Talquetamab

Talquetamab causes release of cytokines that may suppress activity of cytochrome P450 (CYP) enzymes, potentially resulting in increased exposure of CYP substrates. The highest risk of drug-drug interaction is expected to occur from initiation of talquetamab step-up phase up to 9 days after the first treatment dose and during and after CRS. Monitor for toxicity or concentrations of medicinal products that are CYP (e.g., CYP2C9, CYP2C19, CYP3A4/5, CYP2D6) substrates where minimal concentration changes may lead to serious adverse reactions. The dose of concomitant CYP (e.g., CYP2C9, CYP2C19, CYP3A4/5, CYP2D6) substrate drugs should be adjusted as needed.

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

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

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

Women of childbearing potential/Contraception in females

Pregnancy status of females of child-bearing potential should be verified prior to initiating treatment with talquetamab.

Females of reproductive potential should use effective contraception during treatment and for 3 months after the last dose of talquetamab.

Fertility

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

Talquetamab has major influence on the ability to drive and use machines.

Due to the potential for ICANS, patients receiving talquetamab are at risk of depressed level of consciousness. Patients should be instructed to avoid driving or operating machines during the step-up phase and for 48 hours after completion of the step-up phase, and in the event of new onset of any neurological symptoms, until symptoms resolve.

Summary of the safety profile

The most frequent adverse reactions were CRS (77%), dysgeusia (72%), hypogammaglobulinaemia (67%), nail disorder (56%), musculoskeletal pain (48%), anaemia (47%), skin disorder (43%), fatigue (43%), weight decreased (40%), rash (39%), dry mouth (36%), neutropenia (35%), pyrexia (33%), xerosis (32%), thrombocytopenia (30%), upper respiratory tract infection (29%), lymphopenia (27%), dysphagia (24%), diarrhoea (25%), pruritus (23%), cough (23%), pain (22%), decreased appetite (22%) and headache (20%).

Serious adverse reactions reported in patients included CRS (13%), pyrexia (5%), ICANS (3.8%), sepsis (3.8%), COVID-19 (3.2%), bacterial infection (2.4%), pneumonia (2.4%), viral infection (2.4%), neutropenia (2.1%) and pain (2.1%).

The most frequent adverse reactions leading to treatment discontinuation were ICANS (1.1%) and weight decreased (0.9%).

Tabulated list of adverse reactions

The safety of talquetamab was evaluated in 339 adult patients with relapsed or refractory multiple myeloma, including patients treated with talquetamab at the recommended dosing regimen with or without prior T cell redirection therapy in MonumenTAL-1. The median duration of treatment was 7.4 (range: 0.0 to 32.9) months.

The table below summarises adverse reactions reported in patients who received talquetamab. The safety data of talquetamab was also evaluated in the All Treated population (N=501) with no additional adverse reactions identified.

Adverse reactions observed during clinical studies are listed below by frequency category. Frequency categories are defined as follows: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1000 to <1/100); rare (≥1/10 000 to <1/1 000); very rare (<1/10 000) and not known (frequency cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Adverse reactions in patients with multiple myeloma treated with talquetamab in MonumenTAL-1 (N=339):

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/dL following 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 and vestibular 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 site inflammation, 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 transaminases increased.

Description of selected adverse reactions

Cytokine release syndrome

In MonumenTAL-1 (N=339), CRS occurred in 77% of patients. Most events were Grade 1 or 2, with Grade 3 events occurring in 1.5% of patients. Thirty one percent (31%) of patients experienced more than one CRS event. Most events occurred during the step-up phase following the 0.01 mg/kg dose (29%), the 0.06 mg/kg dose (44%), the 0.3 mg/kg dose (for patients who received biweekly [every 2 weeks] dosing; 33%), or the initial treatment dose (0.4 mg/kg [30%] or 0.8 mg/kg [12%]). Less than 4% of CRS events occurred from week 5 onward; all events were Grade 1. The median time to onset of CRS was 27 hours from the last dose, 91% of events occurred within 48 hours from the last dose, and the median duration was 17 hours. Tocilizumab, corticosteroids and tocilizumab in combination with corticosteroids were used to treat CRS in 39%, 5% and 3.5% of CRS events, respectively. Clinical signs and symptoms of CRS may include but are not limited to pyrexia (76%), hypotension (15%), chills (12%), hypoxia (7%), headache (4.7%), tachycardia (5%) and elevated transaminases (aspartate aminotransferase [1.5%] and alanine aminotransferase [0.9%]).

Neurologic toxicities

In MonumenTAL-1 (N=339), neurologic toxicity events were reported in 29% of patients receiving talquetamab. Neurologic toxicity events were Grade 1 (17%), Grade 2 (11%), Grade 3 (2.3%) or Grade 4 (0.3%). The most frequently reported neurologic toxicity event was headache (9%).

ICANS were only collected for Phase 2 in MonumenTAL-1. Of the 265 patients in Phase 2, ICANS occurred in 9.8% (n=26) of patients. Most events were Grade 1 or 2, with Grade 3 and 4 events occurring in 2.3% of patients. The most frequent clinical manifestation of ICANS reported were confusional state (3.8%), disorientation (1.9%), somnolence (1.9%) and depressed level of consciousness (1.9%). Sixty-eight percent (68%) were concurrent with CRS (during or within 7 days of CRS resolution). Three percent (3%) of patients experienced more than one ICANS event. In addition, one fatal ICANS event was reported in MonumenTAL-1. Most patients experienced ICANS during the step-up phase following the 0.01 mg/kg dose, the 0.06 mg/kg dose, or the initial treatment dose (0.4 mg/kg and 0.8 mg/kg) (3% each). The median time to onset of ICANS was 28 hours from the last dose, 68% of events started within 48 hours from the last dose, 32% of events occurred after 48 hours, and the median duration of ICANS was 9 hours.

Oral toxicity

In MonumenTAL-1 (N=339), seventy-eight percent (78%) of patients had Grade 1 or 2 events, with Grade 3 events occurring in 2% of patients. Oral toxicity events included dysgeusia, dry mouth, dysphagia, and stomatitis were reported.

Serious infections

In MonumenTAL-1 (N=339), Grade 3 or Grade 4 infections occurred in 19% of patients; fatal infections occurred in 1.5% of patients - COVID-19 pneumonia, fungal sepsis, infection and septic shock. The most frequently reported (≥2%) Grade 3 or 4 infection was pneumonia. Febrile neutropenia was observed in 1% of patients with 1.2% experiencing serious febrile neutropenia.

Hypogammaglobulinaemia

Post baseline IgG values of less than 500 mg/dl consistent with hypogammaglobulinaemia have been reported in 64% of patients treated with talquetamab at the 0.4 mg/kg weekly dose schedule, 66% of patients at the 0.8 mg/kg biweekly dose schedule and in 71% of patients with prior T cell redirection therapy.

Skin reactions

In MonumenTAL-1 (N=339), the majority of rash cases were Grade 1 or 2, with Grade 3 events occurring in 3.5% of patients. The median time to onset from the first treatment dose for rash was 22 days. The majority of non-rash skin toxicities were Grade 1 or 2, with Grade 3 pruritus occurring in 0.3% of patients. Nail disorders occurred in 56% of patients and were Grade 1 or 2.