CARVYKTI

CARVYKTI ® (ciltacabtagene autoleucel) is a BCMA-directed genetically modified autologous T cell immunotherapy. CARVYKTI is prepared from the patient's peripheral blood mononuclear cells, which are obtained via a standard leukapheresis procedure. The mononuclear cells are enriched for T cells and genetically modified ex vivo by transduction with a replication-incompetent lentiviral vector to express a CAR comprising an anti-BCMA targeting domain, which consists of two single-domain antibodies linked to a 4-1BB costimulatory domain and a CD3-zeta signaling domain. The transduced anti-BCMA CAR T cells are expanded in cell culture, washed, formulated into a suspension and cryopreserved. The product must pass a sterility test before release for shipping as a frozen suspension in a patient-specific infusion bag. The product is thawed and then infused back into the patient, where the anti-BCMA CAR T cells can recognize and eliminate BCMA-expressing target cells [see Dosage and Administration (2.2) , How Supplied/Storage and Handling (16) ]. In addition to T cells, CARVYKTI may contain Natural Killer (NK) cells. The formulation contains 5% dimethyl sulfoxide (DMSO).

CARVYKTI is indicated for the treatment of adult patients with relapsed or refractory multiple myeloma, who have received at least 1 prior line of therapy, including a proteasome inhibitor and an immunomodulatory agent, and are refractory to lenalidomide. CARVYKTI is a B-cell maturation antigen (BCMA)-directed genetically modified autologous T cell immunotherapy indicated for the treatment of adult patients with relapsed or refractory multiple myeloma who have received at least 1 prior line of therapy, including a proteasome inhibitor and an immunomodulatory agent, and are refractory to lenalidomide. ( 1 )

For autologous use only. For intravenous use only. Administer a lymphodepleting regimen of cyclophosphamide and fludarabine before infusion of CARVYKTI. ( 2.2 ) Do NOT use a leukodepleting filter. ( 2.2 ) Verify the patient's identity prior to infusion. ( 2.2 ) Premedicate with acetaminophen and an H1-antihistamine. ( 2.2 ) Avoid prophylactic use of systemic corticosteroids. ( 2.2 ) Confirm availability of tocilizumab prior to infusion. ( 2.2 , 5.2 ) Dosing of CARVYKTI is based on the number of chimeric antigen receptor (CAR)-positive viable T cells. ( 2.1 ) Recommended dose range is 0.5–1.0×10 6 CAR-positive viable T cells per kg of body weight, with a maximum dose of 1×10 8 CAR-positive viable T cells per single-dose infusion. ( 2.1 ) 2.1 Dose CARVYKTI is provided as a single dose for infusion containing a suspension of chimeric antigen receptor (CAR)-positive viable T cells in one infusion bag. The recommended dose range is 0.5–1.0×10 6 CAR-positive viable T cells per kg of body weight, with a maximum dose of 1×10 8 CAR-positive viable T cells per single infusion. 2.2 Administration CARVYKTI is for autologous use only. For intravenous use only. The patient's identity must match the patient identifiers on the CARVYKTI cassette and infusion bag. Do not infuse CARVYKTI if the information on the patient-specific labels does not match the intended patient. Preparing the Patient for CARVYKTI Infusion Confirm availability of CARVYKTI prior to starting the lymphodepleting chemotherapy regimen. Pretreatment Administer the lymphodepleting chemotherapy regimen: cyclophosphamide 300 mg/m 2 intravenously (IV) and fludarabine 30 mg/m 2 IV daily for 3 days. See the prescribing information of cyclophosphamide and fludarabine for information on dose adjustment in renal impairment. Lymphodepleting regimen must be delayed if a patient has serious adverse reactions from preceding bridging therapies (including clinically significant active infection, cardiac toxicity, and pulmonary toxicity) or active graft versus host disease in patient with prior allogeneic stem cell transplant. Consider repeating lymphodepleting regimen if CARVYKTI dosing is delayed by more than 14 days and patient has recovered from toxicity of the first lymphodepleting regimen. Administer CARVYKTI infusion 2 to 4 days after the completion of the lymphodepleting chemotherapy regimen. CARVYKTI infusion should be delayed if a patient has any of the following conditions: Clinically significant active infection or inflammatory disorders. Grade ≥3 non-hematologic toxicities of cyclophosphamide and fludarabine conditioning, except for Grade 3 nausea, vomiting, diarrhea, or constipation. CARVYKTI infusion should be delayed until resolution of these events to Grade ≤1. Premedication Administer the following pre-infusion medications to all patients 30 – 60 minutes prior to CARVYKTI infusion: Antipyretics (oral or intravenous acetaminophen 650 to 1000 mg). Antihistamine (oral or intravenous diphenhydramine 25 to 50 mg or equivalent). Avoid prophylactic use of systemic corticosteroids because their use may interfere with the activity of CARVYKTI. Receipt of CARVYKTI All sites approved for infusion will support required storage conditions for vapor phase of liquid nitrogen. CARVYKTI is shipped directly to the cell laboratory or clinical pharmacy associated with the infusion center in the vapor phase of a liquid nitrogen shipper. Confirm the patient's identity with the patient identifiers on the shipper. If the patient is not expected to be ready for same-day administration, before the shipper expires, transfer CARVYKTI to onsite vapor phase of liquid nitrogen storage. Preparation of CARVYKTI for Infusion Do not thaw the product until it is ready to be used. Coordinate the timing of CARVYKTI thaw and infusion. Confirm the infusion time in advance and adjust the start time for thaw so that CARVYKTI is available for infusion when the patient is ready. Once thawed, the CARVYKTI infusion must be completed within 2.5 hours at room/ambient temperature (20 °C to 25 °C). Prior to thawing the product, confirm that tocilizumab and emergency equipment are available prior to the infusion and during the recovery period. Confirm patient identity: Prior to CARVYKTI preparation, match the patient's identity with the patient identifiers on the CARVYKTI cassette. Do not remove the CARVYKTI infusion bag from the cassette if the information on the patient-specific label does not match the intended patient. Contact Janssen Biotech, Inc. at 1-800-526-7736 if there are any discrepancies between the labels and the patient identifiers. Once patient identification is confirmed, remove the CARVYKTI product bag from the cassette and check that the patient information on the cassette label matches the patient information on the bag label. Inspect the product bag for any breaches of container integrity, such as breaks or cracks before and after thawing. Do not administer if the bag is compromised, and contact Janssen Biotech, Inc. at 1-800-526-7736. Place the infusion bag inside a sealable plastic bag (preferably sterile) prior to thawing. Thaw CARVYKTI at 37 °C±2 °C using either a water bath or dry thaw method until there is no visible ice in the infusion bag. Total time from start of thaw until completion of thawing should be no more than 15 minutes. Remove the infusion bag from the sealable plastic bag and wipe dry. Gently mix the contents of the bag to disperse clumps of cellular material. If visible cell clumps remain, continue to gently mix the contents of the bag. Small clumps of cellular material should disperse with gentle manual mixing. Do not pre-filter into a different container, wash, spin down, or resuspend CARVYKTI in new media prior to infusion. Do not re-freeze or refrigerate thawed product. Administration For autologous infusion only. Do NOT use a leukocyte-depleting filter. Confirm that a minimum of two doses of tocilizumab and emergency equipment are available prior to infusion and during the recovery period. Central venous access may be utilized for the infusion of CARVYKTI and is encouraged in patients with poor peripheral access. Confirm the patient's identity with the patient identifiers on the infusion bag. Do not infuse CARVYKTI if the information on the patient-specific label does not match the intended patient. Prime the tubing of the infusion set with normal saline prior to infusion. Once thawed, administer the entire contents of the CARVYKTI bag by intravenous infusion within 2.5 hours using infusion sets fitted with an in-line filter. Gently mix the contents of the bag during CARVYKTI infusion to disperse cell clumps. After the entire content of the product bag is infused, flush the administration line, inclusive of the in-line filter, with normal saline with a volume equal or greater to the total hold up volume of the primary administration set used inclusive of the drip tube, to ensure that all product is delivered. CARVYKTI contains human blood cells that are genetically modified with replication-incompetent, self-inactivating, lentiviral vector. Follow universal precautions and local biosafety guidelines for handling and disposal of CARVYKTI to avoid potential transmission of infectious diseases. Monitoring After Infusion Monitor patients at least daily for 7 days following CARVYKTI infusion for signs and symptoms of cytokine release syndrome (CRS) and neurologic toxicities. Instruct patients to remain within proximity of a healthcare facility for at least 2 weeks following infusion. Advise patients to avoid driving for at least 2 weeks following infusion. 2.3 Management of Severe Adverse Reactions Cytokine Release Syndrome (CRS) Identify CRS based on clinical presentation [see Warnings and Precautions (5.2) ] . Evaluate for and treat other causes of fever, hypoxia and hypotension. Consider laboratory testing to monitor for disseminated intravascular coagulation, hematology parameters, as well as pulmonary, cardiac, renal, and hepatic function. If CRS is suspected, manage according to the recommendations in Table 1. Physicians may also consider management per current practice guidelines. Patients who experience CRS should be closely monitored for cardiac and other organ function until resolution of symptoms. Consider anti-seizure prophylaxis with levetiracetam in patients who experience CRS. Patients who experience Grade 2 or higher CRS (e.g., hypotension not responsive to fluids, or hypoxia requiring supplemental oxygenation) should be monitored with continuous telemetry and pulse oximetry. For severe or life-threatening CRS, consider intensive care unit level monitoring and supportive therapy. For CRS refractory to first line interventions such as tocilizumab or tocilizumab and corticosteroids, consider alternate treatment options (i.e., higher corticosteroid dose, alternative anti-cytokine agents, e.g., anti-IL1 and/or anti-TNFα, anti-T cell therapies). Refractory CRS is characterized by fevers, end-organ toxicity (e.g., hypoxia, hypotension) not improving within 12 hours of first line interventions or development of HLH/MAS. If concurrent neurologic toxicity is suspected during CRS, administer: Corticosteroids according to the more aggressive intervention based on the CRS and neurologic toxicity grades in Tables 1 and 2 Tocilizumab according to the CRS grade in Table 1 Anti-seizure medication according to the neurologic toxicity in Table 2 Table 1: CRS grading and management guidance CRS Grade Based on ASTCT 2019 grading system (Lee et.al, 2019), modified to include organ toxicity. Tocilizumab Refer to tocilizumab prescribing information for details. / Corticosteroids Continue corticosteroids use until the event is Grade 1 or less; taper steroids if total corticosteroid exposure is greater than 3 days. Grade 1 Temperature ≥38 °C Attributed to CRS. Fever may not always be present concurrently with hypotension or hypoxia, as it may be masked by interventions such as antipyretics or anti-cytokine therapy (e.g., tocilizumab or steroids). Absence of fever does not impact CRS management decision. In this case, CRS management is driven by hypotension and/or hypoxia and by the more severe symptom not attributable to any other cause. In patients with: Early onset of fever (if onset less than 72 hours after infusion) Tocilizumab 8 mg/kg intravenously (IV) over 1 hour (not to exceed 800 mg) may be considered. Corticosteroids: N/A Grade 2 Symptoms require and respond to moderate intervention. Temperature ≥38 °C with: Hypotension not requiring vasopressors, and/or, Hypoxia requiring oxygen via cannula or blow-by, or, Grade 2 organ toxicity. Organ toxicity grading based on National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0. Administer tocilizumab 8 mg/kg IV over 1 hour (not to exceed 800 mg). Repeat tocilizumab every 8 hours as needed if not responsive to intravenous fluids up to 1 liter or increasing supplemental oxygen. Consider dexamethasone 10 mg IV every 12–24 hours. If no improvement within 24 hours or rapid progression, repeat tocilizumab and escalate dose and frequency of dexamethasone (20 mg IV every 6 to 12 hours). If no improvement within 24 hours or continued rapid progression, switch to methylprednisolone 2 mg/kg IV every 12 hours. After 2 doses of tocilizumab, consider alternative anti-cytokine agents Monoclonal antibodies targeting cytokines may be considered based on institutional practice for unresponsive CRS. . Do not exceed 3 doses of tocilizumab in 24 hours, or 4 doses in total. Grade 3 Symptoms require and respond to aggressive intervention. Temperature ≥38 °C with: Hypotension requiring one vasopressor with or without vasopressin, and/or, Hypoxia requiring oxygen via high-flow nasal cannula Low-flow nasal cannula is ≤6 L/min; high-flow nasal cannula is >6 L/min. , facemask, non-rebreather mask, or Venturi mask, or, Grade 3 organ toxicity or Grade 4 transaminitis. Administer tocilizumab 8 mg/kg IV over 1 hour (not to exceed 800 mg). Repeat tocilizumab every 8 hours as needed if not responsive to intravenous fluids up to 1 liter or increasing supplemental oxygen. Consider dexamethasone 10 mg IV every 12 hours. If no improvement within 24 hours or rapid progression, repeat tocilizumab and escalate dose and frequency of dexamethasone (20 mg IV every 6 to 12 hours). If no improvement within 24 hours or continued rapid progression, switch to methylprednisolone 2 mg/kg IV every 12 hours. After 2 doses of tocilizumab, consider alternative anti-cytokine agents. Do not exceed 3 doses of tocilizumab in 24 hours, or 4 doses in total. Grade 4 Life-threatening symptoms. Requirements for ventilator support, continuous veno-venous hemodialysis (CVVHD). Temperature ≥38 °C with: Hypotension requiring multiple vasopressors (excluding vasopressin), and/or, Hypoxia requiring positive pressure (e.g., CPAP, BiPAP, intubation, and mechanical ventilation), or, Grade 4 organ toxicity (excluding transaminitis). Administer tocilizumab 8 mg/kg IV over 1 hour (not to exceed 800 mg). Repeat tocilizumab every 8 hours as needed if not responsive to intravenous fluids up to 1 liter or increasing supplemental oxygen. Administer dexamethasone 20 mg IV every 6 hours. After 2 doses of tocilizumab, consider alternative anti-cytokine agents . Do not exceed 3 doses of tocilizumab in 24 hours, or 4 doses in total. If no improvement within 24 hours, consider methylprednisolone (1–2 g IV, repeat every 24 hours if needed; taper as clinically indicated) or other immunosuppressants (e.g. other anti-T cell therapies). Neurologic Toxicities Monitor patients for signs and symptoms of neurologic toxicities (ICANS and other neurologic toxicities) (Table 2). Rule out other causes of neurologic signs or symptoms. Provide intensive care and supportive therapy for severe or life-threatening neurologic toxicities. Please see section 5.3 for non ICANS neurologic toxicities. If ICANS is suspected, manage according to the recommendations in Table 2. Physicians may also consider management per current practice guidelines. If concurrent CRS is suspected during the neurologic toxicity event, administer: Corticosteroids according to the more aggressive intervention based on the CRS and neurologic toxicity grades in Tables 1 and 2 Tocilizumab according to CRS grade in Table 1 Anti-seizure medication according to neurologic toxicity in Table 2 Table 2: Guideline for management of ICANS ICANS Grade ASTCT 2019 criteria for grading Neurologic Toxicity (Lee et.al, 2019). Corticosteroids Note: ICANS grade and management is determined by the most severe event (ICE score, level of consciousness, seizure, motor findings, raised ICP/cerebral edema), not attributable to any other cause. Grade 1 ICE score 7–9 If patient is arousable and able to perform Immune Effector Cell-Associated Encephalopathy (ICE) Assessment, assess: Orientation (oriented to year, month, city, hospital = 4 points); Naming (name 3 objects, e.g., point to clock, pen, button = 3 points); Following Commands (e.g., "show me 2 fingers" or "close your eyes and stick out your tongue" = 1 point); Writing (ability to write a standard sentence = 1 point); and Attention (count backwards from 100 by ten = 1 point). If patient is unarousable and unable to perform ICE Assessment (Grade 4 ICANS) = 0 points. or depressed level of consciousness: awakens spontaneously. Consider dexamethasone All references to dexamethasone administration are dexamethasone or equivalent. 10 mg IV every 12 to 24 hours for 2 to 3 days. Consider non-sedating, anti-seizure medicines (e.g., levetiracetam) for seizure prophylaxis. Grade 2 ICE score-3–6 or depressed level of consciousness: awakens to voice Administer dexamethasone 10 mg IV every 12 hours for 2–3 days, or longer for persistent symptoms. Consider steroid taper if total corticosteroid exposure is greater than 3 days. If no improvement after 24 hours or worsening of neurologic toxicity, increase the dose and/or frequency of dexamethasone up to a maximum of 20 mg IV every 6 hours. Consider non-sedating, anti-seizure medicines (e.g., levetiracetam) for seizure prophylaxis. Grade 3 ICE score-0–2 (If ICE score is 0, but the patient is arousable (e.g., awake with global aphasia) and able to perform assessment) or depressed level of consciousness: awakens only to tactile stimulus, or seizures, either: any clinical seizure, focal or generalized, that resolves rapidly, or non-convulsive seizures on EEG that resolve with intervention, or raised intracranial pressure (ICP): focal/local edema on neuroimaging Intracranial hemorrhage with or without associated edema is not considered a neurotoxicity feature and is excluded from ICANS grading. It may be graded according to NCI CTCAE v5.0. . Administer dexamethasone 10 mg–20 mg IV every 6 hours. If no improvement after 24 hours or worsening of neurologic toxicity, escalate dexamethasone dose to at least 20 mg IV every 6 hours, OR escalate to high-dose methylprednisolone (1–2 g/day, repeat every 24 hours if needed; taper as clinically indicated) Consider non-sedating, anti-seizure medicines (e.g., levetiracetam) for seizure prophylaxis. If cerebral edema is suspected, consider hyperventilation and hyperosmolar therapy. Give high-dose methylprednisolone (1–2 g, repeat every 24 hours if needed; taper as clinically indicated). Grade 4 ICE score-0 (Patient is unarousable and unable to perform ICE assessment) or depressed level of consciousness either: patient is unarousable or requires vigorous or repetitive tactile stimuli to arouse, or stupor or coma, or seizures, either: life-threatening prolonged seizure (>5 min), or repetitive clinical or electrical seizures without return to baseline in between, or motor findings Tremors and myoclonus associated with immune effector cell therapies may be graded according to NCI CTCAE v5.0, but they do not influence ICANS grading. : deep focal motor weakness such as hemiparesis or paraparesis, or raised ICP/cerebral edema, with signs/symptoms such as: diffuse cerebral edema on neuroimaging, or decerebrate or decorticate posturing, or cranial nerve VI palsy, or papilledema, or Cushing's triad Administer dexamethasone 20 mg IV every 6 hours. If no improvement after 24 hours or worsening of neurologic toxicity, escalate to high-dose methylprednisolone (1–2 g/day, repeated every 24 hours if needed; taper as clinically indicated). Consider non-sedating, anti-seizure medicines (e.g., levetiracetam) for seizure prophylaxis. If raised ICP/cerebral edema is suspected, consider hyperventilation and hyperosmolar therapy. Give high-dose methylprednisolone (1–2 g/day, repeat every 24 hours if needed; taper as clinically indicated), and consider neurology and/or neurosurgery consultation.

None. None ( 4 )

The most common nonlaboratory adverse reactions (incidence greater than 20%) are pyrexia, cytokine release syndrome, hypogammaglobulinemia, hypotension, musculoskeletal pain, fatigue, infections-pathogen unspecified, cough, chills, diarrhea, nausea, encephalopathy, decreased appetite, upper respiratory tract infection, headache, tachycardia, dizziness, dyspnea, edema, viral infections, coagulopathy, constipation, and vomiting. The most common Grade 3 or 4 laboratory adverse reactions (incidence greater than or equal to 50%) include lymphopenia, neutropenia, white blood cell decreased, thrombocytopenia, and anemia. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Janssen Biotech, Inc. at 1-800-526-7736 (1-800-JANSSEN) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety data described in the WARNINGS and PRECAUTIONS section reflect exposure to CARVYKTI in 285 patients with relapsed or refractory multiple myeloma: one randomized, open-label with 188 patients in CARTITUDE-4 and one single-arm, open-label study with 97 patients in CARTITUDE-1. CARTITUDE-4 The safety of CARVYKTI was evaluated in CARTITUDE-4, a randomized, open-label multicenter study, in which patients with relapsed and lenalidomide refractory multiple myeloma received CARVYKTI meeting the product specifications (N=188) or standard therapy (N=211) [see Clinical Studies (14) ] . Patients with known active or prior history of central nervous system involvement, patients who exhibit clinical signs of meningeal involvement of multiple myeloma and patients with a history of Parkinson's disease or other neurodegenerative disorder, were excluded from the trial. Patients received CARVYKTI at a median dose of 0.71×10 6 CAR-positive viable T-cells/kg (range: 0.41 to 1.08×10 6 cells/kg). The median age of the 188 participants was 62 years (range: 27 to 78 years); 40% were 65 years or older, and 57% were male; 76% were White, were 9% Hispanic or Latino, 8% were Asian, and 3% were Black. The Eastern Cooperative Oncology Group (ECOG) performance status at baseline was 0 in 56%, 1 in 44%. For the details about the study population, see Clinical Studies (14) . The most common nonlaboratory adverse reactions (≥20%) included pyrexia, CRS, hypogammaglobulinemia, musculoskeletal pain, fatigue, upper respiratory tract infection, diarrhea, viral infections, headache, hypotension, and nausea. Serious adverse reactions occurred in 34% of patients. The most common nonlaboratory serious adverse reactions (≥5%) were pneumonia (9%), viral infection (6%), CRS (6%), and cranial nerve palsies (5%). Table 3 summarizes the adverse reactions that occurred in at least 10% of patients treated with CARVYKTI. Table 3: Adverse reactions observed in at least 10% of patients treated with CARVYKTI (N=188) and standard therapy (N=208) in CARTITUDE-4 CARVYKTI N=188 CARVYKTI N=188 Standard Therapy N=208 Standard Therapy N=208 System Organ Class (SOC) Preferred term Any Grade (%) Grade 3 or higher (%) Any Grade (%) Grade 3 or higher (%) Gastrointestinal disorders - - - - Diarrhea Diarrhea includes Colitis, and Diarrhea. 27 3 27 2 Nausea 20 0 18 1 Constipation 10 0 21 1 General disorders and administrative site conditions - - - - Pyrexia 79 5 16 1 Fatigue Represents multiple related terms. 28 3 50 3 Edema Edema includes Face edema, Generalized edema, Localized edema, Edema peripheral, Periorbital edema, Peripheral swelling, Pulmonary edema, and Scrotal edema. 11 1 20 1 Pain 10 1 14 <1 Immune system disorders - - - - Hypogammaglobulinemia Hypogammaglobulinemia includes subjects with adverse event of hypogammaglobulinemia and/or laboratory IgG levels that fell below 500 mg/dL following CARVYKTI infusion or standard therapy. 94 9 72 <1 Cytokine release syndrome 78 3 <1 0 Infections and infestations - - - - Upper respiratory tract infection 25 1 40 5 Viral infection 23 4 31 6 Bacterial infection 15 6 17 4 Pneumonia 14 9 18 11 Metabolism and nutrition disorders - - - - Decreased appetite 10 0 5 0 Musculoskeletal and connective tissue disorders - - - - Musculoskeletal pain 34 2 47 4 Nervous system disorders - - - - Headache 23 0 13 0 Encephalopathy Encephalopathy includes Amnesia, Bradyphrenia, Confusional state, Depressed level of consciousness, Disturbance in attention, Immune effector cell-associated neurotoxicity syndrome, Lethargy, and Psychomotor retardation. 11 2 4 1 Respiratory, thoracic and mediastinal disorders - - - - Cough 15 0 18 0 Hypoxia 12 3 1 1 Vascular disorders - - - - Hypotension 23 4 3 0 Other clinically important adverse reactions that occurred in less than 10% of patients treated with CARVYKTI include the following: Blood and lymphatic system disorders : coagulopathy Represents multiple related terms. (5%), febrile neutropenia (2%), lymphocytosis (2%) Cardiac disorders : tachycardia (5%), cardiac arrhythmias(3%) Gastrointestinal disorders : abdominal pain (6%), vomiting (5%) General disorders and administration site conditions : chills (6%) Immune system disorders: HLH (1%) Infections and infestations: gastroenteritis (7%), sepsis (9%), urinary tract infection (5%), fungal infection (3%) Investigations : c-reactive protein increased (6%) Metabolism and nutrition disorders : hypophosphatemia (10%), hyperferritinemia (7%) Neoplasms benign, malignant, and unspecified (incl cysts and polyps) : hematologic malignancy Hematologic malignancy includes Myelodysplastic syndrome, Acute myeloid leukaemia and T-cell lymphoma (3%) Nervous system disorders : dizziness (9%), cranial nerve palsies (9%), motor dysfunction Motor dysfunction includes Bradykinesia, Coordination abnormal, Dysgraphia, Extrapyramidal disorder, Micrographia, Muscle spasms, Muscular weakness, and Parkinsonism (9%), peripheral neuropathy (7%), sleep disorder (6%), tremor (4%), aphasia (3%), ataxia (3%) Psychiatric disorders : delirium (2%), personality changes (2%) Renal and urinary disorders : renal failure (5%) Respiratory, thoracic and mediastinal disorders : dyspnea (10%) Skin and subcutaneous tissues : rash (7%) Vascular disorders : hemorrhage (9%), hypertension (7%), thrombosis (3%), capillary leak syndrome (1%) Laboratory Abnormalities Table 4 presents the most common Grade 3 or 4 laboratory abnormalities based on laboratory data, occurring in at least 10% of patients. Table 4: Grade 3 or 4 laboratory abnormalities in at least 10% of patients treated with CARVYKTI (N=188) and standard therapy (N=208) in CARTITUDE-4 CARVYKTI (N=188) Standard Therapy (N=208) Laboratory Abnormality Grade 3 or 4 (%) Grade 3 or 4 (%) Laboratory abnormalities graded using NCI Common Terminology Criteria for Adverse Events version 5.0. Laboratory abnormalities are sorted by decreasing frequency in the Grade column. Lymphocyte count decreased 99 62 Neutrophil count decreased 95 88 White blood cell decreased 94 69 Platelet count decreased 47 20 Hemoglobin decreased 34 17 Other clinically important Grade 3 or 4 laboratory abnormalities (based on laboratory data) that occurred in less than 10% of patients treated with CARVYKTI include gamma glutamyl transferase increased, fibrinogen decreased, aspartate aminotransferase increased, hypokalemia, alanine aminotransferase increased, hyponatremia, alkaline phosphatase increased, hypertriglyceridemia, hypomagnesemia, hypoalbuminemia, hypocalcemia, and blood bilirubin increased. CARTITUDE-1 The safety data described in this section reflect the exposure of 97 adult patients with relapsed/refractory multiple myeloma in the CARTITUDE-1 study (USA cohort) to CARVYKTI and includes 17 patients (18%) with manufacturing failures either because they received CARVYKTI that did not meet product release specifications or there were insufficient data to confirm product release specifications for CARVYKTI. Patients received CARVYKTI across a dose range of 0.51 to 0.95×10 6 CAR-positive viable T cells/kg body weight [see Clinical Studies (14) ] . Patients with a history of CNS disease (such as seizure or cerebrovascular ischemia) or requiring ongoing treatment with chronic immunosuppression were excluded. The median duration of follow-up was 18 months. The median age of the study population was 61 years (range: 43 to 78 years); 36% were 65 years or older, and 59% were men. The Eastern Cooperative Oncology Group (ECOG) performance status at baseline was 0 in 40%, 1 in 56%, and 2 in 4% of patients. Three of the patients treated with CARVYKTI had a creatinine clearance of <45 mL/min at baseline. For the details about the study population, see Clinical Studies (14) . The most common (greater or equal to 10%) Grade 3 or higher nonlaboratory adverse reactions were infections-pathogen unspecified (19%), pneumonia (13%), hematologic malignancy (10%) and hypotension (10%). The most common nonlaboratory adverse reactions (incidence greater than or equal to 20%) included pyrexia, CRS, hypogammaglobulinemia, hypotension, musculoskeletal pain, fatigue, infections of unspecified pathogen, cough, chills, diarrhea, nausea, encephalopathy, decreased appetite, upper respiratory tract infection, headache, tachycardia, dizziness, dyspnea, edema, viral infections, coagulopathy, constipation, and vomiting. Serious adverse reactions occurred in 55% of patients. The most common non-laboratory (greater than or equal to 5%) serious adverse reactions included CRS (21%), sepsis (7%), encephalopathy (10%), and pneumonia (8%). Fatal adverse reactions occurred in 9% of patients. Table 5 summarizes the adverse reactions that occurred in at least 10% of patients treated with CARVYKTI. Table 5: Adverse reactions observed in at least 10% of patients treated with CARVYKTI in CARTITUDE-1 (N=97) System Organ Class (SOC) Preferred term Any Grade (%) Grade 3 or higher (%) Blood and lymphatic system disorders - - Coagulopathy Coagulopathy includes Activated partial thromboplastin time prolonged, Coagulopathy, Disseminated intravascular coagulation, Hypofibrinogenemia, International normalized ratio increased, and Prothrombin time prolonged. 22 2 Febrile Neutropenia 10 9 Cardiac disorders - - Tachycardia Represents multiple related terms 27 1 Gastrointestinal disorders - - Diarrhea Diarrhea includes Colitis and Diarrhea. 33 1 Nausea 31 1 Constipation 22 0 Vomiting 20 0 General disorders and administrative site conditions - - Pyrexia 96 5 Fatigue 47 7 Chills 33 0 Edema Edema includes Face edema, Generalized edema, Localized edema, Edema peripheral, Periorbital edema, Peripheral swelling, Pulmonary edema, and Scrotal edema. 23 0 Immune system disorders - - Cytokine release syndrome 95 5 Hypogammaglobulinemia Hypogammaglobulinemia includes subjects with adverse event of hypogammaglobulinemia and/or laboratory IgG levels that fell below 500 mg/dL following CARVYKTI infusion. 93 2 Infections and infestations - - Infections-pathogen unspecified 41 19 Upper respiratory tract infection 28 3 Viral infections 23 7 Pneumonia 14 13 Sepsis 10 7 Metabolism and nutrition disorders - - Decreased appetite 29 1 Musculoskeletal and connective tissue disorders - - Musculoskeletal pain 48 2 Nervous system disorders - - Encephalopathy Encephalopathy includes Amnesia, Bradyphrenia, Confusional state, Depressed level of consciousness, Disturbance in attention, Encephalopathy, Immune effector cell-associated neurotoxicity syndrome, Lethargy, Memory impairment, Mental impairment, Mental status changes, Noninfective encephalitis, and Somnolence. 30 6 Headache 27 0 Dizziness 23 1 Motor dysfunction Motor dysfunction includes Motor dysfunction, Muscle spasms, Muscle tightness, Muscular weakness, and Myoclonus. 16 3 Psychiatric disorders - - Insomnia 13 0 Respiratory, thoracic and mediastinal disorders - - Cough 39 0 Dyspnea Dyspnea includes Acute respiratory failure, Dyspnea, Dyspnea exertional, Respiratory failure, and Tachypnea. 23 3 Nasal congestion 15 0 Hypoxia 12 4 Neoplasms benign, malignant, and unspecified (incl cysts and polyps) - - Hematologic malignancy Hematologic malignancy includes Myelodysplastic syndrome and Acute myeloid leukemia. 10 10 Vascular disorders - - Hypotension 51 10 Hypertension 19 6 Hemorrhage Hemorrhage includes Conjunctival hemorrhage, Contusion, Ecchymosis, Epistaxis, Eye contusion, Hematochezia, Hemoptysis, Infusion site hematoma, Oral contusion, Petechiae, Post procedural hemorrhage, Pulmonary hemorrhage, Retinal hemorrhage, and Subdural hematoma. 16 4 Other clinically important adverse reactions that occurred in less than 10% of patients treated with CARVYKTI include the following: Cardiac disorders : cardiac arrhythmias Represents multiple related terms (8%), chest pain (7%) Eye disorders : diplopia (1%) Gastrointestinal disorders : dysphagia (1%) Immune system disorders: HLH (1%), hypersensitivity reaction (5%) Infections and Infestations: bacterial infections (9%), urinary tract infection (4.1%) Injury, Poisoning and Procedural complications : fall (3.1%) Metabolism and Nutrition Disorders : tumor lysis syndrome (1%) Musculoskeletal and Connective tissue disorders : posture abnormal (1%) Nervous system disorders : aphasia (8%), ataxia (8%), peripheral neuropathy (7%), tremor (6%), parkinsonism (4.1%), micrographia (4.1%), dysgraphia (3.1%), reduced facial expression (3.1%), cranial nerve palsies (3.1%), bradykinesia (2.1%), paresis (1%), cogwheel rigidity (1%), cerebrovascular accident (1%), seizure (1%), slow speech (1%), nystagmus (1%) Psychiatric disorders : delirium (5%), depression (4.1%), psychomotor retardation (1%) Renal and urinary disorders : renal failure (7%) Skin and subcutaneous tissues : rash (8%) Vascular Disorders : thrombosis (5%) Laboratory Abnormalities Table 6 presents the most common Grade 3 or 4 laboratory abnormalities based on laboratory data, occurring in at least 10% of patients. Table 6: Grade 3 or 4 laboratory abnormalities in at least 10% of patients treated with CARVYKTI in CARTITUDE-1 (N=97) Laboratory Abnormality Grade 3 or 4 (%) Laboratory abnormalities graded using NCI Common Terminology Criteria for Adverse Events version 5.0. Laboratory abnormalities are sorted by decreasing frequency in the Grade column. Lymphopenia 99 Neutropenia 98 White blood cell decreased 98 Anemia 72 Thrombocytopenia 63 Aspartate aminotransferase increased 21 Other clinically important Grade 3 or 4 laboratory abnormalities (based on laboratory data) that occurred in less than 10% of patients treated with CARVYKTI include the following: fibrinogen decreased, hypoalbuminemia, alanine aminotransferase increased, hyponatremia, hypocalcemia, gamma glutamyl transferase increased, alkaline phosphatase increased, hypokalemia, blood bilirubin increased. 6.2 Postmarketing Experience Because adverse events to marketed products are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to product exposure. The following adverse events have been identified during postmarketing use of CARVYKTI. Neoplasms: T cell malignancies including T-cell lymphoma of the gastrointestinal tract (including fatal cases). Gastrointestinal disorders: immune effector cell-associated enterocolitis and gastrointestinal perforation (including fatal cases) [see Warnings and Precautions (5.9) ] . Immune System disorders: infusion related reactions. Infections and infestations: John Cunningham (JC) virus progressive multifocal leukoencephalopathy (including fatal cases) [see Warnings and Precautions (5.6) ].

HIV and the lentivirus used to make CARVYKTI have limited, short spans of identical genetic material (RNA). Therefore, some commercial HIV nucleic acid tests (NATs) may yield false-positive results in patients who have received CARVYKTI.

Store and transport below -120 °C, e.g., in a container for cryogenic storage in the vapor phase of liquid nitrogen. Store CARVYKTI in the original packaging containing the cassette protecting the infusion bag. Thaw CARVYKTI prior to infusion [see Dosage and Administration (2) ] .