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WARNING: CYTOKINE RELEASE SYNDROME and NEUROLOGIC TOXICITY including IMMUNE EFFECTOR CELL-ASSOCIATED NEUROTOXICITY SYNDROME
Cytokine release syndrome (CRS), including life-threatening or fatal reactions, can occur in patients receiving Tecvayli. Initiate treatment with Tecvayli step-up dosing schedule to reduce risk of CRS. Withhold Tecvayli until CRS resolves or permanently discontinue based on severity.
Neurologic toxicity, including Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) and serious, life-threatening or fatal reactions, can occur in patients receiving Tecvayli. Monitor patients for signs or symptoms of neurologic toxicity, including ICANS, during treatment. Withhold Tecvayli until neurologic toxicity resolves or permanently discontinue based on severity.
Tecvayli is available only through a restricted program called the Tecvayli and Talvey Risk Evaluation and Mitigation Strategy (REMS).
Teclistamab-cqyv, a bispecific B-cell maturation antigen (BCMA)-directed CD3 T-cell engager, is a humanized immunoglobulin G4-proline, alanine, alanine (IgG4-PAA) antibody. Teclistamab-cqyv is produced in Chinese Hamster Ovary (CHO) cells using recombinant DNA technology. Teclistamab-cqyv consists of an anti-BCMA heavy chain and light chain and an anti-CD3 heavy chain and light chain with two interchain disulfide bonds connecting the two arms. The molecular weight of teclistamab-cqyv is approximately 146 kDa.
Tecvayli® (teclistamab-cqyv) injection is a sterile, preservative-free, clear to slightly opalescent, colorless to light yellow solution supplied in a single-dose vial for subcutaneous administration.
Each Tecvayli 3 mL single-dose vial contains 30 mg of teclistamab-cqyv, edetate disodium (0.054 mg), glacial acetic acid (0.72 mg), polysorbate 20 (1.2 mg), sodium acetate (2.7 mg), sucrose (240 mg), and Water for Injection, USP.
Each Tecvayli 1.7 mL single-dose vial contains 153 mg of teclistamab-cqyv, edetate disodium (0.031 mg), glacial acetic acid (0.41 mg), polysorbate 20 (0.68 mg), sodium acetate (1.5 mg), sucrose (140 mg), and Water for Injection, USP.
Tecvayli is indicated for the treatment of adult patients with relapsed or refractory multiple myeloma:
Tecvayli is for subcutaneous injection only. Administer pretreatment medications prior to each dose of the Tecvayli step-up dosing schedule, which includes step-up dose 1, step-up dose 2, and the first treatment dose. Administer Tecvayli subcutaneously according to the step-up dosing schedule to reduce the incidence and severity of cytokine release syndrome (CRS). Due to the risk of CRS and neurologic toxicity, including ICANS, patients should be hospitalized for 48 hours after administration of both step-up dose 1 and step-up dose 2. Instruct patients to remain within proximity of a healthcare facility and monitor them daily for 48 hours after the first treatment dose within the Tecvayli step-up dosing schedule.
In Combination with Daratumumab and Hyaluronidase-fihj
The recommended dosing schedule for Tecvayli in combination with subcutaneous daratumumab and hyaluronidase-fihj is provided in Table 1. Tecvayli should be administered until disease progression or unacceptable toxicity.
| Dosing schedule | Week/Day | Tecvayli Dosage | Concomitant Therapy |
| N/A | Day 0 | N/A | Daratumumab and hyaluronidase-fihj |
| Step-up dosing scheduleb | Day 1 | Step-up dose 1 (0.06 mg/kg)c | N/A |
| Day 3 | Step-up dose 2 (0.3 mg/kg)d | N/A | |
| Day 7 | First treatment dose (1.5 mg/kg)e,f | Daratumumab and hyaluronidase-fihj | |
| Weekly dosing schedule | Weeks 2 to 8 | 1.5 mg/kg once weeklyf,g | Daratumumab and hyaluronidase-fihj once weekly |
| Biweekly (every two weeks) dosing schedule | Weeks 9 to 24 | 3 mg/kg every two weeksh | Daratumumab and hyaluronidase-fihj every two weeks |
| Every four weeks dosing schedule | Week 25 onwards | 3 mg/kg every four weeksf,i | Daratumumab and hyaluronidase-fihj every four weeks |
aSee Table 3 for recommendations on restarting TECVAYLI after dose delays.
b The Step-up dosing schedule is a component of the recommended Tecvayli dosage but is not applicable for the daratumumab and hyaluronidase-fihj dosing.
c Step-up dose 1 must be administered 20 hours or more after the daratumumab and hyaluronidase-fihj dose.
d Step-up dose 2 may be given between 2 to 4 days after step-up dose 1 and if adverse reactions occur, step-up dose 2 may be given up to 7 days after step-up dose 1 to allow for resolution of adverse reactions.
e First treatment dose (1.5 mg/kg) may be given between 2 to 4 days after step-up dose 2 and if adverse reactions occur, first full treatment dose may be given up to 7 days after step-up dose 2 to allow for resolution of adverse reactions.
f Administer Tecvayli at least 3 hours after the daratumumab and hyaluronidase-fihj dose for the first treatment dose. For subsequent doses, administer Tecvayli at least 15 minutes after the daratumumab and hyaluronidase-fihj dose.
g Maintain a minimum of 5 days between 1.5 mg/kg once weekly doses.
h Maintain a minimum of 12 days between 3 mg/kg every two weeks doses.
i Maintain a minimum of 25 days between 3 mg/kg every four weeks doses.
The recommended dosing schedule for Tecvayli monotherapy is provided in Table 2. Tecvayli should be administered until disease progression or unacceptable toxicity.
| Dosing schedule | Day | Dosage |
| All Patients | ||
| Step-up dosing scheduleb | Day 1 | Step-up dose 1: 0.06 mg/kg |
| Day 4c | Step-up dose 2: 0.3 mg/kg | |
| Day 7d | First treatment dose: 1.5 mg/kg | |
| Weekly dosing schedule | One week after first treatment dose and once weekly thereaftere | Subsequent treatment doses: 1.5 mg/kg once weeklye |
| Patients who have achieved and maintained a complete response or better for a minimum of 6 months | ||
| Biweekly (every two weeks) dosing schedule | The dosing frequency | may be decreased to 1.5 mg/kg every two weeks.f |
a See Table 3 for recommendations on restarting Tecvayli after dose delays.
b Step-up dose 2 may be given between 2 to 4 days after step-up dose 1 and may be given up to 7 days after step-up dose 1 to allow for resolution of adverse reactions.
c First treatment dose may be given between 2 to 4 days after step-up dose 2 and may be given up to 7 days after step-up dose 2 to allow for resolution of adverse reactions.
d Maintain a minimum of 5 days between 1.5 mg/kg once weekly doses.
e Maintain a minimum of 12 days between 1.5 mg/kg every two week doses.
Administer the following pretreatment medications 1 to 3 hours before each dose of the Tecvayli step-up dosing schedule to reduce the risk of CRS:
Administration of pretreatment medications may be required prior to administration of subsequent doses of Tecvayli in patients who:
Prior to starting treatment with Tecvayli, consider initiation of antiviral prophylaxis to prevent herpes zoster reactivation per guidelines./
If a dose of Tecvayli is delayed, restart therapy based on the recommendations in Table 3 and resume the treatment schedule accordingly. Administer pretreatment medications as indicated.
Dosage reductions of Tecvayli are not recommended. Dosage delays may be required to manage toxicities related to Tecvayli. Refer to Tables 4, 5, 6, and 7 for management of CRS, neurologic toxicity, ICANS, and other adverse reactions.
| Last dose administered | Time since the last dose administered | Action |
| Step-up dose 1 | More than 7 days | Restart Tecvayli step-up dosing schedule at step-up dose 1 (0.06 mg/kg).a |
| Step-up dose 2 | 8 days to 28 days | Repeat step-up dose 2 (0.3 mg/kg)a and continue Tecvayli step-up dosing schedule. |
| More than 28 daysb | Restart Tecvayli step-up dosing schedule at step-up dose 1 (0.06 mg/kg). | |
| Weekly treatment dose | 28 days or less | Continue Tecvayli 1.5 mg/kg once weekly. |
| 29 days to 56 daysb | Restart Tecvayli step-up dosing schedule at step-up dose 2 (0.3 mg/kg). | |
| More than 56 daysb | Restart Tecvayli step-up dosing schedule at step-up dose 1 (0.06 mg/kg). | |
| Any biweekly (every two weeks) or every four weeks treatment dose | 63 days or lessb | Continue Tecvayli at last dose given every two weeks or every four weeks schedule. |
| 64 days to 112 daysb | Restart Tecvayli step-up dosing schedule at step-up dose 2 (0.3 mg/kg). | |
| More than 112 daysb | Restart Tecvayli step-up dosing schedule at step-up dose 1 (0.06 mg/kg). |
a Administer pretreatment medications prior to Tecvayli dose and monitor patients accordingly.
b Consider benefit-risk of restarting Tecvayli in patients who require a dose delay of more than 28 days due to an adverse reaction.
Dosage reductions of Tecvayli are not recommended.
Refer to daratumumab hyaluronidase-fihj Prescribing Information for information about dosage modifications for daratumumab hyaluronidase-fihj.
Dosage delays may be required to manage toxicities related to Tecvayli
See Tables 4, 5 and 6 for recommended actions for adverse reactions of CRS, neurologic toxicity, and ICANS. See Table 7 for recommended actions for other adverse reactions following administration of Tecvayli.
Management of CRS, Neurologic Toxicity, and ICANS Cytokine Release SyndromeManagement recommendations for cytokine release syndrome (CRS) are summarized in Table 4.
Identify CRS based on clinical presentation . Evaluate and treat other causes of fever, hypoxia, and hypotension.
If CRS is suspected, withhold TECVAYLI until CRS resolves. Manage according to the recommendations in Table 4 and consider further management per current practice guidelines. Administer supportive therapy for CRS, which may include intensive care for severe or lifethreatening CRS. Consider laboratory testing to monitor for disseminated intravascular coagulation (DIC), hematology parameters, as well as pulmonary, cardiac, renal, and hepatic function.
Management recommendations for cytokine release syndrome (CRS) are summarized in Table 4. Identify CRS based on clinical presentation. Evaluate and treat other causes of fever, hypoxia, and hypotension. If CRS is suspected, withhold Tecvayli until CRS resolves.
| Gradea | Presenting Symptomsb | Actions |
| Grade 1 | Temperature ≥100.4°F (38°C) | Withhold Tecvayli until CRS resolves. |
| Grade 2 | Temperature ≥100.4°F (38°C) with: Hypotension responsive to fluids and not requiring vasopressors,and/or,Oxygen requirement of low-flow nasal cannulad or blow-by. | Withhold Tecvayli until CRS resolves. Administer pretreatment medications prior to next dose of Tecvayli. Monitor patients for 48 hours following the next Tecvayli dose. Instruct patients to remain within proximity of a healthcare facility during daily monitoring and consider hospitalization. |
| Grade 3 | Temperature ≥100.4°F (38°C) with: Hypotension requiring one vasopressor with or without vasopressin,and/or,Oxygen requirement of high-flow nasal cannulad, facemask, non-rebreather mask, or Venturi mask. | First Occurrence of Grade 3 CRS with Duration <48 Hours:Withhold Tecvayli until CRS resolves. Provide supportive therapy, which may include intensive care. Administer pretreatment medications prior to next Tecvayli dose. Patients should be hospitalized for 48 hours following the next Tecvayli dose. Recurrent Grade 3 CRS or Grade 3 CRS with Duration 48 Hours or Longer:Permanently discontinue Tecvayli. Provide supportive therapy, which may include intensive care. |
| Grade 4 | Temperature ≥100.4°F (38°C) with: Hypotension requiring multiple vasopressors (excluding vasopressin),and/or,Oxygen requirement of positive pressure (e.g., CPAP, BiPAP, intubation, and mechanical ventilation). | Permanently discontinue Tecvayli. Provide supportive therapy, which may include intensive care. |
a Based on American Society for Transplantation and Cellular Therapy (ASTCT) 2019 grading for CRS. b 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. d Low-flow nasal cannula is =6 L/minute, and high-flow nasal cannula is >6 L/minute.
Neurologic Toxicity and Immune Effector Cell-Associated Neurotoxicity SyndromeManagement recommendations for neurologic toxicity and immune effector cell-associated neurotoxicity syndrome (ICANS) are summarized in Tables 5 and 6.
At the first sign of neurologic toxicity, including ICANS, withhold TECVAYLI 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. Manage ICANS according to the recommendations in Table 6 and consider further management per current practice guidelines.
| Severitya | Actions |
| Grade 1 | Withhold Tecvayli until neurologic toxicity symptoms resolve or stabilize.b |
| Grade 2Grade 3 (First occurrence) | Withhold Tecvayli until neurologic toxicity symptoms improve to Grade 1 or less.b Provide supportive therapy. |
| Grade 3 (Recurrent)Grade 4 | Permanently discontinue Tecvayli. Provide supportive therapy, which may include intensive care. |
a Based on National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), version 4.03. b See Table 3 for recommendations on restarting Tecvayli after dose delays.
| Gradea | Presenting Symptomsb | Actions |
| Grade 1 | ICE score 7-9c,or depressed level of consciousnessd: awakens spontaneously. | Withhold Tecvayli until ICANS resolves. Monitor neurologic symptoms and consider consultation with neurologist and other specialists for further evaluation and management, including consideration for starting non-sedating, anti-seizure drugs for seizure prophylaxis. |
| Grade 2 | ICE score 3-6c,or depressed level of consciousnessd: awakens to voice. | Withhold Tecvayli until ICANS resolves. Administer dexamethasone 10 mg intravenously every 6 hours and continue dexamethasone use until resolution to Grade 1 or less then taper.f Monitor neurologic symptoms and consider consultation with neurologist and other specialists evaluation. Monitor patients for 48 hours following the next Tecvayli dose. Instruct patients to remain within proximity of a healthcare facility during daily monitoring and consider hospitalization. |
| Grade 3 | ICE score 0-2c,or depressed level of consciousnessd: awakens only to tactile stimulus,or seizuresd, either: any clinical seizure, focal or generalized, that resolves rapidly, or non-convulsive seizures on EEG that resolve with intervention,or raised intracranial pressure: focal/local edema on neuroimaging. | First Occurrence of Grade 3 ICANS:Withhold Tecvayli until ICANS resolves. Administer dexamethasone 10 mg intravenously every 6 hours and continue dexamethasone use until resolution to Grade 1 or less, then taper.f Monitor neurologic symptoms and consult specialists. Provide supportive therapy, which may include intensive care. Patients should be hospitalized for 48 hours following the next Tecvayli dose. Recurrent Grade 3 ICANS:Permanently discontinue Tecvayli. Administer dexamethasone 10 mg intravenously and repeat dose every 6 hours until resolution to Grade 1 or less, then taper.f |
| Grade 4 | ICE score 0c,or depressed level of consciousnessd: either: patient is unarousable or requires vigorous or repetitive tactile stimuli to arouse, or stupor or coma,or seizuresd, either: life-threatening prolonged seizure (>5 minutes), or repetitive clinical or electrical seizures without return to baseline in between,or motor findingsd: deep focal motor weakness such as hemiparesis or paraparesis,or raised intracranial pressure/cerebral edemad, 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 Tecvayli. Administer dexamethasone 10 mg intravenously every 6 hours until resolution to Grade 1 or less, then taper.f Alternatively, consider administration of methylprednisolone 1,000 mg per day intravenously for 2 or more days. Monitor neurologic symptoms and consult specialists. Provide supportive therapy, which may include intensive care. |
a Based on American Society for Transplantation and Cellular Therapy (ASTCT) 2019 grading for ICANS.
b Management is determined by the most severe reaction, not attributable to any other cause.
cIf 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.
d Not attributable to any other cause.
eSee Table 3 for recommendations on restarting TECVAYLI after dose delays.
f All references to dexamethasone administration are for dexamethasone or equivalent.
| Adverse Reactions | Severitya | Actions |
| Infections | All Grades | Withhold Tecvayli in patients with active infection during the step-up dosing schedule.b |
| Grade 3 | Withhold subsequent Tecvayli doses administered after step-up dosing schedule until infection improves to Grade 1 or less.b | |
| Grade 4 | Consider permanent discontinuation of Tecvayli. If not discontinued, withhold subsequent doses after step-up schedule until infection improves to Grade 1 or less.b | |
| Hematologic Toxicities | Absolute neutrophil count (ANC) < 0.5 × 109/L | Withhold Tecvayli until ANC is > 0.5 × 109/L. |
| Febrile neutropenia | Withhold Tecvayli until ANC is ≥ 1 × 109/L and fever resolves.b | |
| Hemoglobin < 8 g/dL | Withhold Tecvayli until hemoglobin is ≥ 8 g/dL. | |
| Platelet count < 25,000/mcL (Monotherapy) or < 50,000/mcL (Combination) | Withhold Tecvayli until platelet count meets threshold and no evidence of bleeding.b | |
| Other Non-Hematologic Adverse Reactions | Grade 3 | Withhold Tecvayli until adverse reaction improves to Grade 1 or less.b |
| Grade 4 | Consider permanent discontinuation of Tecvayli. If not discontinued, withhold subsequent doses after step-up schedule until reaction improves to Grade 1 or less.b |
a Based on National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 4.03.
b See Table 3 for recommendations on restarting Tecvayli after dose delays.
Tecvayli is for subcutaneous use by a healthcare provider only. Tecvayli should be administered by a healthcare provider with adequate medical personnel and appropriate medical equipment to manage severe reactions, including CRS and ICANS.
Tecvayli is a clear to slightly opalescent, colorless to light yellow solution. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use if the solution is discolored, or cloudy, or if foreign particles are present.
Tecvayli 30 mg/3 mL (10 mg/mL) vial and Tecvayli 153 mg/1.7 mL (90 mg/mL) vial are supplied as ready-to-use solution that do not need dilution prior to administration. Do not combine Tecvayli vials of different concentrations to achieve treatment dose. Use aseptic technique to prepare and administer Tecvayli.
Refer to the following reference tables to determine the dosage based on predetermined weight ranges.
Table 8: Step-up Dose 1 (0.06 mg/kg) Injection Volumes and Number of Vials Using Tecvayli 30 mg/3 mL (10 mg/mL) Vial
| Patient Body Weight (kg) | Total Dose (mg) | Volume of Injection (mL) | Number of Vials (1 vial=3 mL) |
| 35 to 39.9 | 2.2 | 0.22 | 1 |
| 40 to 44.9 | 2.5 | 0.25 | 1 |
| 45 to 49.9 | 2.8 | 0.28 | 1 |
| 50 to 59.9 | 3.3 | 0.33 | 1 |
| 60 to 69.9 | 3.9 | 0.39 | 1 |
| 70 to 79.9 | 4.5 | 0.45 | 1 |
| 80 to 89.9 | 5.1 | 0.51 | 1 |
| 90 to 99.9 | 5.7 | 0.57 | 1 |
| 100 to 109.9 | 6.3 | 0.63 | 1 |
| 110 to 119.9 | 6.9 | 0.69 | 1 |
| 120 to 129.9 | 7.5 | 0.75 | 1 |
| 130 to 139.9 | 8.1 | 0.81 | 1 |
| 140 to 149.9 | 8.7 | 0.87 | 1 |
| 150 to 160 | 9.3 | 0.93 | 1 |
Table 9: Step-up Dose 2 (0.3 mg/kg) Injection Volumes and Number of Vials Using Tecvayli 30 mg/3 mL (10 mg/mL) Vial
| Patient Body Weight (kg) | Total Dose (mg) | Volume of Injection (mL) | Number of Vials (1 vial=3 mL) |
| 35 to 39.9 | 11 | 1.1 | 1 |
| 40 to 44.9 | 13 | 1.3 | 1 |
| 45 to 49.9 | 14 | 1.4 | 1 |
| 50 to 59.9 | 16 | 1.6 | 1 |
| 60 to 69.9 | 19 | 1.9 | 1 |
| 70 to 79.9 | 22 | 2.2 | 1 |
| 80 to 89.9 | 25 | 2.5 | 1 |
| 90 to 99.9 | 28 | 2.8 | 1 |
| 100 to 109.9 | 31 | 3.1 | 2 |
| 110 to 119.9 | 34 | 3.4 | 2 |
| 120 to 129.9 | 37 | 3.7 | 2 |
| 130 to 139.9 | 40 | 4 | 2 |
| 140 to 149.9 | 43 | 4.3 | 2 |
| 150 to 160 | 47 | 4.7 | 2 |
Table 10: 1.5 mg/kg Dose Injection Volumes and Number of Vials Using Tecvayli 153 mg/1.7 mL (90 mg/mL) Vial
| Patient Body Weight (kg) | Total Dose (mg) | Volume of Injection (mL) | Number of Vials (1 vial=1.7 mL) |
| 35 to 39.9 | 56 | 0.62 | 1 |
| 40 to 44.9 | 64 | 0.71 | 1 |
| 45 to 49.9 | 71 | 0.79 | 1 |
| 50 to 59.9 | 83 | 0.92 | 1 |
| 60 to 69.9 | 99 | 1.1 | 1 |
| 70 to 79.9 | 108 | 1.2 | 1 |
| 80 to 89.9 | 126 | 1.4 | 1 |
| 90 to 99.9 | 144 | 1.6 | 1 |
| 100 to 109.9 | 153 | 1.7 | 1 |
| 110 to 119.9 | 171 | 1.9 | 2 |
| 120 to 129.9 | 189 | 2.1 | 2 |
| 130 to 139.9 | 198 | 2.2 | 2 |
| 140 to 149.9 | 216 | 2.4 | 2 |
| 150 to 160 | 234 | 2.6 | 2 |
Table 11: 3 mg/kg Dose Injection Volumes and Number of Vials Using Tecvayli 153 mg/1.7 mL (90 mg/mL) Vial
| Patient Body Weight (kg) | Total Dose (mg) | Volume of Injection (mL) | Number of Vials (1 vial=1.7 mL) |
| 35 to 39.9 | 108 | 1.2 | 1 |
| 40 to 44.9 | 126 | 1.4 | 1 |
| 45 to 49.9 | 144 | 1.6 | 1 |
| 50 to 59.9 | 162 | 1.8 | 2 |
| 60 to 69.9 | 198 | 2.2 | 2 |
| 70 to 79.9 | 225 | 2.5 | 2 |
| 80 to 89.9 | 252 | 2.8 | 2 |
| 90 to 99.9 | 288 | 3.2 | 2 |
| 100 to 109.9 | 315 | 3.5 | 3 |
| 110 to 119.9 | 342 | 3.8 | 3 |
| 120 to 129.9 | 378 | 4.2 | 3 |
| 130 to 139.9 | 405 | 4.5 | 3 |
| 140 to 149.9 | 432 | 4.8 | 3 |
| 150 to 160 | 468 | 5.2 | 4 |
Injection:
Tecvayli® (teclistamab-cqyv) injection is a sterile, preservative-free, clear to slightly opalescent, colorless to light yellow solution supplied as follows:
Store refrigerated at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light. Do not freeze.
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.
In Combination with Daratumumab and Hyaluronidase-fihj
The safety of Tecvayli in combination with daratumumab and hyaluronidase-fihj (N=283) compared with either daratumumab and hyaluronidase-fihj, pomalidomide and dexamethasone (DPd) or daratumumab and hyaluronidase-fihj, bortezomib and dexamethasone (DVd) (N=290) was evaluated in patients with relapsed or refractory multiple myeloma in MajesTEC-3. Patients received step-up doses of 0.06 mg/kg and 0.3 mg/kg of Tecvayli followed by Tecvayli 1.5 mg/kg once weekly, followed by Tecvayli 3 mg/kg every two weeks, followed by Tecvayli 3 mg/kg every four weeks, subcutaneously. Among patients who received Tecvayli in combination with daratumumab and hyaluronidase-fihj the median exposure was 32 (range 0.03 to 43) months. Among patients who received DPd or DVd the median exposure was 16 (range 0.03 to 45) months.
Serious adverse reactions occurred in 71% of patients who received Tecvayli in combination with daratumumab and hyaluronidase-fihj. Serious adverse reactions reported in =3% of patients included pneumonia (33%), upper respiratory tract infection (15%), cytokine release syndrome (10%), COVID-19 (7%), sepsis (6%), second primary malignancy (5%), pyrexia (4.9%), febrile neutropenia (4.6%), and gastroenteritis (4.2%).
Fatal adverse reactions occurred in 2.5% of patients who received Tecvayli in combination with daratumumab and hyaluronidase-fihj, and included sepsis (0.7%), pneumonia (0.4%), sudden death (0.4%), myocardial infarction (0.4%), enterovirus myocarditis (0.4%) and hemophagocytic lymphohistiocytosis (0.4%).
Permanent discontinuation of Tecvayli due to adverse reactions occurred in 6% of patients. Adverse reactions leading to discontinuation of Tecvayli in more than one patient were pneumonia (1.1%), diarrhea (0.7%), fatigue (0.7%), second primary malignancy (0.7%), upper respiratory tract infection (0.7%) and cough (0.7%). Dosage interruptions of Tecvayli due to an adverse reaction occurred in 94% of patients. Adverse reactions which required dosage interruption of Tecvayli in =5% of patients included neutropenia (53%), upper respiratory tract infection (48%), COVID-19 (34%), pneumonia (34%), thrombocytopenia (14%), cytokine release syndrome (13%), gastroenteritis (10%), cough (10%), pyrexia (8%), diarrhea (7%), sepsis (6%) and fatigue (5%).
The most common adverse reactions (=20%) were hypogammaglobulinemia, upper respiratory tract infection, cytokine release syndrome, cough, diarrhea, musculoskeletal pain, COVID-19, pneumonia, injection site reaction, fatigue, pyrexia, headache, nausea, gastroenteritis, and weight decreased. The most common Grade 3 to 4 laboratory abnormalities (=20%) were decreased lymphocytes, decreased neutrophils, decreased white blood cells and decreased platelets.
Table 12 summarizes the adverse reactions in MajesTEC-3.
| Adverse Reaction | Tecvayli with daratumumab and hyaluronidase-fihj (N=283) | DPd or DVd (N=290) | ||
| Any Grade (%) | Grade 3 or 4 (%) | Any Grade (%) | Grade 3 or 4 (%) | |
| Immune system disorders | ||||
| Hypogammaglobulinemia1 | 84 | 6 | 60 | 1.4 |
| Cytokine release syndrome | 60 | 0 | 0 | 0 |
| Infections | ||||
| Upper respiratory tract infection2 | 79 | 17 | 13 | 62 |
| COVID-19* | 45 | 6 | 33 | 2.1 |
| Pneumonia3+ | 42 | 33 | 35 | 28 |
| Gastroenteritis* | 20 | 4.9 | 8 | 0.7 |
| Urinary tract infection* | 17 | 2.8 | 13 | 1 |
| Herpes virus infection* | 11 | 2.1 | 6 | 0.3 |
| Respiratory, thoracic and mediastinal disorders | ||||
| Cough* | 53 | 0.7 | 24 | 0 |
| Dyspnea* | 13 | 1.8 | 20 | 2.1 |
| Gastrointestinal disorders | ||||
| Diarrhea* | 52 | 3.9 | 31 | 2.4 |
| Nausea | 23 | 0 | 12 | 0.3 |
| Vomiting | 17 | 0 | 7 | 0 |
| Abdominal pain* | 16 | 0.7 | 13 | 0 |
| Constipation | 14 | 0 | 20 | 0.3 |
| Musculoskeletal and connective tissue disorders | ||||
| Musculoskeletal pain* | 50 | 1.4 | 47 | 4.5 |
| General disorders and administration site conditions | ||||
| Injection site reaction** | 41 | 0 | 4.5 | 0 |
| Fatigue* | 39 | 3.9 | 40 | 4.1 |
| Pyrexia | 37 | 1.4 | 19 | 0.3 |
| Edema* | 13 | 0.4 | 22 | 0.3 |
| Nervous system disorders | ||||
| Headache* | 26 | 1.4 | 12 | 0.3 |
| Sensory neuropathy4 | 17 | 0.7 | 25 | 0.3 |
| Motor dysfunction5 | 14 | 0 | 30 | 1 |
| Investigations | ||||
| Weight decreased | 20 | 2.8 | 7 | 1.4 |
| Metabolism and nutrition disorders | ||||
| Decreased appetite | 19 | 1.1 | 7 | 0 |
| Cardiac disorders | ||||
| Cardiac arrhythmia* | 11 | 1.1 | 8 | 2.1 |
| Neoplasms | ||||
| Second primary malignancy* | 11 | 4.6 | 9 | 4.8 |
| Vascular disorders | ||||
| Hypertension* | 11 | 4.6 | 6 | 2.4 |
DPd = daratumumab and hyaluronidase-fihj, pomalidomide, dexamethasone; DVd = daratumumab and hyaluronidase-fihj, bortezomib, dexamethasone.Adverse reactions were graded according to NCI-CTCAE Version 5.0, with the exception of ICANS and CRS, which were graded by ASTCT 2019 consensus grading system; adverse reactions that were considered symptoms of CRS or ICANS were not included.Includes other related terms.** Includes injection site reactions related to teclistamab, daratumumab and hyaluronidase-fihj, or bortezomib.1 Hypogammaglobulinemia includes hypogammaglobulinemia, hypoglobulinemia; and/or patients with laboratory IgG levels below 400 mg/dL following treatment with Tecvayli.2 Upper respiratory tract infection includes bronchitis, bronchiolitis, pharyngitis, rhinitis, sinusitis, sinobronchitis, tracheitis, and tracheobronchitis and other related terms.3 Pneumonia includes atypical pneumonia, bacterial pneumonia, fungal pneumonia, viral pneumonia, and other related terms.4 Sensory neuropathy includes dysaesthesia, hyperaesthesia, hypoaesthesia, paraesthesia, neuralgia, peripheral neuropathy, polyneuropathy, sciatica and other related terms.5 Motor dysfunction includes balance disorder, dysarthria, dysphonia, gait disturbance, muscle contracture, muscle spasms, muscle spasticity, muscle twitching, muscular weakness, myopathy, peripheral motor neuropathy, tremor and other related terms. + Includes the following fatal adverse reactions: Tec-Dara: Pneumonia (n=1); DPd/DVd: Pneumonia (n=2).
Clinically relevant adverse reactions in 2% of patients included pneumonia (15%), cytokine release syndrome (8%), sepsis (6%), general physical health deterioration (6%), COVID-19 (6%), acute kidney injury (4.8%), pyrexia (4.8%), musculoskeletal pain (2.4%), and encephalopathy (2.4%). Fatal adverse reactions occurred in 5% of patients who received Tecvayli, including COVID-19 (1.8%), pneumonia (1.8%), septic shock (0.6%), acute renal failure (0.6%), and hemoperitoneum (0.6%).
Permanent discontinuation of Tecvayli due to adverse reactions occurred in 1.2% of patients. Adverse reactions resulting in permanent discontinuation of Tecvayli included pneumonia (adenoviral and pneumocystis jirovecii pneumonia in the same patient) and hypercalcemia. Dosage interruptions of Tecvayli due to an adverse reaction occurred in 73% of patients. Adverse reactions which required dosage interruption in >5% of patients included neutropenia, pneumonia, pyrexia, cytokine release syndrome, upper respiratory tract infection, and COVID-19.
The most common adverse reactions (=20%) were pyrexia, CRS, musculoskeletal pain, injection site reaction, fatigue, upper respiratory tract infection, nausea, headache, pneumonia, and diarrhea. The most common Grade 3 to 4 laboratory abnormalities (=20%) were decreased lymphocytes, decreased neutrophils, decreased white blood cells, decreased hemoglobin, and decreased platelets.
Table 14 summarizes the adverse reactions in MajesTEC-1.
| Adverse Reactions | Any Grade (%) | Grade 3 or 4 (%) |
| General disorders and administration site conditions | ||
| Pyrexia | 76 | 3 |
| Injection site reaction | 37 | 0.6* |
| Fatigue | 33 | 2.4* |
| Chills | 16 | 0 |
| Pain | 15 | 1.8* |
| Edema | 13 | 0 |
| Immune system disorders | ||
| Cytokine release syndrome | 72 | 0.6 |
| Hypogammaglobulinemia1 | 11 | 1.2 |
| Musculoskeletal and connective tissue disorders | ||
| Musculoskeletal pain | 44 | 4.2* |
| Bone pain | 16 | 3# |
| Infections | ||
| Upper respiratory tract infection2 | 26 | 2.4 |
| Pneumonia3+ | 24 | 15 |
| Urinary tract infection | 11 | 5# |
| Gastrointestinal disorders | ||
| Nausea | 25 | 0.6* |
| Diarrhea | 21 | 2.4* |
| Constipation | 18 | 0 |
| Vomiting | 12 | 0.6 |
| Nervous system disorders | ||
| Headache | 25 | 0.6 |
| Motor dysfunction4 | 16 | 0 |
| Sensory neuropathy5 | 15 | 1.2* |
| Encephalopathy6 | 13 | 0 |
| Vascular disorders | ||
| Hypotension | 18 | 1.2* |
| Hemorrhage | 12 | 1.8 |
| Hypertension | 12 | 4.8 |
| Respiratory, thoracic, and mediastinal disorders | ||
| Hypoxia | 18 | 1.8 |
| Cough | 15 | 0 |
| Cardiac disorders | ||
| Cardiac arrhythmia | 16 | 1.8 |
| Metabolism and nutrition disorders | ||
| Decreased appetite | 11 | 0.6 |
| Renal and urinary disorders | ||
| Acute kidney injury | 11 | 3.6 |
Adverse reactions were graded based on NCI-CTCAE Version 4.03, with the exception of CRS, which was graded per ASTCT 2019 criteria.Only grade 3 adverse reactions occurred.Only grade 3 adverse reactions occurred.Includes fatal adverse reactions: hemorrhage (n=1), pneumonia (n=3).1 Hypogammaglobulinemia includes hypogammaglobulinemia and hypoglobulinemia.2 Upper respiratory tract infection includes bronchitis, nasopharyngitis, pharyngitis, rhinitis, sinusitis, tracheitis and other related terms.3 Pneumonia includes bacterial pneumonia, viral pneumonia, and other related terms.4 Motor dysfunction includes cogwheel rigidity, dysgraphia, dysphonia, gait disturbance, hypokinesia, muscle rigidity, muscle spasms, muscular weakness, peroneal nerve palsy, psychomotor hyperactivity, tremor and VIth nerve paralysis.5 Sensory neuropathy includes dysesthesia, hypoesthesia, hypoesthesia oral, neuralgia, paresthesia, paresthesia oral, peripheral sensory neuropathy, sciatica and vestibular neuronitis.6 Encephalopathy includes agitation, apathy, aphasia, confusional state, delirium, depressed level of consciousness, disorientation, dyscalculia, hallucination, lethargy, memory impairment, mental status changes and somnolence.
Clinically relevant adverse reactions in 400 mg/dL.
Tecvayli can cause neutropenia and febrile neutropenia. In patients who received Tecvayli at the recommended dosage in the clinical trials (monotherapy and combination therapy trials; N=448), decreased neutrophils occurred in 88% of patients, with Grade 3 or 4 decreased neutrophils in 70%. Febrile neutropenia occurred in 6% of patients.
Monitor complete blood cell counts at baseline and periodically during treatment and provide supportive care per local institutional guidelines.
Monitor patients with neutropenia for signs of infection. Withhold Tecvayli based on severity.
Tecvayli can cause both systemic administration-related reactions and local injection-site reactions.
Systemic ReactionsIn patients who received the recommended Tecvayli dosage in the clinical trials (monotherapy and combination therapy trials; N=448), 2.5% of patients experienced systemic-administration reactions, which included recurrent pyrexia and rash.
Local ReactionsIn patients who received Tecvayli at the recommended dosage in the clinical trials (monotherapy and combination therapy trials; N=448), injection-site reactions occurred in 37% of patients with Grade 1 injection-site reactions in 29% and Grade 2 in 9%.
Withhold Tecvayli or consider permanent discontinuation of Tecvayli based on severity.
Based on its mechanism of action, Tecvayli may cause fetal harm when administered to a pregnant patient. Advise pregnant patients of the potential risk to the fetus. Advise females of reproductive potential to use effective contraception during treatment with Tecvayli and for 5 months after the last dose.
Risk Summary
Based on the mechanism of action, Tecvayli may cause fetal harm when administered to a pregnant patient. There are no available data on the use of Tecvayli in pregnant patients to evaluate for a drug associated risk. No animal reproductive or developmental toxicity studies have been conducted with Tecvayli. Teclistamab-cqyv causes T-cell activation and cytokine release; immune activation may compromise pregnancy maintenance. Human immunoglobulin G (IgG) is known to cross the placenta; therefore, teclistamab-cqyv has the potential to be transmitted from the mother to the developing fetus. Advise women of the potential risk to the fetus.
Tecvayli is associated with hypogammaglobulinemia, therefore, assessment of immunoglobulin levels in newborns of mothers treated with Tecvayli should be considered.
In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
Risk Summary
There are no data on the presence of teclistamab-cqyv in human milk, the effect on the breastfed child, or the effects on milk production. Maternal IgG is known to be present in human milk. The effects of local gastrointestinal exposure and limited systemic exposure in the breastfed child to Tecvayli are unknown. Because of the potential for serious adverse reactions in a breastfed child, advise women not to breastfeed during treatment with Tecvayli and for 5 months after the last dose.
TECVAYLI may cause fetal harm when administered to a pregnant patient
Pregnancy Testing
Verify pregnancy status of females of reproductive potential prior to initiating Tecvayli.
Contraception
Females
Advise females of reproductive potential to use effective contraception during treatment and for 5 months after the last dose of Tecvayli.
The safety and efficacy of Tecvayli have not been established in pediatric patients.
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
No Information Provided
None.
Teclistamab-cqyv is a bispecific T-cell engaging antibody that binds to the CD3 receptor expressed on the surface of T-cells and B-cell maturation antigen (BCMA) expressed on the surface of multiple myeloma cells and some healthy B-lineage cells. In vitro, teclistamab-cqyv activated T-cells, caused the release of various proinflammatory cytokines, and resulted in the lysis of multiple myeloma cells.
Serum concentrations of cytokines (IL-6, IL-10, TNF-a, and IFN-?) and IL-2R were measured before and after administration of step-up dose 1, step-up dose 2, and the three weekly doses of 1.5 mg/kg of Tecvayli. Increased concentrations of IL-6, IL-10, and IL-2R were observed during this period.
The Cmax and Cavg of teclistamab-cqyv after the first subcutaneous 1.5 mg/kg Tecvayli dose increase proportionally over a dosage range of 0.08 mg/kg to 3 mg/kg in monotherapy (0.05 to 2 times the approved recommended treatment dosage). Following the recommended dosage of Tecvayli monotherapy, 90% of steady state exposure was achieved after 12 weekly Tecvayli doses (1.5 mg/kg once weekly). The mean accumulation ratio between the first and 13th weekly dose of Tecvayli 1.5 mg/kg was 4.2-fold for Cmax, 4.1-fold for Ctrough, and 5.3-fold for Cavg. The pharmacokinetic characteristics of teclistamab-cqyv were consistent whether used as monotherapy or in combination with daratumumab and hyaluronidase-fihj. The Cmax, Ctrough, and Cavg of teclistamab-cqyv are presented in Table 16.
| Parameter | Cmax (µg/mL) | Ctrough (µg/mL) | Cavg (µg/mL) |
| Tecvayli Monotherapy | |||
| First 1.5 mg/kg dose | 6.34 (60%) | 5.77 (63%) | 4.98 (61%) |
| Steady state of 1.5 mg/kg weekly dosing | 23.8 (55%) | 21.1 (63%) | 22.8 (57%) |
| Tecvayli in Combination with Daratumumab and Hyaluronidase-fihj | |||
| First 1.5 mg/kg dose | 6.36 (54%) | 5.79 (59%) | 4.96 (55%) |
| End of 1.5 mg/kg weekly dosing | 19.6 (54%) | 17.3 (62%) | 18.6 (56%) |
| End of 3 mg/kg every two weeks dosing | 29.9 (55%) | 19.8 (85%) | 26.2 (62%) |
| Steady state of 3 mg/kg every 4 weeks dosing | 20.2 (52%) | 5.82 (152%) | 13.7 (67%) |
Absorption
The mean bioavailability of teclistamab-cqyv was 72% after subcutaneous administration of Tecvayli. The median (range) Tmax of teclistamab-cqyv after the first and 13th Tecvayli monotherapy treatment doses were 139 (19 to 168) hours and 72 (24 to 168) hours, respectively.
Distribution
The mean (coefficient of variation [CV]%) volume of distribution of teclistamab-cqyv was 5.63 L (29%).
Elimination
Teclistamab-cqyv clearance decreases over time, with a mean (CV%) maximal reduction from baseline to the 13th weekly Tecvayli monotherapy treatment dose of 40.8% (56%). The geometric mean (CV%) clearance is 0.472 L/day (64%) at the 13th weekly Tecvayli monotherapy treatment dose. Patients who discontinue Tecvayli after the 13th weekly monotherapy treatment dose are expected to have a 50% reduction from Cmax in teclistamab-cqyv concentration at a median 15 days after Tmax and a 97% reduction from Cmax in teclistamab-cqyv concentration at a median time of 69 days after Tmax.
Specific Populations
There were no clinically significant differences in the exposure of teclistamab-cqyv based on age (24 to 84 years), sex, race (White, Black or African American), ethnicity (Hispanic/Latino, not Hispanic/Latino), mild or moderate renal impairment, or mild hepatic impairment. The effects of severe renal impairment or moderate to severe hepatic impairment on the exposures of teclistamab-cqyv are unknown.
Body Weight
The volume of distribution and clearance of teclistamab-cqyv increase with increasing body weight (37.6 kg to 164 kg), supporting a weight-based dose.
The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of teclistamab-cqyv or of other teclistamab products. Among patients treated with subcutaneous Tecvayli at various dosages, anti-teclistamab-cqyv antibodies developed in 1/186 (0.5%) of patients who received monotherapy (up to 27 months) and in 2/379 (0.5%) of patients who received combination therapy with daratumumab and hyaluronidase-fihj (up to 43 months). Because of the low occurrence of anti-teclistamab-cqyv antibodies, the effect of these antibodies on the pharmacokinetics, pharmacodynamics, safety, and/or effectiveness of teclistamab products is unknown.
In Combination with Daratumumab and Hyaluronidase-fihj
The efficacy of Tecvayli in combination with subcutaneous daratumumab and hyaluronidase-fihj compared with investigator's choice of either daratumumab and hyaluronidase-fihj, pomalidomide and dexamethasone (DPd) or daratumumab and hyaluronidase-fihj, bortezomib and dexamethasone (DVd) was evaluated in adult patients with relapsed or refractory multiple myeloma in a randomized, open-label, multi-center study (MajesTEC-3). The study included patients who had previously received one to three prior lines of therapy including a proteasome inhibitor and lenalidomide. Patients who had received only one prior line of therapy must have been refractory to lenalidomide. Patients who had disease refractory to a prior anti-CD38 monoclonal antibody therapy, or who had received any prior BCMA-directed therapy were excluded.
Patients received Tecvayli in combination with daratumumab and hyaluronidase-fihj as follows:
The major efficacy outcome measure was progression-free survival (PFS) by Independent Review Committee (IRC) assessment based on International Myeloma Working Group (IMWG) 2016 criteria.
| Efficacy Parameter | Tecvayli with daratumumab and hyaluronidase-fihj (N=291) | DPd or DVd (N=296) |
| Progression-free survival (PFS) | ||
| Number of events, n (%) | 44 (15) | 187 (63) |
| Median, months (95% CI) | NR (NE, NE) | 18.1 (14.6, 22.8) |
| Hazard ratio (95% CI); p-value | 0.17 (0.12, 0.23); <0.0001 | |
| Overall survival (OS) | ||
| Number of events, n (%) | 46 (16) | 98 (33) |
| Median, months (95% CI) | NR (NE, NE) | NR (41.4, NE) |
| Hazard ratio (95% CI); p-value | 0.46 (0.32, 0.65); <0.0001 | |
| Overall response rate (sCR+CR+VGPR+PR), n (%) | 259 (89.0) | 223 (75.3) |
 |
 |
Monotherapy
The efficacy of Tecvayli was evaluated in patients with relapsed or refractory multiple myeloma in a single-arm, open-label, multi-center study (MajesTEC-1). The study included patients who had previously received at least three prior therapies, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody. Efficacy was established based on overall response rate (ORR) as determined by the Independent Review Committee (IRC) assessment using IMWG 2016 criteria. The efficacy population included 110 patients.
| Efficacy Parameter | N=110 |
| Overall response rate (ORR) n (%) | 68 (61.8) |
| 95% CI (%) | (52.1, 70.9) |
| Complete response (CR) or better | 31 (28.2) |
| Very good partial response (VGPR) | 32 (29.1) |
| Partial response (PR) | 5 (4.5) |
| Median Duration of Response (DOR) (months) | NE (9.0, NE) |
MEDICATION GUIDE
Tecvayli® [tek vay lee]
(teclistamab-cqyv) injection, for subcutaneous use
Tecvayli can cause side effects that are serious, life-threatening or cause death, including cytokine release syndrome (CRS) and neurologic problems.
Due to the risk of CRS, you will receive Tecvayli on a “step-up dosing” schedule. You should be hospitalized for 48 hours after the first and second step-up doses and should stay close to a healthcare facility and be monitored by a healthcare provider for 48 hours after you receive your first treatment dose.
Tecvayli is available only through the Tecvayli and Talvey Risk Evaluation and Mitigation Strategy (REMS) due to the risk of CRS and neurologic problems. You will receive a Patient Wallet Card from your healthcare provider. Carry the Patient Wallet Card with you at all times and show it to all of your healthcare providers.
Tecvayli is a prescription medicine used to treat adults with multiple myeloma that has come back or did not respond to prior treatment:
It is not known if Tecvayli is safe and effective in children.
Do not drive or operate heavy or dangerous machinery during and for 48 hours after your Tecvayli step-up dosing schedule is completed, or at any time during treatment with Tecvayli if you develop new neurologic symptoms until the symptoms go away.
Tecvayli can cause serious side effects, including:
The most common side effects of Tecvayli when used alone include: fever, CRS, muscle, joint, and bone pain, injection site reaction, tiredness, upper respiratory tract infection, nausea, headache, pneumonia, and diarrhea.
The most common side effects of Tecvayli when used with daratumumab and hyaluronidase-fihj include: low blood levels of antibodies called immunoglobins, upper respiratory tract infection, CRS, cough, diarrhea, muscle, joint, and bone pain, COVID-19, pneumonia, injection site reaction, tiredness, fever, headache, nausea, stomach area pain or cramps, and decreased weight.
The most common severe abnormal blood test results include: decreased white blood cells, red blood cells, and platelets.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
Active ingredient: teclistamab-cqyv
Inactive ingredients: edetate disodium, glacial acetic acid, polysorbate 20, sodium acetate, sucrose, Water for Injection
