ABECMA

ABECMA is a BCMA-directed genetically modified autologous T cell immunotherapy product consisting of a patient's own T cells that are harvested and genetically modified ex vivo through transduction with an anti-BCMA02 chimeric antigen receptor (CAR) lentiviral vector (LVV). Autologous T cells transduced with the anti-BCMA02 CAR LVV express the anti-BCMA CAR on the T cell surface. The CAR is comprised of a murine extracellular single-chain variable fragment (scFv) specific for recognizing B cell maturation antigen (BCMA) followed by a human CD8α hinge and transmembrane domain fused to the T cell cytoplasmic signaling domains of CD137 (4-1BB) and CD3ζ chain, in tandem. Binding of ABECMA to BCMA-expressing target cells leads to signaling initiated by CD3ζ and 4-1BB domains, and subsequent CAR-positive T cell activation. Antigen-specific activation of ABECMA results in CAR-positive T cell proliferation, cytokine secretion, and subsequent cytolytic killing of BCMA-expressing cells. ABECMA is prepared from the patient's peripheral blood mononuclear cells (PBMCs), which are obtained via a standard leukapheresis procedure. The mononuclear cells are enriched for T cells, through activation with anti-CD3 and anti-CD28 antibodies in the presence of IL-2, which are then transduced with the replication-incompetent lentiviral vector containing the anti-BCMA CAR transgene. The transduced T cells are expanded in cell culture, washed, formulated into a suspension, and cryopreserved. The product must pass a sterility test before release for shipping as a frozen suspension in one or more patient-specific infusion bag(s). The product is thawed prior to infusion back into the patient [see Dosage and Administration (2.3) and How Supplied/Storage and Handling (16) ] . The ABECMA formulation contains 50% Plasma-Lyte A and 50% CryoStor ® CS10, resulting in a final DMSO concentration of 5%.

ABECMA is indicated for the treatment of adult patients with relapsed or refractory multiple myeloma after two or more prior lines of therapy including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody. ABECMA is a B-cell maturation antigen (BCMA)-directed genetically modified autologous T cell immunotherapy indicated for the treatment of adult patients with relapsed or refractory multiple myeloma after two or more prior lines of therapy including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody. ( 1 )

For autologous use only. For intravenous use only. • Do NOT use a leukodepleting filter. ( 2.2 ) • Administer a lymphodepleting chemotherapy regimen of cyclophosphamide and fludarabine before infusion of ABECMA. ( 2.2 ) • Confirm the patient's identity prior to infusion. ( 2.2 ) • Premedicate with acetaminophen and an H 1 -antihistamine. ( 2.2 ) • Avoid prophylactic use of dexamethasone or other systemic corticosteroids. ( 2.2 ) • Confirm availability of tocilizumab prior to infusion. ( 2.2 , 5.2 ) • Dosing of ABECMA is based on the number of chimeric antigen receptor (CAR)-positive T cells. ( 2.1 ) • The recommended dose range is 300 to 510 × 10 6 CAR-positive T cells. ( 2.1 ) 2.1 Dose For autologous use only. For intravenous use only. ABECMA is provided as a single dose for infusion containing a suspension of chimeric antigen receptor (CAR)-positive T cells in one or more infusion bags. The recommended dose range is 300 to 510 × 10 6 CAR-positive T cells. See the accompanying Release for Infusion Certificate (RFI Certificate) for additional information pertaining to dose [see How Supplied/Storage and Handling (16) ] . 2.2 Administration ABECMA is for autologous use only. The patient's identity must match the patient identifiers on the ABECMA cassette(s) and infusion bag(s). Do not infuse ABECMA if the information on the patient-specific label(s) does not match the intended patient. Preparing Patient for ABECMA Infusion Confirm the availability of ABECMA prior to starting the lymphodepleting chemotherapy regimen. Pretreatment Administer the lymphodepleting chemotherapy regimen: cyclophosphamide 300 mg/m 2 intravenously (IV) and fludarabine 30 mg/m 2 IV for three days. See the prescribing information of cyclophosphamide and fludarabine for information on dose adjustment in renal impairment. Administer ABECMA two days after completion of lymphodepleting chemotherapy. Delay the infusion of ABECMA up to seven days if a patient has any of the following conditions: • unresolved serious adverse events (especially pulmonary events, cardiac events, or hypotension), including those after preceding chemotherapies. • active infections or inflammatory disorders [see Warnings and Precautions (5.6) ] . Premedication Administer acetaminophen (650 mg orally) and diphenhydramine (12.5 mg IV or 25 to 50 mg orally, or another H 1 -antihistamine) approximately 30 to 60 minutes before infusion of ABECMA. Avoid prophylactic use of dexamethasone or other systemic corticosteroids, as the use may interfere with the activity of ABECMA. Receipt of ABECMA • ABECMA is shipped directly to the cell laboratory or clinical pharmacy associated with the infusion center in the vapor phase of a liquid nitrogen shipper. • Confirm the patient's identity with the patient identifiers on the shipper. • If the patient is not expected to be ready for same-day administration before the shipper expires and the infusion site is qualified for onsite storage, transfer ABECMA to onsite vapor phase of liquid nitrogen storage. • If the patient is not expected to be ready for same-day administration before the shipper expires and the infusion site is not qualified for onsite storage, contact Bristol-Myers Squibb at 1-888-805-4555 to arrange for return shipment. Preparation of ABECMA for Infusion 1. Coordinate the timing of ABECMA thaw and infusion. Confirm the infusion time in advance and adjust the start time of the thaw of ABECMA so that it will be available for infusion when the patient is ready. 2. Prior to thawing the product, confirm that tocilizumab and emergency equipment are available prior to the infusion and during the recovery period. 3. An ABECMA dose may be contained in one or more patient-specific infusion bag(s). The infusion bag is overwrapped with a transparent plastic sleeve that is folded to the back of the infusion bag. Verify the number of bags received for the indicated dose of ABECMA prior to preparation of ABECMA for infusion. 4. Confirm patient identity: Prior to preparation of ABECMA, match the patient's identity with the patient identifiers on the ABECMA cassette(s), infusion bag(s), and the RFI Certificate. Note: The patient identifier number may be preceded by the letters DIN or Aph ID. 5. Do not remove the ABECMA infusion bag(s) from the cassette(s) if the information on the patient-specific cassette label(s) does not match the intended patient. Contact Bristol-Myers Squibb at 1-888-805-4555 if there are any discrepancies between the labels and the patient identifiers. 6. Once patient identity is confirmed, remove the ABECMA infusion bag(s) with the overwrap sleeve from the cassette(s) and check that the patient information on the cassette label(s) matches the patient information on the bag label(s). Figure 1: ABECMA Bag Label(s) 7. Inspect the infusion bag(s) in the overwrap sleeve for any breaches of container integrity such as breaks or cracks before thawing. If the bag(s) is compromised, do not administer and contact Bristol-Myers Squibb at 1-888-805-4555. 8. If more than one infusion bag has been received to achieve the treatment dose, thaw each infusion bag one at a time. Do not initiate thaw of the next bag until infusion of the previous bag is complete. 9. Place the infusion bag(s) inside a second sterile bag per local guidelines. 10. Thaw ABECMA infusion bag(s) in the overwrap at approximately 37°C using an approved thaw device or water bath until there is no visible ice in the infusion bag. Gently mix the contents of the bag to disperse visible clumps of cellular material. Small clumps of cellular material may persist despite gentle manual mixing. Do not wash, spin down, and/or resuspend ABECMA in new media prior to infusion. 11. Remove the infusion bag from the overwrap by unfolding the plastic sleeve at the back to expose the infusion bag. Gently pull the infusion bag out of the overwrap. 12. ABECMA should be administered within one hour of the initiation of the thaw process. ABECMA is stable for two hours at room temperature once thawed. Figure 1 ABECMA ABECMA Administration • For autologous use only. • Do NOT use a leukodepleting filter. • Confirm tocilizumab and emergency equipment are available prior to infusion and during the recovery period. • Central venous access may be utilized for the infusion of ABECMA and is encouraged in patients with poor peripheral access. 1. Confirm that the patient's identity matches the patient identifiers on the ABECMA infusion bag(s). 2. Prime the tubing of the infusion set with normal saline prior to infusion. An infusion set with an in-line filter (non-leukodepleting filter with a pore size range of 170 to 260 µm) can be used for thawed products with visible clumps of cellular material that do not disperse after gentle manual mixing. 3. Infuse the entire contents of the ABECMA infusion bag within one hour after start of thaw by gravity flow. 4. After the entire content of the infusion bag is infused, rinse the tubing, inclusive of the in-line filter if used, with 30 to 60 mL of normal saline at the same infusion rate to ensure as many cells as possible are infused into the patient. 5. If more than one infusion bag is received, administer all bags as directed, following steps 1-4 for each bag. Do not initiate thaw of the next bag until infusion of the previous bag is complete. ABECMA 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 of ABECMA to avoid potential transmission of infectious diseases. Monitoring • Monitor patients at least daily for seven days following ABECMA infusion for signs and symptoms of CRS and neurologic toxicities [see Warnings and Precautions (5.2 , 5.3) ] . • Instruct patients to remain within proximity of a healthcare facility for at least one week following infusion. • Advise patients to avoid driving for at least one week following infusion. 2.3 Management of Severe Adverse Reactions Cytokine Release Syndrome (CRS) Identify CRS based on clinical presentation [see Warnings and Precautions (5.2) ] . Evaluate for and treat other causes of fever, hypoxia, and hypotension. If CRS is suspected, manage according to the recommendations in Table 1. Physicians may also consider management per current practice guidelines. Patients who experience CRS should be closely monitored for cardiac and organ function until resolution of symptoms. Consider antiseizure prophylaxis with levetiracetam in patients who experience CRS. Patients who experience Grade 2 or higher CRS (e.g., hypotension not responsive to fluids, or hypoxia requiring supplemental oxygenation) should be monitored with continuous cardiac telemetry and pulse oximetry. For severe or life-threatening CRS, consider intensive care unit level monitoring and supportive therapy. For CRS refractory to first line interventions such as tocilizumab or tocilizumab and corticosteroids, consider alternate treatment options (i.e., higher corticosteroid dose, alternative anti-cytokine agents, anti-T cell therapies). Refractory CRS is characterized by fevers, end-organ toxicity (e.g., hypoxia, hypotension) not improving within 12 hours of first line interventions or development of hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS). 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 • Antiseizure medication according to the neurologic toxicity in Table 2 Table 1: CRS Grading and Management Guidance CRS Grade a Tocilizumab b Corticosteroids c Grade 1 Symptoms require symptomatic treatment only (e.g., fever, nausea, fatigue, headache, myalgia, malaise). If onset 72 hours or more after infusion, treat symptomatically. If onset less than 72 hours after infusion, consider tocilizumab 8 mg/kg IV over 1 hour (not to exceed 800 mg). Consider dexamethasone 10 mg IV every 24 hours. Grade 2 Symptoms require and respond to moderate intervention. Oxygen requirement less than 40% FiO 2 or hypotension responsive to fluids, or low dose of one vasopressor, or Grade 2 organ toxicity. Administer tocilizumab 8 mg/kg IV over 1 hour (not to exceed 800 mg). Repeat tocilizumab every 8 hours as needed if not responsive to intravenous fluids or increasing supplemental oxygen. Limit to a maximum of 3 doses in a 24-hour period; maximum total of 4 doses. Consider dexamethasone 10 mg IV every 12-24 hours. If no improvement within 24 hours or rapid progression, repeat tocilizumab and escalate dose and frequency of dexamethasone (20 mg IV every 6 to 12 hours). If no improvement within 24 hours or continued rapid progression, switch to methylprednisolone 2 mg/kg followed by 2 mg/kg divided 4 times per day. After 2 doses of tocilizumab, consider alternative anti-cytokine agents. Do not exceed 3 doses of tocilizumab in 24 hours, or 4 doses in total. Grade 3 Symptoms require and respond to aggressive intervention. Fever, oxygen requirement ≥40% FiO 2 , or hypotension requiring high-dose or multiple vasopressors, or Grade 3 organ toxicity or Grade 4 transaminitis. Per Grade 2 Administer dexamethasone 10 mg IV every 12 hours. If no improvement within 24 hours or rapid progression, repeat tocilizumab and escalate dose and frequency of dexamethasone (20 mg IV every 6 to 12 hours). If no improvement within 24 hours or continued rapid progression, switch to methylprednisolone 2 mg/kg followed by 2 mg/kg divided 4 times per day. After 2 doses of tocilizumab, consider alternative anti-cytokine agents. Do not exceed 3 doses of tocilizumab in 24 hours, or 4 doses in total. Grade 4 Life-threatening symptoms. Requirements for ventilator support, continuous veno-venous hemodialysis (CVVHD), or Grade 4 organ toxicity (excluding transaminitis). Per Grade 2 Administer dexamethasone 20 mg IV every 6 hours. After 2 doses of tocilizumab, consider alternative anti-cytokine agents. Do not exceed 3 doses of tocilizumab in 24 hours, or 4 doses in total. If no improvement within 24 hours, consider methylprednisolone (1-2 g, repeat every 24 hours if needed; taper as clinically indicated) or other anti-T cell therapies. a Lee criteria for grading CRS (Lee et al., 2014). b Refer to tocilizumab Prescribing Information for details. c If corticosteroids are initiated, continue corticosteroids for at least 3 doses, and taper over a maximum of seven days. Neurologic Toxicity Monitor patients for signs and symptoms of neurologic toxicities (Table 2). Rule out other causes of neurologic signs or symptoms. Provide intensive care supportive therapy for severe or life-threatening neurologic toxicities. If neurologic toxicity is suspected, manage according to the recommendations in Table 2. Physicians may also consider management per current practice guidelines. 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 • Antiseizure medication according to neurologic toxicity in Table 2 Table 2: Neurologic Toxicity Grading and Management Guidance Neurologic Toxicity Grade a Corticosteroids and Antiseizure Medications a NCI CTCAE criteria for grading neurologic toxicities version 4.03. Grade 1 Start non-sedating, antiseizure medicines (e.g., levetiracetam) for seizure prophylaxis. If 72 hours or more after infusion, observe patient. If less than 72 hours after infusion, consider dexamethasone 10 mg IV every 12 to 24 hours for 2 to 3 days. Grade 2 Start non-sedating, antiseizure medicines (e.g., levetiracetam) for seizure prophylaxis. Start dexamethasone 10 mg IV every 12 hours for 2-3 days, or longer for persistent symptoms. Consider taper for a total corticosteroid exposure of >3 days. Corticosteroids are not recommended for isolated Grade 2 headaches. If no improvement after 24 hours or worsening of neurologic toxicity, increase the dose and/or frequency of dexamethasone up to a maximum of 20 mg IV every 6 hours. Grade 3 Start non-sedating, antiseizure medicines (e.g., levetiracetam) for seizure prophylaxis. Start dexamethasone 10 to 20 mg IV every 6 to 12 hours. Corticosteroids are not recommended for isolated Grade 3 headaches. If no improvement after 24 hours or worsening of neurologic toxicity, escalate to methylprednisolone (2 mg/kg loading dose, followed by 2 mg/kg divided into 4 times a day; taper within 7 days). If cerebral edema is suspected, consider hyperventilation and hyperosmolar therapy. Give high-dose methylprednisolone (1-2 g, repeat every 24 hours if needed; taper as clinically indicated) and cyclophosphamide 1.5 g/m 2 . Grade 4 Start non-sedating, antiseizure medicines (e.g., levetiracetam) for seizure prophylaxis. Start dexamethasone 20 mg IV every 6 hours. If no improvement after 24 hours or worsening of neurologic toxicity, escalate to high-dose methylprednisolone (1-2 g, repeat every 24 hours if needed; taper as clinically indicated). If cerebral edema is suspected, consider hyperventilation and hyperosmolar therapy. Give high-dose methylprednisolone (1-2 g, repeat every 24 hours if needed; taper as clinically indicated), and cyclophosphamide 1.5 g/m 2 .

None. None. ( 4 )

The following adverse reactions are described elsewhere in the labeling: • Early Death [see Warnings and Precautions (5.1) , Clinical Studies (14) ] • Cytokine Release Syndrome [see Warnings and Precautions (5.2) ] • Neurologic Toxicities [see Warnings and Precautions (5.3) ] • Hemophagocytic Lymphohistiocytosis (HLH)/Macrophage Activation Syndrome (MAS) [see Warnings and Precautions (5.4) ] • Hypersensitivity Reactions [see Warnings and Precautions (5.5) ] • Infections [see Warnings and Precautions (5.6) ] • Prolonged Cytopenias [see Warnings and Precautions (5.7) ] • Hypogammaglobulinemia [see Warnings and Precautions (5.8) ] The most common nonlaboratory adverse reactions (incidence ≥20%) include pyrexia, CRS, hypogammaglobulinemia, infections–pathogen unspecified, musculoskeletal pain, fatigue, febrile neutropenia, hypotension, tachycardia, diarrhea, nausea, headache, chills, upper respiratory tract infection, encephalopathy, edema, dyspnea and viral infections. ( 6.1 ) The most common Grade 3 or 4 laboratory adverse reactions (incidence ≥50%) include leukocyte count decreased, neutrophil count decreased, lymphocyte count decreased, platelet count decreased, and hemoglobin decreased. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Bristol-Myers Squibb at 1-800-721-5072 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The safety data described in the WARNINGS and PRECAUTIONS section reflect exposure to ABECMA in 349 patients with relapsed or refractory multiple myeloma: one randomized, open-label study with 222 patients in Study 1 and one single-arm, open-label study with 127 patients in Study 2. Study 1 The safety data described in this section reflect the exposure to ABECMA in Study 1, in which 222 patients with relapsed or refractory multiple myeloma received ABECMA across a dose range of 175 to 529 × 10 6 CAR-positive T cells (median dose: 445 × 10 6 CAR-positive T cells) [see Clinical Studies (14) ] . Patients with a history of CNS disease or requiring ongoing treatment with chronic immunosuppression were excluded. The median age of the safety population was 63 years (range: 30 to 81 years); 43% were 65 years or older, and 63% were men. The Eastern Cooperative Oncology Group (ECOG) performance status at baseline was 0 in 47%, 1 in 51%, 2 in 1.4% and 3 in 0.5% of patients. Four (1.8%) patients treated with ABECMA had creatinine clearance <45 mL/min. For details about the study population, [see Clinical Studies (14) ] . The most common (≥10%) Grade 3 or 4 nonlaboratory adverse reactions was febrile neutropenia (51%) and any infections (16%). The most common nonlaboratory adverse reactions (incidence ≥20%) included CRS, pyrexia, any infection, febrile neutropenia, hypogammaglobulinemia, musculoskeletal pain, hypotension, infections–pathogen unspecified, fatigue, tachycardia, diarrhea, nausea, headache, encephalopathy, dyspnea and edema. Serious adverse reactions occurred in 43% of patients. The most common nonlaboratory (≥5%) serious adverse reactions included infections–pathogen unspecified (10%), pneumonia (9%), viral infections (8%), encephalopathy (6%), pyrexia (6%) and sepsis (5%). Fatal adverse reactions occurred in 9%. Table 3 summarizes the adverse reactions that occurred in at least 10% of patients treated with ABECMA. Table 4 describes the most common Grade 3 or 4 laboratory abnormalities. Table 3: Adverse Reactions Observed in at Least 10% of Patients Treated in Study 1 CAR=chimeric antigen receptor. * Represents multiple related terms. a Coagulopathy includes activated partial thromboplastin time prolonged, blood fibrinogen decreased, coagulopathy, disseminated intravascular coagulation, hypofibrinogenemia, international normalized ratio increased, prothrombin time prolonged. b Encephalopathy includes amnesia, cognitive disorder, confusional state, depressed level of consciousness, disturbance in attention, dysgraphia, encephalopathy, Immune effector cell-associated neurotoxicity syndrome incoherent, lethargy, memory impairment, mental status changes, metabolic encephalopathy, somnolence, stupor, toxic encephalopathy. c Neuropathy includes carpal tunnel syndrome, dysesthesia, hyperesthesia, hypoesthesia, hypoesthesia oral, mononeuropathy, neuralgia, neuritis, neuropathy peripheral, paresthesia, paresthesia oral, peripheral motor neuropathy, peripheral sensorimotor neuropathy, peripheral sensory neuropathy, peroneal nerve palsy, radicular pain, radiculopathy, sacral radiculopathy, sciatica, sensory loss, toxic neuropathy. ABECMA (N=222) Standard Regimens (N=126) Any Grade (%) Grade 3 or 4 (%) Any Grade (%) Grade 3 or 4 (%) Blood and lymphatic system disorders Febrile neutropenia 51 51 28 28 Coagulopathy a 14 2.7 4.8 0.8 Cardiac disorders Tachycardia * 32 0 21 0 Gastrointestinal disorders Diarrhea * 31 2.3 35 3.2 Nausea 27 0.9 48 0 Constipation 17 0 15 0 Vomiting * 14 0 17 0 Abdominal pain * 10 0.5 14 0 General disorders and administration site conditions Pyrexia 91 9 53 6 Fatigue * 33 1.4 48 4 Edema * 20 0.5 28 2.4 Chills 19 0.5 13 0 Immune system disorders Cytokine release syndrome 91 4.1 40 0.8 Hypogammaglobulinemia 48 0.9 25 0 Infections and infestations Any infection 56 16 64 18 Infections–pathogen unspecified * 35 9 40 11 Upper respiratory tract infection * 19 1.8 17 0.8 Infections–viral * 18 5 28 6 Infections–bacterial * 15 4.5 19 8 Pneumonia * 13 8 13 11 Metabolism and nutrition disorders Decreased appetite 17 1.8 21 0 Musculoskeletal and connective tissue disorders Musculoskeletal pain * 36 1.8 49 8 Nervous system disorders Headache * 24 0 29 1.6 Encephalopathy b 22 3.6 21 4.8 Dizziness * 14 1.8 18 3.2 Neuropathy c 10 0 21 0.8 Psychiatric disorders Sleep disorder * 11 0 22 2.4 Renal and urinary disorders Renal failure * 13 5 15 4 Respiratory, thoracic, and mediastinal disorders Dyspnea * 21 1.8 31 2.4 Cough * 14 0 21 0 Hypoxia * 18 6 8 1.6 Vascular disorders Hypotension * 36 2.3 19 1.6 Hypertension 14 7 21 11 Skin disorders Rash * 10 0 19 0.8 Other clinically important adverse reactions that occurred in less than 10% of patients treated with ABECMA include the following: • Cardiac disorders: cardiac arrhythmia (7%) • Gastrointestinal disorders: gastrointestinal hemorrhage (0.5%) • Immune system disorders: hemophagocytic lymphohistiocytosis (2.3%) • Infections and infestations: infections-fungal (5%), sepsis (6%) • Musculoskeletal and connective tissue disorders: motor dysfunction (9%) • Nervous system disorders: tremor (4.1%), aphasia (3.2%), ataxia (2.3%), seizure (0.5%) • Psychiatric disorders: anxiety (4.1%), delirium (7%) • Respiratory, thoracic, and mediastinal disorders: pulmonary edema (1.4%) • Vascular disorders: thrombosis (3.2%) Laboratory Abnormalities Table 4 presents the most common Grade 3 or 4 laboratory abnormalities, based on laboratory data, occurring in at least 10% of patients. Table 4: Grade 3 or 4 a Laboratory Abnormalities Worsening from Baseline in at Least 10% of Patients Treated in Study 1 CAR=chimeric antigen receptor; CTCAE=Common Terminology Criteria for Adverse Events; NCI=National Cancer Institute. a Laboratory tests were graded according to NCI CTCAE Version 4.03. Laboratory Abnormality ABECMA N=222 (%) Standard Regimens N=126 (%) Grade 3 or 4 (%) Grade 3 or 4 (%) Lymphocyte decreased 98 78 Leukocyte decreased 96 64 Neutrophil decreased 96 72 Platelet decreased 59 46 Hemoglobin decreased 52 45 Phosphate decreased 45 30 Triglyceride increased 21 10 Alanine aminotransferase increased 13 8 Sodium decreased 11 7 Gamma-glutamyltransferase increased 10 6 Other clinically important Grade 3 or 4 laboratory abnormalities (based on laboratory data) that occurred in less than 10% of patients treated with ABECMA include the following: aspartate aminotransferase increased, potassium decreased, albumin decreased, alkaline phosphatase increased, calcium decreased, glucose increased, activated partial thromboplastin time increased (seconds), fibrinogen decreased, bilirubin increased and hypomagnesemia. Study 2 The safety data described in this section reflect the exposure to ABECMA in Study 2, in which 127 patients with relapsed/refractory multiple myeloma received ABECMA across a dose range of 150 to 518 × 10 6 CAR-positive T cells [see Clinical Studies (14) ] . Patients with a history of CNS disease (such as seizure or cerebrovascular ischemia) or requiring ongoing treatment with chronic immunosuppression were excluded. The median duration of follow-up was 11.4 months. The median age of the study population was 61 years (range: 33 to 78 years); 35% were 65 years or older, and 60% were men. The Eastern Cooperative Oncology Group (ECOG) performance status at baseline was 0 in 45%, 1 in 53%, and 2 in 2% of patients. Seven percent of the patients treated with ABECMA had creatinine clearance <45 mL/min. For details about the study population, [see Clinical Studies (14) ] . The most common (≥10%) Grade 3 or 4 nonlaboratory adverse reactions were febrile neutropenia (16%) and infections–pathogen unspecified (15%). The most common nonlaboratory adverse reactions (incidence ≥20%) included CRS, infections–pathogen unspecified, fatigue, musculoskeletal pain, hypogammaglobulinemia, diarrhea, upper respiratory tract infection, nausea, viral infections, encephalopathy, edema, pyrexia, cough, headache, and decreased appetite. Serious adverse reactions occurred in 67% of patients. The most common nonlaboratory (≥5%) serious adverse reactions included CRS (18%), general physical health deterioration (10%), pneumonia (12%), infections–pathogen unspecified (19%), viral infections (9%), sepsis (7%), and febrile neutropenia (6%). Fatal adverse reactions occurred in 6%. Table 5 summarizes the adverse reactions that occurred in at least 10% of patients treated with ABECMA. Table 6 describes the most common Grade 3 or 4 laboratory abnormalities. Table 5: Adverse Reactions Observed in at Least 10% of Patients Treated with ABECMA in Study 2 CAR=chimeric antigen receptor. * Represents multiple related terms. a Encephalopathy includes amnesia, bradyphrenia, cognitive disorder, confusional state, depressed level of consciousness, disturbance in attention, dyscalculia, dysgraphia, encephalopathy, lethargy, memory impairment, mental status changes, metabolic encephalopathy, somnolence, toxic encephalopathy. b Neuropathy peripheral includes carpal tunnel syndrome, hypoesthesia, hypoesthesia oral, neuralgia, neuropathy peripheral, paresthesia, peripheral sensorimotor neuropathy, peripheral sensory neuropathy, sciatica. System Organ Class Preferred Term Target Dose of ABECMA (CAR-Positive T Cells) Any Grade Grade 3 or Higher [150 to 450 × 10 6 ] (N=127) % [150 to 450 × 10 6 ] (N=127) % Blood and lymphatic system disorders Febrile neutropenia 16 16 Cardiac disorders Tachycardia * 19 0 Gastrointestinal disorders Diarrhea 35 1.6 Nausea 29 0 Constipation 16 0 Vomiting 15 0 Oral pain * 12 0 General disorders and administration site conditions Fatigue * 45 3.1 Pyrexia 25 1.6 General physical health deterioration 11 10 Edema * 25 0 Chills 11 0 Immune system disorders Cytokine release syndrome 85 9 Hypogammaglobulinemia * 41 0.8 Infections and infestations * Infections–Pathogen unspecified 51 15 Viral infections 27 9 Bacterial infections 15 3.9 Pneumonia * 17 9 Upper respiratory tract infection * 34 1.6 Investigations Weight decreased 13 1.6 Metabolism and nutrition disorders Decreased appetite * 22 0.8 Musculoskeletal and connective tissue disorders Musculoskeletal pain * 45 3.1 Motor dysfunction * 11 0 Nervous system disorders Encephalopathy a 26 6 Headache * 23 0 Dizziness * 17 0.8 Neuropathy peripheral b 17 0.8 Tremor * 10 0 Psychiatric disorders Insomnia * 13 0 Anxiety * 12 0.8 Renal and urinary disorders Renal failure * 10 2.4 Respiratory, thoracic, and mediastinal disorders Cough * 23 0 Dyspnea * 13 2.4 Skin and subcutaneous tissue disorder Rash * 14 0.8 Xerosis * 11 0 Vascular disorders Hypotension * 17 0 Hypertension 11 3.1 Other clinically important adverse reactions that occurred in less than 10% of patients treated with ABECMA include the following: • Blood and lymphatic system disorders: coagulopathy (9%) • Cardiac disorders: atrial fibrillation (4.7%), cardiomyopathy (1.6%) • Gastrointestinal disorders: gastrointestinal hemorrhage (3.1%) • Immune system disorders: hemophagocytic lymphohistiocytosis (3.1%) • Infections and infestations: fungal infections (8%), sepsis (9%) • Nervous system disorders: aphasia (7%), ataxia (3.1%), paresis (2.4%), seizure (1.6%) • Psychiatric disorders: delirium (6%) • Respiratory, thoracic, and mediastinal disorders: hypoxia (2.4%), pulmonary edema (2.4%) • Vascular disorders: thrombosis (3.1%) Laboratory Abnormalities Table 6 presents the most common Grade 3 or 4 laboratory abnormalities, based on laboratory data, occurring in at least 10% of patients. Table 6: Grade 3 or 4 a Laboratory Abnormalities Worsening from Baseline in at Least 10% of Patients Treated with ABECMA in Study 2 Laboratory Abnormality Dose=[150 to 450 × 10 6 CAR-Positive T cells] (N=127) % aPTT=activated partial thromboplastin time; CAR=chimeric antigen receptor; CTCAE=Common Terminology Criteria for Adverse Events; NCI=National Cancer Institute a NCI CTCAE=Common Terminology Criteria for Adverse Events version 4.03. Grade 3 or 4 (%) Neutrophil decreased 96 Leukocyte decreased 96 Lymphocyte decreased 92 Platelet decreased 63 Hemoglobin decreased 63 Phosphate decreased 45 Sodium decreased 10 aPTT increased (seconds) 10 Other clinically important Grade 3 or 4 laboratory abnormalities (based on laboratory data) that occurred in less than 10% of patients treated with ABECMA include the following: alanine aminotransferase increased, aspartate aminotransferase increased, albumin decreased, alkaline phosphatase increased, glucose increased, potassium decreased, bilirubin increased, fibrinogen decreased, and calcium decreased. 6.2 Postmarketing Experience Because adverse events to marketed products are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to product exposure. The following adverse event has been identified during postmarketing use of ABECMA: Nervous system disorders : Immune effector cell-associated neurotoxicity syndrome (ICANS). The following adverse event has been identified during postmarketing use of BCMA- or CD19-directed genetically modified autologous T cell immunotherapies: Neoplasms : T cell malignancies.

Drug/Laboratory Test Interactions HIV and the lentivirus used to make ABECMA have limited, short spans of identical genetic material (RNA). Therefore, some commercial HIV nucleic acid tests may yield false-positive results in patients who have received ABECMA.

Store ABECMA frozen in the vapor phase of liquid nitrogen (less than or equal to minus 130°C). Thaw ABECMA prior to infusion [see Dosage and Administration (2.2) ] .