CARVYKTI is indicated for the treatment of adult patients with relapsed and refractory multiple myeloma, who have received at least one prior therapy, including an immunomodulatory agent and a proteasome inhibitor, have demonstrated disease progression on the last therapy, and are refractory to lenalidomide.

CARVYKTI must be administered in a qualified treatment centre.

Therapy should be initiated under the direction and supervision of a healthcare professional experienced in the treatment of haematological malignancies and trained for administration and management of patients treated with CARVYKTI.

Prior to infusion, the qualified treatment centre must have at least 1 dose of tocilizumab available for use in the event of cytokine release syndrome (CRS), with access to an additional dose within 8 hours of each previous dose (see section 4.4). In the exceptional case where tocilizumab is not available due to a shortage that is listed in the European Medicines Agency shortage catalogue, suitable alternative measures to treat CRS instead of tocilizumab must be available prior to infusion.

Emergency equipment must be available prior to infusion and during the recovery period.

Posology

CARVYKTI is intended for autologous use (see section 4.4).

Treatment consists of a single dose for infusion containing a dispersion of CAR-positive viable T cells in one infusion bag.

The target dose is 0.75 x 10⁶ CAR-positive viable T cells/kg of body weight (not exceeding 1 × 10⁸ CAR-positive viable T cells).

Patients 100 kg and below: 0.5 - 1 x 10⁶ CAR-positive viable T cells/kg body weight.

Patients above 100 kg: 0.5 - 1 x 10⁸ CAR-positive viable T cells (non-weight based).

See the accompanying Lot information sheet (LIS) for additional information pertaining to dose.

Bridging therapy

Consider bridging therapy according to prescriber’s choice prior to infusion with CARVYKTI to reduce tumour burden or stabilise the disease (see section 4.4).

Pre-treatment (lymphodepleting regimen)

Lymphodepleting regimen must be delayed if a patient has serious adverse reactions from preceding bridging therapies (including clinically significant active infection, cardiac toxicity, and pulmonary toxicity) (see section 5.1).

The availability of CARVYKTI should be confirmed prior to starting the lymphodepleting regimen.

A lymphodepleting regimen of cyclophosphamide 300 mg/m² intravenous and fludarabine 30 mg/m² intravenous should be administered daily for 3 days. CARVYKTI infusion should be administered 5 to 7 days after the start of the lymphodepleting regimen. If resolution of toxicities due to the lymphodepleting regimen to Grade 1 or lower takes more than 14 days, thereby resulting in delays to CARVYKTI dosing, the lymphodepleting regimen should be re-administered after a minimum of 21 days following the first dose of the first lymphodepleting regimen.

For dose modifications of cyclophosphamide and fludarabine, see corresponding Summaries of Product Characteristics of cyclophosphamide and fludarabine.

Premedication

The following pre-infusion medications should be administered to all patients 30 to 60 minutes prior to CARVYKTI infusion:

·             Antipyretic (oral or intravenous paracetamol 650 to 1,000 mg).

·             Antihistamine (oral or intravenous diphenhydramine 25 to 50 mg or equivalent).

The use of prophylactic systemic corticosteroids should be avoided as it may interfere with the activity of CARVYKTI.

Special populations

Elderly

No dose adjustment is required in patients ≥ 65 years of age.

Patients seropositive for hepatitis B virus (HBV), hepatitis C virus (HCV), or human immunodeficiency virus (HIV)

There is currently no experience with manufacturing CARVYKTI for patients testing positive for HIV, active HBV, or active HCV. Screening for HBV, HCV and HIV and other infectious agents must be performed before collection of cells for manufacturing.

Paediatric population

The safety and efficacy of CARVYKTI in children aged below 18 years of age have not been established.

No data are available.

Method of administration

CARVYKTI is for intravenous use only.

Do NOT use a leukodepleting filter.

Preparation of CARVYKTI for infusion

Prior to infusion and during the recovery period, the availability of tocilizumab, or suitable alternatives, in the exceptional case where tocilizumab is not available due to a shortage that is listed in the European Medicines Agency shortage catalogue, and emergency equipment must be ensured.

Before infusion, it must be confirmed that the patient’s identity matches the unique patient information on the CARVYKTI cryo cassette, infusion bag and on the Lot Information Sheet. (see section 4.4).

The medicinal product must not be thawed until it is ready to be used. The timing of CARVYKTI thaw and infusion should be coordinated; the infusion time should be confirmed in advance, and the start time for thaw must be adjusted so that CARVYKTI is available for infusion when the patient is ready. The medicinal product should be administered immediately after thawing and the infusion should be completed within 2.5 hours of thawing.

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

Traceability

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

General

Autologous use

CARVYKTI is intended solely for autologous use and must not, under any circumstances, be administered to other patients. CARVYKTI must not be infused if the information on the product labels and Lot Information Sheet does not match the patient’s identity.

Clinical assessment prior to CARVYKTI infusion

CARVYKTI infusion should be delayed if a patient has any of the following conditions:

·             clinically significant active infection or inflammatory disorders,

·             grade ≥ 3 non-haematologic toxicities of cyclophosphamide and fludarabine lymphodepletion regimen, except for Grade 3 nausea, vomiting, diarrhoea, or constipation. CARVYKTI infusion should be delayed until resolution of these events to Grade ≤ 1,

·             active graft versus host disease.

Patients with active or prior history of significant central nervous system (CNS) disease 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. There is no experience of use of CARVYKTI in patients with CNS involvement of myeloma or other pre-existing, clinically relevant CNS illnesses.

The efficacy/safety of CARVYKTI in patients previously exposed to other anti-BCMA treatments is unknown.

There is limited evidence available on efficacy/safety of CARVYKTI in re-treated patients.

Rapidly progressing disease

When considering patients for CARVYKTI treatment, physicians should assess the impact of rapidly progressing disease on the ability of patients to receive CAR-T infusion. Some patients may not benefit from CARVYKTI treatment due to potential increased risk of early death if disease progresses rapidly during bridging therapy.

Monitoring after infusion

Patients should be monitored daily for 14 days after the CARVYKTI infusion at a qualified clinical facility, and then periodically for an additional 2 weeks after CARVYKTI infusion, for signs and symptoms of CRS, neurologic events and other toxicities (see section 4.4).

Patients should be instructed to remain within proximity of a qualified clinical facility for at least 4 weeks following infusion.

Cytokine release syndrome

Cytokine release syndrome, including fatal or life-threatening reactions, can occur after CARVYKTI infusion.

Nearly all patients experienced CRS after CARVYKTI infusion, with majority of these being Grade 1 or Grade 2 (see section 4.8). The median time from CARVYKTI infusion (Day 1) to onset of CRS was 7 days (range: 1 to 23 days). Approximately 83% of patients experienced CRS onset after Day 3 of receiving the CARVYKTI infusion.

In almost all cases, duration of CRS ranged from 1 to 18 days (median duration, 4 days). Eighty‑nine percent of patients had a CRS duration of ≤ 7 days.

Clinical signs and symptoms of CRS may include, but are not limited to, fever (with or without rigors), chills, hypotension, hypoxia and elevated liver enzymes. Potentially life-threatening complications of CRS may include cardiac dysfunction, neurologic toxicity and haemophagocytic lymphohistiocytosis (HLH). Patients who develop HLH may have an increased risk of severe bleeding. Patients should be closely monitored for signs or symptoms of these events, including fever. Risk factors for severe CRS include high pre‑infusion tumour burden, active infection and early onset of fever or persistent fever after 24 hours of symptomatic treatment.

The infusion of CARVYKTI should be delayed if the patient has unresolved serious adverse reactions from preceding lymphodepleting or bridging therapies (including cardiac toxicity and pulmonary toxicity), rapid disease progression and clinically significant active infection (see section 4.2). Appropriate prophylactic and therapeutic treatment for infections should be provided, and complete resolution of any active infections should be ensured prior to CARVYKTI infusion. Infections may also occur concurrently with CRS and may increase the risk of a fatal event.

The availability of at least one dose of tocilizumab for use in the event of CRS should be ensured prior to infusion. The qualified 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 European Medicines Agency shortage catalogue, the treatment centre must have access to suitable alternative measures instead of tocilizumab to treat CRS. Patients should be monitored for signs and symptoms of CRS daily for 14 days after the CARVYKTI infusion at a qualified clinical facility, and then periodically for an additional two weeks after CARVYKTI infusion.

Patients should be counselled to seek immediate medical attention should signs or symptoms of CRS occur at any time. At the first sign of CRS, the patient should be immediately evaluated for hospitalisation and treatment with supportive care, tocilizumab, or tocilizumab and corticosteroids should be instituted as indicated in Table 1 below.

Evaluation for HLH should be considered in patients with severe or unresponsive CRS. For patients with high pre-infusion tumour burden, early onset of fever, or persistent fever after 24 hours, early tocilizumab should be considered. The use of myeloid growth factors, particularly granulocyte macrophage-colony stimulating factor (GM-CSF), should be avoided during CRS. Consider reducing baseline burden of disease with bridging therapy prior to infusion with CARVYKTI in patients with high tumour burden (see section 4.2).

Management of cytokine release syndrome associated with CARVYKTI

If CRS is suspected, manage according to the recommendations in Table 1. Supportive care for CRS (including but not limited to anti-pyretic agents, IV fluid support, vasopressors, 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. Other monoclonal antibodies targeting cytokines (for example, anti-IL1 and/or anti-TNFα), or therapy directed at reduction and elimination of CAR-T cells, may be considered for patients who develop high grade CRS and HLH that remain severe or life-threatening following prior administration of tocilizumab and corticosteroids.

If concurrent neurologic toxicity is suspected during CRS, administer:

·             Corticosteroids according to the more aggressive intervention based on the CRS and neurologic toxicity grades in Tables 1 and 2,

·             Tocilizumab according to the CRS grade in Table 1,

·             Anti-seizure medication according to the neurologic toxicity in Table 2.

Neurologic toxicities

Neurologic toxicities occur frequently following treatment with CARVYKTI and can be fatal or life‑threatening (see section 4.8). Neurologic toxicities included ICANS, movement and neurocognitive toxicity (MNT) with signs and symptoms of parkinsonism, Guillain-Barré syndrome, peripheral neuropathies and cranial nerve palsies. Patients should be counselled on the signs and symptoms of these neurologic toxicities, and on the delayed nature of onset of some of these toxicities. Patients should be instructed to seek immediate medical attention for further assessment and management if signs or symptoms of any of these neurologic toxicities occur at any time.

Immune effector cell-associated neurotoxicity syndrome (ICANS)

Patients receiving CARVYKTI may experience fatal or life-threatening ICANS following treatment with CARVYKTI, including before CRS onset, concurrent with CRS, following resolution of CRS or in the absence of CRS. Symptoms included aphasia, slow speech, dysgraphia, encephalopathy, depressed level of consciousness and confusional state.

Reduction of baseline burden of disease with bridging therapy prior to infusion with CARVYKTI in patients with high tumour burden should be considered, which may mitigate the risk of developing neurologic toxicity (see section 4.8). Patients should be monitored for signs or symptoms of ICANS for four weeks after infusion. At the first sign of ICANS, the patient should be immediately evaluated for hospitalisation and treatment instituted with supportive care as indicated in Table 2 below. Early detection and aggressive treatment of CRS or ICANS may be important to prevent neurologic toxicity from occurring or worsening. Continue to monitor patients for signs and symptoms of neurologic toxicities after recovery from CRS and/or ICANS.

Management of neurologic toxicity associated with CARVYKTI

At the first sign of neurologic toxicity including ICANS, neurology evaluation should be considered. Rule out other causes of neurologic symptoms. Provide intensive care and supportive therapy for severe or life-threatening neurologic toxicities.

If concurrent CRS is suspected during the neurologic toxicity event, administer:

·             Corticosteroids according to the more aggressive intervention based on the CRS and neurologic toxicity grades in Tables 1 and 2,

·             Tocilizumab according to CRS grade in Table 1,

·             Anti-seizure medication according to neurologic toxicity in Table 2.

Movement and neurocognitive toxicity with signs and symptoms of parkinsonism

Neurologic toxicity of movement and neurocognitive toxicity with signs and symptoms of parkinsonism has been reported in trials of CARVYKTI. A cluster of symptoms with variable onset spanning more than one symptom domain was observed, including movement (e.g., micrographia, tremor, bradykinesia, rigidity, stooped posture, shuffling gait), cognitive (e.g., memory loss, disturbance in attention, confusion), and personality change (e.g., reduced facial expression, flat affect, masked facies, apathy), often with subtle onset (e.g., micrographia, flat affect), that in some patients progressed to an inability to work or care for oneself. Most of these patients presented a combination of two or more factors such as high tumour burden at baseline (bone marrow plasma cell ≥80% or serum M-spike ≥ 5 g/dL or serum free light chain ≥ 5,000 mg/L), prior Grade 2 or higher CRS, prior ICANS, and high CAR-T cell expansion and persistence. Treatment with levodopa/carbidopa (n=4), was not effective in improving symptomatology in these patients.

Patients should be monitored for signs and symptoms of parkinsonism that may be delayed in onset and managed with supportive care measures.

Guillain-Barré syndrome

Guillain-Barré syndrome (GBS) has been reported after treatment with CARVYKTI. Symptoms reported include those consistent with Miller-Fisher variant of GBS, motor weakness, speech disturbances, and polyradiculoneuritis (see section 4.8).

Patients should be monitored for GBS. Patients presenting with peripheral neuropathy should be evaluated for GBS. Treatment with intravenous immunoglobulin (IVIG) and escalation to plasmapheresis should be considered, depending on toxicity severity.

Peripheral neuropathy

Occurrence of peripheral neuropathy, including sensory, motor, or sensorimotor, have been reported in trials of CARVYKTI.

Patients should be monitored for signs and symptoms of peripheral neuropathies. Management with short-course systemic corticosteroids should be considered, depending on the severity and progression of signs and symptoms.

Cranial nerve palsies

Occurrence of 7^th, 3^rd, 5^th, and 6^th cranial nerve palsy, some of which were bilateral, worsening of cranial nerve palsy after improvement, and occurrence of peripheral neuropathy in patients with cranial nerve palsy have been reported in trials of CARVYKTI.

Patients should be monitored for signs and symptoms of cranial nerve palsies. Management with short-course systemic corticosteroids should be considered, depending on the severity and progression of signs and symptoms.

Prolonged and recurrent cytopenias

Patients may exhibit cytopenias for several weeks following lymphodepleting chemotherapy and CARVYKTI infusion and should be managed according to local guidelines. In trials of CARVYKTI, nearly all patients had one or more Grade 3 or 4 cytopenic adverse reactions. Most patients had a median time from infusion to first onset of Grade 3 or 4 cytopenia of less than two weeks with the majority of patients recovering to Grade 2 or lower by Day 30 (see section 4.8).

Blood counts should be monitored prior to and after CARVYKTI infusion. For thrombocytopenia, supportive care with transfusions should be considered. Prolonged neutropenia has been associated with increased risk of infection. Myeloid growth factors, particularly GM-CSF, have the potential to worsen CRS symptoms and are not recommended during the first 3 weeks after CARVYKTI or until CRS has resolved.

Serious infections and febrile neutropenia

Serious infections, including life-threatening or fatal infections, occurred in patients after CARVYKTI infusion (see section 4.8).

Patients should be monitored for signs and symptoms of infection prior to and during treatment with CARVYKTI and treated appropriately. Prophylactic antimicrobials should be administered according to local guidelines. Infections are known to complicate the course and management of concurrent CRS. Patients with clinically significant active infection should not start CARVYKTI treatment until the infection is controlled.

In the event of febrile neutropenia, infection should be evaluated and managed appropriately with broad‑spectrum antibiotics, fluids and other supportive care, as medically indicated.

Patients treated with CARVYKTI may be at an increased risk of severe/fatal COVID-19 infections. Patients should be counselled on the importance of prevention measures.

Viral reactivation

HBV reactivation, in some cases resulting in fulminant hepatitis, hepatic failure and death, can occur in patients treated with medicinal products directed against B cells.

There is currently no experience with manufacturing CARVYKTI for patients testing positive for HIV, active HBV, or active HCV. Screening for HBV, HCV and HIV and other infectious agents must be performed before collection of cells for manufacturing (see section 4.2).

Hypogammaglobulinaemia

Hypogammaglobulinaemia may occur in patients receiving CARVYKTI.

Immunoglobulin levels should be monitored after treatment with CARVYKTI; IVIG should be administered for IgG <400 mg/dL. Manage according to standard guidelines, including antibiotic or antiviral prophylaxis and monitoring for infection.

Secondary malignancies including of T-cell origin

Patients treated with CARVYKTI 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 CARVYKTI. T-cell malignancies, including CAR-positive malignancies, have been reported within weeks and up to several years following administration of a CD19- or BMCA-, directed CAR T-cell therapy. There have been fatal outcomes.

Patients should be monitored life-long for secondary malignancies. In the event a secondary malignancy occurs, the company should be contacted to obtain instructions on patient samples to collect for testing.

Interference with virological testing

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

Blood, organ, tissue and cell donation

Patients treated with CARVYKTI should not donate blood, organs, tissues and cells for transplantation. This information is provided in the Patient Alert Card which should be given to the patient.

Hypersensitivity

Allergic reactions may occur with infusion of CARVYKTI. Serious hypersensitivity reactions, including anaphylaxis, may occur due to the dimethyl sulfoxide (DMSO) or residual kanamycin in CARVYKTI. Patients should be carefully monitored for 2 hours after infusion for signs and symptoms of severe reaction. Treat promptly and manage patients appropriately according to the severity of the hypersensitivity reaction.

Long-term follow-up

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

No pharmacokinetic or pharmacodynamic drug interaction studies have been performed with CARVYKTI.

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.

Some patients in the clinical trials on CARVYKTI required tocilizumab, corticosteroids and anakinra for management of CRS. CARVYKTI continues to expand and persist following tocilizumab administration. In Study MMY2001, patients treated with tocilizumab (n=68) had 81% and 72% higher CARVYKTI C_max and AUC_0-28d, respectively, as compared to patients (n=29) who did not receive tocilizumab. Patients who received corticosteroids (n=28) had 75% and 112% higher C_max and AUC_0-28d, respectively, compared with patients who did not receive corticosteroids (n=69). In addition, patients who received anakinra (n=20) had 41% and 72% higher C_max and AUC_0-28d, respectively, compared with patients who did not receive anakinra (n=77). In Study MMY3002, the results related to tocilizumab and corticosteroid were consistent with Study MMY2001.

Live vaccines

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

Women of childbearing potential/Contraception in males and females

Pregnancy status for females of childbearing potential should be verified prior to starting treatment with CARVYKTI.

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

In clinical trials, female patients of childbearing potential were advised to practice a highly effective method of contraception, and male patients with partners of childbearing potential or whose partners were pregnant were instructed to use a barrier method of contraception, until one year after the patient has received CARVYKTI.

See the prescribing information for lymphodepleting chemotherapy for information on the need for contraception in patients who receive the lymphodepleting chemotherapy.

Pregnancy

There are no available data on the use of CARVYKTI in pregnant women. No reproductive and developmental toxicity animal studies have been conducted with CARVYKTI. It is not known whether CARVYKTI has the potential to be transferred to the foetus and cause foetal toxicity.

Therefore, CARVYKTI is not recommended for women who are pregnant, or for women of childbearing potential not using contraception. Pregnant women should be advised there may be risks to the foetus. Pregnancy after CARVYKTI therapy should be discussed with the treating physician.

Pregnant women who have received CARVYKTI may have hypogammaglobulinaemia. Assessment of immunoglobulin levels in newborns of mothers treated with CARVYKTI should be considered.

Breast-feeding

It is unknown whether CARVYKTI is excreted in human milk. Women who are breast-feeding should be advised of the potential risk to the breast-fed infant.

Following administration of CARVYKTI, the decision to consider breast-feeding should be discussed with the treating physician.

Fertility

There are no data on the effect of CARVYKTI on fertility. Effects of CARVYKTI on male and female fertility have not been evaluated in animal studies (see section 5.3).

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

Due to the potential for neurologic events, patients receiving CARVYKTI are at risk for altered or decreased consciousness or coordination in the 8 weeks following CARVYKTI infusion (see section 4.4). Patients should be advised to refrain from driving and engaging in hazardous occupations or activities, such as operating heavy or potentially dangerous machinery during this initial period, and in the event of new onset of any neurological symptoms.

Summary of the safety profile

The safety of CARVYKTI was evaluated in 396 adult patients with multiple myeloma infused with CARVYKTI in three open label clinical trials: Study MMY2001 (N=106), which included patients from the main Phase 1b/2 cohort (United States; n=97) and an additional cohort (Japan; n=9), Phase 2 Study MMY2003 (N=94) and Phase 3 Study MMY3002 (N=196).

The most common CARVYKTI adverse reactions (≥20%) were neutropenia (89%), pyrexia (84%), CRS (83%), thrombocytopenia (60%), anemia (60%), musculoskeletal pain (38%), fatigue (35%), lymphopenia (34%), leukopenia (33%), hypotension (33%), diarrhea (31%), upper respiratory tract infection (30%), hypogammaglobulinaemia (29%), transaminase elevation (25%), headache (24%), nausea (23%), and cough (21%).

Serious adverse reactions occurred in 41% of patients; serious adverse reactions reported in ≥2% of patients were CRS (11%), pneumonia (7%), sepsis (5%), viral infection (4%), neutropenia (4%), cranial nerve palsies, (4%), ICANS (4%), encephalopathy (3%), bacterial infections (2%), upper respiratory tract infection (2%), gastroenteritis (2%), febrile neutropenia (2%), thrombocytopenia (2%), haemophagocytic lymphohistiocytosis (2%), motor dysfunction (2%), dyspnea (2%), diarrhea (2%), and renal failure (2%).

The most common (≥5%) Grade ≥ 3 non-haematological adverse reactions were transaminase elevation (11%), pneumonia (9%), febrile neutropenia (8%), sepsis (7%), Gamma-glutamyltransferase increased (6%), hypotension (6%), pyrexia (6%), bacterial infection (5%), and hypogammaglobulinaemia (5%).

The most common (≥20%) Grade ≥3 haematological abnormalities were neutropenia (88%), thrombocytopenia (44%), anaemia (44%), lymphopenia (33%), and leukopenia (32%).

Tabulated list of adverse reactions

Table 4 summarises the adverse reactions that occurred in patients receiving CARVYKTI.

Within each system organ class, the adverse reactions are ranked by frequency. Within each frequency grouping, where relevant, adverse reactions are presented in order of decreasing seriousness using the following convention: 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); not known (cannot be estimated from the available data).

Of the 196 patients in Study MMY3002, 20 patients who had higher risk disease progressed early and rapidly on bridging therapy prior to infusion with CARVYKTI and received CARVYKTI as subsequent therapy (see section 5.1). In these patients, MNT was reported in one patient (5%) and was mild in severity (Grade 1 or 2). CRS was reported at a higher rate for Grade 3 and Grade 4 (25%), including events of CRS complicated by HLH (10%) or DIC (10%). ICANS was reported at a higher rate (35%) and severity (10%) for Grade 3. Five patients died of fatal events related to CARVYKTI (2 due to haemorrhage in the context of HLH or DIC and 3 due to fatal infections).

Description of selected adverse reactions

Cytokine release syndrome

CRS was reported in 83% of patients (n=330); 79% (n=314) of patients had CRS events that were Grade 1 or Grade 2, 4% (n=15) of patients had Grade 3 or Grade 4 CRS events and <1% (n=1) of patients had a Grade 5 CRS event. Ninety-eight percent of patients (n=323) recovered from CRS. The duration of CRS was ≤18 days for all but one patient, who had a duration of CRS of 97 days, complicated by secondary HLH with a subsequent fatal outcome. The most frequent (≥10%) signs or symptoms associated with CRS included pyrexia (81%), hypotension (28%), Aspartate aminotransferase (AST) increased (12%), and hypoxia (10%). See section 4.4 for monitoring and management guidance.

Neurologic toxicities

Neurologic toxicity occurred in 23% of patients (n=89); 5% (n=21) of patients had Grade 3 or Grade 4 neurologic toxicity and 1% (n=3) of patients had Grade 5 neurologic toxicity (one due to ICANS, one due to neurologic toxicity with ongoing parkinsonism, and one due to encephalopathy). In addition, eleven patients had fatal outcomes with ongoing neurologic toxicity at the time of death; eight deaths were due to infection (including two deaths in patients with ongoing signs and symptoms of parkinsonism, as discussed below), and one death each due to respiratory failure, cardio-respiratory arrest and intraparenchymal hemorrhage. See section 4.4 for monitoring and management guidance.

Immune effector cell-associated neurotoxicity syndrome (ICANS)

In the pooled studies (N=396), ICANS occurred in 11% of patients (n=45), with 2% (n=7) experiencing Grade 3 or 4 ICANS and <1% (n=1) Grade 5 ICANS. Symptoms included aphasia, slow speech, dysgraphia, encephalopathy, depressed level of consciousness and confusional state. The median time from CARVYKTI infusion to first onset of ICANS was 8 days (range: 2 to 15 days, except for 1 patient with onset at 26 days) and the median duration was 3 days (range: 1 to 29 days, except for 1 patient who had a subsequent fatal outcome at 40 days).

Movement and neurocognitive toxicity with signs and symptoms of parkinsonism

Of the 89 patients in the pooled studies (N=396) experiencing any neurotoxicity, nine male patients had neurologic toxicity with several signs and symptoms of parkinsonism, distinct from ICANS. The maximum toxicity grades of parkinsonism were: Grade 1 (n=1), Grade 2 (n=2), Grade 3 (n=6). The median onset of parkinsonism was 38.0 days (range: 14 to 914 days) from infusion of CARVYKTI. One patient (Grade 3) died of neurologic toxicity with ongoing parkinsonism 247 days after administration of CARVYKTI, and two patients (Grade 2 and Grade 3) with ongoing parkinsonism died of infectious causes 162 and 119 days after administration of CARVYKTI. One patient recovered (Grade 3). The remaining 5 patients, symptoms of parkinsonism were ongoing up to 996 days after administration of CARVYKTI. All 9 patients had a history of prior CRS (n=1 Grade 1; n=6 Grade 2; n=1 Grade 3; n=1 Grade 4), while 6 of 9 patients had prior ICANS (n=5 Grade 1; n=1 Grade 3).

Guillain-Barré syndrome

In the pooled studies (N=396), one patient was reported to have GBS after treatment with CARVYKTI. Although GBS symptoms improved after receiving treatment with steroids and IVIG, the patient died 139 days after administration of CARVYKTI due to encephalopathy post gastroenteritis with ongoing GBS symptoms.

Peripheral neuropathy

In the pooled studies (N=396), 27 patients developed peripheral neuropathy, presenting as sensory, motor, or sensorimotor neuropathies. Median time of onset of symptoms was 57 days (range: 1 to 914 days), median duration of peripheral neuropathies was 140 days (range: 1 to 766 days) including those with ongoing neuropathy. Of these 27 patients, 5 experienced Grade 3 or Grade 4 peripheral neuropathy (which resolved in 1 patient with no treatment reported, and was ongoing in the other 4 patients, including one patient who improved after treatment with dexamethasone). Of the remaining 22 with ≤ Grade 2 peripheral neuropathy, peripheral neuropathy resolved with no treatment reported in 6 patients and following treatment with duloxetine in 2 patients, and was ongoing in the other 10 patients.

Cranial nerve palsies

In the pooled studies (N=396), 27 patients experienced cranial nerve palsies. Median time to onset was 22 days (range: 17 to 101 days) following infusion of CARVYKTI, and median time to resolution was 56 days (range: 1 to 209 days) following onset of symptoms.

Prolonged and recurrent cytopenias

Grade 3 or 4 cytopenias at Day 1 after dosing, not resolved to Grade 2 or lower by Day 30 following CARVYKTI infusion, included, thrombocytopenia (33%), neutropenia (29%), lymphopenia (25%), and anemia (3%). After Day 60 following CARVYKTI, 23%, 21%, 7%, and 4% of patients had an occurrence of Grade 3 or 4 lymphopenia, neutropenia, anemia, and thrombocytopenia respectively, after initial recovery of their Grade 3 or 4 cytopenia.

Table 5 lists the incidences of Grade 3 or Grade 4 cytopenias occurring after dosing not resolved to Grade 2 or lower by Day 30 and Day 60, respectively.

Serious infections

Infections occurred in 52% of patients (n=206); 17% of patients (n=66) experienced Grade 3 or Grade 4 infections, and fatal infections (COVID-19 pneumonia, pneumonia, sepsis, Clostridium difficile colitis, septic shock, bronchopulmonary aspergillosis, pseudomonal sepsis, neutropenic sepsis, and lung abscess) occurred in 4% of patients (n=17). The most frequently reported (≥ 2%) Grade 3 or higher infections were pneumonia, COVID-19 pneumonia, and sepsis. Febrile neutropenia was observed in 6% of patients with 2% experiencing serious febrile neutropenia.

See section 4.4 for monitoring and management guidance.

Hypogammaglobulinaemia

In the pooled studies (N=396), hypogammaglobulinaemia occurred in 30% of patients, with 5% of patients experiencing Grade 3 hypogammaglobulinaemia. Laboratory IgG levels fell below 500 mg/dL after infusion in 91% (359/396) of patients treated with CARVYKTI. Hypogammaglobulinaemia either as an adverse reaction or a laboratory IgG level below 500 mg/dL occurred in 92% (363/396) of patients after infusion. Fifty-three percent of patients received IVIG post CARVYKTI for either an adverse reaction or prophylaxis. See section 4.4 for monitoring and management guidance.

Immunogenicity

The immunogenicity of CARVYKTI has been evaluated using a validated assay for the detection of binding antibodies against CARVYKTI pre-dose, and at multiple timepoints post-infusion. In the pooled studies (n=363), 23% (83/363) of patients with appropriate samples were positive for treatment-emergent anti-CAR antibodies. There was no clear evidence that the observed anti-CAR antibodies impact CARVYKTI kinetics of initial expansion and persistence, efficacy or safety.

4.8.2: Clinical Studies Experience

Additional adverse reactions from Study MMY2001 (based on USA cohort, N=97) added upon the request from the Saudi Food and Drug Authority include chest pain (7%), tremor (6%), hypersensitivity reactions (5%), depression (4.1%), fall (3.1%), diplopia (1%), dysphagia (1%), tumor lysis syndrome (1%), seizure (1%), nystagmus (1%), and cerebrovascular accident (1%)

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 national reporting system listed in Appendix V.

To report any side effect(s):

        Saudi Arabia:

·       The National Pharmacovigilance Centre (NPC):

-       SFDA Call Center: 19999

-       E-mail: npc.drug@sfda.gov.sa

Website: https://ade.sfda.gov.sa/

       Other GCC States:

-       Please contact the relevant competent authority.

There are no data regarding the signs or sequelae of overdose with CARVYKTI.

Pharmacotherapeutic group: Antineoplastic agents, other antineoplastic agents, ATC code: L01XL05

Mechanism of action

CARVYKTI is a BCMA-directed, genetically modified autologous T cell immunotherapy, which involves reprogramming a patient’s own T cells with a transgene encoding a chimeric antigen receptor (CAR) that identifies and eliminates cells that express BCMA. BCMA is primarily expressed on the surface of malignant multiple myeloma B-lineage cells, as well as late-stage B cells and plasma cells. The CARVYKTI CAR protein features two BCMA-targeting single domain antibodies designed to confer high avidity against human BCMA, a 4-1BB co-stimulatory domain and a CD3‑zeta (CD3ζ) signaling cytoplasmic domain. Upon binding to BCMA expressing cells, the CAR promotes T cell activation, expansion, and elimination of target cells.

Pharmacodynamic effects

In vitro co-culture experiments demonstrated that ciltacabtagene autoleucel-mediated cytotoxicity and cytokine release (interferon-gamma, [IFN-γ], tumour necrosis factor alpha [TNF-α], interleukin [IL]-2) were BCMA-dependent.

Clinical efficacy and safety

CARTITUDE-1 (Study MMY2001)

MMY2001 was an open label, single-arm, multicentre, Phase 1b/2 study evaluating the efficacy and safety of CARVYKTI for the treatment of adult patients with relapsed and refractory multiple myeloma who had received at least 3 prior lines of antimyeloma therapies, including a proteasome inhibitor, an immunomodulatory agent and an anti-CD38 antibody and who had disease progression on or within 12 months after the last regimen. Patients with known active, or prior history of significant central nervous system (CNS) disease including CNS multiple myeloma, patients previously exposed to other anti-BCMA treatments, allogeneic stem cell transplant within 6 months before apheresis or ongoing treatment with immunosuppressants, creatinine clearance < 40 mL/min, absolute lymphocyte concentration < 300/µL, hepatic transaminases > 3 times the upper limit of normal, cardiac ejection fraction < 45%, or with active serious infection were excluded from the trial.

In total, 113 patients underwent leukapheresis; CARVYKTI was manufactured for all patients. Sixteen patients were not treated with CARVYKTI (n=12 after leukapheresis and n=4 after lymphodepleting therapy), due to either withdrawal by patient (n=5), progressive disease (n=2) or death (n=9).

Of the 97 patients treated, the median time from the day after receipt of leukapheresis material at manufacturing facility to release of medicinal product for infusion was 29 days (range: 23 to 64 days) and the median time from initial leukapheresis to CARVYKTI infusion was 47 days (range: 41 to 167 days).

Following leukapheresis and prior to administration of CARVYKTI, 73 of the 97 patients (75%) received bridging therapy. The most commonly used agents as bridging therapies (≥20% of patients) included dexamethasone: 62 patients (63.9%), bortezomib: 26 patients (26.8%), cyclophosphamide: 22 patients (22.7%), and pomalidomide: 21 patients (21.6%).

CARVYKTI was administered as a single IV infusion 5 to 7 days after the start of a lymphodepleting chemotherapy (cyclophosphamide 300 mg/m² intravenously daily and fludarabine 30 mg/m² intravenously daily for 3 days). Ninety-seven patients received CARVYKTI at a median dose of 0.71 × 10⁶ CAR-positive viable T cells/kg (range: 0.51 to 0.95 × 10⁶ cells/kg). All patients were hospitalised for the CARVYKTI infusion and for a minimum of 10 days afterward.

Efficacy results were based on overall response rate as determined by the Independent Review Committee assessment using IMWG criteria (see Table 7).

CARTITUDE-4 (Study MMY3002)

MMY3002 is a Phase 3 randomised, open label, multicentre trial evaluating the efficacy of CARVYKTI for the treatment of patients with relapsed and lenalidomide-refractory multiple myeloma, who previously received at least 1 prior line of therapy including a proteasome inhibitor and an immunomodulatory agent. A total of 419 patients were randomised to received either a sequence of apheresis, bridging therapy, lymphodepletion and CARVYKTI (n=208) or standard of care which included physician’s choice of daratumumab, pomalidomide and dexamethasone or bortezomib, pomalidomide and dexamethasone (n=211).

The trial excluded patients with known active or prior history of central nervous system involvement, clinical signs of meningeal involvement of multiple myeloma, a history of Parkinson’s disease or other neurodegenerative disorder, previous exposure to other anti‑BCMA treatments or CAR‑T cell therapy directed at any target, allogenic stem cell transplant within 6 months before apheresis or ongoing treatment with immunosuppressants, or autologous stem cell transplant within 12 weeks before apheresis.

Of the 419 patients who were randomised (208 to CARVYKTI and 211 to standard of care), 57% were male, 75% were caucasian, 3% were black or african-american, and 7% were hispanic or latino. The median patient age was 61 years (range: 28 to 80 years). Patients had received a median of 2 (range: 1 to 3) prior lines of therapy and 85% of patients had received prior autologous stem cell transplantation (ASCT). Ninety-nine percent of patients were refractory to their last line of prior therapy. Forty-eight percent were refractory to a proteasome inhibitor (PI) and 100% were refractory to an immunomodulatory agent.

All 208 patients randomised to the CARVYKTI arm underwent apheresis. Following apheresis and prior to administration of CARVYKTI, all 208 randomised patients received protocol‑mandated bridging therapy (standard of care). Of these 208 patients, 12 were not treated with CARVYKTI due to progressive disease (n=10) or death (n=2), and 20 progressed prior to infusion with CARVYKTI but were able to receive CARVYKTI as subsequent therapy.

In the 176 patients that received CARVYKTI as study treatment, the median time from the day after receipt of apheresis material at manufacturing facility to release of product for infusion was 44 days (range: 25 to 127 days) and the median time from first apheresis to CARVYKTI infusion was 79 days (range: 45 days to 246 days).

CARVYKTI was administered as a single IV infusion 5 to 7 days after the start of a lymphodepleting chemotherapy (cyclophosphamide 300 mg/m² intravenously daily and fludarabine 30 mg/m² intravenously daily for 3 days) at a median dose of 0.71×10⁶ CAR-positive viable T-cells/kg (range: 0.39 to 1.07×10⁶ cells/kg).

The primary efficacy measure was progression-free survival (PFS) analysed based on the Intent-To-Treat Analysis Set (Table 8 and Figure 1). After a median follow-up of 15.9 months, median PFS was 11.8 months (95% CI: 9.7, 13.8) for the standard of care arm and NE (95% CI: 22.8, NE) for the CARVYKTI arm (Hazard ratio: 0.26 [95% CI: 0.18, 0.38]). The estimated PFS rate at 12 months was 75.9% (95% CI: 69.4%, 81.1%) in the CARVYKTI arm and 48.6% (95% CI: 41.5%, 55.3%) in the standard of care arm. In the CARVYKTI arm, the estimated median duration of response (DOR) has not been reached. In the standard of care arm, the estimated median DOR was 16.6 months (95% CI: 12.9, NE). After a median follow-up of 15.9 months, median overall survival (OS) was NE (95% CI: NE, NE) for the CARVYKTI arm and 26.7 months (95% CI: 22.5, NE) for the standard of care arm (Hazard ratio: 0.78 [95% CI: 0.50, 1.20]; p-value = 0.2551). Updated OS results with a median follow-up of 28.7 months are presented in Table 8 and Figure 2.

Figure 1: Kaplan-Meier Curve of PFS in Study MMY3002 (Intent-To-Treat Analysis Set)

Of the 176 patients who received CARVYKTI as study treatment, the median progression‑free survival (PFS) was not estimable (95% CI: not estimable, not estimable) with a 12 months PFS rate of 89.7%. The overall response rate (ORR) in these patients was 99.4% (95% CI: 96.9%, 100.0%). The rate of CR/sCR was 86.4% (95% CI: 80.4%, 91.1%).

Figure 2: Kaplan-Meier Curve of OS in Study MMY3002 (Intent-To-Treat Analysis Set)

Note: Intent-to-treat analysis set consists of subjects who were randomised in the study. Overall survival based on a median duration of follow-up of 28.7 months.

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with CARVYKTI in all subsets of the paediatric population in multiple myeloma (see section 4.2 for information on paediatric use).

CARVYKTI pharmacokinetics (PK) was assessed in 97 adult patients with relapsed or refractory multiple myeloma in Study MMY2001 receiving a single CARVYKTI infusion at the median dose of 0.71 × 10⁶ CAR-positive viable T cells/kg (range: 0.51 × 10⁶ to 0.95 × 10⁶ cells/kg).

Following a single infusion, CARVYKTI exhibited an initial expansion phase followed by a rapid decline and then a slower decline. However, high interindividual variability was observed.

After the cell expansion, the persistence phase of the CARVYKTI was observed for all patients. At the time of analysis (n=65), the median time for CAR transgene levels in peripheral blood to return to the pre-dose baseline level was approximately 100 days (range: 28-365 days) post‑infusion. The PK of CARVYKTI was assessed in 176 adult patients with lenalidomide refractory multiple myeloma in MMY3002 and were generally consistent with those in Study MMY2001.

Detectable CARVYKTI exposures in bone marrow indicate a distribution of CARVYKTI from systemic circulation to bone marrow. Similar to blood transgene levels, bone marrow transgene levels declined over time and exhibited high interindividual variability.

Special populations

The pharmacokinetics of CARVYKTI (C_max and AUC_0-28d) were not impacted by age (range: 27‑78 years, including patients < 65 years of age (n=215; 64.8%), 65-75 years (n=105; 31.6%) and > 75 years of age (n=12; 3.6%).

Similarly, the pharmacokinetics of CARVYKTI (C_max and AUC_0-28d) were not impacted by gender, body weight, and race.

Renal impairment

Renal impairment studies of CARVYKTI were not conducted. CARVYKTI C_max and AUC_0-28d in patients with mild renal dysfunction (60 mL/min ≤ creatinine clearance [CRCL] < 90 mL/min) or moderate renal dysfunction (30 mL/min ≤ creatinine clearance < 60 mL/min) were similar to patients with normal renal function (CRCL ≥ 90 mL/min).

Hepatic impairment

Hepatic impairment studies of CARVYKTI were not conducted. CARVYKTI C_max and AUC_0-28d were similar in patients with mild hepatic dysfunction [(total bilirubin ≤ upper limit of normal (ULN) and aspartate aminotransferase > ULN) or (ULN < total bilirubin ≤ 1.5 times ULN)] and patients with normal hepatic function.

CARVYKTI comprises engineered human T cells; therefore, there are no representative in vitro assays, ex vivo models, or in vivo models that can accurately address the toxicological characteristics of the human product. Hence, traditional toxicology studies used for medicinal product development were not performed.

Carcinogenicity and mutagenicity

No genotoxicity or carcinogenicity studies have been performed.

The risk for insertional mutagenesis occurring during the manufacturing of CARVYKTI following transduction of autologous human T cells with an integrating lentiviral vector (LV) was assessed by evaluating the integration pattern of the vector in pre-infusion CARVYKTI. This genomic insertional site analysis was performed on CARVYKTI products from 7 samples from 6 multiple myeloma patients and from 3 samples from 3 healthy donors. There was no evidence for preferential integration near genes of concern.

Reproductive toxicology

No reproductive and developmental toxicity animal studies have been conducted with CARVYKTI.

No studies have been conducted to evaluate the effects of CARVYKTI on fertility.

Cryostor CS5 (contains dimethyl sulfoxide)

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

CARVYKTI must be stored and transported in the vapour phase of liquid nitrogen (≤ -120 °C) and must remain frozen until the patient is ready for treatment to ensure viable cells are available for patient administration.

Thawed medicinal product must not be shaken, refrozen or refrigerated.

Keep infusion bag in the aluminium cryo cassette.

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

Ethylene vinyl acetate (EVA) infusion bag with sealed addition tube and two available spike ports containing either 30 mL (50 mL bag) or 70 mL (250 mL bag) of cell dispersion.

Each infusion bag is packed in an aluminium cryo cassette.

CARVYKTI should not be irradiated as irradiation could inactivate the medicinal product.

Precautions to be taken before handling or administering the medicinal product

CARVYKTI should be transported within the facility in closed, break-proof and leak-proof containers.

This medicinal product contains human blood cells. Healthcare professionals handling CARVYKTI should take appropriate precautions (wearing gloves, protective clothing and eye protection) to avoid potential transmission of infectious diseases.

CARVYKTI must remain ≤ -120 °C at all times, until the content of the bag is thawed for infusion.

Preparation prior to administration

The timing of CARVYKTI thaw and infusion should be coordinated; the infusion time should be confirmed in advance, and the start time for thaw must be adjusted so that CARVYKTI is available for infusion when the patient is ready. Once thawed, the medicinal product should be administered immediately and the infusion should be completed within 2.5 hours.

·             Prior to CARVYKTI preparation, patient identity should be confirmed by matching the patient’s identity with the patient identifiers on the CARVYKTI cryo cassette and Lot Information Sheet. The CARVYKTI infusion bag should not be removed from the cryo cassette if the information on the patient-specific label does not match the intended patient.

·             Once patient identification is confirmed, the CARVYKTI infusion bag should be removed from the cryo cassette.

·             The infusion bag should be inspected for any breaches of container integrity such as breaks or cracks before and after thawing. Do not administer if the bag is compromised and contact Janssen-Cilag International NV.

Thawing

·             The infusion bag should be placed inside a sealable plastic bag prior to thawing.

·             CARVYKTI should be thawed at 37 °C±2 °C using either a water bath or dry thaw device until there is no visible ice in the infusion bag. Total time from start of thaw until completion of thawing should be no more than 15 minutes.

·             The infusion bag should be removed from the sealable plastic bag and wiped dry. The contents of the infusion bag should be gently mixed to disperse clumps of cellular material. If visible cell clumps remain, the contents of the bag should continue to be gently mixed. Small clumps of cellular material should disperse with gentle manual mixing. CARVYKTI must not be pre-filtered into a different container, washed, spun down, and/or resuspended in new media prior to infusion.

·             Once thawed, the medicinal product should not be re-frozen or refrigerated.

Administration

·             CARVYKTI is for autologous single use only.

·             Prior to infusion and during the recovery period, ensure tocilizumab and emergency equipment are available for use.

·             Confirm the patient’s identity with the patient identifiers on the CARVYKTI infusion bag and Lot Information Sheet. Do not infuse CARVYKTI if the information on the patient-specific label does not match the intended patient.

·             Once thawed, the entire contents of the CARVYKTI bag should be administered by intravenous infusion within 2.5 hours at room temperature (20 °C to 25 °C), using infusion sets fitted with an in-line filter. The infusion usually takes less than 60 minutes.

·             Do NOT use a leukodepleting filter.

·             Gently mix the contents of the bag during CARVYKTI infusion to disperse cell clumps.

·             After the entire content of the product bag is infused, flush the administration line, inclusive of the in-line filter, with sodium chloride 9 mg/mL (0.9%) solution for injection to ensure all medicinal product is delivered.

Precautions to be taken for the disposal of the medicinal product

Unused medicinal product and all material that has been in contact with CARVYKTI (solid and liquid waste) should be handled and disposed of as potentially infectious waste in accordance with local guidelines on handling of human-derived material.

Measures to take in case of accidental exposure

In case of accidental exposure local guidelines on handling of human-derived material should be followed. Work surfaces and materials which have potentially been in contact with CARVYKTI must be decontaminated with appropriate disinfectant.