Talvey

The solution is colourless to light yellow, with pH of 5.2 and osmolality of 287-290 mOsm/kg.
TALVEY solution for injection 3 mg/1.5 mL: One 1.5 mL vial contains 3 mg of talquetamab (2 mg/mL).
TALVEY solution for injection 40 mg/1 mL: One 1 mL vial contains 40 mg of talquetamab (40 mg/mL).
Talquetamab is a humanised immunoglobulin g4-proline, alanine, alanine (IgG4-PAA) bispecific antibody directed against G protein-coupled receptor family C group 5 member D (GPRC5D) and the cluster of differentiation 3 (CD3) receptors, produced in Chinese hamster ovary cells by recombinant DNA technology.
Excipients/Inactive Ingredients: EDTA disodium salt dihydrate (E385), Glacial acetic acid (E260), Polysorbate 20 (E432), Sodium acetate trihydrate (E262), Sucrose (E473), Water for injections.

Pharmacotherapeutic group: Other monoclonal antibodies and antibody drug conjugates. ATC code: L01FX29.
Pharmacology: Pharmacodynamics: Mechanism of action: Talquetamab is a immunoglobulin G4 proline, alanine, alanine (IgG4 PAA) bispecific antibody directed against GPRC5D and the CD3 receptor on T Cells.
Talquetamab promotes enhanced T cell-mediated cytotoxicity through recruitment of CD3-expressing T cells to GPRC5D-expressing cells. This leads to the activation of T cells and induces subsequent lysis of GPRC5D-expressing cells mediated by secreted perforin and various granzymes stored in the secretory vesicles of cytotoxic T cells. Based on the expression of GPRC5D on plasma cells with minimal to no expression detected on B cells and B cell precursors, talquetamab targets multiple myeloma cells particularly.
Pharmacodynamic effects: Within the first month of treatment with talquetamab, activation and redistribution of T cells and induction of serum cytokines were observed.
Clinical efficacy and safety: The efficacy of TALVEY monotherapy was evaluated in patients with relapsed or refractory multiple myeloma in a single-arm, open-label, multicentre study, MonumenTAL-1. The study included patients who had previously received at least three prior therapies, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody. The study excluded patients who received T cell redirection therapy within 3 months, prior Grade 3 or higher CRS related to any T cell redirection therapy, an allogeneic stem cell transplant within the past 6 months, autologous stem cell transplant within 3 months, stroke or seizure within the past 6 months, CNS involvement or clinical signs of meningeal involvement of multiple myeloma, plasma cell leukaemia, POEMS syndrome, primary light chain amyloidosis, and active or documented history of autoimmune disease, with the exception of vitiligo, resolved childhood atopic dermatitis, and prior Grave's disease that was euthyroid based on clinical symptoms and laboratory testing.
Patients received TALVEY 0.4 mg/kg subcutaneously weekly, following two step-up doses (0.01 and 0.06 mg/kg) in the first week of therapy, or TALVEY 0.8 mg/kg subcutaneously biweekly (every 2 weeks), following three step-up doses (0.01, 0.06 and 0.3 mg/kg), until disease progression or unacceptable toxicity. Patients were hospitalised for monitoring for at least 48 hours after each TALVEY dose during the step-up phase.
Of 143 patients treated with TALVEY 0.4 mg/kg weekly who were not exposed to prior T cell redirection therapy, the median age was 67 (range: 46 to 86) years, 55% were male, 90% were White, and 8% were Black or African American. Patients had received a median of 5 (range: 2 to 13) prior therapies, and 78% of patients had received prior autologous stem cell transplantation (ASCT). Ninety-four percent (94%) of patients were refractory to their last therapy, and 74% were refractory to a PI, immunomodulatory agent, and anti-CD38 antibody. Of the 132 patients for whom baseline cytogenetic data were available, high-risk cytogenetic factors (presence of t(4:14), t(14:16), and/or del(17p)) were present in 31% of patients. Twenty-three percent (23%) of patients had extramedullary plasmacytomas.
Of 145 patients treated with TALVEY 0.8 mg/kg biweekly (every 2 weeks) who were not exposed to prior T cell redirection therapy, the median age was 67 (range: 38 to 84) years, 57% were male, 86% were White, and 6% were Black or African American. Patients had received a median of 5 (range: 2 to 17) prior therapies, and 79% of patients had received prior autologous stem cell transplantation (ASCT). Ninety-four percent (94%) of patients were refractory to their last therapy, and 69% were refractory to a proteasome inhibitor, immunomodulatory agent, and anti-CD38 antibody. Of the 128 patients for whom baseline cytogenetic data were available, high-risk cytogenetic factors (presence of t(4:14), t(14:16), and/or del(17p)) were present in 29% of patients. Twenty-six percent (26%) of patients had extramedullary plasmacytomas.
Efficacy results were based on an overall response rate as determined by the Independent Review Committee assessment using IMWG criteria. The median duration of follow-up among patients receiving TALVEY 0.4 mg/kg weekly was 18.8 months; an estimated 51.5% of responders maintained response for at least 9 months. (See Table 1.)

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The median duration of follow-up among patients receiving TALVEY 0.8 mg/kg biweekly was 12.7 months; an estimated 76.3% of responders maintained response for at least 9 months. (See Table 2.)

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ORR results were consistent across pre-specified subgroups, including number of prior lines of therapy, refractoriness to prior therapy, and cytogenetic risk at baseline.
Immunogenicity: In MonumenTAL-1, 328 patients treated with subcutaneous talquetamab monotherapy at 0.4 mg/kg weekly or 0.8 mg/kg biweekly (every 2 weeks), with or without prior T cell redirection therapy, were evaluated for antibodies to talquetamab. Following treatment 0.4 mg/kg weekly or 0.8 mg/kg biweekly (every 2 weeks), 106 of 328 patients (32.3%) developed anti-talquetamab antibodies.
The limited number of anti-talquetamab antibody (ADA) positive subjects and the lack of information of the neutralising ADA, preclude drawing a definite conclusion regarding the effect of the neutralising ADAs on clinical parameters.
Pharmacokinetics: 0.4 mg/kg weekly dose: Talquetamab exhibited approximately dose-proportional pharmacokinetics following subcutaneous administration across a dose ranging from 0.005 to 0.8 mg/kg weekly (0.0125 to 2 times the recommended 0.4 mg/kg weekly dose). The mean accumulation ratio between the 1^st and 7^th weekly dose of talquetamab 0.4 mg/kg was 3.9- and 4.5-fold for C_max and AUC_tau, respectively.
Pharmacokinetic parameters of talquetamab following the 1^st and 7^th recommended weekly dose of 0.4 mg/kg are shown in Table 3. (See Table 3.)

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0.8 mg/kg biweekly dose: Talquetamab exhibited approximately dose-proportional pharmacokinetics following subcutaneous administration across a dose ranging from 0.8 mg/kg to 1.2 mg/kg biweekly (1.0 to 1.5 times the recommended 0.8 mg/kg biweekly dose). The mean accumulation ratio between the 1^st and 5^th biweekly dose of talquetamab 0.8 mg/kg was 2.3- and 2.2-fold for C_max and AUC_tau, respectively.
Pharmacokinetic parameters of talquetamab following the 1^st and 5^th recommended biweekly maintenance dose of 0.8 mg/kg are shown in Table 4. (See Table 4.)

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Absorption: Based on the population pharmacokinetic model, the typical value of the bioavailability of talquetamab was 62% when administered subcutaneously relative to intravenous dosing.
At 0.4 mg/kg weekly dose regimen, the median (range) T_max of talquetamab after the 1^st and 7^th treatment doses were 3 (1 to 8) days and 2 (1 to 6) days, respectively.
At 0.8 mg/kg biweekly (every 2 weeks) dose regimen, the median (range) T_max of talquetamab after the 1^st and 5^th treatment doses were 3 (2 to 14) days and 3 (1 to 8) days, respectively.
Distribution: Based on the population pharmacokinetic model, the typical value of the volume of distribution was 4.3 L (22% CV [coefficient of variation]) for the central compartment, and 5.8 L (83% CV) for the peripheral compartment.
Elimination: Talquetamab exhibited both linear time-independent and time-dependent clearance. Based on the population pharmacokinetic model and the post hoc parameters of participants receiving SC doses (N=392), the median total clearance is 1.64 L/day at initial treatment and 0.80 L/day at steady state. The time-dependent clearance accounted for 48.8% of total clearance at initial treatment and then decreased exponentially to < 5% at around Week 16. The concentration-time profile at Week 16 would reach 90% of steady-state concentration for both 0.4 mg/kg weekly and 0.8 mg/kg biweekly regimens. The median terminal phase half-life was 7.56 days at initial treatment, and 12.2 days at steady state.
Special populations: The pharmacokinetic analysis includes 86% White (n=424), 9% Black (n=43), 2.2% Asian (n=11), and 2.8% Others (n=14). Based on population PK analysis, the race or ethnicity, sex and body weight (range: 40 to 143 kg) did not have clinically meaningful effects on the pharmacokinetics of talquetamab.
Paediatric population: The pharmacokinetics of TALVEY in paediatric patients aged 17 years and younger have not been investigated.
Elderly: Results of population pharmacokinetic analyses indicate that age (33 to 86 years) did not influence the pharmacokinetics of talquetamab. Only limited data for patients ≥ 85 years was available (see Table 5).

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Renal impairment: No formal studies of talquetamab in patients with renal impairment have been conducted.
Results of population pharmacokinetic analyses indicate that mild (60 mL/min ≤ absolute glomerular filtration rate (GFR) < 90 mL/min) or moderate (30 mL/min ≤ absolute GFR < 60 mL/min) renal impairment did not significantly influence the pharmacokinetics of talquetamab. No data is available in patients with severe renal impairment.
Hepatic impairment: No formal studies of talquetamab in patients with hepatic impairment have been conducted. Using the NCI classification, results of population pharmacokinetic analyses indicate that mild hepatic impairment (total bilirubin > 1 to 1.5 times upper limit of normal (ULN) and any aspartate aminotransferase (AST), or total bilirubin ≤ ULN and AST > ULN) did not significantly influence the pharmacokinetics of talquetamab. Limited data (n=2) are available in participants with moderate hepatic impairment while no data are available in participants with severe hepatic impairment.
Toxicology: Preclinical safety data: A tool molecule was well tolerated in general toxicity studies in cynomolgus monkeys, but the results of these studies conducted with normal healthy monkeys have limited translatability to multiple myeloma patients.
Carcinogenicity and mutagenicity: No animal studies have been performed to assess the carcinogenic or genotoxic potential of talquetamab.
Reproductive toxicology and fertility: No animal studies have been conducted to evaluate the effects of talquetamab on reproduction and foetal development. No studies have been conducted to evaluate the effects of talquetamab on fertility.

TALVEY is indicated as monotherapy for the treatment of adult patients with relapsed and refractory multiple myeloma, who have received at least 3 prior lines of therapy, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 antibody and have demonstrated disease progression on the last therapy.

Treatment with TALVEY should be initiated and supervised by physicians experienced in the treatment of multiple myeloma.
TALVEY should be administered by a healthcare professional with adequately-trained medical personnel and appropriate medical equipment to manage severe reactions, including cytokine release syndrome (CRS) and neurologic toxicity, including immune effector cell-associated neurotoxicity syndrome (ICANS).
Posology: Pre-treatment medicinal products should be administered prior to each dose of TALVEY during the step-up phase (see as follows).
TALVEY should be administered subcutaneously on a weekly or biweekly (every 2 weeks) dosing schedule according to Table 6. Patients who receive talquetamab according to the 0.4 mg/kg body weight weekly dosing schedule and have attained an adequate clinical response that is confirmed in at least two consecutive disease assessments can be considered for switch to the 0.8 mg/kg body weight biweekly dosing schedule. (See Table 6.)

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Patients should be instructed to remain within proximity of a healthcare facility and monitored for 48 hours after administration of all doses within the TALVEY step-up phase for signs and symptoms of CRS and ICANS (see Precautions).
Duration of treatment: Patients should be treated with TALVEY until disease progression or unacceptable toxicity.
Pre-treatment: The following pre-treatment medicinal products must be administered 1 to 3 hours before each dose of TALVEY during the step-up phase to reduce the risk of CRS (see Precautions): Corticosteroid (oral or intravenous dexamethasone 16 mg or equivalent); Antihistamine (oral or intravenous diphenhydramine 50 mg or equivalent); Antipyretics (oral or intravenous paracetamol 650 mg to 1 000 mg or equivalent).
Pre-treatment medicinal products should be administered prior to subsequent doses for patients who repeat doses within the TALVEY step-up phase due to dose delays (see Table 7) or for patients who experienced CRS (see Table 8).
Prevention of infection: Prior to starting treatment with TALVEY, prophylaxis should be considered for the prevention of infections, per local institutional guidelines.
Dose delays: If a dose of TALVEY is delayed, therapy should be restarted based on recommendations in Table 7, and weekly or biweekly dosing should be resumed accordingly (see Posology as previously mentioned). Pre-treatment medicinal products should be administered prior to restarting TALVEY, and patients should be monitored accordingly. (See Table 7.)

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Dose modifications for adverse reactions: Dose delays may be required to manage toxicities related to TALVEY (see Precautions). See Table 7 for recommendations on restarting TALVEY after a dose delay.
See Tables 8 and 9 for recommended actions for the management of CRS and ICANS. See Table 11 for recommended dose modifications for other adverse reactions.
Cytokine release syndrome (CRS): CRS should be identified based on clinical presentation (see Precautions). Other causes of fever, hypoxia, and hypotension should be evaluated and treated If CRS is suspected, TALVEY should be withheld until CRS resolves and should be managed according to the recommendations in Table 8. Supportive therapy for CRS should be administered, which may include intensive care for severe or life-threatening CRS. Laboratory testing should be considered to monitor for disseminated intravascular coagulation (DIC), haematology parameters, as well as pulmonary, cardiac, renal, and hepatic function. (See Table 8.)

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Neurologic toxicity, including ICANS: At the first sign of neurologic toxicity, including ICANS, TALVEY should be withheld and neurology evaluation should be considered. Other causes of neurologic symptoms should be ruled out.
Supportive therapy should be provided, which may include intensive care, for severe or life-threatening ICANS (see Precautions). Management recommendations for ICANS are summarised in Table 9. (See Tables 9 and 10.)

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Other adverse reactions: The recommended dose modifications for other adverse reactions are provided in Table 11. (See Table 11.)

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Special populations: Paediatric population: There is no relevant use of TALVEY in the paediatric population in the treatment of multiple myeloma.
Elderly: No dose adjustment is required (see Pharmacology: Pharmacokinetics under Actions).
Renal impairment: No dose adjustment is recommended for patients with mild or moderate renal impairment (see Pharmacology: Pharmacokinetics under Actions).
Hepatic impairment: No dose adjustment is recommended for patients with mild hepatic impairment (see Pharmacology: Pharmacokinetics under Actions). Limited or no data are available in patients with moderate and severe hepatic impairment.
Method of administration: TALVEY is for subcutaneous use.
The required volume of TALVEY should be injected into the subcutaneous tissue of the abdomen (preferred injection site). Alternatively, TALVEY may be injected into the subcutaneous tissue at other sites (e.g., thigh). If multiple injections are required, TALVEY injections should be at least 2 cm apart.
TALVEY must not be injected into tattoos or scars or areas where the skin is red, bruised, tender, hard or not intact.
For instructions on handling of the medicinal product before administration, see Special precautions for disposal and other handling under Cautions for Usage.

Symptoms and signs: The maximum tolerated dose of talquetamab has not been determined. In clinical studies, doses of up to 1.2 mg/kg: once every 2 weeks and 1.6 mg/kg every month have been administered.
Treatment: In the event of an overdose, the patient should be monitored for any signs or symptoms of adverse effects and appropriate symptomatic treatment should be instituted immediately.

Hypersensitivity to the active substance or to any of the excipients listed in Description.

Traceability: In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.
Cytokine release syndrome (CRS): CRS, including life-threatening or fatal reactions, may occur in patients receiving TALVEY (see Adverse Reactions). Clinical signs and symptoms of CRS may include but are not limited to pyrexia, hypotension, chills, hypoxia, headache, tachycardia and elevated transaminases. Potentially life-threatening complications of CRS may include cardiac dysfunction, acute respiratory distress syndrome, neurologic toxicity, renal and/or hepatic failure, and disseminated intravascular coagulation (DIC).
TALVEY therapy should be initiated with step-up phase dosing and pre-treatment medicinal products (corticosteroids, antihistamine, and antipyretics) should be administered prior to each dose of TALVEY during the step-up phase to reduce the risk of CRS. Patients should be monitored following administration accordingly. In patients who experience CRS following their previous dose, pre-treatment medicinal products should be administered prior to the next TALVEY dose (see Dosage & Administration).
Subjects who experienced Grade 3 or higher CRS with any previous T cell redirection therapy were excluded from clinical studies. It cannot be excluded that prior severe CRS with chimeric antigen receptor (CAR) T-cell therapy or other T-cell engagers might impact on the safety of TALVEY. The potential benefits of treatment should be carefully weighed against the risk of neurologic events, and heightened caution should be exercised when administering TALVEY to these patients.
Patients should be counselled to seek medical attention should signs or symptoms of CRS occur. At the first sign of CRS, patients should be immediately evaluated for hospitalisation and treatment with supportive care, tocilizumab and/or corticosteroids, should be instituted based on severity. The use of myeloid growth factors, particularly granulocyte macrophage-colony stimulating factor (GM-CSF), should be avoided during CRS. TALVEY should be withheld until CRS resolves (see Dosage & Administration).
Neurologic toxicity including ICANS: Serious or life-threatening neurologic toxicities, including ICANS have occurred following treatment with TALVEY (see Adverse Reactions).
ICANS, including fatal reactions, have occurred following treatment with TALVEY. The onset of ICANS can be concurrent with CRS, following resolution of CRS, or in the absence of CRS. Clinical signs and symptoms of ICANS may include but are not limited to confusional state, depressed level of consciousness, disorientation, somnolence, lethargy, and bradyphrenia.
Patients should be monitored for signs and symptoms of neurologic toxicities and treated promptly. Patients should be counselled to seek medical attention should signs or symptoms of neurologic toxicities including ICANS occur. At the first sign of neurologic toxicities including ICANS, the patient should be immediately evaluated and supportive care should be provided based on severity. Patients who experience Grade 2 or higher ICANS should be instructed to remain within proximity of a healthcare facility and monitored for signs and symptoms for 48 hours following the next dose of TALVEY.
For ICANS and other neurologic toxicities, TALVEY should be withheld or discontinued based on severity and management recommendations should be followed as indicated in Table 9 (see Dosage & Administration).
There are no data on use of talquetamab in patients with CNS involvement of myeloma or other clinically relevant CNS pathologies as a result of their exclusion from the study due to the potential risk of ICANS.
Due to the potential for ICANS, patients should be instructed to avoid driving or operating machines during the step-up phase and for 48 hours after completion of the step-up phase, and in the event of new onset of any neurological symptoms, until symptoms resolve (see Effects on ability to drive and use machines as follows).
Management of neurologic toxicities: At the first sign of neurologic toxicity, including ICANS, neurology evaluation should be considered. Other causes of neurologic symptoms should be ruled out. TALVEY should be withheld until adverse reaction resolves (see Table 9 under Dosage & Administration). Intensive care and supportive therapy should be provided for severe or life-threatening neurologic toxicities.
Oral toxicity: Oral toxicities, including dysgeusia, dry mouth, dysphagia, and stomatitis occur very commonly following treatment with TALVEY (see Adverse Reactions).
Patients should be monitored for signs and symptoms of oral toxicity. Patients should be counselled to seek medical attention should signs or symptoms of oral toxicity occur, and supportive care should be provided. Supportive care may include saliva stimulating agents, steroid mouth wash, or consultation with a nutritionist. TALVEY should be interrupted or less frequent dosing should be considered (see Dosage & Administration).
Over time, notable weight loss may occur (see Adverse Reactions). Weight change should be monitored regularly during therapy. Clinically significant weight loss should be further evaluated. TALVEY should be interrupted or less frequent dosing should be considered (see Dosage & Administration).
Serious infections: Serious infections, including life-threatening or fatal infections, have been reported in patients receiving TALVEY (see Adverse Reactions). Patients should be monitored for signs and symptoms of infection prior to and during treatment with TALVEY and treated appropriately. Prophylactic antimicrobials should be administered according to local guidelines. TALVEY should not be administered in patients with active serious infection. TALVEY should be withheld as indicated (see Dosage & Administration). Patients should be instructed to seek medical advice if signs or symptoms suggestive of an infection occur.
Hypogammaglobulinaemia: Hypogammaglobulinaemia has been reported in patients receiving TALVEY (see Adverse Reactions). Immunoglobulin levels should be monitored during treatment with TALVEY. Intravenous or subcutaneous immunoglobulin therapy was used to treat hypogammaglobulinaemia patients. Patients should be treated according to local institutional guidelines, including infection precautions, antibiotic or antiviral prophylaxis, and administration of immunoglobulin replacement.
Cvtopenias: Treatment-emergent Grade 3 or 4 neutropenia, febrile neutropenia and thrombocytopenia have been observed in patients who received TALVEY. A majority of cytopenias occurred during the first 8 to 10 weeks. Complete blood counts should be monitored at baseline and periodically during treatment. Supportive care should be provided per local institutional guidelines.
Patients with neutropenia should be monitored for signs of infection. TALVEY should be withheld as warranted (see Dosage & Administration).
Skin reactions: TALVEY can cause skin reactions including rash, maculo-papular rash, erythema, erythematous rash, as well as nail disorders (see Adverse Reactions). Skin reactions including rash progression should be monitored for early intervention and treatment with corticosteroids. For Grade 3 or higher, or worsening Grade 1 or 2 rashes, oral steroids should also be administered. For non-rash skin reactions dose modification may be considered (see Table 11 under Dosage & Administration).
For skin reactions and nail disorders, TALVEY should be withheld based on severity and institutional guidelines should be followed (see Dosage & Administration).
Vaccines: Immune response to vaccines may be reduced when taking TALVEY. The safety of immunisation with live viral vaccines during or following TALVEY treatment has not been studied. Vaccination with live virus vaccines is not recommended for at least 4 weeks prior to the start of treatment, during treatment, and at least 4 weeks after treatment.
For unexpected exposure during pregnancy, see Use in Pregnancy & Lactation.
Excipients: This medicinal product contains less than 1 mmol (23 mg) sodium per dose, that is to say essentially 'sodium-free'.
Effects on ability to drive and use machines: TALVEY has major influence on the ability to drive and use machines.
Due to the potential for ICANS, patients receiving TALVEY are at risk of depressed level of consciousness (see previously mentioned). Patients should be instructed to avoid driving or operating machines during the step-up phase and for 48 hours after completion of the step-up phase (see Dosage & Administration), and in the event of new onset of any neurological symptoms, until symptoms resolve.
Use in Pregnancy & Lactation: See USE IN PREGNANCY & LACTATION section for further information.

Women of childbearing potential/Contraception in females: Pregnancy status of females of child-bearing potential should be verified prior to initiating treatment with TALVEY.
Females of reproductive potential should use effective contraception during treatment and for 3 months after the last dose of TALVEY.
Pregnancy: There are no available data on the use of TALVEY in pregnant women or animal data to assess the risk of TALVEY in pregnancy. Human IgG is known to cross the placenta after the first trimester of pregnancy. Therefore, talquetamab has the potential to be transmitted from the mother to the developing foetus. The effects of TALVEY on the developing foetus are unknown. TALVEY is not recommended for women who are pregnant or for women of childbearing potential not using contraception.
If TALVEY is taken during pregnancy, a reduced immune response to vaccines may be expected in newborns. Consequently, newborn vaccinations with live vaccines such as BCG vaccine should be postponed until 4 weeks.
Breast-feeding: It is not known whether talquetamab is excreted in human milk. Because the potential for serious adverse reactions in breast-fed infants is unknown for TALVEY, patients should not breast-feed during treatment with TALVEY and for at least 3 months after the last dose.
Fertility: There are no data on the effect of talquetamab on fertility. Effects of talquetamab on male and female fertility have not been evaluated in animal studies.

Summary of the safety profile: The most frequent adverse reactions were CRS (77%), dysgeusia (72%), hypogammaglobulinaemia (67%), nail disorder (56%), musculoskeletal pain (48%), anaemia (47%), skin disorder (43%), fatigue (43%), weight decreased (40%), rash (39%), dry mouth (36%), neutropenia (35%), pyrexia (33%), xerosis (32%), thrombocytopenia (30%), upper respiratory tract infection (29%), lymphopenia (27%), dysphagia (24%), diarrhoea (25%), pruritus (23%), cough (23%), pain (22%), decreased appetite (22%) and headache (20%).
Serious adverse reactions reported in patients included CRS (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 most frequent adverse reactions leading to treatment discontinuation were ICANS (1.1%) and weight decreased (0.9%).
Tabulated list of adverse reactions: The safety of TALVEY was evaluated in 339 adult patients with relapsed or refractory multiple myeloma, including patients treated with TALVEY at the recommended dosing regimen with or without prior T cell redirection therapy in MonumenTAL-1. The median duration of treatment was 7.4 (range: 0.0 to 32.9) months.
Table 12 summarises adverse reactions reported in patients who received TALVEY. The safety data of TALVEY was also evaluated in the All Treated population (N=501) with no additional adverse reactions identified.
Adverse reactions observed during clinical studies are listed as follows by frequency category. Frequency categories are defined as follows: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000 to < 1/100); rare (≥ 1/10 000 to < 1/1 000); very rare (< 1/10 000) and not known (frequency cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. (See Table 12.)

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Description of selected adverse reactions: Cytokine release syndrome: In MonumenTAL-1 (N=339), CRS occurred in 77% of patients. Most events were Grade 1 or 2, with Grade 3 events occurring in 1.5% of patients. Thirty one percent (31%) of patients experienced more than one CRS event. Most events occurred during the step-up phase following the 0.01 mg/kg dose (29%), the 0.06 mg/kg dose (44%), the 0.3 mg/kg dose (for patients who received biweekly [every 2 weeks] dosing; 33%), or the initial treatment dose (0.4 mg/kg [30%] or 0.8 mg/kg [12%]). Less than 4% of CRS events occurred from week 5 onward; all events were Grade 1. The median time to onset of CRS was 27 hours from the last dose, 91% of events occurred within 48 hours from the last dose, and the median duration was 17 hours. Tocilizumab, corticosteroids and tocilizumab in combination with corticosteroids were used to treat CRS in 39%, 5% and 3.5% of CRS events, respectively. Clinical signs and symptoms of CRS may include but are not limited to pyrexia (76%), hypotension (15%), chills (12%), hypoxia (7%), headache (4.7%), tachycardia (5%) and elevated transaminases (aspartate aminotransferase [1.5%] and alanine aminotransferase [0.9%]).
Neurologic toxicities: In MonumenTAL-1 (N=339), neurologic toxicity events were reported in 29% of patients receiving TALVEY. Neurologic toxicity events were Grade 1 (17%), Grade 2 (11%), Grade 3 (2.3%) or Grade 4 (0.3%). The most frequently reported neurologic toxicity event was headache (9%).
ICANS were only collected for Phase 2 in MonumenTAL-1. Of the 265 patients in Phase 2, ICANS occurred in 9.8% (n=26) of patients. Most events were Grade 1 or 2, with Grade 3 and 4 events occurring in 2.3% of patients. The most frequent clinical manifestation of ICANS reported were confusional state (3.8%), disorientation (1.9%), somnolence (1.9%) and depressed level of consciousness (1.9%). Sixty-eight percent (68%) were concurrent with CRS (during or within 7 days of CRS resolution). Three percent (3%) of patients experienced more than one ICANS event. In addition, one fatal ICANS event was reported in MonumenTAL-1. Most patients experienced ICANS during the step-up phase following the 0.01 mg/kg dose, the 0.06 mg/kg dose, or the initial treatment dose (0.4 mg/kg and 0.8 mg/kg) (3% each). The median time to onset of ICANS was 28 hours from the last dose, 68% of events started within 48 hours from the last dose, 32% of events occurred after 48 hours, and the median duration of ICANS was 9 hours.
Oral toxicity: In MonumenTAL-1 (N=339), 78% of patients had Grade 1 or 2 events, with Grade 3 events occurring in 2% of patients. Oral toxicity events included dysgeusia, dry mouth, dysphagia, and stomatitis were reported.
Serious infections: In MonumenTAL-1 (N=339), Grade 3 or Grade 4 infections occurred in 19% of patients; fatal infections occurred in 1.5% of patients - COVID-19 pneumonia, fungal sepsis, infection and septic shock. The most frequently reported (≥ 2%) Grade 3 or 4 infection was pneumonia. Febrile neutropenia was observed in 1% of patients with 1.2% experiencing serious febrile neutropenia. See Precautions for monitoring and management guidance.
Hypogammaglobulinaemia: Post baseline IgG values of less than 500 mg/dl consistent with hypogammaglobulinaemia have been reported in 64% of patients treated with talquetamab at the 0.4 mg/kg weekly dose schedule, 66% of patients at the 0.8 mg/kg biweekly dose schedule and in 71% of patients with prior T cell redirection therapy (see Precautions).
Skin reactions: In MonumenTAL-1 (N=339), the majority of rash cases were Grade 1 or 2, with Grade 3 events occurring in 3.5% of patients. The median time to onset from the first treatment dose for rash was 22 days. The majority of non-rash skin toxicities were Grade 1 or 2, with Grade 3 pruritus occurring in 0.3% of patients. Nail disorders occurred in 56% of patients and were Grade 1 or 2. See Precautions for management guidance.
Reporting of suspected adverse reactions: Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions.

No interaction studies have been performed.
Talquetamab causes release of cytokines (see Pharmacology: Pharmacodynamics under Actions) that may suppress activity of cytochrome P450 (CYP) enzymes, potentially resulting in increased exposure of CYP substrates. The highest risk of drug-drug interaction is expected to occur from initiation of talquetamab step-up phase up to 9 days after the first treatment dose and during and after CRS (see Precautions). Monitor for toxicity or concentrations of medicinal products that are CYP (e.g., CYP2C9, CYP2C19, CYP3A4/5, CYP2D6) substrates where minimal concentration changes may lead to serious adverse reactions. The dose of concomitant CYP (e.g., CYP2C9, CYP2C19, CYP3A4/5, CYP2D6) substrate drugs should be adjusted as needed.

Incompatibilities: In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
Special precautions for disposal and other handling: The TALVEY vials are supplied as ready-to-use solution for injection that do not need dilution prior to administration.
TALVEY vials of different concentrations should not be combined to achieve treatment dose.
Aseptic technique should be used to prepare and administer TALVEY.
Preparation of TALVEY: Refer to the following reference tables for the preparation of TALVEY: Use Table 13 to determine total dose, injection volume, and number of vials required based on patient's actual body weight for the 0.01 mg/kg dose using TALVEY 2 mg/mL vial. (See Table 13.)

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Use Table 14 to determine total dose, injection volume, and number of vials required based on patient's actual body weight for the 0.06 mg/kg dose using TALVEY 2 mg/mL vial. (See Table 14).

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Use Table 15 to determine total dose, injection volume and number of vials required based on patient's actual body weight for the 0.4 mg/kg dose using TALVEY 40 mg/mL vial. (See Table 15.)

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Use Table 16 to determine total dose, injection volume, and number of vials required based on patient's actual body weight for the 0.8 mg/kg dose using TALVEY 40 mg/mL vial. (See Table 16.)

Click on icon to see table/diagram/image

Check that the TALVEY solution for injection is colourless to light yellow. Do not use if the solution is discoloured, cloudy, or if foreign particles are present.
Remove the appropriate strength TALVEY vial from refrigerated storage (2°C to 8°C) and equilibrate to ambient temperature (15°C to 30°C) for at least 15 minutes. Do not warm TALVEY vial in any other way.
Once equilibrated, gently swirl the vial for approximately 10 seconds to mix. Do not shake.
Withdraw the required injection volume of TALVEY from the vial(s) into an appropriately sized syringe using a transfer needle. Each injection volume should not exceed 2.0 mL. Divide doses requiring greater than 2.0 mL equally into multiple syringes.
TALVEY is compatible with stainless steel injection needles and polypropylene or polycarbonate syringe material.
Replace the transfer needle with an appropriately sized needle for injection.
If the prepared syringe is stored in the refrigerator, allow the solution to come to ambient temperature before administration.
Any unused medicinal product or waste material should be disposed in accordance with local requirements.

Shelf life: Prepared syringe: Chemical and physical in-use stability has been demonstrated up to 24 hours at 2 to 8°C followed by up to 24 hours at temperature of 15°C to 30°C.
From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8°C, unless preparation has taken place in controlled and validated aseptic conditions. Discard if stored for more than 24 hours refrigerated or more than 24 hours of being at ambient temperature.
The prepared syringe should be stored protected from light.
Special precautions for storage: Store in a refrigerator (2°C to 8°C).
Do not freeze.
Store in the original package in order to protect from light.
For storage conditions after opening of the medicinal product, see Shelf life as previously mentioned.

Cancer Immunotherapy

L01FX29 - talquetamab ; Belongs to the class of other monoclonal antibodies and antibody drug conjugates. Used in the treatment of cancer.

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