Teclistamab

The initial release of cytokines associated with the start of teclistamab treatment could suppress CYP450 enzymes. The highest risk of interaction is expected to be from initiation of teclistamab step-up schedule up to 7 days after the first maintenance dose or during a CRS event. During this time period, toxicity or medicinal product concentrations (e.g., cyclosporine) should be monitored in patients who are receiving concomitant CYP450 substrates with a narrow therapeutic index. The dose of the concomitant medicinal product should be adjusted as needed.

Immune response to vaccines may be reduced when taking teclistamab.

Hepatitis B virus reactivation can occur in patients treated with medicinal products directed against B cells, and in some cases, may result in fulminant hepatitis, hepatic failure, and death.

Patients with evidence of positive HBV serology should be monitored for clinical and laboratory signs of HBV reactivation while receiving teclistamab, and for at least six months following the end of teclistamab treatment.

In patients who develop reactivation of HBV while on teclistamab, treatment with teclistamab should be withheld and manage per local institutional guidelines.

There are no available data on the use of teclistamab in pregnant women or animal data to assess the risk of teclistamab in pregnancy. Human IgG is known to cross the placenta after the first trimester of pregnancy. Therefore, teclistamab, a humanised IgG4-based antibody, has the potential to be transmitted from the mother to the developing foetus. Teclistamab is not recommended for women who are pregnant. Teclistamab is associated with hypogammaglobulinaemia, therefore, assessment of immunoglobulin levels in newborns of mothers treated with teclistamab should be considered.

It is not known whether teclistamab is excreted in human or animal milk, affects breast-fed infants or affects milk production. Because of the potential for serious adverse reactions in breast-fed infants from teclistamab, patients should be advised not to breast-feed during treatment with teclistamab and for at least three months after the last dose.

Women of child-bearing potential / Contraception in males and females

Pregnancy status for females of child-bearing potential should be verified prior to starting treatment with teclistamab.

Women of child-bearing potential should use effective contraception during treatment and for 3 months after the final dose of teclistamab. In clinical studies, male patients with a female partner of child-bearing potential used effective contraception during treatment and for three months after the last dose of teclistamab.

Fertility

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

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

Due to the potential for ICANS, patients receiving teclistamab are at risk of depressed level of consciousness. Patients should be instructed to avoid driving and operating heavy or potentially dangerous machinery during and for 48 hours after completion of teclistamab step-up dosing schedule and in the event of new onset of any neurological symptoms.

The most frequent adverse reactions of any grade in patients were hypogammaglobulinaemia (75%), cytokine release syndrome (72%), neutropenia (71%), anaemia (55%), musculoskeletal pain (52%), fatigue (41%), thrombocytopenia (40%), injection site reaction (38%), upper respiratory tract infection (37%), lymphopenia (35%), diarrhoea (28%), pneumonia (28%), nausea (27%), pyrexia (27%), headache (24%), cough (24%), constipation (21%) and pain (21%).

Serious adverse reactions were reported in 65% patients who received teclistamab, including pneumonia (16%), COVID-19 (15%), cytokine release syndrome (8%), sepsis (7%), pyrexia (5%), musculoskeletal pain (5%), acute kidney injury (4.8%), diarrhoea (3.0%), cellulitis (2.4%), hypoxia (2.4%), febrile neutropenia (2.4%), and encephalopathy (2.4%).

Tabulated list of adverse reactions

The safety data of teclistamab was evaluated in MajesTEC-1, which included 165 adult patients with multiple myeloma who received the recommended dosing regimen of teclistamab as monotherapy. The median duration of teclistamab treatment was 8.5 (Range: 0.2 to 24.4) months.

The following table summarises adverse reactions reported in patients who received teclistamab. The safety data of teclistamab was also evaluated in the all treated population (N=302) 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 (≥1/1 000 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 teclistamab in MajesTEC-1 at the recommended dose for monotherapy use:

Adverse events are coded using MedDRA Version 24.0.
Note: The output includes the diagnosis of CRS and ICANS; the symptoms of CRS or ICANS are excluded.
¹ Pneumonia includes Enterobacter pneumonia, lower respiratory tract infection, lower respiratory tract infection viral, Metapneumovirus pneumonia, Pneumocystis jirovecii pneumonia, pneumonia, Pneumonia adenoviral, Pneumonia bacterial, Pneumonia klebsiella, Pneumonia moraxella, Pneumonia pneumococcal, Pneumonia pseudomonal, Pneumonia respiratory syncytial viral, Pneumonia staphylococcal and Pneumonia viral.
² Sepsis includes bacteraemia, Meningococcal sepsis, neutropenic sepsis, Pseudomonal bacteraemia, Pseudomonal sepsis, sepsis and Staphylococcal bacteraemia.
³ COVID-19 includes asymptomatic COVID-19 and COVID-19.
⁴ Upper respiratory tract infection includes bronchitis, nasopharyngitis, pharyngitis, respiratory tract infection, respiratory tract infection bacterial, rhinitis, rhinovirus infection, sinusitis, tracheitis, upper respiratory tract infection and viral upper respiratory tract infection.
⁵ Anaemia includes anaemia, iron deficiency and iron deficiency anaemia.
⁶ Hypogammaglobulinaemia includes patients with adverse events of hypogammaglobulinaemia, hypoglobulinaemia, immunoglobulins decreased, and/or patients with laboratory IgG levels below 500 mg/dL following treatment with teclistamab.
⁷ Encephalopathy includes confusional state, depressed level of consciousness, lethargy, memory impairment and somnolence.
⁸ Neuropathy peripheral includes dysaesthesia, hypoaesthesia, hypoaesthesia oral, neuralgia, paraesthesia, paraesthesia oral, peripheral sensory neuropathy and sciatica.
⁹ Hemorrhage includes conjunctival haemorrhage, epistaxis, haematoma, haematuria, haemoperitoneum, haemorrhoidal haemorrhage, lower gastrointestinal haemorrhage, melaena, mouth haemorrhage and subdural haematoma.
¹⁰ Hypertension includes essential hypertension and hypertension.
¹¹ Dyspnoea includes acute respiratory failure, dyspnoea and dyspnoea exertional.
¹² Cough includes allergic cough, cough, productive cough and upper-airway cough syndrome.
¹³ Musculoskeletal pain includes arthralgia, back pain, bone pain, musculoskeletal chest pain, musculoskeletal pain, myalgia, neck pain and pain in extremity.
¹⁴ Injection site reaction includes injection site bruising, injection site cellulitis, injection site discomfort, injection site erythema, injection site haematoma, injection site induration, injection site inflammation, injection site oedema, injection site pruritus, injection site rash, injection site reaction and injection site swelling.
¹⁵ Pain includes ear pain, flank pain, groin pain, non-cardiac chest pain, oropharyngeal pain, pain, pain in jaw, toothache and tumour pain.
¹⁶ Oedema includes face oedema, fluid overload, oedema peripheral and peripheral swelling.
¹⁷ Fatigue includes asthenia, fatigue and malaise
¹⁸ Transaminase elevation includes alanine aminotransferase increased and aspartate aminotransferase increased.

Description of selected adverse reactions

Cytokine release syndrome

In MajesTEC-1 (N=165), CRS was reported in 72% of patients following treatment with teclistamab. One-third (33%) of patients experienced more than one CRS event. Most patients experienced CRS following Step-up Dose 1 (44%), Step-up Dose 2 (35%), or the initial maintenance dose (24%). Less than 3% of patients developed first occurrence of CRS following subsequent doses of teclistamab. CRS events were Grade 1 (50%) and Grade 2 (21%) or Grade 3 (0.6%). The median time to onset of CRS was 2 (Range: 1 to 6) days after the most recent dose, with a median duration of 2 (Range: 1 to 9) days.

The most frequent signs and symptoms associated with CRS were fever (72%), hypoxia (13%), chills (12%), hypotension (12%), sinus tachycardia (7%), headache (7%), and elevated liver enzymes (aspartate aminotransferase and alanine aminotransferase elevation) (3.6% each).

In MajesTEC-1, tocilizumab, corticosteroids and tocilizumab in combination with corticosteroids were used to treat CRS in 32%, 11% and 3% of CRS events, respectively.

Neurologic toxicities

In MajesTEC-1 (N=165), neurologic toxicity events were reported in 15% of patients receiving teclistamab. Neurologic toxicity events were Grade 1 (8.5%), Grade 2 (5.5%), or Grade 4 (<1%). The most frequently reported neurologic toxicity event was headache (8%).

ICANS was reported in 3% of patients receiving teclistamab at the recommended dose. The most frequent clinical manifestation of ICANS reported were confusional state (1.2%) and dysgraphia (1.2%). The onset of neurologic toxicity can be concurrent with CRS, following resolution of CRS, or in the absence of CRS. Seven of nine ICANS events (78%) were concurrent with CRS (during or within 7 days of CRS resolution). The median time to onset of ICANS was 4 (Range: 2 to 5) days after the most recent dose, with a median duration of 3 (Range: 1 to 20) days.

Immunogenicity

Patients treated with subcutaneous teclistamab monotherapy (N=238) in MajesTEC-1 were evaluated for antibodies to teclistamab using an electrochemiluminescence-based immunoassay. One subject (0.4%) developed neutralising antibodies to teclistamab of low-titre.