Ciltacabtagene autoleucel

The safety of immunisation with live viral vaccines during or following ciltacabtagene autoleucel 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 ciltacabtagene autoleucel treatment, and until immune recovery following treatment with ciltacabtagene autoleucel.

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 and require special attention. There is no experience of use of ciltacabtagene autoleucel in patients with CNS involvement of myeloma or other pre-existing, clinically relevant CNS illnesses.

There is currently no experience with manufacturing ciltacabtagene autoleucel 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.

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

Therefore, ciltacabtagene autoleucel 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 ciltacabtagene autoleucel therapy should be discussed with the treating physician.

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

It is unknown whether ciltacabtagene autoleucel 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 ciltacabtagene autoleucel, the decision to consider breast-feeding should be discussed with the treating physician.

Women of childbearing potential/Contraception in males and females

Pregnancy status for females of childbearing potential should be verified prior to starting treatment with ciltacabtagene autoleucel. There are insufficient exposure data to provide a recommendation concerning duration of contraception following treatment with ciltacabtagene autoleucel.

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 ciltacabtagene autoleucel.

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

Fertility

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

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

Due to the potential for neurologic events, patients receiving ciltacabtagene autoleucel are at risk for altered or decreased consciousness or coordination in the 8 weeks following ciltacabtagene autoleucel infusion. 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 ciltacabtagene autoleucel was evaluated in 396 adult patients with multiple myeloma infused with ciltacabtagene autoleucel 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). Patients who complete Study MMY2001, MMY2003, or MMY3002 are eligible to enroll in a separate long-term follow-up study (MMY4002).

The most common ciltacabtagene autoleucel adverse reactions (≥20%) were neutropenia (90%), pyrexia (85%), CRS (83%), thrombocytopenia (60%), anemia (60%), musculoskeletal pain (40%), lymphopenia (38%), fatigue (35%), leukopenia (34%), hypotension (34%), hypogammaglobulinaemia (33%), diarrhea (32%), upper respiratory tract infection (32%), transaminase elevation (26%), headache (25%), nausea (23%), and cough (22%).

Serious adverse reactions occurred in 44% of patients; serious adverse reactions reported in ≥2% of patients were CRS (11%), pneumonia (9%), sepsis (5%), viral infection (5%), neutropenia (4%), cranial nerve palsies, (4%), ICANS (4%), encephalopathy (3%), upper respiratory tract infection (3%), bacterial infections (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 (11%), febrile neutropenia (8%), sepsis (7%), pyrexia (7%), Gamma-glutamyltransferase increased (6%), hypotension (6%), bacterial infection (5%), and hypogammaglobulinaemia (5%).

The most common (≥20%) Grade ≥3 haematological abnormalities were neutropenia (89%), thrombocytopenia (45%), anaemia (44%), lymphopenia (36%), and leukopenia (33%).

Tabulated list of adverse reactions

Table 1 summarises the adverse reactions that occurred in patients receiving ciltacabtagene autoleucel. 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).

Table 1. Adverse reaction in patients with multiple myeloma treated with ciltacabtagene autoleucel:

Adverse reactions are reported using MedDRA version 26.1
^# Contains fatal outcome(s).
^* Based on grouped term.
¹ Sepsis includes bacteraemia, bacterial sepsis, candida sepsis, device related bacteraemia, enterococcal bacteraemia, enterococcal sepsis, haemophilus sepsis, neutropenic sepsis, pseudomonal bacteraemia, pseudomonal sepsis, sepsis, septic shock, staphylococcal bacteraemia, streptococcal sepsis, systemic candida, and urosepsis.
² Gastroenteritis includes enterocolitis bacterial, enterocolitis infectious, enterocolitis viral, enterovirus infection, gastroenteritis, gastroenteritis cryptosporidial, gastroenteritis rotavirus, gastroenteritis salmonella, gastroenteritis viral, gastroenteritis escherichia coli, gastrointestinal infection, and large intestine infection.
³ Urinary tract infection includes cystitis, escherichia urinary tract infection, urinary tract infection, urinary tract infection bacterial, and urinary tract infection viral.
⁴ Anaemia includes anaemia, hypochromic anaemia, iron deficiency anaemia and pallor.
⁵ Coagulopathy includes activated partial thromboplastin time prolonged, blood fibrinogen decreased, coagulation test abnormal, coagulation time prolonged, coagulopathy, disseminated intravascular coagulation, hypofibrinogenaemia, international normalised ratio increased, prothrombin level increased, and prothrombin time prolonged.
⁶ Hyperferritinemia includes hyperferritinaemia, and serum ferritin increased.
⁷ Delirium includes agitation, delirium, disorientation, euphoric mood, hallucination, irritability, and restlessness.
⁸ Personality changes includes affect lability, apathy, flat affect, indifference, personality change, and reduced facial expression.
⁹ Encephalopathy includes amnesia, bradyphrenia, cognitive disorder, confusional state, depressed level of consciousness, disturbance in attention, encephalopathy, lethargy, memory impairment, mental impairment, mental status changes, psychomotor retardation, and slow response to stimuli.
¹⁰ Motor dysfunction includes agraphia, bradykinesia, cogwheel rigidity, coordination abnormal, dysgraphia, extrapyramidal disorder, eyelid ptosis, micrographia, motor dysfunction, muscle rigidity, muscle spasms, muscle tightness, muscular weakness, myoclonus, parkinsonism, posture abnormal and stereotypy.
¹¹ Sleep disorder includes hypersomnia, insomnia, sleep disorder, and somnolence.
¹² Aphasia includes aphasia, dysarthria, slow speech, and speech disorder.
¹³ Cranial nerve palsies include Bell’s palsy, cranial nerve paralysis, facial nerve disorder, facial paralysis, facial paresis, IIIrd nerve paralysis, trigeminal palsy, and VIth nerve paralysis.
¹⁴ Paresis includes paresis, hemiparesis,and peroneal nerve palsy.
¹⁵ Ataxia includes ataxia, balance disorder, dysmetria, and gait disturbance.
¹⁶ Neuropathy peripheral includes neuropathy peripheral, peripheral motor neuropathy, peripheral sensorimotor neuropathy, peripheral sensory neuropathy, and polyneuropathy.
¹⁷ Cardiac arrhythmias include atrial fibrillation, atrial flutter, atrioventricular block complete, atrioventricular block second degree, supraventricular tachycardia, ventricular extrasystoles, and ventricular tachycardia.
¹⁸ Haemorrhage includes catheter site haemorrhage, cerebral haemorrhage, conjunctival haemorrhage, contusion, epistaxis, eye contusion, gastrointestinal haemorrhage, haematemesis, haematochezia, haematoma, haematuria, haemoptysis, infusion site haematoma, lower gastrointestinal haemorrhage, oral contusion, post procedural, haemorrhage, pulmonary haemorrhage, retinal haemorrhage, retroperitoneal haemorrhage, subarachnoid haemorrhage, and Subdural haematoma.
¹⁹ Dyspnoea includes acute respiratory failure, dyspnoea, dyspnoea exertional, respiratory failure, tachyponea and wheezing.
²⁰ Diarrhoea includes colitis, and diarrhoea.
²¹ Renal failure includes acute kidney injury, blood creatinine increased, chronic kidney disease, renal failure, and renal impairment.
²² Oedema includes face oedema, fluid retention, generalised oedema, hypervolaemia, localised oedema, oedema, oedema peripheral, palatal oedema, periorbital oedema, peripheral swelling, pulmonary congestion, pulmonary oedema, scrotal oedema, and swollen tongue.

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 ciltacabtagene autoleucel and received ciltacabtagene autoleucel as subsequent therapy. 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 ciltacabtagene autoleucel (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=324) 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 (82%), hypotension (28%), Aspartate aminotransferase (AST) increased (12%), and hypoxia (10%).

Neurologic toxicities

Neurologic toxicity occurred in 23% of patients (n=90); 6% (n=22) 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.

Immune effector cell-associated neurotoxicity syndrome (ICANS)

In the pooled studies (N=396), ICANS occurred in 11% of patients (n=45), with 2% (n=8) 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 ciltacabtagene autoleucel 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 ciltacabtagene autoleucel. One patient (Grade 3) died of neurologic toxicity with ongoing parkinsonism 247 days after administration of ciltacabtagene autoleucel, and two patients (Grade 2 and Grade 3) with ongoing parkinsonism died of infectious causes 162 and 119 days after administration of ciltacabtagene autoleucel. One patient recovered (Grade 3). The remaining 5 patients, symptoms of parkinsonism were ongoing up to 996 days after administration of ciltacabtagene autoleucel. 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 ciltacabtagene autoleucel. Although GBS symptoms improved after receiving treatment with steroids and IVIG, the patient died 139 days after administration of ciltacabtagene autoleucel due to encephalopathy post gastroenteritis with ongoing GBS symptoms.

Peripheral neuropathy

In the pooled studies (N=396), 28 patients developed peripheral neuropathy, presenting as sensory, motor, or sensorimotor neuropathies. Median time of onset of symptoms was 58 days (range: 1 to 914 days), median duration of peripheral neuropathies was 142 days (range: 1 to 1062 days) including those with ongoing neuropathy. Of these 28 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 23 with ≤ Grade 2 peripheral neuropathy, peripheral neuropathy resolved with no treatment reported in 7 patients and following treatment with duloxetine in 3 patients, and was ongoing in the other 9 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 ciltacabtagene autoleucel, and median time to resolution was 61 days (range: 1 to 443 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 ciltacabtagene autoleucel infusion, included, thrombocytopenia (33%), neutropenia (28%), lymphopenia (25%), and anemia (3%). After Day 60 following ciltacabtagene autoleucel, 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 2 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.

Table 2. Incidences of prolonged and recurrent cytopenias following treatment with ciltacabtagene autoleucel (N=396):

^a The laboratory result with the worst toxicity grade is used for a calendar day. Recovery definition: must have 2 consecutive Grade ≤2 results on different days if recovery period ≤10 days.
Notes: Lab results assessed after Day 1 until Day 100 for MMY2001 and MMY2003 or Day 112 for MMY3002, or the start of subsequent therapy, whichever occurs first, are included in the analysis.
Thrombocytopenia: Grade ¾ – Platelets count <50,000 cells/μL.
Neutropenia: Grade ¾ – Neutrophil count <1,000 cells/μL.
Lymphopenia: Grade ¾ – Lymphocytes count <0.5×10⁹ cells/L.
Anemia: Grade 3 – hemoglobin <8g/dL. Grade 4 not defined by laboratory count per NCI-CTCAE v5.
Percentages are based on the number of treated patients.

Serious infections

Infections occurred in 54% of patients (n=213); 18% of patients (n=73) 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.

Hypogammaglobulinaemia

In the pooled studies (N=396), hypogammaglobulinaemia occurred in 34% of patients, with 5% of patients experiencing Grade 3 hypogammaglobulinaemia. Laboratory IgG levels fell below 500 mg/dL after infusion in 91% (360/396) of patients treated with ciltacabtagene autoleucel. Hypogammaglobulinaemia either as an adverse reaction or a laboratory IgG level below 500 mg/dL occurred in 92% (364/396) of patients after infusion. Fifty-eight percent of patients received IVIG post ciltacabtagene autoleucel for either an adverse reaction or prophylaxis.

Immunogenicity

The immunogenicity of ciltacabtagene autoleucel has been evaluated using a validated assay for the detection of binding antibodies against ciltacabtagene autoleucel 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 ciltacabtagene autoleucel kinetics of initial expansion and persistence, efficacy or safety.