INTRODUCTION
Cytokine release syndrome (CRS) is a systemic inflammatory response to excessive antigen-mediated immune stimulation, usually characterized by an elevation in inflammatory cytokines, such as interleukin-6 (IL-6) and interferon gamma (IFN) [ 1 , 2 ]. The onset and duration of cytokine storms vary, depending on the cause and treatments administered. Signs and symptoms of CRS typically include fever, hypotension, and hypoxia and may progress to organ dysfunction or death. In addition, patients may have fatigue, anorexia, headache, rash, diarrhea, arthralgia, myalgia, and neuropsychiatric findings [ 6 ]. These symptoms may result from cytokine-induced tissue damage, acute-phase physiological changes, or immune-cell-mediated responses. Elevated serum interleukin-6 levels are usually found in CAR T-cell therapy-induced cytokine Storm and several other cytokine Storm disorders [ 3 , 4 ]. Teclistamab, a fully humanized IgG4 bispecific antibody targeting B-cell maturation antigen (BCMA), is approved for refractory multiple myeloma, demonstrating a 63% response rate (≥complete response) in 39.4% of patients at a median 14.1-month follow-up [ 5 ]. However, its efficacy is tempered by CRS, which occurs in 72.1% of treated patients, often during initial dosing [ 6 ]. Understanding Teclistamab-induced CRS is critical for optimizing monitoring, prophylaxis (e.g., tocilizumab), and treatment strategies in myeloma.
CASE PRESENTATION
A 66-year-old female with a past medical history of arthritis, obesity, and an ex-smoker, was diagnosed with multiple myeloma and was treated with rituximab, bortezomib, and methylprednisolone for about 1 year. She also underwent an autologous transplant and was in remission for about 8 years. However, a PET scan revealed recurrence of multiple myeloma, and she was restarted on chemotherapy with carfilzomib, daratumumab, and dexamethasone. The patient developed shortness of breath on exertion during the chemotherapy regimen with carfilzomib and daratumumab. Both were discontinued, but she persistently took methylprednisolone. A second opinion from another oncologist recommended starting Teclistamab for refractory multiple myeloma. The patient received 1.5 mg/kg of Teclistamab subcutaneously after step-up doses. The patient was premedicated with steroids, IV fluids, and tocilizumab. She was monitored in the hospital for a week after the infusion of Teclistamab. She was discharged home; however, she presented again in the emergency department and was readmitted 24 hours after discharge with complaints of fever, chills, rigor, and shortness of breath. In the emergency department, the patient was febrile to 38.4°C, shivering, tachycardic with a heart rate of 120 bpm, hypoxemic, with oxygen saturation of 89% on room air, and blood pressure was 100/70 mmHg. Initial labs were consistent with a white blood cell count (WBC) of 2.35x10 3 /mm 3 , hemoglobin 7.7 g/dL, hematocrit 24.9%, platelet count 47x10 3 /mm 3 , BUN 24 mg/dL, and creatinine 4.59 mg/dL. The chest radiograph showed left lung base pulmonary infiltrates consistent with pneumonia.
The patient was hospitalized with a diagnosis of sepsis and started on antibiotic treatment with piperacillin/tazobactam and vancomycin. During hospitalization, the patient clinically deteriorated and was transferred to the ICU for hypotension, with a blood pressure of 60/30 mmHg, not responding to IV fluids, persistently tachycardic, and hypoxemic despite a high flow nasal cannula at 60 L/min and FiO 2 70%.
Repeat labs were consistent with an elevated CRP of 233 mg/dL, WBC of 1.9x10 3 /mm 3 , and lactic acid 9.1 mmol/L. The patient was intubated for acute hypoxic respiratory failure and hemodynamic instability. Initially, ICU treatment included hemodynamic stabilization with IV fluids and norepinephrine for septic shock. Stress-dose hydrocortisone (100 mg every 8 hours) was initiated. A bedside echocardiogram showed no pericardial effusion, normal heart contractility, and no D sign. The patient remained in septic shock, and vasopressin and epinephrine were added for refractory shock. The patient remained on maximum support for 24 hours, and the family decided not to continue active treatment and transition to comfort care.
DISCUSSION
Cytokine release syndrome (CRS), also referred to as a cytokine storm, is a profound inflammatory reaction triggered by an excessive release of cytokines beyond physiological levels. Due to the blurred boundary between normal and pathological immune responses, a universally accepted definition of CRS remains elusive. The syndrome involves intricate interactions among numerous inflammatory mediators, which collectively drive a large-scale activation of immune pathways [ 6 , 7 ]. At the molecular level, CRS is substantially driven by the IL-6 signaling cascade involving the JAK/STAT pathway, which results in the upregulation of inflammatory genes and further cytokine release. Similarly, activation by IFN-γ leads to the recruitment of immune cells and amplified inflammatory responses, underscoring the complex interplay of these pathways in CRS pathogenesis.
CRS manifests as a systemic inflammatory illness driven by multiple cytokines, most notably IL-6, as well as TNF-α, IFN-γ, IL-2, IL-8, IL-10, and granulocyte-macrophage colony-stimulating factor (GM-CSF) [ 8 ]. The activation of these cytokines can lead to downstream effects such as endothelial activation, increased vascular permeability, and organ damage, factors contributing to the clinical presentation of CRS.
Teclistamab, the first bispecific antibody approved for relapsed or refractory multiple myeloma (RRMM), simultaneously binds to CD3 on T cells and BCMA on myeloma cells, promoting T-cell engagement and subsequent destruction of malignant cells [ 5 ]. Unlike conventional myeloma therapies, Teclistamab uniquely induces cytokine production and T-cell stimulation. However, peak cytokine concentrations or T-cell activation levels do not consistently correlate with clinical response. Notably, patients who do respond to treatment often present with elevated baseline levels of IFN-γ, IL-6, IL-10, and IL-2 [ 9 ].
Commonly observed adverse effects include low-grade CRS and high-grade cytopenia, particularly due to underlying immunosuppression in this patient population. While CRS episodes are frequently mild, more severe forms—and even neurotoxicity similar to that seen in CAR-T therapy—have been reported [ 10 , 11 ]. From a diagnostic perspective, distinguishing CRS from sepsis in clinical settings poses significant challenges, mainly due to overlapping symptoms such as fever and hypotension. During the patient's hospitalization, diagnostic criteria such as ASTCT were considered to help differentiate the two conditions, focusing primarily on the presence and persistence of fever, hypotension, and hypoxia in the context of recent immunotherapy exposure.
Results from the MajesTEC-1 trial indicate a complete response or better in 46% of treated patients. The most frequently reported side effects included infections (80%), CRS (72%), neutropenia (72%), anemia (55%), and thrombocytopenia (42%). Neurotoxic effects were reported in 16% of patients, with 3% experiencing immune effector cell-associated neurotoxicity syndrome (ICANS) [ 3 ].
CRS involves widespread immune activation characterized by a surge in pro-inflammatory cytokines, which clinically manifests as acute systemic symptoms and may progress to multi-organ failure ( Table 1 ) [ 7 , 12 ]. Symptoms may range from flu-like signs, such as fever, to life-threatening conditions involving hypotension, acute respiratory distress syndrome, liver injury, circulatory collapse, cardiac dysfunction, and neurologic deficits [ 8 ]. In the MajesTEC-1 study, most CRS cases were grade 1–2 and responded quickly to management, with grade 3 pneumonia typically resolving within 48 hours. CRS grading is typically based on the ASTCT criteria, focusing on the presence of fever, hypotension, and hypoxia ( Table 2 ) [ 13 ].
Table 1
Clinical presentation of Cytokine Release Syndrome (CRS), characterized by acute systemic inflammatory symptoms and secondary multi-organ dysfunction [adapted from 7,12].
| Organ | Systemic response |
| Lungs | Pneumonitis |
| Liver | Hepatomegaly Elevated liver enzymes Increase hepcidin Hypoalbuminemia Liver failure |
| Kidney | Renal failure |
| Vascular and lymphatic system | Cytopenia, anemia, leukocytosis Coagulopathy Hyper ferritin anemia Elevated cytokines Vasodilatory shock Spontaneous hemorrhage |
| Nervous system | Confusion Delirium Aphasia Seizure |
| Constitutional systems | Fever Anorexia Fatigue |
| Heart | Hypotension Tachycardia Cardiomyopathy |
| Rheumatologic system | Vasculitis Arthritis Arthralgia |
| Gastrointestinal system | Nausea Vomiting Diarrhea Ascites |
| Skin | Rash Edema |
Table 2
American Society of Transplant and Cellular Therapy, Cytokine Release Syndrome consensus grading [adapted from 13].
| CRS parameter | Grade 1 | Grade 2 | Grade 3 | Grade 4 |
| Fever | Temperature 38°C or above | Temperature 38°C or above | Temperature 38°C or above | Temperature 38°C or above |
| Hypotension | None | Not requiring a vasopressor | Requiring a vasopressor with or without vasopressin | Required multiple vasopressors |
| Hypoxia | None | Requiring a Nasal cannula | Requiring a high-flow nasal cannula | Requiring positive pressure ventilation |
CRS management is typically tailored to symptom severity and local clinical protocols. Currently, there are no universal treatment guidelines specifically for immunotherapy-induced CRS. However, exploring additional pathways, such as IL-1, suggests potential benefits from targeted inhibitors like Anakinra in certain cases. This approach could expand the therapeutic options beyond current standards.
The 2020 Society for Immunotherapy of Cancer (SITC) guidelines for CAR-T-induced CRS provide foundational recommendations. These include the use of tocilizumab, intravenous fluids, supplemental oxygen, and corticosteroids ( Table 3 ) [ 4 , 12 ]. Therapeutic strategies for CRS are largely informed by past experiences with other immunotherapeutic agents [ 7 ].
Table 3
CRS supportive measures as administered in the MajesTEC–1 study [adapted from 12].
* Patients could have received one or more supportive measures.
| Supportive measure * | % |
| 1. Tocilizumab | 36.4 |
| 2. Intravenous IV fluid | 13.9 |
| 3. Oxygen therapy | 12.7 |
| 4. Steroid | 8.5 |
| 5. Vasopressor | 0.6 |
Corticosteroids, such as dexamethasone and methylprednisolone, are often administered either before, alongside, or after tocilizumab. Additional supportive interventions can include oxygen via nasal cannula, vasopressors, and further steroid therapy ( Table 4 ) [ 12 ]. Interleukin-6 plays a central role in the pathogenesis of CRS. Targeting this cytokine with tocilizumab—as a monoclonal antibody that blocks IL-6 receptor binding—has proven effective in managing severe CRS. Tocilizumab is primarily considered for grade 1 cases and may reduce CRS recurrence without affecting Teclistamab's therapeutic efficacy [ 14 , 15 ].
Table 4
Guidelines for the management of CRS by CRS grading [adapted from 12].
| CRS Grade | Treatment | Teclistamab infusion interruption or discontinuation |
| Grade 1 | Supportive care | Infusion should be interrupted |
| Grade 2 | • Supportive care, including IV fluids • Low-dose vasopressor therapy • Oxygen supplement • Immunosuppressive therapy such as steroids, anti–IL–6, and anti-TNF antibodies • Hospitalization for observation | • Reduce the infusion rate to half versus interruption • Administration of pre- and post-infusion medications • Consider prophylactic use of immunosuppressive agents |
| Grade 3 | • Intensive Care Unit admission • Multiple vasopressors or high-dose vasopressors • High-flow nasal cannula • Immunosuppressive therapy | • Discontinue Teclistamab immediately • Restart is not allowed, except for a limited grade 3 CRS |
| Grade 4 | • Intensive care unit • Multiple high-dose vasopressors • Oxygen therapy, including high-flow nasal cannula • Immunosuppressive therapy if appropriate | • Permanently discontinue Teclistamab immediately. • Restart not allowed, even in the event of resolution of all symptoms to the baseline. |
While most CRS episodes resolve with appropriate treatment, some patients may experience relapses, particularly after tapering steroids. Tocilizumab is generally well tolerated but can lead to adverse effects such as neutropenia, infections, elevated cholesterol, and liver enzyme abnormalities [ 16 ]. Corticosteroids are usually reserved for more severe cases due to their broad immunosuppressive actions. These agents suppress multiple pro-inflammatory molecules, including IL-1, IL-6, IL-8, TNF-α, its receptors, and nitric oxide. However, their use may cause side effects, including impaired immunity, hyperglycemia, and adrenal insufficiency [ 17 , 18 ].
CONCLUSION
Distinguishing protective inflammatory responses from pathological cytokine release syndrome (CRS) is critical yet challenging in clinical practice, especially given the symptom overlap with infections. As guidelines for managing CRS associated with T-cell–redirecting bispecific antibodies, such as Teclistamab, evolve, clinicians must utilize available resources—including institutional protocols, ASTCT recommendations, and real-world evidence—to guide timely and effective interventions. Increased awareness and education among healthcare teams are vital to enhancing clinical monitoring and implementing preventive strategies, ensuring optimal patient outcomes as these therapies become more widespread.
Informed consent
Written informed consent was obtained from the patient for publication of this case report. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Conflicts of interest
The authors declare that they have no competing interests.
Funding
Nothing to declare.
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