CAR-T in myeloma: cilta-cel, CRS and ICANS in practice

A 63-year-old man with multiple myeloma refractory to lenalidomide received ciltacabtagene autoleucel (cilta-cel, brand name Carvykti) seven days ago. He had been well until this morning, when a fever of 39 °C appeared. In the afternoon, his blood pressure dropped to 85/50 mmHg and improved with 1 liter of fluids, without a vasopressor. Oxygen saturation is normal on room air. In the evening, his wife notices that he swaps words and does not remember the name of the hospital. The scene is fictional and was written for teaching.

This text uses the scenario as a clinical reasoning exercise for students and health professionals. The scene brings together the two most typical toxicities of CAR-T cells, cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), and raises other questions: how to grade, when to give tocilizumab and corticosteroids, what to monitor afterwards and where the product is approved. The text does not replace the assessment of the cell therapy team, the label in your country or your institution's protocol. If you play the case of the day on NEXO, you will recognize the challenge: deciding with clues that arrive in sequence.

Key points

• Cilta-cel is a therapy with the patient's own T cells modified to recognize B-cell maturation antigen (BCMA).
• In the United States, since April 5, 2024, it is indicated from one prior line, including a proteasome inhibitor and an immunomodulatory agent, with refractoriness to lenalidomide.
• In the European Union, the indication is equivalent, and the conditional authorization of 2022 became standard authorization on April 19, 2024.
• CRS is graded by fever, hypotension and hypoxia; ICANS, by the ICE score and other neurological domains.
• The label directs tocilizumab 8 mg/kg from CRS grade 2 and dexamethasone according to the CRS and ICANS grade.
• Parkinsonism, recurrent cytopenias, hypogammaglobulinemia, infections and secondary malignancies require long-term monitoring.

Why this is a reasoning scenario

CAR-T cells have left research centers and reached earlier lines of myeloma treatment. This means that more professionals, including those outside transplant centers, will see patients with fever, hypotension or confusion in the weeks after infusion (Shune et al., 2026). Recognizing early and grading well changes management.

The scenario is good for training because every clue counts. The day of the fever suggests CRS. The blood pressure response to fluids defines the grade. Swapping words may be ICANS, but also infection, a metabolic disorder or a drug effect. The post on signs, symptoms and history shows how to listen to what the family reports, and the post on clinical deterioration on the ward shows how to escalate when vital signs change.

What the scene teaches

The scene trains five habits. The first is grading CRS by consensus criteria, not by overall impression. The second is applying the ICE score whenever there is a neurological change. The third is treating according to the label and the protocol, without delaying tocilizumab when indicated. The fourth is never forgetting infection. The fifth is remembering that some toxicities appear weeks or months later.

What is not at stake

Fever after CAR-T is not always CRS, and CRS does not exclude infection. Neutropenic fever can coexist with CRS, and the label directs investigating infection and treating with broad-spectrum antibiotics when indicated (US Carvykti label, revised 10/2025). The post on sepsis in nursing triage reminds how to act in the first hour.

What cilta-cel is and who it is approved for

Cilta-cel is made with the patient's own T cells, collected by leukapheresis and genetically modified to express a chimeric antigen receptor (CAR) directed at BCMA, which is present on myeloma cells (US Carvykti prescribing information, revised 10/2025). After infusion, the cells expand, recognize cells that express BCMA and destroy them (US Carvykti prescribing information, revised 10/2025). BCMA is also present on normal plasma cells and on some B lymphocytes, which helps explain the hypogammaglobulinemia (Kuipers et al., 2026).

What the studies showed

In CARTITUDE-4, patients with one to three prior lines of therapy who were refractory to lenalidomide were randomized between cilta-cel and standard treatment with daratumumab, pomalidomide and dexamethasone or bortezomib, pomalidomide and dexamethasone (US Carvykti prescribing information, revised 10/2025). The overall response rate was 84.6 percent with cilta-cel and 67.8 percent with standard treatment (US Carvykti prescribing information, revised 10/2025). In the second interim analysis, with a median follow-up of 33.6 months, overall survival was longer with cilta-cel, with a hazard ratio of 0.55 (US Carvykti prescribing information, revised 10/2025).

There was, however, a signal of early mortality: in the first 10 months after randomization, 29 of 208 patients (14 percent) died in the cilta-cel arm and 25 of 211 (12 percent) in the standard arm (US Carvykti prescribing information, revised 10/2025). An effective bridge, which reduces tumor burden before infusion, helps lower the toxicities (Shune et al., 2026).

In real life

In the Center for International Blood and Marrow Transplant Research (CIBMTR) registry, with 595 patients treated outside trials and a median age of 64 years, CRS of any grade occurred in 80 percent and grade 3 or higher in 4 percent; ICANS in 22 and 4 percent (Hansen et al., 2026). Progression-free survival at 12 months was 73 percent, and infections were the main cause of death unrelated to the disease (Hansen et al., 2026). A network meta-analysis of four phase 3 studies compared cilta-cel with bispecific antibody combinations in early relapse (Merz et al., 2026).

Regulatory status: FDA and EMA

United States. The FDA approved Carvykti on February 28, 2022 and issued a new approval letter on April 5, 2024, tied to the indication in earlier lines (FDA, Carvykti page). In the current prescribing information, revised 10/2025, the indication is for adults with relapsed or refractory myeloma who have received at least one prior line, including a proteasome inhibitor and an immunomodulatory agent, and are refractory to lenalidomide (US Carvykti prescribing information, revised 10/2025). On April 18, 2024, the FDA announced that it began requiring a boxed warning about T-cell malignancies after BCMA- or CD19-directed CAR-T (FDA, 2024). There are also letters dated June 26 and October 10, 2025 (FDA, Carvykti page); the prescribing information notes that the risk management program (REMS) was withdrawn in 6/2025 (US Carvykti prescribing information, revised 10/2025).

European Union. Carvykti received conditional authorization on May 25, 2022, converted to standard authorization on April 19, 2024 (EMA, Carvykti). The current indication is for adults with relapsed and refractory myeloma who have received at least one prior therapy, including an immunomodulatory agent and a proteasome inhibitor, who progressed on the last therapy and are refractory to lenalidomide (EMA, Carvykti).

Other countries. Outside these regions, the indication and access depend on the local agency and on the availability of qualified centers. The patient in the scene would fall within the US and European indications.

From preparation to infusion

The pathway starts with leukapheresis and continues with manufacturing, bridging therapy, lymphodepleting chemotherapy, infusion and monitoring of the acute phase (Shune et al., 2026). Bridging therapy is individualized and serves to control the disease while the product is manufactured; an effective bridge can reduce tumor burden and the risk of toxicities (Shune et al., 2026).

Lymphodepletion and infusion

The label directs cyclophosphamide 300 mg/m² and fludarabine 30 mg/m² intravenously, once a day for 3 days, and infusion of cilta-cel 2 to 4 days after the end of lymphodepletion (US Carvykti label, revised 10/2025). The dose is 0.5 to 1.0 million viable CAR-positive T cells per kg, with a maximum of 100 million (US Carvykti label, revised 10/2025).

Premedication includes paracetamol 650 to 1,000 mg and diphenhydramine 25 to 50 mg or equivalent (US Carvykti label, revised 10/2025). The label directs avoiding prophylactic corticosteroid, because it may interfere with the activity of the product, and confirming the availability of tocilizumab before infusion (US Carvykti label, revised 10/2025).

Monitoring

• Assess for signs of CRS and neurologic toxicity at least once a day for 7 days after infusion.
• Keep the patient near a health service for at least 2 weeks.
• Advise against driving for at least 2 weeks.
• Apply the ICE score every 8 to 12 hours in the acute phase.
• Teach the patient and family to recognize late signs, such as change in handwriting, slowness and mood change.

Sources for the list: (US Carvykti label, revised 10/2025), (Ussowicz et al., 2026) and (Kuipers et al., 2026).

Cytokine release syndrome: grading and treatment

In the CARTITUDE-1 and CARTITUDE-4 studies, which together totaled 285 patients, CRS occurred in 84 percent, with grade 3 or higher in 4 percent (US Carvykti label, revised 10/2025). Median onset was on day 7 (range 1 to 23), and median duration was 4 days (US Carvykti label, revised 10/2025). The most common manifestations were fever, hypotension and increased aspartate aminotransferase (US Carvykti label, revised 10/2025). The patient in the scene is exactly in the typical window.

How to grade

The ASTCT consensus defines grade 1 CRS as fever of at least 38 °C, with or without constitutional symptoms (Lee et al., 2019). From grade 2 onward, hypotension and hypoxia define the grade: grade 2 when there is hypotension without need for a vasopressor or hypoxia requiring low-flow nasal cannula; grade 3 when a vasopressor or high-flow oxygen, face mask or mask with reservoir is needed; grade 4 when multiple vasopressors or positive pressure are needed (Lee et al., 2019), (US Carvykti label, revised 10/2025). Fever may be masked by antipyretic, tocilizumab or corticosteroid; in that case, management is guided by hypotension and hypoxia (US Carvykti label, revised 10/2025).

The patient in the scene has fever and hypotension that responded to fluids, without vasopressor and without hypoxia: by the consensus, this is grade 2 CRS (Lee et al., 2019).

CRS grade	Main criterion	Tocilizumab in the label	Corticosteroid in the label
1	Fever of at least 38 °C	8 mg/kg may be considered in situations such as early fever, before 72 hours	Not indicated
2	Fever with hypotension without vasopressor or low-flow hypoxia	8 mg/kg in 1 hour, maximum of 800 mg; repeat every 8 hours if needed	Consider dexamethasone 10 mg every 12 to 24 hours
3	One vasopressor or high-flow oxygen	Same as grade 2	Consider dexamethasone 10 mg every 12 hours
4	Multiple vasopressors or positive pressure	Same as grade 2	Dexamethasone 20 mg every 6 hours; methylprednisolone 1 to 2 g if no improvement

Sources for the table: (Lee et al., 2019) and (US Carvykti label, revised 10/2025). The label limits tocilizumab to 3 doses in 24 hours and 4 doses in total, and directs considering other anticytokine agents after 2 doses (US Carvykti label, revised 10/2025).

When there is no improvement

In grades 2 and 3, if there is no improvement within 24 hours or if the worsening is rapid, the label advises repeating tocilizumab and increasing dexamethasone to 20 mg every 6 to 12 hours; if there is still no response, switch to methylprednisolone 2 mg/kg every 12 hours (US label for Carvykti, revised 10/2025). The corticosteroid should continue until the event returns to grade 1 or less, with gradual tapering if exposure exceeds 3 days (US label for Carvykti, revised 10/2025).

HLH and hemophagocytic syndrome

Hemophagocytic lymphohistiocytosis, or macrophage activation syndrome, occurred in 1 percent of patients in the studies and may accompany CRS or neurotoxicity (US label for Carvykti, revised 10/2025). Very high ferritin, worsening cytopenias and liver dysfunction beyond the pattern of CRS are clues to investigate immune effector cell-associated hemophagocytic syndrome (Ussowicz and colleagues, 2026), (Kuipers and colleagues, 2026).

ICANS and other neurologic toxicities

In the studies, ICANS occurred in 13 percent of patients, with grade 3 or higher in 2 percent; median onset was on day 8, and 97 percent of those who had ICANS also had CRS (US label for Carvykti, revised 10/2025). ICANS may appear before, during or after CRS, or even without it (US label for Carvykti, revised 10/2025).

The ICE score

The immune effector cell-associated encephalopathy (ICE) score ranges from 0 to 10 and assesses orientation, object naming, ability to follow commands, writing and attention (Ussowicz and colleagues, 2026), (Lee and colleagues, 2019). By consensus, grade 1 ICANS corresponds to an ICE of 7 to 9, grade 2 to an ICE of 3 to 6 and grade 3 to an ICE of 0 to 2; grade 4 includes the patient who does not wake and cannot do the test (Lee and colleagues, 2019). The final grade is defined by the worst domain, which also includes level of consciousness, seizures, motor findings and cerebral edema (Lee and colleagues, 2019), (US label for Carvykti, revised 10/2025).

In the patient in the scene, the word substitution and disorientation call for the ICE immediately, a neurologic exam, glucose, electrolytes and investigation of infection (Ussowicz and colleagues, 2026). The post on differential diagnosis with clues helps avoid settling on ICANS before ruling out other causes.

How to treat ICANS

The label advises, in grade 1, considering dexamethasone 10 mg every 12 to 24 hours for 2 to 3 days; in grade 2, giving dexamethasone 10 mg every 12 hours for 2 to 3 days, increasing to 20 mg every 6 hours if there is no improvement within 24 hours; in grade 3, dexamethasone 10 to 20 mg every 6 hours; and in grade 4, dexamethasone 20 mg every 6 hours and, without improvement, methylprednisolone 1 to 2 g per day (US label for Carvykti, revised 10/2025). In all grades, levetiracetam may be considered for seizure prophylaxis (US label for Carvykti, revised 10/2025).

Tocilizumab is the basis of CRS treatment, but in ICANS it is reserved for when there is concomitant CRS, because blocking the interleukin 6 receptor may worsen neurotoxicity (Hej-Ali and colleagues, 2026). If CRS and ICANS occur together, the label advises using the corticosteroid from the more aggressive table and tocilizumab according to the CRS grade (US label for Carvykti, revised 10/2025). In corticosteroid-refractory ICANS, anakinra is a second-line option (Hej-Ali and colleagues, 2026).

Parkinsonism and other late toxicities

In addition to ICANS, the label describes parkinsonism, Guillain-Barré syndrome, immune-mediated myelitis, peripheral neuropathies and cranial nerve palsies (US label for Carvykti, revised 10/2025). In the studies, any neurologic toxicity occurred in 24 percent, with parkinsonism in 3 percent and cranial nerve palsy in 7 percent (US label for Carvykti, revised 10/2025). Parkinsonism usually appears weeks to months after the infusion, with bradykinesia, rigidity, slowed thinking, apathy, gait changes and changes in handwriting (Hej-Ali and colleagues, 2026), (Reinhardt and colleagues, 2026).

High tumor burden at the time of infusion, especially without a response to bridging, raises the risk of parkinsonism, prolonged cytopenias and infections (Kuipers et al., 2026). Prophylactic dexamethasone at the time of lymphocyte expansion did not reduce late neurotoxicity or parkinsonism in a recent cohort (Lim et al., 2026). In American databases, the rates of non-ICANS neurologic events after cilta-cel were comparable to or lower than those in the pivotal trials (Sidana et al., 2026).

After the first weeks: cytopenias, infections and malignancies

Prolonged and recurrent cytopenias

In the trials, 62 percent of patients had grade 3 or higher cytopenias still unresolved on day 30, and many returned after an initial recovery (US Carvykti prescribing information, revised 10/2025). Prolonged neutropenia raises the risk of infection (US Carvykti prescribing information, revised 10/2025). The EHA and EBMT classification separates early cytopenias, up to day 30, from late ones, after day 30, by the depth and duration of neutropenia (Ussowicz et al., 2026).

Infections and hypogammaglobulinemia

In the trials, infections occurred in 57 percent of patients, with grade 3 or higher in 24 percent, and 5 percent had a fatal infection (US Carvykti prescribing information, revised 10/2025). IgG fell below 500 mg/dL in 93 percent, and the prescribing information advises monitoring levels and giving intravenous immunoglobulin when IgG is below 400 mg/dL (US Carvykti prescribing information, revised 10/2025). The systematic review by Benda et al. points to early immunoglobulin replacement, pneumocystis prophylaxis and antiviral prophylaxis as central parts of prevention (Benda et al., 2026).

Practical recommendations suggest acyclovir 800 mg twice a day or valacyclovir 500 mg once a day against herpes simplex and varicella-zoster, starting at lymphodepletion and continuing for at least 6 months after CAR-T (Bergantim et al., 2026). The prescribing information also calls for screening for cytomegalovirus, hepatitis B, hepatitis C and HIV before collection and does not recommend live-virus vaccines from at least 6 weeks before lymphodepletion (US Carvykti prescribing information, revised 10/2025).

Secondary malignancies

In the trials, myeloid neoplasms, such as myelodysplastic syndrome and acute myeloid leukemia, occurred in 5 percent of patients, with a median onset 447 days after infusion (US Carvykti prescribing information, revised 10/2025). T-cell malignancies, including CAR-positive tumors, have been reported after CAR-T directed at BCMA or CD19 and can appear weeks after infusion (US Carvykti prescribing information, revised 10/2025), (FDA, 2024). The prescribing information advises lifelong monitoring (US Carvykti prescribing information, revised 10/2025).

Immune-mediated enterocolitis

The prescribing information describes immune effector cell-associated enterocolitis, with severe or prolonged diarrhea, abdominal pain and weight loss, and post-marketing reports of intestinal perforation, including fatal cases (US Carvykti prescribing information, revised 10/2025). Persistent diarrhea after CAR-T deserves investigation, not just symptomatic treatment.

How NEXO helps train this reasoning

In NEXO, the case of the day is fictional, with a real clinical presentation and up to six progressive clues, and you propose the diagnosis by searching for the ICD-10 code. CAR-T cell toxicities are a good exercise because the time since infusion, vital signs and neurologic examination change management. The post on case-based learning explains why this format fixes knowledge, and the post on clinical decision-making shows how to choose tests and management.

Three case exercises

Change the pressure. State the CRS grade and the management if he needed norepinephrine.

Change the ICE. State the ICANS grade and the dexamethasone dose if the ICE were 5.

Change the time. State what to consider if, on day 60, he presented with slowness and small handwriting.

The post about diagnostic pause reminds you to stop before closing the management plan, and the post about interprofessional clinical reasoning shows why nursing, pharmacy and neurology are part of care.

The limits on using the game are described on the NEXO Economy page. If you research the teaching of clinical reasoning, the page for Researchers explains how to get in touch. Professionals who write or review cases find information on Curator and on Creators, and institutions can learn about the proposal on the partnerships page.

Frequently asked questions

Is every fever after CAR-T CRS?

No. Infection must be investigated, especially with neutropenia, and treated when indicated (US prescribing information for Carvykti, revised 10/2025).

When should tocilizumab be given?

Per the prescribing information, from CRS grade 2 onward, and it may be considered at grade 1 in situations such as early fever (US prescribing information for Carvykti, revised 10/2025).

Does tocilizumab treat ICANS?

Not on its own. In ICANS, the treatment is a corticosteroid; tocilizumab is added when there is CRS as well (Hej-Ali et al., 2026), (US prescribing information for Carvykti, revised 10/2025).

Can prophylactic corticosteroids be given?

The prescribing information advises avoiding prophylactic corticosteroids before infusion (US prescribing information for Carvykti, revised 10/2025).

How long does the patient stay near the center?

Per the current prescribing information, at least 2 weeks, and no driving during the same period (US prescribing information for Carvykti, revised 10/2025).

Final checklist

• I confirmed the infusion day and the typical CRS and ICANS window.
• I graded CRS by fever, hypotension and hypoxia.
• I applied the ICE score and assessed consciousness, seizures, strength and signs of cerebral edema.
• I investigated infection and started antibiotics if there was febrile neutropenia.
• I checked the tocilizumab and dexamethasone doses in the prescribing information and in the local protocol.
• I ordered ferritin and monitored for signs of hemophagocytic syndrome.
• I scheduled a blood count, IgG, and antiviral and pneumocystis prophylaxis.
• I advised the family about late signs and lifelong monitoring for malignancies.

Want to practice reasoning with progressive clues? Play the case of the day.

References

1. Benda M, Reimann P, Willenbacher W, et al. Infectious toxicities associated with bispecific antibodies and CAR-T Cells in multiple myeloma: a systematic review. Ann Hematol. 2026. PMID 42315764.
2. Bergantim R, Roque A, Jorge A, et al. Practical recommendations for infectious prophylaxis and vaccination in multiple myeloma patients. Front Med (Lausanne). 2026. PMID 42454131.
3. European Medicines Agency. Carvykti. EPAR. Accessed on 10/24/2026. Official source.
4. Hansen DK, Dima D, Mian H, et al. Safety and efficacy of ciltacabtagene autoleucel for relapsed/refractory multiple myeloma: a CIBMTR study. Blood Cancer J. 2026. PMID 41980929.
5. Hej-Ali S, Banwell K, Mohamed H, et al. Toxicities of CAR-T, Bispecific Antibodies, and Antibody-Drug Conjugates in Multiple Myeloma: A Practical Approach to Risk Mitigation and Management. Cancers (Basel). 2026. PMID 42449627.
6. Janssen Biotech. CARVYKTI® (ciltacabtagene autoleucel) suspension for intravenous infusion. Prescribing Information. Revised 10/2025. Accessed on 10/24/2026. Official source.
7. Kuipers MT, Migchelbrink J, Kramer AM, et al. Balancing Efficacy and Safety in Multiple Myeloma Patients Receiving B cell Maturation Antigen-Directed CAR T-Cell Therapy. BioDrugs. 2026. PMID 42141360.
8. 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. PMID 30592986.
9. Lim KJ, Tan M, Parrondo R, et al. Prophylactic dexamethasone at the time of absolute lymphocyte expansion does not mitigate risk or event-free survival for immune effector cell associated delayed neurotoxicity. Blood Cancer J. 2026. PMID 42728267.
10. Merz M, Souto Filho JT, Voorhees PM, et al. T-cell-redirecting therapies in early relapsed multiple myeloma: a systematic review and network meta-analysis. J Hematol Oncol. 2026. PMID 42844619.
11. Reinhardt B, Naing PT, Baljevic M. Long-term safety and efficacy of BCMA-directed CAR T-cell therapies in multiple myeloma: comparative insights from Cilta-cel, Ide-cel, Anito-cel, and FCARH143. Transl Cancer Res. 2026. PMID 42724501.
12. Shune LO, Mahmoudjafari Z, McGuirk JP. Optimizing ciltacabtagene autoleucel outcomes: real-world experience and best practices from a single academic center. Front Oncol. 2026. PMID 42518817.
13. Sidana S, Nagar SP, Ghosh S, et al. Real-World Description of Non-ICANS Neurologic Events Among Patients with Relapsed or Refractory Multiple Myeloma Treated with Ciltacabtagene Autoleucel Using Two Large US Databases. Oncol Ther. 2026. PMID 42000954.
14. U.S. Food and Drug Administration. CARVYKTI. Product page. Accessed on 10/24/2026. Official source.
15. U.S. Food and Drug Administration. FDA Requires Boxed Warning for T cell Malignancies Following Treatment with BCMA-Directed or CD19-Directed Autologous Chimeric Antigen Receptor (CAR) T cell Immunotherapies. 04/18/2024. Official source.
16. Ussowicz M, Jakubczyk E, Wróbel T, et al. Recognition and management of early complications in CAR-T cell therapy and virus-specific T-lymphocyte therapy: a practical clinical reference. Front Immunol. 2026. PMID 42729916.