Talvey Product Monograph

Recent Major Label Changes

Table of Contents

Certain sections or subsections that are not applicable at the time of the preparation of the most recent authorized product monograph are not listed.

Recent Major Label Changes ................................................................................................. 2

Table of Contents ................................................................................................................. 2

Part 1: Healthcare Professional Information.......................................................................... 5

1. 1.

   Indications ................................................................................................................ 5

   1.1. Pediatrics ................................................................................................................ 5

   1.2. Geriatrics ................................................................................................................ 5

2. 2. Contraindications ...................................................................................................... 5
3. 3. Serious Warnings and Precautions Box ...................................................................... 5
4. 4.

   Dosage and Administration ....................................................................................... 6

   4.1. Dosing Considerations ........................................................................................... 6

   4.2. Recommended Dose and Dosage Adjustment ...................................................... 6

   4.4. Administration ..................................................................................................... 14

   4.5. Missed Dose ......................................................................................................... 18

5. 5. Overdose ................................................................................................................ 18
6. 6. Dosage Forms, Strengths, Composition, and Packaging ............................................ 19
7. 7.

   Warnings and Precautions ....................................................................................... 19

   Driving and Operating Machinery .................................................................................... 19

   Gastrointestinal ................................................................................................................ 20

   Hematologic ..................................................................................................................... 20

   Immune ............................................................................................................................ 21

   Neurologic ........................................................................................................................ 22

   Reproductive Health ........................................................................................................ 22

   Skin ................................................................................................................................... 23

   7.1. Special Populations .............................................................................................. 23

   7.1.1. Pregnancy ......................................................................................................... 23

   7.1.2. Breastfeeding ................................................................................................... 23

   7.1.3. Pediatrics .......................................................................................................... 23

   7.1.4. Geriatrics .......................................................................................................... 24

8. 8.

   Adverse Reactions ................................................................................................... 24

   8.1. Adverse Reaction Overview ................................................................................. 24

   8.2. Clinical Trial Adverse Reactions ........................................................................... 24

   8.3. Less Common Clinical Trial Adverse Reactions .................................................... 28

   8.4. Abnormal Laboratory Findings: Hematologic, Clinical Chemistry, and Other Quantitative Data ............................................................................................................. 29

9. 9.

   Drug Interactions .................................................................................................... 29

   9.2. Drug Interactions Overview ................................................................................. 29

   9.4. Drug-Drug Interactions ........................................................................................ 29

   9.5. Drug-Food Interactions ........................................................................................ 30

   9.6. Drug-Herb Interactions ........................................................................................ 30

   9.7. Drug-Laboratory Test Interactions....................................................................... 30

10. 10.

    Clinical Pharmacology ............................................................................................. 30

    10.1. Mechanism of Action ....................................................................................... 30

    10.2. Pharmacodynamics .......................................................................................... 30

    10.3. Pharmacokinetics ............................................................................................. 30

    10.4. Immunogenicity ............................................................................................... 33

11. 11. Storage, Stability, and Disposal ................................................................................ 34
12. 12. Special Handling Instructions ................................................................................... 34

Part 2: Scientific Information .............................................................................................. 35

1. 13. Pharmaceutical Information .................................................................................... 35
2. 14.

   Clinical Trials ........................................................................................................... 35

   14.1. Clinical Trials by Indication .............................................................................. 35

   Monotherapy for Multiple Myeloma After Three or More Prior Lines of Therapy......... 35

3. 15. Microbiology ........................................................................................................... 39
4. 16. Non-Clinical Toxicology ........................................................................................... 39

Patient Medication Information ......................................................................................... 40

Part 1: Healthcare Professional Information

1. Indications

TALVEY (talquetamab injection) is indicated for:

• the treatment of adult patients with relapsed or refractory multiple myeloma who have received at least three prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent and an anti-CD38 monoclonal antibody, and have demonstrated disease progression on or after the last therapy.

1.1. Pediatrics

Pediatrics (<18 years of age): No data are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric use.

1.2. Geriatrics

Geriatrics (≥65 years of age): Of the 339 patients treated with TALVEY in MonumenTAL-1, 36% were 65 to less than 75 years of age, and 17% were 75 years of age or older. No clinically important differences in safety or effectiveness were observed in patients 65 to 75 years of age compared to younger patients. There are limited clinical data with talquetamab in patients 75 years of age or over. No dose adjustment is required (see 10.3. Pharmacokinetics).

2. Contraindications

TALVEY is contraindicated in patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container. For a complete listing, see 6. Dosage Forms, Strengths, Composition, and Packaging.

3. Serious Warnings and Precautions Box

• Cytokine release syndrome (CRS), including life-threatening or fatal reactions, can occur in patients receiving TALVEY. Initiate TALVEY treatment with step-up dosing to reduce the risk of CRS. Monitor patients for signs and symptoms of CRS. Withhold TALVEY and provide supportive care and treatment until CRS resolves or permanently discontinue based on severity (see 4.2. Recommended Dose and Dosage Adjustment - Dose modifications for adverse reactions and 7. Warnings and Precautions - CRS).
• Neurologic toxicity, including immune effector cell-associated neurotoxicity syndrome (ICANS), including serious or fatal reactions, have occurred following treatment with TALVEY. Monitor patients for signs and symptoms of neurologic toxicity, including ICANS, and treat promptly. The onset of ICANS may be concurrent with CRS, following resolution of CRS, or in the absence of CRS. Withhold TALVEY until the neurologic toxicity resolves or discontinue based on severity (see 4.2. Recommended Dose and Dosage Adjustment - Dose modifications for adverse reactions and 7. Warnings and Precautions - ICANS).

4. Dosage and Administration

4.1. Dosing Considerations

• Counsel potential TALVEY patients on the risks of CRS and neurologic toxicity, including ICANS and provide patients with the Patient Card.
• TALVEY is administered via subcutaneous injection.
• TALVEY should be administered by a healthcare professional, experienced in the treatment of multiple myeloma, with appropriate medical support to manage severe reactions, including CRS and neurologic toxicity, including ICANS (see 7. Warnings and Precautions). Additional TALVEY educational materials for healthcare professionals are available.
• Verify the pregnancy status of females of child-bearing potential prior to initiating TALVEY.
• Do not initiate treatment with TALVEY in patients with active infection.
• Prior to initiating treatment with TALVEY, prophylactic antimicrobials (e.g., prevention of pneumocystis jirovecii pneumonia) and antivirals (e.g., prevention of herpes zoster reactivation) should be considered per local institutional guidelines.
• Administer pretreatment medications prior to each dose of TALVEY during the step-up phase (see 4.4. Administration - Pretreatment medications).

4.2. Recommended Dose and Dosage Adjustment

Recommended dose

Administer TALVEY subcutaneously on a weekly OR biweekly (once every 2 weeks) dosing schedule according to the corresponding schedule in Table 1.

Table 1: Recommended Dose of TALVEY

Instruct patients to remain within proximity of a healthcare facility and monitor patients for 48 hours after the administration of each dose during the TALVEY step-up phase. Monitor patients for signs and symptoms of CRS and/or ICANS. Alternatively, consider monitoring patients in hospital for 48 hours after each step-up dose (see 4. Dosage and Administration and 7. Warnings and Precautions).

Continue treatment until disease progression or unacceptable toxicity.

Dose modifications for adverse reactions

Dose delays may be required to manage toxicities related to TALVEY (see 7. Warnings and Precautions).

See Table 2, Table 3, and Table 4 for recommended actions for the management of CRS, ICANS, and neurologic toxicities, respectively. See Table 5 for recommended dose modifications for other adverse reactions.

Cytokine release syndrome (CRS)

Identify CRS based on clinical presentation (see 7. Warnings and Precautions - CRS). Evaluate and treat other causes of fever, hypoxia, and hypotension. If CRS is suspected, withhold TALVEY until CRS resolves, and manage according to the recommendations in Table 2 and consider current practice guidelines. Administer supportive therapy for CRS, which may include intensive care for severe or life-threatening CRS. Consider laboratory testing to monitor for disseminated intravascular coagulation (DIC), hematology parameters, as well as pulmonary, cardiac, renal, and hepatic function.

Table 2: Recommendations for Management of CRS

Neurologic toxicities, including immune effector cell-associated neurotoxicity syndrome (ICANS)

At the first sign of neurologic toxicity, including ICANS, withhold TALVEY and consider neurology evaluation. Rule out other causes of neurologic symptoms. Provide supportive therapy, which may include intensive care, for severe or life-threatening neurologic toxicities, including ICANS (see 7. Warnings and Precautions - ICANS). Management recommendations for ICANS are summarized in Table 3. Management recommendations for other neurologic toxicities are summarized in Table 4.

Table 3: Recommendations for Management of ICANS

^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 standard sentence = 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 4: Recommendations for Management of Neurologic Toxicity (excluding ICANS)

^a Based on National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 4.03.

^b See Table 10 for recommendations on restarting TALVEY after dose delays for adverse reactions (see 4.5. Missed Dose).

^c For ataxia/balance disorder, perform benefit risk assessment prior to resuming treatment with TALVEY.

Other adverse reactions

The recommended dose modifications for other adverse reactions are provided in Table 5.

Table 5: Recommended Dose Modifications for Other Adverse Reactions

Special populations

Pediatrics (<18 years of age)

Health Canada has not authorized an indication for pediatric use.

Geriatrics (≥65 years of age)

No dose adjustment is required in patients over 65 years of age (see 10.3. Pharmacokinetics).

Renal impairment

No formal studies of TALVEY in patients with renal impairment have been conducted. Results of population pharmacokinetic analyses indicate that mild or moderate renal impairment did not significantly influence the pharmacokinetics of talquetamab (see 10.3. Pharmacokinetics). No data is available in patients with severe renal impairment.

Hepatic impairment

No formal studies of TALVEY in patients with hepatic impairment have been conducted. Results of population pharmacokinetic analyses indicate that mild and moderate hepatic impairment did not significantly influence the pharmacokinetics of talquetamab (see 10.3. Pharmacokinetics). No data is available in participants with severe hepatic impairment.

4.4. Administration

Pretreatment medications

Administer the following pretreatment medications 1 to 3 hours before each dose of TALVEY during the step-up phase to reduce the risk of CRS (see 7. Warnings and Precautions - CRS).

• Corticosteroid (oral or intravenous dexamethasone, 16 mg or equivalent)
• Antihistamine (oral or intravenous diphenhydramine, 50 mg or equivalent)
• Antipyretics (oral or intravenous acetaminophen, 650 mg to 1000 mg or equivalent)

Administer pretreatment medications to patients who repeat doses within the TALVEY step-up phase due to dose delays (Table 10) or for patients who experienced CRS (Table 2).

Administration

Administer TALVEY via subcutaneous injection.

TALVEY should be administered by a healthcare professional with adequate medical equipment and personnel to manage severe reactions, including cytokine release syndrome (see 7. Warnings and Precautions - CRS).

TALVEY 2 mg/mL vial and 40 mg/mL vial are supplied as ready-to-use solution for injection that do not need dilution prior to administration.

Do not combine TALVEY vials of different concentrations to achieve treatment dose.

Use aseptic technique to prepare and administer TALVEY.

Preparation of TALVEY

• Refer to the following reference tables to determine the number of vials needed and the volume of TALVEY required to deliver the intended dose.

  • Use Table 6 to determine total dose, injection volume, and number of vials required based on the patient’s actual body weight for the 0.01 mg/kg dose using TALVEY 2 mg/mL vial.

Table 6: Injection Volumes Using TALVEY 3 mg/1.5 mL (2 mg/mL) Vial for Step-up Dose 1 (0.01 mg/kg)

• Use Table 7 to determine total dose, injection volume, and number of vials required based on the patient’s actual body weight for the 0.06 mg/kg dose using TALVEY 2 mg/mL vial.

Table 7: Injection Volumes Using TALVEY 3 mg/1.5 mL (2 mg/mL) Vial for Step-up Dose 2 (0.06 mg/kg)

• Use Table 8 to determine total dose, injection volume, and number of vials required based on the patient’s actual body weight for the 0.4 mg/kg dose using TALVEY 40 mg/mL vial.

Table 8: Injection Volumes Using TALVEY 40 mg/mL Vial for Treatment Doses (0.4 mg/kg) for Weekly Dosing Schedule and Step-up Dose 3 (0.4 mg/kg) for Biweekly Dosing Schedule

• Use Table 9 to determine total dose, injection volume, and number of vials required based on the patient’s actual body weight for the 0.8 mg/kg dose using TALVEY 40 mg/mL vial.

Table 9: Injection Volumes Using TALVEY 40 mg/mL Vial for Treatment Doses (0.8 mg/kg) for Biweekly Dosing Schedule

• 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(s) 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 in any other way.
• Once equilibrated, gently swirl the vial for approximately 10 seconds to mix. Do not shake.
• TALVEY is compatible with stainless steel injection needles and polypropylene or polycarbonate syringe material.

• 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.
• Replace the transfer needle with an appropriately sized needle for injection.

Storage of prepared syringe

• The prepared syringes should be administered immediately. If immediate administration is not possible, store the TALVEY solution for up to 24 hours refrigerated at 2°C to 8°C followed by up to 24 hours at ambient temperature of 15°C to 30°C. Discard if stored for more than 24 hours refrigerated or more than 24 hours of being at ambient temperature. If stored in the refrigerator, allow the solution to come to ambient temperature before administration.

Administration of TALVEY

• Inject the required volume of TALVEY 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.
• Do not inject into tattoos or scars or areas where the skin is red, bruised, tender, hard or not intact.
• Any unused medicinal product or waste material should be disposed in accordance with local requirements.

4.5. Missed Dose

If a dose of TALVEY is delayed, restart therapy based on recommendations in Table 10 and resume weekly or biweekly (every 2 weeks) dosing accordingly (see 4.2. Recommended Dose and Dosage Adjustment). Administer pretreatment medications prior to restarting TALVEY, and monitor patients following administration of TALVEY (see 4.4. Administration - Pretreatment medications).

Table 10: Recommendations for Restarting TALVEY After Dose Delay

^a Administer pretreatment medications prior to restarting TALVEY. After restarting TALVEY, resume weekly or biweekly (every 2 weeks) dosing accordingly (see 4.2. Recommended Dose and Dosage Adjustment).

5. Overdose

Symptoms and signs

The maximum tolerated dose of talquetamab has not been determined. In clinical trials, doses of up to 1.2 mg/kg once every 2 weeks and 1.6 mg/kg monthly have been administered.

Treatment

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

For the most recent information in the management of a suspected drug overdose, contact your regional poison control centre or Health Canada’s toll-free number, 1-844 POISON-X (1-844-764-7669).

1. 6. Dosage Forms, Strengths, Composition, and Packaging

To help ensure the traceability of biologic products, healthcare professionals should record both the brand name and the non-proprietary (active ingredient) name as well as other product-specific identifiers such as the Drug Identification Number (DIN) and the batch/lot number of the product supplied.

Table 11: Dosage Forms, Strengths, and Composition

TALVEY is a colourless to light yellow preservative-free solution for injection.

TALVEY is available in a 1.5 mL vial (2 mg of talquetamab per mL) and a 1.0 mL vial (40 mg of talquetamab per mL).

7. Warnings and Precautions

See 3. Serious Warnings and Precautions Box.

Driving and Operating Machinery

Due to the potential for ICANS, patients receiving TALVEY are at risk of depressed level of consciousness (see 7. Warnings and Precautions). Advise patients to refrain from driving or

operating heavy or potentially dangerous machinery during the step-up phase and for 48 hours after completion of the step-up phase (see 4.2. Recommended Dose and Dosage Adjustment) and in the event of new onset of any neurological symptoms, until symptoms resolve.

Gastrointestinal

Oral toxicity

Oral toxicities, including dysgeusia, dry mouth, dysphagia, and stomatitis, occur very commonly while undergoing treatment with TALVEY (see 8. Adverse Reactions and 16. Non-Clinical Toxicology).

Monitor patients for signs and symptoms of oral toxicity. Counsel patients to seek medical attention should signs or symptoms of oral toxicity occur and provide supportive care. Supportive care may include saliva stimulating agents, steroid mouth wash, or consultation with a nutritionist. Interrupt TALVEY or consider less frequent dosing (see 4.2. Recommended Dose and Dosage Adjustment - Dose modifications for adverse reactions).

Over time, notable weight loss may occur (see 8. 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 4.2. Recommended Dose and Dosage Adjustment - Dose modifications for adverse reactions).

Hematologic

Cytopenias

Treatment-emergent Grade 3 or 4 neutropenia, febrile neutropenia and thrombocytopenia have been observed in patients who received TALVEY (see 8. Adverse Reactions). A majority of events occurred during the first 8 to 10 weeks. Monitor complete blood counts during treatment and withhold TALVEY as warranted. Provide supportive care according to current practice guidelines. Monitor patients with neutropenia for signs of infection (see 4.2. Recommended Dose and Dosage Adjustment - Dose modifications for adverse reactions).

Hypogammaglobulinaemia

Hypogammaglobulinaemia has been reported in patients receiving TALVEY (see 8. Adverse Reactions). Immunoglobulin levels should be monitored during treatment with TALVEY. Intravenous or subcutaneous immunoglobulin therapy was used to treat hypogammaglobulinemia. Patients should be treated according to local institutional guidelines, including infection precautions, antibiotic or antiviral prophylaxis, and administration of immunoglobulin replacement.

Immune

Cytokine release syndrome (CRS)

Cytokine release syndrome, including life-threatening or fatal reactions, have occurred in patients following treatment with TALVEY (see 8. Adverse Reactions). Clinical signs and symptoms of CRS may include but are not limited to pyrexia, hypotension, chills, hypoxia, headache, and tachycardia. 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).

Initiate TALVEY therapy with step-up phase dosing and administer pretreatment medications (corticosteroids, antihistamine, and antipyretics) prior to each dose of TALVEY during the step-up phase to reduce the risk of CRS. Monitor patients following administration of TALVEY accordingly. In patients who experience CRS, administer pretreatment medications prior to the next TALVEY dose (see 4.2. Recommended Dose and Dosage Adjustment and 4.4. Administration).

Counsel patients to seek medical attention should signs or symptoms of CRS occur. At the first sign of CRS, immediately evaluate patient for hospitalization and institute treatment with supportive care, tocilizumab and/or corticosteroids, based on severity. The use of myeloid growth factors, particularly granulocyte macrophage-colony stimulating factor (GM-CSF), should be avoided during CRS. Withhold TALVEY until CRS resolves (see 4.2. Recommended Dose and Dosage Adjustment - Dose modifications for adverse reactions).

Serious infections

Serious infections, including life-threatening, opportunistic or fatal infections, have been reported in patients receiving TALVEY (see 8. Adverse Reactions). Monitor patients for signs and symptoms of infection prior to and during treatment with TALVEY and treat appropriately. Administer prophylactic antimicrobials according to local guidelines. Withhold TALVEY as indicated (see 4.2. Recommended Dose and Dosage Adjustment - Dose modifications for adverse reactions).

New or reactivated viral infections occurred in clinical trials with TALVEY. Before starting treatment with TALVEY, screening for HBV infection, active HIV, and active HCV infection should be performed according to clinical guidelines. Due to the possibility of fulminant courses, patients with positive HBV serology should be monitored during treatment with TALVEY and for at least six months after discontinuation for clinical symptoms and laboratory values that may be signs of HBV reactivation.

In patients who develop reactivation of HBV, have active HCV infection, or are known to be seropositive for HIV or acquired immune deficiency syndrome while on TALVEY, treatment should be withheld as indicated in Table 5 and managed per local institutional guidelines (see 4.2. Recommended Dose and Dosage Adjustment - Dose modifications for adverse reactions).

Vaccines

Immune response to vaccines may be reduced when taking TALVEY. The safety of immunization 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.

Neurologic

Neurologic toxicities, including immune effector cell-associated neurotoxicity syndrome (ICANS)

Serious, life-threatening or fatal neurologic toxicities, including ICANS, have occurred following treatment with TALVEY (see 8. Adverse Reactions). 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.

Monitor patients for signs and symptoms of neurologic toxicities and ICANS and treat promptly. Counsel patients to seek medical attention should signs or symptoms of neurologic toxicity and/or ICANS occur. At the first sign of neurologic toxicity and/or ICANS, immediately evaluate the patient. Provide supportive care based on severity and withhold or discontinue TALVEY based on severity and follow management recommendations (see 4.2. Recommended Dose and Dosage Adjustment - Dose modifications for adverse reactions).

Ataxia/balance disorder has been reported in subjects receiving TALVEY (see 8. Adverse Reactions). Monitor for any new onset of, or changes in pre-existing, neurological signs or symptoms including ataxia, balance disorder, and cerebellar symptoms that may include but are not limited to dyskinesia, dysmetria, gait disturbance, intentional tremor, nystagmus, and dysarthria.

At the first sign of ataxia/balance disorder, withhold TALVEY, immediately evaluate the patient, and consider neurology evaluation. Rule out other causes of neurologic symptoms and provide supportive care based on severity. Withhold or permanently discontinue TALVEY based on severity and consider further management per current practice guidelines (see 4.2. Recommended Dose and Dosage Adjustment - Dose modifications for adverse reactions).

Ataxia/balance disorder has been observed to persist in some cases despite withholding TALVEY. Recurrent ataxia/balance disorder events have been reported following re-administration of TALVEY (see 8. Adverse Reactions).

Reproductive Health

Fertility

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

Skin

Skin reactions

Skin reactions including dry skin, exfoliation, rash, maculo-papular rash, erythema, erythematous rash, as well as nail disorders have occurred in patients who received TALVEY (see 8. Adverse Reactions and 16. Non-Clinical Toxicology). 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 5). For skin reactions and nail disorders, TALVEY should be withheld based on severity and institutional guidelines should be followed (see 4.2. Recommended Dose and Dosage Adjustment - Dose modifications for adverse reactions).

7.1. Special Populations

7.1.1. 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 fetus. The effects of talquetamab on the developing fetus are unknown. Based on the mechanism of action, talquetamab may cause fetal harm when administered to a pregnant woman. Pregnant women should be advised there may be risks to the fetus.

TALVEY is not recommended for women who are pregnant or for women of childbearing potential not using contraception.

Contraception

Advise females of reproductive potential to use effective contraception during treatment and for 3 months after the last dose of TALVEY.

Advise male patients with a female partner of reproductive potential to use effective contraception during treatment and for 3 months after the last dose of TALVEY.

7.1.2. Breastfeeding

It is not known whether talquetamab is excreted in human or animal milk, affects breastfed infants, or affects milk production. Because the potential for serious adverse reactions in breastfed infants is unknown for TALVEY, advise patients not to breastfeed during treatment with TALVEY and for at least 3 months after the last dose.

7.1.3. Pediatrics

Pediatrics (<18 years of age): No data are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric use.

7.1.4. Geriatrics

Geriatrics (≥65 years of age): Of the 339 patients treated with TALVEY in MonumenTAL-1, 36% were 65 to less than 75 years of age, and 17% were 75 years of age or older. No clinically important differences in safety or effectiveness were observed in patients 65 to 75 years of age compared to younger patients. There are limited clinical data with talquetamab in patients 75 years of age or over. No dose adjustment is required (see 10.3. Pharmacokinetics).

8. Adverse Reactions

8.1. Adverse Reaction Overview

The safety of TALVEY was evaluated in 339 adult patients with relapsed or refractory multiple myeloma, including 51 patients exposed to prior T cell redirection therapy (i.e., chimeric antigen receptor (CAR)-T cells or bispecific T cell engaging monoclonal antibodies), who were treated with TALVEY at the recommended dosing of 0.4 mg/kg weekly or 0.8 mg/kg once every 2 weeks. The median duration of treatment was 7.4 (range: 0.0 to 32.9) months.

The most frequent adverse reactions (≥ 20%) were CRS, dysgeusia, hypogammaglobulinemia, nail disorder, musculoskeletal pain, anemia, fatigue, skin disorder, weight decreased, rash, dry mouth, neutropenia, pyrexia, xerosis, thrombocytopenia, upper respiratory tract infection, lymphopenia, diarrhea, dysphagia, pruritus, cough, decreased appetite, pain, and headache. Serious adverse reactions reported in ≥ 2% of patients included CRS, pyrexia, sepsis, ICANS, COVID-19, viral infection, pneumonia, neutropenia, and pain. The most frequent adverse reactions leading to treatment discontinuation were ICANS (1.1%) and weight decreased (0.9%).

8.2. Clinical Trial Adverse Reactions

Clinical trials are conducted under very specific conditions. Therefore, the frequencies of adverse reactions observed in the clinical trials may not reflect frequencies observed in clinical practice and should not be compared to frequencies reported in clinical trials of another drug.

Table 12 summarizes adverse reactions reported in ≥10% of patients who received TALVEY in MonumenTAL-1.

Table 12: Adverse Reactions (≥10%) in Patients With Multiple Myeloma Treated With TALVEY in MonumenTAL-1 (N=339)

Adverse events are coded using MedDRA Version 25.0.

^a Contains fatal outcome.

Note: The output includes the diagnosis of CRS; the symptoms of CRS are excluded.

Note: Per CTCAE v4.03, maximum toxicity grade for dysgeusia is 2 and maximum toxicity grade for dry mouth is 3.

¹ Anemia: anemia, blood iron decreased and iron deficiency.

² Neutropenia: febrile neutropenia and neutropenia.

³ Dysgeusia: ageusia, dysgeusia, hypogeusia and taste disorder.

⁴ Stomatitis: cheilitis, glossitis, glossodynia, mouth ulceration, oral discomfort, oral mucosal erythema, oral pain, stomatitis, swollen tongue, tongue discomfort, tongue erythema, tongue edema and tongue ulceration.

⁵ Abdominal pain: abdominal discomfort, abdominal pain, abdominal pain lower and abdominal pain upper.

⁶ Fatigue: asthenia, fatigue, malaise and muscle fatigue.

⁷ Pyrexia: pyrexia and tumor associated fever.

⁸ Pain: burning feet syndrome, cancer pain, catheter site pain, coccydynia, ear pain, eye pain, flank pain, gastrointestinal pain, gingival pain, groin pain, lymph node pain, non-cardiac chest pain, pain, pain in jaw, pelvic pain, procedural pain, puncture site pain, sinus pain, tendon pain, testicular pain, toothache, tumor pain and urinary tract pain.

⁹ Edema: face edema, fluid retention, gingival swelling, hypervolemia, joint swelling, lip swelling, edema, edema peripheral, periorbital edema, peripheral swelling and swelling.

¹⁰ Injection site reaction: injection site discomfort, injection site erythema, injection site hemorrhage, injection site inflammation, injection site irritation, injection site plaque, injection site pruritus, injection site rash and injection site reaction.

¹¹ Hypogammaglobulinemia: hypogammaglobulinemia and/or subjects with laboratory IgG levels below 500 mg/dL following treatment with talquetamab.

¹² Upper respiratory tract infection: bronchiolitis, bronchitis, nasopharyngitis, pharyngitis, respiratory tract infection, respiratory tract infection bacterial, rhinitis, rhinovirus infection, sinusitis, tonsillitis, upper respiratory tract infection and viral upper respiratory tract infection.

¹³ COVID-19: asymptomatic COVID-19, COVID-19, COVID-19 pneumonia, coronavirus infection and multisystem inflammatory syndrome.

¹⁴ Fungal infection: body tinea, candida infection, ear infection fungal, fungal foot infection, fungal infection, fungal skin infection, genital candidiasis, esophageal candidiasis, onychomycosis, oral candidiasis, oral fungal infection, oropharyngeal candidiasis, tinea pedis, vulvovaginal candidiasis and vulvovaginal mycotic infection.

¹⁵ Bacterial infection: campylobacter infection, carbuncle, cellulitis, citrobacter infection, clostridium difficile colitis, clostridium difficile infection, cystitis escherichia, cystitis klebsiella, diverticulitis, escherichia pyelonephritis, folliculitis, gastroenteritis escherichia coli, helicobacter gastritis, human ehrlichiosis, impetigo, moraxella infection, otitis media acute, pitted keratolysis, pyuria, relapsing fever, renal abscess, skin infection, staphylococcal infection, tooth abscess, tooth infection, urinary tract infection enterococcal and urinary tract infection pseudomonal.

¹⁶ Transaminase elevation includes: alanine aminotransferase increased and aspartate aminotransferase increased.

¹⁷ Hypophosphatemia: blood phosphorus decreased and hypophosphatemia.

¹⁸ Musculoskeletal pain: arthralgia, arthritis, back pain, bone pain, musculoskeletal chest pain, musculoskeletal pain, musculoskeletal stiffness, myalgia, neck pain, osteoarthritis, pain in extremity and sacral pain.

¹⁹ Headache: headache, migraine, procedural headache, and tension headache.

²⁰ Sensory neuropathy: dysesthesia, hyperesthesia, hypoesthesia, hypoesthesia oral, immune-mediated neuropathy, neuralgia, neuropathy peripheral, paresthesia, peripheral sensory neuropathy, polyneuropathy, sciatica and vestibular neuronitis.

²¹ Motor dysfunction: dysarthria, dysgraphia, dysmetria, dysphonia, gait disturbance, muscle atrophy, muscle spasms, muscular weakness, peripheral motor neuropathy and tremor.

²² Dizziness: dizziness, syncope and vertigo.

²³ Encephalopathy: agitation, amnesia, aphasia, bradyphrenia, confusional state, delirium, disorientation, disturbance in attention, encephalopathy, hallucination, lethargy, memory impairment, mood altered, restlessness, sleep disorder and somnolence.

²⁴ Cough: cough, productive cough, and upper-airway cough syndrome.

²⁵ Oral disorder: oral disorder, oral dysesthesia, oral mucosal exfoliation, oral toxicity and oropharyngeal pain.

²⁶ Dyspnea: acute respiratory failure, dyspnea, dyspnea exertional, respiratory failure, and tachypnea.

²⁷ Nail disorder: koilonychia, nail bed disorder, nail cuticle fissure, nail discolouration, nail disorder, nail dystrophy, nail hypertrophy, nail pitting, nail ridging, nail toxicity, onychoclasis, onycholysis and onychomadesis.

²⁸ Skin disorder: palmar-plantar erythrodysesthesia syndrome, palmoplantar keratoderma, skin discolouration, skin exfoliation and skin fissures.

²⁹ Rash: dermatitis, dermatitis acneiform, dermatitis contact, dermatitis exfoliative, dermatitis exfoliative generalized, erythema, exfoliative rash, rash, rash erythematous, rash macular, rash maculo-papular, rash papular, rash pruritic, rash pustular, rash vesicular and stasis dermatitis.

³⁰ Xerosis: dry eye, dry skin and xerosis.

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 first (29%), or second (44%) step-up dose. In the biweekly regimen, 33% of patients had CRS after the third step-up dose. CRS occurred in 30% of patients with the first 0.4 mg/kg treatment dose and in 12% of patients treated with the first 0.8 mg/kg treatment dose. CRS was observed in less than 3% of patients during the remaining doses in cycle 1 and in less than 4% of patients from week 5 onward. After week 5, all instances of CRS were Grade 1. The median time to onset of CRS was 27 (range: 0.1 to 333) hours from the last dose, 91% of events occurred within 48 hours from the last dose, and the median duration was 17 (range: 0 to 622) hours. Tocilizumab and corticosteroids were used to treat 39% and 5% of CRS events, respectively.

Neurologic toxicities, including immune effector cell-associated neurotoxicity syndrome (ICANS)

In MonumenTAL-1, neurologic toxicities were reported in 29% (n=98) of 339 patients receiving TALVEY at the recommended dosages. Neurologic toxicity events were Grade 1 (17%), Grade 2

(10%), Grade 3 (2.4%) or Grade 4 (0.3%). The most frequently reported neurologic toxicity event was headache (9%).

In MonumenTAL-1, ICANS occurred in 10% (n=26) of 265 patients who received TALVEY at the recommended dosages and for whom ICANS data was collected. Most events were Grade 1 or 2, with Grade 3 and 4 events occurring in 2.3% of patients. The most frequently reported clinical manifestations of ICANS were confusional state (4.2%), disorientation (1.9%), and somnolence (1.9%). Sixty-eight percent (68%) of patients with ICANS had concurrent CRS (during or within 7 days of CRS resolution). Three percent (3%) of patients experienced more than one ICANS event. Most ICANS occurred during the step-up phase following the first or second dose, or the initial treatment dose (0.4 mg/kg and 0.8 mg/kg) (3% each). The median time to onset was 28 (range: 3 to 355) hours from the last dose, 68% of events started within 48 hours from the last dose, and the median duration was 9 (range: 2 to 194) hours.

One fatal ICANS event was reported in MonumenTAL-1.

In MonumenTAL-1 (N=339), ataxia/balance disorder occurred in 4.1% of patients (n=14). Ataxia/balance disorder events were Grade 1 (1.5%), Grade 2 (2.4%), and Grade 3 (0.3%). No Grade 4 or 5 events occurred. The most frequent clinical manifestation of ataxia/balance disorder events reported were dysarthria (1.5%), gait disturbance (1.5%), and balance disorder (0.9%), and 0.9% of patients experienced more than one ataxia/balance disorder event. The median time to onset was 77 (range: 2 to 463) days from the first dose and 4 (range: 1 to 13) days from the last dose, and 7 (38.9%) of 18 events did not resolve.

Serious infections

In MonumenTAL-1 (N=339), Grade 3 or Grade 4 infections occurred in 19% of patients, and fatal infections occurred in 1.5% of patients.

Skin reactions

In MonumenTAL-1 (N=339), 31% of patients experienced rashes that were Grade 1 or 2, with Grade 3 events occurring in 3.5% of patients. The median time to onset for rash was 22 days.

8.3. Less Common Clinical Trial Adverse Reactions

Clinically relevant adverse reactions reported in <10% of patients who received TALVEY in MonumenTAL-1 included:

• ICANS (9.8%)
• Viral infection (8.3%; includes adenovirus infection, conjunctivitis viral, cytomegalovirus infection, cytomegalovirus viraemia, disseminated varicella zoster virus infection, gastroenteritis rotavirus, gastroenteritis viral, HCoV-HKU1 infection, herpes ophthalmic, influenza, metapneumovirus infection, norovirus infection, parainfluenzae virus infection, respiratory syncytial virus bronchiolitis, respiratory syncytial virus infection, retinitis viral and viral infection)
• Pneumonia (6.8%; includes pneumonia and pneumonia streptococcal)

• Sepsis^a (5.0%; includes bacteremia, enterobacter bacteremia, escherichia sepsis, fungal sepsis, klebsiella bacteraemia, klebsiella sepsis, pneumococcal sepsis, pseudomonal

  • bacteraemia, salmonella sepsis, sepsis, septic shock, staphylococcal bacteremia, staphylococcal sepsis and streptococcal bacteremia)

^a Contains fatal outcome.

8.4. Abnormal Laboratory Findings: Hematologic, Clinical Chemistry, and Other Quantitative Data

Table 13 summarizes clinical laboratory measurements that worsened from baseline in ≥30% of patients who received TALVEY in MonumenTAL-1.

Table 13: Laboratory Abnormalities (≥30%) That Worsened From Baseline in Patients With Multiple Myeloma Who Received TALVEY in MonumenTAL-1

Laboratory toxicity grades are derived based on the NCI CTCAE (National Cancer Institute Common Terminology Criteria for Adverse Events) Version 4.03.

9. Drug Interactions

9.2. Drug Interactions Overview

No drug interaction studies have been performed with TALVEY.

9.4. Drug-Drug Interactions

Talquetamab causes release of cytokines (see 10.2. Pharmacodynamics) that may suppress the activity of cytochrome P450 (CYP) enzymes, potentially resulting in increased exposure to CYP substrates. Based on simulations from a semi-mechanistic PK model, the highest risk of drug-drug interaction is expected to occur beginning at the initiation of the talquetamab step-up phase ending approximately 9 days after the first treatment dose and during and after CRS (see 7. Warnings and Precautions - CRS). Monitor for toxicity and monitor the concentrations of drugs that are CYP (e.g., CYP2C9, CYP2C19, CYP3A4/5) substrates where minimal concentration changes may lead to serious adverse reactions. Adjust the dose of the concomitant CYP (e.g., CYP2C9, CYP2C19, CYP3A4/5) substrate drugs as needed.

9.5. Drug-Food Interactions

Interactions with food have not been established.

9.6. Drug-Herb Interactions

Interactions with herbal products have not been established.

9.7. Drug-Laboratory Test Interactions

Interactions with laboratory tests have not been established.

10. Clinical Pharmacology

10.1. Mechanism of Action

Talquetamab is a humanized immunoglobulin G4 proline, alanine, alanine (IgG4-PAA) bispecific antibody directed against GPRC5D on multiple myeloma cells 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. GPRC5D protein is also expressed in healthy tissues such as epithelial cells in keratinized tissues of the skin and tongue.

10.2. Pharmacodynamics

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

10.3. Pharmacokinetics

0.4 mg/kg Weekly

The mean accumulation ratio between the doses on day 1 and day 43 of talquetamab 0.4 mg/kg was 3.94 ± 2.79 (n=13) and 4.50 ± 3.85 (n=13) 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 14.

Table 14: Estimation of Pharmacokinetic Parameters of Talquetamab by Non-Compartmental Analysis Following the First and Seventh Recommended 0.4 mg/kg Weekly SC Dose in Patients With Relapsed or Refractory Multiple Myeloma in MonumenTAL-1 (Step-up Dose 0.01/0.06 Then 0.4 mg/kg).

0.8 mg/kg Biweekly (Every Two Weeks)

The mean accumulation ratio between the doses on day 1 and day 57 of talquetamab 0.8 mg/kg was 2.33 ± 1.79 (n=19) and 2.17 ± 1.78 (n=19) for C_max and AUC_tau, respectively.

Pharmacokinetic parameters of talquetamab following the 1^st and 5^th recommended biweekly (every 2 weeks) dose of 0.8 mg/kg are shown in Table 15.

Table 15: Estimation of Pharmacokinetic Parameters of Talquetamab by Non-Compartmental Analysis Following the First and Fifth Recommended 0.8 mg/kg Biweekly (Every 2 Weeks) SC Dose in Patients With Relapsed or Refractory Multiple Myeloma in MonumenTAL-1 (Step-up Dose 0.01/0.06/0.3 Then 0.8 mg/kg).

Absorption

Based on the population pharmacokinetic model, the typical value of the bioavailability of talquetamab was 62% when administered subcutaneously relative to intravenous dosing. The rate of absorption from the SC administration was 0.138 day^-1.

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

The population pharmacokinetic model for talquetamab incorporated both linear time-independent and time-dependent clearance parameters. Based on the population pharmacokinetic model, the typical total clearance parameter is 2.08 ± 1.08 L/day at initial treatment and 1.06 ± 0.548 L/day at steady state for participants with IgG subtype of myeloma and ISS stage I. The time-dependent component of the clearance parameter accounted for 48.8% of total clearance estimate at initial treatment and then decreased exponentially to <5% at around Week 16.

Based on the population pharmacokinetic model, 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 based on the post hoc parameters of all SC population (N=392) was 7.56 days at initial treatment, and 12.2 days at steady state.

An alternative estimate of the half-life, based on the observed data, was provided by the non-compartmental analysis of the IV population (n=86) which estimated the half-life as 3.51 ± 2.07 days.

Special populations and conditions

• Pediatrics: The pharmacokinetics of talquetamab in pediatric patients <18 years of age have not been investigated.
• Geriatrics: Results of population pharmacokinetic analyses indicate that age (33 to 86 years) likely did not influence the pharmacokinetic parameters in the population pharmacokinetic model of talquetamab.

• Hepatic Insufficiency: No formal studies of talquetamab in patients with hepatic impairment have been conducted.

  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) and moderate hepatic impairment (total bilirubin 1.5 to 3 times ULN and any AST>ULN) did not significantly influence the pharmacokinetics of talquetamab. No data is available in patients with severe hepatic impairment.

• Renal Insufficiency: No formal studies of talquetamab in patients with renal impairment have been conducted.

Results of population pharmacokinetic analyses indicate that mild (60 mL/min/1.73 m² ≤ estimated glomerular filtration rate (eGFR) <90 mL/min/1.73 m²) or moderate (30 mL/min/1.73 m² ≤ eGFR <60 mL/min/1.73 m²) renal impairment did not significantly influence the pharmacokinetics of talquetamab. No data is available in patients with severe renal impairment.

10.4. Immunogenicity

All therapeutic proteins have the potential for immunogenicity.

The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies in the studies described below with the incidences of antibodies in other studies or to other products may be misleading.

In MonumenTAL-1, 260 patients treated with subcutaneous talquetamab monotherapy at 0.4 mg/kg weekly or 0.8 mg/kg biweekly (every 2 weeks) were evaluated for antibodies to talquetamab. Following treatment of 0.4 mg/kg weekly or 0.8 mg/kg biweekly (every 2 weeks),

64 of 260 patients (24.6%) developed anti-talquetamab antibodies. None of these participants were positive for neutralizing antibodies to talquetamab.

1. 11. Storage, Stability, and Disposal

Store refrigerated at 2°C to 8°C. Do not freeze.

Store in the original carton in order to protect from light.

Keep out of the sight and reach of children.

Prepared syringe:

The prepared syringes should be administered immediately. If immediate administration is not possible, store the TALVEY solution for up to 24 hours refrigerated at 2°C to 8°C followed by up to 24 hours at ambient temperature of 15°C to 30°C. Discard if stored for more than 24 hours refrigerated or more than 24 hours of being at ambient temperature. If stored in the refrigerator, allow the solution to come to ambient temperature before administration.

12. Special Handling Instructions

Any unused medicinal product or waste material should be disposed in accordance with local requirements.

Part 2: Scientific Information

13. Pharmaceutical Information

Drug Substance

Non-proprietary name of the drug substance: talquetamab

Molecular formula and molecular mass: approximately 147 kDa

Structure: TALVEY (talquetamab) is a humanized immunoglobulin G4-proline, alanine, alanine (IgG4-PAA)-based bispecific antibody directed against G Protein-coupled receptor family C group 5 member D (GPRC5D) and the cluster of differentiation 3 (CD3) receptors.

Physicochemical properties: TALVEY is a colourless to light yellow preservative-free solution for injection.

Product Characteristics:

TALVEY is produced by cultivation of recombinant Chinese hamster ovary cells, followed by isolation, chromatographic purification, and formulation.

14. Clinical Trials

14.1. Clinical Trials by Indication

Monotherapy for Multiple Myeloma After Three or More Prior Lines of Therapy

The clinical efficacy of TALVEY monotherapy was evaluated in adult patients with relapsed or refractory multiple myeloma in an open-label, non-randomized, multicenter, Phase I/II study (MonumenTAL-1). See Table 16 for a summary of study design and dosing.

Table 16: Summary of Patient Demographics for Clinical Trials in Adult Patients With Relapsed or Refractory Multiple Myeloma Who Have Received at Least Three Prior Lines of Therapy, Including a Proteasome Inhibitor, an Immunomodulatory Agent and an Anti-CD38 Monoclonal Antibody

Study MonumenTAL-1 enrolled patients with relapsed or refractory multiple myeloma. Patients in Phase 1 had progressed on, or could not tolerate, all previous lines of therapy. Patients in Phase 2 had received at least three prior lines of therapy and must have previously received a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody. All patients in the pivotal cohorts were naïve to T cell redirecting therapies such as chimeric antigen receptor-T cells or other bispecific monoclonal antibodies.

The study included adults with measurable multiple myeloma who had an Eastern Cooperative Oncology Group (ECOG) score of ≤ 2, adequate baseline laboratory values (absolute neutrophil count ≥ 1.0 x 10⁹/L, platelet count ≥ 50 x 10⁹/L, hemoglobin level ≥ 8 g/dL) and renal (CrCL ≥ 40 mL/min), and hepatic (AST and ALT ≤ 3.0 x ULN, total bilirubin ≤ 2.0 x ULN) function. The study excluded patients who: received T cell redirection therapy in the preceding 3 months; had prior Grade 3 or higher CRS related to any T cell redirection therapy; allogenic stem cell transplant in the preceding 6 months; autologous stem cell transplant in the preceding 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; 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 (once 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 hospitalized 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, 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 proteasome inhibitor, 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.

Of 145 patients treated with TALVEY 0.8 mg/kg biweekly (every 2 weeks), 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.

The primary efficacy outcome of MonumenTAL-1 was the overall response rate (ORR) as assessed by an Independent Review Committee (IRC) applying International Myeloma Working Group (IMWG) criteria (See Table 17 and Table 18).

The median duration of follow-up among all patients receiving TALVEY 0.4 mg/kg weekly was 18.8 months. The median time to response was 1.2 months (range: 0.2, 10.9) and the median time to best response was 2.2 months (range: 0.8, 12.7).

Table 17: Efficacy Results for MonumenTAL-1 (Study MMY1001) in Patients Receiving 0.4 mg/kg Weekly TALVEY

CI=confidence interval

^a Kaplan-Meier estimate

The median duration of follow-up among all patients receiving TALVEY 0.8 mg/kg once every 2 weeks was 12.7 months. The median time to response was 1.3 months (range: 0.2, 9.2) and the median time to best response was 3.0 months (range: 0.3, 12.9).

Table 18: Efficacy Results for MonumenTAL-1 (Study MMY1001) in Patients Receiving 0.8 mg/kg Biweekly (Every 2 Weeks) TALVEY

CI=confidence interval; NE=not estimable

^a Kaplan-Meier estimate

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

The ORR was generally consistent in a separate cohort of MonumenTAL-1, which included a limited number of patients (n=51) who were exposed to prior T cell redirection therapy and had received at least three prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent and an anti-CD38 monoclonal antibody.

15. Microbiology

No microbiological information is required for this drug product.

16. Non-Clinical Toxicology

Tissue Profiling: Normal (non-diseased) human tissue expression studies were conducted to detect GPRC5D mRNA by in situ hybridization and protein by immunohistochemistry. In human skin, GPRC5D is expressed in epithelial cells of hair follicles and eccrine sweat glands. Consistent with this pattern of expression, clinical adverse events including skin exfoliation, dry skin and nail disorder have been reported following administration of TALVEY.

GPRC5D was also shown in non-clinical studies to be expressed in filiform papillae of the tongue and in plasma cells of the oral cavity. On-target off-tumour binding of GPRC5D by talquetamab at these sites is consistent with the oral toxicities associated with this bispecific antibody.

Carcinogenicity: No animal studies have been performed to assess the carcinogenic potential of talquetamab.

Genotoxicity: No animal studies have been performed to assess the genotoxic potential of talquetamab.

Reproductive and Developmental Toxicology: No animal studies have been conducted to evaluate the effects of talquetamab on reproduction and fetal development.

No studies have been conducted to evaluate the effects of talquetamab on fertility.