Introduction
Chimeric antigen receptor T-cell therapy (CART) targeting B cell maturation antigen (BCMA) is an effective treatment for relapsed multiple myeloma (MM). However, immune-mediated toxicities resembling autoimmune diseases or graft-versus-host disease (GVHD) are increasingly recognized but remain poorly understood. We describe the largest multicenter series to date of immune effector cell-associated enterocolitis (IEC-EC) after BCMA-CART, characterizing its clinical course, pathology, and outcomes.
Methods
Data from six U.S. academic centers were retrospectively collected. This study was approved by the institutional review board (IRB) in each institution. Due to IRB exemption status, informed consent was not obtained. Patients with unexplained diarrhea after CART were identified after exclusion of infectious causes (CMV, C. difficile , and parasites). All underwent endoscopic evaluation with esophagogastroduodenoscopy and/or colonoscopy. Common Terminology Criteria for Adverse Events (CTCAE) v5.0 and American Society for Transplantation and Cellular Therapy (ASTCT) grading were used for diarrhea/colitis and cytokine release syndrome (CRS)/immune effector cell–associated neurotoxicity syndrome (ICANS), respectively. International Myeloma Working Group (IMWG) response to CART, progression, and survival data were obtained.
Results
Nineteen patients were identified, all treated with commercial ciltacabtagene autoleucel during April 2022 to December 2024, representing an estimated incidence of 4.3%. Median follow-up was 473 days. Figure 1 shows the trajectory of each individual patient. Table 1 outlines the demographics and clinical characteristics of the cohort. The median age at CART infusion was 68 years. Any grade/Grade 3 or higher CRS and ICANS rates were 74%/0% and 26%/11%, respectively. The median peak absolute lymphocyte number (ALC) was 2.2 (range 0.6–157.0 × 10 3 /ul). Delayed neurotoxicity preceded diarrhea onset in 5 (26%) patients (4 cranial nerve palsies and 1 Parkinsonism). Median onset of diarrhea was 81 days [24–211] from CART infusion. Seven (37%) had a preceding infection within 45 days (3 upper respiratory and 4 C. difficile ); the latter showed microbiologic clearance and atypical upper-GI inflammation, excluding ongoing C. difficile colitis. Fig. 1 Swimmer’s plot showing the trajectory of subjects developing IEC-EC after BCMA CART cell therapy. Table 1 Baseline characteristics and initial post-CART course. Patient characteristics Total N = 19 Median age at CART infusion 68 (39–77) Ciltacabtagene autoleucel 100% Female 40% High-risk cytogenetics 26% EMD 11% Median prior lines of therapy 4 (3–8) Prior stem cell transplant 63% Triple class refractory 79% CRS all grade/ ≥ G3 74/0% ICANS all grade/ ≥ G3 26/11% Delayed neurotoxicity 26% CN palsies 21% MNT 5% Disease response to CART ≥ VGPR 100% Infection within 45 d of diarrhea 37% Viral URI 16% Preceding (treated) C. difficile 21% Triple-class refractory was defined as refractory to a proteasome inhibitor, immunomodulatory agent, and anti-CD38 monoclonal antibody. EMD extramedullary disease, VGPR very good partial response, CR complete response, ALC absolute lymphocyte count, CRS cytokine release syndrome, ICANS immune effector cell-associated neurotoxicity syndrome, MNT movement and neurocognitive treatment-emergent adverse events, CN cranial nerve, URI upper respiratory infection.
Table 1
Baseline characteristics and initial post-CART course.
Triple-class refractory was defined as refractory to a proteasome inhibitor, immunomodulatory agent, and anti-CD38 monoclonal antibody. EMD extramedullary disease, VGPR very good partial response, CR complete response, ALC absolute lymphocyte count, CRS cytokine release syndrome, ICANS immune effector cell-associated neurotoxicity syndrome, MNT movement and neurocognitive treatment-emergent adverse events, CN cranial nerve, URI upper respiratory infection.
| Patient characteristics | Total N = 19 |
| Median age at CART infusion | 68 (39–77) |
| Ciltacabtagene autoleucel | 100% |
| Female | 40% |
| High-risk cytogenetics | 26% |
| EMD | 11% |
| Median prior lines of therapy | 4 (3–8) |
| Prior stem cell transplant | 63% |
| Triple class refractory | 79% |
| CRS all grade/ ≥ G3 | 74/0% |
| ICANS all grade/ ≥ G3 | 26/11% |
| Delayed neurotoxicity | 26% |
| CN palsies | 21% |
| MNT | 5% |
| Disease response to CART | |
| ≥ VGPR | 100% |
| Infection within 45 d of diarrhea | 37% |
| Viral URI | 16% |
| Preceding (treated) C. difficile | 21% |
Sixteen (84%) experienced Grade (G) 3 or higher diarrhea and/or colitis, and 3 (16%) had G2. Impaired bowel integrity occurred in 6 (32%) patients (4 pneumatosis intestinalis, 2 bowel perforations). Thirteen (68%) patients had upper and lower GI involvement, 3 (16%) only upper, and 3 (16%) with only lower GI involvement. Fourteen (74%) patients had cryptitis/crypt apoptosis on biopsy, 5 (26%) had mucosal ulcerations, and 5 (26%) had lymphocytic infiltrates. No lymphoproliferative neoplasms were detected. In 4 cases, tissue assays (3 RNAscope and 1 by flow cytometry) demonstrated the presence of CAR+ T cells. A summary of endoscopic and pathological findings is available in Supplementary Table 1 .
Treatment approaches were heterogeneous. Eleven (58%) patients received systemic corticosteroids (IV or oral), with only one achieving symptomatic improvement. Four steroid-refractory patients were treated with infliximab, of whom 2 (50%) improved to G1. One responder relapsed and achieved improvement with ruxolitinib followed by photopheresis. Another patient received ruxolitinib for 7 days with no improvement. Other treatments included budesonide in 9 and octreotide in 2. Total parenteral nutrition (TPN) was utilized in 9 (47%) patients, with clinical benefit seen in 7 patients.
At last follow-up, 7 (37%) achieved complete resolution (median of 101 [30–312] days), 5 (26%) improved to G1 (median of 100 [30–147] days), and 7 (37%) had persistent ≥G2 symptoms. Of the latter, 4 (57%) died from IEC-EC-related complications (perforation or infection). Of the 5 patients with initial improvement to G1, 1 died of infection related to IEC-EC and 1 developed recurrent grade 3 colitis at day 441, later diagnosed with secondary AML and died as a result. Sixteen (84%) patients required ≥1 hospitalization. There were 9 infectious complications seen in 6 patients, including gram-negative bacteremia, nocardia, asymptomatic CMV reactivation, and disseminated zoster. Overall mortality was 37%—five patients died from IEC-EC, one from progressive myeloma, one from secondary AML. Among survivors, 3 had progressive myeloma at a median of 606 days [394–765], while the others remain in remission.
Discussion
This multicenter case series identifies immune effector cell–associated enterocolitis (IEC-EC) as a late-onset, high-morbidity complication of BCMA-directed CAR T-cell therapy in relapsed/refractory multiple myeloma. The syndrome is characterized by protracted, often steroid-refractory diarrhea, frequent hospitalizations, and substantial treatment-related toxicity. Despite immunosuppressive therapies—including corticosteroids, infliximab, ruxolitinib, and photopheresis—and nutritional support, responses were limited, with symptoms often persisting for weeks to months. Most patients required total parenteral nutrition, underscoring the severity of gastrointestinal dysfunction and suggesting potential benefit from bowel rest. Mortality attributable to IEC-EC was high, with five patients (26%) dying from either infection or intestinal perforation. These outcomes occurred independently of myeloma progression, underscoring that immune-related toxicity and complications of immunosuppressive treatment, rather than underlying malignancy, were the primary causes of death.
The pathophysiology of IEC-EC remains incompletely defined but likely involves dysregulated T-cell activity, with clinical and histopathologic features overlapping graft-versus-host disease (GVHD) and common variable immunodeficiency (CVID) [ 1 , 2 ]. Frequent upper GI involvement, corticosteroid resistance, and mucosal T-cell infiltration suggest an immunopathologic profile distinct from checkpoint inhibitor colitis. In a healthy gut, plasma cells in the lamina propria secrete IgA, which plays a crucial protective role in neutralizing pathogens and preventing their translocation across the epithelial barrier. These IgA-secreting plasma cells also produce anti-inflammatory cytokines, such as IL-10, which help regulate immune responses. Disruption of gut plasma cells, particularly long-lived IgA-producing cells, could lead to an excessive or inappropriate immune response, impairing gut homeostasis and leading to tissue damage, akin to the mechanisms seen in CVID, autoimmune diseases, or GVHD [ 3 ]. Isolated detection of CAR + T cells in gastrointestinal biopsies did not correspond to overt lymphoproliferative disease in our cohort, in contrast to recent reports of post–CAR T-cell lymphomas. This highlights the challenge of interpreting T-cell–rich infiltrates following CAR T therapy and the risk of overdiagnosis. Accurate distinction between reactive and neoplastic processes requires a multimodal approach, including TCR clonality testing in conjunction with expert hematopathologic review, as not all clonal T-cells represent neoplasia. Incorporation of T-cell lymphoma specialists is important, particularly in the setting of persistent or atypical inflammation [ 4 – 7 ].
Our findings align with those of Fortuna et al., including three overlapping cases [ 8 ]. Both cohorts reported high mortality related to IEC-EC (36% vs. 26%), limited steroid responsiveness, and prolonged symptom duration. Notably, 21% of our patients improved with supportive care alone, suggesting heterogeneous disease trajectories and the need for risk-adapted management—early escalation for severe cases versus conservative approaches in selected patients. While steroid-sparing agents such as ruxolitinib or vedolizumab are increasingly used in refractory cases, our findings do not suggest a clear benefit, highlighting the importance of careful consideration when adding immunosuppressive therapies that may increase infection-related morbidity.
Due to the retrospective nature of our study and the limited number of patients who developed enterocolitis, we were unable to perform a statistically meaningful comparison of patient characteristics for those who developed colitis and those who did not. However, overall demographics and disease characteristics, including age, number of lines of therapy, depth of response, and CRS rates, were similar to those reported in the pivotal CAR T-cell trials such as KarMMa-1 [ 9 ] and CARTITUDE-1 [ 10 ], with the exception of ICANS, which was numerically higher in the current study (Supplementary Table 2 ). Additionally, we observed a higher incidence of delayed neurotoxicities within the colitis cohort than previously reported with ciltacabtagene autoleucel [ 11 ]. While all patients with delayed neurotoxicity developed severe IEC-EC (grade ≥3), this trend did not reach statistical significance, likely due to the small sample size. In addition, no significant association was found between absolute lymphocyte count and IEC-EC severity.
As BCMA CAR T-cell therapy moves earlier in treatment paradigms, timely recognition, mechanistic understanding, and tailored interventions will be critical. Endoscopic evaluation, including TCR clonality studies, should be pursued when biopsies reveal T-cell infiltrates. Further research is urgently needed to elucidate the mechanisms driving IEC-EC, identify predisposing factors and biomarkers for early detection, and optimize tailored treatment strategies to enhance the efficacy and safety profile of these therapies. Furthermore, future studies incorporating high-resolution immune profiling, TCR sequencing, and spatial transcriptomics may help distinguish reactive from neoplastic infiltrates and clarify the pathogenic potential of long-lived CAR T cells in non-hematopoietic tissues.
Supplementary information
Table S1: Endoscopic and pathologic characteristics of patients with IEC-associated enterocolitis Table S2: Baseline characteristics and initial post-CART outcomes in the current cohort, KarMMa-1 and CARTITUDE-1 studies
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Supplementary information
The online version contains supplementary material available at 10.1038/s41408-026-01473-3.
Author contributions
Conception and design: SSA and NB. Provision of study materials or patients: SSA, BAD, ADC, DTV, SR, AR, MJF, AJY, BD, and NB. Collection and assembly of data: SSA, BAD, ADC, DTV, SR, AR, MJF, AJY, BD, and NB. Data analysis and interpretation: SSA and NB. Manuscript writing: SSA and NB. Final approval of manuscript: SSA, BAD, ADC, DTV, SR, AR, MJF, AJY, BD, and NB.
Competing interests
The authors declare no competing interests.
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