Talquetamab

Talquetamab is a humanised IgG4 bispecific antibody (IgG4-PAA format) produced in Chinese hamster ovary cells. One binding arm recognises GPRC5D, a receptor found on plasma cells including malignant myeloma cells, and the other recognises CD3 on T cells. By bringing T cells to the tumour cells it triggers T-cell-mediated killing.

Mechanism of Action

• T-cell recruitment: binding CD3 on T cells and GPRC5D on target cells brings the two together and activates the T cells.
• Cell killing: activated T cells lyse GPRC5D-expressing cells with perforin and granzymes stored in the secretory vesicles of cytotoxic T cells.
• Selectivity: GPRC5D is expressed on plasma cells, with minimal to no expression detected on B cells and B-cell precursors. In normal tissue it is found mainly in keratin-producing epithelial cells of the skin and tongue.
• Cytokine release: T-cell activation releases pro-inflammatory cytokines. Within the first month of treatment, activation and redistribution of T cells and induction of serum cytokines were observed. The released cytokines may suppress cytochrome P450 enzymes (see Drug Interactions).
• Exposure and reactions: higher exposure has been associated with a higher incidence of some reactions, including oral toxicity, nail toxicity and skin reactions.

Pharmacokinetics

• Absorption: after subcutaneous injection, bioavailability is about 62% relative to intravenous dosing (population model). The median time to peak concentration is about 2 to 3 days. Exposure is approximately dose-proportional (0.005–0.8 mg/kg weekly; 0.8–1.2 mg/kg every 2 weeks). Between the first and seventh weekly dose of 0.4 mg/kg, peak concentration and AUC accumulate 3.9-fold and 4.5-fold. Concentrations reach 90% of steady state by week 16 on both regimens.
• Distribution: typical volume of distribution 4.3 L (central compartment) and 5.8 L (peripheral compartment).
• Metabolism: as an antibody, it is expected to be broken down into small peptides by catabolic pathways.
• Elimination: clearance has a linear time-independent part and a time-dependent part. Median total clearance is 1.64 L/day at the start of treatment and 0.80 L/day at steady state; the time-dependent part (48.8% of total clearance at the start) falls to below 5% at around week 16. Median terminal half-life is 7.56 days at the start and 12.2 days at steady state.
• Special populations: race or ethnicity, sex, body weight (40–143 kg) and age (33–86 years) have no clinically meaningful effect. Mild or moderate renal impairment does not significantly influence pharmacokinetics (no data in severe impairment). Mild hepatic impairment has no significant influence; data are limited in moderate impairment (2 participants) and absent in severe impairment. Pharmacokinetics have not been investigated in patients aged 17 years and younger.

• Multiple myeloma: as monotherapy for adults with relapsed and refractory multiple myeloma who have received at least 3 prior therapies, including an immunomodulatory agent, a proteasome inhibitor and an anti-CD38 antibody, and have demonstrated disease progression on the last therapy.

• Hypersensitivity to talquetamab or to any of the excipients.

Safety was evaluated in 339 adults with relapsed or refractory multiple myeloma who received the recommended regimen in the MonumenTAL-1 study (median treatment duration 7.4 months); the wider treated population (501 patients) showed no additional reactions. The most frequent reactions were cytokine release syndrome (77%), dysgeusia (72%), hypogammaglobulinaemia (67%), nail disorder (56%), musculoskeletal pain (48%), anaemia (47%), fatigue (43%), weight decrease (40%), rash (39%), dry mouth (36%), neutropenia (35%), pyrexia (33%), xerosis (32%) and thrombocytopenia (30%).

Very common (≥1/10): bacterial infection, fungal infection, COVID-19, upper respiratory tract infection; neutropenia, anaemia, thrombocytopenia, lymphopenia, leukopenia; cytokine release syndrome, hypogammaglobulinaemia; decreased appetite, hypokalaemia, hypophosphataemia, hypomagnesaemia; immune effector cell-associated neurotoxicity syndrome (ICANS), encephalopathy, headache, motor dysfunction, dizziness, sensory neuropathy; cough, dyspnoea, oral pain; dysgeusia, dry mouth, dysphagia, diarrhoea, stomatitis, nausea, constipation, abdominal pain, vomiting; rash, skin disorder, xerosis, pruritus, nail disorder; musculoskeletal pain; fatigue, weight decreased, pyrexia, pain, oedema, injection-site reaction, chills; decreased fibrinogen, prolonged activated partial thromboplastin time, raised transaminases, raised INR, raised gamma-glutamyltransferase.

Common (≥1/100 to <1/10): sepsis, pneumonia, viral infection; haemorrhage; febrile neutropenia; alopecia.

Serious reactions reported in patients included cytokine release syndrome (13%), pyrexia (5%), ICANS (3.8%), sepsis (3.8%), COVID-19 (3.2%), bacterial infection (2.4%), pneumonia (2.4%), viral infection (2.4%), neutropenia (2.1%) and pain (2.1%). The reactions that most often led to stopping treatment were ICANS (1.1%) and weight decrease (0.9%). Hypogammaglobulinaemia includes patients whose IgG fell below 500 mg/dL after treatment. Cytokine release syndrome, ICANS and infections can be life-threatening or fatal (see Special Instructions).

No interaction studies have been performed.

• CYP substrates: talquetamab causes release of cytokines that may suppress cytochrome P450 enzymes and so raise exposure to CYP substrates. The highest risk is from the start of step-up dosing to 9 days after the first treatment dose, and during and after CRS. Monitor for toxicity, or for drug concentrations, of CYP substrates (for example CYP2C9, CYP2C19, CYP3A4/5 and CYP2D6 substrates) where small changes in concentration may cause serious reactions, and adjust their doses as needed.
• Myeloid growth factors: avoid them, particularly granulocyte macrophage-colony stimulating factor (GM-CSF), during CRS.
• Live vaccines: not recommended from at least 4 weeks before the start of treatment until at least 4 weeks after it (see Special Instructions).

Treatment is started and supervised by physicians experienced in treating multiple myeloma. Talvey is given by a healthcare professional, with adequately trained medical personnel and appropriate equipment to manage severe reactions, including CRS and neurologic toxicity such as ICANS. It is injected subcutaneously, preferably into the abdomen (the thigh is an alternative). Multiple injections are placed at least 2 cm apart, and never into tattoos, scars or skin that is red, bruised, tender, hard or not intact. Doses are based on actual body weight.

Recommended Dose

• Weekly schedule: step-up doses of 0.01 mg/kg on day 1, 0.06 mg/kg on day 3 and 0.4 mg/kg on day 5, then 0.4 mg/kg once a week.
• Every-2-weeks schedule: step-up doses of 0.01 mg/kg on day 1, 0.06 mg/kg on day 3, 0.4 mg/kg on day 5 and 0.8 mg/kg on day 7, then 0.8 mg/kg every 2 weeks.
• Timing: the day 3, 5 and 7 doses may be given 2 to 4 days after the previous dose, or up to 7 days after it to allow adverse reactions to resolve. Keep at least 6 days between weekly doses and at least 12 days between doses on the 2-weekly schedule.
• Switching: patients on the weekly schedule with an adequate clinical response, confirmed at two consecutive disease assessments, can be considered for the 0.8 mg/kg every-2-weeks schedule.
• Duration: until disease progression or unacceptable toxicity.

Pre-treatment and Monitoring

• Pre-treatment: 1 to 3 hours before each step-up dose, give a corticosteroid (oral or intravenous dexamethasone 16 mg or equivalent), an antihistamine (oral or intravenous diphenhydramine 50 mg or equivalent) and an antipyretic (oral or intravenous paracetamol 650 mg to 1,000 mg or equivalent). Repeat the pre-treatment before later doses if step-up doses are repeated after a delay or if the patient had CRS.
• Monitoring: after every step-up dose the patient remains within proximity of a healthcare facility and is monitored for 48 hours for signs and symptoms of CRS and ICANS.
• Infection prophylaxis: consider it before starting, according to local institutional guidelines.

Dose Delays

After a delayed dose, restart according to the last dose given and the time since it, give pre-treatment before restarting, and then resume weekly or 2-weekly dosing.

• After 0.01 mg/kg (either schedule): more than 7 days, restart at 0.01 mg/kg.
• After 0.06 mg/kg (either schedule): 8 to 28 days, repeat 0.06 mg/kg; more than 28 days, restart at 0.01 mg/kg.
• After 0.4 mg/kg (either schedule): 8 to 35 days, repeat 0.4 mg/kg; 36 to 56 days, restart at 0.06 mg/kg; more than 56 days, restart at 0.01 mg/kg.
• After 0.8 mg/kg (2-weekly schedule): 14 to 35 days, repeat 0.8 mg/kg; 36 to 56 days, restart at 0.4 mg/kg; more than 56 days, restart at 0.01 mg/kg.

Dose Modifications for Adverse Reactions

• Cytokine release syndrome: withhold until CRS resolves, evaluate other causes of fever, hypoxia and hypotension, and give supportive care (intensive care for severe cases). For grade 1, give pre-treatment before the next dose; tocilizumab may be considered. For grade 2, also give tocilizumab 8 mg/kg intravenously over 1 hour (not above 800 mg), repeatable every 8 hours as needed (at most 3 doses in 24 hours and 4 in total), add methylprednisolone 1 mg/kg intravenously twice daily or dexamethasone 10 mg intravenously every 6 hours if there is no improvement within 24 hours, and monitor for 48 hours after the next dose. For grade 3, manage as grade 2 if it lasts below 48 hours; discontinue permanently if it recurs or lasts 48 hours or longer. For grade 4, discontinue permanently.
• ICANS and other neurologic toxicity: at the first sign, withhold talquetamab, consider a neurology evaluation and rule out other causes. For ICANS, withhold until it resolves and give dexamethasone 10 mg intravenously every 6 hours for grade 2 and above, with tocilizumab if CRS occurs together with it; consider non-sedating anti-seizure medicines such as levetiracetam. Recurrent grade 3 and any grade 4 ICANS require permanent discontinuation. For neurologic toxicity other than ICANS, grade 1 and 2 and a first grade 3 event are withheld until improvement; recurrent grade 3 and grade 4 events require permanent discontinuation.
• Serious infections: do not give step-up dosing to a patient with an active infection; withhold in the step-up phase until the infection resolves. In the treatment phase, withhold for grade 3–4 infections until they improve to grade 2 or better.
• Cytopenias: withhold if neutrophils fall below 0.5 × 10⁹/L (until 0.5 × 10⁹/L or higher), in febrile neutropenia (until neutrophils reach 1.0 × 10⁹/L or higher and fever resolves), if haemoglobin falls below 8 g/dL (until 8 g/dL or higher), or if platelets fall below 25,000/µL, or are 25,000–50,000/µL with bleeding (until 25,000/µL or higher and no bleeding).
• Oral toxicity and weight loss not responding to supportive care: interrupt until stabilisation or improvement and consider restarting on a modified schedule (0.4 mg/kg every 2 weeks instead of weekly, or 0.8 mg/kg every 4 weeks instead of every 2 weeks).
• Skin reactions including nail disorders, and other non-haematological reactions, grade 3–4: withhold until improvement to grade 1 or baseline.

Special Populations

• Elderly: no dose adjustment.
• Renal impairment: no adjustment for mild or moderate impairment.
• Hepatic impairment: no adjustment for mild impairment; limited or no data in moderate and severe impairment.
• Children and adolescents: there is no relevant use of talquetamab in the paediatric population for multiple myeloma.

Traceability

The name and batch number of the administered biological medicinal product should be clearly recorded.

Cytokine Release Syndrome

CRS, including life-threatening or fatal reactions, may occur. Signs include pyrexia, hypotension, chills, hypoxia, headache, tachycardia and raised transaminases; potentially life-threatening complications include cardiac dysfunction, acute respiratory distress syndrome, neurologic toxicity, renal or hepatic failure and disseminated intravascular coagulation. Step-up dosing and pre-treatment reduce the risk. Patients who had grade 3 or higher CRS with an earlier T-cell redirection therapy were excluded from the studies; prior severe CRS with CAR T-cell therapy or other T-cell engagers might affect safety, so the potential benefit is weighed carefully and heightened caution is advised in these patients. Patients are counselled to seek medical attention at the first sign of CRS and are evaluated at once for hospitalisation; supportive care, tocilizumab and/or corticosteroids are given according to severity.

Neurologic Toxicity, Including ICANS

Serious or life-threatening neurologic toxicity, including fatal ICANS, has occurred. ICANS can start together with CRS, after CRS has resolved, or without CRS; signs include confusional state, depressed level of consciousness, disorientation, somnolence, lethargy and bradyphrenia. Patients are monitored and treated promptly. Patients with grade 2 or higher ICANS remain within proximity of a healthcare facility and are monitored for 48 hours after the next dose. There are no data in patients with central nervous system involvement of myeloma or other relevant central nervous system disease, who were excluded from the study.

Oral Toxicity and Weight Loss

Oral toxicities (dysgeusia, dry mouth, dysphagia and stomatitis) occur very commonly. Patients are monitored and given supportive care, which may include saliva-stimulating agents, a steroid mouthwash or dietary advice; talquetamab may be interrupted or given less often. Notable weight loss may occur over time, so weight is monitored regularly and clinically significant loss is evaluated further.

Serious Infections and Hypogammaglobulinaemia

Serious infections, including life-threatening or fatal ones, have been reported. Patients are monitored for infection before and during treatment, prophylactic antimicrobials are given according to local guidelines, and talquetamab is not given to patients with an active serious infection. Immunoglobulin levels are monitored; hypogammaglobulinaemia is managed according to local institutional guidelines, including infection precautions, antibiotic or antiviral prophylaxis and immunoglobulin replacement.

Cytopenias

Grade 3 or 4 neutropenia, febrile neutropenia and thrombocytopenia occurred, mostly in the first 8 to 10 weeks. Complete blood counts are monitored at baseline and periodically, with supportive care according to local guidelines.

Skin Reactions and Nail Disorders

Rash, erythema, palmar-plantar erythrodysaesthesia syndrome and nail disorders can occur. Progression of rash is monitored for early treatment with corticosteroids; oral steroids are added for grade 3 or higher rash or worsening grade 1 or 2 rash.

Vaccines

The immune response to vaccines may be reduced. The safety of live viral vaccines during or after treatment has not been studied, and they are not recommended from at least 4 weeks before the start of treatment until at least 4 weeks after it.

Pregnancy, Breastfeeding and Fertility

• Pregnancy status of women of childbearing potential should be verified before starting treatment, and effective contraception is used during treatment and for 3 months after the last dose.
• Pregnancy: there are no data on use in pregnant women and no animal data. Human IgG crosses the placenta after the first trimester, so talquetamab may reach the foetus; its effects are unknown. It is not recommended in pregnancy or for women of childbearing potential not using contraception. After exposure in pregnancy, a reduced immune response to vaccines may be expected in the newborn, and live vaccines such as BCG should be postponed until the infant is 4 weeks old (see the SmPC).
• Breastfeeding: patients should not breast-feed during treatment and for at least 3 months after the last dose.
• Fertility: there are no data on fertility, and animal studies have not evaluated it.

Excipients

The medicine contains 0.4 mg/mL of polysorbate 20, which may cause allergic reactions. It contains less than 1 mmol (23 mg) of sodium per dose, so it is essentially sodium-free.

Effect on Driving

Talvey has a major influence on the ability to drive and use machines because of the risk of depressed level of consciousness from ICANS. Patients should avoid driving or operating machines during the step-up phase and for 48 hours after it ends, and after any new neurological symptoms until they resolve.

Store in a refrigerator at 2–8 °C. Do not freeze. Keep the vials in the original package to protect from light. Talvey is transported and held cold-chain, and storage after the syringe is prepared is described under Shelf Life.

Unopened vial: 3 years. Prepared syringe: chemical and physical in-use stability has been shown for up to 24 hours at 2–8 °C followed by up to 24 hours at 15–30 °C, protected from light. From a microbiological point of view the product should be used immediately; otherwise in-use storage times and conditions are the responsibility of the user and would normally not be longer than 24 hours at 2–8 °C, unless preparation took place in controlled and validated aseptic conditions. Discard a syringe stored for more than 24 hours refrigerated or more than 24 hours at ambient temperature.

Prescription only (Rx), on restricted medical prescription, with treatment initiated and supervised by physicians experienced in the treatment of multiple myeloma. Talquetamab is given by a healthcare professional with the staff and equipment to manage cytokine release syndrome and neurologic toxicity, and patients stay near a healthcare facility during step-up dosing, so it is supplied to the hospital or clinic that administers it, under refrigerated (2–8 °C) cold-chain handling.