Ciltacabtagene Autoleucel

1 INDICATIONS AND USAGE 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 )

12.1 Mechanism of Action CARVYKTI is a BCMA-directed, genetically modified autologous T cell immunotherapy, which involves reprogramming a patient's own T cells with a transgene encoding a CAR that identifies and eliminates cells that express BCMA. The CARVYKTI CAR protein features two BCMA-targeting single-domain antibodies designed to confer high avidity against human BCMA, a 4-1BB co-stimulatory domain and a CD3-zeta (CD3ζ) signaling cytoplasmic domain. Upon binding to BCMA-expressing cells, the CAR promotes T cell activation, expansion, and elimination of target cells.

2 DOSAGE AND ADMINISTRATION 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 thaw

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 CARVYKT

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 min

4 CONTRAINDICATIONS None. None ( 4 )