Leaflet TALVEY 40mg / ml solution for injection

TALVEY 2 mg/mL solution for injection

TALVEY 40 mg/mL solution for injection

TALVEY 2 mg/mL solution for injection

One 1.5 mL vial contains 3 mg of talquetamab (2 mg/mL).

TALVEY 40 mg/mL solution for injection

One 1 mL vial contains 40 mg of talquetamab (40 mg/mL).

Talquetamab is a humanised immunoglobulin g4-proline, alanine, alanine (IgG4-PAA) bispecificantibody directed against G protein-coupled receptor family C group 5 member D (GPRC5D) and thecluster of differentiation 3 (CD3) receptors, produced in Chinese hamster ovary cells by recombinant

DNA technology.

Each dose contains 0.4 mg/mL of polysorbate 20.

For the full list of excipients, see section 6.1.

Solution for injection (injection).

The solution is colourless to light yellow, with pH of 5.2 and osmolality of 287-290 mOsm/kg.

TALVEY is indicated as monotherapy for the treatment of adult patients with relapsed and refractorymultiple myeloma, who have received at least 3 prior therapies, including an immunomodulatoryagent, a proteasome inhibitor, and an anti-CD38 antibody and have demonstrated disease progressionon the last therapy.

Treatment with TALVEY should be initiated and supervised by physicians experienced in thetreatment of multiple myeloma.

TALVEY should be administered by a healthcare professional with adequately-trained medicalpersonnel and appropriate medical equipment to manage severe reactions, including cytokine releasesyndrome (CRS) and neurologic toxicity, including immune effector cell-associated neurotoxicitysyndrome (ICANS).

Pre-treatment medicinal products should be administered prior to each dose of TALVEY during thestep-up phase (see below).

TALVEY should be administered subcutaneously on a weekly or biweekly (every 2 weeks) dosingschedule according to Table 1. Patients who receive talquetamab according to the 0.4 mg/kg bodyweight weekly dosing schedule and have attained an adequate clinical response that is confirmed in atleast two consecutive disease assessments can be considered for switch to the 0.8 mg/kg body weightbiweekly dosing schedule.

Table 1: Recommended TALVEY dose

Dosing

Phase Day TALVEY doseaschedule

Day 1 0.01 mg/kg

Weekly dosing Step-up phase Day 3b 0.06 mg/kgschedule Day 5b 0.4 mg/kg

Treatment phase Once a week thereafterc 0.4 mg/kg

Day 1 0.01 mg/kg

Biweekly (every Day 3b 0.06 mg/kg

Step-up phase2 weeks) dosing Day 5b 0.4 mg/kgschedule Day 7b 0.8 mg/kg

Treatment phase Once every 2 weeks thereafterc 0.8 mg/kga Based on actual body weight and administered subcutaneously.b Dose may be administered between 2 to 4 days after the previous dose and may be given up to 7 days after the previous dose to allowfor resolution of adverse reactions.c Maintain a minimum of 6 days between weekly doses and a minimum of 12 days between biweekly (every 2 weeks) doses.

Patients should be instructed to remain within proximity of a healthcare facility and monitored for48 hours after administration of all doses within the TALVEY step-up phase for signs and symptomsof CRS and ICANS (see section 4.4).

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 section 4.4).

- 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 whorepeat doses within the TALVEY step-up phase due to dose delays (see Table 2) or for patients whoexperienced CRS (see Table 3).

Prevention of infection

Prior to starting treatment with TALVEY, prophylaxis should be considered for the prevention ofinfections, per local institutional guidelines.

Dose delays

If a dose of TALVEY is delayed, therapy should be restarted based on recommendations in Table 2,and weekly or biweekly dosing should be resumed accordingly (see Posology above). Pre-treatmentmedicinal products should be administered prior to restarting TALVEY, and patients should bemonitored accordingly.

Table 2: Recommendations for restarting TALVEY after dose delay

Last dose Time from last dose TALVEY recommendation*

Dosing schedule administered administered0.01 mg/kg More than 7 days Restart at 0.01 mg/kg8 to 28 days Repeat 0.06 mg/kg0.06 mg/kg

Weekly More than 28 days Restart at 0.01 mg/kgdosing schedule 8 to 35 days Repeat 0.4 mg/kg0.4 mg/kg 36 to 56 days Restart at 0.06 mg/kg

More than 56 days Restart at 0.01 mg/kg0.01 mg/kg More than 7 days Restart at 0.01 mg/kg8 to 28 days Repeat 0.06 mg/kg0.06 mg/kg

More than 28 days Restart at 0.01 mg/kg

Biweekly 8 to 35 days Repeat 0.4 mg/kg(every 2 weeks) 0.4 mg/kg 36 to 56 days Restart at 0.06 mg/kgdosing schedule More than 56 days Restart at 0.01 mg/kg14 to 35 days Repeat 0.8 mg/kg0.8 mg/kg 36 to 56 days Restart at 0.4 mg/kg

More than 56 days Restart at 0.01 mg/kg

* Administer pretreatment medicinal products prior to restarting TALVEY. After restarting TALVEY, resume weekly or biweekly(every 2 weeks) dosing accordingly (see section 4.2).

Dose modifications for adverse reactions

Dose delays may be required to manage toxicities related to TALVEY (see section 4.4). See Table 2for recommendations on restarting TALVEY after a dose delay.

See Tables 3 and 4 for recommended actions for the management of CRS and ICANS. See Table 6 forrecommended dose modifications for other adverse reactions.

CRS should be identified based on clinical presentation (see section 4.4). Other causes of fever,hypoxia, and hypotension should be evaluated and treated. If CRS is suspected, TALVEY should bewithheld until CRS resolves and should be managed according to the recommendations in Table 3.

Supportive therapy for CRS should be administered, which may include intensive care for severe orlife-threatening CRS. Laboratory testing should be considered to monitor for disseminatedintravascular coagulation (DIC), haematology parameters, as well as pulmonary, cardiac, renal, andhepatic function.

Table 3: Recommendations for management of CRS

CRS Gradea TALVEY actions Tocilizumabb Corticosteroidsc

Grade 1 Withhold TALVEY until May be considered. Not applicable

CRS resolves.

Temperature ≥ 38°Cd

Administer pre-treatmentmedicinal product priorto next dose of

TALVEY.

Grade 2 Withhold TALVEY until Administer tocilizumabc If no improvement

CRS resolves. 8 mg/kg intravenously within 24 hours of

Temperature ≥ 38°Cd over 1 hour (not to starting tocilizumab,with either: Administer pre-treatment exceed 800 mg). administermedicinal products prior methylprednisolone

- Hypotension to next dose of Repeat tocilizumab every 1 mg/kg intravenouslyresponsive to fluids TALVEY. 8 hours as needed, if not twice daily, orand not requiring responsive to intravenous dexamethasone 10 mgvasopressors, or Monitor patient for fluids or increasing intravenously every48 hours following the supplemental oxygen. 6 hours.

- Oxygen requirement next dose of TALVEY.

of low-flow nasal Instruct patients to Limit to a maximum of Continue corticosteroidcannulae or blow-by. remain within proximity 3 doses in a 24-hour use until the event isof a healthcare facility period; maximum total of Grade 1 or less, thenduring monitoring. 4 doses. taper over 3 days.

Grade 3 Duration < 48 hours Administer tocilizumab If no improvement,8 mg/kg intravenously administer

Temperature ≥ 38°Cd Per Grade 2. over 1 hour (not to methylprednisolonewith either: exceed 800 mg). 1 mg/kg intravenously

Recurrent or twice daily or

- Hypotension Duration ≥ 48 hours Repeat tocilizumab every dexamethasonerequiring one 8 hours as needed, if not (e.g., 10 mgvasopressor, with or Permanently discontinue responsive to intravenous intravenously everywithout vasopressin, TALVEY. fluids or increasing 6 hours).or supplemental oxygen.

Continue corticosteroid

- Oxygen requirement Limit to a maximum of use until the event isof high-flow nasal 3 doses in a 24-hour Grade 1 or less, thencannulae, facemask, period; maximum total of taper over 3 days.

non-rebreather mask, 4 doses.

or Venturi mask

Grade 4 Permanently discontinue Administer tocilizumab As above or administer

TALVEY. 8 mg/kg intravenously methylprednisolone

Temperature ≥ 38°Cd over 1 hour (not to 1 000 mg intravenouslywith either: exceed 800 mg). per day for 3 days, perphysician discretion.

- Hypotension Repeat tocilizumab everyrequiring multiple 8 hours as needed, if not If no improvement or ifvasopressors responsive to intravenous condition worsens,(excluding fluids or increasing consider alternatevasopressin), or supplemental oxygen. immunosuppressants.c

- oxygen requirement Limit to a maximum ofof positive pressure 3 doses in a 24-hour(e.g., continuous period; maximum total ofpositive airway 4 doses.

pressure [CPAP],bilevel positiveairway pressure[BiPAP], intubation,and mechanicalventilation)a Based on ASTCT grading for CRS (Lee et al 2019).b Refer to tocilizumab prescribing information for details.c Treat unresponsive CRS per institutional guidelines.d Attributed to CRS. Fever may not always be present concurrently with hypotension or hypoxia as it may be masked by interventionssuch as antipyretics or anticytokine therapy (e.g., tocilizumab or corticosteroids).e Low-flow nasal cannula is ≤ 6 L/min, and high-flow nasal cannula is > 6 L/min.

Neurologic toxicity, including ICANS

At the first sign of neurologic toxicity, including ICANS, TALVEY should be withheld and neurologyevaluation should be considered. Other causes of neurologic symptoms should be ruled out.

Supportive therapy should be provided, which may include intensive care, for severe orlife-threatening ICANS (see section 4.4). Management recommendations for ICANS are summarisedin Table 4.

Table 4: Recommendations for management of ICANS

ICANS Gradea, b Concurrent CRS No concurrent CRS

Grade 1 Management of CRS per Table 3. Monitor neurologic symptomsand consider neurology

ICEc score 7-9 Monitor neurologic symptoms and consultation and evaluation, perconsider neurology consultation and physician discretion.or depressed level of evaluation, per physician discretion.consciousnessd: awakens Withhold TALVEY until ICANS resolves.spontaneously.

Consider non-sedating, anti-seizure medicines (e.g., levetiracetam) forseizure prophylaxis.

Grade 2 Administer tocilizumab per Table 3 for Administer dexamethasoneemanagement of CRS. 10 mg intravenously every

ICEc score 3-6 6 hours. Continue

If no improvement after starting dexamethasone use untilor depressed level of tocilizumab, administer resolution to Grade 1 or less,consciousnessd: awakens to dexamethasonee 10 mg intravenously then taper.voice. every 6 hours if not already takingother corticosteroids. Continuedexamethasone use until resolution to

Grade 1 or less, then taper.

Withhold TALVEY until ICANS resolves.

Consider non-sedating, anti-seizure medicines (e.g., levetiracetam) forseizure prophylaxis. Consider neurology consultation and other specialistsfor further evaluation, as needed.

Monitor patient for 48 hours following the next dose of TALVEY. Instructpatients to remain within proximity of a healthcare facility duringmonitoring.

Grade 3 Administer tocilizumab per Table 3 for Administer dexamethasoneemanagement of CRS. 10 mg intravenously every

ICEc score 0-2 6 hours. Continue(If ICE score is 0, but the Administer dexamethasonee 10 mg dexamethasone use untilpatient is arousable (e.g., intravenously with the first dose of resolution to Grade 1 or less,awake with global aphasia) and tocilizumab and repeat dose every then taper.able to perform assessment) 6 hours. Continue dexamethasone useuntil resolution to Grade 1 or less, thenor depressed level of taper.consciousnessd: awakens only

Consider non-sedating, anti-seizure medicines (e.g., levetiracetam) forto tactile stimulus,seizure prophylaxis. Consider neurology consultation and other specialistsd for further evaluation, as needed.or seizures , either:

- any clinical seizure, focal First Occurrence:

or generalised, that resolves Withhold TALVEY until ICANS resolves.rapidly, or

- non-convulsive seizures on Monitor patient for 48 hours following the next dose of TALVEY. Instructelectroencephalogram patients to remain within proximity of a healthcare facility during(EEG) that resolve with monitoring.intervention,

Recurrent:or raised intracranial pressure: Permanently discontinue TALVEY.focal/local oedema onneuroimagingd.

Grade 4 Administer tocilizumab per Table 3 for Administer dexamethasoneemanagement of CRS. 10 mg intravenously and repeat

ICEc score 0 dose every 6 hours. Continue(Patient is unarousable and Administer dexamethasonee 10 mg dexamethasone use untilunable to perform ICE intravenously and repeat dose every resolution to Grade 1 or less,assessment) 6 hours. Continue dexamethasone use then taper.

until resolution to Grade 1 or less, thenor depressed level of taper. Alternatively, considerconsciousnessd either: administration of

- patient is unarousable or Alternatively, consider administration methylprednisolone 1 000 mgrequires vigorous or of methylprednisolone 1 000 mg per per day intravenously for 3 days;repetitive tactile stimuli to day intravenously with first dose of if improves, then manage asarouse, or tocilizumab, and continue above.

- stupor or coma, methylprednisolone 1 000 mg per dayintravenously for 2 or more days.

or seizuresd, either: Permanently discontinue TALVEY.

- life-threatening prolongedseizure (> 5 minutes), or Consider non-sedating, anti-seizure medicines (e.g., levetiracetam) for

- repetitive clinical or seizure prophylaxis. Consider neurology consultation and other specialistselectrical seizures without for further evaluation, as needed.

return to baseline inbetween, In case of raised intracranial pressure/cerebral oedema, refer to localinstitutional guidelines for management.

or motor findingsd:

- deep focal motor weaknesssuch as hemiparesis orparaparesis,or raised intracranialpressure/cerebral oedemad,with signs/symptoms such as:

- diffuse cerebral oedema onneuroimaging, or

- decerebrate or decorticateposturing, or

- cranial nerve VI palsy, or

- papilloedema, or

- Cushing’s triad.a Management is determined by the most severe event, not attributable to any other cause.b ASTCT 2019 grading for ICANS.c If patient is arousable and able to perform Immune Effector Cell-Associated Encephalopathy (ICE) Assessment, assess: Orientation(oriented to year, month, city, hospital = 4 points); Naming (name 3 objects, e.g., point to clock, pen, button = 3 points); Following

Commands (e.g., “show me 2 fingers” or “close your eyes and stick out your tongue” = 1 point); Writing (ability to write a standardsentence = 1 point; and Attention (count backwards from 100 by ten = 1 point). If patient is unarousable and unable to perform ICE

Assessment (Grade 4 ICANS) = 0 points.

d Attributable to no other cause.e All references to dexamethasone administration are dexamethasone or equivalent

Table 5: Recommendations for management of neurologic toxicity (excluding ICANS)

Adverse Reaction Severitya Actions

Neurologic Grade 1 - Withhold TALVEY until neurologic toxicity

Toxicitya symptoms resolve or stabilise.b(excluding Grade 2 - Withhold TALVEY until neurologic toxicity

ICANS) Grade 3 (First symptoms improve to Grade 1 or less.boccurrence) - Provide supportive therapy.

Grade 3 (Recurrent) - Permanently discontinue TALVEY.

Grade 4 - Provide supportive therapy, which may includeintensive care.a Based on National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 4.03.b See Table 2 for recommendations on restarting TALVEY after dose delays.

Other adverse reactions

The recommended dose modifications for other adverse reactions are provided in Table 6.

Table 6: Recommended dose modifications for other adverse reactions

Adverse reaction Severity Dose modification

Serious infections All Grades - Do not administer TALVEY step-up dosing(see section 4.4) schedule in patients with active infection.

- Withhold TALVEY in the step-up phase untilinfection resolves.

Grade 3-4 - Withhold TALVEY during the treatment phaseuntil infection improves to Grade 2 or better.

Cytopenias Absolute neutrophil - Withhold TALVEY until absolute neutrophil(see section 4.4) count less than count is 0.5 × 109/L or higher.

0.5 × 109/L

Febrile neutropenia - Withhold TALVEY until absolute neutrophilcount is 1.0 × 109/L or higher and fever resolves.

Haemoglobin less - Withhold TALVEY until haemoglobin is 8 g/dL orthan 8 g/dL higher.

Platelet count less - Withhold TALVEY until platelet count isthan 25 000/µL 25 000/µL or higher and no evidence of bleeding.

Platelet countbetween 25 000/µLand 50 000/µL withbleeding

Oral toxicity, including Toxicity not Interrupt TALVEY until stabilisation or improvement,weight loss responding to and consider restarting on modified schedule as(see section 4.4) supportive care follows:

- If current dose is 0.4 mg/kg every week, change to0.4 mg/kg every two weeks

- If current dose is 0.8 mg/kg every two weeks,change to 0.8 mg/kg every four weeks

Skin reactions, including Grade 3-4 - Withhold TALVEY until adverse reactionnail disorders improves to Grade 1 or baseline.(see section 4.4)

Other non-haematologic Grade 3-4 - Withhold TALVEY until adverse reactionadverse reactionsa improves to Grade 1 or baseline.(see section 4.8)a Based on National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), Version 4.03.

There is no relevant use of TALVEY in the paediatric population in the treatment of multiplemyeloma.

No dose adjustment is required (see section 5.2).

No dose adjustment is recommended for patients with mild or moderate renal impairment (seesection 5.2).

No dose adjustment is recommended for patients with mild hepatic impairment (see section 5.2).

Limited or no data are available in patients with moderate and severe hepatic impairment.

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 atother sites (e.g., thigh). If multiple injections are required, TALVEY injections should be at least 2 cmapart.

TALVEY must not be injected into tattoos or scars or areas where the skin is red, bruised, tender, hardor not intact.

For instructions on handling of the medicinal product before administration, see section 6.6.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

In order to improve the traceability of biological medicinal products, the name and the batch numberof the administered product should be clearly recorded.

CRS, including life-threatening or fatal reactions, may occur in patients receiving TALVEY (seesection 4.8). Clinical signs and symptoms of CRS may include but are not limited to pyrexia,hypotension, chills, hypoxia, headache, tachycardia and elevated transaminases. Potentiallylife-threatening complications of CRS may include cardiac dysfunction, acute respiratory distresssyndrome, 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 followingadministration accordingly. In patients who experience CRS following their previous dose,pre-treatment medicinal products should be administered prior to the next TALVEY dose (seesection 4.2).

Subjects who experienced Grade 3 or higher CRS with any previous T cell redirection therapy wereexcluded from clinical studies. It cannot be excluded that prior severe CRS with chimeric antigenreceptor (CAR) T-cell therapy or other T-cell engagers might impact on the safety of TALVEY. Thepotential benefits of treatment should be carefully weighed against the risk of neurologic events, andheightened 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. Atthe first sign of CRS, patients should be immediately evaluated for hospitalisation and treatment withsupportive care, tocilizumab and/or corticosteroids, should be instituted based on severity. The use ofmyeloid growth factors, particularly granulocyte macrophage-colony stimulating factor (GM-CSF),should be avoided during CRS. TALVEY should be withheld until CRS resolves (see section 4.2).

Neurologic toxicity, including ICANS

Serious or life-threatening neurologic toxicities, including ICANS have occurred following treatmentwith TALVEY (see section 4.8).

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. Clinicalsigns and symptoms of ICANS may include but are not limited to confusional state, depressed level ofconsciousness, 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 neurologictoxicities including ICANS occur. At the first sign of neurologic toxicities including ICANS, thepatient 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 ofa 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 onseverity and management recommendations should be followed as indicated in Table 4 (seesection 4.2).

There are no data on use of talquetamab in patients with CNS involvement of myeloma or otherclinically relevant CNS pathologies as a result of their exclusion from the study due to the potentialrisk of ICANS.

Due to the potential for ICANS, patients should be instructed to avoid driving or operating machinesduring the step-up phase and for 48 hours after completion of the step-up phase, and in the event ofnew onset of any neurological symptoms, until symptoms resolve (see section 4.7).

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 adversereaction resolves (see Table 4). Intensive care and supportive therapy should be provided for severe orlife-threatening neurologic toxicities.

Oral toxicity

Oral toxicities, including dysgeusia, dry mouth, dysphagia, and stomatitis occur very commonlyfollowing treatment with TALVEY (see section 4.8).

Patients should be monitored for signs and symptoms of oral toxicity. Patients should be counselled toseek medical attention should signs or symptoms of oral toxicity occur, and supportive care should beprovided. Supportive care may include saliva stimulating agents, steroid mouth wash, or consultationwith a nutritionist. TALVEY should be interrupted or less frequent dosing should be considered (seesection 4.2).

Over time, notable weight loss may occur (see section 4.8). Weight change should be monitoredregularly during therapy. Clinically significant weight loss should be further evaluated. TALVEYshould be interrupted or less frequent dosing should be considered (see section 4.2).

Serious infections, including life-threatening or fatal infections, have been reported in patientsreceiving TALVEY (see section 4.8). Patients should be monitored for signs and symptoms ofinfection prior to and during treatment with TALVEY and treated appropriately. Prophylacticantimicrobials should be administered according to local guidelines. TALVEY should not beadministered in patients with active serious infection. TALVEY should be withheld as indicated (seesection 4.2). Patients should be instructed to seek medical advice if signs or symptoms suggestive ofan infection occur.

Hypogammaglobulinaemia has been reported in patients receiving TALVEY (see section 4.8).

Immunoglobulin levels should be monitored during treatment with TALVEY. Intravenous orsubcutaneous immunoglobulin therapy was used to treat hypogammaglobulinaemia patients. Patientsshould be treated according to local institutional guidelines, including infection precautions, antibioticor antiviral prophylaxis, and administration of immunoglobulin replacement.

Cytopenias

Treatment-emergent Grade 3 or 4 neutropenia, febrile neutropenia and thrombocytopenia have beenobserved in patients who received TALVEY. A majority of cytopenias occurred during the first 8 to10 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 aswarranted (see section 4.2).

TALVEY can cause skin reactions including rash, erythema, palmar-plantar erythrodysesthesiasyndrome, as well as nail disorders (see section 4.8). Skin reactions including rash progression shouldbe monitored for early intervention and treatment with corticosteroids. For Grade 3 or higher, orworsening Grade 1 or 2 rashes, oral steroids should also be administered. For non-rash skin reactionsdose modification may be considered (see Table 6).

For skin reactions and nail disorders, TALVEY should be withheld based on severity and institutionalguidelines should be followed (see section 4.2).

Vaccines

Immune response to vaccines may be reduced when taking TALVEY. The safety of immunisationwith live viral vaccines during or following TALVEY treatment has not been studied. Vaccinationwith live virus vaccines is not recommended for at least 4 weeks prior to the start of treatment, duringtreatment, and at least 4 weeks after treatment.

For unexpected exposure during pregnancy, see section 4.6.

Women of child-bearing potential/contraception

Pregnancy status of females of child-bearing potential should be verified prior to initiating treatmentwith TALVEY. Females of reproductive potential should use effective contraception during treatmentand for 3 months after the last dose of TALVEY (see section 4.6).

This medicinal product contains less than 1 mmol (23 mg) sodium per dose, that is to say essentially‘sodium-free’.

Polysorbate 20

This medicine contains 0.4 mg/mL of polysorbate 20. Polysorbates may cause allergic reactions.

No interaction studies have been performed.

Talquetamab causes release of cytokines (see section 5.1) that may suppress activity of cytochrome

P450 (CYP) enzymes, potentially resulting in increased exposure of CYP substrates. The highest riskof drug-drug interaction is expected to occur from initiation of talquetamab step-up phase up to 9 daysafter the first treatment dose and during and after CRS (see section 4.4). Monitor for toxicity orconcentrations 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 ofconcomitant CYP (e.g., CYP2C9, CYP2C19, CYP3A4/5, CYP2D6) substrate drugs should beadjusted as needed.

Pregnancy status of females of child-bearing potential should be verified prior to initiating treatmentwith TALVEY.

Females of reproductive potential should use effective contraception during treatment and for3 months after the last dose of TALVEY.

There are no available data on the use of TALVEY in pregnant women or animal data to assess therisk of TALVEY in pregnancy. Human IgG is known to cross the placenta after the first trimester ofpregnancy. Therefore, talquetamab has the potential to be transmitted from the mother to thedeveloping foetus. The effects of TALVEY on the developing foetus are unknown. TALVEY is notrecommended for women who are pregnant or for women of childbearing potential not usingcontraception.

If TALVEY is taken during pregnancy, a reduced immune response to vaccines may be expected innewborns. Consequently, newborn vaccinations with live vaccines such as BCG vaccine should bepostponed until 4 weeks.

It is not known whether talquetamab is excreted in human milk. Because the potential for seriousadverse reactions in breast-fed infants is unknown for TALVEY, patients should not breast-feedduring treatment with TALVEY and for at least 3 months after the last dose.

There are no data on the effect of talquetamab on fertility. Effects of talquetamab on male and femalefertility have not been evaluated in animal studies.

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 ofconsciousness (see section 4.4). Patients should be instructed to avoid driving or operating machinesduring the step-up phase and for 48 hours after completion of the step-up phase (see section 4.2), andin the event of new onset of any neurological symptoms, until symptoms resolve.

The most frequent adverse reactions were CRS (77%), dysgeusia (72%), hypogammaglobulinaemia(67%), nail disorder (56%), musculoskeletal pain (48%), anaemia (47%), fatigue (43%), weightdecreased (40%), rash (39%), skin disorder (37%), 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%), decreasedappetite (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%) andweight decreased (0.9%).

The safety of TALVEY was evaluated in 339 adult patients with relapsed or refractory multiplemyeloma, including patients treated with TALVEY at the recommended dosing regimen with orwithout prior T cell redirection therapy in MonumenTAL-1. The median duration of treatment was 7.4(range: 0.0 to 32.9) months.

Table 7 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 adversereactions identified.

Adverse reactions observed during clinical studies are listed below by frequency category. Frequencycategories 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 (frequencycannot be estimated from the available data). Within each frequency grouping, adverse reactions arepresented in order of decreasing seriousness.

Table 7: Adverse reactions in patients with multiple myeloma treated with TALVEY in

MonumenTAL-1 (N=339)

System Organ Class Frequency Any Grade Grade 3 or 4

Adverse Reaction category (%) (%)

Bacterial infection* Very common 40 (12%) 11 (3.2%)

Fungal infection* Very common 39 (12%) 1 (0.3%)

COVID-19*# Very common 63 (19%) 10 (2.9%)

Upper respiratory tract infection* Very common 98 (29%) 7 (2.1%)

Sepsis*# Common 15 (4.4%) 14 (4.1%)

Pneumonia* Common 23 (7%) 11 (3.2%)

Viral infection* Common 23 (7%) 6 (1.8%)

Neutropenia* Very common 119 (35%) 103 (30%)

Anaemia* Very common 158 (47%) 99 (29%)

Thrombocytopenia Very common 101 (30%) 71 (21%)

Lymphopenia Very common 91 (27%) 83 (25%)

Leukopenia Very common 62 (18%) 38 (11%)

Haemorrhage1 Common 27 (8%) 5 (1.5%)

Febrile neutropenia Common 7 (2.1%) 7 (2.1%)

Cytokine release syndrome Very common 260 (77%) 5 (1.5%)

Hypogammaglobulinaemia2 Very common 227 (67%) 0

Decreased appetite Very common 76 (22%) 4 (1.2%)

Hypokalaemia Very common 55 (16%) 12 (3.5%)

Hypophosphataemia* Very common 49 (15%) 21 (6%)

Hypomagnesaemia Very common 35 (11%) 0

Immune effector cell-associated neurotoxicitysyndrome* Very common 26 (10%) 6 (2.3%)

Encephalopathy3 Very common 36 (11%) 0

Headache* Very common 69 (20%) 2 (0.6%)

Motor dysfunction4 Very common 38 (11%) 2 (0.6%)

Dizziness* Very common 42 (12%) 8 (2.4%)

Sensory neuropathy5 Very common 34 (10%) 0

Ataxia Uncommon 1 (0.3%) 0

Cough* Very common 78 (23%) 0

Dyspnoea6# Very common 39 (12%) 5 (1.5%)

Dysgeusia‡7 Very common 245 (72%) 0

Dry mouth‡ Very common 122 (36%) 0

Dysphagia Very common 82 (24%) 3 (0.9%)

Diarrhoea Very common 84 (25%) 4 (1.2%)

Stomatitis8 Very common 67 (20%) 4 (1.2%)

Nausea Very common 64 (19%) 0

Constipation Very common 61 (18%) 0

Oral pain* Very common 42 (12%) 0

Abdominal pain* Very common 35 (10%) 1 (0.3%)

Vomiting Very common 34 (10%) 2 (0.6%)

Rash* Very common 132 (39%) 12 (3.5%)

Skin disorder* Very common 124 (37%) 0

Xerosis9 Very common 109 (32%) 0

Pruritus Very common 79 (23%) 1 (0.3%)

Nail disorder* Very common 191 (56%) 0

Palmar-plantar erythrodysesthesia syndrome Common 31 (9%) 0

Alopecia Common 30 (9%) 0

Musculoskeletal pain* Very common 164 (48%) 12 (3.5%)

General disorders and administrate siteconditions

Fatigue* Very common 147 (43%) 12 (3.5%)

Weight decreased Very common 134 (40%) 11 (3.2%)

Pyrexia* Very common 113 (33%) 6 (1.8%)

Pain* Very common 76 (22%) 7 (2.1%)

Oedema10 Very common 59 (17%) 0

Injection site reaction11 Very common 45 (13%) 0

Chills Very common 39 (12%) 1 (0.3%)

Fibrinogen decreased Very common 52 (15%) 12 (3.5%)aPTT prolonged Very common 49 (15%) 0

Transaminase elevation12 Very common 48 (14%) 12 (3.5%)

INR increased Very common 47 (14%) 1 (0.3%)

Gamma-glutamyltransferase increased Very common 36 (11%) 16 (4.7%)

Adverse reactions are coded using MedDRA Version 24.0.‡ Per CTCAE v4.03, maximum toxicity grade for dysgeusia is 2 and maximum toxicity grade for dry mouth is 3.

* Grouped term# Contains fatal outcome(s)1 Haemorrhage includes: Conjunctival haemorrhage, Epistaxis, Haematoma, Haematuria, Lower gastrointestinal haemorrhage,

Periorbital haemorrhage, Petechiae, Rectal haemorrhage, Subdural haematoma and Vaginal haemorrhage.2 Hypogammaglobulinaemia includes: hypogammaglobulinaemia and/or subjects with laboratory IgG levels below 500 mg/dLfollowing treatment with talquetamab.3 Encephalopathy includes: agitation, amnesia, aphasia, bradyphrenia, confusional state, delirium, disorientation, encephalopathy,hallucination, lethargy, memory impairment, restlessness, sleep disorder and somnolence.4 Motor dysfunction includes: dysgraphia, dysphonia, gait disturbance, muscle spasms, muscular weakness and tremor.5 Sensory neuropathy includes: dysaesthesia, hypoaesthesia, hypoaesthesia oral, neuralgia, peripheral sensory neuropathy, sciatica andvestibular neuronitis.6 Dyspnoea includes: acute respiratory failure, dyspnoea, dyspnoea exertional, respiratory failure and tachypnoea.7 Dysgeusia includes: ageusia, dysgeusia, hypogeusia and taste disorder.8 Stomatitis includes: cheilitis, glossitis, glossodynia, mouth ulceration, oral discomfort, oral mucosal erythema, oral pain, stomatitis,swollen tongue, tongue discomfort, tongue erythema, tongue oedema and tongue ulceration.9 Xerosis includes: dry eye, dry skin and xerosis.

10 Oedema includes: fluid retention, gingival swelling, hypervolaemia, joint swelling, lip swelling, oedema, oedema peripheral,periorbital oedema, peripheral swelling and swelling.

11 Injection site reaction includes: injection site discomfort, injection site erythema, injection site haemorrhage, injection siteinflammation, injection site irritation, injection site plaque, injection site pruritus, injection site rash and injection site reaction.

12 Transaminase elevation includes: alanine aminotransferase increased, aspartate aminotransferase increased, and transaminasesincreased.

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 morethan 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 [every2 weeks] dosing; 33%), or the initial treatment dose (0.4 mg/kg [30%] or 0.8 mg/kg [12%]). Less than4% of CRS events occurred from week 5 onward; all events were Grade 1. The median time to onsetof 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 combinationwith 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, ICANSoccurred in 9.8% (n=26) of patients. Most events were Grade 1 or 2, with Grade 3 and 4 eventsoccurring in 2.3% of patients. The most frequent clinical manifestation of ICANS reported wereconfusional state (3.8%), disorientation (1.9%), somnolence (1.9%) and depressed level ofconsciousness (1.9%). Sixty-eight percent (68%) were concurrent with CRS (during or within 7 daysof CRS resolution). Three percent (3%) of patients experienced more than one ICANS event. Inaddition, one fatal ICANS event was reported in MonumenTAL-1. Most patients experienced ICANSduring the step-up phase following the 0.01 mg/kg dose, the 0.06 mg/kg dose, or the initial treatmentdose (0.4 mg/kg and 0.8 mg/kg) (3% each). The median time to onset of ICANS was 28 hours fromthe last dose, 68% of events started within 48 hours from the last dose, 32% of events occurred after48 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 occurringin 2% of patients. Oral toxicity events included dysgeusia, dry mouth, dysphagia, and stomatitis werereported.

In MonumenTAL-1 (N=339), Grade 3 or Grade 4 infections occurred in 19% of patients; fatalinfections occurred in 1.5% of patients - COVID-19 pneumonia, fungal sepsis, infection and septicshock. The most frequently reported (≥ 2%) Grade 3 or 4 infection was pneumonia. Febrileneutropenia was observed in 1% of patients with 1.2% experiencing serious febrile neutropenia. Seesection 4.4 for monitoring and management guidance.

Post baseline IgG values of less than 500 mg/dl consistent with hypogammaglobulinaemia have beenreported in 64% of patients treated with talquetamab at the 0.4 mg/kg weekly dose schedule, 66% ofpatients at the 0.8 mg/kg biweekly dose schedule and in 71% of patients with prior T cell redirectiontherapy (see section 4.4).

In MonumenTAL-1 (N=339), the majority of rash cases were Grade 1 or 2, with Grade 3 eventsoccurring in 3.5% of patients. The median time to onset from the first treatment dose for rash was22 days. The majority of non-rash skin toxicities were Grade 1 or 2, with Grade 3 pruritus occurring in0.3% of patients. Nail disorders occurred in 56% of patients and were Grade 1 or 2. See section 4.4 formanagement guidance.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Symptoms and signs

The maximum tolerated dose of talquetamab has not been determined. In clinical studies, doses of upto 1.2 mg/kg once every 2 weeks and 1.6 mg/kg every month have been administered.

In the event of an overdose, the patient should be monitored for any signs or symptoms of adverseeffects and appropriate symptomatic treatment should be instituted immediately.

Pharmacotherapeutic group: Other monoclonal antibodies and antibody drug conjugates, ATC code:

L01FX29

Talquetamab is a immunoglobulin G4 proline, alanine, alanine (IgG4 PAA) bispecific antibodydirected 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 subsequentlysis of GPRC5D-expressing cells mediated by secreted perforin and various granzymes stored in thesecretory vesicles of cytotoxic T cells. Based on the expression of GPRC5D on plasma cells withminimal to no expression detected on B cells and B cell precursors, talquetamab targets multiplemyeloma cells particularly.

Within the first month of treatment with talquetamab, activation and redistribution of T cells andinduction of serum cytokines were observed.

The efficacy of TALVEY monotherapy was evaluated in patients with relapsed or refractory multiplemyeloma in a single-arm, open-label, multicentre study, MonumenTAL-1. The study included patientswho had previously received at least three prior therapies, including a proteasome inhibitor, animmunomodulatory agent, and an anti-CD38 monoclonal antibody. The study excluded patients whoreceived T cell redirection therapy within 3 months, prior Grade 3 or higher CRS related to any T cellredirection therapy, an allogeneic stem cell transplant within the past 6 months, autologous stem celltransplant within 3 months, stroke or seizure within the past 6 months, CNS involvement or clinicalsigns of meningeal involvement of multiple myeloma, plasma cell leukaemia, POEMS syndrome,primary light chain amyloidosis, and active or documented history of autoimmune disease, with theexception of vitiligo, resolved childhood atopic dermatitis, and prior Grave’s disease that waseuthyroid based on clinical symptoms and laboratory testing.

Patients received TALVEY 0.4 mg/kg subcutaneously weekly, following two step-up doses (0.01 and0.06 mg/kg) in the first week of therapy, or TALVEY 0.8 mg/kg subcutaneously biweekly (every2 weeks), following three step-up doses (0.01, 0.06 and 0.3 mg/kg), until disease progression orunacceptable 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 cellredirection 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) priortherapies, 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 toa PI, immunomodulatory agent, and anti-CD38 antibody. Of the 132 patients for whom baselinecytogenetic data were available, high-risk cytogenetic factors (presence of t(4:14), t(14:16), and/ordel(17p)) were present in 31% of patients. Twenty-three percent (23%) of patients had extramedullaryplasmacytomas.

Of 145 patients treated with TALVEY 0.8 mg/kg biweekly (every 2 weeks) who were not exposed toprior 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 to17) 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% wererefractory to a proteasome inhibitor, immunomodulatory agent, and anti-CD38 antibody. Of the128 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 patientsreceiving TALVEY 0.4 mg/kg weekly was 18.8 months; an estimated 51.5% of responders maintainedresponse for at least 9 months.

Table 8: Efficacy results for MMY1001 (MonumenTAL-1) in patients receiving TALVEY0.4 mg/kg weekly0.4 mg/kg weeklya(N=143)

Overall response rate (ORR=sCR+CR+VGPR+PR) 106 (74.1%)95% CI (%) (66.1, 81.1)

Stringent complete response (sCR) 23.8%

Complete response (CR) 9.8%

Very good partial response (VGPR) 25.9%

Partial response (PR) 14.7%

Duration of response (DOR)

Number of responders 106

Median DOR (95% CI) (months) 9.5 (6.7, 13.3)

Time to first response

Number of responders 106

Median (range) (months) 1.2 (0.2, 10.9)

MRD negativity ratea

MRD negativity rate in all treated patients, n (%) 44 (30.8%)95% CI (%) (23.3, 39.0)

MRD negativity rateb in patients achieving CR or sCR

Number of patients with CR or better N=48

MRD negativity rate, n (%) 26 (54.2%)95% CI (%) (39.2, 68.6)

CI=confidence interval; MRD=minimal residual disease;a MRD-negativity rate is defined as the proportion of participants who achieved MRD negative status (at 10-5) at any timepoint afterinitial dose and prior to progressive disease (PD) or subsequent anti-myeloma therapy.b Only MRD assessments (10-5 testing threshold) within 3 months of achieving CR/sCR until death/progression/subsequent therapy(exclusive) are considered.

The median duration of follow-up among patients receiving TALVEY 0.8 mg/kg biweekly was12.7 months; an estimated 76.3% of responders maintained response for at least 9 months.

Table 9: Efficacy results for MMY1001 (MonumenTAL-1) in patients receiving TALVEY0.8 mg/kg biweekly (every 2 weeks)0.8 mg/kg biweekly (every 2 weeks)a(N=145)

Overall response rate (ORR=sCR+CR+VGPR+PR) 104 (71.7%)95% CI (%) (63.7, 78.9)

Stringent complete response (sCR) 29.7%

Complete response (CR) 9.0%

Very good partial response (VGPR) 22.1%

Partial response (PR) 11.0%

Duration of response (DOR)

Number of responders 104

Median DOR (95% CI) (months) NE (13.0, NE)

Time to first response

Number of responders 104

Median (range) (months) 1.3 (0.2, 9.2)

MRD negativity ratea

MRD negativity rate in all treated patients, n (%) 43 (29.7%)95% CI (%) (22.4, 37.8)

MRD negativity rateb in patients achieving CR or sCR

Number of patients with CR or better N=56

MRD negativity rate, n (%) 24 (42.9%)95% CI (%) (29.7, 56.8)

CI=confidence interval; MRD=minimal residual disease; NE=not estimablea MRD-negativity rate is defined as the proportion of participants who achieved MRD negative status (at 10-5) at any timepoint afterinitial dose and prior to progressive disease (PD) or subsequent anti-myeloma therapy.b Only MRD assessments (10-5 testing threshold) within 3 months of achieving CR/sCR until death/progression/subsequent therapy(exclusive) are considered.

ORR results were consistent across pre-specified subgroups, including number of prior lines oftherapy, refractoriness to prior therapy, and cytogenetic risk at baseline.

In MonumenTAL-1, 363 patients treated with subcutaneous talquetamab monotherapy at 0.4 mg/kgweekly or 0.8 mg/kg biweekly (every 2 weeks), with or without prior T cell redirection therapy, wereevaluated for antibodies to talquetamab. Following treatment 0.4 mg/kg weekly or 0.8 mg/kg biweekly(every 2 weeks), 130 of 363 patients (35.8%) developed anti-talquetamab antibodies. The incidenceof treatment-emergent neutralising antibodies against talquetamab was 18.2% (66/363).

There was no clinically meaningful impact of anti-talquetamab antibodies on the pharmacokinetics,safety, or effectiveness of talquetamab.

The European Medicines Agency has waived the obligation to submit the results of studies with

TALVEY in all subsets of the paediatric population in the treatment of multiple myeloma (seesection 4.2 for information on paediatric use).

This medicinal product has been authorised under a so-called ‘conditional approval’ scheme.

This means that further evidence on this medicinal product is awaited.

The European Medicines Agency will review new information on this medicinal product at least everyyear and this SmPC will be updated as necessary.

0.4 mg/kg weekly dose

Talquetamab exhibited approximately dose-proportional pharmacokinetics following subcutaneousadministration across a dose ranging from 0.005 to 0.8 mg/kg weekly (0.0125 to 2 times therecommended 0.4 mg/kg weekly dose). The mean accumulation ratio between the 1st and 7th weeklydose of talquetamab 0.4 mg/kg was 3.9- and 4.5-fold for Cmax and AUCtau, respectively.

Pharmacokinetic parameters of talquetamab following the 1st and 7th recommended weekly dose of0.4 mg/kg are shown in Table 10.

Table 10: Pharmacokinetic parameters of talquetamab following the first and seventh recommendedweekly dose (0.4 mg/kg) in patients with relapsed or refractory multiple myeloma in

MonumenTAL-1

Pharmacokinetic parameters 1st dose of 0.4 mg/kg 7th dose of 0.4 mg/kg2.93 (0.98 - 7.75) 2.01 (0.94 - 5.97)

Tmax (days)(n=21) (n=13)1 568 ± 1 185 3 799 ± 2 411

Cmax (ng/mL)(n=21) (n=13)178 ± 124 2 548 ± 1 308

Ctrough (ng/mL)(n=19) (n=13)178 101 ± 130 802 607 297 ± 371 399

AUCtau (ng·h/mL)(n=17) (n=10)

Tmax = Time to reach the Cmax; Cmax = Maximum observed serum talquetamab concentration; Ctrough = Observed serum talquetamabconcentration prior to next dose; AUCtau = Area under the concentration-time curve over the weekly dosing interval. Data are presented asmean ± standard deviation, except for Tmax which is presented as median (minimum- maximum).

0.8 mg/kg biweekly dose

Talquetamab exhibited approximately dose-proportional pharmacokinetics following subcutaneousadministration across a dose ranging from 0.8 mg/kg to 1.2 mg/kg biweekly (1.0 to 1.5 times therecommended 0.8 mg/kg biweekly dose). The mean accumulation ratio between the 1st and 5thbiweekly dose of talquetamab 0.8 mg/kg was 2.3- and 2.2-fold for Cmax and AUCtau, respectively.

Pharmacokinetic parameters of talquetamab following the 1st and 5th recommended biweeklymaintenance dose of 0.8 mg/kg are shown in Table 11.

Table 11: Pharmacokinetic parameters of talquetamab following the first and fifth recommendedbiweekly (every 2 weeks) dose (0.8 mg/kg) in patients with relapsed or refractory multiplemyeloma in MonumenTAL-1

Pharmacokinetic parameters 1st dose of 0.8 mg/kg 5th dose of 0.8 mg/kg2.83 (1.68 - 13.98) 2.85 (0.96 - 7.82)

Tmax (days)(n=33) (n=19)2 507 ± 1 568 4 161 ± 2 021

Cmax (ng/mL)(n=33) (n=19)597 ± 437 1 831 ± 841

Ctrough (ng/mL)(n=32) (n=17)675 764 ± 399 680 1 021 059 ± 383 417

AUCtau (ng·h/mL)(n=28) (n=17)

Tmax = Time to reach the Cmax; Cmax = Maximum observed serum talquetamab concentration; Ctrough = Observed serum talquetamabconcentration prior to next dose; AUCtau = Area under the concentration-time curve over the Q2W dosing interval. Data are presented asmean ± standard deviation, except for Tmax which is presented as median (minimum-maximum).

Based on the population pharmacokinetic model, the typical value of the bioavailability oftalquetamab was 62% when administered subcutaneously relative to intravenous dosing.

At 0.4 mg/kg weekly dose regimen, the median (range) Tmax of talquetamab after the 1st and 7thtreatment 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) Tmax of talquetamab afterthe 1st and 5th treatment doses were 3 (2 to 14) days and 3 (1 to 8) days, respectively.

Based on the population pharmacokinetic model, the typical value of the volume of distribution was4.3 L (22% CV [coefficient of variation]) for the central compartment, and 5.8 L (83% CV) for theperipheral compartment.

Talquetamab exhibited both linear time-independent and time-dependent clearance. Based on thepopulation 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 thendecreased exponentially to < 5% at around Week 16. The concentration-time profile at Week 16 wouldreach 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.

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 oftalquetamab.

The pharmacokinetics of TALVEY in paediatric patients aged 17 years and younger have not beeninvestigated.

Results of population pharmacokinetic analyses indicate that age (33 to 86 years) did not influence thepharmacokinetics of talquetamab. Only limited data for patients ≥ 85 years was available (see

Table 12).

Table 12: Proportion of elderly subjects in the pharmacokinetic (PK) studies of talquetamab

Age 65-74 Age 75-84 Age 85+(Older subjects number (Older subjects number (Older subjects number/total number) /total number) /total number)

PK Studies 181/492 73/492 1/492

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 glomerularfiltration rate (GFR) < 90 mL/min) or moderate (30 mL/min ≤ absolute GFR < 60 mL/min) renalimpairment did not significantly influence the pharmacokinetics of talquetamab. No data is availablein patients with severe renal 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 hepaticimpairment (total bilirubin > 1 to 1.5 times upper limit of normal (ULN) and any aspartateaminotransferase (AST), or total bilirubin ≤ ULN and AST > ULN) did not significantly influence thepharmacokinetics of talquetamab. Limited data (n=2) are available in participants with moderatehepatic impairment while no data are available in participants with severe hepatic impairment.

A tool molecule was well tolerated in general toxicity studies in cynomolgus monkeys, but the resultsof these studies conducted with normal healthy monkeys have limited translatability to multiplemyeloma patients.

No animal studies have been performed to assess the carcinogenic or genotoxic potential oftalquetamab.

Reproductive toxicology and fertility

No animal studies have been conducted to evaluate the effects of talquetamab on reproduction andfoetal development. No studies have been conducted to evaluate the effects of talquetamab on fertility.

EDTA disodium salt dihydrate

Glacial acetic acid (E260)

Polysorbate 20 (E432)

Sodium acetate trihydrate

Sucrose

Water for injections

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinalproducts.

Unopened vial3 years

Prepared syringe

Chemical and physical in-use stability has been demonstrated up to 24 hours at 2 to 8°C followed byup 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 usedimmediately, in-use storage times and conditions prior to use are the responsibility of the user andwould normally not be longer than 24 hours at 2 to 8°C, unless preparation has taken place incontrolled and validated aseptic conditions. Discard if stored for more than 24 hours refrigerated ormore than 24 hours of being at ambient temperature.

The prepared syringe should be stored protected from light.

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 section 6.3.

TALVEY 2 mg/mL solution for injection1.5 mL solution for injection in a Type 1 glass vial with an elastomeric stopper and an aluminium sealwith a light green flip-off cap containing 3 mg of talquetamab.

Pack size of 1 vial.

TALVEY 40 mg/mL solution for injection1 mL solution for injection in a Type 1 glass vial with an elastomeric stopper and an aluminium sealwith a violet flip-off cap containing 40 mg of talquetamab.

Pack size of 1 vial.

The TALVEY vials are supplied as ready-to-use solution for injection that do not need dilution priorto 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 TALVEYo Use Table 13 to determine total dose, injection volume, and number of vials requiredbased on patient’s actual body weight for the 0.01 mg/kg dose using TALVEY 2 mg/mLvial.

Table 13: Injection volumes using TALVEY 3 mg/1.5 mL (2 mg/mL) vial for step-updose 1 (0.01 mg/kg)

Body weight Total dosea Volume of Number of vials(kg) (mg) injection (mL) (1 vial = 1.5 mL)35 to 39 0.38 0.19 140 to 45 0.42 0.21 146 to 55 0.5 0.25 156 to 65 0.6 0.3 166 to 75 0.7 0.35 176 to 85 0.8 0.4 10.01 mg/kg dose86 to 95 0.9 0.45 196 to 105 1.0 0.5 1106 to 115 1.1 0.55 1116 to 125 1.2 0.6 1126 to 135 1.3 0.65 1136 to 145 1.4 0.7 1146 to 155 1.5 0.75 1156 to 160 1.6 0.8 1a The Total dose (mg) is calculated based on the rounded Volume of injection (mL)o Use Table 14 to determine total dose, injection volume, and number of vials requiredbased on patient’s actual body weight for the 0.06 mg/kg dose using TALVEY 2 mg/mLvial.

Table 14: Injection volumes using TALVEY 3 mg/1.5 mL (2 mg/mL) vial for step-updose 2 (0.06 mg/kg)

Body weight Total dosea Volume of Number of vials(kg) (mg) injection (mL) (1 vial = 1.5 mL)35 to 39 2.2 1.1 140 to 45 2.6 1.3 146 to 55 3 1.5 156 to 65 3.6 1.8 266 to 75 4.2 2.1 276 to 85 4.8 2.4 20.06 mg/kg dose86 to 95 5.4 2.7 296 to 105 6 3 2106 to 115 6.6 3.3 3116 to 125 7.2 3.6 3126 to135 7.8 3.9 3136 to145 8.4 4.2 3146 to155 9 4.5 3156 to160 9.6 4.8 4a The Total dose (mg) is calculated based on the rounded Volume of injection (mL)o Use Table 15 to determine total dose, injection volume and number of vials requiredbased on patient’s actual body weight for the 0.4 mg/kg dose using TALVEY 40 mg/mLvial.

Table 15: Injection volumes using TALVEY 40 mg/mL vial for step-up dose 3 (0.4 mg/kg) andtreatment phase (0.4 mg/kg) for weekly dosing schedule

Body weight Total dosea Volume of Number of vials(kg) (mg) injection (mL) (1 vial = 1.0 mL)35 to 39 14.8 0.37 140 to 45 16 0.4 146 to 55 20 0.5 156 to 65 24 0.6 166 to 75 28 0.7 176 to 85 32 0.8 10.4 mg/kg dose86 to 95 36 0.9 196 to 105 40 1 1106 to 115 44 1.1 2116 to 125 48 1.2 2126 to 135 52 1.3 2136 to 145 56 1.4 2146 to 155 60 1.5 2156 to 160 64 1.6 2a The Total dose (mg) is calculated based on the rounded Volume of injection (mL)o Use Table 16 to determine total dose, injection volume, and number of vials requiredbased on patient’s actual body weight for the 0.8 mg/kg dose using TALVEY 40 mg/mLvial.

Table 16: Injection volumes using TALVEY 40 mg/mL vial for treatment phase (0.8 mg/kg) forbi-weekly dosing schedule

Body weight Total dosea Volume of Number of vials(kg) (mg) injection (mL) (1 vial = 1.0 mL)35 to 39 29.6 0.74 140 to 45 34 0.85 146 to 55 40 1 156 to 65 48 1.2 266 to 75 56 1.4 276 to 85 64 1.6 20.8 mg/kg dose86 to 95 72 1.8 296 to 105 80 2 2106 to 115 88 2.2 3116 to 125 96 2.4 3126 to 135 104 2.6 3136 to 145 112 2.8 3146 to 155 120 3 3156 to 160 128 3.2 4a The Total dose (mg) is calculated based on the rounded Volume of injection (mL)

- Check that the TALVEY solution for injection is colourless to light yellow. Do not use if thesolution is discoloured, cloudy, or if foreign particles are present.

- Remove the appropriate strength TALVEY vial from refrigerated storage (2°C to 8°C) andequilibrate 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 appropriatelysized syringe using a transfer needle.o Each injection volume should not exceed 2.0 mL. Divide doses requiring greater than2.0 mL equally into multiple syringes.

- TALVEY is compatible with stainless steel injection needles and polypropylene orpolycarbonate 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 ambienttemperature before administration.

- Any unused medicinal product or waste material should be disposed in accordance with localrequirements.

Janssen-Cilag International NV

Turnhoutseweg 30

B-2340 Beerse

Belgium

EU/1/23/1748/001 (2 mg/mL)

EU/1/23/1748/002 (40 mg/mL)

Date of first authorisation: 21 August 2023

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu.