Understanding Carvykti® (ciltacabtagene autoleucel)

Founded in 1990, the International Myeloma Foundation (IMF) is the first and largest organization focusing specifically on myeloma. The IMF’s reach extends to more than 525,000 members in 140 countries. The IMF is dedicated to improving the quality of life of myeloma patients while working toward prevention and a cure through our four founding principles: Research, Education, Support, and Advocacy.

RESEARCH

The IMF is dedicated to finding a cure for myeloma, and we have a range of initiatives to make this happen. The International Myeloma Working Group, which emerged from the IMF’s Scientific Advisory Board established in 1995, is the most prestigious organization with more than 300 myeloma researchers conducting collaborative research to improve outcomes for patients while providing critically appraised consensus guidelines that are followed around the world. Our Black Swan Research Initiative® is bridging the gap from long-term remission to cure. Our annual Brian D. Novis Research Grant Program is supporting the most promising projects by junior and senior investigators. Our Nurse Leadership Board, comprised of nurses from leading myeloma treatment centers, develops recommendations for the nursing care of myeloma patients.

EDUCATION

The IMF’s webinars, seminars, and workshops provide up-to-date information presented by leading myeloma scientists and clinicians directly to patients and their families. We have a library of more than 100 publications for patients, care partners, and healthcare professionals. IMF publications are always free-of-charge, and available in English and select other languages.

SUPPORT The IMF InfoLine responds to your myeloma-related questions and concerns via phone and email, providing the most accurate information in a caring and compassionate manner. We also sustain a network of myeloma support groups, training hundreds of dedicated patients, care partners, and nurses who volunteer to lead these groups in their communities.

ADVOCACY We empower thousands of individuals who make a positive impact each year on issues critical to the myeloma community. In the U.S., we lead coalitions to represent the interests of the myeloma community at both federal and state levels. Outside the U.S., the IMF’s Global Myeloma Action Network works to help patients gain access to treatment.

Learn more about the ways the IMF is helping to improve the quality of life of myeloma patients while working toward prevention and a cure. Call us at 1.818.487.7455 or 1.800.452.CURE, or visit myeloma.org .

You are not alone

The International Myeloma Foundation (IMF) is here to help you. The IMF is committed to providing information and support for patients with multiple myeloma (which we refer to simply as “myeloma”) and their care partners, friends, and family members.

We achieve this through a broad range of resources available on our website myeloma.org, and through numerous programs and services such as seminars, webinars, workshops, and the IMF InfoLine, which consistently provides the most up-to-date and accurate information about myeloma in a caring and compassionate manner. Contact the IMF InfoLine at 1.818.487.7455 or InfoLine@myeloma.org.

What you will learn from this booklet

Myeloma is a cancer that is not known to most patients at the time of diagnosis. To play an active role in your own medical care and to make good decisions about your care with your doctor, it is important and helpful to learn about myeloma, as well as its treatment options and supportive care measures.

The IMF’s Understanding-series publications address treatments for myeloma, supportive care measures, and the tests that are used to diagnose, monitor, and assess disease status throughout its course.

This booklet discusses Carvykti® (also known as ciltacabtagene autoleucel, the generic drug name) or “cilta-cel” for short. Carvykti was approved by the U.S. Food and Drug Administration (FDA) in February 2022 for the treatment of adult patients with relapsed or refractory multiple myeloma (RRMM).

If you are newly diagnosed with myeloma, we suggest that you read the IMF’s publication Patient Handbook for the Newly Diagnosed, which will help you to better understand this complex disease.

To learn about myeloma in later disease settings, read the IMF’s publication Concise Review of Relapsed and Refractory Myeloma.

Words in bold+blue type are explained in the “Terms and definitions” section at the end of this booklet. A more comprehensive glossary can be found in the IMF’s publication Understanding Myeloma Vocabulary located online at glossary.myeloma.org.

If you are reading this booklet in electronic format, the light blue links will take you to the corresponding resources. All IMF publications are free-of-charge and can be downloaded or requested in printed format at publications.myeloma.org.

Indications for the use of Carvykti

The FDA approval of Carvykti in February 2022 was based on data from the phase Ib/II CARTITUDE-1 clinical trial. Early, deep, and durable responses were observed in heavily pretreated patients after a single infusion of Carvykti. Of the 61 patients who were evaluable for minimal residual disease (MRD), 92% were MRD-negative at 10 -5. Updated results from this clinical trial demonstrated that responses deepened over time.

In April 2024, the FDA approved an expanded indication for the use of Carvykti® for the treatment of patients with RRMM who have received at least 1 prior line of therapy, including an immunomodulatory agent , a proteasome inhibitor, and an anti-CD38 monoclonal antibody. Carvykti was previously FDA-approved to be used after at least 4 prior lines of therapy.

The expanded FDA approval is based on data from the CARTITUDE-4 phase III clinical trial. In the Carvykti arm of the study, progression-free survival (PFS) was not reached at 24 months vs. PFS of 12 months with Pomalyst® (pomalidomide) + Velcade + dexamethasone [PVd] or Darzalex + Pomalyst + dexamethasone [DPd] in patients with relapsed and Revlimid-refractory myeloma who received 1 to 3 prior lines of therapy.

Carvykti is the first B-cell maturation antigen (BCMA) -targeted therapy approved for the treatment of patients with myeloma as early as first relapse. The new approval makes this important chimeric antigen receptor (CAR) T-cell therapy available to patients earlier in their treatment journey.

Carvykti continues to be studied in earlier-line treatment settings, including in newly diagnosed myeloma.

Figure 1. Blood cells that play a role in the immune system

Treatment with Carvykti

Carvykti is an immunotherapy that enhances the immune system, our body’s natural defense designed to destroy infected and malignant (cancerous) cells, and to remove cellular debris. The immune system is very complex. It includes white blood cells (WBC) and organs and tissues of the lymphatic system. Myeloma interferes with the normal function of the immune system.

Carvykti is a BCMA-directed genetically modified CAR T-cell therapy. Carvykti works by recognizing and binding to BCMA, a protein that is found almost universally on myeloma cells. This leads to the destruction of BCMA-expressing cells, thereby eliminating the myeloma cells. (BCMA is found on healthy cells as well.)

T cells are a type of WBC that originate in the bone marrow but mature in the thymus, a gland beneath the breastbone (sternum). T cells can be distinguished from other lymphocytes by the presence of a T-cell receptor (TCR) on the cell surface. T cells can recognize specific antigens and bind to them in order to surround and disable pathogens (infectious agents that cause disease).

T cells are one of the most important parts of our immune system; they recognize myeloma cells as foreign and cancerous. However, as myeloma grows, the number of T cells is reduced and their function blocked, thus allowing the myeloma to continue to grow. What is needed are T cells, which are capable of both recognizing myeloma cells as foreign and destroying them.

Each dose of Carvykti is customized using the patient’s own T cells that are administered as an intravenous (IV) infusion.

How Carvykti is given

Carvykti is currently administered only at certified treatment centers. Carvykti is delivered as a one-time intravenous infusion, manufactured for each individual patient using the patient’s own T cells. The treatment process generally takes 2 to 3 months and is comprised of the following steps:

1. Leukapheresis

Much like collecting stem cells for an autologous transplant, the patient’s own T cells are collected by a procedure called apheresis or leukapheresis. Whole blood is drawn from the patient, then passed through a machine that separates the blood into its individual components. The patient’s white blood cells are collected, and the remaining blood components are then immediately re-infused back into the bloodstream of the patient. This process may take 3 to 6 hours. If more T cells need to be collected, the procedure can be repeated.

Figure 2. The mechanism of action of CAR T-cell therapy

A. The patient’s T cells are collected from the bloodstream; B. the T cells are modified to produce receptors on their surface that recognize the patient’s myeloma cells; C. the T cells are manufactured in large numbers; D. the engineered T cells are reinfused into the patient to seek out and kill the patient’s myeloma cells; E. reinfused T cells seek out and kill the patient’s myeloma cells.

2. Modification and manufacturing of T cells

The white blood cells collected during leukapheresis are sent to a manufacturing facility where your T cells are separated out. These T cells are genetically modified to make Carvykti, which will recognize and attack BCMA on the surface of your myeloma cells. This is done by inserting a gene into the T cells, which makes the cells express a CAR on the cell surface, then multiplying the T cells in the lab to manufacture millions of cells. Making your Carvykti CAR-T cells takes approximately 4 to 5 weeks from the time your cells are received at the manufacturing laboratory, but the time may vary.

3. Pre-infusion chemotherapy

While your Carvykti is being made, you may receive chemotherapy to treat your myeloma so that it doesn’t get worse. Then, for the 3 days prior to your infusion of Carvykti, your doctor will give you chemotherapy to help prepare your body to receive the infusion of the genetically modified T cells.

4. Infusion of Carvykti

After your treatment with pre-infusion chemotherapy is completed, and before you begin to receive Carvykti, you may be given medicines

to prevent or lessen a possible allergic reaction to Carvykti and to reduce fever. You will then receive your one-time infusion of Carvykti T cells through an intravenous catheter (tube). Due to the specialized nature of T-cell therapy, Carvykti must be administered at a certified treatment center. The infusion lasts approximately 30 to 60 minutes. After the infusion of Carvykti, the genetically modified T cells will begin to seek out your myeloma cells and attack them.

5. Monitoring

After your infusion of Carvykti, your doctor will monitor you for at least 10 days to observe that your treatment is working, and to check for any signs or symptoms of an adverse reaction that may occur. Blood tests will be used to track your progress. You must stay close to the center where you received your Carvykti treatment for at least 4 weeks.

Be sure to discuss with your doctor a plan for your long-term monitoring and follow-up.

Effects on ability to drive and operate machinery

For at least 8 weeks following your Carvykti infusion, you may be at risk for temporary memory and coordination problems, sleepiness, confusion, dizziness, and seizures. Don’t drive, operate heavy machinery, or engage in any activities that could be dangerous or hazardous if you are not mentally alert.

Warnings and precautions

Having Carvykti in your blood may cause some commercial tests for the human immunodeficiency virus (HIV) to give you a false-positive result, even when you may be HIV-negative.

Risk Evaluation and Mitigation Strategy (REMS)

The FDA requires a Risk Evaluation and Mitigation Strategy (REMS) program if a specific drug or treatment has serious safety concerns. REMS programs support the use of such drugs or treatments and help ensure that the potential benefits outweigh the risks. The FDA has determined that a REMS program is necessary with Carvykti. Therefore, Carvykti is available only through the CARVYKTI REMS program. Visit carvyktirems.com or call 1.844.672.0067 for more information.

Cytokine release syndrome (CRS)

Cytokines are proteins secreted by cells which can stimulate or inhibit growth/activity in other cells. In patients with myeloma, cytokines are produced in the bone marrow and circulate in the bloodstream. Cytokines are normally released in response to infection.

Cytokine release syndrome (CRS) is a potentially fatal, uncontrolled immune reaction in which cytokines become highly elevated and trigger

an overwhelming immune system response. A “cytokine storm” can seriously damage body tissues and organs.

CRS has occurred in some patients following treatment with Carvykti in clinical trials, including severe, life-threatening, or fatal reactions. Symptoms of CRS include fever, difficulty breathing, dizziness or lightheadedness, nausea, headache, tachycardia (fast heartbeat), low blood pressure, or fatigue. Severe or life-threatening CRS is treated with tocilizumab or tocilizumab together with steroids. It is important to promptly alert your doctor if there is any change in your health or if you’re not feeling well while receiving treatment with Carvykti.

Neurologic toxicities

Immune effector cell-associated neurotoxicity syndrome (ICANS) has occurred in patients following treatment with Carvykti. ICANS often correlates with CRS but it can occur in the absence of CRS. After treatment with Carvykti, ICANS can occur before, during, or after CRS onset, or after CRS resolution. ICANS may be severe, life-threatening, or fatal.

Symptoms of neurologic side effects include but are not limited to the following: confusion, disorientation, loss of consciousness, seizures, tremor, slower movements, changes in personality, depression, tingling and numbness of hands and feet, leg and arm weakness, facial numbness, and difficulty speaking, reading, or writing. It is important to promptly alert your doctor if there is any change in your health or if you’re not feeling well.

HLH/MAS

Hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS) are aggressive and life-threatening inflammatory conditions of excessive immune system activation. Fatal HLH/MAS reactions have occurred in patients following treatment with Carvykti. HLH/MAS can occur with CRS or with neurologic toxicities. It is important to promptly alert your doctor if there is any change in your health or if you’re not feeling well.

Cytopenias

Cytopenia is a condition in which there is a lower-than-normal number of one or more than one of your blood cell types. Prolonged or recurrent cytopenias have occurred following treatment with Carvykti, with bleeding and infection requiring support with growth factors or blood product transfusion. One or more recurrences of cytopenias are possible after partial or complete recovery of cytopenias. Neutropenia, a reduced level of a type of white blood cells called neutrophils, is associated with increased risk of infection. It is important to promptly alert your doctor if you develop fever, chills, or any other signs or symptoms of an infection.

Hypogammaglobulinemia

Hypogammaglobulinemia is a laboratory diagnosis made when the immune system is not producing enough immunoglobulin G (IgG) in the blood.

Hypersensitivity reactions

Hypersensitivity reactions are any undesirable reactions produced by the immune system. These reactions may be uncomfortable, damaging, or fatal. Patients receiving Carvykti must be monitored for hypersensitivity reactions during the infusion of Carvykti and for at least 2 hours after.

Secondary malignancies

A secondary malignancy is a new cancer that is unrelated to a pre-existing cancer diagnosis. Secondary cancers that are a consequence of treatment for the initial cancer may occur months or years after the initial treatment.

Possible common side effects of Carvykti

The most common nonlaboratory side effects that occurred in more than 20% of myeloma patients who received Carvykti are pyrexia (fever), CRS, hypogammaglobulinemia, hypotension, musculoskeletal pain, fatigue, pathogen-unspecified infections, cough, chills, diarrhea, nausea, encephalopathy, decreased appetite, upper respiratory tract infection, headache, tachycardia (fast heartbeat), dizziness, dyspnea, edema, viral infections, coagulopathy, constipation, and vomiting.

The most common laboratory side effects that occurred in 50% or more of myeloma patients who received Carvykti include thrombocytopenia, neutropenia, anemia, aminotransferase (enzyme) elevation, and hypoalbuminemia.

It is important to promptly alert your doctor if there is any change in your health or if you’re not feeling well. Be sure to inform your entire healthcare team that you have received Carvykti, as it may cause side effects that are severe or life-threatening. Immediately contact your doctor or get emergency help if you experience any of the following:

¡ Fever of 100.4°F/38°C or higher,

¡ Chills or shivering,

¡ Fast or irregular heartbeat,

¡ Difficulty breathing, shortness of breath,

¡ Very low blood pressure,

¡ Dizziness or lightheadedness,

¡ Effects on your nervous system, which may be subtle and can occur weeks after your infusion of Carvykti: feeling confused, disoriented, less alert, difficulty speaking, slurred speech, memory loss, difficulty reading or writing or understanding words; loss of coordination affecting movement and balance, slower movements, changes in handwriting; personality changes including a reduced ability to express

emotions, being less talkative, disinterest in activities, and reduced facial expression; tingling, numbness and pain in hands and/or feet, difficulty walking, leg and/or arm weakness, and difficulty breathing; facial numbness, difficulty moving muscles of face and eyes.

You must not be given live vaccines for some time before and after Carvykti treatment. Talk to your doctor if you need to have any vaccinations.

Do not donate blood, organs, tissues, or cells for transplantation.

Support for Carvykti patients and care partners

The MyCARVYKTI™ Patient Support Program, sponsored by Janssen Biotech Inc. and Legend Biotech, is designed to help eligible patients and their care partners with support during treatment. Patients who meet financial and other eligibility requirements, and their care partners, may receive assistance with transportation, lodging, and out-of-pocket costs related to meals and other travel expenses associated with treatment at a certified treatment center. MyCARVYKTI™ Patient Support Specialists are available to help guide eligible patients through the enrollment process and assist with program benefits. Call 1.800.559.7875.

In closing

This booklet is not meant to replace the advice of your doctors and nurses who are best able to answer questions about your specific healthcare management plan. The IMF intends only to provide you with information that will guide you in discussions with your healthcare team. To help ensure effective treatment with good quality of life, you must play an active role in your own medical care.

We encourage you to visit myeloma.org for more information about myeloma and to contact the IMF InfoLine with your myeloma-related questions and concerns. The IMF InfoLine consistently provides the most up-to-date and accurate information about myeloma in a caring and compassionate manner. Contact the IMF InfoLine at 1.818.487.7455 or InfoLine@myeloma.org.

Terms and definitions

The following selected terms are used in this booklet, while a more complete compendium of myeloma-related terms can be found in the IMF’s publication Understanding Myeloma Vocabulary located online at glossary.myeloma.org.

B-cell maturation antigen (BCMA): A protein involved in myeloma cell growth and survival. BCMA is found on the surface of cells in all patients with myeloma. Also called “tumor necrosis factor receptor superfamily member 17 (TNFRSF17).”

Cancer: A term for diseases in which malignant cells divide without control. Cancer cells can invade nearby tissues and spread through the bloodstream and lymphatic system to other parts of the body.

Chimeric antigen receptor (CAR) T-cell therapy: In myeloma, this immunotherapy involves collecting the patient’s T cells, engineering them in a laboratory, and multiplying the engineered T cells for re-infusion into the patient to attack the patient’s own myeloma cells.

Chromosome: A strand of DNA and proteins in the nucleus of a cell. Chromosomes contain genes and function in the transmission of genetic information. Normally, human cells contain 46 chromosomes (23 pairs).

• Chromosomal deletion – Genetic mutation in which part or all of a chromosome is lost during DNA replication. Chromosomal deletions that occur in myeloma include loss of the long arm of chromosome 13 (written as 13q–) or loss of the short arm of chromosome 17 (written as 17p–).

• Chromosomal translocation – Genetic mutation in which parts of different chromosomes are rearranged. Written with a lowercase “t” followed by the numbers of the chromosomes with translocated genetic material. Translocations that occur in myeloma include t(4;14), t(11;14), t(14;16), and t(14;20).

Cytogenetics: Laboratory testing that looks for missing, rearranged, or extra chromosomes. See “Chromosome.”

Enzyme: A protein molecule manufactured by a cell. An enzyme acts as a catalyst that increases the rate of a specific biochemical reaction in the body.

Frontline therapy: A general term for the initial treatment used in an effort to achieve response in a newly diagnosed myeloma patient. See “Induction therapy ” and “ Response or remission.”

Generic drug name: A brand name identifies a drug as property of the company that receives approval for it from a governmental regulatory agency, such as the U.S. Food and Drug Administration (FDA). After a drug goes “off patent,” other companies may make generic versions of the drug under a generic name that refers to the chemical makeup of a drug.

Immune system: A complex network of cells, tissues, organs, and the substances they make. The immune system helps the body defend itself by destroying infected and diseased cells and removing cellular debris, while protecting healthy cells.

Immunomodulatory agent: A drug that can modify, enhance, or suppress the functioning of the immune system. An immunomodulatory agent is sometimes called an “immunomodulatory drug (IMiD®).”

Induction therapy: The initial treatment given to a patient in preparation for an autologous stem cell transplant (ASCT). See “ Frontline therapy ” and “ Line of therapy.”

Line of therapy: A term used to calculate the number of therapies a patient has received. A line of therapy is 1 or more complete cycles of a regimen that can consist of a single agent, a combination of several drugs, or a planned sequential therapy of various regimens. Also see “ Induction therapy.”

Lymphatic system: Also called “lymphoid system,” is a subsystem of the circulatory system that includes our lymph nodes and the channels that connect them. One of its main functions is the production and circulation of immune cells (e.g., lymphocytes, monocytes, and plasma cells). Lymphoid organs include the bone marrow and the thymus.

Median: The mean (middle) of two central numbers in a series of numbers. For example, “median progression-free survival (mPFS)” means that half the patients had remissions that were shorter and half the patients had remissions that were longer than the mPFS.

Minimal residual disease (MRD): The presence of residual tumor cells after treatment has been completed and complete response (CR) has been attained. Even patients who have attained a stringent CR (sCR) may have MRD. Highly sensitive testing methods are able to detect 1 myeloma cell among 1,000,000 sampled cells in blood or bone marrow. See “MRD-negative.”

Monoclonal antibody: An antibody manufactured in a lab rather than produced in the human body. Monoclonal antibodies are specifically designed to find and bind to cancer cells and/or immune system cells for diagnostic or treatment purposes. Monoclonal antibodies can be used alone, or they can be used to deliver drugs, toxins, or radioactive material directly to tumor cells.

MRD-negative: Minimal residual disease-negative. Depending on the test, not even one myeloma cell found in 100,000 or 1,000,000 sampled bone marrow plasma cells. See “Minimal residual disease (MRD).”

Multiple myeloma: A cancer of the bone marrow plasma cells, white blood cells that make antibodies. Cancerous plasma cells are called myeloma cells.

Progression-free survival (PFS): The length of time during and after the treatment of myeloma that a patient lives with the disease but the myeloma does not get worse. In a clinical trial, PFS is one way to measure how well the treatment is working. See “ Progressive disease.”

Progressive disease: Myeloma that is becoming worse or relapsing, as documented by tests. Defined as an increase of ≥ 25% from the lowest confirmed response value in the myeloma protein level and/or new evidence of disease.

Proteasome: A joined group (“complex”) of enzymes (“proteases”) that break down the damaged or unwanted proteins in both normal cells and cancer cells into smaller components. Proteasomes also carry out the regulated breakdown of undamaged proteins in the cell, a process that is necessary for the control of many critical cellular functions. These smaller protein components are then used to create new proteins required by the cell. This is important for maintaining balance within the cell and for regulating cell growth.

Proteasome inhibitor: Any drug that interferes with the normal function of the proteasome. See “ Proteasome.”

Proteins: Substances composed of amino acids. Proteins are an essential part of all living organisms, especially as structural components of body tissues such as muscle, hair, collagen, etc., as well as enzymes and antibodies.

Refractory: Disease that is no longer responsive to standard treatments. Myeloma is refractory in patients who have had progressive disease either during treatment or within 60 days following treatment. Most clinical trials for advanced disease are for patients with relapsed and/or refractory myeloma.

Relapse: The reappearance of signs and symptoms of myeloma after a period of improvement. Patients with relapsed disease have been treated, then developed signs and symptoms of myeloma at least 60 days after treatment ended. Most clinical trials for advanced myeloma are for patients with relapsed and/or refractory disease.

Response or remission: Interchangeable terms to describe the complete or partial disappearance of the signs and symptoms of cancer.

• Stringent complete response (sCR) – sCR is CR (as defined below) plus normal FLC ratio and absence of clonal cells in bone marrow by immunohistochemistry or immunofluorescence.

• Complete response (CR) – For myeloma, CR is negative immunofixation on serum (blood) and urine, and disappearance of any soft tissue plasmacytomas, and ≤ 5% plasma cells in bone marrow. CR is not the same as a cure.

• Very good partial response (VGPR) – VGPR is less than CR. VGPR is serum M-protein and urine M-protein detectable by immunofixation but not on electrophoresis, or 90% or greater reduction in serum M-protein, plus urine M-protein less than 100 mg per 24 hours.

• Partial response (PR) – PR is a level of response in which there is at least a 50% reduction in M-protein, and reduction in 24-hour urinary M-protein by at least 90% (or to less than 200 mg per 24 hours).

Steroid: A type of hormone. Steroidal hormones are produced by the body. Synthetic analogues (equivalents) of some steroids can be manufactured in a laboratory. Dexamethasone, prednisone, and methylprednisolone are synthetic steroids that have multiple effects and are used for many conditions, including myeloma.

T cell (T lymphocyte): A type of white blood cell that originates in the bone marrow but matures in the thymus, a gland beneath the breastbone (sternum). T cells can be distinguished from other lymphocytes by the presence of a T-cell receptor (TCR) on the cell surface. T cells can recognize and bind to specific antigens, thereby triggering an immune response.

White blood cells (WBC): General term for a variety of leukocytes responsible for fighting invading germs, infections, and allergy-causing agents. These cells begin their development in bone marrow and then travel to other parts of the body. Specific white blood cells include neutrophils, basophils, eosinophils, lymphocytes, and monocytes.

INTERACTIVE RESOURCES AT A GLANCE