4.1. Therapeutic indications

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

4.2. Posology and method of administration

Abecma must be administered in a qualified treatment centre.

Abecma therapy should be initiated under the direction of and supervised by a healthcare professional experienced in the treatment of haematological malignancies and trained for the administration and management of patients treated with Abecma.

A minimum of one dose of tocilizumab for use in the event of cytokine release syndrome (CRS) and emergency equipment must be available prior to infusion of Abecma. The treatment centre must have access to an additional dose of tocilizumab within 8 hours of each previous dose. In the exceptional case where tocilizumab is not available due to a shortage that is listed in the MHRA Central Alerting System, suitable alternative measures to treat CRS instead of tocilizumab must be available prior to infusion.

Posology

Abecma is intended for autologous use only (see section 4.4).

Treatment consists of a single dose for infusion containing a dispersion of CAR-positive viable T cells in one or more infusion bags. The target dose is 420 x 106 CAR‑positive viable T cells within a range of 260 to 500 x 106 CAR‑positive viable T cells. See the accompanying release for infusion certificate (RfIC) for additional information pertaining to dose.

Pre-treatment (lymphodepleting chemotherapy)

Lymphodepleting chemotherapy consisting of cyclophosphamide 300 mg/m2/day intravenously (IV) and fludarabine 30 mg/m2/day IV should be administered for 3 days. See the prescribing information for cyclophosphamide and fludarabine for information on dose adjustment in renal impairment.

Abecma is to be administered 2 days after completion of lymphodepleting chemotherapy, up to a maximum of 9 days. The availability of Abecma must be confirmed prior to starting the lymphodepleting chemotherapy. If there is a delay in Abecma infusion of more than 9 days, then the patient should be re-treated with lymphodepleting chemotherapy after a minimum of 4 weeks from last lymphodepleting chemotherapy prior to receiving Abecma.

Pre-medication

It is recommended that premedication with paracetamol (500 to 1,000 mg orally) and diphenhydramine (12.5 mg IV or 25 to 50 mg orally) or another H1‑antihistamine, be administered approximately 30 to 60 minutes before the infusion of Abecma to reduce the possibility of an infusion reaction.

Prophylactic use of systemic corticosteroids should be avoided as the use may interfere with the activity of Abecma. Therapeutic doses of corticosteroids should be avoided 72 hours prior to the start of lymphodepleting chemotherapy and following Abecma infusion except for the management of CRS, neurologic toxicities and other life-threatening emergencies (see section 4.4).

Clinical assessment prior to infusion

Abecma treatment should be delayed in some patient groups at risk (see section 4.4).

Monitoring after infusion

- Patients should be monitored for the first week following infusion at the qualified treatment centre for signs and symptoms of CRS, neurologic events and other toxicities.

- After the first week following infusion, the patient should be monitored at the physician's discretion.

- Patients should be instructed to remain within proximity (within 2 hours of travel) of the qualified treatment centre for at least 2 weeks following infusion.

Special populations

Patients with human immunodeficiency virus (HIV), hepatitis B virus (HBV) and hepatitis C virus (HCV) infection

There is no clinical experience in patients with active HIV, HBV or HCV infection. Screening for HBV, active HIV and active HCV must be performed before collection of cells for manufacturing. Leukapheresis material from patients with active HIV or active HCV infection will not be accepted for Abecma manufacturing (see section 4.4).

Elderly

No dose adjustment is required in patients over 65 years of age (see section 5.1).

Paediatric population

The safety and efficacy of Abecma in children and adolescents below 18 years of age have not been established. No data are available.

Method of administration

Abecma is for intravenous use only.

Administration

• Do NOT use a leukodepleting filter.

• Ensure that tocilizumab or suitable alternatives, in the exceptional case where tocilizumab is not available due to a shortage that is listed in the MHRA Central Alerting System, and emergency equipment are available prior to infusion and during the recovery period.

• Central venous access may be utilised for the infusion of Abecma and is encouraged in patients with poor peripheral access.

• Before administration, it must be confirmed that the patient's identity matches the unique patient information on the Abecma infusion bag and accompanying documentation. The total number of infusion bags to be administered must also be confirmed with the patient specific information on the release for infusion certificate (RfIC) (see section 4.4).

For detailed instructions on preparation, administration, measures to take in case of accidental exposure and disposal of Abecma, see section 6.6.

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Contraindications of the lymphodepleting chemotherapy must be considered.

4.4. Special warnings and precautions for use

Traceability

The traceability requirements of cell-based advanced therapy medicinal products must apply. To ensure traceability the name of the product, the batch number and the name of the treated patient must be kept for a period of 30 years after expiry date of the product.

Autologous use

Abecma is intended solely for autologous use and must not, under any circumstances, be administered to other patients. Abecma must not be administered if the information on the product labels and the release for infusion certificate (RfIC) do not match the patient's identity.

Rapidly progressing disease

Before selecting patients for Abecma treatment, physicians should consider the impact of high-risk cytogenetic abnormalities, Revised International Staging System (R-ISS) stage III, presence of extramedullary plasmacytoma or high tumour burden, particularly for patients who have rapidly progressing disease that may affect their ability to receive CAR T infusion in due time. For these patients, optimising bridging therapy may be particularly important. Some patients may not benefit from Abecma treatment due to potential increased risk of early death (see section 5.1).

Reasons to delay treatment

Due to the risks associated with Abecma treatment, infusion should be delayed up to 7 days if a patient has any of the following conditions:

• Unresolved serious adverse events (especially pulmonary events, cardiac events or hypotension) including those after preceding chemotherapies.

• Active infections or inflammatory disorders (including pneumonitis, myocarditis or hepatitis).

• Active graft-versus-host disease (GVHD).

Concomitant disease

Patients with active central nervous system (CNS) disorder or inadequate renal, hepatic, pulmonary or cardiac function are likely to be more vulnerable to the consequences of the adverse reactions described below and require special attention.

Central nervous system pathology

There is no experience of use of Abecma in patients with CNS involvement of myeloma or other pre-existing, clinically relevant CNS pathologies.

Prior allogeneic stem cell transplantation

It is not recommended that patients receive Abecma within 4 months after an allogeneic stem cell transplant (SCT) because of the potential risk of Abecma worsening GVHD. Leukapheresis for Abecma manufacturing should be performed at least 12 weeks after allogeneic SCT.

Prior treatment with an anti-BCMA therapy

There is limited experience with Abecma in patients exposed to prior BCMA directed therapy.

There is limited experience of retreating patients with a second dose of Abecma. Responses after Abecma retreatment were infrequent and less durable when compared to initial treatment.

Additionally, fatal outcomes were observed in retreated patients.

Cytokine release syndrome

CRS, including fatal or life-threatening reactions occurred following Abecma infusion. Nearly all patients experienced some degree of CRS. In clinical studies, the median time to onset of CRS was 1 day (range: 1 to 17) (see section 4.8).

Monitoring and management of CRS

CRS should be identified based on clinical presentation. Patients should be evaluated and treated for other causes of fever, hypoxia and hypotension. CRS has been reported to be associated with findings of haemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS) and the physiology of the syndromes may overlap. MAS is a potentially life-threatening condition, and patients should be closely monitored for evidence of MAS. Treatment of MAS should be administered per institutional guidelines.

One dose of tocilizumab per patient must be on-site and available for administration prior to Abecma infusion. The treatment centre must have access to an additional dose of tocilizumab within 8 hours of each previous dose. In the exceptional case where tocilizumab is not available due to a shortage that is listed in the MHRA Central Alerting System, the treatment centre must have access to suitable alternative measures instead of tocilizumab to treat CRS. Patients should be monitored for the first week following Abecma infusion at the qualified treatment centre for signs and symptoms of CRS. After the first week following infusion, the patient should be monitored at the physician's discretion. Patients should be counselled to remain within proximity (within 2 hours of travel) of the qualified treatment centre for at least 2 weeks following infusion. Patients and caregivers should be informed about the potential late onset of CRS and instructed to seek immediate medical attention if patients experience any signs or symptoms of CRS at any time.

At the first sign of CRS, treatment with supportive care, tocilizumab or tocilizumab and corticosteroids should be instituted, as indicated in Table 1. Abecma can continue to expand and persist following administration of tocilizumab and corticosteroids (see section 4.5).

Patients who experience CRS should be closely monitored for cardiac and organ functioning until resolution of symptoms. For severe or life-threatening CRS, intensive care unit level monitoring and supportive therapy should be considered.

If concurrent neurologic toxicity is suspected during CRS, the neurologic toxicity should be managed according to the recommendations in Table 2 and use the more aggressive intervention of the two reactions specified in Tables 1 and 2.

Earlier escalation (i.e. higher corticosteroid dose, alternative anticytokine agents, anti-T cell therapies) is recommended in patients with refractory CRS within 72 hours post Abecma infusion characterised by persistent fever, end‑organ toxicity (e.g. hypoxia, hypotension) and/or HLH/MAS not improving in grade within 12 hours of first line interventions.

Table 1. CRS grading and management guidance

CRS gradea

Tocilizumab

Corticosteroids

Grade 1

Symptoms require symptomatic treatment only (e.g. fever, nausea, fatigue, headache, myalgia, malaise).

If onset 72 hours or more after infusion, treat symptomatically.

If onset less than 72 hours after infusion and symptoms not controlled by supportive care alone, consider tocilizumab 8 mg/kg IV over 1 hour (not to exceed 800 mg).

─

Grade 2

Symptoms require and respond to moderate intervention.

Oxygen requirement less than 40% FiO2 or hypotension responsive to fluids or low dose of one vasopressor or Grade 2 organ toxicity.

Administer tocilizumab 8 mg/kg IV over 1 hour (not to exceed 800 mg).

Consider dexamethasone 10 mg IV every 12 to 24 hours.

Grade 3

Symptoms require and respond to aggressive intervention.

Fever, oxygen requirement greater than or equal to 40% FiO2 or hypotension requiring high-dose or multiple vasopressors or Grade 3 organ toxicity or Grade 4 transaminitis.

Administer tocilizumab 8 mg/kg IV over 1 hour (not to exceed 800 mg).

Administer dexamethasone (e.g. 10 mg IV every 12 hours).

For Grade 2 and 3:

If no improvement within 24 hours or rapid progression, repeat tocilizumab and escalate dose and frequency of dexamethasone (20 mg IV every 6 to 12 hours).

If no improvement within 24 hours or continued rapid progression, switch to methylprednisolone 2 mg/kg followed by 2 mg/kg divided 4 times per day.

If steroids are initiated, continue steroids for at least 3 doses, and taper over a maximum of 7 days.

After 2 doses of tocilizumab, consider alternative anticytokine agents.

Do not exceed 3 doses tocilizumab in 24 hours or 4 doses in total.

Grade 4

Life-threatening symptoms.

Requirements for ventilator support, continuous veno‑venous haemodialysis (CVVHD) or Grade 4 organ toxicity (excluding transaminitis).

Administer tocilizumab 8 mg/kg IV over 1 hour (not to exceed 800 mg).

Administer dexamethasone 20 mg IV every 6 hours.

For Grade 4:

After 2 doses of tocilizumab, consider alternative anticytokine agents. Do not exceed 3 doses of tocilizumab in 24 hours or 4 doses in total.

If no improvement within 24 hours, consider methylprednisolone (1 to 2 g, repeat every 24 hours if needed; taper as clinically indicated) or anti‑T cell therapies such as cyclophosphamide 1.5 g/m2 or others.

a Lee et al, 2014.

Neurologic adverse reactions

Neurologic toxicities, such as aphasia, encephalopathy and immune effector cell-associated neurotoxicity syndrome (ICANS), which may be severe or life-threatening, occurred following treatment with Abecma. The median time to onset of the first event of neurotoxicity was 3 days (range: 1 to 317 days; one patient developed encephalopathy at Day 317 as a result of worsening pneumonia and Clostridium difficile colitis). Grade 3 parkinsonism has also been reported, with delayed onset. Neurologic toxicity may occur concurrently with CRS, after CRS resolution or in the absence of CRS (see section 4.8).

Monitoring and management of neurologic toxicities

Patients should be monitored for the first week following Abecma infusion at the qualified treatment centre for signs and symptoms of neurologic toxicities. After the first week following infusion, the patient should be monitored at the physician's discretion. Patients should be counselled to remain within proximity (within 2 hours of travel) of the qualified treatment centre for at least 2 weeks following infusion. Patients and caregivers should be informed about the potential late onset of neurologic toxicities and instructed to seek immediate medical attention if patients experience any signs or symptoms of neurologic toxicities at any time.

If neurologic toxicity is suspected, manage according to the recommendations in Table 2. Other causes of neurologic symptoms should be ruled out. Intensive care supportive therapy should be provided for severe or life-threatening neurologic toxicities.

If concurrent CRS is suspected during the neurologic toxicity reaction, it should be managed according to the recommendations in Table 1 and the more aggressive intervention used for the two reactions specified in Tables 1 and 2.

Table 2. Neurologic toxicity including ICANS grading and management guidance

Neurologic toxicity grade including presenting symptomsa

Corticosteroids and antiseizure medications

Grade 1

Mild or asymptomatic.

ICE score 7-9b

or

Depressed level of consciousnessc: awakens spontaneously.

Start non-sedating, antiseizure medicines (e.g. levetiracetam) for seizure prophylaxis.

If 72 hours or more after infusion, observe patient.

If less than 72 hours after infusion, and symptoms not controlled by supportive care alone, consider dexamethasone 10 mg IV every 12 to 24 hours for 2 to 3 days.

Grade 2

Moderate.

ICE score 3-6b

or

Depressed level of consciousnessc: awakens to voice.

Start non-sedating, antiseizure medicines (e.g. levetiracetam) for seizure prophylaxis.

Start dexamethasone 10 mg IV every 12 hours for 2 to 3 days or longer for persistent symptoms. Consider taper for a total steroid exposure of greater than 3 days. Steroids are not recommended for isolated Grade 2 headaches.

If no improvement after 24 hours or worsening of neurologic toxicity, increase the dose and/or frequency of dexamethasone up to a maximum of 20 mg IV every 6 hours.

Grade 3

Severe or medically significant but not immediately life-threatening; hospitalisation or prolongation; disabling.

ICE score 0-2b

if ICE score is 0, but the patient is arousable (e.g., awake with global aphasia) and able to perform assessment.

or

Depressed level of consciousnessc: awakens only to tactile stimulus,

Or seizuresc, either:

• any clinical seizure, focal or generalised, that resolves rapidly, or

• non-convulsive seizures on EEG that resolve with intervention,

Or raised ICPc: focal/local oedema on neuroimaging.

Start non-sedating, antiseizure medicines (e.g. levetiracetam) for seizure prophylaxis.

Start dexamethasone 10 to 20 mg IV every 8 to 12 hours. Steroids are not recommended for isolated Grade 3 headaches.

If no improvement after 24 hours or worsening of neurologic toxicity, escalate to methylprednisolone (2 mg/kg loading dose, followed by 2 mg/kg divided into 4 times a day; taper within 7 days).

If cerebral oedema is suspected, consider hyperventilation and hyperosmolar therapy. Give high-dose methylprednisolone (1 to 2 g, repeat every 24 hours if needed; taper as clinically indicated) and cyclophosphamide 1.5 g/m2.

Grade 4

Life-threatening.

ICE scoreb 0

or

Depressed level of consciousnessc, either:

• patient is unarousable or requires vigorous or repetitive tactile stimuli to arouse, or

• stupor or coma,

Or seizuresc, either:

• life-threatening prolonged seizure (>5 min), or

• repetitive clinical or electrical seizures without return to baseline in between,

Or motor findingsc:

• deep focal motor weakness such as hemiparesis or paraparesis,

Or, raised ICP/cerebral oedemac, with signs/symptoms such as:

• diffuse cerebral oedema on neuroimaging, or

• decerebrate or decorticate posturing, or

• cranial nerve VI palsy, or

• papilledema, or

Cushing's triad.

Start non-sedating, antiseizure medicines (e.g. levetiracetam) for seizure prophylaxis.

Start dexamethasone 20 mg IV every 6 hours.

If no improvement after 24 hours or worsening of neurologic toxicity, escalate to high-dose methylprednisolone (1 to 2 g, repeated every 24 hours if needed; taper as clinically indicated). Consider cyclophosphamide 1.5 g/m2.

If cerebral oedema is suspected, consider hyperventilation and hyperosmolar therapy. Give high-dose methylprednisolone (1 to 2 g, repeat every 24 hours if needed; taper as clinically indicated) and cyclophosphamide 1.5 g/m2.

EEG = Electroencephalogram; ICE = Immune Effector Cell-Associated Encephalopathy; ICP = intracranial pressure

a Management is determined by the most severe event, not attributable to any other cause.

b If patient is arousable and able to perform ICE Assessment, assess: Orientation (oriented to year, month, city, hospital = 4 points); Naming (name 3 objects, e.g., point to clock, pen, button = 3 points); Following Commands (e.g., “show me 2 fingers” or “close your eyes and stick out your tongue” = 1 point); Writing (ability to write a standard sentence = 1 point); and Attention (count backwards from 100 by ten = 1 point). If patient is unarousable and unable to perform ICE Assessment (Grade 4 ICANS) = 0 points.

c Attributable to no other cause.

Prolonged cytopenias

Patients may exhibit prolonged cytopenias for several weeks following lymphodepleting chemotherapy and Abecma infusion (see section 4.8). Blood counts should be monitored prior to and after Abecma infusion. Cytopenias should be managed with myeloid growth factor and blood transfusion support according to institutional guidelines.

Infections and febrile neutropenia

Abecma should not be administered to patients with active infections or inflammatory disorders. Severe infections, including life-threatening or fatal infections, have occurred in patients after receiving Abecma (see section 4.8). Patients should be monitored for signs and symptoms of infection before and after Abecma infusion and treated appropriately. Prophylactic, pre-emptive and/or therapeutic antimicrobials should be administered according to institutional guidelines.

Febrile neutropenia was observed in patients after Abecma infusion (see section 4.8) and may be concurrent with CRS. In the event of febrile neutropenia, infection should be evaluated and managed with broad-spectrum antibiotics, fluids and other supportive care as medically indicated.

Viral reactivation

Cytomegalovirus (CMV) infection resulting in pneumonia and death have occurred following Abecma administration (see section 4.8). Patients should be monitored and treated for CMV infection according to clinical guidelines.

HBV reactivation, in some cases resulting in fulminant hepatitis, hepatic failure and death, can occur in patients treated with medicinal products directed against plasma cells (see section 4.8).

Screening for CMV, HBV, active HIV and active HCV must be performed before collection of cells for manufacturing (see section 4.2).

Reactivation of John Cunningham (JC) virus, leading to progressive multifocal leukoencephalopathy (PML), has been reported in patients treated with Abecma who have also received prior treatment with other immunosuppressive medications.

Hypogammaglobulinaemia

Plasma cell aplasia and hypogammaglobulinaemia can occur in patients receiving treatment with Abecma (see section 4.8). Immunoglobulin levels should be monitored after treatment with Abecma and managed per institutional guidelines including infection precautions, antibiotic or antiviral prophylaxis and immunoglobulin replacement.

Secondary malignancies including of T cell origin

Patients treated with Abecma may develop secondary malignancies. T cell malignancies have been reported following treatment of haematological malignancies with a BCMA- or CD19-directed CAR T cell therapy, including Abecma. T cell malignancies, including CAR-positive malignancies, have been reported within weeks and up to several years following administration of a CD19- or BCMA-, directed CAR T cell therapy. There have been fatal outcomes. Patients should be monitored life-long for secondary malignancies. In the event that a secondary malignancy of T cell origin occurs, the company should be contacted to obtain instructions on the collection of patient samples for testing.

Hypersensitivity reactions

Allergic reactions may occur with the infusion of Abecma. Serious hypersensitivity reactions, including anaphylaxis, may be due to dimethyl sulfoxide (DMSO), an excipient in Abecma. Patients not previously exposed to DMSO should be observed closely. Vital signs (blood pressure, heart rate, and oxygen saturation) and the occurrence of any symptom should be monitored prior to the start of the infusion, approximately every ten minutes during the infusion and every hour, for 3 hours, after the infusion.

Transmission of an infectious agent

Although Abecma is tested for sterility and mycoplasma, a risk of transmission of infectious agents exists. Healthcare professionals administering Abecma must, therefore, monitor patients for signs and symptoms of infections after treatment and treat appropriately, if needed.

Interference with virological testing

Due to limited and short spans of identical genetic information between the lentiviral vector used to create Abecma and HIV, some HIV nucleic acid tests (NAT) may give a false positive result.

Blood, organ, tissue and cell donation

Patients treated with Abecma must not donate blood, organs, tissues and cells for transplantation.

Long-term follow-up

Patients are expected to be enrolled in a registry in order to better understand the long-term safety and efficacy of Abecma.

Excipients

This medicinal product contains up to 33 mmol (752 mg) sodium per dose, equivalent to 37.6% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

This medicinal product contains up to 7 mmol (274 mg) potassium per dose. To be taken into consideration by patients with reduced kidney function or patients on a controlled potassium diet.

4.5. Interaction with other medicinal products and other forms of interaction

No interaction studies have been performed.

The co-administration of agents known to inhibit T cell function has not been formally studied. The co-administration of agents known to stimulate T cell function has not been investigated and the effects are unknown.

Tocilizumab or siltuximab and corticosteroid use

Some patients required tocilizumab or siltuximab and/or corticosteroid for the management of CRS (see section 4.8). The use of tocilizumab or siltuximab and/or corticosteroids for CRS management was more common in patients with higher cellular expansion.

In the KarMMa-3 study, patients with CRS treated with tocilizumab or siltuximab had higher Abecma cellular expansion levels, as measured by 3.1‑fold and 2.9‑fold higher median Cmax (N = 156) and AUC0-28days (N = 155), respectively, compared to patients who did not receive tocilizumab or siltuximab (N = 64 for Cmax and N = 63 for AUC0-28 days). Patients with CRS treated with corticosteroids had higher Abecma cellular expansion levels, as measured by 2.3‑fold and 2.4‑fold higher median Cmax (N = 60) and AUC0-28 days (N = 60), respectively, compared to patients who did not receive corticosteroids (N = 160 for Cmax and N = 158 for AUC0-28 days).

Similarly, in the KarMMa study, patients with CRS treated with tocilizumab had higher Abecma cellular expansion levels, as measured by 1.4-fold and 1.6-fold higher median Cmax (N = 66) and AUC0-28 days (N = 65), respectively, compared to patients who did not receive tocilizumab (N = 61 for Cmax and N = 60 for AUC0-28 days). Patients with CRS treated with corticosteroids had higher Abecma cellular expansion levels, as measured by 1.7-fold and 2.2-fold higher median Cmax (N = 18) and AUC0-28 days (N = 18), respectively, compared to patients who did not receive corticosteroids (N = 109 for Cmax and N = 107 for AUC0‑28 days).

Live vaccines

The safety of immunisation with live viral vaccines during or following treatment with Abecma has not been studied. As a precautionary measure, vaccination with live vaccines is not recommended for at least 6 weeks prior to the start of lymphodepleting chemotherapy, during Abecma treatment and until immune recovery following treatment.

4.6. Fertility, pregnancy and lactation

Women of childbearing potential/Contraception in males and females

Pregnancy status for women of childbearing potential should be verified using a pregnancy test prior to starting treatment with Abecma.

See the prescribing information for fludarabine and cyclophosphamide for information on the need for effective contraception in patients who receive the lymphodepleting chemotherapy.

There are insufficient exposure data to provide a recommendation concerning duration of contraception following treatment with Abecma.

Pregnancy

There are no data from the use of idecabtagene vicleucel in pregnant women. No animal reproductive and developmental toxicity studies have been conducted with idecabtagene vicleucel to assess whether it can cause foetal harm when administered to a pregnant woman (see section 5.3).

It is not known if idecabtagene vicleucel has the potential to be transferred to the foetus. Based on the mechanism of action, if the transduced cells cross the placenta, they may cause foetal toxicity, including plasma cell aplasia or hypogammaglobulinaemia. Therefore, Abecma is not recommended for women who are pregnant or for women of childbearing potential not using contraception. Pregnant women should be advised on the potential risks to the foetus. Pregnancy after Abecma therapy should be discussed with the treating physician.

Assessment of immunoglobulin levels in newborn infants of mothers treated with Abecma should be considered.

Breast-feeding

It is unknown whether idecabtagene vicleucel cells are excreted in human milk or transferred to the breast-feeding child. A risk to the breast-fed infant cannot be excluded. Women who are breast-feeding should be advised of the potential risk to the breast-fed child.

Fertility

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

4.7. Effects on ability to drive and use machines

Abecma may have major influence on the ability to drive and use machines.

Due to the potential for neurologic adverse reactions, including altered mental status or seizures with Abecma, patients receiving Abecma should refrain from driving or operating heavy or potentially dangerous machines for at least 4 weeks after Abecma infusion or longer until resolution of neurologic adverse reactions at the physician's discretion.

4.8. Undesirable effects

Summary of the safety profile

The safety data described in this section reflect the exposure to Abecma in the KarMMa, CRB‑401 and KarMMa-3 studies in which 409 patients with relapsed and refractory multiple myeloma received Abecma. In KarMMa (N = 128) and CRB-401 (N = 56), the median duration of follow-up (from Abecma infusion to data cutoff date) was 20.8 months. In KarMMa-3 (N = 225), the median duration of follow-up was 29.3 months.

The most common adverse reactions (≥ 20%) included CRS (84.6%), neutropenia (80.0%), anaemia (63.6%), thrombocytopenia (55.0%), infections ‑ pathogen unspecified (43.8%), hypophosphataemia (33.3%), diarrhoea (33.0%), leukopenia (32.8%), hypokalaemia (32.0%), fatigue (29.8%), nausea (28.1%), lymphopenia (26.9%), pyrexia (24.7%), infections ‑ viral (23.2%), headache (22.5%), hypocalcaemia (22.0%), hypomagnesaemia (21.3%), and arthralgia (20.0%); other common adverse events occurring at lower frequency and considered clinically important included hypotension (18.6%), upper respiratory tract infection (15.6%), hypogammaglobulinemia (13.7%), febrile neutropenia (11.2%), pneumonia (11.0%), tremor (5.6%), somnolence (5.6%), encephalopathy (3.4%), syncope (3.2%), and aphasia (2.9%).

Serious adverse reactions occurred in 57.2% of patients. The most common serious adverse reactions (≥ 5%) included CRS (10.3%), and pneumonia (7.1%); other serious adverse events occurring at lower frequency and considered clinically important include febrile neutropenia (4.2%), pyrexia (3.7%), neutropenia (2.7%), sepsis (2.7%), confusional state (2.4%), haemophagocytic lymphohistiocytosis (1.7%), thrombocytopenia (1.5%), encephalopathy (1.5%), dyspnoea (1.5%), seizure (1.0%), mental status changes (1.0%), hypoxia (0.7%) and disseminated intravascular coagulation (0.5%).

The most common Grade 3 or 4 adverse reactions (≥ 5%) were neutropenia (77.3%), anaemia (50.9%), thrombocytopenia (42.5%), leukopenia (31.5%), lymphopenia (25.9%), hypophosphataemia (19.8%), infections ‑ pathogen unspecified (15.2%), febrile neutropenia (10.5%), infections ‑ viral (7.6%), pneumonia (6.8%), hypertension (6.6%), hypocalcaemia (5.6%) and infections - bacterial (5.4%).

Grade 3 or 4 adverse reactions were more often observed within the initial 8 weeks post‑infusion (93.2%) compared to after 8 weeks post-infusion (58.1%). The most frequently reported Grade 3 or 4 adverse reactions reported within the first 8 weeks after infusion were neutropenia (75.8%), anaemia (47.4%), thrombocytopenia (38.6%), leukopenia (30.3%) lymphopenia (23.5%) and hypophosphataemia (18.3%).

Tabulated list of adverse reactions

Table 3 summarises the adverse reactions observed in the clinical studies of 409 patients treated with Abecma within the allowed dose range of 150 to 540 x 106 CAR-positive T cells (see Table 6 in section 5.1 for the corresponding dose range of CAR-positive viable T cells in KarMMa) and from post-marketing reports. Adverse reactions are presented by MedDRA system organ class and by frequency. Frequencies 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 (cannot be estimated from available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 3. Adverse reactions observed in patients treated with Abecma

System organ class

Adverse reaction

All grades frequency

Infections and infestationsa

Infections – bacterial

Infections – viral

Infections – pathogen unspecified

Infections – fungal

Very common

Very common

Very common

Common

Neoplasms benign, malignant and unspecified (including cysts and polyps)

Secondary malignancy of T cell origin

Rare

Blood and lymphatic system disorders

Neutropenia

Leukopenia

Thrombocytopenia

Febrile neutropenia

Lymphopenia

Anaemia

Disseminated intravascular coagulation

Very common

Very common

Very common

Very common

Very common

Very common

Common

Immune system disorders

Cytokine release syndrome

Hypogammaglobulinaemia

Haemophagocytic lymphohistiocytosis*

Very common

Very common

Common

Metabolism and nutrition disorders

Hypophosphataemia

Hypokalaemia

Hyponatraemia

Hypocalcaemia

Hypoalbuminaemia

Decreased appetite

Hypomagnesaemia

Very common

Very common

Very common

Very common

Very common

Very common

Very common

Psychiatric disorders

Insomnia

Deliriumb

Very Common

Common

Nervous system disorders

Encephalopathyc

Headache*

Dizzinessd

Aphasiae Ataxiaf

Motor dysfunctiong

Tremor

Seizure

Hemiparesis

Immune effector cell-associated neurotoxicity syndrome**

Very common

Very common

Very common

Common

Common

Common

Common

Common

Common

Uncommon

Uncommon

Cardiac disorders

Tachycardia*

Atrial fibrillation*

Very common

Common

Vascular disorders

Hypertension

Hypotension*h

Very common

Very common

Respiratory, thoracic, and mediastinal disorders

Dyspnoea

Cough

Pulmonary oedema

Hypoxia*

Very common

Very common

Common

Common

Gastrointestinal disorders

Vomiting

Diarrhoea

Nausea

Constipation

Gastrointestinal haemorrhagei

Very common

Very common

Very common

Very common

Common

Musculoskeletal and connective tissue disorders

Arthralgia

Myalgia

Very common

Common

General disorders and administration site conditions

Pyrexia*

Fatigue*j

Oedemak

Chills*

Asthenia

Very common

Very common

Very common

Very common

Common

Investigations

Alanine aminotransferase increased

Aspartate aminotransferase increased

Blood alkaline phosphatase increased

C-reactive protein increased*

Very common

Very common

Very common

Common

* Event that has been reported as a manifestation of CRS.

** Event was not systematically collected in clinical trials.

a Infections and infestations system organ class adverse events are grouped by pathogen type and selected clinical syndromes.

b Delirium includes delirium, disorientation, agitation, hallucination, restlessness.

c Encephalopathy includes amnesia, bradyphrenia, cognitive disorder, confusional state, depressed level of consciousness, disturbance in attention, dyscalculia, dysgraphia, encephalopathy, incoherent, lethargy, memory impairment, mental impairment, mental status changes, metabolic encephalopathy, neurotoxicity, somnolence, stupor.

d Dizziness includes dizziness, presyncope, syncope, vertigo.

e Aphasia includes aphasia, dysarthria, slow speech, and speech disorder.

f Ataxia includes ataxia, dysmetria, gait disturbance.

g Motor dysfunction includes motor dysfunction, muscular spasms, muscular weakness, parkinsonism.

h Hypotension includes hypotension, orthostatic hypotension.

i Gastrointestinal haemorrhage includes gastrointestinal haemorrhage, gingival bleeding, haematochezia, haemorrhoidal haemorrhage, melaena, mouth haemorrhage.

j Fatigue includes fatigue, malaise.

k Oedema includes oedema, oedema peripheral, face oedema, generalised oedema, peripheral swelling.

Description of selected adverse reactions

Cytokine release syndrome

In the pooled studies (KarMMa, CRB‑401 and KarMMa-3), CRS occurred in 84.6% of patients receiving Abecma. Grade 3 or higher CRS (Lee et al, 2014) occurred in 5.1% of patients, with fatal (Grade 5) CRS reported in 0.7% of patients. The median time-to-onset, any grade, was 1 day (range: 1 to 17) and the median duration of CRS was 4 days (range: 1 to 63).

The most common manifestations of CRS (≥ 10%) included pyrexia (82.6%), hypotension (29.1%), tachycardia (24.7%), chills (18.8%), hypoxia (15.9%), headache (11.2%) and increased C-reactive protein (10.5%). Grade 3 or higher events that may be observed in association with CRS included atrial fibrillation, capillary leak syndrome, hypotension, hypoxia and HLH/MAS.

Of the 409 patients, 59.7% of patients received tocilizumab; 37.2% received a single dose while 22.5% received more than 1 dose of tocilizumab for treatment of CRS. Overall, 22.7% of patients received at least 1 dose of corticosteroids for treatment of CRS. Of the 92 patients in KarMMa and CRB-401 who received the target dose of 450 x 106 CAR-positive T cells, 54.3% of patients received tocilizumab and 22.8% received at least 1 dose of corticosteroids for treatment of CRS. Of the 225 patients in KarMMa-3 who received Abecma infusion, 71.6% of patients received tocilizumab and 28.4% received at least 1 dose of corticosteroids for the treatment of CRS. See section 4.4 for monitoring and management guidance.

Neurologic adverse reactions including ICANS

In the pooled studies, of the 409 patients, independent of investigator attribution of neurotoxicity, the most frequent neurologic or psychiatric adverse reactions (≥ 5%) included headache (22.5%), dizziness (12.5%), confusional state (11.0%), insomnia (10.3%), anxiety (5.9%), tremor (5.6%), and somnolence (5.6%). Other neurological adverse reactions occurring at a lower frequency and considered clinically important included encephalopathy (3.4%) and aphasia (2.9%).

Neurotoxicity identified by the investigators, which was the primary method of assessing CAR T cell associated - neurotoxicity in the KarMMa and KarMMa-3 studies, occurred in 57 (16.1%) of the 353 patients receiving Abecma, including Grade 3 or 4 in 3.1% of patients (with no Grade 5 events). The median time to onset of the first event was 3 days (range: 1 to 317; one patient developed encephalopathy at Day 317 as a result of worsening pneumonia and Clostridium difficile colitis). The median duration was 3 days (range: 1 to 252; one patient developed neurotoxicity [highest Grade 3] 43 days after ide-cel infusion which resolved after 252 days). Overall, 7.1% of patients received at least 1 dose of corticosteroid for treatment of CAR T cell-associated neurotoxicity.

In KarMMa, across the target dose levels, 7.8% of patients received at least 1 dose of corticosteroid for treatment of CAR T cell-associated neurotoxicity, while at the target dose of 450 x 106 CAR-positive T cells, 14.8% of patients received at least 1 dose of corticosteroids.

In KarMMa-3, across all patients who received Abecma infusion at the target dose range, 6.7% of patients received at least 1 dose of corticosteroid for treatment of CAR T cell-associated neurotoxicity.

Of the 353 patients in the KarMMa and KarMMa-3 studies, the most common manifestations of investigator identified neurotoxicity (≥ 2%) included confusional state (8.5%), encephalopathy (3.4%), somnolence (2.8%), aphasia (2.5%), tremor (2.3%), disturbance in attention (2.0%) and dysgraphia (2.0%). See section 4.4 for monitoring and management guidance.

Febrile neutropenia and infections

In the pooled studies, infections occurred in 62.8% of patients. Grade 3 or 4 infections occurred in 23.2% of patients. Grade 3 or 4 infections with an unspecified pathogen occurred in 15.2%, viral infections in 7.6%, bacterial infections in 4.6% and fungal infections in 1.2% of patients. Fatal infections of unspecified pathogen were reported in 2.0% of patients, 0.7% of patients had fatal fungal or viral infection and 0.2% of patients had fatal bacterial infection. See section 4.4 for monitoring and management guidance.

Febrile neutropenia (Grade 3 or 4) was observed in 10.8% of patients after Abecma infusion. Febrile neutropenia may be concurrent with CRS. See section 4.4 for monitoring and management guidance.

Prolonged cytopenia

Patients may exhibit prolonged cytopenias following lymphodepleting chemotherapy and Abecma infusion. In the pooled studies, 38.2% of the 395 patients who had Grade 3 or 4 neutropenia and 71.3% of the 230 patients who had Grade 3 or 4 thrombocytopenia during the first month following Abecma infusion had not resolved by last assessment during the first month. Among the 151 patients with neutropenia not resolved by month 1, 88.7% recovered from Grade 3 or 4 neutropenia with a median time to recovery from Abecma infusion of 1.9 months. Of the 164 patients with thrombocytopenia not resolved by month 1, 79.9% recovered from Grade 3 or 4 thrombocytopenia with the median time to recovery of 2.0 months. See section 4.4 for monitoring and management guidance.

Hypogammaglobulinaemia

Hypogammaglobulinaemia was reported in 13.7% of patients treated with Abecma in the pooled studies with a median time to onset of 90 days (range 1 to 326). See section 4.4 for monitoring and management guidance.

Immunogenicity

Abecma has the potential to induce anti-CAR antibodies. In clinical studies, humoral immunogenicity of Abecma was measured by determination of anti-CAR antibody in serum pre- and post-administration. In the pooled studies of KarMMa, CRB-401 and KarMMa-3, 3.2% of patients tested positive for pre-infusion anti-CAR antibodies and post-infusion anti-CAR antibodies were detected in 56.2% of the patients. There is no evidence that the presence of pre-existing or post-infusion anti-CAR antibodies impact the cellular expansion, safety or effectiveness of Abecma.

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 Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

There are limited data regarding overdose with Abecma.