Talquetamab

1 INDICATIONS AND USAGE TALVEY is indicated for the treatment of adult patients with relapsed or refractory multiple myeloma who have received at least four prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent and an anti-CD38 monoclonal antibody. This indication is approved under accelerated approval based on response rate and durability of response [see Clinical Studies (14) ]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s). TALVEY is a bispecific GPRC5D-directed CD3 T-cell engager indicated for the treatment of adult patients with relapsed or refractory multiple myeloma who have received at least four prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent and an anti-CD38 monoclonal antibody. This indication is approved under accelerated approval based on response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s). ( 1 )

2 DOSAGE AND ADMINISTRATION For subcutaneous injection. ( 2.2 ) Patients should be hospitalized for 48 hours after all doses within the step-up dosing schedule. ( 2.1 ) Administer pretreatment medications as recommended. ( 2.3 ) See Full Prescribing Information for instructions on preparation and administration. ( 2.6 ) TALVEY Weekly Dosing Schedule ( 2.2 ) Dosing schedule Day Dose Based on actual body weight. Step-up dosing schedule Day 1 Step-up dose 1 0.01 mg/kg Day 4 Dose may be administered between 2 to 4 days after the previous dose and may be given up to 7 days after the previous dose to allow for resolution of adverse reactions. Step-up dose 2 0.06 mg/kg Day 7 First treatment dose 0.4 mg/kg Weekly dosing schedule One week after first treatment dose and weekly thereafter Maintain a minimum of 6 days between weekly doses. Subsequent treatment doses 0.4 mg/kg once weekly TALVEY Biweekly (Every 2 Weeks) Dosing Schedule ( 2.2 ) Dosing schedule Day Dose Based on actual body weight. Step-up dosing schedule Day 1 Step-up dose 1 0.01 mg/kg Day 4 Dose may be administered between 2 to 4 days after the previous dose and may be given up to 7 days after the previous dose to allow for resolution of adverse reactions. Step-up dose 2 0.06 mg/kg Day 7 Step-up dose 3 0.4 mg/kg Day 10 Dose may be administered between 2 to 7 days after step-up dose 3. First treatment dose 0.8 mg/kg Biweekly (every 2 weeks) dosing schedule Two weeks after first treatment dose and every 2 weeks thereafter Maintain a minimum of 12 days between biweekly (every 2 weeks) doses. Subsequent treatment doses 0.8 mg/kg every 2 weeks 2.1 Important Dosing Information Administer TALVEY subcutaneously according to the step-up dosing schedule in Tables 1 and 2 to reduce the incidence and severity of cytokine release syndrome (CRS) [see Dosage and Administration (2.2) ] . Administer pretreatment medications prior to each dose of TALVEY in the step-up dosing schedule as recommended [see Dosage and Administration (2.2 , 2.3) ]. TALVEY should only be administered by a qualified healthcare professional with appropriate medical support to manage severe reactions such as CRS and neurologic toxicity including immune effector cell-associated neurotoxicity syndrome (ICANS) [see Warnings and Precautions (5.1 , 5.2) ] . Due to the risk of CRS and neurologic toxicity, including ICANS, patients should be hospitalized for 48 hours after administration of all doses within the TALVEY step-up dosing schedule [see Dosage and Administration (2.5) and Warnings and Precautions (5.1 , 5.2) ] . 2.2 Recommended Dosage For subcutaneous injection. Administer pretreatment medications prior to each dose of TALVEY in the step-up dosing schedule [see Dosage and Administration (2.3) ] . Administer TALVEY subcutaneously on a weekly or biweekly (every 2 weeks) dosing schedule according to Table 1 or Table 2. Continue treatment until disease progression or unacceptable toxicity. Table 1: TALVEY Weekly Dosing Schedule Dosing schedule Day Dose Based on actual body weight. Step-up dosing schedule Day 1 Step-up dose 1 0.01 mg/kg Day 4 Dose may be administered between 2 to 4 days after the previous dose and may be given up to 7 days after the previous dose to allow for resolution of adverse reactions. Step-up dose 2 0.06 mg/kg Day 7 First treatment dose 0.4 mg/kg Weekly dosing schedule One week after first treatment dose and weekly thereafter Maintain a minimum of 6 days between weekly doses. Subsequent treatment doses 0.4 mg/kg once weekly Table 2: TALVEY Biweekly (Every 2 Weeks) Dosing Schedule Dosing schedule Day Dose Based on actual body weight. Step-up dosing schedule Day 1 Step-up dose 1 0.01 mg/kg Day 4 Dose may be administered between 2 to 4 days after the previous dose and may be given up to 7 days after the previous dose to allow for resolution of adverse reactions. Step-up dose 2 0.06 mg/kg Day 7 Step-up dose 3 0.4 mg/kg Day 10 Dose may be administered between 2 to 7 days after step-up dose 3. First treatment dose 0.8 mg/kg Biweekly (every 2 weeks) dosing schedule Two weeks after first treatment dose and every 2 weeks thereafter Maintain a minimum of 12 days between biweekly (every 2 weeks) doses. Subsequent treatment doses 0.8 mg/kg every 2 weeks 2.3 Recommended Pretreatment Medications Administer the following pretreatment medications 1 to 3 hours before each dose of TALVEY in the step-up dosing schedule to reduce the risk of CRS [see Warnings and Precautions (5.1) ] . Corticosteroid (oral or intravenous dexamethasone, 16 mg or equivalent) Antihistamines (oral or intravenous diphenhydramine, 50 mg or equivalent) Antipyretics (oral or intravenous acetaminophen, 650 mg to 1,000 mg or equivalent) Administration of pretreatment medications may be required for subsequent doses for patients who repeat doses within the TALVEY step-up dosing schedule due to dose delays (see Table 3 or Table 4 ) or for patients who experienced CRS (see Table 5 ). 2.4 Dosage Delays If a dose of TALVEY is delayed, restart therapy based on the recommendations in Table 3 and Table 4 and resume weekly or biweekly (every 2 weeks) dosing schedule accordingly [see Dosage and Administration (2.1) ] ; if a dose is delayed by more than 28 days for an adverse reaction, evaluate the benefit-risk of restarting TALVEY. Administer pretreatment medications prior to restarting TALVEY and monitor patients following administration of TALVEY [see Dosage and Administration (2.2) ]. Table 3: Recommendations for Restarting TALVEY after Dose Delay – Weekly Dosing Schedule Last Dose Administered Time from Last Dose Administered TALVEY Recommendation Administer pretreatment medications prior to restarting TALVEY. After restarting TALVEY, resume weekly dosing schedule accordingly [see Dosage and Administration (2.2)] . 0.01 mg/kg More than 7 days Restart TALVEY step-up dosing schedule at step-up dose 1 (0.01 mg/kg). 0.06 mg/kg 8 to 28 days Repeat step-up dose 2 (0.06 mg/kg) and continue TALVEY step-up dosing schedule. More than 28 days Restart TALVEY step-up dosing schedule at step-up dose 1 (0.01 mg/kg). 0.4 mg/kg 8 to 28 days Continue TALVEY dosing schedule at treatment dose (0.4 mg/kg weekly). 29 to 56 days Restart TALVEY step-up dosing schedule at step-up dose 2 (0.06 mg/kg). More than 56 days Consider permanent discontinuation. If restarting TALVEY, begin with the step-up dosing schedule at step-up dose 1 (0.01 mg/kg). Table 4: Recommendations for Restarting TALVEY after Dose Delay – Biweekly (Every 2 Weeks) Dosing Schedule Last Dose Administered Time from Last Dose Administered TALVEY Recommendation Administer pretreatment medications prior to restarting TALVEY. After restarting TALVEY, resume biweekly (every 2 weeks) dosing schedule accordingly [see Dosage and Administration (2.2)] . 0.01 mg/kg More than 7 days Restart TALVEY step-up dosing schedule at step-up dose 1 (0.01 mg/kg). 0.06 mg/kg 8 to 28 days Repeat step-up dose 2 (0.06 mg/kg) and continue TALVEY step-up dosing schedule. More than 28 days Restart TALVEY step-up dosing schedule at step-up dose 1 (0.01 mg/kg). 0.4 mg/kg 8 to 28 days Repeat step-up dose 3 (0.4 mg/kg) and continue TALVEY step-up dosing schedule. 29 to 56 days Restart TALVEY step-up dosing schedule at step-up dose 2 (0.06 mg/kg). More than 56 days Consider permanent discontinuation. If restarting TALVEY, begin with the step-up dosing schedule at step-up dose 1 (0.01 mg/kg). 0.8 mg/kg 15 to 28 days Continue TALVEY dosing schedule at treatment dose (0.8 mg/kg every 2 weeks). 29 to 56 days Restart TALVEY step-up dosing schedule at step-up dose 3 (0.4 mg/kg). More than 56 days Consider permanent discontinuation. If restarting TALVEY, begin with the step-up dosing schedule at step-up dose 1 (0.01 mg/kg). 2.5 Dosage Modifications for Adverse Reactions Dose delays may be required to manage toxicities related to TALVEY [see Warnings and Precautions (5) ] . See Table 5 , Table 6 , and Table 7 for recommended actions for the management of CRS, ICANS, and neurologic toxicity. See Table 8 for recommended dose modifications for other adverse reactions. Cytokine Release Syndrome (CRS) Identify CRS based on clinical presentation [see Warnings and Precautions (5.1) ] . Evaluate and treat other causes of fever, hypoxia, and hypotension. If CRS is suspected, withhold TALVEY until CRS resolves or permanently discontinue based on severity, manage according to the recommendations in Table 5, consider further management per current practice guidelines. Administer supportive therapy for CRS, which may include intensive care for severe or life-threatening CRS. Consider laboratory testing to monitor for disseminated intravascular coagulation (DIC), hematology parameters, as well as pulmonary, cardiac, renal, and hepatic function. Table 5: Recommendations for Management of CRS CRS Grade Based on American Society for Transplantation and Cellular Therapy (ASTCT) grading for CRS (Lee et al 2019). Presenting Symptoms Actions Grade 1 Temperature ≥100.4°F (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 anticytokine therapy (e.g., corticosteroids). Withhold TALVEY until CRS resolves. See Table 3 and Table 4 for recommendations on restarting TALVEY after dose delays for adverse reactions [see Dosage and Administration (2.4)]. Administer pretreatment medication prior to next dose. Grade 2 Temperature ≥100.4°F (38°C) with either: Hypotension responsive to fluids and not requiring vasopressors, or Oxygen requirement of low-flow nasal cannula Low-flow nasal cannula is ≤6 L/min, and high-flow nasal cannula is >6 L/min. or blow-by. Withhold TALVEY until CRS resolves. Administer pretreatment medications prior to next dose. Patients should be hospitalized for 48 hours following the next dose. Grade 3 Temperature ≥100.4°F (38°C) with either: Hypotension requiring one vasopressor, with or without vasopressin, or Oxygen requirement of high-flow nasal cannula , facemask, non-rebreather mask, or Venturi mask Duration less than 48 hours Withhold TALVEY until CRS resolves. Provide supportive therapy, which may include intensive care. Administer pretreatment medications prior to the next dose. Patients should be hospitalized for 48 hours following the next dose. Recurrent or duration greater than or equal to 48 hours Permanently discontinue TALVEY. Provide supportive therapy, which may include intensive care. Grade 4 Temperature ≥100.4°F (38°C) with either: Hypotension requiring multiple vasopressors (excluding vasopressin). Or, oxygen requirement of positive pressure (e.g., continuous positive airway pressure [CPAP], bilevel positive airway pressure [BiPAP], intubation, and mechanical ventilation) Permanently discontinue TALVEY. Provide supportive therapy, which may include intensive care. Neurologic Toxicity, including ICANS At the first sign of neurologic toxicity, including ICANS, withhold TALVEY and consider neurology evaluation. Rule out other causes of neurologic symptoms. Provide supportive therapy, which may include intensive care, for severe or life-threatening neurologic toxicities, including ICANS [see Warnings and Precautions (5.2) ] . Manage ICANS and neurologic toxicity according to the recommendations in Table 6 and Table 7 and consider further management per current practice guidelines. Table 6: Recommendations for Management of ICANS Grade Based on ASTCT 2019 grading for ICANS. Presenting Symptoms Management is determined by the most severe event, not attributable to any other cause. Actions 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 Attributable to no other cause. : awakens spontaneously. Withhold TALVEY until ICANS resolves. See Table 3 and Table 4 for recommendations on restarting TALVEY after dose delays for adverse reactions [see Dosage and Administration (2.4)]. Monitor neurologic symptoms, and consider consultation with neurologist and other specialists for further evaluation and management. 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. Withhold TALVEY until ICANS resolves. Administer dexamethasone All references to dexamethasone administration are dexamethasone or equivalent. 10 mg intravenously every 6 hours. Continue dexamethasone use until resolution to Grade 1 or less, then taper. Monitor neurologic symptoms and consider consultation with neurologist and other specialists for further evaluation and management. Consider non-sedating, anti-seizure medicines (e.g., levetiracetam) for seizure prophylaxis. Patients should be hospitalized for 48 hours following the next dose of TALVEY [see Dosage and Administration (2.1) ] . 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 electroencephalogram (EEG) that resolve with intervention, or raised intracranial pressure: focal/local edema on neuroimaging . First Occurrence of Grade 3 ICANS: Withhold TALVEY until ICANS resolves. Administer dexamethasone 10 mg intravenously every 6 hours. Continue dexamethasone use until resolution to Grade 1 or less, then taper. Monitor neurologic symptoms and consider consultation with neurologist and other specialists for further evaluation and management. Consider non-sedating, anti-seizure medicines (e.g., levetiracetam) for seizure prophylaxis. Provide supportive therapy, which may include intensive care. Patients should be hospitalized for 48 hours following the next dose of TALVEY [see Dosage and Administration (2.1) ] . Recurrent Grade 3 ICANS: Permanently discontinue TALVEY. Administer dexamethasone 10 mg intravenously and repeat dose every 6 hours. Continue dexamethasone use until resolution to Grade 1 or less, then taper. Monitor neurologic symptoms and consider consultation with neurologist and other specialists for further evaluation and management. Consider non-sedating, anti-seizure medicines (e.g., levetiracetam) for seizure prophylaxis. Provide supportive therapy, which may include intensive care. 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 minutes), or repetitive clinical or electrical seizures without return to baseline in between, or motor findings : deep focal motor weakness such as hemiparesis or paraparesis, or raised intracranial pressure/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. Permanently discontinue TALVEY. Administer dexamethasone 10 mg intravenously and repeat dose every 6 hours. Continue dexamethasone use until resolution to Grade 1 or less, then taper. Alternatively, consider administration of methylprednisolone 1,000 mg per day intravenously and continue methylprednisolone 1,000 mg per day intravenously for 2 or more days. Monitor neurologic symptoms and consider consultation with neurologist and other specialists for further evaluation and management. Consider non-sedating, anti-seizure medicines (e.g., levetiracetam) for seizure prophylaxis. Provide supportive therapy, which may include intensive care. Table 7: Recommendations for Management of Neurologic Toxicity (excluding ICANS) Adverse Reaction Severity Based on National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 4.03. Actions Neurologic Toxicity (excluding ICANS) Grade 1 Withhold TALVEY until neurologic toxicity symptoms resolve or stabilize. See Table 3 and Table 4 for recommendations on restarting TALVEY after dose delays for adverse reactions [see Dosage and Administration (2.4)] . For ataxia/balance disorder, perform benefit risk assessment prior to resuming treatment with TALVEY. Grade 2 Grade 3 (First occurrence) Withhold TALVEY until neurologic toxicity symptoms improve to Grade 1 or less. Provide supportive therapy. Grade 3 (Recurrent) Grade 4 Permanently discontinue TALVEY. Provide supportive therapy, which may include intensive care. Other Adverse Reactions The recommended dose modifications for other adverse reactions are provided in Table 8. Table 8: Recommended Dose Modifications for Other Adverse Reactions Adverse Reaction Severity Dose Modification Oral Toxicity and Weight Loss [see Warnings and Precautions (5.4) ] Grade 1–2 Provide supportive care. Consider withholding TALVEY if not responsive to supportive care. See Table 3 and Table 4 for recommendations on restarting TALVEY after dose delays for adverse reactions [see Dosage and Administration (2.4)]. Grade 3 Withhold TALVEY until resolution to Grade 1 or better and provide supportive care. Grade 4 Permanently discontinue TALVEY. Infections [see Warnings and Precautions (5.5) ] All Grades Withhold TALVEY in the step-up phase in patients until infection resolves. Grade 3 Withhold TALVEY during the treatment phase until infection improves to Grade 1 or better within 28 days. For Grade 3 or 4 infection, if TALVEY is withheld for more than 28 days, restart step-up dosing when infection improves to Grade 1 or better. Grade 4 Consider permanent discontinuation of TALVEY. If TALVEY is not permanently discontinued, withhold subsequent treatment doses of TALVEY (i.e., doses administered after TALVEY step-up dosing schedule) until adverse reaction improves to Grade 1 or better. Cytopenias [see Warnings and Precautions (5.6) ] Absolute neutrophil count less than 0.5 × 10 9 /L Withhold TALVEY until absolute neutrophil count is 0.5 × 10 9 /L or higher. Febrile neutropenia Withhold TALVEY until absolute neutrophil count is 1 × 10 9 /L or higher and fever resolves. Hemoglobin less than 8 g/dL Withhold TALVEY until hemoglobin is 8 g/dL or higher. Platelet count less than 25,000/mcL Platelet count between 25,000/mcL and 50,000/mcL with bleeding Withhold TALVEY until platelet count is 25,000/mcL or higher and no evidence of bleeding. Skin Reactions [see Warnings and Precautions (5.7) ] Grade 3–4 Withhold TALVEY until adverse reaction improves to Grade 1 or baseline. Other Non-hematologic Adverse Reactions Based on National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), Version 4.03. [see Warnings and Precautions (5.8) and Adverse Reactions (6.1) ] Grade 3 Withhold TALVEY until adverse reaction improves to Grade 1 or baseline. Grade 4 Consider permanent discontinuation of TALVEY. If TALVEY is not permanently discontinued, withhold subsequent treatment doses of TALVEY (i.e., doses administered after TALVEY step-up dosing schedule) until adverse reaction improves to Grade 1 or less. 2.6 Preparation and Administration Administer TALVEY via subcutaneous injection by a healthcare provider. TALVEY should be administered by a healthcare provider with adequate medical personnel and appropriate medical equipment to manage severe reactions, including CRS and neurologic toxicity, including ICANS [see Warnings and Precautions (5.1 , 5.2) ] . TALVEY 3 mg/1.5 mL (2 mg/mL) vial and TALVEY 40 mg/mL vial are supplied as ready-to-use solution for injection that do not need dilution prior to administration. Do not combine TALVEY vials of different concentrations to achieve treatment dose. Use aseptic technique to prepare and administer TALVEY. Preparation Refer to the following reference tables for the preparation of TALVEY. Use Table 9 to determine total dose, injection volume, and number of vials required based on patient's actual body weight for the 0.01 mg/kg dose using TALVEY 3 mg/1.5 mL (2 mg/mL) vial. Table 9: 0.01 mg/kg Dose: Injection Volumes using TALVEY 3 mg/1.5 mL (2 mg/mL) Vial Body Weight (kg) Total Dose (mg) Volume of Injection (mL) Number of Vials (1 vial = 1.5 mL) 0.01 mg/kg Dose 35 to 39 0.38 0.19 1 40 to 45 0.42 0.21 1 46 to 55 0.5 0.25 1 56 to 65 0.6 0.3 1 66 to 75 0.7 0.35 1 76 to 85 0.8 0.4 1 86 to 95 0.9 0.45 1 96 to 105 1 0.5 1 106 to 115 1.1 0.55 1 116 to 125 1.2 0.6 1 126 to 135 1.3 0.65 1 136 to 145 1.4 0.7 1 146 to 155 1.5 0.75 1 156 to 160 1.6 0.8 1 Use Table 10 to determine total dose, injection volume, and number of vials required based on patient's actual body weight for the 0.06 mg/kg dose using TALVEY 3 mg/1.5 mL (2 mg/mL) vial. Table 10: 0.06 mg/kg Dose: Injection Volumes using TALVEY 3 mg/1.5 mL (2 mg/mL) Vial Body Weight (kg) Total Dose (mg) Volume of Injection (mL) Number of Vials (1 vial = 1.5 mL) 0.06 mg/kg Dose 35 to 39 2.2 1.1 1 40 to 45 2.6 1.3 1 46 to 55 3 1.5 1 56 to 65 3.6 1.8 2 66 to 75 4.2 2.1 2 76 to 85 4.8 2.4 2 86 to 95 5.4 2.7 2 96 to 105 6 3 2 106 to 115 6.6 3.3 3 116 to 125 7.2 3.6 3 126 to 135 7.8 3.9 3 136 to 145 8.4 4.2 3 146 to 155 9 4.5 3 156 to 160 9.6 4.8 4 Use Table 11 to determine total dose, injection volume, and number of vials required based on patient's actual body weight for the 0.4 mg/kg dose using TALVEY 40 mg/mL vial. Table 11: 0.4 mg/kg Dose: Injection Volumes using TALVEY 40 mg/mL Vial Body Weight (kg) Total Dose (mg) Volume of Injection (mL) Number of Vials (1 vial = 1 mL) 0.4 mg/kg Dose 35 to 39 14.8 0.37 1 40 to 45 16 0.4 1 46 to 55 20 0.5 1 56 to 65 24 0.6 1 66 to 75 28 0.7 1 76 to 85 32 0.8 1 86 to 95 36 0.9 1 96 to 105 40 1 1 106 to 115 44 1.1 2 116 to 125 48 1.2 2 126 to 135 52 1.3 2 136 to 145 56 1.4 2 146 to 155 60 1.5 2 156 to 160 64 1.6 2 Use Table 12 to determine total dose, injection volume, and number of vials required based on patient's actual body weight for the 0.8 mg/kg dose using TALVEY 40 mg/mL vial. Table 12: 0.8 mg/kg Dose: Injection Volumes using TALVEY 40 mg/mL Vial Body Weight (kg) Total Dose (mg) Volume of Injection (mL) Number of Vials (1 vial = 1 mL) 0.8 mg/kg Dose 35 to 39 29.6 0.74 1 40 to 45 34 0.85 1 46 to 55 40 1 1 56 to 65 48 1.2 2 66 to 75 56 1.4 2 76 to 85 64 1.6 2 86 to 95 72 1.8 2 96 to 105 80 2 2 106 to 115 88 2.2 3 116 to 125 96 2.4 3 126 to 135 104 2.6 3 136 to 145 112 2.8 3 146 to 155 120 3 3 156 to 160 128 3.2 4 Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Check that the TALVEY solution for injection is colorless to light yellow. Do not use if the solution is discolored, cloudy, or if foreign particles are present. Remove the appropriate strength TALVEY vial(s) from refrigerated storage [2°C to 8°C (36°F to 46°F)] and equilibrate to ambient temperature [15°C to 30°C (59°F to 86°F)] for at least 15 minutes. Do not warm TALVEY in any other way. Once equilibrated, gently swirl the vial for approximately 10 seconds to mix. Do not shake. Withdraw the required injection volume of TALVEY from the vial(s) into an appropriately sized syringe using a transfer needle. Each injection volume should not exceed 2 mL. Divide doses requiring greater than 2 mL equally into multiple syringes. TALVEY is compatible with stainless steel injection needles and polypropylene or polycarbonate syringe material. Replace the transfer needle with an appropriately sized needle for injection. Administration Inject the required volume of TALVEY into the subcutaneous tissue of the abdomen (preferred injection site). Alternatively, TALVEY may be injected into the subcutaneous tissue at other sites (e.g., thigh). If multiple injections are required, TALVEY injections should be at least 2 cm apart. Do not inject into tattoos or scars or areas where the skin is red, bruised, tender, hard or not intact. Any unused medicinal product or waste material should be disposed in accordance with local requirements. Storage The prepared syringes should be administered immediately. If immediate administration is not possible, store the TALVEY solution refrigerated at 2°C to 8°C (36°F to 46°F) for up to 24 hours followed by at room temperature of 15°C to 30°C (59°F to 86°F) for up to 24 hours. Discard if stored for more than 24 hours refrigerated or more than 24 hours at room temperature. If stored in the refrigerator, allow the solution to come to room temperature before administration.

6 ADVERSE REACTIONS The following adverse reactions are also described elsewhere in the labeling: Cytokine Release Syndrome [see Warnings and Precautions (5.1) ] Neurologic Toxicity, including ICANS [see Warnings and Precautions (5.2) ] Oral Toxicity and Weight Loss [see Warnings and Precautions (5.4) ] Infections [see Warnings and Precautions (5.5) ] Cytopenias [see Warnings and Precautions (5.6) ] Skin Toxicity [see Warnings and Precautions (5.7) ] Hepatotoxicity [see Warnings and Precautions (5.8) ] The most common adverse reactions (≥20%) are pyrexia, CRS, dysgeusia, nail disorder, musculoskeletal pain, skin disorder, rash, fatigue, weight decreased, dry mouth, xerosis, dysphagia, upper respiratory tract infection, diarrhea, hypotension, and headache. ( 6.1 ) The most common Grade 3 or 4 laboratory abnormalities (≥30%) are lymphocyte count decreased, neutrophil count decreased, white blood cell decreased, and hemoglobin decreased. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Janssen Biotech, Inc. at 1-800-JANSSEN (1-800-526-7736) 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. Relapsed/Refractory Multiple Myeloma MonumenTAL-1 The safety of TALVEY was evaluated in 339 adult patients with relapsed or refractory multiple myeloma. Patients treated with the weekly dosing schedule received step-up doses of 0.01 mg/kg and 0.06 mg/kg of TALVEY followed by TALVEY 0.4 mg/kg subcutaneously weekly thereafter. Patients treated with the biweekly (every 2 weeks) dosing schedule received step-up doses of 0.01 mg/kg, 0.06 mg/kg, and 0.3 mg/kg (0.75 times the recommended step-up dose 3) followed by TALVEY 0.8 mg/kg subcutaneously every 2 weeks thereafter. The duration of exposure for the 0.4 mg/kg weekly regimen was 5.9 (range: 0.0 to 25.3) months (N=186) and for the 0.8 mg/kg biweekly (every 2 weeks) regimen, it was 3.7 (range: 0.0 to 17.9) months (N=153). Serious adverse reactions occurred in 47% of patients who received TALVEY. Serious adverse reactions in ≥ 2% of patients included CRS (13%), bacterial infection (8%) including sepsis, pyrexia (4.7%), ICANS (3.8%), COVID-19 (2.7%), neutropenia (2.1%), and upper respiratory tract infection (2.1%). Fatal adverse reactions occurred in 3.2% of patients who received TALVEY, including COVID - 19 (0.6%), dyspnea (0.6%), general physical health deterioration (0.6%), bacterial infection (0.3%) including sepsis, basilar artery occlusion (0.3%), fungal infection (0.3%), infection (0.3%), and pulmonary embolism (0.3%). Permanent discontinuation of TALVEY due to an adverse reaction occurred in 9% of patients. Adverse reactions which resulted in permanent discontinuation of TALVEY in > 1% of patients included ICANS. Dosage interruptions of TALVEY due to an adverse reaction occurred in 56% of patients. Adverse reactions which required dosage interruption in > 5% of patients included pyrexia (15%), CRS (12%), upper respiratory tract infection (9%), COVID-19 (9%), bacterial infection (7%) including sepsis, neutropenia (6%), and rash (6%). The most common adverse reactions (≥ 20%) were pyrexia, CRS, dysgeusia, nail disorder, musculoskeletal pain, skin disorder, rash, fatigue, weight decreased, dry mouth, xerosis, dysphagia, upper respiratory tract infection, diarrhea, hypotension, and headache. The most common Grade 3 or 4 laboratory abnormalities (≥ 30%) were lymphocyte count decreased, neutrophil count decreased, white blood cell decreased, and hemoglobin decreased. Table 13 summarizes the adverse reactions in MonumenTAL-1. Table 13: Adverse Reactions (≥10%) in Patients with Relapsed or Refractory Multiple Myeloma Who Received TALVEY in MonumenTAL-1 TALVEY N=339 System Organ Class Adverse Reaction Any Grade (%) Grade 3 or 4 (%) Adverse reactions were graded based on CTCAE Version 4.03, with the exception of CRS, which was graded per ASTCT 2019 criteria. General disorders and administration site conditions Pyrexia Includes other related terms. 83 4.7 Only grade 3 adverse reactions occurred. Fatigue 37 3.5 Chills 19 0 Pain 18 1.8 Edema 14 0 Injection site reaction 13 0 Immune system disorders Cytokine release syndrome 76 1.5 Gastrointestinal disorders Dysgeusia Dysgeusia: ageusia, dysgeusia, hypogeusia and taste disorder. Per CTCAE v4.03, maximum toxicity grade for dysgeusia is 2 and maximum toxicity grade for dry mouth is 3. 70 0 Dry mouth 34 0 Dysphagia 23 0.9 Diarrhea 21 0.9 Stomatitis Stomatitis: cheilitis, glossitis, glossodynia, mouth ulceration, oral discomfort, oral mucosal erythema, oral pain, stomatitis, swollen tongue, tongue discomfort, tongue erythema, tongue edema and tongue ulceration. 18 1.2 Nausea 18 0 Constipation 16 0 Oral disorder Oral disorder: oral disorder, oral dysesthesia, oral mucosal exfoliation, oral toxicity and oropharyngeal pain. 12 0 Skin and subcutaneous tissue disorders Nail disorder Nail disorder: koilonychia, nail bed disorder, nail cuticle fissure, nail discoloration, nail disorder, nail dystrophy, nail hypertrophy, nail pitting, nail ridging, nail toxicity, onychoclasis, onycholysis and onychomadesis. 50 0 Skin disorder Skin disorder: palmar-plantar erythrodysesthesia syndrome, palmoplantar keratoderma, skin discoloration, skin exfoliation and skin fissures. 41 0.3 Rash Rash: dermatitis, dermatitis acneiform, dermatitis contact, dermatitis exfoliative, dermatitis exfoliative generalized, erythema, exfoliative rash, rash, rash erythematous, rash macular, rash maculo-papular, rash papular, rash pruritic, rash pustular, rash vesicular and stasis dermatitis. 38 3.5 Xerosis Xerosis: dry eye, dry skin and xerosis. 30 0 Pruritus 19 0.3 Musculoskeletal and connective tissue disorders Musculoskeletal pain 43 3.2 Investigations Weight decreased 35 1.5 Infections and infestations Upper respiratory tract infection 22 2.7 Bacterial infection including sepsis Bacterial infection including sepsis: bacteremia, bacterial prostatitis, carbuncle, cellulitis, citrobacter infection, clostridium difficile colitis, clostridium difficile infection, cystitis escherichia, cystitis klebsiella, diverticulitis, enterobacter bacteremia, escherichia pyelonephritis, escherichia sepsis, folliculitis, gastroenteritis escherichia coli, helicobacter gastritis, human ehrlichiosis, klebsiella bacteremia, klebsiella sepsis, moraxella infection, otitis media acute, pitted keratolysis, pneumococcal sepsis, pneumonia, pneumonia streptococcal, pseudomonal bacteremia, pyuria, renal abscess, salmonella sepsis, sepsis, septic shock, skin infection, staphylococcal bacteremia, staphylococcal infection, staphylococcal sepsis, streptococcal bacteremia, tooth abscess, tooth infection, urinary tract infection enterococcal, and urinary tract infection pseudomonal. Includes fatal outcome(s): COVID-19 (N=2), dyspnea (N=2), bacterial infection including sepsis (N=1), fungal infection (N=1). 19 9 COVID-19 11 2.7 Fungal infection Fungal infection: body tinea, candida infection, ear infection fungal, esophageal candidiasis, fungal infection, fungal sepsis, fungal skin infection, genital candidiasis, onychomycosis, oral candidiasis, oral fungal infection, oropharyngeal candidiasis, tinea pedis, vulvovaginal candidiasis, and vulvovaginal mycotic infection. 10 0.6 Vascular disorders Hypotension 21 2.9 Nervous system disorders Headache 21 0.6 Encephalopathy Encephalopathy: agitation, altered state of consciousness, amnesia, aphasia, bradyphrenia, confusional state, delirium, depressed level of consciousness, disorientation, encephalopathy, hallucination, lethargy, memory impairment, mood altered, restlessness, sleep disorder and somnolence. 15 1.8 Sensory neuropathy Sensory neuropathy: dysesthesia, hyperesthesia, hypoesthesia, hypoesthesia oral, immune-mediated neuropathy, neuralgia, neuropathy peripheral, paresthesia, peripheral sensory neuropathy, polyneuropathy, sciatica and vestibular neuronitis. 14 0 Motor dysfunction Motor dysfunction: dysarthria, dysgraphia, dysmetria, dysphonia, gait disturbance, muscle atrophy, muscle spasms, muscular weakness and tremor. 10 0.6 Metabolism and nutrition disorders Decreased appetite 19 1.2 Respiratory, thoracic and mediastinal disorders Cough 17 0 Dyspnea 11 1.8 Hypoxia 10 1.5 Cardiac disorders Tachycardia 11 0.6 Clinically relevant adverse reactions reported in <10% of patients who received TALVEY included ICANS and viral infection. Table 14 summarizes select laboratory abnormalities in MonumenTAL-1. Table 14: Select Laboratory Abnormalities (≥30%) That Worsened from Baseline in Patients with Relapsed or Refractory Multiple Myeloma Who Received TALVEY in MonumenTAL-1 TALVEY The denominator used to calculate the rate varied from 326 to 338 based on the number of patients with a baseline value and at least one post-treatment value. Laboratory Abnormality Any Grade (%) Grade 3 or 4 (%) Laboratory toxicity grades are derived based on the NCI CTCAE (National Cancer Institute Common Terminology Criteria for Adverse Events) Version 4.03. Hematology Lymphocyte count decreased 90 80 White blood cell decreased 73 35 Hemoglobin decreased 67 30 Neutrophil count decreased 64 35 Platelet count decreased 62 22 Chemistry Albumin decreased 66 2.1 Alkaline phosphatase increased 49 1.5 Phosphate decreased 44 13 Gamma-glutamyl transferase increased 38 7 Alanine aminotransferase increased 33 2.7 Potassium decreased 31 4.4 Sodium decreased 31 6 Aspartate aminotransferase increased 31 3.3

12.3 Pharmacokinetics The C max and AUC tau of talquetamab-tgvs after subcutaneous administration increased proportionally over a dose range of 0.005 to 0.8 mg/kg weekly (0.01 to 2 times the recommended 0.4 mg/kg weekly treatment dose) and 0.8 to 1.2 mg/kg every two weeks (1 to 1.5 times the recommended 0.8 mg/kg every 2 weeks treatment dose). Ninety percent of steady state exposure was achieved 16 weeks after the first treatment dose for both regimens. The C max , C trough , C avg , and accumulation ratios of talquetamab-tgvs are presented in Table 15. Table 15: Pharmacokinetic Parameters of Talquetamab-tgvs Following the Dose at 16 Weeks After the First Treatment Dose for the Approved Recommended Subcutaneous Dosages in Patients with Relapsed or Refractory Multiple Myeloma Talquetamab-tgvs Dosage Parameter 0.4 mg/kg every week 0.8 mg/kg every 2 weeks C avg = Average concentration over the dosing interval; : C max = Maximum serum talquetamab-tgvs concentration; C trough = Serum talquetamab-tgvs concentration prior to next dose Exposure Data are presented as geometric mean (coefficient of variation %). C max (ng/mL) 2,940 (67%) 3,410 (63%) C trough (ng/mL) 2,410 (83%) 1,930 (103%) C avg (ng/mL) 2,730 (71%) 2,770 (72%) Accumulation Ratio For the 0.4 mg/kg every week regimen, accumulation ratios are presented as the arithmetic mean of the 17 th treatment dose / the first treatment dose. For the 0.8 mg/kg every 2 weeks regimen, accumulation ratios are presented as the arithmetic mean of the 9 th treatment dose / the first treatment dose. C max 4.4 1.8 C trough 4.6 2.3 C avg 5.1 2.0 Absorption The geometric mean (coefficient of variation [CV] %) bioavailability of talquetamab-tgvs was 59% (22%) when administered subcutaneously. The median (range) T max of talquetamab-tgvs after the first and 17 th treatment dose of 0.4 mg/kg weekly were 3.7 (0.9 to 7) days and 2.5 (0.9 to 5.9) days, respectively. The median (range) T max of talquetamab-tgvs after the first and 9 th treatment dose of 0.8 mg/kg every 2 weeks were 3.4 (0.8 to 14) days and 3.6 (1 to 7.7) days, respectively. Distribution The geometric mean (CV%) volume of distribution of talquetamab-tgvs was 10.1 L (25%). Elimination Talquetamab-tgvs clearance decreases over time, with a mean (CV%) maximal reduction from the first treatment dose to 16 weeks after the first treatment dose of 40% (56%). The geometric mean (CV%) clearance is 0.90 L/day (63%) at 16 weeks after the first treatment dose. The mean (CV%) terminal half-life was 8.4 (41%) days after the first treatment dose and 12.2 (49%) days at 16 weeks after the first treatment dose. Metabolism Talquetamab-tgvs is expected to be metabolized into small peptides by catabolic pathways. Specific Populations The volume of distribution and clearance of talquetamab-tgvs increased with increasing bodyweight (40 kg to 143 kg). There were no clinically significant differences in the pharmacokinetics of talquetamab-tgvs based on age (33 to 86 years), sex, race (White, Black or African American), ethnicity (Not Hispanic/Latino, Hispanic/Latino), mild or moderate renal impairment (creatinine clearance [CLcr] by Cockcroft-Gault equation: 30 to 89 mL/min) or mild (total bilirubin less than or equal to upper limit of normal [ULN] with AST greater than ULN or total bilirubin greater than 1 to 1.5 times ULN with any AST) or moderate (total bilirubin greater than 1.5 to less than 3 times ULN with any AST) hepatic impairment. The effects of severe renal impairment (CLcr less than 30 mL/min) or severe hepatic impairment (total bilirubin greater than 3 times ULN with any AST) on the pharmacokinetics of talquetamab-tgvs are unknown.