Elranatamab

Elranatamab is a bispecific T-cell engaging antibody of the IgG2 kappa type, derived from two monoclonal antibodies and produced in two recombinant Chinese hamster ovary cell lines. One arm recognises B-cell maturation antigen (BCMA), a protein found on plasma cells and highly expressed on multiple myeloma cells; the other recognises CD3 on T cells.

Mechanism of Action

• Two targets: elranatamab binds CD3-epsilon on T cells with one arm and BCMA on plasma cells, plasmablasts and multiple myeloma cells with the other, bringing the T cell and the tumour cell together.
• T-cell killing: the binding activates the T cells, which release pro-inflammatory cytokines and destroy the myeloma cells. This works independently of the specificity of the native T-cell receptor and does not rely on MHC class I molecules.
• Target biology: BCMA activates several survival pathways in plasma cells (NF-kappa B, STAT3, ERK1/2 and AKT/PI3K) and is often overexpressed on malignant plasma cells, which makes it a suitable target for T-cell engaging antibodies.
• Cytokine release: treatment causes a transient rise in circulating cytokines (IL-2, IL-6, IL-8, IL-10, TNF-α and interferon-γ), which underlies cytokine release syndrome.

Pharmacokinetics

• Absorption: after subcutaneous injection the predicted mean bioavailability is 56.2%, and the median time to peak concentration ranges from 3 to 7 days. Cmax and AUC after the first dose rose in proportion to dose over about 6 to 76 mg. After 24 weeks of weekly 76 mg doses, the median accumulation relative to the first dose was 6.6-fold for Cmax and 11.2-fold for AUC over the dosing interval. In patients who respond, the predicted average concentration (geometric mean, unbound elranatamab) is about 32.0 mcg/mL at week 24, 17.7 mcg/mL at steady state on the every-two-weeks schedule and 8.8 mcg/mL on the every-four-weeks schedule.
• Distribution: the predicted mean volume of distribution of unbound elranatamab is 4.78 L in the central compartment and 2.83 L in the peripheral compartment.
• Metabolism: like other antibodies, elranatamab is expected to be broken down by catabolic pathways into small peptides.
• Elimination: the predicted mean clearance is 0.324 L/day, and the geometric mean half-life is 22 days at week 24 of 76 mg weekly dosing.
• Immunogenicity: anti-drug antibodies were detected in 9.5% of participants in the pivotal study at the recommended dose. There was no evidence of an effect on pharmacokinetics, efficacy or safety, but data are still limited.
• Special populations: no dose adjustment is needed for age, mild to moderate renal impairment or mild hepatic impairment. Data are limited in severe renal impairment.

• Relapsed and refractory multiple myeloma: monotherapy in adults who have received at least three prior therapies, including an immunomodulatory agent, a proteasome inhibitor and an anti-CD38 antibody, and who have shown disease progression on the last therapy.

Elrexfio holds a conditional marketing authorisation in the EU.

• Hypersensitivity to elranatamab or to any of the excipients (edetate disodium, L-histidine, L-histidine hydrochloride monohydrate, polysorbate 80, sucrose).

The frequencies below come from 183 patients treated at the recommended dosing regimen in the MagnetisMM-3 study, including 64 who had previously received a BCMA-directed antibody-drug conjugate or CAR T-cell therapy. The median treatment duration was 4.1 months (range 0.03 to 35.9). The larger all-treated population (265 patients) showed no additional adverse reactions. The most frequent reactions were cytokine release syndrome (CRS), anaemia, neutropenia, fatigue, upper respiratory tract infection, diarrhoea, injection site reaction and pneumonia. Serious reactions were pneumonia (31.7%), sepsis (15.8%), CRS (12.6%), anaemia (5.5%), upper respiratory tract infection (5.5%), urinary tract infection (3.8%), febrile neutropenia (3.3%), diarrhoea (2.7%), dyspnoea (2.7%) and pyrexia (2.2%).

Very common (≥1/10): cytokine release syndrome (57.9%), anaemia (54.1%), neutropenia (45.9%), fatigue (44.8%), upper respiratory tract infection (43.2%), diarrhoea (42.1%), injection site reaction (38.3%), pneumonia (38.3%), thrombocytopenia (36.6%), lymphopenia (30.1%), pyrexia (29.0%), rash (27.9%), decreased appetite (27.3%), arthralgia (26.8%), hypokalaemia (23.5%), nausea (21.9%), dry skin (21.9%), dyspnoea (20.8%), headache (19.7%), sepsis (18.6%), leukopenia (18.6%), peripheral neuropathy (17.5%, a grouped term that includes Guillain-Barré syndrome), raised transaminases (17.5%), hypogammaglobulinaemia (16.9%) and urinary tract infection (13.7%).

Common (≥1/100 to <1/10): cytomegalovirus infection (9.3%), hypophosphataemia (6.6%), febrile neutropenia (3.3%) and immune effector cell-associated neurotoxicity syndrome, or ICANS (3.3%).

Uncommon (≥1/1,000 to <1/100): progressive multifocal leukoencephalopathy (0.5%; one case with a fatal outcome).

Grade 3 or 4 events were frequent for neutropenia (44.3%), anaemia (42.6%), lymphopenia (27.9%), thrombocytopenia (26.2%), pneumonia (25.7%), sepsis (13.1%), leukopenia (13.1%) and hypokalaemia (9.3%). CRS was grade 3 in 0.5% and ICANS grade 3 in 1.1%. The SmPC groups related terms: pneumonia includes, for example, COVID-19 pneumonia and Pneumocystis jirovecii pneumonia, and sepsis includes bacteraemia and septic shock.

Cytokine release syndrome. CRS occurred in 57.9% of patients (grade 1 in 43.7%, grade 2 in 13.7%, grade 3 in 0.5%). Most episodes followed the first step-up dose (43.2% of patients) or the second (19.1%); 7.1% had CRS after the first full treatment dose and 1.6% after a later dose, and 13.1% had recurrent CRS. The median time to onset was 2 days (range 1 to 9) after the most recent dose and the median duration 2 days (range 1 to 19). Among patients with CRS, fever occurred in 98.1%, hypotension in 20.8% and hypoxia in 11.3%; 34.0% received tocilizumab (or siltuximab) and 15.1% received corticosteroids.

ICANS. ICANS occurred in 3.3% of patients (grade 1 in 0.5%, grade 2 in 1.6%, grade 3 in 1.1%), mostly after the first step-up dose (2.7%), and recurred in 1.1%. The median time to onset was 3 days (range 1 to 4) after the most recent dose and the median duration 2 days (range 1 to 18). ICANS can occur together with CRS, after CRS has resolved, or without CRS. The most frequent symptoms were a depressed level of consciousness and grade 1 or 2 scores on the ICE (immune effector cell-associated encephalopathy) assessment. Among patients with ICANS, 66.7% received corticosteroids, 33.3% tocilizumab (or siltuximab), 33.3% levetiracetam and 16.7% anakinra.

No interaction studies have been performed with elranatamab.

• Cytokine-related suppression of CYP enzymes: the cytokine release that accompanies the start of treatment may suppress cytochrome P450 (CYP) enzymes. The highest risk of interaction is expected during, and for up to 14 days after, the step-up dosing, and during, and for up to 14 days after, CRS. In that period, toxicity or blood levels are monitored in patients taking sensitive CYP substrates with a narrow therapeutic index, such as ciclosporin, phenytoin, sirolimus and warfarin, and their dose is adjusted as needed.
• Live viral vaccines: not recommended from 4 weeks before the first dose until at least 4 weeks after treatment (see Special Instructions).

Treatment should be started and supervised by physicians experienced in the treatment of multiple myeloma. Elranatamab is given by subcutaneous injection by a healthcare professional, with adequately trained medical personnel and appropriate medical equipment to manage severe reactions, including CRS and ICANS. Before treatment starts, a complete blood count is performed, and active infection and, in women of childbearing potential, pregnancy are ruled out.

Recommended Dosing Schedule

• Step-up dose 1: 12 mg on day 1 of week 1.
• Step-up dose 2: 32 mg on day 4 of week 1, at least 2 days after step-up dose 1.
• Weekly dosing: 76 mg once weekly from week 2 to week 24, with at least 3 days between step-up dose 2 and the first 76 mg dose.
• Every 2 weeks: 76 mg every two weeks from week 25 to week 48, for patients who have received at least 24 weeks of treatment and achieved a response.
• Every 4 weeks: 76 mg every four weeks from week 49 onward, for patients who have received at least 24 weeks at the every-two-week schedule and maintained the response.
• At least 6 days are kept between doses. Treatment continues until disease progression or unacceptable toxicity.

Monitoring After the Step-Up Doses

Step-up dosing is used to reduce the incidence and severity of CRS and ICANS. Because of the risk of CRS and ICANS, patients are monitored for signs and symptoms for 48 hours after each of the 2 step-up doses and are told to remain within proximity of a healthcare facility.

Pre-Treatment Medicines

About 1 hour before each of the first three doses (step-up dose 1, step-up dose 2 and the first 76 mg dose), to reduce the risk of CRS:

• paracetamol 500 mg orally (or equivalent);
• dexamethasone 20 mg orally or intravenously (or equivalent);
• diphenhydramine 25 mg orally (or equivalent).

Prophylactic antimicrobials and antivirals should be considered according to local institutional guidelines.

Dose Modifications for Toxicity

Dose reductions are not recommended; doses are delayed to manage toxicity.

• CRS grade 1 (temperature 38 °C or higher): withhold treatment until CRS resolves and give supportive therapy.
• CRS grade 2 (as grade 1 with hypotension that responds to fluids and does not need vasopressors, and/or oxygen by low-flow nasal cannula or blow-by): withhold until CRS resolves, give supportive therapy, and monitor the patient daily for 48 hours after the next dose, with the patient staying close to a healthcare facility.
• CRS grade 3, first occurrence (hypotension needing one vasopressor, and/or oxygen by high-flow nasal cannula, facemask, non-rebreather mask or Venturi mask): withhold until CRS resolves, give supportive therapy that may include intensive care, give the pre-treatment medicines before the next dose, and monitor daily for 48 hours after it.
• CRS grade 3, recurrent, and CRS grade 4 (hypotension needing multiple vasopressors, or oxygen by positive pressure such as CPAP, BiPAP or mechanical ventilation): permanently discontinue and give supportive therapy, which may include intensive care.
• ICANS grade 1 (ICE score 7 to 9, or awakens spontaneously): withhold until ICANS resolves, monitor neurological symptoms, consider a neurologist’s opinion and consider a non-sedating anti-seizure medicine such as levetiracetam for seizure prophylaxis.
• ICANS grade 2 (ICE score 3 to 6, or awakens to voice): withhold until ICANS resolves, give dexamethasone 10 mg intravenously every 6 hours until grade 1 or less and then taper, consider specialist input and seizure prophylaxis, and monitor daily for 48 hours after the next dose with the patient staying close to a healthcare facility.
• ICANS grade 3, first occurrence (ICE score 0 to 2, awakens only to touch, seizures or raised intracranial pressure with focal oedema): as for grade 2, with supportive therapy that may include intensive care.
• ICANS grade 3, recurrent, and ICANS grade 4: permanently discontinue, give dexamethasone as above and supportive therapy that may include intensive care. For grade 4, methylprednisolone 1,000 mg per day intravenously for 3 days may be considered instead.
• Neutrophils below 0.5 × 10⁹/L: withhold until the count is 0.5 × 10⁹/L or higher. Febrile neutropenia: withhold until neutrophils are 1 × 10⁹/L or higher and the fever has resolved.
• Haemoglobin below 8 g/dL: withhold until it is 8 g/dL or higher. Platelets below 25,000/mcL, or between 25,000 and 50,000/mcL with bleeding: withhold until platelets are 25,000/mcL or higher and there is no evidence of bleeding.
• Other non-haematological reactions of grade 3 or 4: withhold until recovery to grade 1 or less (or baseline), and discontinue permanently if recovery does not occur.

Restarting After a Dose Delay

Therapy is resumed according to the dosing schedule after the delay. Pre-treatment medicines are given before the restarted dose, except when 76 mg is restarted after a delay of up to 12 weeks following a 76 mg dose.

• After step-up dose 1 (12 mg): a delay of up to 14 days means restarting at step-up dose 2 (32 mg) and, if tolerated, increasing to 76 mg 4 days later; a longer delay means restarting the step-up schedule at 12 mg.
• After step-up dose 2 (32 mg): a delay of up to 14 days means restarting at 76 mg; a delay of 15 to 28 days means restarting at 32 mg and, if tolerated, increasing to 76 mg 1 week later; a delay of more than 28 days means restarting the step-up schedule at 12 mg.
• After any 76 mg dose: a delay of up to 12 weeks (84 days) means restarting at 76 mg; a longer delay means restarting the step-up schedule at 12 mg.

Missed Dose

If a dose is missed, it is given as soon as possible, and the schedule is adjusted to keep the dosing interval as needed.

Special Populations

• Elderly: no dose adjustment.
• Renal impairment: no adjustment in mild to moderate impairment (eGFR above 30 mL/min/1.73 m²); limited data in severe impairment.
• Hepatic impairment: no adjustment in mild impairment (total bilirubin above 1 to 1.5 × ULN with any AST, or total bilirubin up to ULN with AST above ULN). The posology section gives no dose recommendation for moderate or severe impairment.
• Children and adolescents: there is no relevant use in the paediatric population for multiple myeloma.

Method of Administration

For subcutaneous injection only, by a healthcare professional. The dose is injected into the subcutaneous tissue of the abdomen (preferred site) or, alternatively, the thigh, and not into skin that is red, bruised, tender, hard or scarred. Handling instructions are in the SmPC.

Step-Up Dosing and Monitoring After the First Doses

• Treatment starts with step-up doses of 12 mg (day 1) and 32 mg (day 4) before the 76 mg dose, to reduce the incidence and severity of CRS and ICANS.
• Patients are monitored for signs and symptoms for 48 hours after each of the 2 step-up doses and are told to remain within proximity of a healthcare facility.
• Elranatamab is given only by a healthcare professional, with trained medical personnel and appropriate equipment to manage severe reactions, including CRS and ICANS.
• Pre-treatment medicines (paracetamol, dexamethasone, diphenhydramine) are given about 1 hour before the first three doses.
• At the first sign of CRS, elranatamab is withheld and the patient is evaluated at once for hospitalisation. After a grade 2 or higher CRS or ICANS event, monitoring for 48 hours and staying close to a healthcare facility are repeated after the next dose.

Cytokine Release Syndrome

• CRS, including life-threatening or fatal reactions, may occur. Signs and symptoms include fever, hypoxia, chills, hypotension, tachycardia, headache and raised liver enzymes.
• Patients are counselled to seek urgent medical attention if signs or symptoms of CRS occur.
• Management follows the grade-based recommendations above and local institutional guidelines. Supportive therapy includes antipyretics, intravenous fluids, vasopressors, IL-6 or IL-6 receptor inhibitors and supplemental oxygen as appropriate. Laboratory testing for disseminated intravascular coagulation, blood counts and lung, heart, kidney and liver function should be considered.

Neurological Toxicity Including ICANS

• Serious or life-threatening neurological toxicity, including ICANS, may occur. Patients are monitored for signs and symptoms such as a lowered level of consciousness, seizures and motor weakness, and are counselled to seek urgent medical attention if they occur.
• At the first sign of neurological toxicity, elranatamab is withheld and a neurological evaluation should be considered.
• Patients should not drive or operate heavy or potentially dangerous machinery during the step-up dosing schedule and for 48 hours after completing each of the 2 step-up doses, nor after any new onset of neurological symptoms.

Infections

• Severe, life-threatening and fatal infections have been reported. New or reactivated viral infections have occurred, including cytomegalovirus infection or reactivation, and progressive multifocal leukoencephalopathy (PML), which can be fatal.
• Treatment is not started in patients with active infection. Patients are monitored for signs of infection before and during treatment, and elranatamab is withheld according to severity, as for other non-haematological reactions.
• Prophylactic antimicrobials (for example against Pneumocystis jirovecii pneumonia) and antivirals (for example against herpes zoster reactivation) are given according to local institutional guidelines.

Neutropenia

Neutropenia and febrile neutropenia have been reported. Blood counts are checked at baseline and periodically, treatment is withheld as set out above, patients with neutropenia are monitored for signs of infection, and supportive therapy follows local guidelines.

Hypogammaglobulinaemia

Hypogammaglobulinaemia has been reported. Immunoglobulin levels are monitored during treatment. Subcutaneous or intravenous immunoglobulin should be considered if IgG falls below 400 mg/dL, together with infection precautions and antimicrobial prophylaxis according to local guidelines.

Live Vaccines

The safety of immunisation with live viral vaccines during or after treatment has not been studied. Live virus vaccines are not recommended within 4 weeks before the first dose, during treatment and for at least 4 weeks after treatment.

Pregnancy, Breastfeeding and Fertility

• Contraception: the pregnancy status of women of childbearing potential is verified before treatment. They should use effective contraception during treatment and for 6 months after the last dose.
• Pregnancy: there are no human or animal data on the risk. Human IgG crosses the placenta after the first trimester, and elranatamab may cause foetal harm, so it is not recommended in pregnancy. Because it is associated with hypogammaglobulinaemia, immunoglobulin levels in newborns of treated mothers should be considered.
• Breastfeeding: it is not known whether elranatamab passes into milk or affects the infant or milk production. Human IgG is excreted in breast milk and a risk to the infant cannot be excluded, so breastfeeding is not recommended during treatment and for 6 months after the last dose.
• Fertility: there are no data on human fertility, and effects on male and female fertility have not been evaluated in animals.

Sodium

Each dose contains less than 1 mmol (23 mg) of sodium, that is, it is essentially sodium-free.

Traceability

The name and batch number of the administered medicine should be clearly recorded.

Effect on Driving

Elranatamab has a major influence on the ability to drive and use machines. Because of the potential for ICANS, patients are at risk of a depressed level of consciousness. They should not drive or operate heavy or potentially dangerous machinery during, and for 48 hours after completing, each of the 2 step-up doses, or after new-onset neurological toxicity until any neurological symptoms have resolved.

Store the vials in a refrigerator at 2–8 °C. Do not freeze. Keep them in the original carton to protect them from light. Elranatamab is a cold-chain product, so the temperature should be kept within this range during transport and storage. Vials hold 44 mg in 1.1 mL or 76 mg in 1.9 mL, one vial per pack. For storage after the vial is opened, see Shelf Life.

• Unopened vial: 3 years.
• After opening: chemical and physical in-use stability, including in prepared syringes, has been shown for 7 days at 2–8 °C and for 24 hours at up to 30 °C.
• From a microbiological point of view, the product should be used immediately. If it is not, the user is responsible for in-use times and conditions, which would normally not exceed 24 hours at 2–8 °C, unless preparation took place under controlled and validated aseptic conditions.

Prescription only (Rx), on restricted medical prescription (Annex II B): treatment is started and supervised by a physician experienced in the treatment of multiple myeloma. Elranatamab is injected under the skin by a healthcare professional who has trained personnel and equipment to manage severe reactions, including CRS and ICANS. Patients are monitored for 48 hours after each of the 2 step-up doses and stay within proximity of a healthcare facility. It is therefore supplied to the hospital or clinic that administers it, with cold-chain delivery at 2–8 °C.