CARVYKTI

WARNING: CYTOKINE RELEASE SYNDROME, NEUROLOGIC TOXICITIES, HLH/MAS, PROLONGED and RECURRENT CYTOPENIA, and SECONDARY HEMATOLOGICAL MALIGNANCIES Cytokine Release Syndrome (CRS), including fatal or life-threatening reactions, occurred in patients following treatment with CARVYKTI. Do not administer CARVYKTI to patients with active infection or inflammatory disorders. Treat severe or life-threatening CRS with tocilizumab or tocilizumab and corticosteroids [see Dosage and Administration (2.2 , 2.3) , Warnings and Precautions (5.2) ] . Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS), which may be fatal or life-threatening, occurred following treatment with CARVYKTI, including before CRS onset, concurrently with CRS, after CRS resolution, or in the absence of CRS. Monitor for neurologic events after treatment with CARVYKTI. Provide supportive care and/or corticosteroids as needed [see Dosage and Administration (2.2 , 2.3) , Warnings and Precautions (5.3) ] . Parkinsonism and Guillain-Barré syndrome (GBS) and their associated complications resulting in fatal or life-threatening reactions have occurred following treatment with CARVYKTI [see Warnings and Precautions (5.3) ] . Hemophagocytic Lymphohistiocytosis/Macrophage Activation Syndrome (HLH/MAS), including fatal and life-threatening reactions, occurred in patients following treatment with CARVYKTI. HLH/MAS can occur with CRS or neurologic toxicities [see Warnings and Precautions (5.4) ]. Prolonged and/or recurrent cytopenias with bleeding and infection and requirement for stem cell transplantation for hematopoietic recovery occurred following treatment with CARVYKTI [see Warnings and Precautions (5.5) ] . Immune Effector Cell-associated Enterocolitis (IEC-EC), including fatal or life-threatening reactions, occurred following treatment with CARVYKTI [see Warnings and Precautions (5.9) ]. Secondary hematological malignancies, including myelodysplastic syndrome and acute myeloid leukemia, have occurred in patients following treatment with CARVYKTI. T-cell malignancies have occurred following treatment of hematologic malignancies with BCMA- and CD19-directed genetically modified autologous T-cell immunotherapies, including CARVYKTI [see Warnings and Precautions (5.10) ] . WARNING: CYTOKINE RELEASE SYNDROME, NEUROLOGIC TOXICITIES, HLH/MAS, PROLONGED and RECURRENT CYTOPENIA, and SECONDARY HEMATOLOGICAL MALIGNANCIES See full prescribing information for complete boxed warning. Cytokine Release Syndrome (CRS), including fatal or life-threatening reactions, occurred in patients following treatment with CARVYKTI. Do not administer CARVYKTI to patients with active infection or inflammatory disorders. Treat severe or life-threatening CRS with tocilizumab or tocilizumab and corticosteroids. ( 2.2 , 2.3 , 5.2 ) Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS), which may be fatal or life-threatening, occurred following treatment with CARVYKTI, including before CRS onset, concurrently with CRS, after CRS resolution, or in the absence of CRS. Monitor for neurologic events after treatment with CARVYKTI. Provide supportive care and/or corticosteroids as needed. ( 2.2 , 2.3 , 5.3 ) Parkinsonism and Guillain-Barré syndrome and their associated complications resulting in fatal or life-threatening reactions have occurred following treatment with CARVYKTI. ( 5.3 ) Hemophagocytic Lymphohistiocytosis/Macrophage Activation Syndrome (HLH/MAS), including fatal and life-threatening reactions, occurred in patients following treatment with CARVYKTI. HLH/MAS can occur with CRS or neurologic toxicities. ( 5.4 ) Prolonged and/or recurrent cytopenias with bleeding and infection and requirement for stem cell transplantation for hematopoietic recovery occurred following treatment with CARVYKTI. ( 5.5 ) Immune Effector Cell-associated Enterocolitis (IEC-EC), including fatal or life-threatening reactions, occurred following treatment with CARVYKTI. ( 5.9 ) Secondary hematological malignancies, including myelodysplastic syndrome and acute myeloid leukemia, have occurred following treatment with CARVYKTI. T-cell malignancies have occurred following treatment of hematologic malignancies with BCMA- and CD19-directed genetically modified autologous T-cell immunotherapies, including CARVYKTI. ( 5.10 )

5 WARNINGS AND PRECAUTIONS Prolonged and Recurrent Cytopenias : Patients may exhibit ≥Grade 3 cytopenias following CARVYKTI infusion. One or more recurrences of Grade 3 or higher cytopenias may occur after partial or complete recovery of cytopenias. Monitor blood counts prior to and after CARVYKTI infusion. Prolonged neutropenia has been associated with increased risk of infection. ( 5.5 ) Infections : Monitor patients for signs and symptoms of infection; treat appropriately. ( 5.6 ) Hypogammaglobulinemia : Monitor and consider immunoglobulin replacement therapy. ( 5.7 ) Hypersensitivity Reactions : Hypersensitivity reactions have occurred. Monitor for hypersensitivity reactions during infusion. ( 5.8 ) Immune Effector Cell-associated Enterocolitis: Patients may exhibit prolonged and severe diarrhea in the months following CARVYKTI infusion. Monitor for signs and symptoms of IEC-Enterocolitis after CARVYKTI infusion and manage per institutional guidelines. ( 5.9 ) Secondary Malignancies : Secondary hematological malignancies, including myelodysplastic syndrome and acute myeloid leukemia, have occurred. T-cell malignancies have occurred following treatment of hematologic malignancies with BCMA- and CD19-directed genetically modified autologous T-cell immunotherapies, including CARVYKTI. In the event that a secondary malignancy occurs after treatment with CARVYKTI, contact Janssen Biotech, Inc. at 1-800-526-7736. ( 5.10 ) 5.1 Increased Early Mortality In CARTITUDE-4, a randomized (1:1), controlled trial, there was a numerically higher percentage of early deaths in patients randomized to the CARVYKTI treatment arm compared to the control arm. Among patients with deaths occurring within the first 10 months from randomization, a greater proportion (29/208; 14%) occurred in the CARVYKTI arm compared to (25/211; 12%) in the control arm [see Clinical Studies (14) ]. Of the 29 deaths that occurred in the CARVYKTI arm within the first 10 months of randomization, 10 deaths occurred prior to CARVYKTI infusion, and 19 deaths occurred after CARVYKTI infusion. Of the 10 deaths that occurred prior to CARVYKTI infusion, all occurred due to disease progression, and none occurred due to adverse events. Of the 19 deaths that occurred after CARVYKTI infusion, 3 occurred due to disease progression, and 16 occurred due to adverse events. The most common adverse events were due to infection (n=12). 5.2 Cytokine Release Syndrome Cytokine release syndrome (CRS), including fatal or life-threatening reactions, occurred following treatment with CARVYKTI. Among patients receiving CARVYKTI for relapsed or refractory multiple myeloma in the CARTITUDE-1 and CARTITUDE-4 studies (N=285), CRS occurred in 84% (238/285), including ≥ Grade 3 CRS (ASTCT 2019) in 4% (11/285) of patients. The median time to onset of CRS, any grade, was 7 days (range: 1 to 23 days). Cytokine release syndrome resolved in 82% with a median duration of 4 days (range: 1 to 97 days). The most common manifestations of CRS in all patients combined (≥ 10%) included fever (84%), hypotension (29%) and aspartate aminotransferase increased (11%). Serious events that may be associated with CRS include pyrexia, hemophagocytic lymphohistiocytosis, respiratory failure, disseminated intravascular coagulation, capillary leak syndrome, and supraventricular and ventricular tachycardia [see Adverse Reactions (6.1) ]. Cytokine release syndrome occurred in 78% of patients in CARTITUDE-4 (3% Grade 3 to 4) and in 95% of patients in CARTITUDE-1 (4% Grade 3 to 4). Identify CRS based on clinical presentation. Evaluate for and treat other causes of fever, hypoxia, and hypotension. CRS has been reported to be associated with findings of HLH/MAS, and the physiology of the syndromes may overlap. HLH/MAS is a potentially life-threatening condition. In patients with progressive symptoms of CRS or refractory CRS despite treatment, evaluate for evidence of HLH/MAS [see Warnings and Precautions (5.4) ]. Confirm that a minimum of two doses of tocilizumab are available prior to infusion of CARVYKTI. Of the 285 patients who received CARVYKTI in clinical trials, 53% (150/285) patients received tocilizumab; 35% (100/285) received a single dose, while 18% (50/285) received more than 1 dose of tocilizumab. Overall, 14% (39/285) of patients received at least one dose of corticosteroids for treatment of CRS. Monitor patients at least daily for 7 days following CARVYKTI infusion for signs and symptoms of CRS. Monitor patients for signs or symptoms of CRS for at least 2 weeks after infusion. At the first sign of CRS, immediately institute treatment with supportive care, tocilizumab, or tocilizumab and corticosteroids, as indicated in Table 1 [see Dosage and Administration (2.3) ] . Counsel patients to seek immediate medical attention should signs or symptoms of CRS occur at any time [see Patient Counseling Information (17) ]. 5.3 Neurologic Toxicities Neurologic toxicities, which may be severe, life-threatening or fatal, occurred following treatment with CARVYKTI. Neurologic toxicities included ICANS, neurologic toxicity with signs and symptoms of parkinsonism, GBS, immune mediated myelitis, peripheral neuropathies and cranial nerve palsies. Counsel patients on the signs and symptoms of these neurologic toxicities, and on the delayed nature of onset of some of these toxicities. Instruct patients to seek immediate medical attention for further assessment and management if signs or symptoms of any of these neurologic toxicities occur at any time [see Patient Counseling Information (17) ] . Among patients receiving CARVYKTI in the CARTITUDE-1 and CARTITUDE-4 studies for relapsed and refractory multiple myeloma, one or more neurologic toxicities occurred in 24% (69/285), including ≥ Grade 3 cases in 7% (19/285) of patients. The median time to onset was 10 days (range: 1 to 101) with 63/69 (91%) of cases developing by 30 days. Neurologic toxicities resolved in 72% (50/69) of patients with a median duration to resolution of 23 days (range: 1 to 544). Of patients developing neurotoxicity, 96% (66/69) also developed CRS. Subtypes of neurologic toxicities included ICANS in 13%, peripheral neuropathy in 7%, cranial nerve palsy in 7%, parkinsonism in 3%, and immune mediated myelitis in 0.4% of the patients [see Adverse Reactions (6.1) ] . Immune Effector Cell-associated Neurotoxicity Syndrome (ICANS) Patients receiving CARVYKTI may experience fatal or life-threatening ICANS following treatment with CARVYKTI, including before CRS onset, concurrently with CRS, after CRS resolution, or in the absence of CRS. Among patients receiving CARVYKTI in the CARTITUDE-1 and CARTITUDE-4 studies, ICANS occurred in 13% (36/285), including Grade ≥ 3 in 2% (6/285) of the patients. The median time to onset of ICANS was 8 days (range: 1 to 28 days). ICANS resolved in 30 of 36 (83%) of patients with a median time to resolution of 3 days (range: 1 to 143 days). The median duration of ICANS was 6 days (range: 1 to 1229 days) in all patients including those with ongoing neurologic events at the time of death or data cut off. Of patients with ICANS 97% (35/36) had CRS. The onset of ICANS occurred during CRS in 69% of patients, before and after the onset of CRS in 14% of patients respectively. Immune Effector Cell-associated Neurotoxicity Syndrome occurred in 7% of patients in CARTITUDE-4 (0.5% Grade 3) and in 23% of patients in CARTITUDE-1 (3% Grade 3). The most frequent ≥2% manifestations of ICANS included encephalopathy (12%), aphasia (4%), headache (3%), motor dysfunction (3%), ataxia (2%) and sleep disorder (2%) [see Adverse Reactions (6.1) ] . Monitor patients at least daily for 7 days following CARVYKTI infusion for signs and symptoms of ICANS. Rule out other causes of ICANS symptoms. Monitor patients for signs or symptoms of ICANS for at least 2 weeks after infusion and treat promptly. Neurologic toxicity should be managed with supportive care and/or corticosteroids as needed [see Dosage and Administration (2.3) ] . Advise patients to avoid driving for at least 2 weeks following infusion. Parkinsonism Neurologic toxicity with parkinsonism has been reported in clinical trials of CARVYKTI. Among patients receiving CARVYKTI in the CARTITUDE-1 and CARTITUDE-4 studies, parkinsonism occurred in 3% (8/285), including Grade ≥ 3 in 2% (5/285) of the patients. The median time to onset of parkinsonism was 56 days (range: 14 to 914 days). Parkinsonism resolved in 1 of 8 (13%) of patients with a median time to resolution of 523 days. The median duration of parkinsonism was 243.5 days (range: 62 to 720 days) in all patients including those with ongoing neurologic events at the time of death or data cut off. The onset of parkinsonism occurred after CRS for all patients and after ICANS for 6 patients. Parkinsonism occurred in 1% of patients in CARTITUDE-4 (no Grade 3 to 4) and in 6% of patients in CARTITUDE-1 (4% Grade 3 to 4). The manifestations of parkinsonism included movement disorders, cognitive impairment, and personality changes [see Adverse Reactions (6.1) ] . Monitor patients for signs and symptoms of parkinsonism that may be delayed in onset and managed with supportive care measures. There is limited efficacy information with medications used for the treatment of Parkinson's disease for the improvement or resolution of parkinsonism symptoms following CARVYKTI treatment. Guillain-Barré Syndrome A fatal outcome following GBS occurred following treatment with CARVYKTI despite treatment with intravenous immunoglobulins. Symptoms reported include those consistent with Miller-Fisher variant of GBS, encephalopathy, motor weakness, speech disturbances, and polyradiculoneuritis. Monitor for GBS. Evaluate patients presenting with peripheral neuropathy for GBS. Consider treatment of GBS with supportive care measures and in conjunction with immunoglobulins and plasma exchange, depending on severity of GBS. Immune Mediated Myelitis Grade 3 myelitis occurred 25 days following treatment with CARVYKTI in CARTITUDE-4 in a patient who received CARVYKTI as subsequent therapy. Symptoms reported included hypoesthesia of the lower extremities and the lower abdomen with impaired sphincter control. Symptoms improved with the use of corticosteroids and intravenous immune globulin. Myelitis was ongoing at the time of death from other cause [see Adverse Reactions (6.1) ] . Peripheral Neuropathy Peripheral neuropathy occurred following treatment with CARVYKTI. Among patients receiving CARVYKTI in the CARTITUDE-1 and CARTITUDE-4 studies, peripheral neuropathy occurred in 7% (21/285), including Grade ≥ 3 in 1% (3/285) of the patients. The median time to onset of peripheral neuropathy was 57 days (range: 1 to 914 days). Peripheral neuropathy resolved in 11 of 21 (52%) of patients with a median time to resolution of 58 days (range: 1 to 215 days). The median duration of peripheral neuropathy was 149.5 days (range: 1 to 692 days) in all patients including those with ongoing neurologic events at the time of death or data cut off [see Adverse Reactions (6.1) ] . Peripheral neuropathies occurred in 7% of patients in CARTITUDE-4 (0.5% Grade 3 to 4) and in 7% of patients in CARTITUDE-1 (2% Grade 3 to 4). Monitor patients for signs and symptoms of peripheral neuropathies. Patients who experience peripheral neuropathy may also experience cranial nerve palsies or GBS. Cranial Nerve Palsies Cranial nerve palsies occurred following treatment with CARVYKTI. Among patients receiving CARVYKTI in the CARTITUDE-1 and CARTITUDE-4 studies, cranial nerve palsies occurred in 7% (19/285), including Grade ≥ 3 in 1% (1/285) of the patients. The median time to onset of cranial nerve palsies was 21 days (range: 17 to 101 days). Cranial nerve palsies resolved in 17 of 19 (89%) of patients with a median time to resolution of 66 days (range: 1 to 209 days). The median duration of cranial nerve palsies was 70 days (range: 1 to 262 days) in all patients including those with ongoing neurologic events at the time of death or data cut off [see Adverse Reactions (6.1) ] . Cranial nerve palsies occurred in 9% of patients in CARTITUDE-4 (1% Grade 3 to 4) and in 3% of patients in CARTITUDE-1 (1% Grade 3 to 4). The most frequent cranial nerve affected was the 7 th cranial nerve. Additionally, cranial nerves III, V, and VI have been reported to be affected. Monitor patients for signs and symptoms of cranial nerve palsies. Consider management with systemic corticosteroids, depending on the severity and progression of signs and symptoms. 5.4 Hemophagocytic Lymphohistiocytosis (HLH)/Macrophage Activation Syndrome (MAS) Among patients receiving CARVYKTI in the CARTITUDE-1 and CARTITUDE-4 studies, HLH/MAS occurred in 1% (3/285) of patients. All events of HLH/MAS had onset within 99 days of receiving CARVYKTI, with a median onset of 10 days (range: 8 to 99 days) and all occurred in the setting of ongoing or worsening CRS. The manifestations of HLH/MAS included hyperferritinemia, hypotension, hypoxia with diffuse alveolar damage, coagulopathy and hemorrhage, cytopenia and multi-organ dysfunction, including renal dysfunction and respiratory failure. Patients who develop HLH/MAS have an increased risk of severe bleeding. Monitor hematologic parameters in patients with HLH/MAS and transfuse per institutional guidelines. Fatal cases of HLH/MAS occurred following treatment with CARVYKTI [see Adverse Reactions (6.1) ]. HLH is a life-threatening condition with a high mortality rate if not recognized and treated early. Treatment of HLH/MAS should be administered per institutional standards. 5.5 Prolonged and Recurrent Cytopenias Patients may exhibit prolonged and recurrent cytopenias following lymphodepleting chemotherapy and CARVYKTI infusion. Among patients receiving CARVYKTI in the CARTITUDE-1 and CARTITUDE-4 studies, Grade 3 or higher cytopenias not resolved by day 30 following CARVYKTI infusion occurred in 62% (176/285) of the patients and included thrombocytopenia 33% (94/285), neutropenia 27% (76/285), lymphopenia 24% (67/285) and anemia 2% (6/285). After Day 60 following CARVYKTI infusion 22%, 20%, 5%, and 6% of patients had a recurrence of Grade 3 or 4 lymphopenia, neutropenia, thrombocytopenia, and anemia respectively, after initial recovery of their Grade 3 or 4 cytopenia. Seventy-seven percent (219/285) of patients had one, two or three or more recurrences of Grade 3 or 4 cytopenias after initial recovery of Grade 3 or 4 cytopenia. Sixteen and 25 patients had Grade 3 or 4 neutropenia and thrombocytopenia, respectively, at the time of death [see Adverse Reactions (6.1) ]. Monitor blood counts prior to and after CARVYKTI infusion. Manage cytopenias with growth factors and blood product transfusion support according to local institutional guidelines. 5.6 Infections CARVYKTI should not be administered to patients with active infection or inflammatory disorders. Severe, life-threatening, or fatal infections, occurred in patients after CARVYKTI infusion. Among patients receiving CARVYKTI in the CARTITUDE-1 and CARTITUDE-4 studies, infections occurred in 57% (163/285), including ≥ Grade 3 in 24% (69/285) of patients. Grade 3 or 4 infections with an unspecified pathogen occurred in 12%, viral infections in 6%, bacterial infections in 5%, and fungal infections in 1% of patients. Overall, 5% (13/285) of patients had Grade 5 infections, 2.5% of which were due to COVID-19. Patients treated with CARVYKTI had an increased rate of fatal COVID-19 infections compared to the standard therapy arm [see Adverse Reactions (6.1) ]. Monitor patients for signs and symptoms of infection before and after CARVYKTI infusion and treat patients appropriately. Administer prophylactic, pre-emptive and/or therapeutic antimicrobials according to the standard institutional guidelines. Febrile neutropenia was observed in 5% of patients after CARVYKTI infusion and may be concurrent with CRS. In the event of febrile neutropenia, evaluate for infection and manage with broad-spectrum antibiotics, fluids and other supportive care, as medically indicated. Counsel patients on the importance of prevention measures. Follow institutional guidelines for the vaccination and management of immunocompromised patients with COVID-19. Viral Reactivation Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure and death, can occur in patients with hypogammaglobulinemia. Perform screening for Cytomegalovirus (CMV), HBV, hepatitis C virus (HCV), and human immunodeficiency virus (HIV) or any other infectious agents if clinically indicated in accordance with clinical guidelines before collection of cells for manufacturing. Consider antiviral therapy to prevent viral reactivation per local institutional guidelines/clinical practice. Reactivation of John Cunningham (JC) virus, leading to progressive multifocal leukoencephalopathy (PML), including cases with fatal outcomes, have been reported following treatment with CARVYKTI [see Adverse Reactions (6.2) ]. Perform appropriate diagnostic evaluations in patients with neurological adverse events. 5.7 Hypogammaglobulinemia Hypogammaglobulinemia can occur in patients receiving treatment with CARVYKTI. Among patients receiving CARVYKTI in the CARTITUDE-1 and CARTITUDE-4 studies, hypogammaglobulinemia adverse event was reported in 36% (102/285) of patients; laboratory IgG levels fell below 500 mg/dL after infusion in 93% (265/285) of patients. Hypogammaglobulinemia either as an adverse reaction or laboratory IgG level below 500 mg/dL, after infusion occurred in 94% (267/285) of patients treated. Fifty six percent (161/285) of patients received intravenous immunoglobulin (IVIG) post CARVYKTI for either an adverse reaction or prophylaxis [see Adverse Reactions (6.1) ] . Monitor immunoglobulin levels after treatment with CARVYKTI and administer IVIG for IgG <400 mg/dL. Manage per local institutional guidelines, including infection precautions and antibiotic or antiviral prophylaxis. Use of Live Vaccines The safety of immunization with live viral vaccines during or following CARVYKTI treatment has not been studied. Vaccination with live virus vaccines is not recommended for at least 6 weeks prior to the start of lymphodepleting chemotherapy, during CARVYKTI treatment, and until immune recovery following treatment with CARVYKTI. 5.8 Hypersensitivity Reactions Hypersensitivity reactions occurred following treatment with CARVYKTI. Among patients receiving CARVYKTI in the CARTITUDE-1 and CARTITUDE-4 studies, hypersensitivity reactions occurred in 5% (13/285), all of which were ≤ Grade 2. Manifestations of hypersensitivity reactions included flushing, chest discomfort, tachycardia, wheezing, tremor, burning sensation, non-cardiac chest pain, and pyrexia. Serious hypersensitivity reactions, including anaphylaxis, may be due to the dimethyl sulfoxide (DMSO) in CARVYKTI. Patients should be carefully monitored for 2 hours after infusion for signs and symptoms of severe reaction. Treat promptly and manage patients appropriately according to the severity of the hypersensitivity reaction. 5.9 Immune Effector Cell-associated Enterocolitis Immune effector cell-associated enterocolitis (IEC-EC) has occurred in patients treated with CARVYKTI [see Adverse Reactions (6.2) ]. Manifestations include severe or prolonged diarrhea, abdominal pain and weight loss requiring parenteral nutrition. IEC-EC has been associated with fatal outcome from perforation or sepsis. Manage according to institutional guidelines including referral to gastroenterology and infectious disease specialists. In cases of refractory IEC-EC, consider additional workup to exclude alternative etiologies, including T-cell lymphoma of the GI tract, which has been reported in the postmarketing setting [see Warnings and Precautions (5.10) and Adverse Reactions (6.2) ]. 5.10 Secondary Malignancies Patients treated with CARVYKTI may develop secondary malignancies. Among patients receiving CARVYKTI in the CARTITUDE-1 and CARTITUDE-4 studies, myeloid neoplasms occurred in 5% (13/285) of patients (9 cases of myelodysplastic syndrome, 3 cases of acute myeloid leukemia, and 1 case of myelodysplastic syndrome followed by acute myeloid leukemia). The median time to onset of myeloid neoplasms was 447 days (range: 56 to 870 days) after treatment with CARVYKTI. Ten of these 13 patients died following the development of myeloid neoplasms; 2 of the 13 cases of myeloid neoplasm occurred after initiation of subsequent antimyeloma therapy. Cases of myelodysplastic syndrome and acute myeloid leukemia have also been reported in the post marketing setting. T-cell malignancies have occurred following treatment of hematologic malignancies with BCMA- and CD19-directed genetically modified autologous T-cell immunotherapies, including CARVYKTI. Mature T-cell malignancies, including CAR-positive tumors, may present as soon as weeks following infusions, and may include fatal outcomes [see Boxed Warning , Adverse Reactions (6.1 , 6.2) ] . Monitor life-long for secondary malignancies. In the event that a secondary malignancy occurs, contact Janssen Biotech, Inc. at 1-800-526-7736 for reporting and to obtain instructions on collection of patient samples.

6 ADVERSE REACTIONS 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) ].

<table width="85%"><caption>Table 3: Adverse reactions observed in at least 10% of patients treated with CARVYKTI (N=188) and standard therapy (N=208) in CARTITUDE-4</caption><col width="36%" align="left" valign="top"/><col width="16%" align="center" valign="top"/><col width="16%" align="center" valign="top"/><col width="16%" align="center" valign="top"/><col width="16%" align="center" valign="top"/><thead><tr><th align="center" styleCode="Lrule Rrule"/><th align="center" styleCode="Rrule">CARVYKTI N=188 </th><th align="center" styleCode="Rrule">CARVYKTI N=188 </th><th align="center" styleCode="Rrule">Standard Therapy N=208 </th><th align="center" styleCode="Rrule">Standard Therapy N=208 </th></tr><tr><th align="center" styleCode="Lrule Rrule">System Organ Class (SOC) Preferred term </th><th align="center" styleCode="Rrule">Any Grade (%)</th><th align="center" styleCode="Rrule">Grade 3 or higher (%)</th><th align="center" styleCode="Rrule">Any Grade (%)</th><th align="center" styleCode="Rrule">Grade 3 or higher (%)</th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">Gastrointestinal disorders</content></td><td styleCode="Rrule">-</td><td styleCode="Rrule">-</td><td styleCode="Rrule">-</td><td styleCode="Rrule">-</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Diarrhea <footnote ID="t3f1">Diarrhea includes Colitis, and Diarrhea.</footnote></td><td styleCode="Rrule">27</td><td styleCode="Rrule">3</td><td styleCode="Rrule">27</td><td styleCode="Rrule">2</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Nausea</td><td styleCode="Rrule">20</td><td styleCode="Rrule">0</td><td styleCode="Rrule">18</td><td styleCode="Rrule">1</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Constipation</td><td styleCode="Rrule">10</td><td styleCode="Rrule">0</td><td styleCode="Rrule">21</td><td styleCode="Rrule">1</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">General disorders and administrative site conditions</content></td><td styleCode="Rrule">-</td><td styleCode="Rrule">-</td><td styleCode="Rrule">-</td><td styleCode="Rrule">-</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Pyrexia</td><td styleCode="Rrule">79</td><td styleCode="Rrule">5</td><td styleCode="Rrule">16</td><td styleCode="Rrule">1</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Fatigue <footnote ID="t3f2">Represents multiple related terms.</footnote></td><td styleCode="Rrule">28</td><td styleCode="Rrule">3</td><td styleCode="Rrule">50</td><td styleCode="Rrule">3</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Edema <footnote ID="K2465">Edema includes Face edema, Generalized edema, Localized edema, Edema peripheral, Periorbital edema, Peripheral swelling, Pulmonary edema, and Scrotal edema.</footnote></td><td styleCode="Rrule">11</td><td styleCode="Rrule">1</td><td styleCode="Rrule">20</td><td styleCode="Rrule">1</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Pain <footnoteRef IDREF="t3f2"/></td><td styleCode="Rrule">10</td><td styleCode="Rrule">1</td><td styleCode="Rrule">14</td><td styleCode="Rrule">&lt;1</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">Immune system disorders</content></td><td styleCode="Rrule">-</td><td styleCode="Rrule">-</td><td styleCode="Rrule">-</td><td styleCode="Rrule">-</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Hypogammaglobulinemia <footnote ID="K2522">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.</footnote></td><td styleCode="Rrule">94</td><td styleCode="Rrule">9</td><td styleCode="Rrule">72</td><td styleCode="Rrule">&lt;1</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Cytokine release syndrome</td><td styleCode="Rrule">78</td><td styleCode="Rrule">3</td><td styleCode="Rrule">&lt;1</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">Infections and infestations</content></td><td styleCode="Rrule">-</td><td styleCode="Rrule">-</td><td styleCode="Rrule">-</td><td styleCode="Rrule">-</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Upper respiratory tract infection <footnoteRef IDREF="t3f2"/></td><td styleCode="Rrule">25</td><td styleCode="Rrule">1</td><td styleCode="Rrule">40</td><td styleCode="Rrule">5</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Viral infection <footnoteRef IDREF="t3f2"/></td><td styleCode="Rrule">23</td><td styleCode="Rrule">4</td><td styleCode="Rrule">31</td><td styleCode="Rrule">6</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Bacterial infection <footnoteRef IDREF="t3f2"/></td><td styleCode="Rrule">15</td><td styleCode="Rrule">6</td><td styleCode="Rrule">17</td><td styleCode="Rrule">4</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Pneumonia <footnoteRef IDREF="t3f2"/></td><td styleCode="Rrule">14</td><td styleCode="Rrule">9</td><td styleCode="Rrule">18</td><td styleCode="Rrule">11</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">Metabolism and nutrition disorders</content></td><td styleCode="Rrule">-</td><td styleCode="Rrule">-</td><td styleCode="Rrule">-</td><td styleCode="Rrule">-</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Decreased appetite</td><td styleCode="Rrule">10</td><td styleCode="Rrule">0</td><td styleCode="Rrule">5</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">Musculoskeletal and connective tissue disorders</content></td><td styleCode="Rrule">-</td><td styleCode="Rrule">-</td><td styleCode="Rrule">-</td><td styleCode="Rrule">-</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Musculoskeletal pain <footnoteRef IDREF="t3f2"/></td><td styleCode="Rrule">34</td><td styleCode="Rrule">2</td><td styleCode="Rrule">47</td><td styleCode="Rrule">4</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">Nervous system disorders</content></td><td styleCode="Rrule">-</td><td styleCode="Rrule">-</td><td styleCode="Rrule">-</td><td styleCode="Rrule">-</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Headache <footnoteRef IDREF="t3f2"/></td><td styleCode="Rrule">23</td><td styleCode="Rrule">0</td><td styleCode="Rrule">13</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Encephalopathy <footnote ID="K2765">Encephalopathy includes Amnesia, Bradyphrenia, Confusional state, Depressed level of consciousness, Disturbance in attention, Immune effector cell-associated neurotoxicity syndrome, Lethargy, and Psychomotor retardation.</footnote></td><td styleCode="Rrule">11</td><td styleCode="Rrule">2</td><td styleCode="Rrule">4</td><td styleCode="Rrule">1</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">Respiratory, thoracic and mediastinal disorders</content></td><td styleCode="Rrule">-</td><td styleCode="Rrule">-</td><td styleCode="Rrule">-</td><td styleCode="Rrule">-</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Cough <footnoteRef IDREF="t3f2"/></td><td styleCode="Rrule">15</td><td styleCode="Rrule">0</td><td styleCode="Rrule">18</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Hypoxia</td><td styleCode="Rrule">12</td><td styleCode="Rrule">3</td><td styleCode="Rrule">1</td><td styleCode="Rrule">1</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">Vascular disorders</content></td><td styleCode="Rrule">-</td><td styleCode="Rrule">-</td><td styleCode="Rrule">-</td><td styleCode="Rrule">-</td></tr><tr><td styleCode="Lrule Rrule">Hypotension <footnoteRef IDREF="t3f2"/></td><td styleCode="Rrule">23</td><td styleCode="Rrule">4</td><td styleCode="Rrule">3</td><td styleCode="Rrule">0</td></tr></tbody></table>

<table width="85%"><caption>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</caption><col width="55%" align="left" valign="top"/><col width="20%" align="center" valign="top"/><col width="25%" align="center" valign="top"/><thead><tr styleCode="Botrule"><th styleCode="Lrule Rrule"/><th styleCode="Rrule">CARVYKTI (N=188) </th><th styleCode="Rrule">Standard Therapy (N=208) </th></tr><tr><th styleCode="Lrule Rrule">Laboratory Abnormality</th><th styleCode="Rrule">Grade 3 or 4 (%)</th><th styleCode="Rrule">Grade 3 or 4 (%)</th></tr></thead><tfoot><tr><td colspan="3" align="left" valign="top">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.</td></tr></tfoot><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Lymphocyte count decreased</td><td styleCode="Rrule">99</td><td styleCode="Rrule">62</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Neutrophil count decreased</td><td styleCode="Rrule">95</td><td styleCode="Rrule">88</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">White blood cell decreased</td><td styleCode="Rrule">94</td><td styleCode="Rrule">69</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Platelet count decreased</td><td styleCode="Rrule">47</td><td styleCode="Rrule">20</td></tr><tr><td styleCode="Lrule Rrule">Hemoglobin decreased</td><td styleCode="Rrule">34</td><td styleCode="Rrule">17</td></tr></tbody></table>

<table width="85%"><caption>Table 5: Adverse reactions observed in at least 10% of patients treated with CARVYKTI in CARTITUDE-1 (N=97)</caption><col width="40%" align="left" valign="top"/><col width="30%" align="center" valign="top"/><col width="30%" align="center" valign="top"/><thead><tr styleCode="Botrule"><th align="center" styleCode="Lrule Rrule">System Organ Class (SOC) Preferred term </th><th styleCode="Rrule">Any Grade (%)</th><th styleCode="Rrule">Grade 3 or higher (%)</th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">Blood and lymphatic system disorders</content></td><td styleCode="Rrule">-</td><td styleCode="Rrule">-</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Coagulopathy <footnote ID="K3235">Coagulopathy includes Activated partial thromboplastin time prolonged, Coagulopathy, Disseminated intravascular coagulation, Hypofibrinogenemia, International normalized ratio increased, and Prothrombin time prolonged.</footnote></td><td styleCode="Rrule">22</td><td styleCode="Rrule">2</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Febrile Neutropenia</td><td styleCode="Rrule">10</td><td styleCode="Rrule">9</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">Cardiac disorders</content></td><td styleCode="Rrule">-</td><td styleCode="Rrule">-</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Tachycardia <footnote ID="t5f1">Represents multiple related terms</footnote></td><td styleCode="Rrule">27</td><td styleCode="Rrule">1</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">Gastrointestinal disorders</content></td><td styleCode="Rrule">-</td><td styleCode="Rrule">-</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Diarrhea <footnote ID="K3299">Diarrhea includes Colitis and Diarrhea.</footnote></td><td styleCode="Rrule">33</td><td styleCode="Rrule">1</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Nausea</td><td styleCode="Rrule">31</td><td styleCode="Rrule">1</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Constipation</td><td styleCode="Rrule">22</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Vomiting</td><td styleCode="Rrule">20</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">General disorders and administrative site conditions</content></td><td styleCode="Rrule">-</td><td styleCode="Rrule">-</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Pyrexia</td><td styleCode="Rrule">96</td><td styleCode="Rrule">5</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Fatigue <footnoteRef IDREF="t5f1"/></td><td styleCode="Rrule">47</td><td styleCode="Rrule">7</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Chills</td><td styleCode="Rrule">33</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Edema <footnote ID="K3393">Edema includes Face edema, Generalized edema, Localized edema, Edema peripheral, Periorbital edema, Peripheral swelling, Pulmonary edema, and Scrotal edema.</footnote></td><td styleCode="Rrule">23</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">Immune system disorders</content></td><td styleCode="Rrule">-</td><td styleCode="Rrule">-</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Cytokine release syndrome <footnoteRef IDREF="t5f1"/></td><td styleCode="Rrule">95</td><td styleCode="Rrule">5</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Hypogammaglobulinemia <footnote ID="K3432">Hypogammaglobulinemia includes subjects with adverse event of hypogammaglobulinemia and/or laboratory IgG levels that fell below 500 mg/dL following CARVYKTI infusion.</footnote></td><td styleCode="Rrule">93</td><td styleCode="Rrule">2</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">Infections and infestations</content></td><td styleCode="Rrule">-</td><td styleCode="Rrule">-</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Infections-pathogen unspecified <footnoteRef IDREF="t5f1"/></td><td styleCode="Rrule">41</td><td styleCode="Rrule">19</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Upper respiratory tract infection <footnoteRef IDREF="t5f1"/></td><td styleCode="Rrule">28</td><td styleCode="Rrule">3</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Viral infections <footnoteRef IDREF="t5f1"/></td><td styleCode="Rrule">23</td><td styleCode="Rrule">7</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Pneumonia <footnoteRef IDREF="t5f1"/></td><td styleCode="Rrule">14</td><td styleCode="Rrule">13</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Sepsis <footnoteRef IDREF="t5f1"/></td><td styleCode="Rrule">10</td><td styleCode="Rrule">7</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">Metabolism and nutrition disorders</content></td><td styleCode="Rrule">-</td><td styleCode="Rrule">-</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Decreased appetite</td><td styleCode="Rrule">29</td><td styleCode="Rrule">1</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">Musculoskeletal and connective tissue disorders</content></td><td styleCode="Rrule">-</td><td styleCode="Rrule">-</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Musculoskeletal pain <footnoteRef IDREF="t5f1"/></td><td styleCode="Rrule">48</td><td styleCode="Rrule">2</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">Nervous system disorders</content></td><td styleCode="Rrule">-</td><td styleCode="Rrule">-</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Encephalopathy <footnote ID="K3586">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.</footnote></td><td styleCode="Rrule">30</td><td styleCode="Rrule">6</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Headache</td><td styleCode="Rrule">27</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Dizziness <footnoteRef IDREF="t5f1"/></td><td styleCode="Rrule">23</td><td styleCode="Rrule">1</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Motor dysfunction <footnote ID="K3623">Motor dysfunction includes Motor dysfunction, Muscle spasms, Muscle tightness, Muscular weakness, and Myoclonus.</footnote></td><td styleCode="Rrule">16</td><td styleCode="Rrule">3</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">Psychiatric disorders</content></td><td styleCode="Rrule">-</td><td styleCode="Rrule">-</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Insomnia</td><td styleCode="Rrule">13</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">Respiratory, thoracic and mediastinal disorders</content></td><td styleCode="Rrule">-</td><td styleCode="Rrule">-</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Cough <footnoteRef IDREF="t5f1"/></td><td styleCode="Rrule">39</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Dyspnea <footnote ID="K3686">Dyspnea includes Acute respiratory failure, Dyspnea, Dyspnea exertional, Respiratory failure, and Tachypnea.</footnote></td><td styleCode="Rrule">23</td><td styleCode="Rrule">3</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Nasal congestion</td><td styleCode="Rrule">15</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Hypoxia</td><td styleCode="Rrule">12</td><td styleCode="Rrule">4</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">Neoplasms benign, malignant, and unspecified (incl cysts and polyps)</content></td><td styleCode="Rrule">-</td><td styleCode="Rrule">-</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Hematologic malignancy <footnote ID="K3734">Hematologic malignancy includes Myelodysplastic syndrome and Acute myeloid leukemia.</footnote></td><td styleCode="Rrule">10</td><td styleCode="Rrule">10</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">Vascular disorders</content></td><td styleCode="Rrule">-</td><td styleCode="Rrule">-</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Hypotension <footnoteRef IDREF="t5f1"/></td><td styleCode="Rrule">51</td><td styleCode="Rrule">10</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Hypertension</td><td styleCode="Rrule">19</td><td styleCode="Rrule">6</td></tr><tr><td styleCode="Lrule Rrule">Hemorrhage <footnote ID="K3783">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.</footnote></td><td styleCode="Rrule">16</td><td styleCode="Rrule">4</td></tr></tbody></table>