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Ciltacabtagene autoleucel is a BCMA-directed CAR T-cell therapy used in the treatment of relapsed or refractory multiple myeloma in previously treated patients.

Multiple myeloma is a malignancy involving the plasma cells of the bone marrow. It is a rare malignancy, with an estimated yearly incidence of 6.5 people per 100,000,^[rx] and is variable in its presentation – some patients may remain entirely asymptomatic, while others may experience a range of symptoms including bone pain, hematologic abnormalities, and end-organ damage. There have been a number of treatments developed for multiple myeloma (e.g. daratumumab), although none are curative.^[rx]

B-cell maturation antigen (BCMA) is a transmembrane glycoprotein member of the tumor necrosis factor receptor superfamily 17 (TNFRSF17) which is used as a biomarker for multiple myeloma.^[rx] While normally expressed on plasma blasts and plasma cells, BCMA is widely expressed on malignant plasma cells and most multiple myeloma cell lines, making it a choice target in the development of immunotherapies against multiple myeloma.^[rx]

Ciltacabtagene autoleucel (Carvykti, Jannsen Biotech Inc.) is a BCMA-directed genetically modified autologous T-cell immunotherapy.^[rx] Patient T-cells are reprogrammed with a transgene encoding a specific chimeric antigen receptor (CAR) which features two BCMA-targeting single-domain antibodies. Re-infusion of these modified T-cells leads to the targeted elimination of malignant plasma cells, on which BCMA is highly expressed.^[rx] Carvykti was first approved by the FDA in February 2022 for the treatment of relapsed or refractory multiple myeloma in treatment-experienced patients.^[rx]

Mechanism of action

Ciltacabtagene autoleucel is a chimeric antigen receptor (CAR) T-cell therapy in which genetically modified autologous T-cells are reprogrammed to target B-cell maturation antigen (BCMA), a biomarker of multiple myeloma.² Patient peripheral blood mononuclear cells are obtained via leukapheresis, after which they are enriched for T-cells and genetically modified ex vivo to express a CAR comprising an anti-BCMA targeting domain consisting of two single-domain anti-BCMA antibodies linked to a 4-1BB costimulatory domain and a CD3-zeta signaling domain.^[rx]

The genetically modified CAR T-cells are then expanded, washed, and cryopreserved for shipping back to the patient. When the product is infused back into the patient, the anti-BCMA CAR T-cells are able to recognize and eliminate BCMA-expressing target cells, including malignant plasma cells involved in multiple myeloma.^[rx]

Treatment with ciltacabtagene autoleucel comprises a single infusion of a dose range between 0.5-1.0×10⁶ CAR-positive viable T-cells per kilogram of body weight.^[rx]

Patients receiving treatment with ciltacabtagene autoleucel are required to undergo monitoring through a Risk Evaluation and Mitigation Strategy (REMS) called the Carvykti REMS.^[rx] There are a number of potentially serious adverse reactions related to ciltacabtagene autoleucel therapy which require close monitoring and intervention. Cytokine Release Syndrome (CRS), which may be fatal, may be mitigated with the use of tocilizumab and/or corticosteroids.^[rx] Similarly, significant neurologic toxicities (including Immune Effector Cell-Associated Neurotoxicity Syndrome [ICANS]) may occur and can be treated with supportive care and/or corticosteroid therapy as required.^[rx] Serious hematologic adverse effects – including hemophagocytic lymphohistiocytosis (HLH), macrophage activation syndrome (MAS), and various recurrent/prolonged cytopenias – have also been observed in patients following treatment with ciltacabtagene autoleucel.^[rx]

Indications

Ciltacabtagene autoleucel is indicated for the treatment of adult patients with relapsed or refractory multiple myeloma after ≥4 prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody.^[rx]
Refractory Multiple Myeloma
Relapsed Multiple Myeloma

Use in Cancer

Ciltacabtagene autoleucel is approved to treat:

Multiple myeloma that has relapsed (come back) or is refractory (does not respond to treatment). It is used in adults who have received at least four treatments that included an anti-CD38 monoclonal antibody, a proteasome inhibitor, and an immunomodulating agent.

Ciltacabtagene autoleucel is only available as part of a special program called Carvykti REMS (Risk Evaluation and Mitigation Strategies Exit Disclaimer).

Contraindications

acute leukemia
decreased function of bone marrow
anemia
decreased blood platelets
low levels of white blood cells
low levels of a type of white blood cell called neutrophils
a decreased number of lymphocytes in the blood
a low seizure threshold
a type of inflammation of the lung called interstitial pneumonitis
a condition where there is a formation of fibrous tissue in the lung called pulmonary fibrosis
damage to the liver and inflammation
liver problems
nephrotic syndrome, a type of kidney disorder
seizures
pregnancy
a patient who is producing milk and breastfeeding
spread of malignant cancer to the bone marrow

Dosage

Multiple Myeloma

Provided as one bag with a single dose for IV infusion:

Recommended dose range: 0.5 to 1.0 × 10(6) CAR-positive viable T cells per kg of body weight
Maximum dose of 1×10(8) CAR-positive viable T cells per single infusion
Treatment duration: The single IV infusion should be administered within 2.5 hours
This drug is for autologous use only. The patient’s identity must match the identifiers on the drug cassette and infusion bag. Do not use if the information on the patient-specific labels does not match.

Precautions

US FDA requires a medication guide to assure safe use. For additional information: www.fda.gov/drugs/drug-safety-and-availability/medication-guides
The US FDA requires a Risk Evaluation and Mitigation Strategy (REMS) for CARVYKTI. It includes a medication guide, a communication plan, elements to assure safe use, and an implementation system. Further information is available at www.carvyktirems.com or 1-844-672-0067 or www.accessdata.fda.gov/scripts/cder/rems/index.cfm

Cytokine Release Syndrome (CRS):

CRS, including fatal or life-threatening reactions, has been reported in patients following treatment with this drug.
Do not administer to patients with active infection or inflammatory disorders.
Treat severe or life-threatening CRS with tocilizumab or tocilizumab and corticosteroids (see manufacturers prescribing information for further grading and management instructions).

Neurologic Toxicities:

Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS), may be fatal or life-threatening and has occurred following treatment with this drug, including before CRS onset, concurrently with CRS, after CRS resolution, or in the absence of CRS.
Patients should be monitored for neurologic events after treatment.
Provide supportive care and/or corticosteroids as needed (see manufacturers prescribing information for further management instructions).
Parkinsonism and Guillain-Barré syndrome and their associated complications resulting in fatal or life-threatening reactions have occurred following treatment with this drug.
Hemophagocytic Lymphohistiocytosis/Macrophage Activation Syndrome (HLH/MAS), including fatal and life-threatening reactions, occurred in patients following treatment with this drug.
HLH/MAS can occur with CRS or neurologic toxicities.
Prolonged and/or recurrent cytopenias with bleeding and infection and requirement for stem cell transplantation for hematopoietic recovery occurred following treatment.
This drug is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the CARVYKTI REMS Program.

Administration advice:

See pretreatment and premedication instructions below.
This drug is for autologous use only. The patient’s identity must match the patient identifiers on the drug’s cassette and infusion bag. Do not infuse if the information on the patient-specific labels does not match the patient.
Do NOT use a leukocyte-depleting filter.
A minimum of two doses of tocilizumab and emergency equipment should be available prior to infusion and during the recovery period.
Central venous access may be utilized for the infusion, especially in patients with poor peripheral access.
Prime the tubing of the infusion set with normal saline prior to the infusion
Once thawed, administer the entire contents of the bag IV within 2.5 hours using infusion sets fitted with an in-line filter.
Gently mix the contents of the bag during infusion to disperse cell clumps.
Once the entire content of the bag is infused, flush the IV line, including the in-line filter, with normal saline with a volume equal or greater to the total volume of the primary administration set used inclusive of the drip tube, to ensure that all product is delivered.
This drug contains human blood cells that are genetically modified with replication incompetent, self-inactivating, lentiviral vector. Follow universal precautions and local biosafety guidelines for handling and disposal to avoid potential transmission of infectious diseases.

Pretreatment

Administer the lymphodepleting chemotherapy regimen: cyclophosphamide 300 mg/m2 IV and fludarabine 30 mg/m2 IV daily for 3 days.
See the prescribing information of cyclophosphamide and fludarabine for further information about this regimen.
Administer infusion with this drug 2 to 4 days after the completion of the lymphodepleting chemotherapy regimen.
Infusion should be delayed if the patient has:
Clinically significant active infection or inflammatory disorders
Grade 3 or greater non-hematologic toxicities of cyclophosphamide and fludarabine conditioning, except for Grade 3 nausea, vomiting, diarrhea, or constipation. Delay infusion until resolution of these events to Grade 1 or less.

Premedication

Administer pre-infusion medications 30 to 60 minutes prior to this drug:
Antipyretics (oral or IV acetaminophen 650 to 1000 mg).
Antihistamine (oral or IV diphenhydramine 25 to 50 mg or equivalent).

Reconstitution/preparation techniques:

Read the US FDA-approved patient labeling for further receipt, preparation, and administration instructions.

Side Effects

The Most Common

diarrhea
loss of appetite
joint, muscle, or bone pain
swelling
constipation
pyrexia,
cytokine release syndrome,
hypogammaglobulinemia,
musculoskeletal pain, fatigue,
infections, diarrhea, nausea,
encephalopathy,
headache,
coagulopathy,
low levels of neutrophils,
lymphopenia and leucopenia (low levels of lymphocytes or other white blood cells),
anemia (low levels of red blood cells), thrombocytopenia (low levels of blood platelets),
hypotension (low blood pressure),
the pain of the muscles and bones,
high level of liver enzymes,
upper respiratory tract infection (nose and throat infection),
hypokalemia (low level of potassium),
hypocalcemia (low levels of calcium),
hypophosphatemia (low levels of phosphate in the blood)
tachycardia (rapid heartbeat),
encephalopathy (a brain disorder),
edema (fluid retention), decreased appetite, chills, fever,
tiredness, as well as cytokine release syndrome (a potentially life-threatening condition that can cause fever, vomiting, shortness of breath, pain, and low blood pressure).^[rx]

More Common

confusion, loss of consciousness, seizures, problems with speech, reading or writing, depression;
tingling and numbness of hands and feet , leg and arm weakness, facial numbness; or
low blood cell counts–fever, chills, tiredness, flu-like symptoms, mouth sores, skin sores, easy bruising, unusual bleeding, pale skin, cold hands, and feet, feeling light-headed or short of breath.
confusion, cough, trouble breathing, fast or irregular heartbeats, feeling light-headed or very tired;
headache, dizziness;
problems with speech;
low blood cell counts;
fever, chills, tiredness, or other signs of infection;
decreased appetite, constipation, nausea or diarrhea; or
pain in your joints or muscles.

Rare

Discouragement
feeling sad or empty
generalized slowing of mental and physical activity
incremental or ratchet-like movement of the muscle
lack of appetite
loss of balance control
loss of interest or pleasure
muscle discomfort
partial or slight paralysis
rigid or stiff muscles
seizures
shuffling walk
slowed movements
slurred speech
stiffness of the arms and legs
tic-like (jerky) movements of the head, face, mouth, and neck
trouble concentrating
trouble sleeping
uncontrolled eye movements

Drug Interactions

This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interacAdd Newtion does not necessarily mean no interactions exist.

adalimumab
adenovirus vaccine
alefacept
alemtuzumab
anakinra
anthrax vaccine adsorbed
azathioprine
baricitinib
bcg
bcg vaccine
beclomethasone
betamethasone
bifidobacterium infantis
brewer’s yeast
budesonide

canakinumab
candida albicans extract
cat’s claw
certolizumab
chloramphenicol
chloramphenicol ophthalmic
cholera vaccine
cholera vaccine, live
ciclesonide
cinoxacin
ciprofloxacin
cladribine
clozapine
coccidioidin skin test
cortisone

deferiprone
deflazacort
delafloxacin
dengue vaccine
denosumab
deucravacitinib
dexamethasone
dimethyl fumarate
diroximel fumarate

echinacea
efalizumab
eflapegrastim
enoxacin
etanercept

fexinidazole
filgrastim
fingolimod
fludrocortisone
flunisolide
fluticasone

ganciclovir
gatifloxacin
gemifloxacin
golimumab
grepafloxacin

haemophilus b conjugate (hboc) vaccine
haemophilus b conjugate (prp-omp) vaccine
haemophilus b conjugate (prp-t) vaccine
hepatitis a adult vaccine
hepatitis a pediatric vaccine
hepatitis b adult vaccine
hepatitis b pediatric vaccine
histoplasmin
human papillomavirus vaccine
hydrocortisone

idelalisib
infliximab
influenza virus vaccine, h1n1, inactivated
influenza virus vaccine, h1n1, live
influenza virus vaccine, h5n1
influenza virus vaccine, inactivated
influenza virus vaccine, live, trivalent

japanese enceph vacc sa14-14-2, inactivated
japanese encephalitis virus vaccine nakayama

lactobacillus acidophilus
lactobacillus reuteri
lactobacillus rhamnosus
lactobacillus rhamnosus gg
leflunomide
levofloxacin
lomefloxacin
lyme disease vaccine

measles virus vaccine
meningococcal conjugate vaccine
meningococcal group B vaccine
meningococcal polysaccharide vaccine
methylprednisolone
mixed respiratory vaccine
mometasone
monomethyl fumarate
moxifloxacin
mumps skin test antigen
mumps virus vaccine

nalidixic acid
natalizumab
niraparib
norfloxacil

ocrelizumab
ofloxacin
olaparib
omacetaxine
ozanimod

palifermin
pegfilgrastim
plague vaccine
pneumococcal 13-valent vaccine
pneumococcal 15-valent conjugate vaccine
pneumococcal 20-valent conjugate vaccine
pneumococcal 23-polyvalent vaccine
pneumococcal 7-valent vaccine
poliovirus vaccine, inactivated
poliovirus vaccine, live, trivalent
ponesimod
prednisolone
prednisone

rabies vaccine, human diploid cell
rabies vaccine, purified chick embryo cell
radium 223 dichloride
rilonacept
roflumilast
ropeginterferon alfa-2b
rotavirus vaccine
rubella virus vaccine

saccharomyces boulardii lyo
samarium sm 153 lexidronam
sargramostim
sars-cov-2 (covid-19) ad26 vaccine, recombinant
sars-cov-2 (covid-19) chadox1 vaccine, recombinant
sars-cov-2 (covid-19) mrna (tozinameran 12y+) bivalent booster vaccine
sars-cov-2 (covid-19) mrna (tozinameran 5y-11y) bivalent booster vaccine
sars-cov-2 (covid-19) mrna (tozinameran 6m-4y) bivalent booster vaccine
sars-cov-2 (covid-19) mrna-1273 (6m-5y bivalent booster) vaccine
sars-cov-2 (covid-19) mrna-1273 (bivalent booster) vaccine
sars-cov-2 (covid-19) mrna-1273 vaccine
sars-cov-2 (covid-19) nvx-cov2373 vaccine, recombinant
sars-cov-2 (covid-19) rs-nanoparticle vaccine, recombinant
sars-cov-2 (covid-19)mrna-1273(6y+ bivalent booster) vaccine
sars-cov-2 mrna (tozinameran 5y-11y) vaccine
sars-cov-2 mrna (tozinameran 6m-4y) vaccine
sars-cov-2 mrna (tozinameran-tris-sucrose) vaccine
sars-cov-2 mrna (tozinameran) vaccine
sars-cov-2 mrna-1273 (6m-5y) vaccine
sars-cov-2 mrna-1273 (6y-11y) vaccine
sars-cov-2 mrna-1273 (booster only) vaccine
sars-cov-2 pres dtm (booster only) vaccine, recombinant
siponimod
sipuleucel-T
skin test antigens, multiple
smallpox and monkeypox vaccine
smallpox vaccine
sodium phosphate p32
sparfloxacin
staphage lysate (spl)
strontium-89 chloride

talimogene laherparepvec
tbo-filgrastim
teriflunomide
tetanus toxoid
thalidomide
tick-borne encephalitis (inactivated) pediatric vaccine
tick-borne encephalitis (inactivated) vaccine
tofacitinib
topotecan
triamcinolone
trichophyton skin test
trovafloxacin
tuberculin purified protein derivative
typhoid vaccine, inactivated
typhoid vaccine, live

upadacitinib
ustekinumab

valganciclovir
varicella virus vaccine
vitamin e
voclosporin

yellow fever vaccine

zidovudine
zinc acetate
zinc chloride
zinc gluconate
zinc sulfate
zoster vaccine live
zoster vaccine, inactivated

Pregnancy and Lactation

US FDA pregnancy category Not Assigned

Pregnancy

The US FDA has amended the pregnancy labeling rule for prescription drug products to require labeling that includes a summary of risk, a discussion of the data supporting that summary, and relevant information to help healthcare providers make prescribing decisions and counsel women about the use of drugs during pregnancy. Pregnancy categories A, B, C, D, and X are being phased out. There is no data on use in pregnant women to know this drug’s risks, including the risk of fetal harm or reproductive effects. Based on the mechanism of action, if the transduced cells cross the placenta, they may cause fetal toxicity, including B-cell lymphocytopenia and hypogammaglobulinemia. This drug is not recommended for women who are pregnant, or for women of childbearing potential not using contraception.

Lactation

There is no information regarding this drug on its presence in human milk, its effects on a breastfed infant, or its effects on milk production.
-Consider the developmental and health benefits of breastfeeding along with the mother’s clinical need for this medication as well as any potential adverse effects from this drug or the underlying maternal condition.

How should this medicine be used?

Ciltacabtagene autoleucel comes as a suspension (liquid) to be injected intravenously (into a vein) by a doctor or nurse in a hospital or infusion center. It is usually given over 30 to 60 minutes as a one-time dose. Before you receive your ciltacabtagene autoleucel dose, your doctor or nurse will administer other chemotherapy medications to prepare your body for ciltacabtagene autoleucel.

Before your dose of ciltacabtagene autoleucel injection is to be given, a sample of your white blood cells will be taken at a cell collection center using a procedure called leukapheresis (a process that removes white blood cells from the body). Because this medication is made from your own cells, it must be given only to you. It is important to be on time and to not to miss your scheduled cell collection appointment(s) or to receive your treatment dose. Your healthcare provider will check you daily for at least 10 days after you receive your ciltacabtagene autoleucel dose to monitor you for any side effects. You should also plan to stay near where you received your ciltacabtagene autoleucel treatment for at least 4 weeks after your dose. Your healthcare provider will check to see if your treatment is working and monitor you for any possible side effects. Talk to your doctor about how to prepare for leukapheresis and what to expect during and after the procedure.

What special precautions should I follow?

Before receiving ciltacabtagene autoleucel,

tell your doctor and pharmacist if you are allergic to ciltacabtagene autoleucel, any other medications, dimethyl sulfoxide (DMSO), or any of the ingredients in ciltacabtagene autoleucel injection. Ask your pharmacist or check the Medication Guide for a list of the ingredients.
tell your doctor and pharmacist what prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take. Your doctor may need to change the doses of your medications or monitor you carefully for side effects.
tell your doctor if have or have ever had hepatitis B or C (HBV or HCV; viruses that infect the liver and may cause severe liver damage) or other viruses such as cytomegalovirus (a common virus that usually only causes serious symptoms in people who have weakened immune systems or who are infected at birth) or human immunodeficiency virus (HIV); lung or breathing problems; or kidney, heart, or liver disease.
tell your doctor if you are pregnant, plan to become pregnant, or are breast-feeding. You will need to have a pregnancy test before you start ciltacabtagene autoleucel. You or your partner should not become pregnant while you are receiving ciltacabtagene autoleucel. If you become pregnant while receiving ciltacabtagene autoleucel, call your doctor immediately. Ciltacabtagene autoleucel may harm the fetus.
you should know that ciltacabtagene autoleucel injection may make you drowsy and cause confusion, weakness, dizziness, seizures, and coordination problems. Do not drive a car or operate machinery for at least 8 weeks after your ciltacabtagene autoleucel dose.
do not donate blood, organs, tissues, or cells for transplantation after you receive your ciltacabtagene autoleucel injection.
check with your doctor to see if you need to receive any vaccinations. Do not have any vaccinations without talking to your doctor for at least 6 weeks before starting chemotherapy, during your ciltacabtagene autoleucel treatment, and until your doctor tells you that your immune system has recovered.

References