Talquetamab-tgvs (Monograph)

Brand name: Talvey
Drug class: Antineoplastic Agents

Warning

Risk Evaluation and Mitigation Strategy (REMS):

Due to risks of CRS and neurologic toxicity (including ICANS), FDA approved a REMS for talquetamab-tgvs to ensure that the benefits outweigh the risks. The REMS may apply to one or more preparations of talquetamab-tgvs and consists of the following: communication plan, elements to assure safe use, and implementation system. See the FDA REMS website for specific information ([Web])

Warning

May cause CRS, including life-threatening or fatal reactions.
To reduce risk of CRS, initiate treatment with step-up dosing.
Withhold talquetamab-tgvs until CRS resolves or permanently discontinue based on severity.

Can cause neurologic toxicity, including ICANS; serious and life threatening or fatal reactions reported.
Monitor for signs and symptoms of neurologic toxicity, including ICANS, during treatment; treat promptly.
Withhold or permanently discontinue talquetamab-tgvs based on severity.

[Web]

Introduction

Antineoplastic agent; a humanized IgG₄bispecific G protein-coupled receptor class C group 5 member D (GPRC5D)-directed CD3 T-cell engager.

Uses for Talquetamab-tgvs

Relapsed or Refractory Multiple Myeloma

Treatment of relapsed or refractory multiple myeloma in adults who have received ≥4 prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody (designated an orphan drug by FDA for this use).

Accelerated approval of current indication was 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.

Guidelines recommend triplet therapy with 2 novel agents (immunomodulatory drug, proteasome inhibitor, or monoclonal antibody) plus a steroid for treatment of relapsed or refractory disease. No preference of one regimen over another is given due to lack of comparative trials.

Talquetamab-tgvs Dosage and Administration

General

Pretreatment Screening

Monitor liver enzymes and bilirubin prior to initiating talquetamab-tgvs.
Verify pregnancy status in females of reproductive potential prior to initiating talquetamab-tgvs.
Monitor patients for signs and symptoms of infection prior to treatment with talquetamab-tgvs.

Patient Monitoring

Monitor liver enzymes and bilirubin as clinically indicated during treatment with talquetamab-tgvs.
Monitor patients for signs and symptoms of infection during treatment with talquetamab-tgvs.
Monitor CBC during treatment with talquetamab-tgvs.
Monitor patients for signs and symptoms of cytokine release syndrome (CRS) during treatment with talquetamab-tgvs.
Monitor patients for signs and symptoms of neurologic toxicity, including immune effector cell-associated neurotoxicity syndrome (ICANS), during treatment with talquetamab-tgvs.
Hospitalize patients for 48 hours after administration of all doses of talquetamab-tgvs within the step-up dosing schedule to monitor for the development of CRS and neurologic toxicity, including ICANs.
Monitor patients for signs and symptoms of oral toxicity, and monitor weight regularly, during treatment with talquetamab-tgvs.
Monitor patients for skin toxicity, including rash progression, during treatment with talquetamab-tgvs.

Premedication and Prophylaxis

Administer the following pretreatment medications 1–3 hours before each dose of talquetamab-tgvs in the step-up dosing schedule to reduce the risk of CRS: corticosteroid (oral or IV dexamethasone, 16 mg or equivalent), antihistamine (oral or IV diphenhydramine, 50 mg or equivalent), and antipyretic (oral or IV acetaminophen, 650–1000 mg or equivalent). Administration of pretreatment medications for subsequent doses may be necessary for patients who repeat dosing within the step-up dosing schedule because of dosage delays or for patients who experienced CRS.

REMS Program

Because of the risks of CRS and neurologic toxicity, including ICANS, talquetamab-tgvs is only available through a restricted distribution program called the Tecvayli and Talvey Risk Evaluation and Mitigation Strategy (REMS). Prescribers, pharmacies, wholesalers, and distributors must agree to comply with requirements prior to prescribing, dispensing, or distributing talquetamab-tgvs. For further information, consult the Talvey REMS program website ([Web]) or call 1-855-810-8064.
Prescribers must enroll and complete training to become certified with the REMS program.
Prescribers must counsel patients on the risk of CRS and neurologic toxicity, including ICANS, and provide patients a patient wallet card.
Pharmacies and healthcare settings that dispense talquetamab-tgvs must be certified and must verify prescriber certification prior to dispensing talquetamab-tgvs.
Wholesalers and distributors may only distribute talquetamab-tgvs to certified pharmacies.

Administration

Sub-Q Administration

Available as a solution supplied in a single-dose vial containing 3 mg/1.5 mL (2 mg/mL) or 40 mg/mL.

For administration by a healthcare professional; should be administered only by qualified healthcare professionals with sufficient and appropriate medical support to manage severe reactions, including CRS and neurologic toxicity (including ICANS).

Administer on a weekly or biweekly (every 2 weeks) step-up dosing schedule to reduce incidence and severity of CRS.

Administer the following pretreatment medications 1–3 hours before each dose in the step-up dosing schedule: corticosteroid (oral or IV dexamethasone, 16 mg or equivalent), antihistamine (oral or IV diphenhydramine, 50 mg or equivalent), and antipyretic (oral or IV acetaminophen, 650–1000 mg or equivalent). Pretreatment medications may be required for subsequent doses for patients who repeat doses within the step-up dosing schedule due to dosage delays or for patients who experienced CRS.

Supplied as a ready-to-use solution for injection; dilution notneeded prior to administration.

Use aseptic technique for preparation and administration. For preparation, consult the reference tables in the prescribing information to determine injection volume, total dosage, and number of vials required based on the patient's actual body weight for the 0.01 mg/kg and 0.06 mg/kg doses using talquetamab-tgvs 3 mg/1.5 mL (2 mg/mL) vial, or for the 0.4 mg/kg and 0.8 mg/kg doses using talquetamab-tgvs 40 mg/mL vial.

Do not use if cloudiness, discoloration, or particles observed in solution. Do not combine vials of differing concentrations for treatment doses.

For preparation, swirl vial gently for approximately 10 seconds to mix solution; do not shake. Withdraw required injection volume from vial(s) into an appropriately sized syringe using a transfer needle. Each injection volume should not exceed 2 mL; divide doses requiring >2 mL equally into multiple syringes. Compatible with stainless steel injection needles and polypropylene or polycarbonate syringe material. Replace transfer needle with an appropriately sized needle for injection.

Abdomen preferred site for injection; may also be administered at other sites (e.g., thigh). If multiple injections required, separate administration sites by ≥2 cm. Do not inject into raised, bruised, tender, hard, or not fully intact skin areas, or tattooed or scarred skin.

Due to risks of CRS and neurologic toxicity (including ICANS), hospitalize patients for 48 hours after administration of all doses within the step-up dosing schedule.

Dosage

Adults

Multiple Myeloma

Sub-Q

Recommended dosage based on a weekly or biweekly (every 2 weeks) dosing schedule according to Table 1 or Table 2. Calculate each dose based on actual body weight (ABW). Continue until disease progression or unacceptable toxicity occurs.

Dosing based on ABW.

Table 1. Talquetamab-tgvs Weekly Dosing Schedule1
Dosing Schedule	Day	Dose
Step-up dosing schedule	Day 1	Step-up dose 1: 0.01 mg/kg
Step-up dosing schedule	Day 4 (dose may be administered 2—4 days and up to 7 days after the previous dose to allow for resolution of adverse reactions)	Step-up dose 2: 0.06 mg/kg
Step-up dosing schedule	Day 7 (dose may be administered 2—4 days and up to 7 days after the previous dose to allow for resolution of adverse reactions)	First treatment dose: 0.4 mg/kg
Weekly dosing schedule	1 week after first treatment dose and weekly thereafter (maintain ≥6 days duration between weekly doses)	Subsequent treatment doses: 0.4 mg/kg once weekly

Dosing based on ABW.

Table 2. Talquetamab-tgvs Biweekly (Every 2 Weeks) Dosing Schedule1
Dosing Schedule	Day	Dose
Step-up dosing schedule	Day 1	Step-up dose 1: 0.01 mg/kg
Step-up dosing schedule	Day 4 (dose may be administered 2—4 days and up to 7 days after the previous dose to allow for resolution of adverse reactions)	Step-up dose 2: 0.06 mg/kg
Step-up dosing schedule	Day 7 (dose may be administered 2—4 days and up to 7 days after the previous dose to allow for resolution of adverse reactions)	Step-up dose 3: 0.4 mg/kg
Step-up dosing schedule	Day 10 (dose may be administered 2—7 days after step-up dose 3)	First treatment dose: 0.8 mg/kg
Biweekly (every 2 weeks) dosing schedule	2 weeks after first treatment dose and every 2 weeks thereafter (maintain ≥12 days duration between biweekly doses)	Subsequent treatment doses: 0.8 mg/kg every 2 weeks

<C> Dosage Modification for Toxicity

Dosage delays may be necessary for management of toxicities.

Refer to Table 3 for recommendations on management of CRS with talquetamab-tgvs. Identify CRS based on clinical presentation. Evaluate and treat other causes of fever, hypoxia, and hypotension. If CRS suspected, withhold talquetamab-tgvs until CRS resolution or permanently discontinue based on severity. Manage in accordance with the recommendations in Table 3; consider further management per current clinical 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 and hematologic parameters, in addition to pulmonary, cardiac, renal, and hepatic function.

See Table 7 and Table 8 for recommendations on restarting talquetamab-tgvs after dosage delays due to adverse reactions.

Table 3. Recommendations for Management of CRS1
Grade	Presenting Symptoms	Recommendations
Grade 1	Temperature ≥38°C (fever may not always be present concurrently with hypotension or hypoxia since it may be masked by interventions such as antipyretics or anticytokine therapy [e.g., corticosteroids])	Withhold talquetamab-tgvs until CRS resolves Give pretreatment medications prior to next dose of talquetamab-tgvs
Grade 2	Temperature ≥38°C (fever may not always be present concurrently with hypotension or hypoxia since it may be masked by interventions such as antipyretics or anticytokine therapy [e.g., corticosteroids]), in addition to either: Hypotension that is responsive to fluid administration and not requiring vasopressor therapy, or Oxygen requirement of low-flow nasal cannula (≤6 L/minute) or blow-by	Withhold talquetamab-tgvs until CRS resolves Give pretreatment medications prior to next dose of talquetamab-tgvs Hospitalize patients for 48 hours following the next dose of talquetamab-tgvs
Grade 3	Temperature ≥38°C (fever may not always be present concurrently with hypotension or hypoxia since it may be masked by interventions such as antipyretics or anticytokine therapy [e.g., corticosteroids]), in addition to either: Hypotension that requires 1 vasopressor agent (with or without vasopressin), or Oxygen requirement of high-flow nasal cannula (>6 L/minute), facemask, non-rebreather mask, or Venturi mask	Duration <48 hours: Withhold talquetamab-tgvs until CRS resolves Provide supportive therapy (may include intensive care) Give pretreatment medications prior to next dose of talquetamab-tgvs Hospitalize patients for 48 hours following the next dose of talquetamab-tgvs Recurrent CRS or duration ≥48 hours: Permanently discontinue talquetamab-tgvs Provide supportive therapy (may include intensive care)
Grade 4	Temperature ≥38°C (fever may not always be present concurrently with hypotension or hypoxia since it may be masked by interventions such as antipyretics or anticytokine therapy [e.g., corticosteroids]), in addition to either: Hypotension that requires multiple vasopressor agents (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 talquetamab-tgvs Provide supportive therapy (may include intensive care)

Refer to Tables 4 and 5 for recommendations on management of ICANS and neurologic toxicity (excluding ICANS) with talquetamab-tgvs, respectively. At first sign of neurologic toxicity (including ICANS), withhold talquetamab-tgvs and consider neurologic evaluation. Rule out other causes of neurologic symptoms. Provide supportive therapy (including intensive care if needed) for severe and life-threatening neurologic toxicities, including ICANS. Manage ICANS and neurologic toxicity in accordance with recommendations in Table 4 and Table 5; consider further management per current practice guidelines.

Management determined by the most severe event, not attributable to any other cause.

If arousable and able to perform the 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 (counting backwards from 100 by 10 = 1 point). If the patient is unarousable and is unable to perform the ICE assessment (Grade 4 ICANS) = 0 points.

See Table 7 and Table 8 for recommendations on restarting talquetamab-tgvs after dosage delays due to adverse reactions.

Table 4. Recommendations for Management of ICANS1
Grade	Presenting Symptoms	Recommendations
Grade 1	Immune Effector-Cell Encephalopathy (ICE) Assessment score 7—9, OR Depressed level of consciousness (not attributable to other causes): spontaneous awakening	Withold talquetamab-tgvs until ICANS resolves Monitor neurologic symptoms; consider consultation with neurologist/other specialists for further evaluation and management Consider administration of seizure prophylaxis medications that are nonsedating (e.g., levetiracetam)
Grade 2	ICE score 3—6, OR Depressed level of consciousness (not attributable to other causes): awakens to voice	Withold talquetamab-tgvs until ICANS resolves Give dexamethasone (or equivalent) 10 mg IV every 6 hours until resolution to grade 1 or lower, then taper Monitor neurologic symptoms; consider consultation with neurologist/other specialists for further evaluation and management Consider administration of seizure prophylaxis medications that are nonsedating (e.g., levetiracetam) Hospitalize patients for 48 hours following the next dose of talquetamab-tgvs
Grade 3	ICE score 0—2 (if ICE score of 0, but arousable [e.g., awake with global aphasia]) and able to perform assessment, OR Depressed level of consciousness (not attributable to other causes): awakens only to tactile stimulus, OR Presence of seizure (not attributable to other causes), either: clinical seizure, focal or generalized, that resolves quickly or nonconvulsive seizures detectable on EEG that resolve with intervention, OR Increased intracranial pressure (not attributable to other causes): focal/localized edema on neuroimaging	First occurrence of grade 3 ICANS: Withold talquetamab-tgvs until ICANS resolves Give dexamethasone (or equivalent) 10 mg IV every 6 hours until resolution to grade 1 or lower, then taper Monitor neurologic symptoms; consider consultation with neurologist/other specialists for further evaluation and management Consider administration of seizure prophylaxis medications that are nonsedating (e.g., levetiracetam) Provide supportive therapy (including intensive care) Hospitalize patients for 48 hours following the next dose of talquetamab-tgvs Recurrent grade 3 ICANS: Permanently discontinue talquetamab-tgvs Give dexamethasone (or equivalent) 10 mg IV every 6 hours until resolution to grade 1 or lower, then taper Monitor neurologic symptoms; consider consultation with neurologist/other specialists for further evaluation and management Consider administration of seizure prophylaxis medications that are nonsedating (e.g., levetiracetam) Provide supportive therapy (including intensive care)
Grade 4	ICE score 0 (unarousable and unable to perform assessment), OR Depressed level of consciousness (not attributable to other causes): either unarousable or requiring vigorous/repetitive tactile stimuli to arouse, or coma/stupor, OR Presence of seizures (not attributable to other causes), either: life-threatening, prolonged seizure (lasting >5 minutes) or repetitive clinical/electrical seizures without return to baseline between seizures), OR Motor findings (not attributable to other causes): deep focal motor weakness such as hemiparesis or paraparesis, OR Increased intracranial pressure/cerebral edema (not attributable to other causes) with signs and 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 talquetamab-tgvs Give dexamethasone (or equivalent) 10 mg IV every 6 hours until resolution to grade 1 or lower, then taper; alternately, may give methylprednisolone 1000 mg IV daily for 2 or more days Monitor neurologic symptoms; consider consultation with neurologist/other specialists for further evaluation and management Consider administration of seizure prophylaxis medications that are nonsedating (e.g., levetiracetam) Provide supportive therapy (including intensive care)

See Table 7 and Table 8 for recommendations on restarting talquetamab-tgvs after dosage delays due to adverse reactions.

Table 5. Recommendations for Management of Neurologic Toxicity, Excluding ICANS1
Severity of Neurologic Toxicity (excluding ICANS)	Recommendations
Grade 1	Withhold talquetamab-tgvs until neurologic symptoms resolve or stabilize
Grade 2 or grade 3 (first occurrence)	Withhold talquetamab-tgvs until neurologic symptoms improve to grade 1 or lower Provide supportive therapy
Grade 3 (recurrent) or grade 4	Permanently discontinue talquetamab-tgvs Provide supportive therapy (including intensive care if needed)

Refer to Table 6 for dosage modification recommendations for other adverse reactions, including oral toxicity and weight loss, infections, cytopenias, skin reactions, and other nonhematologic adverse reactions.

See Table 7 and Table 8 for recommendations on restarting talquetamab-tgvs after dosage delays due to adverse reactions.

For grade 3—4 infection, if talquetamab-tgvs is withheld for >28 days, restart the step-up dosing schedule when infection improves to grade 1 or better.

Table 6. Dosage Modification Recommendations for Other Adverse Reactions1
Adverse Reaction	Severity	Recommendations
Oral toxicity and weight loss	Grade 1—2	Provide supportive care, and consider withholding talquetamab-tgvs if not responsive to supportive care
Oral toxicity and weight loss	Grade 3	Withhold talquetamab-tgvs until resolution to grade 1 or better, and provide supportive care
Oral toxicity and weight loss	Grade 4	Permanently discontinue talquetamab-tgvs
Infections	All grades	Withhold talquetamab-tgvs during the step-up dosing schedule until the infection resolves
Infections	Grade 3	Withhold talquetamab-tgvs during the treatment phase until the infection improves to grade 1 or better within 28 days
Infections	Grade 4	Consider permanently discontinuing talquetamab-tgvs If talquetamab-tgvs is not permanently discontinued, withhold subsequent talquetamab-tgvs treatment doses (i.e., doses given after step-up dosing schedule) until infection improves to grade 1 or better
Cytopenias	ANC <500/mm³	Withhold talquetamab-tgvs until ANC ≥500/mm³
Cytopenias	Febrile neutropenia	Withhold talquetamab-tgvs until ANC ≥1000/mm³ and fever resolves
Cytopenias	Hemoglobin <8 g/dL	Withhold talquetamab-tgvs until hemoglobin ≥8 g/dL
Cytopenias	Platelets <25,000/mm³ or platelets 25,000—50,000/mm³with bleeding	Withhold talquetamab-tgvs until platelets recover to ≥25,000/mm³ and no evidence of bleeding
Skin reactions	Grade 3—4	Withhold talquetamab-tgvs until adverse reaction improves to grade 1 or baseline
Other nonhematologic adverse reactions	Grade 3	Withhold talquetamab-tgvs until adverse reaction improves to grade 1 or baseline
Other nonhematologic adverse reactions	Grade 4	Consider permanently discontinuing talquetamab-tgvs If talquetamab-tgvs is not permanently discontinued, withhold subsequent talquetamab-tgvs treatment doses (i.e., doses given after step-up dosing schedule) until adverse reaction improves to grade 1 or lower

Dosage delays may be necessary for management of toxicities. If there is a dosage delay, restart talquetamab-tgvs and resume weekly dosing based on recommendations in Table 7 or biweekly (every 2 weeks) dosing based on recommendations in Table 8. If talquetamab-tgvs dosage delayed for >28 days because of an adverse reaction, evaluate benefits and risks of restarting treatment. Administer pretreatment medications prior to restarting talquetamab-tgvs and monitor patients following administration of talquetamab-tgvs.

Administer premedications before restarting talquetamab-tgvs. Once talquetamab-tgvs is restarted, resume weekly dosing schedule accordingly.

Table 7. Recommendations for Restarting Talquetamab-tgvs after Dosage Delay Based on Weekly Dosing Schedule1
Last Dose Administered	Time Elapsed Since Administration of Last Dose	Recommendation
0.01 mg/kg	>7 days	Restart step-up dosing schedule at step-up dose 1 (0.01 mg/kg)
0.06 mg/kg	8—28 days	Repeat step-up dose 2 (0.06 mg/kg), and continue step-up dosing schedule
0.06 mg/kg	>28 days	Restart step-up dosing schedule at step-up dose 1 (0.01 mg/kg)
0.4 mg/kg	8—28 days	Continue dosing schedule at treatment dosage (0.4 mg/kg)
0.4 mg/kg	29—56 days	Restart step-up dosing schedule at step-up dose 2 (0.06 mg/kg)
0.4 mg/kg	>56 days	Consider permanently discontinuing talquetamab-tgvs If the decision is made to restart talquetamab-tgvs, start the step-up dosing schedule at step-up dose 1 (0.01 mg/kg)

Administer premedications before restarting talquetamab-tgvs. Once talquetamab-tgvs is restarted, resume biweekly dosing schedule accordingly.

Table 8. Recommmendations for Restarting Talquetamab-tgvs after Dosage Delay Based on Biweekly (Every 2 Weeks) Dosing Schedule1
Last Dose Administered	Time Elapsed Since Administration of Last Dose	Recommendation
0.01 mg/kg	>7 days	Restart step-up dosing schedule at step-up dose 1 (0.01 mg/kg)
0.06 mg/kg	8—28 days	Repeat step-up dose 2 (0.06 mg/kg), and continue step-up dosing schedule
0.06 mg/kg	>28 days	Restart step-up dosing schedule at step-up dose 1 (0.01 mg/kg)
0.4 mg/kg	8—28 days	Repeat step-up dose 3 (0.4 mg/kg), and continue step-up dosing schedule
0.4 mg/kg	29—56 days	Restart step-up dosing schedule at step-up dose 2 (0.06 mg/kg)
0.4 mg/kg	>56 days	Consider permanently discontinuing talquetamab-tgvs If the decision is made to restart talquetamab-tgvs, start the step-up dosing schedule at step-up dose 1 (0.01 mg/kg)
0.8 mg/kg	15—28 days	Continue dosing schedule at treatment dosage (0.8 mg/kg)
0.8 mg/kg	29—56 days	Restart step-up dosing schedule at step-up dose 3 (0.4 mg/kg)
0.8 mg/kg	>56 days	Consider permanently discontinuing talquetamab-tgvs If the decision is made to restart talquetamab-tgvs, start the step-up dosing schedule at step-up dose 1 (0.01 mg/kg)

Special Populations

Hepatic Impairment

No specific dosage recommendations at this time.

Renal Impairment

No specific dosage recommendations at this time.

Geriatric Patients

No specific dosage recommendations at this time.

No overall differences in safety or efficacy observed between patients 65 to <74 years of age compared to younger adults; however, incidence of fatal adverse reactions higher in patients ≥75 years of age compared to younger adults.

Cautions for Talquetamab-tgvs

Contraindications

None.

Warnings/Precautions

Warnings

Cytokine Release Syndrome

Clinical signs and symptoms of cytokine release syndrome (CRS) may include but are not limited to pyrexia, hypotension, chills, hypoxia, headache, and tachycardia. Potential, life-threatening complications of CRS can include cardiac dysfunction, acute respiratory distress syndrome, neurologic toxicity, renal and/or hepatic failure, and disseminated intravascular coagulation (See Boxed Warning.).

To reduce risk of CRS, initiate talquetamab-tgvs with step-up dosing, administer pre-treatment medications (corticosteroid, antihistamine, and antipyretic) prior to each dose of talquetamab-tgvs in the step-up dosing schedule, and monitor patients following administration. In patients who develop CRS, administer pre-treatment medications prior to next dose of talquetamab-tgvs.

Advise patients to seek immediate medical attention if they experience signs or symptoms of CRS. Immediately evaluate patients at the first sign of CRS for hospitalization, and treat with supportive care based on severity; consider further management in accordance with current practice guidelines. Withhold talquetamab-tgvs until CRS resolves or permanently discontinue talquetamab-tgvs based on reaction severity.

Due to risk of CRS, talquetamab-tgvs only available through a Risk Evaluation and Mitigation Strategy (REMS) program. For further information, consult the Talvey REMS program website ([Web]) or call 1-855-810-8064.

Neurologic Toxicity

Most frequently reported neurologic toxicities include headache, encephalopathy, sensory neuropathy, and motor dysfunction. Clinical signs and symptoms of immune effector cell-associated neurotoxicity syndrome (ICANS) may include but are not limited to a state of confusion, depressed level of consciousness, disorientation, somnolence, lethargy, and bradyphrenia (See Boxed Warning.).

Monitor for signs and symptoms of neurologic toxicity during treatment. At first sign of neurologic toxicity (including ICANS), immediately evaluate patient and provide supportive care based on severity. Withhold or permanently discontinue talquetamab-tgvs based on severity. Consider further management in accordance with current practice guidelines.

Increased risk of a depressed level of consciousness. Advise patients to avoid driving or operating heavy or potentially dangerous machinery during the step-up dosing schedule and for 48 hours after completing the step-up dosing schedule, or in the event of new onset of any neurologic symptoms, until symptoms resolve.

Due to risk of neurologic toxicity, including ICANS, talquetamab-tgvs only available through a REMS program. For further information, consult the Talvey REMS program website ([Web]) or call 1-855-810-8064.

<C> Other Warnings and Precautions

Oral Toxicity and Weight Loss

Can cause oral toxicities (e.g., dysgeusia, dry mouth, dysphagia, stomatitis) and weight loss.

Monitor for signs and symptoms of oral toxicity, and monitor weight regularly. Advise patients to seek medical attention for signs or symptoms of oral toxicity. Provide supportive care in accordance with current practice guidelines, including nutritionist consultation. Perform further evaluation for clinically important weight loss. Withhold or permanently discontinue talquetamab-tgvs based on severity.

Infections

Can cause serious infections, including life-threatening or fatal infections.

Prior to and during talquetamab-tgvs therapy, monitor patients for signs and symptoms of infection and administer appropriate treatment as necessary. Consider prophylactic antibiotics in accordance with local guidelines. Withhold or consider permanent discontinuation of talquetamab-tgvs as recommended based on severity.

Cytopenias

Can cause cytopenias, including neutropenia and thrombocytopenia.

Monitor CBC during treatment and withhold talquetamab-tgvs as recommended based on severity.

Skin Toxicity

Can cause serious skin reactions (e.g., rash, maculopapular rash, erythema, erythematous rash).

Monitor for skin toxicity and rash progression. Consider early intervention and treatment to manage skin toxicity. Withhold talquetamab-tgvs as recommended based on severity.

Hepatotoxicity

Can cause hepatoxicity; elevations in liver enzymes may occur with or without concomitant CRS.

Monitor ALT, AST, and bilirubin prior to and during treatment as clinically indicated. Withhold or permanently discontinue talquetamab-tgvs based on severity.

Fetal/Neonatal Morbidity and Mortality

Based on mechanism of action, may cause fetal harm. Causes immune activation, which may compromise pregnancy maintenance. Human IgG known to cross placenta; potential for maternal drug transmission to developing fetus. No animal reproductive or developmental toxicity studies performed to date.

Apprise pregnant women and females of reproductive potential of the potential hazard to a fetus. Verify pregnancy status in females of reproductive potential prior to initiating talquetamab-tgvs. Advise females of reproductive potential to use effective contraception during treatment with talquetamab-tgvs and for 3 months after the final dose.

Immunogenicity

Potential for immunogenicity.

No clinically important effects of anti-talquetamab-tgvs antibodies observed on talquetamab-tgvs pharmacokinetics, pharmacodynamics, safety, or effectiveness.

Specific Populations

Pregnancy

May cause fetal harm based on mechanism of action; no data available on use during pregnancy to evaluate for a drug-associated risk. No animal reproductive or developmental toxicity studies performed to date.

Causes T-cell activation and cytokine release; immune activation may compromise pregnancy maintenance. Human IgG known to cross placenta; potential for maternal transmission of talquetamab-tgvs to developing fetus.

Apprise pregnant women and females of reproductive potential of the potential hazard to a fetus. Verify pregnancy status in females of reproductive potential prior to initiating talquetamab-tgvs.

Lactation

Unknown if present in human milk or if affects breast-fed child or milk production.

Human milk contains maternal IgG. Effects of local GI exposure and limited systemic exposure in the breast-fed infant to talquetamab-tgvs unknown.

Because of potential for serious adverse reactions in breast-fed infants, advise women not to breast-feed during treatment with talquetamab-tgvs and for 3 months after the final dose.

Females and Males of Reproductive Potential

May cause fetal harm.

Verify pregnancy status in females of reproductive potential prior to starting talquetamab-tgvs.

Advise females of reproductive potential to use effective contraception during treatment with talquetamab-tgvs and for 3 months following the final dose.

No studies evaluating effects on fertility performed to date.

Pediatric Use

Safety and effectiveness not established.

Geriatric Use

No overall differences in efficacy or safety observed in patients 65 to <74 years of age compared to younger adults; however, higher rate of fatal adverse reactions observed in patients ≥75 years of age compared to younger adults.

Insufficient number of patients ≥75 years of age included in clinical studies to determine differences in response.

Hepatic Impairment

Mild (total bilirubin ≤ULN with AST>ULN, or total bilirubin >1—1.5 times ULN with any AST concentration) or moderate hepatic impairment (total bilirubin >1.5 to <3 times ULN with any AST concentration): no clinically important effects on talquetamab-tgvs pharmacokinetics.

Severe hepatic impairment (total bilirubin >3 times ULN with any AST concentration): effects on talquetamab-tgvs pharmacokinetics unknown.

Renal Impairment

Mild or moderate renal impairment (Cl_cr 30—89 mL/minute): no clinically important effects on talquetamab-tgvs pharmacokinetics.

Severe renal impairment (Cl_cr <30 mL/minute): effects on talquetamab-tgvs pharmacokinetics unknown.

Common Adverse Effects

Most common adverse effects (incidence ≥20%): pyrexia, CRS, dysgeusia, nail disorder, musculoskeletal pain, skin disorder, rash, fatigue, decreased weight, dry mouth, xerosis, dysphagia, upper respiratory tract infection, diarrhea, hypotension, headache.

Drug Interactions

Drugs Affecting or Affected by Hepatic Microsomal Enzymes

Causes release of proinflammatory cytokines that may suppress the activity of CYP isoenzymes; can result in increased exposure of CYP substrates. Increased CYP substrate exposure more likely to occur from initiation of talquetamab-tgvs step-up dosing schedule up to 14 days following first treatment dose, and also during and following episodes of cytokine release syndrome.

For certain substrates, small changes in substrate plasma concentrations may lead to serious adverse events. Monitor plasma concentrations of such substrates and monitor for signs of toxicity when given concomitantly with talquetamab-tgvs.

Talquetamab-tgvs Pharmacokinetics

Absorption

Bioavailability

Peak plasma concentration and AUC increase proportionally over sub-Q dosage range of 0.005—0.8 mg/kg weekly (0.01—2 times the recommended 0.4 mg/kg weekly treatment dose) and 0.8—1.2 mg/kg every 2 weeks (1—1.5 times the recommended 0.8 mg/kg every 2 weeks treatment dose).

For both weekly and biweekly (every 2 week) regimens, 90% of steady-state exposure achieved 16 weeks following first treatment dose.

Mean bioavailability following sub-Q administration: 59%.

Peak plasma concentration achieved at a median of 3.7 days following first treatment dose and 2.5 days following 17th treatment dose of 0.4 mg/kg once weekly.

Peak plasma concentration achieved at a median of 3.4 days following first treatment dose and 3.6 days following 9th treatment dose of 0.8 mg/kg every 2 weeks.

Distribution

Extent

Not known if talquetamab-tgvs distributed into human milk; maternal IgG present in human milk.

Special Populations

Volume of distribution increased with increasing bodyweight (40–143 kg).

Elimination

Metabolism

Expected to undergo metabolism via catabolic pathways into small peptides.

Half-life

Mean elimination half-life: 8.4 days after first treatment dose; 12.2 days at 16 weeks after first treatment dose.

Clearance decreases over time; mean maximal reduction of 40% from first treatment dose to 16 weeks after first treatment dose.

Special Populations

Clearance increased with increasing bodyweight (40–143 kg).

Age (33—86 years), sex, race (white, Black, or African American), or ethnicity (not Hispanic/Latino or Hispanic/Latino): no clinically important differences in talquetamab-tgvs pharmacokinetics observed.

Stability

Storage

Parenteral

Injection for Sub-Q Use

Store refrigerated at 2—8°C in original carton to protect from light; do not freeze. Once removed from refrigeration, allow vials to equilibrate to room temperature at 15—30°C for ≥15 minutes; do not warm vials in any other manner.

Use prepared syringes of talquetamab-tgvs immediately. If cannot be used immediately, store refrigerated at 2—8°C for ≤24 hours, followed by room temperature at 15—30°C for ≤24 hours. Discard syringes if stored for >24 hours under refrigeration or >24 hours at room temperature.

Actions

Humanized IgG₄ bispecific T-cell engaging antibody.
Binds to CD3 receptor and G protein-coupled receptor class C group 5 member D (GPRC5D). The CD3 receptor is expressed on surface of T-cells; GPRC5D is expressed on surface of multiple myeloma cells, benign plasma cells, and healthy tissues (e.g., epithelial cells in keratinized tissues of skin and tongue).
In vitro, activates T-cells to cause release of proinflammatory cytokines, leading to lysis of multiple myeloma cells. Increased concentrations of IL-6, IL-10, and IL-2R were observed after administration of step-up doses and first 3 treatment doses.
Anti-tumor activity observed in mouse models of multiple myeloma.

Advice to Patients

Advise patients to read the FDA-approved patient labeling (medication guide).
Advise patients to seek medical attention if they experience signs or symptoms of cytokine release syndrome (CRS), which include but are not limited to pyrexia, hypotension, chills, hypoxia, headache, and tachycardia. Inform patients that they should be hospitalized for 48 hours after administration of all doses of talquetamab-tgvs during the step-up dosing schedule.
Advise patients to seek medical attention if signs or symptoms of immune effector cell-associated neurotoxicity syndrome (ICANS) occur. Inform patients of the signs and symptoms of neurologic toxicity (including ICANS), which include headache, encephalopathy, sensory neuropathy, motor dysfunction, confusion, depressed level of consciousness, disorientation, somnolence, lethargy, and bradyphrenia. Advise patients to avoid driving or operating heavy or dangerous machinery during the talquetamab-tgvs step-up dosing schedule and for 48 hours after completing the step-up dosing schedule, or in the case of new onset of neurologic toxicity symptoms, until symptoms resolve.
Inform patients that talquetamab-tgvs is only available through a restricted program called the Tecvayli and Talvey REMS. Inform patients that they will receive a patient wallet card that must be carried with them at all times and shown to all their healthcare providers. Inform patients that the card describes signs and symptoms of CRS and neurologic toxicity (including ICANS), which, if they develop, should prompt them to immediately seek medical care.
Advise patients to seek medical attention if they develop signs or symptoms of oral toxicity, including dysgeusia, dry mouth, dysphagia, and stomatitis. Inform patients that they could lose weight during treatment with talquetamab-tgvs, and to report any weight loss. Advise patients that they may be referred to a nutritionist for consultation.
Inform patients of the signs and symptoms of serious infections.
Inform patients of the signs and symptoms associated with neutropenia and thrombocytopenia.
Inform patients of the signs and symptoms of skin reactions.
Inform patients that liver enzyme elevations can occur during treatment with talquetamab-tgvs. Advise patients to report symptoms that may indicate liver toxicity, including fatigue, anorexia, right upper abdominal discomfort, dark urine, and jaundice.
Advise patients to inform their clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.
Advise women to inform their clinician if they are or plan to become pregnant. Apprise pregnant women and females of reproductive potential of the potential hazard to a fetus. Advise females of reproductive potential to use effective contraception during treatment with talquetamab-tgvs and for 3 months after the last dose.
Advise women to inform their clinician if they are or plan to breast-feed. Advise women not to breast-feed during treatment with talquetamab-tgvs and for 3 months after the last dose.
Inform patients of other important precautionary information.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care. For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Distribution of talquetamab-tgvs is restricted. (See REMS under Dosage and Administration.)

Talquetamab-tgvs
Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Parenteral	Injection, for subcutaneous use	3 mg/1.5 mL (2 mg/mL)	Talvey	Janssen Biotech
		40 mg/mL	Talvey	Janssen Biotech

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