CAR T-cell therapy for multiple myeloma provides the possibility of deep and durable remissions for patients who have relapsed after numerous lines of therapy. Read what our expert has to say about the most recent clinical data and the practical management of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS).
The Evolution of CAR T-Cell Therapies in RRMM
Chimeric antigen receptor (CAR) T-cell therapy for multiple myeloma (MM) provides the possibility of deep and durable remissions for patients who have relapsed after multiple lines of therapy.1 These patients, whose disease is commonly referred to as triple-class refractory (refractory to proteasome inhibitors, immunomodulatory agents, and monoclonal antibodies) or penta-refractory (refractory to bortezomib, carfilzomib, lenalidomide, pomalidomide, and daratumumab or isatuximab), have extremely poor outcomes. Median overall survival (OS) is 9 months for patients with triple-class refractory MM and 6 months for those with penta-refractory disease.2,3
What Are the Current Indications and Efficacy of CAR T-Cell Therapy for Patients with MM?
There are currently 2 CAR T-cell therapies approved by the US Food and Drug Administration (FDA) for patients with MM who have received 4 or more prior lines of therapy including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody.4,5 These agents target B-cell maturation antigen (BCMA), which is preferentially expressed on the cell surface of mature B-lymphocytes and overexpressed in MM cells.6 The FDA approved idecabtagene vicleucel (ide-cel) on March 29, 2021, based on a phase 2 study of 128 patients which showed a 74% overall response rate, median progression-free survival (PFS) of 8.8 months, and median OS of 19.4 months.7 The recently reported phase 3 KarMMa-3 study randomized 386 patients with relapsed/refractory MM after 2 to 4 prior therapies to ide-cel or standard of care treatment. In that study, median PFS was 13.3 months with ide-cel compared with 4.4 months using standard treatment (HR = 0.49; P < 0.001).8 The FDA approved ciltacabtagene autoleucel (cilta-cel) on February 28, 2022, based on the phase 1b/2 CARTITUDE-1 study of 97 patients who had received 3 or more prior lines of therapy. Treatment with cilta-cel resulted in a 98% ORR, and 83% of patients reached a stringent complete response. The median duration of response was not estimable, and median PFS and OS have not been reached (Table 1).9
What Adverse Events Are Most Common?
While the efficacy of CAR T-cell therapy is notable, the treatment is associated with serious side effects. Cytokine release syndrome (CRS), which can develop after any immunotherapy, is the most commonly occurring CAR T-cell therapy-associated adverse event (Table 1). CRS can range in severity from mild to life-threatening and must be appropriately managed to prevent severe morbidity and mortality.10
Although rarer than CRS, immune effector cell-associated neurotoxicity syndrome (ICANS) is another noteworthy side effect that needs to be carefully monitored and managed (Table 1). ICANS is not considered a direct effect of CAR T-cell therapy, but a response to inflammatory cytokines that increase vascular permeability and endothelial activation, leading to a breakdown of the blood-brain barrier.11
Table 1: Response, PFS, CRS, and Neurotoxicities Reported in Clinical Studies Leading to FDA Approval of CAR T-Cell Therapy in MM
CAR, chimeric antigen receptor; cilta-cel, ciltacabtagene autoleucel; CR, complete response; CRS, cytokine release syndrome; ide-cel, idecabtagene vicleucel; mPFS, median progression-free survival; NR, not reached; NT, neurotoxicity; ORR, overall response rate.
a includes ICANS and other neurotoxicities.
How Is CRS Managed After CAR T-Cell Therapy?
CRS is generally acute and can range from mild infusion reactions and fever to life-threatening complications. On both the KarMMa and CARTITUDE-1 studies, there was 1 death due to CRS; there were 2 deaths due to CRS on KarMMa-3.7-9 Onset and duration of CRS can vary by CAR T product. Median onset was 1 day on KarMMa and 7 days on CARTITUDE-1 with a median duration of 5 and 4 days, respectively, but the range of onset can vary from 1 day to 2 weeks.7,12 Risk factors for CRS include increased CAR T-cell expansion and high tumor burden.10
Symptoms of CRS can include fever, hypotension, tachycardia, and/or hypoxia, and close monitoring is critical.10 Patients may be admitted to the hospital for observation or monitored closely outside the hospital with a requirement to remain within close proximity of the certified healthcare facility following administration of both ide-cel and cilta-cel.4,5
CRS is graded using the American Society for Transplantation and Cellular Therapy (ASTCT) consensus scale for CRS outlined in Table 2. Grading is dependent upon the presence of fever, hemodynamic compromise, and hypoxia.13 Patients may receive supportive care in the form of antipyretics, supplemental oxygen, and volume resuscitation but may require therapy with tocilizumab, an interleukin (IL)-6 receptor inhibitor, to treat CRS.
Table 2: ASTCT Consensus Scale for CRS
Not requiring vasopressors
Requiring a vasopressor with or without vasopressin
Requiring multiple vasopressors (excluding vasopressin)
Requiring low-flow nasal cannulac or blow-by
Requiring high-flow nasal cannula,c facemask, non-rebreather mask, or Venturi mask
Requiring positive pressure (eg, CPAP, BiPAP, intubation and mechanical ventilation)
ASTCT, American Society for Transplantation and Cellular Therapy; CRS, cytokine release syndrome.
a Temperature ³38°C not attributable to any other cause. In patients who have CRS then receive antipyretic or anticytokine therapy such as tocilizumab or steroids, fever is no longer required to grade subsequent CRS severity. In this case, CRS grading is driven by hypotension and/or hypoxia.
b CRS grade is determined by the more severe event: hypotension or hypoxia not attributable to any other cause.
c Low-flow nasal cannula is defined as oxygen delivered at <6 L/min. Low-flow also includes blow-by oxygen delivery, sometimes used in pediatrics. High-flow nasal cannula is defined as oxygen delivered at >6 L/min.
Urgent intervention is required to prevent the progression of CRS, although other potential causes of side effects should be ruled out. In patients who are febrile and/or have neutropenia, empiric infection treatment should be considered.10 IL-6 is viewed as a central mediator of CRS, and anti-IL-6 therapy with tocilizumab is a cornerstone of CRS management.10 Corticosteroids, generally dexamethasone, also play a role depending on the severity of CRS, although recommendations vary by grade (Table 3).4,5 The need for subsequent tocilizumab should be assessed after each dose, and no more than 3 doses of tocilizumab in a 24-hour period or 4 doses total should be administered. In patients receiving corticosteroid treatment for CRS or neurotoxicity after CAR T-cell therapy, antifungal prophylaxis should be strongly considered.10
Table 3: Tocilizumab and Corticosteroid Administration According to CRS Grade by Agent4,5
Consider 8 mg/kg IV over 1 hra in patients with fever <72 hours after infusion
Consider dexamethasone 10 mg IV every 24 hr
8 mg/kg IV over 1 hra
Repeat every 8 hrs as needed if not responsive to IV fluids or increasing supplemental oxygenc
Consider dexamethasone 10 mg IV every 12-24 hrs
Per Grade 2
Dexamethasone 10 mg IV every 12 hrs
Per grade 2
Dexamethasone 20 mg IV every 6 hrs
a Not to exceed 800 mg.
b See prescribing information for management if no response within 24 hours.
c Do not exceed 3 doses of tocilizumab in 24 hours or 4 doses in total.
How Is Neurotoxicity Identified and Managed?
ICANS is a pathologic process involving the central nervous system that can occur after immune therapy and results in the activation or engagement of T-cells and/or other immune effector cells. A broad spectrum of symptoms has been observed, including headache, encephalopathy, delirium, aphasia, lethargy, tremor, myoclonus, motor dysfunction, ataxia, anxiety, agitation, seizures, signs of psychosis, depressed level of consciousness, and serious and fatal cases of cerebral edema.10 Other neurotoxicities that do not fit into the definition of ICANS have also been described and may occur after a period of recovery from CRS and/or ICANS. These adverse events may present in a unique pattern, including movement and cognitive disorders or personality changes.9,14
CRS is considered a strong risk factor for ICANS.10 Other risk factors include higher disease burden, a high baseline inflammatory state, preexisting neurologic comorbidities, and higher CAR T-cell dose. The incidence of ICANS is lower with BCMA-directed CAR T-cell therapy compared with CD19-directed CAR T-cell therapy.10 The median time to neurotoxic events was 2 days (range 1-10) in KarMMa and 8 days (ICANS, range 3-12) in CARTITUDE-1, and median duration was 3 (range 1-26) and 4 (range 1-12) days, respectively.7,14 Symptoms are heterogenous and range in severity, although the majority are grade 1 or 2.
Neurotoxicity associated with CAR T-cell therapy has distinct common features which are incorporated into the consensus grading system. To grade ICANS, it is necessary to determine the immune effector cell-associated encephalopathy (ICE) score (Table 4), which is then combined with other neurologic domains, including level of consciousness, motor symptoms, seizures, and signs of elevated intracranial pressure/cerebral edema which may occur with or without encephalopathy (Table 5).13 Patients should be proactively monitored using the ICE assessment tool.
Table 4: Encephalopathy Assessment Tools for Grading ICANS13
Orientation to year, month, city, hospital
Ability to name 3 objects
Ability to write a standard sentence
Ability to follow simple commands
Table 5: ASTCT ICANS Consensus Grading13
(patient is unarousable and unable to perform ICE)
Depressed level of consciousness
Awakens to voice
Awakens only to tactile stimulus
Patient is unarousable or requires vigorous or repetitive tactile stimuli to arouse. Stupor or coma
Any clinical seizure focal or generalized that resolves rapidly or nonconvulsive seizures on electroencephalography that resolve with intervention
Life-threatening prolonged seizure (>5 min) or repetitive clinical or electrical seizures without return to baseline in between
Deep focal motor weakness such as hemiparesis or paraparesis
Elevated ICP/cerebral edema
Focal/local edema on neuroimaging
Diffuse cerebral edema on neuroimaging, decerebrate or decorticate posturing, cranial nerve VI palsy, papilledema, or Cushing triad
ASTCT, American Society for Transplantation and Cellular Therapy; ICANS, immune effector cell-associated neurologic syndrome; ICE, immune effector cell-associated encephalopathy.
Most cases of ICANS spontaneously resolve with supportive care and early intervention with corticosteroids administered based on symptom grading.4,5,11 Tocilizumab is not an effective agent against ICANS.10,11 Patients should be educated to refrain from driving or engaging in hazardous activities, including operating heavy or potentially dangerous machinery for 8 weeks after CAR T-cell administration.4,5
It Takes a Village
Care for patients receiving CAR T-cell therapy includes physicians, advanced practitioners, nurse coordinators, nurse educators, apheresis nurses, inpatient and outpatient nurses, cellular therapy technologists, case managers, social workers, and family/friends as caregivers.15 Management of ICANS and CRS begins early in treatment when patients are undergoing CAR T-cell therapy treatment. Education on the needs and expectations surrounding relocating and driving along with the symptoms of side effects is critical. All clinicians interacting with patients undergoing CAR T-cell therapy should be trained to recognize the signs and symptoms of these adverse events. Consistent messaging and education of the patients and their caregivers is critical to the identification and mitigation of adverse events.15
- Parikh RH, Lonial S. Chimeric antigen receptor T‐cell therapy in multiple myeloma: a comprehensive review of current data and implications for clinical practice. CA Cancer J Clin. Published online January 10, 2023. doi:10.3322/caac.21771
- Mikhael J. Treatment options for triple-class refractory multiple myeloma. Clin Lymphoma Myeloma Leuk. 2020;20(1):1-7.
- Gandhi UH, Cornell RF, Lakshman A, et al. Outcomes of patients with multiple myeloma refractory to CD38-targeted monoclonal antibody therapy. Leukemia. 2019;33(9):2266-2275.
- ABECMA. Idecabtagene vicleucel prescribing information. Celgene Corporation; 2021.
- CARVYKTI. Ciltacabtagene autoleucel prescribing information. Janssen Biotech, Inc; 2023.
- Shah N, Chari A, Scott E, Mezzi K, Usmani SZ. B-cell maturation antigen (BCMA) in multiple myeloma: rationale for targeting and current therapeutic approaches. Leukemia. 2020;34(4):985-1005.
- Munshi NC, Anderson LD Jr, Shah N, et al. Idecabtagene vicleucel in relapsed and refractory multiple myeloma. N Engl J Med. 2021;384(8):705-716.
- 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):1002-1014.
- 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):1265-1274.
- Thompson JA, Schneider BJ, Brahmer J, et al. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Management of Immunotherapy-Related Toxicities (Version 1.2023). © 2023 National Comprehensive Cancer Network, Inc. To view the most recent and complete version of the NCCN Guidelines®, go online to NCCN.org.
- Rees JH. Management of immune effector cell-associated neurotoxicity syndrome (ICANS). In: Kröger N, Gribben J, Chabannon C, Yakoub-Agha I, Einsele H, eds. The EBMT/EHA CAR-T Cell Handbook [Internet]. Springer; 2022:141-145.
- 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):314-324.
- 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):625-638.
- 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.
- Beaupierre A, Kahle N, Lundberg R, Patterson A. Educating multidisciplinary care teams, patients, and caregivers on CAR T-cell therapy. J Adv Pract Oncol. 2019;10(Suppl 3):29-40.