Introduction

Talquetamab-tgvs, a bispecific G protein-coupled receptor class C group 5 member D (GPRC5D)-directed CD3 T-cell engager, is an antineoplastic agent.

Uses for Talquetamab (Systemic)

Talquetamab-tgvs has the following uses:

Talquetamab-tgvs 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. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

Talquetamab (Systemic) Dosage and Administration

General

Talquetamab-tgvs is available in the following dosage form(s) and strength(s):

Injection

• 3 mg/1.5 mL (2 mg/mL) in a single-dose vial for subcutaneous injection

• 40 mg/mL in a single-dose vial for subcutaneous injection

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

Adults

Dosage and Administration

• For subcutaneous injection.

• Patients should be hospitalized for 48 hours after all doses within the step-up dosing schedule.

• Administer pretreatment medications as recommended.

• See Full Prescribing Information for instructions on preparation and administration.

• Administer talquetamab-tgvs subcutaneously on a weekly or biweekly (every 2 weeks) dosing schedule according to Table 1 or Table 2. Calculate the dose based on actual body weight. Continue treatment until disease progression or unacceptable toxicity. Initiate treatment with a step-up dosing schedule to reduce risk of cytokine release syndrome (CRS).

• Dosage delays may be required to manage toxicities. See Full Prescribing Information for specific instructions.

• If a dose of talquetamab-tgvs is delayed, restart therapy as recommended. See Full Prescribing Information for specific instructions.

Contraindications

None.

Warnings/Precautions

Cytokine Release Syndrome (CRS)

Talquetamab-tgvs can cause cytokine release syndrome, including life-threatening or fatal reactions.

In the clinical trial, CRS occurred in 76% of patients who received talquetamab-tgvs at the recommended dosages, with Grade 1 CRS occurring in 57% of patients, Grade 2 in 17%, and Grade 3 in 1.5%. Recurrent CRS occurred in 30% of patients. Most events occurred following step-up dose 1 (29%) or step-up dose 2 (44%) at the recommended dosages. CRS occurred in 33% of patients with step-up dose 3 in the biweekly dosing schedule (N=153). CRS occurred in 30% of patients with the first 0.4 mg/kg treatment dose and in 12% of patients treated with the first 0.8 mg/kg treatment dose. The CRS rate for both dosing schedules combined was less than 3% for each of the remaining doses in Cycle 1 and less than 3% cumulatively from Cycle 2 onward. The median time to onset of CRS was 27 (range: 0.1 to 167) hours from the last dose, and the median duration was 17 (range: 0 to 622) hours. Clinical signs and symptoms of CRS include but are not limited to pyrexia, hypotension, chills, hypoxia, headache, and tachycardia. Potentially life-threatening complications of CRS may include cardiac dysfunction, acute respiratory distress syndrome, neurologic toxicity, renal and/or hepatic failure, and disseminated intravascular coagulation (DIC).

Initiate talquetamab-tgvs therapy with step-up dosing and administer pre-treatment medications (corticosteroids, antihistamine, and antipyretics) prior to each dose of talquetamab-tgvs in the step-up dosing schedule to reduce the risk of CRS. Monitor patients following administration accordingly. In patients who experience CRS, pre-treatment medications should be administered prior to the next talquetamab-tgvs dose.

Counsel patients to seek medical attention should signs or symptoms of CRS occur. At the first sign of CRS, immediately evaluate patient for hospitalization and institute treatment with supportive care based on severity and consider further management per current practice guidelines. Withhold talquetamab-tgvs until CRS resolves or permanently discontinue based on severity.

Talquetamab-tgvs is available only through a restricted program under a REMS.

Neurologic Toxicity Including ICANS

Talquetamab-tgvs can cause serious, life-threatening, or fatal neurologic toxicity, including immune effector cell-associated neurotoxicity syndrome (ICANS).

In the clinical trial, neurologic toxicity, including ICANS, occurred in 55% of patients who received talquetamab-tgvs at the recommended dosages, with Grade 3 or 4 neurologic toxicity occurring in 6% of patients. The most frequent neurologic toxicities were headache (20%), encephalopathy (15%), sensory neuropathy (14%), and motor dysfunction (10%).

ICANS was reported in 9% of 265 patients where ICANS was collected and who received talquetamab-tgvs at the recommended dosages. Recurrent ICANS occurred in 3% of patients. Most patients experienced ICANS following step-up dose 1 (3%), step-up dose 2 (3%), step-up dose 3 of the biweekly dosing schedule (1.8%), or the initial treatment dose of the weekly dosing schedule (2.6%) (N=156) or the biweekly dosing schedule (3.7%) (N=109). The median time to onset of ICANS was 2.5 (range: 1 to 16) days after the most recent dose with a median duration of 2 (range: 1 to 22) days. The onset of ICANS can be concurrent with CRS, following resolution of CRS, or in the absence of CRS. Clinical signs and symptoms of ICANS may include but are not limited to confusional state, depressed level of consciousness, disorientation, somnolence, lethargy, and bradyphrenia.

Monitor patients for signs and symptoms of neurologic toxicity during treatment. At the first sign of neurologic toxicity, including ICANS, immediately evaluate the patient and provide supportive care based on severity; withhold or permanently discontinue talquetamab-tgvs based on severity and consider further management per current practice guidelines.

Due to the potential for neurologic toxicity, patients receiving talquetamab-tgvs are at risk of depressed level of consciousness. Advise patients to refrain from driving or operating heavy or potentially dangerous machinery during the step-up dosing schedule and for 48 hours after completion of the step-up dosing schedule and in the event of new onset of any neurological symptoms, until symptoms resolve.

Talquetamab-tgvs is available only through a restricted program under a REMS.

REMS

Talquetamab-tgvs is available only through a restricted program under a REMS called the TECVAYLI and TALVEY REMS because of the risks of CRS and neurologic toxicity, including ICANS.

Notable requirements of the REMS include the following:

• Prescribers must be certified with the program by enrolling and completing training.

• Prescribers must counsel patients receiving talquetamab-tgvs about the risk of CRS and neurologic toxicity, including ICANS and provide patients with Patient Wallet Card.

• Pharmacies and healthcare settings that dispense talquetamab-tgvs must be certified with the REMS program and must verify prescribers are certified through the REMS program.

• Wholesalers and distributers must only distribute talquetamab-tgvs to certified pharmacies.

Further information about the TECVAYLI and TALVEY REMS program is available at www.TEC-TALREMS.com or by telephone at 1-855-810-8064.

Oral Toxicity and Weight Loss

Talquetamab-tgvs can cause oral toxicities, including dysgeusia, dry mouth, dysphagia, and stomatitis.

In the clinical trial, 80% of patients had oral toxicity, with Grade 3 occurring in 2.1% of patients who received talquetamab-tgvs at the recommended dosages. The most frequent oral toxicities were dysgeusia (49%), dry mouth (34%), dysphagia (23%), and ageusia (18%). The median time to onset of oral toxicity was 15 (range: 1 to 634) days, and the median time to resolution to baseline was 43 (1 to 530) days. Oral toxicity did not resolve to baseline in 65% of patients.

Talquetamab-tgvs can cause weight loss. In the clinical trial, 62% of patients experienced weight loss, regardless of having an oral toxicity, including 29% of patients with Grade 2 (10% or greater) weight loss and 2.7% of patients with Grade 3 (20% or greater) weight loss. The median time to onset of Grade 2 or higher weight loss was 67 (range: 6 to 407) days, and the median time to resolution was 50 (range: 1 to 403) days. Weight loss did not resolve in 57% of patients who reported the adverse effect.

Monitor patients for signs and symptoms of oral toxicity. Counsel patients to seek medical attention should signs or symptoms of oral toxicity occur and provide supportive care as per current clinical practice including consultation with a nutritionist. Monitor weight regularly during therapy. Evaluate clinically significant weight loss further. Withhold talquetamab-tgvs or permanently discontinue based on severity.

Infections

Talquetamab-tgvs can cause serious infections, including life-threatening or fatal infections.

In the clinical trial, serious infections occurred in 16% of patients, with fatal infections in 1.5% of patients. Grade 3 or 4 infections occurred in 17% of patients. The most common serious infections reported were bacterial infection (8%), which included sepsis, and COVID-19 (2.7%).

Monitor patients for signs and symptoms of infection prior to and during treatment with talquetamab-tgvs and treat appropriately. Administer prophylactic antimicrobials according to local guidelines. Withhold or consider permanent discontinuation of talquetamab-tgvs as recommended based on severity.

Cytopenias

Talquetamab-tgvs can cause cytopenias, including neutropenia and thrombocytopenia.

In the clinical trial, Grade 3 or 4 decreased neutrophils occurred in 35% of patients, and Grade 3 or 4 decreased platelets occurred in 22% of patients who received talquetamab-tgvs. The median time to onset for Grade 3 or 4 neutropenia was 22 (range: 1 to 312) days, and the median time to resolution to Grade 2 or lower was 8 (range: 1 to 79) days. The median time to onset for Grade 3 or 4 thrombocytopenia was 12 (range: 2 to 183) days, and the median time to resolution to Grade 2 or lower was 10 (range: 1 to 64) days. Monitor complete blood counts during treatment and withhold talquetamab-tgvs as recommended based on severity.

Skin Toxicity

Talquetamab-tgvs can cause serious skin reactions, including rash, maculo-papular rash, erythema, and erythematous rash.

In the clinical trial, skin reactions occurred in 62% of patients, with Grade 3 skin reactions in 0.3%. The median time to onset was 25 (range: 1 to 630) days. The median time to improvement to Grade 1 or less was 33 days.

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

Hepatotoxicity

Talquetamab-tgvs can cause hepatotoxicity. In the clinical trial, elevated ALT occurred in 33% of patients, with Grade 3 or 4 ALT elevation occurring in 2.7%; elevated AST occurred in 31% of patients, with Grade 3 or 4 AST elevation occurring in 3.3%. Grade 3 or 4 elevations of total bilirubin occurred in 0.3% of patients. Liver enzyme elevation can occur with or without concurrent CRS.

Monitor liver enzymes and bilirubin at baseline and during treatment as clinically indicated. Withhold talquetamab-tgvs or consider permanent discontinuation of the drug based on severity.

Embryo-fetal Toxicity

Based on its mechanism of action, talquetamab-tgvs may cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to the fetus. Advise females of reproductive potential to use effective contraception during treatment with talquetamab-tgvs and for 3 months after the last dose.

Specific Populations

Pregnancy

Based on the mechanism of action, talquetamab-tgvs may cause fetal harm when administered to a pregnant woman. There are no available data on the use of talquetamab-tgvs in pregnant women to evaluate for a drug associated risk. No animal reproductive or developmental toxicity studies have been conducted with the drug.

Talquetamab-tgvs causes T-cell activation and cytokine release; immune activation may compromise pregnancy maintenance. Human immunoglobulin G (IgG) is known to cross the placenta; therefore, talquetamab-tgvs has the potential to be transmitted from the mother to the developing fetus. Advise women of the potential risk to the fetus.

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.

Lactation

There is no information regarding the presence of talquetamab-tgvs in human milk, the effect on the breastfed child, or the effect on milk production. Maternal IgG is known to be present in human milk. The effects of local GI exposure and limited systemic exposure in the breastfed child to talquetamab-tgvs are unknown. Because of the potential for serious adverse reactions in a breastfed child, advise women not to breastfeed during treatment with talquetamab-tgvs and for 3 months after the last dose.

Females and Males of Reproductive Potential

Talquetamab-tgvs may cause fetal harm when administered to a pregnant woman.

Verify pregnancy status of 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 last dose.

Pediatric Use

The safety and efficacy of talquetamab-tgvs have not been established in pediatric patients.

Geriatric Use

There were 339 patients in the clinical trial for relapsed or refractory multiple myeloma. Of the total number of talquetamab-tgvs-treated patients in the study, 178 (53%) patients were 65 years of age and older, while 57 (17%) patients were 75 years of age and older. No overall differences in safety or effectiveness were observed in patients 65 to less than 74 years of age compared to younger patients. There was a higher rate of fatal adverse reactions in patients 75 years of age or older compared to younger patients. Clinical studies did not include sufficient numbers of patients 75 years of age or over to determine whether they respond differently from younger patients.

Common Adverse Effects

The most common adverse reactions (≥20%) are pyrexia, CRS, dysgeusia, nail disorder, musculoskeletal pain, skin disorder, rash, fatigue, decreased weight, dry mouth, xerosis, dysphagia, upper respiratory tract infection, diarrhea, hypotension, and headache.

The most common Grade 3 or 4 laboratory abnormalities (≥30%) are decreased lymphocyte count, decreased neutrophil count, decreased white blood cell, and decreased hemoglobin.

General

Talquetamab-tgvs is available in the following dosage form(s) and strength(s):

Injection

• 3 mg/1.5 mL (2 mg/mL) in a single-dose vial for subcutaneous injection

• 40 mg/mL in a single-dose vial for subcutaneous injection

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

Adults

Dosage and Administration

• For subcutaneous injection.

• Patients should be hospitalized for 48 hours after all doses within the step-up dosing schedule.

• Administer pretreatment medications as recommended.

• See Full Prescribing Information for instructions on preparation and administration.

• Administer talquetamab-tgvs subcutaneously on a weekly or biweekly (every 2 weeks) dosing schedule according to Table 1 or Table 2. Calculate the dose based on actual body weight. Continue treatment until disease progression or unacceptable toxicity. Initiate treatment with a step-up dosing schedule to reduce risk of cytokine release syndrome (CRS).

• Dosage delays may be required to manage toxicities. See Full Prescribing Information for specific instructions.

• If a dose of talquetamab-tgvs is delayed, restart therapy as recommended. See Full Prescribing Information for specific instructions.