Talquetamab-tgvs is a bispecific T-cell engaging (BiTE) antibody that binds the CD3 receptor expressed on the surface of T-cells with G protein-coupled receptor class C group 5 member D (GPRC5D) expressed on the surface of multiple myeloma cells. It is indicated for the treatment of adults with relapsed or refractory multiple myeloma who have received at least 4 prior lines of therapy including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody. Talquetamab has a black box warning for cytokine release syndrome and severe neurologic toxicity. It is available through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the TECVAYLI and TALVEY REMS. Information for this program enrollment is available at www.TEC-TALREMS.com or 1-855-810-8064.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
NOTE: Confirm the product selection prior to removing talquetamab-tgvs (Talvey) from the refrigerator; there is a potential for mix-ups between the products talquetamab-tgvs (Talvey) and teclistamab-cqyv (Tecvayli). Consider carrying only one of these products, storing these products separately, and/or adding auxiliary warning labels on the product containers and storage bins to prevent incorrect product selection.
Route-Specific Administration
Injectable Administration
Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit. Talquetamab is a colorless to light yellow solution; do not use if the solution is discolored, cloudy, or contains foreign particles.
Subcutaneous Administration
-Talquetamab is administered by a health care professional in a facility with medical personnel and equipment capable of managing severe reactions.
-Verify correct product selection; there is a potential for mix-ups between the talquetamab-tgvs (Talvey) and teclistamab-cqyv (Tecvayli) products.
-Premedicate patients with a corticosteroid, H1-antihistamine, and antipyretic (i.e., acetaminophen) approximately 1 to 3 hours prior to the injection as recommended.
Preparation:
-Talquetamab is available as single-dose 3 mg/1.5 mL (2 mg/mL) or 40 mg/mL solution vials; do not combine vials of different concentrations to achieve the dose.
-Further vial dilution is not necessary; talquetamab is compatible with stainless steel injection needles and polypropylene or polycarbonate syringe material.
-Remove the appropriate concentration and number of vials from the refrigerator and allow the vial(s) to warm to ambient temperature (15 to 30 degrees C; 59 to 86 degrees F) for at least 15 minutes; do not warm the vial(s) any other way.
-Once equilibrated, gently swirl the vial(s) for approximately 10 seconds to mix; do not shake.
-Using aseptic technique, withdraw the required injection volume from the vial(s) into a syringe using a transfer needle.
-The injection volume should not exceed 2 mL; divide doses that require more than 2 mL equally into multiple syringes.
-The appropriate injection volume is based on vial concentration, patient weight, and type of dose as follows:
3 mg/1.5 mL vial (2 mg/mL) - Use for 0.01 mg/kg and 0.06 mg/kg doses
35 to 39 kg: 0.01 mg/kg dose, 0.38 mg (0.19 mL); 0.06 mg/kg dose, 2.2 mg (1.1 mL)
40 to 45 kg: 0.01 mg/kg dose, 0.42 mg (0.21 mL); 0.06 mg/kg dose, 2.6 mg (1.3 mL)
46 to 55 kg: 0.01 mg/kg dose, 0.5 mg (0.25 mL); 0.06 mg/kg dose, 3 mg (1.5 mL)
56 to 65 kg: 0.01 mg/kg dose, 0.6 mg (0.3 mL); 0.06 mg/kg dose, 3.6 mg (1.8 mL)*
66 to 75 kg: 0.01 mg/kg dose, 0.7 mg (0.35 mL); 0.06 mg/kg dose, 4.2 mg (2.1 mL)*
76 to 85 kg: 0.01 mg/kg dose, 0.8 mg (0.4 mL); 0.06 mg/kg dose, 4.8 mg (2.4 mL)*
86 to 95 kg: 0.01 mg/kg dose, 0.9 mg (0.45 mL); 0.06 mg/kg dose, 5.4 mg (2.7 mL)*
96 to 105 kg: 0.01 mg/kg dose, 1 mg (0.5 mL); 0.06 mg/kg dose, 6 mg (3 mL)*
106 to 115 kg: 0.01 mg/kg dose, 1.1mg (0.55 mL); 0.06 mg/kg dose, 6.6 mg (3.3 mL)**
116 to 125 kg: 0.01 mg/kg dose, 1.2 mg (0.6 mL); 0.06 mg/kg dose, 7.2 mg (3.6 mL)**
126 to 135 kg: 0.01 mg/kg dose, 1.3 mg (0.65 mL); 0.06 mg/kg dose, 7.8 mg (3.9 mL)**
136 to 145 kg: 0.01 mg/kg dose, 1.4 mg (0.7 mL); 0.06 mg/kg dose, 8.4 mg (4.2 mL)**
146 to 155 kg: 0.01 mg/kg dose, 1.5 mg (0.75 mL); 0.06 mg/kg dose, 9 mg (4.5 mL)**
156 to 160 kg: 0.01 mg/kg dose, 1.6 mg (0.8 mL); 0.06 mg/kg dose, 9.6 mg (4.8 mL)#
*Requires 2 vials for dose
**Requires 3 vials for dose
#Requires 4 vials for dose
40 mg/mL vial - Use for 0.4 mg/kg and 0.8 mg/kg doses
35 to 39 kg: 0.4 mg/kg dose, 14.8 mg (0.37 mL); 0.8 mg/kg dose, 29.6 mg (0.74 mL)
40 to 45 kg: 0.4 mg/kg dose, 16 mg (0.4 mL); 0.8 mg/kg dose, 34 mg (0.85 mL)
46 to 55 kg: 0.4 mg/kg dose, 20 mg (0.5 mL); 0.8 mg/kg dose, 40 mg (1 mL)
56 to 65 kg: 0.4 mg/kg dose, 24 mg (0.6 mL); 0.8 mg/kg dose, 48 mg (1.2 mL)*
66 to 75 kg: 0.4 mg/kg dose, 28 mg (0.7 mL); 0.8 mg/kg dose, 56 mg (1.4 mL)*
76 to 85 kg: 0.4 mg/kg dose, 32 mg (0.8 mL); 0.8 mg/kg dose, 64 mg (1.6 mL)*
86 to 95 kg: 0.4 mg/kg dose, 36 mg (0.9 mL); 0.8 mg/kg dose, 72 mg (1.8 mL)*
96 to 105 kg: 0.4 mg/kg dose, 40 mg (1 mL); 0.8 mg/kg dose, 80 mg (2 mL)*
106 to 115 kg: 0.4 mg/kg dose, 44 mg (1.1 mL)*; 0.8 mg/kg dose, 88 mg (2.2 mL)**
116 to 125 kg: 0.4 mg/kg dose, 48 mg (1.2 mL)*; 0.8 mg/kg dose, 96 mg (2.4 mL)**
126 to 135 kg: 0.4 mg/kg dose, 52 mg (1.3 mL)*; 0.8 mg/kg dose, 104 mg (2.6 mL)**
136 to 145 kg: 0.4 mg/kg dose, 56 mg (1.4 mL)*; 0.8 mg/kg dose, 112 mg (2.8 mL)**
146 to 155 kg: 0.4 mg/kg dose, 60 mg (1.5 mL)*; 0.8 mg/kg dose, 120 mg (3 mL)**
156 to 160 kg: 0.4 mg/kg dose, 64 mg (1.6 mL)*; 0.8 mg/kg dose, 128 mg (3.2 mL)#
*Requires 2 vials for dose
**Requires 3 vials for dose
#Requires 4 vials for dose
-Storage of prepared syringe(s): if not used immediately, store syringe(s) at 2 to 8 degrees C (36 to 46 degrees F) for up to 24 hours followed by storage at room temperature (15 to 30 degrees C; 59 to 86 degrees F) for up to 24 hours; discard syringe(s) not used within this specified timeframe.
Subcutaneous injection:
-Replace the transfer needle with an appropriately sized needle for a subcutaneous injection.
-Inject the talquetamab dose into the subcutaneous tissue of the abdomen (preferred site) or other appropriate site (e.g., thigh).
-Space injections at least 2 cm apart if multiple injections are required for the dose.
-Do not inject into tattoos, scars, or areas where the skin is red, bruised, tender, hard, or not intact.
Fever (83%; grade 3, 4.7%) and chills (19%) were reported in patients with relapsed or refractory multiple myeloma who received weekly or biweekly talquetamab in a clinical trial (n = 339).
Fatigue occurred in 37% (grade 3, 3.5%) of patients with relapsed or refractory multiple myeloma who received weekly or biweekly talquetamab in a clinical trial (n = 339).
Edema occurred in 14% of patients with relapsed or refractory multiple myeloma who received weekly or biweekly talquetamab in a clinical trial (n = 339).
Injection site reaction occurred in 13% of patients with relapsed or refractory multiple myeloma who received weekly or biweekly talquetamab in a clinical trial (n = 339).
Musculoskeletal pain (43%; grade 3, 3.2%) and pain (18%; grade 3, 1.8%) were reported in patients with relapsed or refractory multiple myeloma who received weekly or biweekly talquetamab in a clinical trial (n = 339).
Diarrhea (21%; grade 3, 0.9%), decreased appetite/anorexia (19%; grade 3, 1.2%), nausea (18%), and constipation (16%) were reported in patients with relapsed or refractory multiple myeloma who received weekly or biweekly talquetamab in a clinical trial (n = 339).
Hypotension occurred in 21% (grade 3 or 4, 2.9%) of patients with relapsed or refractory multiple myeloma who received weekly or biweekly talquetamab in a clinical trial (n = 339).
Sinus tachycardia occurred in 11% (grade 3, 0.6%) of patients with relapsed or refractory multiple myeloma who received weekly or biweekly talquetamab in a clinical trial (n = 339).
Myelosuppression has been reported with talquetamab therapy. Evaluate complete blood cell counts during treatment. Therapy interruption may be necessary in patient who develop severe myelosuppression. Hematologic parameters that worsened from baseline including decreased lymphocyte count/lymphopenia (90%; grade 3 or 4, 80%), decreased white blood cell count/leukopenia (73%; grade 3 or 4, 35%), decreased hemoglobin level/anemia (67%; grade 3 or 4, 30%), decreased neutrophil count/neutropenia (64%; grade 3 or 4, 35%), and decreased platelet count/thrombocytopenia (62%; grade 3 or 4, 22%) were reported in patients with relapsed or refractory multiple myeloma who received weekly or biweekly talquetamab in a clinical trial (n = 339).
Hepatotoxicity has been reported with talquetamab therapy. Monitor liver function tests at baseline and during treatment as clinically indicated. Elevated hepatic enzymes may occur with or without concurrent CRS. Therapy interruption or permanent discontinuation may be necessary in patients who develop severe hepatic disease. Elevated hepatic enzymes that worsened from baseline including increased AST (31%; grade 3 or 4, 3.3%), ALT (33%; grade 3 or 4, 2.7%), alkaline phosphatase (49%; grade 3 or 4, 1.5%), and gamma-glutamyl transferase (GGT) (38%; grade 3 or 4, 7%) levels and hyperbilirubinemia (grade 3 or 4, 0.3%) were reported in patients with relapsed or refractory multiple myeloma who received weekly or biweekly talquetamab in a clinical trial (n = 339).
Hypoalbuminemia that worsened from baseline occurred in 66% (grade 3 or 4, 2.1%) of patients with relapsed or refractory multiple myeloma who received weekly or biweekly talquetamab in a clinical trial (n = 339).
Electrolyte abnormalities that worsened from baseline including hypokalemia (31%; grade 3 or 4, 4.4%), hyponatremia (31%; grade 3 or 4, 6%), and hypophosphatemia (44%; grade 3 or 4, 13%) were reported in patients with relapsed or refractory multiple myeloma who received weekly or biweekly talquetamab in a clinical trial (n = 339).
Oral toxicity (80%; grade 3, 2.1%) such as oral disorder (12%), dysgeusia (70%) including ageusia and hypogeusia, dry mouth/xerostomia (34%), dysphagia (23%; grade 3, 0.9%), stomatitis (18%; grade 3 or 4, 1.2%) including cheilitis, glossitis, glossodynia, oral ulceration/pain/erythema were reported in patients with relapsed or refractory multiple myeloma who received weekly or biweekly talquetamab in a clinical trial (n = 339). Evaluate patients for signs and symptoms of oral toxicity. Therapy interruption or permanent discontinuation may be necessary in patients who develop severe oral toxicity. The median time to onset of oral toxicity was 15 (range, 1 to 634) days and the median time to resolution was 43 (range, 1 to 530) days. Oral toxicity did not resolve to baseline in 65% of patients. The term oral disorder included oral dysesthesia, oral mucosal exfoliation, oral toxicity, and oropharyngeal pain.
Weight loss occurred in 62% of patients with relapsed or refractory multiple myeloma who received weekly or biweekly talquetamab in a clinical trial (n = 339); 2.7% of patients experienced grade 3 weight loss defined as a 20% or greater decrease in weight. Monitor patient weight regularly during therapy for signs of clinically significant weight loss. Provide supportive care and consult with a nutritionist as appropriate. Therapy interruption or permanent discontinuation may be necessary in patients who develop 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 weight loss.
Skin reactions occurred in 62% (grade 3, 0.3%) of patients with relapsed or refractory multiple myeloma who received weekly or biweekly talquetamab in a clinical trial (n = 339). Monitor patients for signs of skin toxicity, including rash progression; consider early intervention and treat appropriately. Therapy interruption may be necessary in patients who develop a severe skin reaction. Specific skin reactions reported in the trial were rash (38%; grade 3, 3.5%), skin disorder (41%; grade 3, 0.3%), xerosis (30%) including xerophthalmia, pruritus (19%; grade 3, 0.3%), and nail disorder (50%) including onycholysis, nail discoloration, and onychomadesis. The term rash included acneiform rash/dermatitis, stasis and contact dermatitis, exfoliative dermatitis/rash, erythema, maculopapular rash, and vesicular rash; the term skin disorder included palmar-plantar erythrodysesthesia (hand and foot syndrome), palmoplantar keratoderma, skin discoloration, skin exfoliation, and skin fissures.
Grade 3 or 4 infection occurred in 17% of patients with relapsed or refractory multiple myeloma who received weekly or biweekly talquetamab in a clinical trial (n = 339); fatal infection was reported in 1.5% of patients. Monitor patients for signs and symptoms of infection prior to and during talquetamab therapy; treat appropriately. Therapy interruption or permanent discontinuation may be necessary in patients who develop an infection. Specific infectious events reported in the trial were upper respiratory tract infection (22%; grade 3, 2.7%), bacterial infection (19%; grade 3 or 4, 9%; grade 5, 0.3%) including sepsis, viral infection (less than 10%), COVID-19 infection (11%; grade 3 or 4, 2.7%; grade 5, 0.3%), and fungal infection (10%; grade 3 or 4, 0.6%; grade 5, 0.3%).
Cough (17%), dyspnea (11%; grade 3 or 4, 1.8%; grade 5, 0.6%), and hypoxia (10%; grade 3 or 4, 1.5%) were reported in patients with relapsed or refractory multiple myeloma who received weekly or biweekly talquetamab in a clinical trial (n = 339).
Fatal basilar artery occlusion (0.3%) and pulmonary embolism (0.3%) each occurred in 1 patient (0.3%) of patients with relapsed or refractory multiple myeloma who received weekly or biweekly talquetamab in a clinical trial (n = 339).
Cytokine release syndrome (CRS) has been reported with talquetamab therapy. Signs and symptoms of CRS include fever, hypoxia, chills, hypotension, tachycardia, headache, cardiac dysfunction, acute respiratory distress syndrome (ARDS), neurologic toxicity, disseminated intravascular coagulation (DIC), and renal failure and/or hepatic failure. Evaluate for and treat other causes of fever, hypoxia, and hypotension. Consider laboratory testing to monitor for DIC, hematology parameters, as well as pulmonary, cardiac, renal, and hepatic function. Interruption or discontinuation of therapy may be necessary in patients who develop CRS; evaluate the need for hospitalization, supportive care, and further management (using current practice guidelines) in patients with severe CRS. CRS was reported in 72% (grade 3, 0.6%) of patients with relapsed or refractory multiple myeloma who received weekly or biweekly talquetamab in a clinical trial (n = 339); recurrent CRS occurred in 30% of patients. Most patients experienced CRS during the step-up dosing period (step-up dose 1, 29%; step-up dose 2, 44%; step-up dose 3 [biweekly dosing only], 33%). The median time to CRS onset was 27 (range, 0.1 to 167) hours after the most recent dose with a median duration of 17 (range, 0 to 622) hours.
Neurologic toxicity including immune effector cell-associated neurotoxicity syndrome (ICANS) has been reported with talquetamab therapy. Rule out other causes of neurologic symptoms. Monitor patients for signs and symptoms of neurologic toxicity during treatment. Therapy interruption, corticosteroid administration, or permanent discontinuation of therapy may be necessary in patients who develop neurotoxicity; consider a neurology (or other applicable specialty) consult for further evaluation and management (e.g., non-sedating, anti-seizure medication such as levetiracetam for seizure prophylaxis). Evaluate the need for hospitalization, supportive care, and further management (using current practice guideline) in patients with severe neurotoxicity. ICANS may occur concurrently with cytokine release syndrome (CRS) or after CRS resolves. Clinical manifestations of ICANS may include confusion, depressed level of consciousness, disorientation, somnolence/drowsiness, lethargy, and bradyphrenia. Neurotoxicity occurred in 55% (grade 3 or 4, 6%) of patients with relapsed or refractory multiple myeloma who received weekly or biweekly talquetamab in a clinical trial (n = 339). Specific neurologic events reported in this trial were headache (21%; grade 3, 0.6%), encephalopathy (15%; grade 3, 1.8%), sensory peripheral neuropathy (14%), motor dysfunction (10%; grade 3, 0.6%), and ICANS (9%). Recurrent ICANS occurred in 3% of patients. Most patients experienced ICANS during the step-up dosing period (step-up dose 1, 3%; step-up dose 2, 3%; step-up dose 3 [biweekly dosing only], 1.8%). The median time to ICANS onset 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 term encephalopathy included agitation, altered state/depressed level of consciousness, amnesia, aphasia, bradyphrenia, confusion, delirium, disorientation, hallucinations, lethargy, memory impairment, altered mood, restlessness, sleep disorder, and somnolence/drowsiness. The term sensory peripheral neuropathy included dysesthesia, hyperesthesia, hypoesthesia, immune-mediated neuropathy, neuralgia, paresthesias, polyneuropathy, sciatica, and vestibular neuronitis. The term motor dysfunction included dysarthria, dysgraphia, dysmetria, dysphonia, gait disturbance, muscle atrophy, muscle cramps/spasms, muscular weakness, and tremor.
Antibody formation occurred in 25% and 18% of patients who received subcutaneous talquetamab weekly (n = 177) or biweekly (n = 130), respectively, in a clinical study. The formation of anti-talquetamab antibodies did not appear to have a significant impact on the pharmacokinetic parameters, pharmacodynamics, safety, or effectiveness of talquetamab.
Cytokine release syndrome (CRS) has been reported with talquetamab; cases may be fatal or life-threatening. Evaluate for and treat other causes of fever, hypoxia, and hypotension. To reduce the risk of CRS, administer talquetamab according to a step-up dosing schedule and give pretreatment medications as follows: dexamethasone 16 mg PO/IV or equivalent, diphenhydramine 50 mg PO/IV or equivalent, and acetaminophen 650 mg to 1,000 mg PO/IV or equivalent at 1 to 3 hours prior to each dose in the step-up dosing schedule. Continue premedications with subsequent talquetamab doses in patients who experienced CRS after a prior dose; restart premedications in patients who repeat doses within the step-up dosing schedule following a dose delay. Hospitalization is recommended for 48 hours following each dose in the step-up dosing schedule. Interruption or discontinuation of therapy may be necessary in patients who develop CRS; evaluate the need for hospitalization, supportive care, and further management (using current practice guideline) in patients with severe CRS.
Severe neurotoxicity (e.g., immune effector cell-associated neurotoxicity syndrome (ICANS), encephalopathy) has been reported with talquetamab therapy; cases may be fatal or life-threatening. Rule out other causes of neurologic symptoms. ICANS may occur concurrently with cytokine release syndrome (CRS) or after CRS resolves. Hospitalization is recommended for 48 hours following each dose in the step-up dosing schedule. Monitor patients for signs and symptoms of neurologic toxicity during treatment. Therapy interruption, corticosteroid administration, or permanent discontinuation of therapy may be necessary in patients who develop neurotoxicity. Consider a neurology (or other applicable specialty) consult for further evaluation and management (e.g., non-sedating, anti-seizure medication such as levetiracetam for seizure prophylaxis). Evaluate the need for hospitalization, supportive care, and further management (using current practice guideline) in patients with severe neurotoxicity.
Because of the risk of depressed level of consciousness with talquetamab therapy, advise patients to avoid driving or operating machinery or performing other dangerous duties during and for 48 hours following the step-up dosing schedule and following the onset of any neurologic toxicity symptoms until toxicity resolves.
Because of the risk of cytokine release syndrome and neurological toxicities, use requires an experienced clinician with training in the management of these toxicities. Talquetamab administration also requires a specialized care setting that is enrolled in the TECVAYLI and TALVEY REMS program and can comply with all program requirements.
Severe infections have been reported with talquetamab therapy; some cases were fatal or life-threatening. Do not administer talquetamab therapy in patients who have an active infection during the step-up dosing schedule. Administer prophylactic antibiotics as recommended according to clinical guidelines. Monitor patients for signs and symptoms of infection prior to and during talquetamab therapy; treat appropriately. Therapy interruption or permanent discontinuation may be necessary in patients who develop an infection.
Hematologic toxicity (e.g., anemia, neutropenia, febrile neutropenia, and thrombocytopenia) has been reported with talquetamab therapy. Evaluate complete blood cell counts during treatment. Therapy interruption may be necessary in patient who develop severe myelosuppression.
Hepatotoxicity (e.g., elevated hepatic enzymes, hyperbilirubinemia) has been reported with talquetamab therapy. Monitor liver function tests at baseline and during treatment as clinically indicated. Elevated hepatic enzymes may occur with or without concurrent CRS. Therapy interruption or permanent discontinuation may be necessary in patients who develop hepatic disease/impairment.
Serious rash/skin reactions have been reported with talquetamab therapy. Monitor patients for signs of skin toxicity, including rash progression; consider early intervention and treat appropriately. Therapy interruption may be necessary in patients who develop a severe skin reaction.
Oral toxicity (e.g., dysgeusia, xerostomia, dysphagia, stomatitis) and weight loss have been reported with talquetamab therapy. Evaluate patients for signs and symptoms of oral toxicity; monitor patient weight regularly during therapy for signs of clinically significant weight loss. Provide supportive care and consult with a nutritionist as appropriate. Therapy interruption or permanent discontinuation may be necessary in patients who develop severe oral toxicity or weight loss.
Geriatric patients aged 75 years or older with relapsed or refractory multiple myeloma had a higher rate of fatal adverse reaction compared with younger patients in a clinical trial.
Talquetamab may cause fetal harm if administered during pregnancy based on its mechanism of action. Pregnant patients should be apprised of the potential hazard to the fetus. There are no available data with talquetamab use in pregnant women; animal reproductive and developmental toxicity studies have not been conducted. Talquetamab causes T-cell activation and cytokine release; immune activation may compromise pregnancy maintenance. Human immunoglobulin G is known to cross into the placenta; therefore, talquetamab may be transmitted from the mother to the developing fetus.
Counsel patients about the reproductive risk and contraception requirements during talquetamab treatment. Pregnancy testing should be performed prior to starting talquetamab in patients of reproductive potential. These patients should use effective contraception during and for 3 months after the last talquetamab dose.
Due to the potential for serious adverse reactions in the breastfed child, advise patients to avoid breast-feeding during and for 3 months after the last talquetamab dose. It is not known if talquetamab is secreted in human milk or if it has effects on milk production or the breastfed child. Human immunoglobulin (IgG) is excreted in human milk; however, the effects of local gastrointestinal exposure and limited systemic exposure in the breastfed child to talquetamab are not known.
For the treatment of relapsed or refractory multiple myeloma in patients who have received at least 4 prior therapies, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody:
NOTE: Talquetamab is designated as an orphan drug by the FDA for multiple myeloma.
Subcutaneous dosage (weekly schedule):
Adults: Step-up dose 1, 0.01 mg/kg subcutaneously on day 1; step-up dose 2, 0.06 mg/kg on day 4; and first treatment dose, 0.4 mg/kg on day 7. For step-up dose 2 and the first treatment dose, may give between 2 and 4 days after the previous dose and up to 7 days after the previous dose to allow for resolution of adverse reactions. Begin the weekly dosing schedule starting 1 week after the first treatment dose as follows: 0.4 mg/kg once weekly until disease progression; maintain at least 6 days between weekly doses. Therapy interruption or discontinuation may be necessary in patients who develop toxicity. Administer premedications (i.e, dexamethasone 16 mg PO or IV, diphenhydramine 50 mg PO or IV or equivalent, and acetaminophen 650 mg to 1,000 PO or IV or equivalent) at 1 to 3 hours prior to each dose in the step-up dosing schedule. Premedication with subsequent talquetamab doses may be required in patients who repeat doses within the step-up dosing schedule due to dose delays or experience cytokine release syndrome. Following treatment with weekly subcutaneous talquetamab therapy for relapsed or refractory multiple myeloma, the independent review committee-assessed overall response rates were 73% (stringent complete response or better, 35%) in patients who had not been previously exposed to T-cell redirection therapy (n = 100) and 72% in patients who had received prior T-cell redirection therapy (n = 32) in a multicenter, phase 1/2 (MonumenTAL-1) trial. At a median follow-up time of 13.8 [range, 0.8 to 15.4] months, the median duration of response was 9.5 months in patients who had not been previously exposed to prior T-cell redirection therapy. Patients (median age, 67 [range, 38 to 86] years; high-risk cytogenetics, 29%) had received a median of 5 (range, 4 to 13) prior lines of therapy; 78% of patients had previously received an autologous stem-cell transplantation. At a median follow-up time of 10.4 months, an estimated 59% of responding patients who had received prior T-cell redirection therapy maintained a response for at least 9 months. Patients had received a median of 6 (range, 4 to 15) prior lines of therapy; 81% of patients had received prior CAR-T cell therapy and 25% of patients a bispecific antibody.
Subcutaneous dosage (every 2 weeks schedule):
Adults: Step-up dose 1, 0.01 mg/kg on day 1; step-up dose 2, 0.06 mg/kg on day 4; step-up dose 3, 0.4 mg/kg on day 7; and first treatment dose, 0.8 mg/kg on day 10. For step-up dose 2 and 3, may give between 2 and 4 days after the previous dose and up to 7 days after the previous dose to allow for resolution of adverse reactions; for the first treatment dose, may give between 2 and 7 days after step-up dose 3. Begin the biweekly dosing schedule starting 2 weeks after the first treatment dose as follows: 0.8 mg/kg every 2 weeks until disease progression; maintain at least 12 days between biweekly doses. Therapy interruption or discontinuation may be necessary in patients who develop toxicity. Administer premedications (i.e, dexamethasone 16 mg PO or IV, diphenhydramine 50 mg PO or IV or equivalent, and acetaminophen 650 mg to 1,000 PO or IV or equivalent) at 1 to 3 hours prior to each dose in the step-up dosing schedule. Premedication with subsequent talquetamab doses may be required in patients who repeat doses within the step-up dosing schedule due to dose delays or experience cytokine release syndrome. The independent review committee-assessed overall response rate was 73.6% in 87 patients with relapsed or refractory multiple myeloma who had not been previously exposed to T-cell redirection therapy and received biweekly subcutaneous talquetamab in a multicenter, phase 1/2 (MonumenTAL-1) trial. Additionally, 33% of patients achieved a complete response or better. At a median follow-up time of 5.9 [range, 0 to 9.5] months, the median duration of response was not estimable; however, an estimated 85% of responding patients maintained a response for at least 9 months. In this study, patients (median age, 67 [range, 38 to 86] years; high-risk cytogenetics, 29%) had received a median of 5 (range, 4 to 13) prior lines of therapy; 78% of patients had previously received an autologous stem-cell transplantation.
Therapeutic Drug Monitoring:
Recommendations for Restarting Therapy After Dose Delay
NOTE: Administer pretreatment medications prior to the dose after restarting therapy.
0.01 mg/kg
Delay of more than 7 days: Restart at step-up dose 1 (0.01 mg/kg).
0.06 mg/kg
Delay of 8 to 28 days: Repeat step-up dose 2 (0.06 mg/kg) and continue step-up dosing schedule.
Delay of more than 28 days: Restart at step-up dose 1 (0.01 mg/kg).
0.4 mg/kg (weekly dosing)
Delay of 8 to 28 days: Continue dosing schedule at the treatment dose of 0.4 mg/kg once weekly.
Delay of 29 to 56 days: Repeat step-up dose 2 (0.06 mg/kg) and continue step-up dosing schedule.
Delay of more than 56 days: Consider permanently discontinuing therapy. If therapy is restarted, begin at step-up dose 1 (0.01 mg/kg).
0.4 mg/kg (biweekly dosing)
Delay of 8 to 28 days: Repeat step-up dose 4 (0.4 mg/kg) and continue step-up dosing schedule.
Delay of 29 to 56 days: Restart at step-up dose 2 (0.06 mg/kg).
Delay of more than 56 days: Consider permanently discontinuing talquetamab. If therapy is restarted, begin at step-up dose 1 (0.01 mg/kg).
0.8 mg/kg (biweekly dosing)
Delay of 15 to 28 days: Continue dosing schedule at the treatment dose of 0.8 mg/kg every 2 weeks.
Delay of 29 to 56 days: Restart at step-up dose 3 (0.4 mg/kg).
Delay of more than 56 days: Consider permanently discontinuing talquetamab. If therapy is continued, begin at step-up dose 1 (0.01 mg/kg).
Management of Treatment-Related Toxicity
Cytokine Release Syndrome (CRS)
NOTE: Fever may be masked by interventions such as antipyretics or anticytokine therapy (e.g., corticosteroids) and may not always be present concurrently with hypotension or hypoxia.
Grade 1 toxicity (temperature of 38 degrees C [100.4 degrees F] or higher attributed to CRS): Hold talquetamab until CRS resolves. Administer pretreatment medications prior to next dose.
Grade 2 toxicity (temperature of 38 degrees C [100.4 degrees F] or higher attributed to CRS with either hypotension responsive to fluids and not requiring vasopressors OR oxygen requirement of low-flow [6 L or less] nasal cannula or blow-by): Hold talquetamab until CRS resolves. Administer pretreatment medications prior to next dose. Hospitalization for 48 hours is recommended following the next dose.
Grade 3 toxicity (temperature of 38 degrees C [100.4 degrees F] or higher attributed to CRS with either hypotension requiring 1 vasopressor with or without vasopressin OR oxygen requirement of high-flow [more than 6 L] nasal cannula, facemask, non-rebreather mask, or Venturi mask)
-Duration lasting less than 48 hours: Hold talquetamab until CRS resolves; provide supportive therapy which may include intensive care. Administer pretreatment medications prior to next dose. Hospitalization for 48 hours is recommended following the next dose.
-Recurrence or duration lasting 48 hours or more: Permanently discontinue talquetamab; provide supportive therapy which may include intensive care.
Grade 4 toxicity (temperature of 38 degrees C [100.4 degrees F] or higher attributed to CRS with either hypotension requiring multiple vasopressors (excluding vasopressin) OR oxygen requirement of positive pressure [e.g., continuous positive airway pressure, bilevel positive airway pressure, intubation, and mechanical ventilation]): Permanently discontinue talquetamab; provide supportive therapy which may include intensive care.
Dermatologic Toxicity
Grade 3 or 4 toxicity: Hold talquetamab until the skin toxicity improves to grade 1 or baseline.
Hematologic Toxicity
Anemia
Hemoglobin level less than 8 g/dL: Hold talquetamab until the hemoglobin level is 8 g/dL or higher.
Neutropenia
Absolute neutrophil count (ANC) less than 0.5 X 109 cells/L: Hold talquetamab until the ANC is 0.5 X 109 cells/L or higher.
Febrile neutropenia: Hold talquetamab until the ANC is 1 X 109 cells/L or higher and fever resolves.
Thrombocytopenia
Platelet count less than 25,000 cells/microliter (mcL) OR platelet count between 25,000 and 50,000 cells/mcL with bleeding: Hold talquetamab until the platelet count is 25,000 cells/mcL or higher with no evidence of bleeding.
Infection
Any grade toxicity: Hold talquetamab until the toxicity resolves in patients with active infection during the step-up dosing phase.
Grade 3 toxicity: Hold talquetamab during the treatment phase until the infection improves to grade 1 or less; restart step-up dosing if talquetamab is held for more than 28 days.
Grade 4 toxicity: Consider permanently discontinuing talquetamab. If therapy is continued, hold subsequent talquetamab doses (i.e., doses administered after the step-up dosing schedule) until the infection improves to grade 1 or less; restart step-up dosing if talquetamab is held for more than 28 days.
Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS)
NOTE: Consider a neurology (or other applicable specialty) consult for further evaluation and management (e.g., non-sedating, anti-seizure medication for seizure prophylaxis such as levetiracetam) in patients who develop any grade ICANS toxicity.
Grade 1 toxicity (immune effector cell-associated encephalopathy [ICE] score of 7, 8, or 9 or depressed level of consciousness [awakens spontaneously]): Hold talquetamab until ICANS resolves.
Grade 2 toxicity (ICE score of 3, 4, 5, or 6 or depressed level of consciousness [awakens to voice]): Hold talquetamab until ICANS resolves. Administer dexamethasone 10 mg IV (or equivalent) every 6 hours until symptoms resolve to grade 1 or less, then begin a corticosteroid taper. Hospitalization for 48 hours is recommended following the next dose.
Grade 3 toxicity (ICE score of 0, 1, or 2 [if ICE score is 0 but patient is arousable and able to perform assessment]; depressed level of consciousness [awakens only to tactile stimulus]; any clinical seizure [rapidly resolving focal or generalized seizure OR a non-convulsive seizure on electroencephalogram that resolve with intervention]; or raised intracranial pressure [focal/local edema on neuroimaging])
-First occurrence: Manage the same as with grade 2 toxicity. Provide supportive therapy which may include intensive care.
-Recurrence: Permanently discontinue talquetamab. Administer dexamethasone 10 mg IV (or equivalent) every 6 hours until symptoms resolve to grade 1 or less, then begin a corticosteroid taper. Provide supportive therapy which may include intensive care.
Grade 4 toxicity (ICE score of 0 [if patient is unarousable and unable to perform assessment]; depressed level of consciousness [unarousable or requires vigorous or repetitive tactile stimuli to arouse, or stupor or coma]; seizures [life-threatening prolonged seizure lasting more than 5 minutes or repetitive clinical or electrical seizures without return to baseline in between]; motor findings [deep focal motor weakness such as hemiparesis or paraparesis]; or raised intracranial pressure/cerebral edema [signs/symptoms of diffuse cerebral edema on neuroimaging, decerebrate or decorticate posturing, cranial nerve VI palsy, papilledema, or Cushing triad]): Permanently discontinue talquetamab. Administer dexamethasone 10 mg IV (or equivalent) every 6 hours until symptoms resolve to grade 1 or less, then begin a corticosteroid taper. Alternatively, consider methylprednisolone 1,000 mg IV daily continuing for 2 or more days. Provide supportive therapy which may include intensive care.
Neurologic Toxicity (Excluding ICANS)
Grade 1 toxicity: Hold talquetamab until neurotoxicity symptoms resolve or stabilize.
Grade 2 toxicity: Hold talquetamab until neurotoxicity symptoms improve to grade 1 or less; provide supportive therapy as required.
Grade 3 toxicity: For first occurrence, hold talquetamab until neurotoxicity symptoms improve to grade 1 or less; provide supportive therapy as required. For recurrence, permanently discontinue talquetamab and provide supportive therapy which may include intensive care.
Grade 4 toxicity: Permanently discontinue talquetamab and provide supportive therapy which may include intensive care.
Oral Toxicity and Weight Loss
Grade 1 or 2 toxicity: Provide supportive care; consider holding talquetamab if the patient is not responsive to supportive care.
Grade 3 toxicity: Hold talquetamab until the toxicity improves to grade 1 or less; provide supportive care.
Grade 4 toxicity: Permanently discontinue talquetamab.
Other Non-Hematologic Toxicity
Grade 3 toxicity: Hold talquetamab until the toxicity improves to grade 1 or baseline.
Grade 4 toxicity: Consider permanently discontinuing talquetamab. If therapy is continued, hold subsequent talquetamab doses (i.e., doses administered after the step-up dosing schedule) until the toxicity improves to grade 1 or less.
Maximum Dosage Limits:
-Adults
0.4 mg/kg per week OR 0.8 mg/kg every 2 weeks subcutaneously.
-Geriatric
0.4 mg/kg per week OR 0.8 mg/kg every 2 weeks subcutaneously.
-Adolescents
Safety and efficacy not established.
-Children
Safety and efficacy not established.
-Infants
Safety and efficacy not established.
Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no initial dosage adjustments are needed. Therapy interruption or permanent discontinuation may be necessary in patients who develop severe hepatotoxicity.
Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no initial dosage adjustments are needed.
*non-FDA-approved indication
Monitor for toxicity of CYP substrates, especially after starting talquetamab therapy, for 2 weeks after the first full treatment dose, and during/after cytokine release syndrome. Talquetamab related-cytokine release may suppress CYP activity.
Talquetamab is a bispecific T-cell engaging (BiTE) antibody that works by binding the CD3 receptor expressed on the surface of T-cells to the G protein-coupled receptor class C group 5 member D (GPRC5D) expressed on the surface of multiple myeloma cells, non-malignant plasma cells, and healthy tissues (e.g., epithelial cells in keratinized tissues of the skin and tongue). It is a humanized immunoglobulin G4-proline, alanine, alanine (IgG4-PAA) antibody produced from Chinese Hamster Ovary (CHO) cells using recombinant DNA technology. Talquetamab consists of an anti-GPRC5D heavy chain and light chain and an anti-CD3 heavy chain and light chain with 2 interchain disulfide bonds connecting the two arms. The binding of CD3 and GPRC5D activates T-cells causing a release of proinflammatory cytokines resulting in the lysis of multiple myeloma cells. Additionally, talquetamab exhibited antitumor activity in mouse models of multiple myeloma.
Talquetamab is administered subcutaneously. It has a geometric mean volume of distribution of 10.1 L (coefficient of variation (CV), 25%). At 16 weeks after the first talquetamab treatment dose, the mean maximal clearance is reduced by of 40% (CV, 56%) with a geometric mean clearance of 0.9 L/day (CV, 63%); the mean elimination half-life is 12.2 days (CV, 49%). It appears that talquetamab is metabolized into small peptides by catabolic pathways.
Affected cytochrome P450 isoenzymes and drug transporters: CYP substrates
Talquetamab may cause a cytokine release that suppresses CYP enzyme activity and increases the exposure of CYP substrates.
-Route-Specific Pharmacokinetics
Subcutaneous Route
The geometric mean bioavailability of talquetamab is 59% (coefficient of variation (CV), 22%) when administered subcutaneously. The pharmacokinetic parameters (AUC, Cmax) of talquetamab increase proportionally over a dosage range of 0.005 to 0.8 mg/kg when given weekly (weekly dosing) and 0.8 to 1.2 mg/kg when given every 2 weeks (biweekly dosing). A 90% steady-state exposure rate was achieved at 16 weeks after the first talquetamab treatment dose. In patients with relapsed or refractory multiple myeloma, the geometric mean Cmax values were 2,940 (CV, 67%) and 3,410 (CV, 63%) nanograms/mL following talquetamab weekly and biweekly dosing, respectively, at 16 weeks after the first talquetamab treatment dose; the accumulation ratios were 4.4 and 1.8, respectively. Additionally, the median Tmax values were 2.5 (range, 0.9 to 5.9) days and 3.6 (range, 1 to 7.7) days with talquetamab weekly (after the seventeenth dose) and biweekly (after the ninth dose) dosing, respectively.
-Special Populations
Hepatic Impairment
Mild (total bilirubin level at the ULN or less with AST level more than the ULN OR total bilirubin level more than 1 to 1.5 times the ULN with any AST level) or moderate (total bilirubin level more than 1.5 to 3 times the ULN with any AST level) hepatic impairment does not significantly impact the pharmacokinetic (PK) parameters of talquetamab. The effect of severe hepatic impairment (total bilirubin level more than 3 times ULN with any AST level) on the PK parameters of talquetamab is unknown.
Renal Impairment
Mild or moderate renal impairment (creatinine clearance [CrCl] of 30 to 89 mL/min, using the Cockcroft-Gault equation) does not significantly impact the pharmacokinetic (PK) parameters of talquetamab. The effect of severe renal impairment (CrCl less than 30 mL/min) on the PK parameters of talquetamab is unknown.
Geriatric
Age (range, 33 to 86 years) does not significantly impact the pharmacokinetic parameters of talquetamab.
Gender Differences
Sex does not significantly impact the pharmacokinetic parameters of talquetamab.
Ethnic Differences
Race (White, Black or African American) or ethnicity (Hispanic/Latino or not Hispanic/Latino) does not significantly impact the pharmacokinetic parameters of talquetamab.
Obesity
Increased body weight (range, 40 to 143 kg) correlates with increased volume of distribution and clearance of talquetamab.