Elranatamab

The initial release of cytokines associated with the start of ELREXFIO may suppress cytochrome P450 (CYP) enzymes. The highest risk of interaction is expected to occur during and up to 14 days after the step-up dosing as well as during and up to 14 days after CRS. During this time period, toxicity or medicinal product concentrations should be monitored in patients who are receiving concomitant sensitive CYP substrates with a narrow therapeutic index (e.g., cyclosporine, phenytoin, sirolimus, and warfarin). The dose of the concomitant medicinal product should be adjusted as needed.

The safety of immunisation with live viral vaccines during or following treatment with elranatamab has not been studied. Vaccination with live virus vaccines is not recommended within the 4 weeks prior to the first dose, during treatment, and at least 4 weeks after treatment.

There are no human or animal data to assess the risk of elranatamab use during pregnancy. Human immunoglobulin (IgG) is known to cross the placenta after the first trimester of pregnancy. Based on the mechanism of action, elranatamab may cause foetal harm when administered to a pregnant woman and therefore elranatamab is not recommended for use during pregnancy.

Elranatamab is associated with hypogammaglobulinaemia, therefore, assessment of immunoglobulin levels in newborns of mothers treated with elranatamab should be considered.

It is not known whether elranatamab is excreted in human or animal milk, affects breastfed infants or affects milk production. Human IgGs are known to be excreted in breast milk. A risk to the breastfed child cannot be excluded and therefore breast-feeding is not recommended during treatment with elranatamab and for 6 months after the last dose.

Women of child-bearing potential/Contraception

The pregnancy status of women of child-bearing potential should be verified prior to initiating treatment with elranatamab.

Women of child-bearing potential should use effective contraception during treatment with elranatamab and for 6 months after the last dose.

Fertility

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

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

Due to the potential for ICANS, patients receiving elranatamab are at risk of depressed level of consciousness. Patients should be instructed to refrain from driving or operating heavy or potential dangerous machinery during and for 48 hours after completing each of the 2 step-up doses and in the event of new onset of neurologic toxicity until resolution of any neurological symptoms.

Summary of the safety profile

The most frequent adverse reactions are CRS (57.9%), anaemia (54.1%), neutropenia (44.8%), fatigue (44.3%), upper respiratory tract infection (38.8%), injection site reaction (38.3%), diarrhoea (37.7%), pneumonia (37.2%), thrombocytopenia (36.1%), lymphopenia (30.1%), decreased appetite (26.8%), pyrexia (27.3%), rash (26.2%), arthralgia (25.1%), hypokalaemia (23.0%), nausea (21.3%), and dry skin (21.3%).

Serious adverse reactions are pneumonia (30.6%), sepsis (15.3%), CRS (12.6%), anaemia (5.5%), upper respiratory tract infection (4.9%), urinary tract infection (3.3%), febrile neutropenia (2.7%), dyspnoea (2.2%), and pyrexia (2.2%).

Tabulated list of adverse reactions

The table below summarises adverse reactions reported in patients who received elranatamab at the recommended dosing regimen (N=183 including 64 patients with prior BCMA-directed antibody drug conjugate [ADC] or chimeric antigen receptor [CAR] T cell therapy [supportive Cohort B]). The median duration of treatment was 4.1 (range: 0.03 to 20.3) months. The safety data of elranatamab was also evaluated in the all-treated population (N=265) with no additional adverse reactions identified.

Adverse reactions are listed according to the MedDRA system organ classification and by frequency. Frequency categories are defined as 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, where relevant, adverse reactions are presented in order of decreasing seriousness.

Adverse reactions in multiple myeloma patients treated with elranatamab in MagnetisMM-3 at the recommended dose:

^a Pneumonia includes pneumonia, COVID-19 pneumonia, bronchopulmonary aspergillosis, lower respiratory tract infection bacterial, lower respiratory tract infection viral, pneumocystis jirovecii pneumonia, pneumonia adenoviral, pneumonia bacterial, pneumonia. cytomegaloviral, pneumonia fungal, pneumonia influenzal, pneumonia pseudomonal, pneumonia viral, atypical pneumonia, coronavirus pneumonia, pneumonia haemophilus, pneumonia pneumococcal, pneumonia respiratory syncytial viral.
^b Sepsis includes sepsis, bacteraemia, device related bacteraemia, device related sepsis, escherichia bacteraemia, escherichia sepsis, klebsiella sepsis, pseudomonal sepsis, septic shock, staphylococcal bacteraemia, staphylococcal sepsis, streptococcal sepsis, urosepsis, campylobacter bacteraemia.
^c Peripheral neuropathy includes peripheral sensory neuropathy, paraesthesia, peripheral sensorimotor neuropathy, dysaesthesia, neuropathy peripheral, peripheral motor neuropathy, Guillain-Barre syndrome, hypoaesthesia, neuralgia, polyneuropathy.
^d Rash incudes dermatitis exfoliative, dermatitis exfoliative generalised, erythema, palmar-plantar erythrodysaesthesia syndrome, rash, rash erythematous, rash macular, rash maculo-papular, rash pustular, symmetrical drug-related intertriginous and flexural exanthema, epidermolysis.

Description of selected adverse reactions

Cytokine release syndrome (CRS)

CRS occurred in 57.9% of patients who received elranatamab at the recommended dosing schedule, with Grade 1 CRS in 43.7%, Grade 2 in 13.7% and Grade 3 in 0.5% of patients. Most patients experienced CRS after the first step-up dose (43.2%) or the second step-up dose (19.1%), with 7.1% of patients having CRS after the first full treatment dose and 1.6% of patients after a subsequent dose. Recurrent CRS occurred in 13.1% of patients. The median time to onset of CRS was 2 (range: 1 to 9) days after the most recent dose, with a median duration of 2 (range: 1 to 19 days) days.

Among patients who developed CRS, associated symptoms included fever (99.0%), hypotension (21.0%), and hypoxia (11.4%) and 33% received tocilizumab (or siltuximab) and 15.1% received corticosteroids for treatment of CRS.

Immune effector cell-associated neurotoxicity syndrome (ICANS)

ICANS occurred in 3.3% of patients following treatment with elranatamab at the recommended dosing schedule, with Grade 1 ICANS in 0.5%, Grade 2 in 1.6% and Grade 3 in 1.1% of patients. The majority of patients had ICANS after the first step-up dose (2.7%), 1 (0.5%) patient had ICANS after the second step-up dose and 1 (0.5%) patient had ICANS after a subsequent dose. Recurrent ICANS occurred in 1.1% of patients. The median time to onset was 3 (range: 1 to 4) days after the most recent dose with a median duration of 2 (range: 1 to 18) days.

The onset of ICANS can be concurrent with CRS, following resolution of CRS, or in the absence of CRS. The most frequent symptoms of ICANS included a depressed level of consciousness and Grade 1 or Grade 2 Immune Effector Cell-Associated Encephalopathy (ICE) scores. Among patients who developed ICANS, 66.7% received corticosteroids, 33.3% received tocilizumab (or siltuximab), 33.3% received levetiracetam and 16.7% received anakinra for treatment of ICANS.