REMS: 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]) |
Talquetamab-tgvs, a humanized IgG4 bispecific G protein-coupled receptor class C group 5 member D (GPRC5D)-directed CD3 T-cell engager, is an antineoplastic agent.1
Relapsed or Refractory Multiple Myeloma
Talquetamab-tgvs is used for the 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.1 Talquetamab-tgvs has been designated an orphan drug by FDA for the treatment of this cancer.2
Talquetamab-tgvs was granted accelerated approval for this indication based on response rate and durability of response.1 Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.1
The safety and efficacy of talquetamab-tgvs for this use is based principally on the results of an open-label, single-arm, multicenter clinical trial (MonumenTAL-1) in adults with refractory or relapsed multiple myeloma.1, 3, 4 Guidelines recommend triplet therapy with 2 novel agents (immunomodulatory drug, proteasome inhibitor, or monoclonal antibody) plus a steroid, with no preference given to a specific regimen for relapsed or refractory multiple myeloma treatment.5
The current indication for talquetamab-tgvs is based principally on the results of an open-label, single-arm, multicenter, phase 1/2 trial (MonumenTAL-1).1, 3, 4 Enrolled patients were ≥18 years of age with measurable refractory or relapsed multiple myeloma who had received ≥3 prior systemic therapies, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody.1, 3 Patients received talquetamab-tgvs on either a weekly or biweekly (every 2 weeks) dosing schedule.1 Patients treated with talquetamab-tgvs using the weekly dosing schedule received step-up subcutaneous doses of 0.01 mg/kg and 0.06 mg/kg, followed by 0.4 mg/kg weekly thereafter.1 Patients treated with talquetamab-tgvs using the biweekly (every 2 weeks) dosing schedule received step-up subcutaneous doses of 0.01 mg/kg, 0.06 mg/kg, and 0.3 mg/kg, followed by 0.8 mg/kg every 2 weeks thereafter.1 Talquetamab-tgvs was continued until disease progression or unacceptable toxicity occurred.1 Overall response rate and duration of response were assessed by an independent review committee according to the International Myeloma Working Group Criteria in both the weekly and biweekly dosing cohorts.1
A total of 187 patients were included in the efficacy analysis; the median age was 67 years, 57% of patients were male, and 90% were white.1 Patients had received a median of 5 prior lines of therapy.1 Ninety-four percent of patients were refractory to last therapy, and 73% were refractory to a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 antibody.1 Stage I, stage II, or stage III disease (based on the International Staging System) was present in 44, 34, or 22% of patients, respectively.1
For patients given talquetamab-tgvs 0.4 mg/kg weekly, the median duration of follow-up from first response was 13.8 months.1 The overall response rate was 73%; a stringent complete response, a complete response, a very good partial response, and a partial response was observed in 26, 9, 22, and 16% of patients, respectively.1 The median duration of response was 9.5 months in the weekly dosing cohort.1 For patients given talquetamab-tgvs 0.8 mg/kg biweekly, the median duration of follow-up from first response was 5.9 months; response was maintained for ≥9 months among 85% of responders.1 The overall response rate was 73.6%; a stringent complete response, a complete response, a very good partial response, and a partial response was observed in 20, 13, 25, and 16% of patients, respectively.1 The median duration of response in this cohort was not estimable at the time of the analysis.1 The median time to first response was 1.2 months and 1.3 months for talquetamab-tgvs 0.4 mg/kg weekly and 0.8 mg/kg biweekly, respectively.1
Among 32 patients with prior T cell redirection therapy (94% exposed to T cell redirection therapy directed at B-cell maturation antigen), the overall response rate was 72% with talquetamab-tgvs 0.4 mg/kg weekly.1 With a median duration of follow-up of 10.4 months, 59% of responders maintained a response for ≥9 months.1
In 2019, the American Society of Clinical Oncology (ASCO) and Cancer Care Ontario published evidence-based recommendations on the treatment of multiple myeloma in patients who are transplant-eligible, transplant-ineligible, and those with relapsed or refractory disease.5 For treatment of relapsed or refractory disease, the guideline recommends triplet therapy with 2 novel agents (immunomodulatory drug, proteasome inhibitor, or monoclonal antibody) plus a steroid.5 Choice of therapy should be based on patient, disease, and treatment factors, including prior therapies.5 No preference of one regimen over another is given due to lack of comparative trials.5
Talquetamab-tgvs injection is available as a solution supplied in a single-dose vial containing 3 mg/1.5 mL (2 mg/mL) or 40 mg/mL.1
Talquetamab-tgvs is for subcutaneous administration by a healthcare professional; only qualified healthcare professionals with sufficient and appropriate medical support to manage severe reactions, including CRS and neurologic toxicity (including ICANS) should administer talquetamab-tgvs.1
Administer talquetamab-tgvs on a weekly or biweekly (every 2 weeks) step-up dosing schedule to reduce the incidence and severity of CRS.1
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).1 Pretreatment medications may be required for subsequent doses for patients who repeat doses within the talquetamab-tgvs step-up dosing schedule due to dosage delays or for patients who experienced CRS.1
Talquetamab-tgvs is supplied as a ready-to-use solution for injection; dilution is not needed prior to administration.1 Do not combine vials of different concentrations to achieve the treatment dosage.1
Use aseptic technique to prepare and administer talquetamab-tgvs.1 For preparation of talquetamab-tgvs, consult the reference tables in the prescribing information to determine the 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.1
Prior to administration, check that the talquetamab-tgvs solution is colorless to light yellow; do not use if cloudiness, discoloration, or particles are present.1
Store talquetamab-tgvs under refrigeration at 2—8°C in the original carton to protect from light; do not freeze.1 After removal from refrigeration, allow vial(s) of talquetamab-tgvs to equilibrate to room temperature at 15—30°C for ≥15 minutes; do not warm the vial(s) in any other manner.1 Once equilibrated, swirl the vial gently for approximately 10 seconds to mix the solution; do not shake.1 Withdraw the required injection volume from the vial(s) into an appropriately sized syringe using a transfer needle.1 Each injection volume should not exceed 2 mL; divide doses requiring greater than 2 mL equally into multiple syringes.1 Talquetamab-tgvs is compatible with stainless steel injection needles and polypropylene or polycarbonate syringe material.1 Replace the transfer needle with an appropriately sized needle for injection.1
The preferred subcutaneous injection site for talquetamab-tgvs is the abdomen; talquetamab-tgvs may also be administered into subcutaneous tissue at other sites (e.g., thigh).1 If multiple injections are required, separate the administration sites by ≥2 cm.1 Do not inject talquetamab-tgvs into areas of the skin that are raised, bruised, tender, hard, not fully intact, or areas that are tattooed or scarred.1
Due to the risk of CRS and neurologic toxicity (including ICANS), hospitalize patients for 48 hours after administration of all doses within the talquetamab-tgvs step-up dosing schedule.1
Prepared syringes of talquetamab-tgvs should be used immediately.1 If syringes cannot be used immediately, store under refrigeration at 2—8°C for up to 24 hours, followed by room temperature at 15—30°C for up to 24 hours.1 Discard syringes if stored for >24 hours under refrigeration or >24 hours at room temperature.1
The recommended subcutaneous adult dosage of talquetamab-tgvs is based on a weekly or biweekly (every 2 weeks) dosing schedule according to Table 1 or Table 2.1 Each dose of talquetamab-tgvs is based on actual body weight (ABW).1 The manufacturer recommends initiation of treatment with a step-up dosing schedule in order to reduce the severity and incidence of CRS.1 Continue treatment until disease progression or unacceptable toxicity occurs.1
Dosing Schedule | Day | Dosea |
|---|---|---|
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 |
aDosing based on ABW.1
Dosing Schedule | Day | Dosea |
|---|---|---|
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 |
aDosing based on ABW.1
Dosage Modification for Toxicity
Dosage delays of talquetamab-tgvs may be necessary for the management of toxicities.1
Refer to Table 3 for recommendations on the management of CRS with talquetamab-tgvs.1 Identify CRS based on clinical presentation.1 Evaluate and treat other causes of fever, hypoxia, and hypotension.1 If there is suspicion for CRS, withhold talquetamab-tgvs until resolution of CRS or permanently discontinue the drug based on the severity of the reaction.1 Manage in accordance with the recommendations in Table 3, and consider further management per current clinical practice guidelines.1 Administer supportive therapy for CRS, which may include intensive care for severe or life-threatening CRS.1 Consider laboratory testing to monitor for disseminated intravascular coagulation and hematologic parameters, in addition to pulmonary, cardiac, renal, and hepatic function.1
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 resolvesa Give pretreatment medications prior to the 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 :
| Withhold talquetamab-tgvs until CRS resolves Give pretreatment medications prior to the next dose of talquetamab-tgvs Hospitalize patients for 48 hours following the next dose of talquetamab-tgvsa |
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 :
| Duration <48 hours:
Recurrent CRS or duration ≥48 hours:
|
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 :
| Permanently discontinue talquetamab-tgvs Provide supportive therapy (may include intensive care) |
a See Table 7 and Table 8 for recommendations on restarting talquetamab-tgvs after dosage delays due to adverse reactions.1
Refer to Tables 4 and 5 for recommendations on the management of ICANS and neurologic toxicity (excluding ICANS) with talquetamab-tgvs, respectively.1 At the first sign of neurologic toxicity (including ICANS), withhold talquetamab-tgvs and consider neurologic evaluation.1 Rule out other causes of neurologic symptoms.1 Provide supportive therapy (including intensive care if needed) for severe and life-threatening neurologic toxicities, including ICANS.1 Manage ICANS and neurologic toxicity in accordance with recommendations in Table 4 and Table 5, and consider further management per current practice guidelines.1
Grade | Presenting Symptomsa | Recommendations |
|---|---|---|
Grade 1 | Immune Effector-Cell Encephalopathy (ICE) Assessment score 7—9b, OR Depressed level of consciousness (not attributable to other causes): spontaneous awakening | Withold talquetamab-tgvs until ICANS resolvesc 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, b 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-tgvsc |
Grade 3 | ICE score 0—2b (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:
Recurrent grade 3 ICANS:
|
Grade 4 | ICE score 0b (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:
| 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 if needed) |
aManagement is determined by the most severe event, not attributable to any other cause.1
bIf 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).1 If the patient is unarousable and is unable to perform the ICE assessment (Grade 4 ICANS) = 0 points.1
c See Table 7 and Table 8 for recommendations on restarting talquetamab-tgvs after dosage delays due to adverse reactions.1
Severity of Neurologic Toxicity (excluding ICANS) | Recommendations |
|---|---|
Grade 1 | Withhold talquetamab-tgvs until neurologic symptoms resolve or stabilizea |
Grade 2 or grade 3 (first occurrence) | Withhold talquetamab-tgvs until neurologic symptoms improve to grade 1 or lowera Provide supportive therapy |
Grade 3 (recurrent) or grade 4 | Permanently discontinue talquetamab-tgvs Provide supportive therapy (including intensive care if needed) |
a See Table 7 and Table 8 for recommendations on restarting talquetamab-tgvs after dosage delays due to adverse reactions.1
Refer to Table 6 for dosage modification recommendations for other adverse reactions that may occur, including oral toxicity and weight loss, infections, cytopenias, skin reactions, and other non-hematologic adverse reactions.1
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 carea |
Oral toxicity and weight loss | Grade 3 | Withhold talquetamab-tgvs until resolution to grade 1 or better, and provide supportive carea |
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 daysb |
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 betterb |
Cytopenias | Absolute neutrophil acount (ANC) <500/mm3 | Withhold talquetamab-tgvs until ANC ≥500/mm3 a |
Cytopenias | Febrile neutropenia | Withhold talquetamab-tgvs until ANC ≥1000/mm3 and fever resolvesa |
Cytopenias | Hemoglobin <8 g/dL | Withhold talquetamab-tgvs until hemoglobin ≥8 g/dLa |
Cytopenias | Platelets <25,000/mm3 or platelets 25,000—50,000/mm3 with bleeding | Withhold talquetamab-tgvs until platelets recover to ≥25,000/mm3 and no evidence of bleedinga |
Skin reactions | Grade 3—4 | Withhold talquetamab-tgvs until adverse reaction improves to grade 1 or baselinea |
Other nonhematologic adverse reactions | Grade 3 | Withhold talquetamab-tgvs until adverse reaction improves to grade 1 or baselinea |
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 lowera |
a See Table 7 and Table 8 for recommendations on restarting talquetamab-tgvs after dosage delays due to adverse reactions.1
bFor 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.1
Dosage delays of talquetamab-tgvs may be necessary for the management of toxicities.1 If there is a delay in dosage, restart talquetamab-tgvs and resume weekly dosing based on recommendations in Table 7 or biweekly (every 2 weeks) dosing based on recommendations in Table 8.1 If talquetamab-tgvs dosage is delayed for >28 days because of an adverse reaction, evaluate the benefits and risks of restarting treatment.1 Administer pretreatment medications prior to restarting talquetamab-tgvs and monitor patients following administration of talquetamab-tgvs.1
Last Dose Administered | Time Elapsed Since Administration of Last Dose | Recommendationa |
|---|---|---|
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) |
aAdminister premedications before restarting talquetamab-tgvs.1 Once talquetamab-tgvs is restarted, resume weekly dosing schedule accordingly.1
Last Dose Administered | Time Elapsed Since Administration of Last Dose | Recommendationa |
|---|---|---|
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) |
aAdminister premedications before restarting talquetamab-tgvs.1 Once talquetamab-tgvs is restarted, resume biweekly dosing schedule accordingly.1
The manufacturer makes no specific dosage recommendations for patients with hepatic impairment.1
The manufacturer makes no specific dosage recommendations for patients with renal impairment.1
The manufacturer makes no specific dosage recommendations in geriatric patients.1 Clinical trial data found no overall differences in safety or efficacy of talquetamab-tgvs in patients 65 to <74 years of age compared to younger adults; however, the rate of fatal adverse reactions was higher in patients ≥75 years of age compared to younger adults.1
A boxed warning regarding the risk of cytokine release syndrome (CRS), including life-threatening or fatal reactions, is included in the prescribing information for talquetamab-tgvs.1
In the talquetamab-tgvs clinical trial, CRS occurred in 76% of patients who received talquetamab-tgvs at the recommended dosages, with grade 1, grade 2, and grade 3 CRS occurring in 57, 17, and 1.5% of patients, respectively.1 Recurrent CRS occurred in 30% of patients.1 At the recommended dosages, most CRS events occurred after step-up dose 1 (29%) or step-up dose 2 (44%).1 CRS occurred in 33% of patients receiving step-up dose 3 in the biweekly (every 2 weeks) dosing schedule.1 CRS occurred in 30 and 12% of patients receiving the first 0.4 mg/kg treatment dose and first 0.8 mg/kg treatment dose, respectively.1 The combined CRS rate for the weekly and biweekly dosing schedules was <3% for each of the remaining doses in Cycle 1, and cumulatively <3% from Cycle 2 onward.1 CRS occurred at a median of 27 (range: 0.1—167) hours from the last administered dose of talquetamab-tgvs; the median duration of CRS was 17 (range: 0—622) hours.1
Clinical signs and symptoms of CRS may include but are not limited to pyrexia, hypotension, chills, hypoxia, headache, and tachycardia.1 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.1
To reduce the risk of CRS, initiate talquetamab-tgvs treatment 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.1 In patients who develop CRS, administer pre-treatment medications prior to the next dose of talquetamab-tgvs.1
Advise patients to seek immediate medical attention if they experience signs or symptoms of CRS.1 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.1 Withhold talquetamab-tgvs until CRS resolves or permanently discontinue talquetamab-tgvs based on the severity of the reaction.1
Because of the risk of CRS, talquetamab-tgvs is only available through a Risk Evaluation and Mitigation Strategy (REMS) program.1 For further information, consult the Talvey® REMS program website ([Web]) or call 1-855-810-8064.1, 2
A boxed warning regarding the risk of serious, life-threatening, or fatal neurologic toxicity, including immune effector cell-associated neurotoxicity syndrome (ICANS), is included in the prescribing information for talquetamab-tgvs.1
In the talquetamab-tgvs clinical trial, neurologic toxicity, including ICANS, occurred in 55% of patients receiving talquetamab-tgvs at recommended dosages, with grade 3 or 4 neurologic toxicity reported in 6% of patients.1 The most frequent neurologic toxicities were headache, encephalopathy, sensory neuropathy, and motor dysfunction.1
Where ICANS was collected, the syndrome was reported in 9% of patients who received talquetamab-tgvs at the recommended dosages; recurrent ICANS occurred in 3% of patients.1 In most patients, ICANS occurred following step-up dose 1 (3%), step-up dose 2 (3%), step-up dose 3 of the biweekly dosing schedule (1.8%), or the first treatment dose of the weekly dosing schedule (2.6%) or the biweekly dosing schedule (3.7%).1 ICANS occurred at a median of 2.5 (range: 1—16) days after the last dose of talquetamab-tgvs and lasted for a median duration of 2 (range: 1—22) days.1 The onset of ICANS is variable and can occur concurrently with CRS, after resolution of CRS, or without CRS.1
Clinical signs and symptoms of ICANS may include but are not limited to a state of confusion, depressed level of consciousness, disorientation, somnolence, lethargy, and bradyphrenia.1
During treatment with talquetamab-tgvs, monitor patients for signs and symptoms of neurologic toxicity.1 At the first sign of neurologic toxicity (including ICANS), immediately evaluate the patient and provide supportive care based on severity.1 Withhold or permanently discontinue talquetamab-tgvs based on reaction severity.1 Consider further management in accordance with current practice guidelines.1
Because of the potential for neurologic toxicity, there is an increased risk of depressed level of consciousness in patients receiving talquetamab-tgvs.1 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.1
Because of the risk of neurologic toxicity, including ICANS, talquetamab-tgvs is only available through a REMS program.1 For further information, consult the Talvey® REMS program website ([Web]) or call 1-855-810-8064.1, 2
Other Warnings and Precautions
Talquetamab-tgvs can cause oral toxicities (e.g., dysgeusia, dry mouth, dysphagia, stomatitis) and weight loss.1
In the talquetamab-tgvs clinical trial, 80% of patients receiving talquetamab-tgvs at recommended dosages had oral toxicity, with grade 3 toxicity occurring in 2.1% of patients.1 The most frequent oral toxicities were dysgeusia, dry mouth, dysphagia, and ageusia.1 The median time to onset of oral toxicity was 15 (range: 1-634) days; the median time for resolution was 43 (range: 1-530) days, although resolution to baseline did not occur in 65% of patients.1
In clinical trials, 62% of patients receiving talquetamab-tgvs experienced weight loss (regardless of concomitant oral toxicity), including weight loss of grade 2 (weight loss ≥10%) and grade 3 (weight loss ≥20%) severity.1 The median time to onset of grade 2 or greater weight loss was 67 (range: 6-407) days; the median time to resolution was 50 (range: 1-403) days, although resolution did not occur in 57% of patients.1
Monitor patients for signs and symptoms of oral toxicity, and monitor weight regularly.1 Advise patients to seek medical attention for signs or symptoms of oral toxicity during therapy.1 Provide supportive care in accordance with current practice guidelines, including nutritionist consultation.1 Perform further evaluation for clinically important weight loss.1 Withhold or permanently discontinue talquetamab-tgvs based on severity.1
Talquetamab-tgvs can cause serious infections, including life-threatening or fatal infections.1
In the talquetamab-tgvs clinical trial, serious infections occurred in 16% of patients, with fatal infections in 1.5% of patients.1 Grade 3 or 4 infections were reported in 17% of patients.1 Bacterial infection (including sepsis) was the most common serious infection, occurring in 8% of patients, followed by coronavirus disease (COVID-19), occurring in 2.7% of patients.1
Prior to and during treatment with talquetamab-tgvs, monitor patients for signs and symptoms of infection and administer appropriate treatment as necessary.1 Consider prophylactic antibiotics in accordance with local guidelines.1 Withhold or consider permanent discontinuation of talquetamab-tgvs as recommended based on severity.1
Talquetamab-tgvs can cause cytopenias, including neutropenia and thrombocytopenia.1
In the talquetamab-tgvs clinical trial, grade 3 or 4 neutrophil decreases occurred in 35% of patients, and grade 3 or 4 platelet decreases occurred in 22% of patients.1 The median time to grade 3 or 4 neutropenia onset was 22 (range: 1-312) days, and the median time to resolution to grade 2 or lower was 8 (range: 1-79) days.1 The median time to grade 3 or 4 thrombocytopenia onset was 12 (range: 2-183) days, and the median time to resolution to grade 2 or lower was 10 (range: 1-64) days.1
During treatment with talquetamab-tgvs, monitor CBC and withhold talquetamab-tgvs as recommended based on severity.1
Talquetamab-tgvs can cause serious skin reactions (e.g., rash, maculopapular rash, erythema, erythematous rash).1
In the talquetamab-tgvs clinical trial, skin reactions occurred in 62% of patients, with grade 3 reactions occurring in 0.3% of patients.1 The median time to reaction onset was 25 (range: 1-630) days, and the median time for resolution to grade 1 or lower was 33 days.1
Monitor patients for skin toxicity and rash progression.1 Consider early intervention and treatment to manage skin toxicity.1 Withhold talquetamab-tgvs as recommended based on severity.1
Talquetamab-tgvs can cause hepatotoxicity; elevations in liver enzymes may occur with or without concurrent CRS.1
In the talquetamab-tgvs clinical trial, elevations in ALT and AST occurred in 33 and 31% of patients, respectively, with grade 3 or 4 ALT and AST elevations occurring in 2.7 and 3.3% of patients, respectively.1 Total bilirubin elevations (grade 3 or 4) occurred in 0.3% of patients.1
Monitor ALT, AST, and bilirubin prior to and during treatment with talquetamab-tgvs as clinically indicated.1 Withhold or permanently discontinue talquetamab-tgvs based on severity.1
Fetal/Neonatal Morbidity and Mortality
Based on the mechanism of action of talquetamab-tgvs, the drug may cause fetal harm when given during pregnancy.1 Talquetamab-tgvs causes immune activation, which may compromise pregnancy maintenance.1 In addition, human immunoglobulin G (IgG) crosses the placenta; therefore, there is potential for maternal transmission of talquetamab-tgvs to the developing fetus.1 No animal reproductive or developmental toxicity studies with talquetamab-tgvs have been performed to date.1
Apprise pregnant women and females of reproductive potential of the potential hazard to a fetus.1 Verify pregnancy status in females of reproductive potential prior to initiating talquetamab-tgvs.1 Advise females of reproductive potential to use effective contraception during treatment with talquetamab-tgvs and for 3 months after the final dose.1
There is potential for immunogenicity with talquetamab-tgvs.1
In the talquetamab-tgvs clinical trial, 25% of patients treated with talquetamab-tgvs 0.4 mg/kg weekly (median follow-up of 5.7 months) and 18% of patients treated with talquetamab-tgvs 0.8 mg/kg every 2 weeks (median follow-up of 3.1 months) developed anti-drug antibodies to talquetamab-tgvs.1
No clinically important effects of anti-talquetamab-tgvs antibodies were observed on the pharmacokinetics, pharmacodynamics, safety, or effectiveness of talquetamab-tgvs.
Based on the mechanism of action of talquetamab-tgvs, the drug may cause fetal harm if administered during pregnancy.1 No data are available on the use of talquetamab-tgvs in pregnancy to evaluate for a drug-associated risk.1 No animal reproductive or developmental toxicity studies with talquetamab-tgvs have been performed to date.1
Talquetamab-tgvs causes T-cell activation and cytokine release, and immune activation may compromise the maintenance of pregnancy.1 Because human IgG is known to cross the placenta, there is potential for maternal transmission of talquetamab-tgvs to the developing fetus.1
Apprise pregnant women and females of reproductive potential of the potential hazard to a fetus.1 Verify pregnancy status in females of reproductive potential prior to initiating talquetamab-tgvs.1
It is unknown whether talquetamab-tgvs distributes into human milk or affects the breast-fed child or the production of milk.1
Human milk contains maternal IgG.1 The effects of local GI exposure and limited systemic exposure in the breast-fed infant to talquetamab-tgvs are unknown.1
Because of the potential for serious adverse reactions in the breast-fed infant, advise women not to breast-feed during treatment with talquetamab-tgvs and for 3 months after the final dose.1
Females and Males of Reproductive Potential
Talquetamab-tgvs may cause fetal harm if administered during pregnancy.1
Verify pregnancy status in females of reproductive potential prior to initiating talquetamab-tgvs.1
Advise females of reproductive potential to use effective contraception during treatment with talquetamab-tgvs and for 3 months after the final dose.1
No studies evaluating the effects of talquetamab-tgvs on fertility have been performed to date.1
The safety and effectiveness of talquetamab-tgvs are not established in pediatric patients.1
In the clinical trial of talquetamab-tgvs for relapsed or refractory multiple myeloma, 53% of patients were ≥65 years of age, and 17% were ≥75 years of age.1
No overall differences in efficacy or safety were observed in patients 65 to <74 years of age compared to younger adults; however, a higher rate of fatal adverse reactions was observed in patients ≥75 years of age compared to younger adults.1 An insufficient number of patients ≥75 years of age were included in clinical studies to determine whether they respond differently from younger adults.1
Mild hepatic impairment (total bilirubin less than or equal to upper limit of normal [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) did not have clinically important effects on the pharmacokinetics of talquetamab-tgvs.1 The effects of severe hepatic impairment (total bilirubin >3 times ULN with any AST concentration) on talquetamab-tgvs pharmacokinetics are unknown.1
Mild or moderate renal impairment (creatinine clearance 30—89 mL/minute) did not have clinically important effects on the pharmacokinetics of talquetamab-tgvs.1 The effects of severe renal impairment (creatinine clearance <30 mL/minute) on talquetamab-tgvs pharmacokinetics are unknown.1
The most common adverse effects (incidence ≥20%) of talquetamab-tgvs in clinical studies were 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.1
Drugs Affecting or Affected by Hepatic Microsomal Enzymes
Talquetamab-tgvs causes the release of proinflammatory cytokines that may suppress the activity of cytochrome P-450 (CYP) isoenzymes, which can result in increased exposure of CYP substrates.1 Increased exposure of CYP substrates is more likely to occur from initiation of the talquetamab-tgvs step-up dosing schedule up to 14 days following the first treatment dose, and also during and following episodes of cytokine release syndrome.1
For certain CYP substrates, small changes in substrate plasma concentration may lead to serious adverse events.1 Monitor plasma concentrations of such substrates, and monitor for signs of toxicity when they are given concomitantly with talquetamab-tgvs.1
Talquetamab-tgvs is a humanized IgG4 bispecific T-cell engaging antibody that binds to the CD3 receptor and G protein-coupled receptor class C group 5 member D (GPRC5D).1 The CD3 receptor is expressed on the surface of T-cells, and GPRC5D is expressed on the surface of multiple myeloma cells and benign plasma cells, in addition to healthy tissues such as epithelial cells in keratinized tissues of the skin and tongue.1
In vitro data indicate that talquetamab-tgvs activates T-cells to cause the release of proinflammatory cytokines, leading to the lysis of multiple myeloma cells.1 Serum concentrations of cytokines (IL-6, IL-10, TNF-α, and IFN-γ) and IL-2R were measured before and after administration of each step-up dose of talquetamab-tgvs, the first 3 treatment doses at 0.4 mg/kg once weekly, and the first 2 treatment doses at 0.8 mg/kg every two weeks.1 Increased concentrations of IL-6, IL-10, and IL-2R were observed during this period.1 Anti-tumor activity was observed with talquetamab-tgvs in mouse models of multiple myeloma.1
The peak plasma concentration and AUC of talquetamab-tgvs increase proportionally over the subcutaneous 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).1 For both the weekly and biweekly (every 2 weeks) treatment regimens, 90% of steady-state exposure was achieved 16 weeks following the first treatment dose.1 Higher talquetamab-tgvs exposures (AUC and peak plasma concentrations) are associated with higher incidence of some adverse effects (e.g., oral toxicity, nail toxicity, and skin reactions); the exposure-response relationships for the effectiveness and the time course of pharmacodynamic response of talquetamab-tgvs have not been fully characterized.1
Following subcutaneous administration, the geometric mean bioavailability of talquetamab-tgvs is 59%.1 The median time to the peak plasma concentration of talquetamab-tgvs following the first and the 17th treatment dose (0.4 mg/kg once weekly) was 3.7 and 2.5 days, respectively.1 The median time to the peak plasma concentration of talquetamab-tgvs following the first and the 9th treatment dose (0.8 mg/kg every 2 weeks) was 3.4 and 3.6 days, respectively.1
Talquetamab-tgvs is expected to undergo metabolism via catabolic pathways into small peptides.1 The clearance of talquetamab-tgvs decreases over time, with a mean maximal reduction of 40% from the first treatment dose to 16 weeks after the first treatment dose.1 The mean elimination half-life of talquetamab-tgvs is 8.4 days after the first treatment dose and 12.2 days at 16 weeks after the first treatment dose.1
The volume of distribution and clearance of talquetamab-tgvs increased with increasing bodyweight (40-143 kg).1 No clinically important differences in the pharmacokinetics of talquetamab-tgvs have been identified based on age (33—86 years), sex, race (white, Black, or African American), or ethnicity (not Hispanic/Latino or Hispanic/Latino).1
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].
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.1 (See REMS under Dosage and Administration.)
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 |
AHFS® Drug Information. © Copyright, 1959-2026, Selected Revisions June 10, 2024. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
Only references cited for selected revisions after 1984 are available electronically.
1. Janssen Biotech, Inc. TALVEY®(talquetamab) SUBCUTANEOUS prescribing information. 2023 Aug. [Web]
2. US Food and Drug Administration. Search orphan drug designations and approvals. From FDA website. Accessed 2024 January 8. [Web]
3. Chari A, Minnema M, Berdeja J, et al. Talquetamab, a T-cell redirecting GPRCrD bispecific antibody for multiple myeloma. N Engl J Med. 2022;387:2232-2244.
4. Touzeau C, Schinke C, Minnema M, et al. S191: Pivotal phase 2 MonumenTAL-1 results of talquetamab (tal), a GPRC5DxCD3 bispecific antibody (BsAb), for relapsed/refractory multiple myeloma (RRMM). Hemasphere . 2023;7(Suppl):e5955094.
5. Mikhael J, Ismaila N, Cheung MC, et al. Treatment of multiple myeloma: ASCO and CCO joint clinical practice guideline. J Clin Oncol . 2019;37(14):1228-1263.
6. Janssen Biotech, Inc. TECVAYLI® and TALVEY® REMS Program. Accessed 2024 January 19. [Web]