor [TNF]-α). CRS often starts as a mild reaction with fever, chills, and fatigue, but may progress quickly with development of hypotension, hypoxemia, kidney/liver injury, and even multi-organ failure. Severity of CRS should be assessed according to the American Society for Transplantation and Cellular Therapy (ASTCT) consensus grading system [ 11 ]. In the work-up of patients with potential CRS, it is important to exclude infections (see Table 1 ).

In the registration studies with ide-cel and cilta-cel, CRS was reported in 76–95% of patients, with grade ≥ 3 CRS in 1–5% [ 3 , 4 , 7 , 12 ]. The timing of CRS varies markedly between ide-cel and cilta-cel; median time to onset is approximately 1 day for ide-cel and 7–8 days for cilta-cel [ 3 , 4 , 7 , 12 ]. Similar CRS rates were reported in large cohorts of patients treated with BCMA-directed CAR T-cell therapy outside of clinical studies. In a real-world study of ide-cel, CRS was observed in 80% of patients, with grade ≥ 3 events in 3% and median time to onset of 2 days [ 13 ]. In addition, in a real-world study of cilta-cel, CRS was observed in 75% of patients (grade ≥ 3: 5%) with median time to onset of 7 days [ 14 ]. Predictors for grade ≥ 2 CRS include poor performance status, age ≥ 70 years, high tumor burden (≥ 50% tumor cells), higher R-ISS stage, and high baseline ferritin [ 13 , 14 ].

CRS can be effectively treated with tocilizumab (IL-6 receptor antagonist) and/or corticosteroids. Anakinra (IL-1 receptor antagonist) can be helpful in severe CRS cases [ 15 , 16 ]. Management of CRS also consists of supportive care with antipyretics, oxygen supplementation, and fluid resuscitation [ 15 ]. Early intervention may prevent development of severe CRS, which may be especially important in frail patients due to comorbidities.

Immune Effector Cell-Associated Neurotoxicity Syndrome

ICANS is characterized by a transient encephalopathy which occurs usually concurrently or shortly after CRS, pointing towards systemic proinflammatory cytokines as a driver of ICANS [ 17 ]. Increased levels of IL-6, IFN-γ, and TNF-α may induce endothelial activation and disruption of the blood–brain barrier, resulting in increased permeability for inflammatory cells and fluids (edema) which may contribute to the development of ICANS. Early symptoms of ICANS include decreased concentration and word-finding difficulty, but this may progress to dysphasia or aphasia, confusion, and agraphia. ICANS is mostly low-grade and reversible [ 15 ], but seizures and cerebral oedema have also been reported. The ASTCT grading system for ICANS is used to assess severity [ 11 ].

ICANS was reported in the registrational studies with ide-cel in approximately 15–18% of patients (grade ≥ 3: 3%) [ 3 , 12 ]; median time to onset was 2–3 days. Similar data were reported in patients who received ide-cel outside of clinical studies (all grade ICANS: 28% [grade ≥ 3: 5%]; median time to onset of 3 days) [ 13 ]. Following cilta-cel infusion, ICANS was observed in 17% of patients (grade 3: 2%) in CARTITUDE-1, but at a lower rate in CARTITUDE-4 in patients who received 1–3 prior lines (all grade ICANS: 4.5% [no grade 3 events]) [ 4 , 7 ]. The lower frequency of ICANS in CARTITUDE-4 is probably related to more effective bridging therapy resulting in a lower tumor burden at the time of cilta-cel infusion [ 4 , 7 ]. Median time to onset of ICANS following cilta-cel infusion was 8–10 days [ 4 , 7 , 14 , 18 ]. In a large, real-world cohort of heavily pretreated patients treated with cilta-cel, ICANS was reported in 14% (grade ≥ 3: 4%), with median time to onset of 9 days [ 14 ]. Predictors for ICANS include poor performance status, clinically significant comorbidities, age ≥ 70 years, high tumor burden (≥ 50% tumor cells), >4 prior lines of therapy, penta-refractory disease, and high baseline ferritin [ 13 , 14 ].

After CAR T-cell infusion, patients should be monitored for new neurologic symptoms including handwriting changes, with comprehensive neurologic assessment by a neurologist if a patient develops new neurologic symptoms [ 15 ]. Management includes the use of corticosteroids. Anakinra can be useful in more severe cases that are not improving with corticosteroids [ 16 ]. An impaired level of arousal may necessitate monitoring on the intensive care unit [ 17 ].

Delayed Neurotoxicity

Delayed neurotoxicity (also known as non-ICANS neurotoxicity) appears weeks or months after BCMA-directed CAR T-cell infusion and is defined as neurologic events other than ICANS. Manifestations include cranial nerve palsy, parkinsonism, Guillain-Barré syndrome, peripheral neuropathy, and posterior reversible encephalopathy syndrome [ 4 , 7 , 14 , 19 , 20 ].

Parkinsonism

Immune effector cell-associated parkinsonism (also known as movement and neurocognitive toxicity) is characterized by a cluster of movement and neurocognitive adverse events. Patients present with typical Parkinson disease–like features such as bradykinesia, hypophonia, postural instability, hypomimia, micrographia, resting tremor, difficulty initiating movements, and cognitive deterioration. Patients may also present with frontal lobe dysfunction including apathy, bradyphrenia, echolalia, and decreased decision making [ 19 ]. The typical symptom onset of parkinsonism is 1–6 months after CAR T-cell infusion with a median time to parkinsonism of 24–30 days, and it typically occurs after a period of recovery from CRS and/or ICANS [ 4 , 14 , 18 , 19 , 21 ]. CAR T-cell related parkinsonism is a progressive neurocognitive and movement disorder which may be fatal in 50–60% of cases [ 17 , 19 , 22 ].

Brain-imaging studies are important to rule out other causes (e.g., tumor infiltration in central nervous system), and can also show specific abnormalities in patients with immune effector cell-associated parkinsonism. 18F-Fluorodeoxyglucose-positron emission tomography of the brain may demonstrate hypometabolism in the basal ganglia but also the frontal lobes [ 17 , 18 , 22 ] and magnetic resonance imaging (MRI) may show basal ganglia signal abnormalities [ 19 , 23 ]. Cerebrospinal fluid (CSF) analysis typically demonstrates increased protein levels and elevated white cells, mainly lymphocytes (CAR T-cells) [ 8 , 18 , 19 , 23 , 24 ].

Parkinsonism has been reported in patients treated with cilta-cel in both registrational studies and in real-world analyses [ 4 , 7 , 14 ]. Although no parkinsonism-like disorders were reported in the clinical studies with ide-cel, several reports have described parkinsonism in patients treated with commercial ide-cel [ 17 , 23 , 25 ]. Overall, parkinsonism occurs at a higher frequency with cilta-cel compared with ide-cel [ 17 , 25 ].

Pathogenesis of parkinsonism is still largely unknown but both inflammatory and on-target/off-tumor mechanisms have been reported [ 17 , 22 ]. BCMA expression has been described in basal ganglia and BCMA-directed CAR T-cells have the potential to cross the blood–brain barrier [ 22 ]. Therefore, parkinsonism may be the result of destruction of the basal ganglia by BCMA-directed CAR T-cells [ 22 ]. Indeed, neuropathology findings showed focal gliosis and T-cell infiltrate in the basal ganglia [ 18 ]. Risk factors for parkinsonism include high tumor burden, high grade CRS, any grade ICANS, and high CAR T-cell expansion and persistence [ 18 , 19 ]. Parkinsonism is also more common in elderly patients [ 19 ]. Mitigation strategies include effective bridging therapy to reduce tumor burden prior to CAR T-cell infusion and early intervention to reduce severity of ICANS or CRS [ 18 ]. Overall, these interventions appear to have decreased the rate of parkinsonism from 5 to 1% in patients treated with cilta-cel [ 4 , 7 , 18 , 26 ]. There is increasing evidence that tumor burden at the time of CAR T-cell infusion is probably the most relevant modifiable risk factor for development of parkinsonism. Notably, in CARTITUDE-4, parkinsonism was not reported in patients who achieved partial response or better (≥ PR) with bridging therapy, while one case occurred in a patient who progressed during bridging therapy and one case in a patient with stable disease [ 10 ]. In addition, in a real-world study of cilta-cel, risk of parkinsonism in non-responders to bridging therapy was 10 times higher compared with responders (5% vs 0.5%) [ 21 ].

Although peak CAR T-cell expansion does not have an impact on the efficacy of cilta-cel [ 27 ], CAR T-cell expansion is significantly higher in patients developing delayed neurotoxicity [ 18 , 27 , 28 ]. The peak absolute lymphocyte count (ALC) was also higher in patients developing delayed neurotoxicity, particularly parkinsonism [ 21 , 27 , 28 ]. Notably, peak CAR T-cell level and ALC peak exhibit moderate to strong concordance [ 27 ]. The ALC can therefore be used as a reliable surrogate for CAR T-cell expansion [ 27 ]. Real-world studies demonstrate that ALC thresholds of (1) ≥ 3 × 10 9 /L between days 7 and 21 and/or (2) ≥ 2.5 × 10 9 /L between days 8 and 12, with a ≥ 2-fold increase from the prior value, identified most delayed neurotoxicity cases [ 19 , 27 ]. Preemptive intervention in the setting of a high ALC is a potentially useful strategy to prevent development of parkinsonism. A limitation of this strategy is that not all patients with a high ALC peak will develop delayed neurotoxicity, while interventions aiming at reducing CAR T-cell expansion may increase risk of infection in such patients. In a small study, patients were treated with prophylactic dexamethasone when ALC level exceeded 5 × 10 9 /L [ 28 ]. Prophylactic dexamethasone in the early post-CAR T period demonstrated reversal of uncontrolled ALC expansion and an early trend towards reduced risk of severe toxicity including ICANS/parkinsonism (71.4% without versus 40.0% with dexamethasone prophylaxis) [ 28 ]. In contrast, another retrospective study with 102 patients showed that prophylactic dexamethasone neither reduced CAR T-cell expansion nor decreased risk of delayed neurotoxicity in patients with high post-infusion peak ALC count (>3 × 10 9 /L), compared with a historical cohort [ 29 ]. Future studies with larger numbers of patients are needed to further evaluate the role of prophylactic dexamethasone and other strategies that reduce CAR T-cell expansion or alter CAR T-cell function. Such studies should also evaluate the impact of preemptive strategies on tumor control and infectious complications.

Therapies for parkinsonism are often ineffective with improvement observed in a small proportion of patients [ 14 ]. However, more recent studies suggest that early intervention may be effective and crucial to avoid life-threatening or permanent neurologic sequelae [ 20 , 23 , 24 ]. As parkinsonism is potentially an on-target/off-tumor adverse event of BCMA-directed CAR T-cells, therapeutic strategies aim at rapidly reducing CAR T-cells in peripheral blood, CSF, and in the brain. In contrast to cranial nerve palsies, parkinsonism is generally not responsive to systemic corticosteroids as monotherapy [ 17 , 19 , 22 ]. Small case series suggest that lymphodepleting chemotherapy (e.g., cyclophosphamide and fludarabine [fludarabine crosses the blood–brain barrier]) as well as intrathecal chemotherapy (e.g., cytarabine, methotrexate, and corticosteroids) can be effective and may prevent irreversible neurologic damage [ 17 , 19 , 20 , 22 , 23 , 30 , 31 ]. There is typically only minimal to modest response to dopamine replacement [ 17 , 19 , 22 ]. It is important to rule out infection and tumoral infiltration before starting immunosuppressive therapies. As parkinsonism management is often associated with long-term, severe immunosuppression with increased risk of infections, extended antimicrobial prophylaxis should be considered in these patients [ 19 ].

Cranial Nerve Palsy

Cranial nerve palsy (CNP) is frequently observed after cilta-cel, but to the best of our knowledge not described up until now following ide-cel infusion [ 25 ]. Almost all cilta-cel–treated patients who developed CNP presented with peripheral facial nerve palsy (unilateral or bilateral) [ 19 , 26 ]. Some patients also had another cranial nerve impairment (e.g., oculomotor nerve [CN III]; trigeminal nerve [CN V]; or abducens nerve [CN VI]) [ 19 , 26 ]. The pathogenesis of CNP is not well understood but may be related to CAR T-cellinduced local inflammation in the region where the facial nerve exits the stylomastoid foramen [ 26 ]. Local inflammation in other cranial nerve bony channels (foramina) may explain impairment of additional cranial nerves.

Across CARTITUDE-1, -2, and -4 studies, CNP was more common in patients with 1–3 prior lines of therapy versus >3 prior lines of therapy (8% vs 2%) [ 26 ]. Median time to onset is approximately 3 weeks and median duration is 66 days [ 26 ]. CNP is more common in men [ 19 , 26 ]. There was no association between grade ≥ 2 CRS, ICANS, or viral infection and risk of CNP [ 19 , 26 ]. CAR T-cell peak expansion and exposure levels were significantly higher in patients with versus without CNP [ 19 , 26 ].

Although effective bridging therapy reduced risk of parkinsonism in CARTITUDE-4, cranial nerve palsy was reported in 11.9%, 7.1%, 8.2%, and 5.0% of patients with ≥ VGPR, PR, MR/SD, and PD after bridging therapy, respectively [ 10 ]. Similarly, another study also showed that better response (lower free light-chain levels prior to lymphodepletion) was associated with a higher risk of developing CNP [ 19 ].

Diagnostic work-up with MRI and CSF analysis should be considered to exclude infection and tumor infiltration in the central nervous system [ 26 ]. Brain MRI may show enhancement of affected nerves in approximately half of the patients [ 19 ]. Treatment with a short course of low-dose corticosteroids is recommended [ 26 ]. There was no difference in CNP duration when a higher dose or longer treatment duration was selected, while a higher cumulative steroid dose increases risk of (severe) infections [ 26 ]. Although slow over a period of several weeks, most patients (>90%) experience complete resolution of symptoms [ 14 , 19 , 26 ]. Median time to resolution is 2–3 months [ 19 , 26 ].

Immune Effector Cell-Associated Hematotoxicity

Immune effector cell-associated hematotoxicity (ICAHT) is characterized by profound cytopenias affecting neutrophil, platelet, and erythroid lineages [ 32 ]. Cytopenias can be classified as early (within 30 days post-infusion), typically related to lymphodepleting chemotherapy and acute inflammatory responses, or late/prolonged (beyond 30 days), which may persist for months to years and are associated with increased risk of severe infections and bleeding [ 32 – 34 ]. The pathophysiology is multifactorial, involving direct myelosuppressive effects of CAR T-cell expansion, sustained inflammation (reflected by elevated inflammatory markers [e.g., ferritin]), cytokine release (IL-6, IFN-γ), and disruption of the bone marrow microenvironment [ 33 ]. Baseline hematopoietic reserve, disease burden, and clonal hematopoiesis are important risk factors for delayed recovery [ 35 ]. A bone marrow evaluation should be performed in patients with prolonged cytopenias to exclude relapse or secondary neoplasms.

Management of ICAHT includes growth factor support (e.g., granulocyte colony-stimulating growth factor), antimicrobial prophylaxis, transfusion support, and, in refractory cases, autologous stem cell boost or allogeneic stem cell transplantation [ 32 ]. A recent retrospective study showed that a stem cell boost is a safe and effective strategy to promote hematopoietic recovery in patients who developed prolonged cytopenias following therapy with commercial BCMA-directed CAR T-cell therapies [ 36 ]. Patients who received a stem cell boost had a higher neutrophil count, platelet count, and hemoglobin level by day 90 after CAR T-cell infusion, compared with matched controls who did not receive a stem cell boost [ 36 ].

Immune Effector Cell-Associated Hemophagocytic Lymphohistiocytosis-Like Syndrome

IEC-HS, previously termed CAR T-cell–associated hemophagocytic lymphohistiocytosis (HLH) or macrophage activation syndrome, is an increasingly recognized hyperinflammatory complication of CAR T-cell therapy, including BCMA-directed therapies. IEC-HS is distinct from CRS and ICANS, and occurs independently or sequentially [ 37 ].

IEC-HS is defined as a hyperinflammatory syndrome attributable to immune effector cell therapy, manifesting with features of macrophage activation syndrome or hemophagocytic lymphohistiocytosis, including new or worsening cytopenias, hyperferritinemia, coagulopathy with hypofibrinogenemia, and transaminitis [ 37 ]. In MM patients receiving BCMA-directed therapy, incidence rates are reported up to 15–20% [ 38 – 40 ]. The syndrome typically emerges 7–14 days post-infusion, and is associated with high tumor burden, elevated baseline inflammatory markers, extramedullary disease and high-grade CRS. Laboratory features include extreme elevations in ferritin (often >10,000 ng/mL), lactate dehydrogenase, and triglycerides, along with hypofibrinogenemia and progressive cytopenias.

The pathophysiology remains incompletely understood but appears to involve high CAR T-cell expansion and sustained hypercytokinemia with persistent elevations in IFN-γ, IL-1, IL-10, IL-18, and granzyme B [ 39 , 41 ]. Emerging data suggest a critical role for interferon signaling pathways, with upregulation of interferon-stimulated genes and STAT2 activity observed in patients developing IEC-HS [ 42 ]. The contribution of macrophage activation to propagating the hyperinflammatory state requires further investigation [ 43 ].

Diagnosis of IEC-HS can be challenging due to overlapping features with CRS and active hematologic disease. The ASTCT consensus criteria define IEC-HS as elevated ferritin (>2 × upper limit of normal or baseline) and/or rapidly rising ferritin, in association with cytopenias, coagulopathy, and/or transaminitis, in the absence of alternative explanations. Additional diagnostic features may include hypertriglyceridemia, elevated soluble IL-2 receptor (sCD25), low or absent natural killer cell activity, and hemophagocytosis on bone marrow or tissue biopsy. The HScore and HLH-2004 criteria may be used as adjuncts, though they were not developed specifically for this population.

Management of IEC-HS requires prompt recognition and aggressive immunosuppression. Corticosteroids (e.g., dexamethasone or methylprednisolone) are the cornerstone of therapy. For steroid-refractory cases, anakinra (IL-1 receptor antagonist) is recommended as first-line adjunctive therapy, with ruxolitinib, emapalumab, or low-dose etoposide considered for refractory disease. Tocilizumab may be used, particularly if CRS is concurrent, but responses to IL-6 blockade alone may be incomplete in IEC-HS [ 37 ].

Immune Effector Cell-Associated Enterocolitis

IEC-associated enterocolitis is a relatively rare complication following BCMA-directed CAR T-cell therapy with an estimated overall incidence of approximately 1.2%, 0.2% with ide-cel and 2.2% with cilta-cel [ 44 – 48 ]. There are currently two large case series available; a report from the US Multiple Myeloma Immunotherapy Consortium describing 14 patients who developed enterocolitis after treatment with cilta-cel ( n = 13) or ide-cel ( n = 1), and a subsequent multicenter study with 12 cases following cilta-cel treatment [ 44 , 45 ]. Both case series report similar clinical and histopathologic features [ 44 , 45 ].

Clinically, enterocolitis most often manifests 1–3 months (median 92.5 days) [ 44 ] after CAR T-cell treatment with abdominal pain, weight loss, and non-bloody diarrhea, with negative infectious work-up. CT imaging may show evidence of small or large bowel inflammation; also, diffuse colonic pneumatosis has been reported [ 44 – 48 ]. Histopathologic evaluation of endoscopic biopsies commonly demonstrates features resembling graft-versus-host disease, such as crypt dropout and epithelial apoptosis [ 44 , 47 , 48 ]. In addition, lymphocytic infiltration and presence of CAR-positive T cells is observed, while there is a clear paucity of B-cells and plasma cells. Although some patients experience spontaneous resolution, others progress and require long-term therapy or may even succumb [ 44 ].

The pathogenesis of IEC-associated enterocolitis remains incompletely understood. BCMA is expressed on gut-associated lymphoid tissue, primarily on long-lived IgA-producing plasma cells in the lamina propria which play a key role in gut immunity and microbiome regulation [ 49 ]. Profound depletion of these IgA-producing plasma cells may impair mucosal immune homeostasis and alter the intestinal microbiome, thereby predisposing to IEC-associated enterocolitis. In addition to target cell depletion, histopathologic studies of affected patients demonstrate persistent infiltration of (CAR) T cells in the lamina propria, even after BCMA-expressing plasma cells and B cells have been eliminated. Long-term CAR T-cell persistence (≥ 6 months) is observed in 25% of patients with RRMM treated with cilta-cel and is associated with higher frequency of late onset (>3 months) adverse events including IEC-associated enterocolitis [ 50 , 51 ]. Persistent active (CAR) T cells may contribute to ongoing local epithelial injury, potentially through secondary apoptosis of enterocytes [ 52 ]. Moreover, cross-reactivity of the BCMA-directed CAR T cells with intestinal epithelial antigens has been proposed as an additional contributing mechanism [ 52 ].

Supporting an on-target/off-tumor effect, retrospective analysis of US Food and Drug Administration (FDA) adverse events reports (2020–2024) has identified enterocolitis in patients treated with teclistamab, a BCMA-directed bispecific antibody [ 53 ]. Proposed alternative mechanisms include the expansion of pre-existing autoimmune, gut-homing, T-cell clones after CAR T-cell therapy [ 52 ].

In patients developing enterocolitis after CAR T-cell therapy, the differential diagnosis includes infections and neoplastic etiologies [ 44 , 52 , 54 ]. A full infectious work-up should be performed, because pathogens like adenovirus, parvovirus, cytomegalovirus (CMV), Clostridium difficile , shigella, salmonella and Escherichia coli have been documented in this context [ 48 ]. Furthermore, endoscopic evaluation with targeted biopsies is essential. Notably, upper endoscopy should not be omitted, as case series have reported greater histologic injury in the duodenum compared with the colon [ 48 ]. Case reports indicate that a T-cell lymphoma can closely mimic IEC-associated enterocolitis, both clinically and histologically, making the distinction between reactive T-cell proliferation and (CAR) T-cell lymphoma challenging in this setting [ 52 , 55 – 59 ]. Absence of plasma cells and B cells accompanied by accumulation of granzyme-positive cytotoxic CD4⁺ or CD8⁺ T cells can be observed in intestinal CAR T-cell lymphoma; however, these features are not specific and may also be seen in inflammatory conditions, including inflammatory bowel disease [ 60 ]. Furthermore, clonal CAR + T-cell populations appear to be associated with IEC-associated enterocolitis [ 51 ]. These populations may range from polyclonal to monoclonal, suggesting a disease spectrum [ 51 ]. Interpretation of these findings remains debated; some propose that a subset of IEC-associated cases may represent a CAR T-cell lymphoproliferative disorder driven by persistent clonal CAR⁺ T-cell expansion [ 52 ], whereas others argue that IEC-associated enterocolitis primarily reflects immune-mediated toxicity with possible reactive clonal expansion rather than true neoplasia [ 54 ]. Importantly, the presence of different T-cell populations does not reliably exclude CAR T-cell lymphoma, as bi-clonal and even multi-clonal CAR T-cell lymphomas have been reported [ 57 , 59 ].

An integrated diagnostic approach is therefore essential, in which clinical data, pathological findings, immunophenotypic abnormalities, and molecular studies, such as mutation analysis and T-cell receptor clonality are combined. Referral to a T-cell lymphoma expert is recommended in challenging cases. Misclassifying such cases as immune-mediated or autoimmune enterocolitis may delay appropriate diagnosis and treatment, and exposes patients to unnecessary immunosuppression which increases risk of infections (e.g., CMV reactivation). Most intestinal CAR T-cell lymphoma cases have an aggressive clinical course with poor outcomes, highlighting the need for early recognition [ 55 , 57 , 59 ].

Corticosteroids are the first-line therapy, with biologics such as infliximab or vedolizumab reserved for patients with persistent symptoms [ 54 ]. These agents are also used for immune-mediated colitis following checkpoint inhibitor therapy in solid tumors [ 54 ]. In refractory cases, more potent T-cell suppression with agents such as cyclosporine or cyclophosphamide may be considered, acknowledging the potential impact on CAR T-cell efficacy [ 51 , 52 , 54 ]. Recently, the JAK inhibitor ruxolitinib has demonstrated rapid and durable clinical responses in a small series of refractory patients [ 61 ]. A stepwise treatment strategy, including timing and dosing, has been proposed by Banerjee et al. [ 54 ].

Secondary Primary Malignancies

Secondary primary malignancies (SPMs) have emerged as an important safety consideration following CAR T-cell therapy. The time from CAR T-cell infusion to diagnosis of SPM is highly variable, ranging from 5 to 28 months in patients with MM [ 62 ]. SPM development is likely multifactorial with a potential contributing role of the genetic engineering process, prior therapies, pre-existing clonal hematopoiesis (clonal hematopoiesis of indeterminate potential), impaired immune surveillance, and patient-related factors (e.g., age, smoking history) [ 62 – 64 ].

The use of non-replicating gamma-retroviral or lentiviral vectors for the transfer of new DNA into the host T-cell genome carries a risk of insertional oncogenesis, as vector integration may disrupt genes critical for cell proliferation, differentiation, or survival [ 65 ]. In November 2023, the FDA published a safety warning highlighting rare cases of secondary T-cell malignancies after CAR T-cell therapy. According to Verdun et al., the FDA had identified 22 patients with a T-cell malignancy, including patients with large granular lymphocytosis, peripheral T-cell lymphoma, and cutaneous T-cell lymphoma [ 66 ]. In most cases, the malignant clone did not harbor vector integration in known oncogenic loci, and only three cases demonstrated the presence of the CAR transgene in the malignant clone, without definitive evidence that CAR integration was the driver of oncogenesis [ 66 , 67 ]. Subsequent analyses and institutional cohort studies have confirmed that secondary T-cell lymphomas following CAR T-cell therapy are exceedingly rare [ 64 , 67 – 70 ]. In addition, the European Medicines Agency (EMA) recently published a total of 38 cases of secondary T-cell malignancy identified through its Pharmacovigilance Risk Assessment Committee among approximately 42,500 CAR-T–treated patients across multiple products (both BCMA- and CD19-directed CAR T-cell therapies) [ 71 ]. In seven of these, the CAR transgene was detected in the malignant T cell, but causality remains uncertain. Despite the very low incidence, the FDA and EMA have recognized the signal and recommend lifelong surveillance.

While T-cell malignancies are uncommon, a broader spectrum of secondary malignancies has been observed following CAR T-cell therapy. A recent meta-analysis identified 326 SPMs among 5517 CAR T-cell–treated patients (including both BCMA- and CD19-targeted therapies), with a median follow-up of 21.7 months [ 64 ]. The pooled overall SPM incidence was 6%, with hematological malignancies being the most frequent (37%), followed by solid tumors (27%) and non-melanoma skin cancers (16%) [ 64 ]. No significant differences in SPM incidence were observed between CAR T-cell products or underlying disease entities, with rates of 5.2% for cilta-cel and 5.5% for ide-cel [ 64 ]. In line with these observations, a recent retrospective multicenter cohort study of 1460 patients with RRMM treated with ide-cel or cilta-cel reported an incidence of SPMs of 3.6% at a median follow-up of 13.1 months, with approximately half being myeloid neoplasms [ 72 ]. Patients receiving two or more prior alkylator-containing lines of therapy had a significantly increased risk of developing SPMs [ 72 ].

Consistent with these findings, long-term follow-up of pivotal BCMA-targeted trials also reported SPMs. After a median follow-up of 28 months, 10 out of 97 patients treated in the CARTITUDE-1 trial developed a secondary myeloid malignancy (MDS and AML) and, after a median 18-month follow-up of KarMMa-1, reported that eight patients (12.9%) developed SPMs, including two patients with MDS [ 73 , 74 ]. Both studies enrolled heavily pretreated patients, and most participants had received prior lenalidomide and high-dose chemotherapy with autologous stem cell transplantation, both known to predispose patients to (myeloid) malignancies [ 75 , 76 ]. The phase III CARTITUDE-4 and KarMMa3 studies provide additional context on SPM incidence as BCMA-directed CAR T-cell therapy was compared with standard regimens. In CARTITUDE-4, with a median follow-up of approximately 33.6 months, SPMs were reported in both cilta-cel and standard-of-care arms, with comparable incidences (13.0% vs 12%) [ 6 ]. Hematologic SPMs, including MDS, AML, and lymphoma, occurred more frequently in CAR T-cell recipients compared with patients treated with standard of care (3% vs <1%). The median time to MDS or AML onset after cilta-cel infusion was 385 days (range 56–758). Post-hoc analyses revealed that all five patients who developed MDS or AML in the cilta-cel arm had pre-existing mutations in one or more key myeloid driver genes, including TP53 and DNMT3A [ 6 ]. In KarMMa-3, SPM rates were also similar between ide-cel and standard-of-care arms (6.7% vs 4.0%), with hematologic SPMs slightly higher in the CAR-T group (2.2% vs 0.0%) [ 5 ]. Of note, interpretation of observed differences in SPM rates in these phase III trials should take into account competing risks, as patients in the standard-of-care arm are more likely to die from MM and therefore have a shorter survival and lower risk of developing subsequent malignancies compared with patients who received CAR T-cell therapy.

The similar SPM incidence between study arms suggests that SPMs may reflect background risks associated with prior therapies or patient-related factors (age and smoking) rather than being directly attributable to CAR-T therapy itself. The relatively high incidence of myeloid malignancies following CAR T-cell therapy is probably multifactorial. Most patients have received prior genotoxic treatments, including chemotherapy, radiotherapy, and autologous stem cell transplantation, which induce DNA damage in hematopoietic stem cells. Pre-existing clonal hematopoiesis with mutations in genes such as TP53 , DNMT3A , or TET2 further increases susceptibility to malignant transformation. Lymphodepleting regimens and prolonged cytokine-mediated inflammation during CAR T-cell therapy may disrupt the bone marrow niche, favoring expansion of pre-malignant clones.

Identifying predictive markers for hematologic SPMs could improve risk stratification and inform proactive surveillance. Further research is needed to study the true risk of secondary malignancies after CAR T-cell treatment. This is especially important as CAR-T therapies are moving to earlier lines of therapy and are also explored in new indications such as autoimmune disease. The relatively high incidence of skin cancers highlights the potential benefit of dermatologic monitoring for long-term survivors. Given its high efficacy, the risk–benefit balance of CAR T-cell therapy remains positive.

Infections

Frequency of Infections

Infections are commonly observed in MM patients treated with CAR T-cell therapy, due to disease-related immunoparesis and the immunosuppressive effects of prior anti-myeloma therapies [ 77 ]. In addition, BCMA-directed CAR T-cell therapy is associated with severe defects in humoral immunity due to elimination of normal B cells and polyclonal plasma cells resulting in hypogammaglobulinemia [ 78 ]. Furthermore, lymphodepleting chemotherapy induces a substantial decrease in T-cell counts which also contributes to an increased risk of infections. In a pooled analysis of more than 7600 lymphoma and MM patients treated with CAR T-cell therapy, infections accounted for more than half of all reported non-relapse deaths [ 79 ].

In the CARTITUDE-1 study, at a median follow-up of 12.4 months, infections occurred in 58% of patients, of which 20% were grade 3/4. Pneumonia was the most common grade 3/4 infectious adverse event [ 4 ]. In the CARTITUDE-4 trial, at a median follow-up of 15.9 months, infections occurred in 62.0% of patients treated with cilta-cel (grade 3/4: 26.9%), and in 71.2% of patients receiving standard of care (grade 3/4: 24.5%). Given the treatment period (July 2020–November 2021), COVID-19 infections were frequent, occurring in 13.9% of patients receiving cilta-cel and 26.4% receiving standard of care [ 7 ]. Infection-related mortality was 4.3% in the cilta-cel arm of CARTITUDE-4 [ 7 ].

In the phase II KarMMa study (median follow-up of 13.3 months), 69% of patients treated with ide-cel experienced infections (mostly respiratory infections), which were grade 3/4 in 22% [ 3 ]. In the subsequent KarMMa-3 study, at a median follow-up of 18.6 months, infections occurred in 58% of patients in the ide-cel group versus 54% with standard of care. Grade 3/4 infections occurred in 24% and 18%, respectively [ 12 ]. Infection-related mortality was 4.4% in the ide-cel arm of KarMMa-3 [ 12 ].

Real-world data underscore that infections are a major complication of CAR T-cell therapy. In a cohort of 120 RRMM patients intended for ide-cel therapy, 64% of patients did not fulfill eligibility criteria of the KarMMa trial and ultimately only 58% proceeded to ide-cel infusion. Infections were common in these heavily pretreated patients (all grades: 58%; grade ≥ 3: 30%) [ 80 ]. In another real-world cohort of 80 patients treated with either ide-cel ( n = 42) or cilta-cel ( n = 38), 71.3% of patients developed an infection after CAR T-cell infusion. Infection-related mortality was 5% in this study [ 81 ]. In a recent meta-analysis comparing toxicity profiles of cilta-cel and ide-cel, severe infections were reported more frequently following cilta-cel treatment (33% vs 23%) [ 82 ], potentially reflecting more severe or more prolonged immunosuppression with cilta-cel. However, the influence of patient- and treatment-related confounders cannot be excluded.

The phase III CAR T-cell therapy trials clearly demonstrate that infections are common in patients treated with either CAR T cells or standard of care. Importantly, the risk of infections following CAR T-cell therapy is highest during the first 6 months after the infusion and infection rates decrease thereafter [ 78 ]. In contrast, with standard-of-care treatment, infections are most common during the first 9 months, with a more gradual decrease over time [ 78 ]. Notably, when the cumulative incidence of infections is reported, each patient who experienced at least one infection is included in the analysis, irrespective of the total number of infections per individual patient. This does not reflect the burden that comes with multiple infections occurring over time. Therefore, it has been proposed to report all infections occurring in a single patient and correct for the observation time to overcome this limitation [ 83 ].

Type of Infections

Both viral and bacterial infections are common after CAR T-cell infusion. Although less frequent, patients may also develop (invasive) fungal infections, especially in the setting of prolonged use of corticosteroids or other immunosuppressive agents to manage immune-related toxicities [ 15 , 78 , 79 ]. Various studies have shown that CMV reactivation may occur after BCMA-directed CAR T-cell therapy [ 84 , 85 ]. In a Japanese cohort of 53 patients treated with ide-cel, CMV replication occurred in 38.9% and CMV disease in four patients (all with CMV retinitis). Monitoring for CMV replication has limitations, because only three out of four patients with CMV retinitis had measurable CMV replication in the blood [ 84 ]. Progressive multifocal leukoencephalopathy, characterized by reactivation of the John Cunningham virus leading to demyelinating disease of the central nervous system with typically poor outcome, has also been described after BCMA CAR T-cell treatment [ 86 , 87 ].

Management and Prophylaxis

Prior to CAR T-cell therapy, all patients should be screened for presence of chronic viral infections (e.g., human immunodeficiency virus, hepatitis B virus, and hepatitis C virus) [ 15 ]. Close monitoring and prompt start of therapy for possible infection is essential in patients who received CAR T-cell therapy [ 15 ]. After the CAR T-cell infusion, patients with high risk of viral replication (e.g., prolonged use of corticosteroids or use of second-line agents for management of immune-related adverse events) should be screened for viral reactivation (e.g., CMV or Epstein-Barr virus) [ 15 ]. In case of unexplained cytopenia, fever, diarrhea, or weight loss, patients should also be screened for CMV.

Infectious prophylaxis is critical in patients who received BCMA-directed CAR T-cell therapy. All patients should receive valacyclovir or acyclovir as varicella zoster virus prophylaxis, as well as co-trimoxazole (or alternative) as Pneumocystis jirovecii pneumonia prophylaxis until CD4 counts are >200 cells/µL [ 15 ]. Levofloxacin and fluconazole as antibacterial and antifungal prophylaxis may be considered during neutropenia. In patients with a high-risk of prolonged neutropenia, the use of granulocyte colony-stimulating growth factor (G-CSF) can be considered. Guidelines typically recommend avoiding G-CSF during CRS or ICANS, but G-CSF does not appear to increase the risk of high-grade ICANS/CRS [ 32 ]. Although studies in the setting of CAR T-cell therapy are lacking, it is recommended to start IgG supplementation in case of polyclonal IgG levels <400 mg/dL and/or recurrent (encapsulated) bacterial infections [ 15 ]. Beyond standard antimicrobial prophylaxis, vaccination may play an important role in reducing infectious risk after CAR T-cell infusion; however, the optimal vaccination strategy (timing of vaccination and type of vaccines) remains poorly defined due to limited available evidence. Consequently, international guidelines advise vaccination schedules extrapolated from those used for patients after hematopoietic stem cell transplantation [ 88 ].

Discussion

BCMA-directed CAR T-cell therapy represents a major advance for patients with MM, demonstrating remarkable efficacy. However, this benefit is accompanied by unique toxicities that require careful management. The expanding use of BCMA CAR T-cell therapy in earlier treatment lines and across a broader range of indications underscores the need to optimize patient selection and refine toxicity mitigation strategies to establish long-term safety and efficacy profiles in diverse clinical settings.

Non-relapse mortality (NRM) is an important consideration in this context. A large meta-analysis reported an overall NRM of approximately 8% in CAR T-celltreated MM patients, mainly related to infections, followed by cardiovascular/respiratory events, neurotoxicity events, and secondary primary malignancies [ 79 ]. In a real-world experience with cilta-cel, 1-year NRM was slightly higher, at 9% (2-year NRM: 10%), likely reflecting a higher proportion of patients with comorbidities and poor performance status [ 21 ]. Risk factors for NRM with BCMA-directed CAR T-cell therapy include poor performance status, age ≥ 70 years, and high-risk cytogenetic abnormalities [ 21 ]. Importantly, effective tumor reduction with bridging therapy results in reduced NRM. Several studies have now clearly demonstrated that patients who respond to bridging therapy are less likely to develop (severe) adverse events such as parkinsonism and infections, translating into lower rates of NRM following CAR T-cell infusion [ 10 , 21 , 89 ]. At the same time, deeper treatment responses to bridging therapy, prior to BCMA-directed CAR T-cell infusion, also translate into superior depth and duration of response, probably by optimizing effector-to-target ratio [ 10 , 89 , 90 ].

Comparative analyses of both approved BCMA-directed CAR T-cell products highlight differences in efficacy but also in timing and nature of treatment-related toxicities [ 82 ]. While ide-cel is characterized by an early onset of CRS (typically within 1–2 days following infusion), cilta-cel is associated with a delayed CRS onset with a median of approximately 7 days [ 3 , 4 ]. These temporal differences may have practical implications for monitoring. Although rates of ICANS appear broadly similar between products, delayed-onset parkinsonian-like movement disorders are more frequently observed with cilta-cel. This suggests that BCMA engagement alone does not fully account for differences in safety profile, and that other factors, such as variability in CAR T-cell persistence and construct-specific biology, may also play a role. In this context, newer constructs such as anitocabtagene autoleucel (anito-cel) have been developed with modifications aimed at improving safety while maintaining efficacy [ 91 , 92 ]. Notably, to date no delayed neurotoxicity has been reported with anito-cel across the phase I or phase II iMMagine-1 studies, which may be related to the use of a specific CAR construct, which allows for quick release of CAR T cells from their BCMA target, potentially conferring tumor killing without prolonged inflammation [ 91 , 92 ]. However, longer follow-up in larger cohorts of patients is needed to further characterize the safety profile of anito-cel.

Conclusion

The improved survival achieved with BCMA-directed CAR T-cell therapy highlights the critical challenge of maximizing efficacy while managing distinct and, in some cases delayed, toxicities. Toxicity risk is not solely determined by BCMA targeting per se, but also influenced by product characteristics (e.g., CAR design), as well as patient- and disease-specific factors. Consequently, treatment decisions should incorporate individualized risk assessment, including neurologic vulnerability, infection risk, and the capacity for extended post-treatment monitoring.

Funding

No external funding was used in the preparation of this manuscript.

Declarations

Conflicts of interest

N.W.C.J.v.d.D. has received research support from Janssen Pharmaceuticals, AMGEN, Celgene, CellCentric, Novartis, Cellectis and BMS, and serves on advisory boards for Janssen Pharmaceuticals, AMGEN, Celgene, BMS, Sanofi, Takeda, Roche, Novartis, Bayer, Adaptive, Galapagos, Kite Pharma, Merck, Pfizer, AbbVie, and Servier, all paid to institution. S.Z. has received research funding from Takeda and Janssen, and serves on advisory boards for Janssen, Takeda, and BMS, all paid to institution. M.T.K., J.M., A.M.K., M.C.M.K., and K.G. have no conflicts of interest that might be relevant to the contents of this manuscript.

Ethics Approval

Not applicable.

Consent to Participate

Not applicable.

Consent for Publication

Not applicable.

Availability of Data and Material

No datasets were generated or analyzed during the current study.

Code Availability

Not applicable.

Authors' Contributions

All authors contributed equally to the writing of this review.

References

1. van de Donk NWCJ, Usmani SZ, Yong K. CAR T-cell therapy for multiple myeloma: state of the art and prospects. Lancet Haematol. 2021;8(6):e446–61. 10.1016/S2352-3026(21)00057-0.

2. Mateos M-V, Weisel K, Stefano VD, et al. LocoMMotion: A prospective, non-interventional, multinational study of real-life current standards of care in patients with relapsed/refractory multiple myeloma (RRMM) receiving ≥ 3 prior lines of therapy. J Clin Oncol. 2021;39(15_suppl):8041–8041. 10.1200/JCO.2021.39.15_suppl.8041.

3. Munshi NC, Anderson LD Jr., Shah N, et al. Idecabtagene Vicleucel in relapsed and refractory multiple myeloma. N Engl J Med. 2021;384(8):705–16. 10.1056/NEJMoa2024850.

4. Berdeja JG, Madduri D, Usmani SZ, et al. Ciltacabtagene autoleucel, a B-cell maturation antigen-directed chimeric antigen receptor T-cell therapy in patients with relapsed or refractory multiple myeloma (CARTITUDE-1): a phase 1b/2 open-label study. Lancet. 2021;398(10297):314–24. 10.1016/s0140-6736(21)00933-8.

5. Ailawadhi S, Arnulf B, Patel K, et al. Ide-cel vs standard regimens in triple-class-exposed relapsed and refractory multiple myeloma: updated KarMMa-3 analyses. Blood. 2024;144(23):2389–401. 10.1182/blood.2024024582.

6. Einsele H, San-Miguel J, Dhakal B, et al. Cilta-cel in lenalidomide-refractory multiple myeloma (CARTITUDE-4): an updated analysis including overall survival from an open-label, multicentre, randomised, phase 3 trial. Lancet Oncol. 2026. 10.1016/S1470-2045(25)00653-9.

7. San-Miguel J, Dhakal B, Yong K, et al. Cilta-cel or standard care in Lenalidomide-refractory multiple myeloma. N Engl J Med. 2023;389(4):335–47. 10.1056/NEJMoa2303379.

8. Noll JH, Ho M, Paruzzo L, et al. Delayed neurotoxicity, enterocolitis, and BCMA-CART-associated immune-related adverse events (CirAE) are caused by CD4+ CAR T-cells. Blood. 2025;146(Supplement 1):804–804. 10.1182/blood-2025-804.

9. Paruzzo L, Ho M, Noll JH, et al. CCR5 blockade: a therapeutic approach to uncouple CART-BCMA expansion from CART-mediated immune toxicities. Blood. 2025;146(Supplement 1):5945–5945. 10.1182/blood-2025-5945.

10. Dhakal B, Iida S, Sidiqi MH, et al. Effectiveness of bridging therapy corresponds to improved outcomes after ciltacabtagene autoleucel: phase 3 CARTITUDE-4 study of patients with relapsed, lenalidomide-refractory multiple myeloma. Blood. 2025;146(Supplement 1):2215–2215. 10.1182/blood-2025-2215.

11. Lee DW, Santomasso BD, Locke FL, et al. ASTCT consensus grading for cytokine release syndrome and neurologic toxicity associated with immune effector cells. Biol Blood Marrow Transplant. 2019;25(4):625–38. 10.1016/j.bbmt.2018.12.758.

12. Rodriguez-Otero P, Ailawadhi S, Arnulf B, et al. Ide-cel or standard regimens in relapsed and refractory multiple myeloma. N Engl J Med. 2023;388(11):1002–14. 10.1056/NEJMoa2213614.

13. Sidana S, Ahmed N, Akhtar OS, et al. Standard-of-care idecabtagene vicleucel for relapsed/refractory multiple myeloma. Blood. 2025;146(2):167–77. 10.1182/blood.2024026216.

14. Sidana S, Patel KK, Peres LC, et al. Safety and efficacy of standard-of-care ciltacabtagene autoleucel for relapsed/refractory multiple myeloma. Blood. 2025;145(1):85–97. 10.1182/blood.2024025945.

15. Lin Y, Qiu L, Usmani S, et al. Consensus guidelines and recommendations for the management and response assessment of chimeric antigen receptor T-cell therapy in clinical practice for relapsed and refractory multiple myeloma: a report from the International Myeloma Working Group Immunotherapy Committee. Lancet Oncol. 2024;25(8):e374–87. 10.1016/s1470-2045(24)00094-9.

16. Gazeau N, Liang EC, Wu QV, et al. Anakinra for refractory cytokine release syndrome or immune effector cell-associated neurotoxicity syndrome after chimeric antigen receptor T cell therapy. Transplant Cell Ther. 2023;29(7):430–7. 10.1016/j.jtct.2023.04.001.

17. Karschnia P, Miller KC, Yee AJ, et al. Neurologic toxicities following adoptive immunotherapy with BCMA-directed CAR T cells. Blood. 2023;142(14):1243–8. 10.1182/blood.2023020571.

18. Cohen AD, Parekh S, Santomasso BD, et al. Incidence and management of CAR-T neurotoxicity in patients with multiple myeloma treated with ciltacabtagene autoleucel in CARTITUDE studies. Blood Cancer J. 2022;12(2):32. 10.1038/s41408-022-00629-1.

19. Lim KJC, Tan M, Parrondo R, et al. Clinical course, risk factors and mitigating strategies for immune effector cell-associated late onset neurotoxicities after ciltacabtagene autoleucel CAR-T in multiple myeloma. Blood Cancer J. 2025. 10.1038/s41408-025-01441-3.

20. Blumenberg V, Puliafito BR, Graham CE, et al. Cyclophosphamide mitigates non-ICANS neurotoxicities following ciltacabtagene autoleucel treatment. Blood. 2025;145(23):2788–93. 10.1182/blood.2024028172.

21. Sidana S, Reid B, Dima D, et al. Enhancing the safety of ciltacabtagene autoleucel in relapsed multiple myeloma (MM): identification of potentially modifiable risk-factors associated with delayed neurotoxicity and non-relapse mortality. Blood. 2025;146(Supplement 1):1034–1034. 10.1182/blood-2025-1034.40875552

22. Van Oekelen O, Aleman A, Upadhyaya B, et al. Neurocognitive and hypokinetic movement disorder with features of parkinsonism after BCMA-targeting CAR-T cell therapy. Nat Med. 2021;27(12):2099–103. 10.1038/s41591-021-01564-7.

23. Couturier A, Escoffre M, Leh F, et al. Parkinson-like neurotoxicity in female patients treated with idecabtagene-vicleucel. Hemasphere. 2024;8(7):e131. 10.1002/hem3.131.

24. Gudera JA, Baehring JM, Karschnia P. Parkinsonism following chimeric antigen receptor T cell therapy. JAMA Neurol. 2024. 10.1001/jamaneurol.2024.2506.

25. Ellithi M, Elsallab M, Lunning MA, et al. Neurotoxicity and rare adverse events in BCMA-directed CAR T cell therapy: a comprehensive analysis of real-world FAERS data. Transplant Cell Ther. 2025;31(2):71.e1-71.e14. 10.1016/j.jtct.2024.12.002.

26. Rodríguez-Otero P, Sidana S, Kouwenhoven M, et al. Clinical experience with cranial nerve palsy in patients infused with ciltacabtagene autoleucel for the treatment of relapsed/refractory MM in CARTITUDE-1, -2, and -4. Blood Cancer J. 2025;15(1):209. 10.1038/s41408-025-01410-w.

27. Hosoya H, Velayati A, Dima D, et al. Rapid peak CAR-T expansion is associated with delayed neurotoxicity following ciltacabtagene autoleucel in multiple myeloma. Blood. 2025;146(Supplement 1):96–96. 10.1182/blood-2025-96.

28. Turner J, Forsberg PA, Nicholson S, Schade H, Matous J, Gregory TK. Prophylactic dexamethasone rescues unrestrained lymphocyte expansion in anti-BCMA chimeric antigen receptor T cell therapy in multiple myeloma. Transplant Cell Ther. 2025;31(2, Supplement):S215–6. 10.1016/j.jtct.2025.01.330.

29. Lim KJC, Parrondo RD, Chhabra S, et al. Investigating the role of dexamethasone prophylaxis for the risk reduction of immune effector cell delayed neurotoxicity in Cilta-Cel treated patients. Transplant Cell Ther. 2026;32(2, Supplement):S12. 10.1016/j.jtct.2025.12.027.

30. Graham CE, Lee WH, Wiggin HR, et al. Chemotherapy-induced reversal of ciltacabtagene autoleucel-associated movement and neurocognitive toxicity. Blood. 2023;142(14):1248–52. 10.1182/blood.2023021429.

31. Kelly K, Cooperrider JH, Bishop MR, Kosuri S, Jakubowiak A, Derman BA. Intrathecal chemotherapy for ciltacabtagene autoleucel–associated movement and neurocognitive toxicity. Blood Adv. 2025;9(14):3613–6. 10.1182/bloodadvances.2024015721.

32. Rejeski K, Subklewe M, Aljurf M, et al. Immune effector cell-associated hematotoxicity: EHA/EBMT consensus grading and best practice recommendations. Blood. 2023;142(10):865–77. 10.1182/blood.2023020578.

33. Rejeski K, Jain MD, Shah NN, Perales MA, Subklewe M. Immune effector cell-associated haematotoxicity after CAR T-cell therapy: from mechanism to management. Lancet Haematol. 2024;11(6):e459–70. 10.1016/s2352-3026(24)00077-2.

34. Wang L, Hong R, Zhou L, et al. Cytokine profiles are associated with prolonged hematologic toxicities after B-cell maturation antigen targeted chimeric antigen receptor-T-cell therapy. Cytotherapy. 2023;25(2):192–201. 10.1016/j.jcyt.2022.11.001.

35. Avigan ZM, Catlett J, Bodnar S, et al. Clonal hematopoiesis and inflammation predict hematologic toxicity and secondary myeloid malignancies after B-Cell maturation antigen-directed chimeric antigen receptor T-cell therapy. Clin Cancer Res. 2025;31(20):4333–44. 10.1158/1078-0432.Ccr-25-1587.

36. Varga C, Robinson M, Davis J, et al. Outcomes of stem cell boost (SCB) versus supportive care alone for prolonged cytopenias after chimeric antigen receptor T cell therapy (CAR-T) in relapsed/refractory multiple myeloma (RRMM): a muli-center real-world analysis. Blood. 2025;146(Supplement 1):1035–1035. 10.1182/blood-2025-1035.40875550

37. Hines MR, Knight TE, McNerney KO, et al. Immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome. Transplant Cell Ther. 2023;29(7):438.e1-438.e16. 10.1016/j.jtct.2023.03.006.

38. Irfan S, Ayoobkhan FS, Vojjala N, et al. Immune effector cell-associated HLH-like syndrome (IEC-HS) in CAR-T and TCE-treated myeloma and B-cell malignancies: insights from a pharmacovigilance study. Transplant Cell Ther. 2025. 10.1016/j.jtct.2025.12.947.

39. Zu C, Wu S, Zhang M, et al. A distinct cytokine network distinguishes chimeric antigen receptor T cell (CAR-T)-associated hemophagocytic lymphohistiocytosis-like toxicity (carHLH) from severe cytokine release syndrome following CAR-T therapy. Cytotherapy. 2023;25(11):1167–75. 10.1016/j.jcyt.2023.06.008.

40. Munárriz D, Rodríguez-Lobato LG, López-Corral L, et al. Macrophage activation syndrome-like in multiple myeloma patients treated with the academic CAR-T against BCMA ARI0002h. Front Immunol. 2025;16:1654096. 10.3389/fimmu.2025.1654096.

41. Wang JM, Jiang HW, Zhang YQ, Hu Y, Mei H. Hemophagocytic lymphohistiocytosis post chimeric antigen receptor T cell therapies. Expert Rev Clin Immunol. 2025;21(3):277–89. 10.1080/1744666x.2024.2444673.

42. Kramer AM, Murty T, Chen Y, et al. CD22-directed CAR T Cell single cell multiomic features associated with immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome (IEC-HS). Blood. 2024;144(Supplement 1):911–911. 10.1182/blood-2024-198688.

43. Fugere T, Baltz A, Mukherjee A, et al. Immune effector cell-associated HLH-like syndrome: a review of the literature of an increasingly recognized entity. Cancers (Basel). 2023. 10.3390/cancers15215149.

44. Fortuna GG, Banerjee R, Savid-Frontera C, et al. Immune effector cell-associated enterocolitis following chimeric antigen receptor T-cell therapy in multiple myeloma. Blood Cancer J. 2024;14(1):180. 10.1038/s41408-024-01167-8.

45. Bar N, Yee A, Dhakal B, et al. P-008 a rare and unexplored entity of colitis post-BCMA directed CAR T-cell therapy; Insights from a multicenter case series. Clin Lymphoma Myeloma Leuk. 2024;24:S44–5. 10.1016/S2152-2650(24)01911-6.

46. Bashir Hamidu R, Von Rosenvinge E. S2743 CAR T-cell therapy-induced pseudomembranous colitis mimicking C. difficile infection. Am J Gastroenterol. 2024;119(10S):S1906. 10.14309/01.ajg.0001040340.34259.b1.

47. Karimi SS, Larman TC, Jain T, Voltaggio L, Birkness-Gartman JE. Chimeric antigen receptor (CAR) T-cell therapy-related gastrointestinal toxicity: histologic features and morphologic mimics. Hum Pathol. 2025;158:105791. 10.1016/j.humpath.2025.105791.

48. Osnis L, Hart J, Olivas A, et al. Patterns of gastrointestinal injury associated with CAR-T therapy for patients with multiple myeloma. Am J Surg Pathol. 2025. 10.1097/pas.0000000000002499.

49. Jahnsen FL, Bækkevold ES, Hov JR, Landsverk OJ. Do long-lived plasma cells maintain a healthy microbiota in the gut? Trends Immunol. 2018;39(3):196–208. 10.1016/j.it.2017.10.006.

50. Fandrei D, Seiffert S, Kuhn C, et al. Spatiotemporal and genetic tracking of long-term persisting CAR-T cells following ciltacabtagene autoleucel treatment for multiple myeloma reveals molecular insights into late-onset toxicities. Blood. 2025;146(Supplement 1):690–690. 10.1182/blood-2025-690.

51. Hamilton MP, Dong S, Sainz TP, et al. Ciltacabtagene Autoleucel immune effector cell enteritis/colitis is driven by persistent clonal CAR+ T-Cells. Transplant Cell Ther. 2026;32(2):S167–8. 10.1016/j.jtct.2025.12.229.

52. Somay K, Azakli H, Chahine JJ, Loughney TM, Ozdemirli M. Is immune effector cell-associated enterocolitis a CAR T-cell lymphoproliferative disorder? Blood Cancer J. 2025;15(1):117. 10.1038/s41408-025-01319-4.

53. Jaberi-Douraki M, Ampadi Ramachandran R, Xu X, et al. Comparative assessment of colitis-related adverse events in multiple myeloma patients treated with teclistamab, ciltacabtagene, and idecabtagene: Incidence, outcomes, and risk assessment. J Clin Oncol. 2025. 10.1200/JCO.2025.43.16_suppl.e19510.

54. Banerjee R, Hosoya H, Mikkilineni L, Hansen DK, Wolf JL, Lin Y. Managing IEC-associated enterocolitis following CAR-T therapy in multiple myeloma. Blood Cancer J. 2025;15(1):112. 10.1038/s41408-025-01320-x.

55. Perica K, Jain N, Scordo M, et al. CD4+ T-Cell lymphoma harboring a chimeric antigen receptor integration in TP53. N Engl J Med. 2025;392(6):577–83. 10.1056/NEJMoa2411507.

56. Hosoya H, Bastidas Torres AN, Fernandez-Pol S, et al. Long-term follow-up of gastrointestinal CAR T-cell lymphoma: homing, clonal expansion, and response to cyclosporine. Blood. 2025. 10.1182/blood.2025031423.

57. Braun T, Rade M, Merz M, et al. Multiomic profiling of T cell lymphoma after therapy with anti-BCMA CAR T cells and GPRC5D-directed bispecific antibody. Nat Med. 2025;31(4):1145–53. 10.1038/s41591-025-03499-9.

58. Ozdemirli M, Loughney TM, Deniz E, et al. Indolent CD4+ CAR T-Cell lymphoma after Cilta-cel CAR T-Cell therapy. N Engl J Med. 2024;390(22):2074–82. 10.1056/NEJMoa2401530.

59. Hosoya H, Fernandez-Pol S, Gubatan J, et al. Indolent CD8+ CAR T-cell lymphoma of the gastrointestinal tract after Ciltacabtagene Autoleucel therapy for relapsed/refractory multiple myeloma. Blood. 2024;144:4846. 10.1182/blood-2024-207885.

60. Boland BS, He Z, Tsai MS, et al. Heterogeneity and clonal relationships of adaptive immune cells in ulcerative colitis revealed by single-cell analyses. Sci Immunol. 2020. 10.1126/sciimmunol.abb4432.

61. Blumenberg V, Birocchi F, Shih A, et al. Ruxolitinib for refractory immune effector cell enterocolitis following ciltacabtagene autoleucel CAR T-cell therapy for multiple myeloma. Blood. 2025;146(Supplement 1):2392–2392. 10.1182/blood-2025-2392.40758944

62. Agha ME, McGregor S, De Braganca KC, et al. Systematic literature review of secondary primary malignancies related to a CAR-T treatment in patients with multiple myeloma, lymphoma or leukemia. Cancer Treat Res Commun. 2026;47:101161. 10.1016/j.ctarc.2026.101161.

63. Jadlowsky JK, Hexner EO, Marshall A, et al. Long-term safety of lentiviral or gammaretroviral gene-modified T cell therapies. Nat Med. 2025;31(4):1134–44. 10.1038/s41591-024-03478-6.

64. Tix T, Alhomoud M, Shouval R, et al. Second primary malignancies after CAR T-cell therapy: a systematic review and meta-analysis of 5,517 lymphoma and myeloma patients. Clin Cancer Res. 2024;30(20):4690–700. 10.1158/1078-0432.Ccr-24-1798.

65. Bushman F, Lewinski M, Ciuffi A, et al. Genome-wide analysis of retroviral DNA integration. Nat Rev Microbiol. 2005;3(11):848–58. 10.1038/nrmicro1263.

66. Verdun N, Marks P. Secondary cancers after chimeric antigen receptor T-cell therapy. N Engl J Med. 2024;390(7):584–6. 10.1056/NEJMp2400209.

67. Hamilton MP, Sugio T, Noordenbos T, et al. Risk of second tumors and T-cell lymphoma after CAR T-cell therapy. N Engl J Med. 2024;390(22):2047–60. 10.1056/NEJMoa2401361.

68. Ghilardi G, Fraietta JA, Gerson JN, et al. T cell lymphoma and secondary primary malignancy risk after commercial CAR T cell therapy. Nat Med. 2024;30(4):984–9. 10.1038/s41591-024-02826-w.

69. Dulery R, Guiraud V, Choquet S, et al. T cell malignancies after CAR T cell therapy in the DESCAR-T registry. Nat Med. 2025;31(4):1130–3. 10.1038/s41591-024-03458-w.

70. Lorenc R, Shouval R, Flynn JR, et al. Subsequent malignancies after CD19-targeted chimeric antigen receptor T cells in patients with lymphoma. Transplant Cell Ther. 2024;30(10):990–1000. 10.1016/j.jtct.2024.06.027.

71. Berg P, Bakker C, Sander M, et al. Secondary malignancy of T-cell origin after CAR T-cell therapy: EMA’s conclusions from the evaluation of 38 suspected cases. Gene Ther. 2025. 10.1038/s41434-025-00586-x.

72. Zolotov E, Biran N, Roney P, et al. Subsequent primary malignancies after CAR-T therapy: a study from the US multiple myeloma immunotherapy consortium. Blood. 2025;146(Supplement 1):5852–5852. 10.1182/blood-2025-5852.

73. Lin Y, Raje NS, Berdeja JG, et al. Idecabtagene vicleucel for relapsed and refractory multiple myeloma: post hoc 18-month follow-up of a phase 1 trial. Nat Med. 2023;29(9):2286–94. 10.1038/s41591-023-02496-0.

74. Martin T, Usmani SZ, Berdeja JG, et al. Ciltacabtagene autoleucel, an anti-B-cell maturation antigen chimeric antigen receptor T-Cell therapy, for relapsed/refractory multiple myeloma: CARTITUDE-1 2-year follow-up. J Clin Oncol. 2023;41(6):1265–74. 10.1200/jco.22.00842.

75. Saleem K, Franz J, Klem ML, et al. Second primary malignancies in patients with haematological cancers treated with lenalidomide: a systematic review and meta-analysis. Lancet Haematol. 2022;9(12):e906–18. 10.1016/s2352-3026(22)00289-7.

76. Trab T, Baech J, Jakobsen LH, et al. Second primary malignancies in patients with lymphoma in Denmark after high-dose chemotherapy and autologous haematopoietic stem-cell transplantation: a population-based, retrospective cohort study. Lancet Haematol. 2023;10(10):e838–48. 10.1016/s2352-3026(23)00212-0.

77. Chahin M, Branham Z, Fox A, Leurinda C, Keruakous AR. Clinical considerations for immunoparesis in multiple myeloma. Cancers (Basel). 2022. 10.3390/cancers14092278.

78. van de Donk N, Martínez-Lopez J, Dhakal B, et al. P-090 infections and immune reconstitution in the phase 3 CARTITUDE-4 trial of Ciltacabtagene Autoleucel vs standard care in patients with Lenalidomide-Refractory multiple myeloma (MM) and 1–3 prior lines. Clin Lymphoma Myeloma Leuk. 2024;24:S94. 10.1016/S2152-2650(24)01993-1.

79. Cordas Dos Santos DM, Tix T, Shouval R, et al. A systematic review and meta-analysis of nonrelapse mortality after CAR T cell therapy. Nat Med. 2024;30(9):2667–78. 10.1038/s41591-024-03084-6.

80. Dima D, Rashid A, Davis JA, et al. Efficacy and safety of idecabtagene vicleucel in patients with relapsed-refractory multiple myeloma not meeting the KarMMa-1 trial eligibility criteria: a real-world multicentre study. Br J Haematol. 2024;204(4):1293–9. 10.1111/bjh.19302.

81. Richardson T, Schütte D, Kobbe G, et al. Characteristics of infections after BCMA-directed CAR T-cell therapy for multiple myeloma: a real-world analysis. Blood Adv. 2025;9(6):1370–5. 10.1182/bloodadvances.2024015008.

82. Yadav A, Khetarpal M, Jain A. CT-062: navigating the toxicity landscape of BCMA-directed CAR-T therapies in multiple myeloma: a systematic review of CAR-T therapies. Clin Lymphoma Myeloma Leuk. 2025;25:S1001. 10.1016/S2152-2650(25)02752-1.

83. Ludwig H, Munshi NC, Terpos E, et al. Proposal for harmonizing the reporting of infections during treatment with bispecific antibodies in multiple myeloma. Blood Adv. 2024;8(18):4979–82. 10.1182/bloodadvances.2024013461.

84. Kikuchi T, Watanabe M, Tsukada N, et al. Cytomegalovirus retinitis during Idecabtagene Vicleucel therapy in patients with relapsed/refractory multiple myeloma. Transpl Infect Dis. 2025;27(4):e70040. 10.1111/tid.70040.

85. Wang D, Mao X, Que Y, et al. Viral infection/reactivation during long-term follow-up in multiple myeloma patients with anti-BCMA CAR therapy. Blood Cancer J. 2021;11(10):168. 10.1038/s41408-021-00563-8.

86. Hoeynck BW, Cohen AD, Stadtmauer EA, et al. Progressive multifocal leukoencephalopathy in multiple myeloma. Eur J Haematol. 2023;110(3):322–9. 10.1111/ejh.13909.

87. Abreu M, Patel CB, Patel K, Khawaja F, Tummala S. Progressive multifocal leukoencephalopathy in chimeric antigen receptor T-Cell therapy recipients: a case study. J Adv Pract Oncol. 2025. 10.6004/jadpro.2025.16.7.16.

88. Reynolds G, Hall VG, Teh BW. Vaccine schedule recommendations and updates for patients with hematologic malignancy post-hematopoietic cell transplant or CAR T-cell therapy. Transpl Infect Dis. 2023;25(Suppl 1(Suppl 1)):e14109. 10.1111/tid.14109.

89. Hansen D, Reid B, Grajales-Cruz A, et al. Bridging therapy response and low pre-lymphodepletion plasma cell burden are associated with improved safety and efficacy outcomes of ciltacabtagene autoleucel in multiple myeloma. Blood. 2025;146(Supplement 1):2214–2214. 10.1182/blood-2025-2214.

90. Fandrei D, Seiffert S, Rade M, et al. Bispecific antibodies as bridging to BCMA CAR-T cell therapy for relapsed/refractory multiple myeloma. Blood Cancer Discov. 2025;6(1):38–54. 10.1158/2643-3230.Bcd-24-0118.

91. Patel K, Dhakal B, Kaur G, et al. Phase 2 registrational study of anitocabtagene autoleucel for the treatment of patients with relapsed and/or refractory multiple myeloma: updated results from iMMagine–1. Blood. 2025;146(Supplement 1):256–256. 10.1182/blood-2025-256.

92. Hart K, Hyde M, Pham C, et al. The fast off-rate of anito-cel’s D-Domain binder contributes to its distinctive pharmacology profile in preclinical models of multiple myeloma. Blood. 2025;146(Supplement 1):7644–7644. 10.1182/blood-2025-7644.