Talvey

Antineoplastic Bispecific Antibodies Targeting GPRC5D and CD3

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.

Talquetamab is administered by a health care professional in a facility with medical personnel and equipment capable of managing severe reactions.
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.

lymphopenia / Delayed / 80.0-80.0
leukopenia / Delayed / 35.0-35.0
neutropenia / Delayed / 35.0-35.0
anemia / Delayed / 30.0-30.0
thrombocytopenia / Delayed / 22.0-22.0
infection / Delayed / 17.0-17.0
hypophosphatemia / Delayed / 13.0-13.0
hyponatremia / Delayed / 6.0-6.0
neurotoxicity / Early / 6.0-6.0
fever / Early / 4.7-4.7
hypokalemia / Delayed / 4.4-4.4
fatigue / Early / 3.5-3.5
rash / Early / 3.5-3.5
elevated hepatic enzymes / Delayed / 2.7-3.3
musculoskeletal pain / Early / 3.2-3.2
hypotension / Rapid / 2.9-2.9
weight loss / Delayed / 2.7-2.7
hypoalbuminemia / Delayed / 2.1-2.1
dyspnea / Early / 1.8-1.8
encephalopathy / Delayed / 1.8-1.8
hypoxia / Early / 1.5-1.5
anorexia / Delayed / 1.2-1.2
stomatitis / Delayed / 1.2-1.2
diarrhea / Early / 0.9-0.9
dysphagia / Delayed / 0.9-0.9
sinus tachycardia / Rapid / 0.6-0.6
cytokine release syndrome / Rapid / 0.6-0.6
headache / Early / 0.6-0.6
hyperbilirubinemia / Delayed / 0.3-0.3
pruritus / Rapid / 0.3-0.3
exfoliative dermatitis / Delayed / Incidence not known
sepsis / Delayed / Incidence not known
pulmonary embolism / Delayed / Incidence not known
acute respiratory distress syndrome (ARDS) / Early / Incidence not known
disseminated intravascular coagulation (DIC) / Delayed / Incidence not known
hepatic failure / Delayed / Incidence not known
renal failure / Delayed / Incidence not known

antibody formation / Delayed / 18.0-25.0
constipation / Delayed / 16.0-16.0
edema / Delayed / 14.0-14.0
peripheral neuropathy / Delayed / 14.0-14.0
glossitis / Early / Incidence not known
oral ulceration / Delayed / Incidence not known
contact dermatitis / Delayed / Incidence not known
erythema / Early / Incidence not known
Onychomadesis / Delayed / Incidence not known
palmar-plantar erythrodysesthesia (hand and foot syndrome) / Delayed / Incidence not known
amnesia / Delayed / Incidence not known
aphasia / Delayed / Incidence not known
confusion / Early / Incidence not known
delirium / Early / Incidence not known
dysarthria / Delayed / Incidence not known
dysphonia / Delayed / Incidence not known
hallucinations / Early / Incidence not known
hyperesthesia / Delayed / Incidence not known
memory impairment / Delayed / Incidence not known

dysgeusia / Early / 70.0-70.0
xerostomia / Early / 34.0-34.0
xerosis / Delayed / 30.0-30.0
chills / Rapid / 19.0-19.0
nausea / Early / 18.0-18.0
cough / Delayed / 17.0-17.0
injection site reaction / Rapid / 13.0-13.0
cheilitis / Delayed / Incidence not known
dysesthesia / Delayed / Incidence not known
acneiform rash / Delayed / Incidence not known
maculopapular rash / Early / Incidence not known
nail discoloration / Delayed / Incidence not known
onycholysis / Delayed / Incidence not known
skin discoloration / Delayed / Incidence not known
xerophthalmia / Early / Incidence not known
agitation / Early / Incidence not known
drowsiness / Early / Incidence not known
gait disturbance / Delayed / Incidence not known
hypoesthesia / Delayed / Incidence not known
lethargy / Early / Incidence not known
muscle cramps / Delayed / Incidence not known
paresthesias / Delayed / Incidence not known
restlessness / Early / Incidence not known
tremor / Early / Incidence not known
weakness / Early / Incidence not known

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.

Talvey

Rx

Bispecific GPRC5D-directed CD3 T-cell engaging antibody
Used in adult patients with heavily pretreated relapsed or refractory multiple myeloma
Boxed warning for cytokine release syndrome and severe neurologic toxicity

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.

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.

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.

Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no initial dosage adjustments are needed.

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 Subcutaneous Inj Sol: 1mL, 2mg, 40mg

0.4 mg/kg per week OR 0.8 mg/kg every 2 weeks subcutaneously.

0.4 mg/kg per week OR 0.8 mg/kg every 2 weeks subcutaneously.

Safety and efficacy not established.

Safety and efficacy not established.

Safety and efficacy not established.

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.

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.

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.

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.