ELREXFIO is indicated as monotherapy for the treatment of adult patients with relapsed and refractory multiple myeloma, who have received at least three prior therapies, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 antibody and have demonstrated disease progression on the last therapy.

Treatment should be initiated and supervised by physicians experienced in the treatment of multiple myeloma.

ELREXFIO should be administered via subcutaneous injection by a healthcare professional with adequately trained medical personnel and appropriate medical equipment to manage severe reactions, including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) (see section 4.4).

Prior to initiating treatment, complete blood count should be performed. Any possibility of active infections and/or pregnancy in women of child-bearing potential should be ruled out (see sections 4.4 and 4.6).

Posology

Recommended dosing schedule

The recommended doses are step-up doses of 12 mg on day 1 and 32 mg on day 4, followed by a full treatment dose of 76 mg weekly from week 2 to week 24 (see Table 1).

For patients who have received at least 24 weeks of treatment and have achieved a response, the dosing interval should transition to an every two‑week schedule.

ELREXFIO should be administered according to the step-up dosing schedule in Table 1 to reduce the incidence and severity of CRS and ICANS. Due to the risk of CRS and ICANS, patients should be monitored for signs and symptoms for 48 hours after administration of each of the 2 step-up doses and instructed to remain within proximity of a healthcare facility (see section 4.4).

Recommended pre-treatment medicinal products

The following pre-treatment medicinal products should be administered approximately 1 hour prior to the first three doses of ELREXFIO, which includes step-up dose 1, step-up dose 2, and the first full treatment dose as described in Table 1 to reduce the risk of CRS (see section 4.4):

• paracetamol 500 mg orally (or equivalent)

• dexamethasone 20 mg orally or intravenously (or equivalent)

• diphenhydramine 25 mg orally (or equivalent)

Prophylactic antimicrobials and anti-virals should be considered according to local institutional guidelines (see section 4.4).

Dose modifications based on toxicity

Dose reductions of ELREXFIO are not recommended. Dose delays may be required to manage toxicities (see section 4.4).

See Tables 2 and 3 for recommended actions for adverse reactions of CRS and ICANS, respectively.

See Table 4 for recommended actions for other adverse reactions.

Cytokine release syndrome (CRS)

CRS should be identified based on clinical presentation (see section 4.4). Patients should be evaluated and treated for other causes of fever, hypoxia, and hypotension. Supportive therapy for CRS (including but not limited to anti-pyretic agents, intravenous fluid support, vasopressors, IL-6 or IL-6 receptor inhibitors, supplemental oxygen, etc.) should be administered as appropriate. Laboratory testing to monitor for disseminated intravascular coagulation (DIC), haematology parameters, as well as pulmonary, cardiac, renal, and hepatic function should be considered.

Neurologic toxicities, including ICANS

Other causes of neurologic symptoms should be ruled out. Patients should be immediately evaluated and treated based on severity. Supportive therapy, which may include intensive care, for severe or life‑threatening neurologic toxicities, should be provided. Patients who experience Grade 2 or higher ICANS with the previous dose of ELREXFIO should be instructed to remain within proximity of a healthcare facility and be monitored for signs and symptoms daily for 48 hours following the next dose.

Restarting ELREXFIO after dose delay

If a dose is delayed, therapy should be restarted based on the recommendations listed in Table 5, and therapy should be resumed according to the dosing schedule (see Table 1). Pre‑treatment medicinal products should be administered as indicated in Table 5.

Duration of treatment

Treatment should be continued until disease progression or unacceptable toxicity.

Missed doses

If a dose is missed, the dose should be administered as soon as possible, and the dosing schedule should be adjusted to maintain the dosing interval as needed (see Table 1).

Special populations

Elderly

No dose adjustment is necessary (see sections 5.1 and 5.2).

Renal impairment

No dose adjustment is recommended in patients with mild to moderate renal impairment (estimated glomerular filtration rate [eGFR] > 30 mL/min/1.73 m²). Limited data are available from patients with severe renal impairment, see section 5.2).

Hepatic impairment

No dose adjustments are required for mild hepatic impairment (total bilirubin > 1 to 1.5 × ULN and any AST, or total bilirubin ≤ ULN and AST > ULN, see section 5.2).

Paediatric population

There is no relevant use of ELREXFIO in the paediatric population for the treatment of multiple myeloma.

Method of administration

ELREXFIO is for subcutaneous injection only and should be administered by a healthcare professional.

The required dose should be injected into the subcutaneous tissue of the abdomen (preferred injection site). Alternatively, it may be injected into the subcutaneous tissue of the thigh.

ELREXFIO should not be injected into areas where the skin is red, bruised, tender, hard, or areas where there are scars.

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.

Traceability

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

Cytokine release syndrome (CRS)

CRS, including life-threatening or fatal reactions, may occur in patients receiving ELREXFIO. Clinical signs and symptoms of CRS may include, but are not limited to, fever, hypoxia, chills, hypotension, tachycardia, headache, and elevated liver enzymes (see section 4.8).

Therapy should be initiated according to the step-up dosing schedule to reduce risk of CRS and patients should be monitored following administration of ELREXFIO accordingly. Pre-treatment medicinal products should be administered prior to the first three doses to reduce risk of CRS (see section 4.2).

Patients should be counselled to seek urgent medical attention should signs or symptoms of CRS occur.

At the first sign of CRS, ELREXFIO should be withheld and patients should be immediately evaluated for hospitalisation. CRS should be managed according to the recommendations in section 4.2, and further management should be considered per local institutional guidelines. Supportive therapy for CRS (including but not limited to anti-pyretic agents, intravenous fluid support, vasopressors, IL-6 or IL-6 receptor inhibitors, supplemental oxygen, etc.) should be administered as appropriate. Laboratory testing to monitor for disseminated intravascular coagulation (DIC), haematology parameters, as well as pulmonary, cardiac, renal, and hepatic function should be considered.

Neurologic toxicities, including ICANS

Serious or life-threatening neurologic toxicities, including ICANS, may occur following treatment with ELREXFIO (see section 4.8). Patients should be monitored for signs and symptoms (e.g., decrease level of consciousness, seizures and/or motor weakness) of neurologic toxicities during treatment.

Patients should be counselled to seek urgent medical attention should signs or symptoms of neurologic toxicity occur.

At the first sign of neurologic toxicity, including ICANS, ELREXFIO should be withheld and neurology evaluation should be considered. General management for neurologic toxicity (e.g., ICANS) is summarised in Table 3 (see section 4.2).

Due to the potential for ICANS, patients should be advised not to drive or operate heavy or potential dangerous machinery during the step-up dosing schedule and for 48 hours after completing each of the 2 step-up doses and in the event of new onset of any neurological symptoms (see sections 4.2 and 4.7).

Infections

Severe, life-threatening, or fatal infections have been reported in patients receiving ELREXFIO (see section 4.8). New or reactivated viral infections occurred during therapy with ELREXFIO, including cytomegalovirus (CMV) infection/reactivation. Progressive multifocal leukoencephalopathy (PML) has also occurred during therapy with ELREXFIO.

Treatment should not be initiated in patients with active infections. Patients should be monitored for signs and symptoms of infection prior to and during treatment with ELREXFIO and treated appropriately. ELREXFIO should be withheld based on the severity of the infection as indicated in Table 4 for other non-haematologic adverse reactions (see section 4.2).

Prophylactic antimicrobials (e.g., prevention of pneumocystis jirovecii pneumonia) and anti-virals (e.g., prevention of herpes zoster reactivation) should be administered according to local institutional guidelines.

Neutropenia

Neutropenia and febrile neutropenia have been reported in patients receiving ELREXFIO (see section 4.8).

Complete blood cell counts should be monitored at baseline and periodically during treatment. Treatment with ELREXFIO should be withheld as indicated in Table 4 (see section 4.2). Patients with neutropenia should be monitored for signs of infection. Supportive therapy should be provided according to local institutional guidelines.

Hypogammaglobulinaemia

Hypogammaglobulinemia has been reported in patients receiving ELREXFIO (see section 4.8).

Immunoglobulin levels should be monitored during treatment. Treatment with subcutaneous or intravenous immunoglobulin (IVIG) should be considered if IgG levels fall below 400 mg/dL and patients should be treated according to local institutional guidelines, including infection precautions and antimicrobial prophylaxis.

Concomitant use of live viral vaccines

The safety of immunisation with live viral vaccines during or following treatment with ELREXFIO 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.

Excipients

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

No interaction studies have been performed with ELREXFIO.

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.

Women of child-bearing potential/Contraception

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

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

Pregnancy

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 ELREXFIO is not recommended for use during pregnancy.

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

Breast-feeding

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 ELREXFIO 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.

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

Due to the potential for ICANS, patients receiving ELREXFIO are at risk of depressed level of consciousness (see section 4.8). 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 (see sections 4.2 and 4.4).

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

Table 6 summarises adverse reactions reported in patients who received ELREXFIO 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 ELREXFIO 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.

Description of selected adverse reactions

Cytokine release syndrome (CRS)

CRS occurred in 57.9% of patients who received ELREXFIO 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 ELREXFIO 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 (see Table 3). 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.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

Symptoms and signs

There has been no experience of overdose in clinical studies. The maximum tolerated dose of elranatamab has not been determined. In clinical studies, doses up to 76 mg once weekly 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 supportive treatment should be instituted immediately.

Pharmacotherapeutic group: Monoclonal antibodies and antibody drug conjugates, ATC code: not yet assigned

Mechanism of action

Elranatamab is a bi-specific T-cell engaging antibody that binds CD3-epsilon on T cells and B-cell maturation antigen (BCMA) on plasma cells, plasmablasts, and multiple myeloma cells. Binding of elranatamab to BCMA on tumour cells and CD3 on T cells is independent of native T cell receptor (TCR) specificity or reliance on major histocompatibility (MHC) Class 1 molecules. Elranatamab activated T cells, led to proinflammatory cytokine release, and resulted in multiple myeloma cell lysis.

Pharmacodynamic effects

Immunogenicity

During treatment with elranatamab at the recommended dose, anti-drug antibodies (ADA) were detected in 8.3% participants. No evidence of ADA impact on pharmacokinetics, efficacy or safety was observed; however, data are still limited.

Clinical efficacy and safety

Relapsed or refractory multiple myeloma

The efficacy of ELREXFIO monotherapy was evaluated in patients with relapsed or refractory multiple myeloma in an open-label, non-randomised, multi-centre, Phase 2 study (MagnetisMM-3). The study included patients who were refractory to at least one proteasome inhibitor (PI), one immunomodulatory agent (IMiD) and one anti-CD38 monoclonal antibody. MagnetisMM-3 included 123 patients naï ve to prior BCMA-directed therapy (pivotal Cohort A). Patients had measurable disease by international myeloma working group (IMWG) criteria at enrolment. The study included patients with an ECOG score of ≤ 2, adequate baseline bone marrow (absolute neutrophil count ≥ 1.0 × 10⁹/L, platelet count ≥ 25 × 10⁹/L, haemoglobin level ≥ 8 g/dL), renal (CrCL ≥ 30 mL/min), and hepatic [aspartate aminotransferase (AST) and alanine transaminase (ALT) ≤ 2.5 × upper limit of normal (ULN)], total bilirubin ≤ 2 × ULN] function, and left‑ventricular ejection fraction ≥ 40%. Patients with smouldering multiple myeloma, active plasma cell leukaemia, amyloidosis, POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder, skin changes) syndrome, stem cell transplant within 12 weeks prior to enrolment, active infections, and clinically significant neuropathies and cardiovascular disease, were excluded from the study.

Patients received subcutaneous administration of ELREXFIO at step-up doses of 12 mg on Day 1 and 32 mg on Day 4 of treatment, followed by the first full treatment dose of ELREXFIO (76 mg) on Day 8 of treatment. Thereafter, patients received 76 mg once weekly. After 24 weeks, in patients who achieved an IMWG response category of partial response or better with responses persisting for at least 2 months, the dosing interval was changed from every week to every 2 weeks (see section 4.2).

Among the 123 patients treated in pivotal Cohort A, the median age was 68 (range: 36 to 89) years with 19.5% of patients ≥ 75 years of age. 44.7% were female; 58.5% were White, 13.0% were Asian, 8.9% were Hispanic/Latino, and 7.3% were Black. Disease stage (R-ISS) at study entry was 22.8% in Stage I, 55.3% in Stage II, and 15.4% in Stage III. The median time since initial diagnosis of multiple myeloma to enrolment was 72.9 (range: 16 to 228) months. Patients had received a median of 5 prior lines of therapy (range: 2 to 22); with 96.0% who received ≥ 3 prior lines of therapy. 96.7% were triple-class refractory and 95.9% refractory to their last line of therapy. 68.3% received prior autologous stem cell transplantation, and 5.7% received prior allogenic stem cell transplantation. High-risk cytogenetics [t(4;14), t(14;16), or del(17p)] were present in 25.2% of patients. 31.7% of patients had extramedullary disease [presence of any plasmacytoma (extramedullary and/or paramedullary) with a soft-tissue component] by blinded independent central review (BICR) at baseline.

Efficacy results were based on response rate and duration of response (DOR), as assessed by BICR based on the IMWG criteria. Efficacy results from pivotal Cohort A are shown in Table 7. The median (range) follow-up from initial dose for responders was 15.2 (2.4, 24.2) months.

Paediatric population

The licensing authority has waived the obligation to submit the results of studies with ELREXFIO in all subsets of the paediatric population in multiple myeloma (see section 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 licensing authority will review new information on this medicinal product at least every year and this SmPC will be updated as necessary.

Pharmacokinetic parameters are presented as geometric mean (coefficient of variation [CV]%) for unbound elranatamab unless otherwise specified. The C_max and AUC_tau of elranatamab after the first subcutaneous dose increased in a dose proportional manner over the evaluated dose range via subcutaneous administration (~ 6 to 76 mg). The median accumulation ratio after 24 weeks of weekly dosing relative to the first subcutaneous dose of elranatamab 76 mg for C_max and AUC_tau was 6.6-fold and 11.2-fold, respectively. The predicted C_avg, C_max, and C_trough of elranatamab are presented in Table 8.

Absorption

The predicted mean bioavailability of elranatamab was 56.2% when administered subcutaneously. The median T_max after elranatamab SC administration across all dose levels ranged from 3 to 7 days.

Distribution

Based on the population pharmacokinetic model, the predicted mean volume of distribution of unbound elranatamab was 4.78 L, 69% (CV) for the central compartment, and 2.83 L for the peripheral compartment.

Elimination

The predicted geometric mean half-life of elranatamab is 22, 64% (CV) days at week 24 following doses of 76 mg weekly. Based on the population pharmacokinetic model, the predicted mean elranatamab clearance was 0.324 L/day, 69% (CV).

Special populations

No clinically relevant differences in the pharmacokinetics of elranatamab were observed based on age (36 to 89 years), sex (167 male, 154 female), race (193 White, 49 Asian, 29 Black), and body weight (37 to 160 kg).

Renal impairment

No studies of elranatamab in patients with renal impairment have been conducted. Results of population pharmacokinetic analyses indicate that mild renal impairment (60 mL/min/1.73 m² ≤ eGFR < 90 mL/min/1.73 m²) or moderate renal impairment (30 mL/min/1.73 m² ≤ eGFR < 60 mL/min/1.73 m²) did not significantly influence the pharmacokinetics of elranatamab. Limited data are available from patients with severe renal impairment (eGFR less than 30 mL/min/1.73 m²).

Hepatic impairment

No studies of elranatamab in patients with hepatic impairment have been conducted. Results of population pharmacokinetic analyses indicate that mild hepatic impairment (total bilirubin > 1 to 1.5 × ULN and any AST, or total bilirubin ≤ ULN and AST > ULN) did not significantly influence the pharmacokinetics of elranatamab. No data are available in patients with moderate (total bilirubin > 1.5 to 3.0 × ULN and any AST) or severe (total bilirubin > 3.0 × ULN and any AST) hepatic impairment.

Carcinogenicity and mutagenicity

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

Reproductive toxicology and fertility

No animal studies have been performed to evaluate the effects of elranatamab on fertility or reproduction and foetal development.

In a 13-week repeat-dose toxicity study in sexually mature cynomolgus monkeys, there were no notable effects on male and female reproductive organs following subcutaneous doses up to 6 mg/kg/week (approximately 6.5 times the maximum recommended human dose, based on AUC exposure).

Edetate disodium

L-histidine

L-histidine hydrochloride monohydrate

Polysorbate 80

Sucrose

Water for injections

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

Unopened vial

2 years.

Prepared syringe

Chemical and physical in-use stability has been demonstrated for 24 hours at 30 ° C.

From a microbiological point of view, unless the method of opening precludes the risks of microbial contamination, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user.

Store in a refrigerator (2 ° C to 8 ° C).

Do not freeze.

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

For storage conditions after first opening of the medicinal product, see section 6.3.

ELREXFIO 40 mg/mL solution for injection

1.1 mL solution in a vial (Type 1 glass) with a stopper (butyl rubber) and an aluminium seal with a flip-off cap containing 44 mg of elranatamab.

Pack size of 1 vial.

ELREXFIO 40 mg/mL solution for injection

1.9 mL solution in a vial (Type 1 glass) with a stopper (butyl rubber) and an aluminium seal with a flip-off cap containing 76 mg of elranatamab.

Pack size of 1 vial.

ELREXFIO 40 mg/mL solution for injection is supplied as a ready‑to-use solution that does not need dilution prior to administration. Do not shake.

ELREXFIO is a clear to slightly opalescent, and colourless to pale brown solution. The solution should not be administered if it is discoloured or contains particulate matter.

Aseptic technique should be used to prepare and administer ELREXFIO.

Preparation instructions

ELREXFIO 40 mg/mL solution for injection vials are for single use only.

ELREXFIO should be prepared following the instructions below (see Table 9) depending on the required dose. It is suggested to use a 44 mg/1.1 mL (40 mg/mL) single dose vial for each one of the step-up doses.

Once punctured, the vial and dosing syringe should be used immediately. If the prepared dosing syringe is not used immediately, store syringe between 2 ° C to 30 ° C for a maximum of 24 hours.

Disposal

The vial and any remaining contents should be discarded after a single use. Any unused medicinal product or waste material should be disposed of in accordance with local requirements.