IDECABTAGENE VICLEUCEL Drug Interactions: What You Need to Know

INTERACTIONS 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.

None. None. ( 4 )

AND PRECAUTIONS

• Hypersensitivity Reactions : Monitor for hypersensitivity reactions during infusion. ( 5.5 )
• Infections : Monitor patients for signs and symptoms of infection; treat appropriately. ( 5.6 )
• Prolonged Cytopenias : Patients may exhibit prolonged Grade 3 or higher cytopenias following ABECMA infusion. Monitor blood counts prior to and after ABECMA infusion. ( 5.7 )
• Hypogammaglobulinemia : Monitor and consider immunoglobulin replacement therapy. ( 5.8 )
• Secondary Malignancies : T cell malignancies have occurred following treatment of hematologic malignancies with BCMA- and CD19-directed genetically modified autologous T cell immunotherapies, including ABECMA. In the event that a secondary malignancy occurs after treatment with ABECMA, contact Bristol-Myers Squibb at 1-888-805-4555. ( 5.9 )

5.1 Early Death In Study 1, a randomized (2:1), controlled trial, a higher proportion of patients experienced death within nine months after randomization in the ABECMA arm (45/254; 18%) compared to the standard regimens arm (15/132; 11%) <span class="opacity-50 text-xs">[see Clinical Studies (14) ]</span> . Early deaths occurred in 8% (20/254) and 0% prior to ABECMA infusion and standard regimen administration, respectively, and 10% (25/254) and 11% (15/132) after ABECMA infusion and standard regimen administration, respectively. Out of the 20 deaths that occurred prior to ABECMA infusion, 15 occurred from disease progression, 3 occurred from adverse events and 2 occurred from unknown causes. Out of the 25 deaths that occurred after ABECMA infusion, 10 occurred from disease progression, 11 occurred from adverse events, and 4 occurred from unknown causes.

5.2 Cytokine Release Syndrome (CRS) CRS, including fatal or life-threatening reactions, occurred following treatment with ABECMA. Among patients receiving ABECMA for relapsed or refractory multiple myeloma in Study 1 and Study 2 (N=349), CRS occurred in 89% (310/349), including ≥ Grade 3 CRS (Lee grading system) in 7% (23/349) of patients and Grade 5 CRS in 0.9% (3/349) of patients. The median time-to-onset of CRS, any grade, was 1 day (range: 1 to 27 days), and the median duration of CRS was 5 days (range: 1 to 63 days). In the pooled studies, the rate of ≥ Grade 3 CRS was 10% (7/71) for patients treated in dose range of 460 to 510 × 10 6 CAR-positive T cells and 5.4% (13/241) for patients treated in dose range of 300 to 460 × 10 6 CAR-positive T cells. The most common manifestations of CRS (≥10%) included pyrexia (87%), hypotension (30%), tachycardia (26%), chills (19%), and hypoxia (16%).

Grade

3 or higher events that may be associated with CRS include hypotension, hypoxia, hyperbilirubinemia, hypofibrinogenemia, ARDS, atrial fibrillation, hepatocellular injury, metabolic acidosis, pulmonary edema, coagulopathy, renal failure, multiple organ dysfunction syndrome and hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS) [see Adverse Reactions (6.1) ] . Identify CRS based on clinical presentation. Evaluate for and treat other causes of fever, hypoxia, and hypotension. CRS has been reported to be associated with findings of HLH/MAS, and the physiology of the syndromes may overlap. HLH/MAS is a potentially life-threatening condition. In patients with progressive symptoms of CRS or refractory CRS despite treatment, evaluate for evidence of HLH/MAS. Please see Section 5.4 ; Hemophagocytic Lymphohistiocytosis/Macrophage Activation Syndrome. Of the 349 patients who received ABECMA in clinical trials, 226 (65%) patients received tocilizumab; 39% (135/349) received a single dose, while 26% (91/349) received more than 1 dose of tocilizumab. Overall, 24% (82/349) of patients received at least 1 dose of corticosteroids for treatment of CRS. Almost all patients who received corticosteroids for CRS also received tocilizumab. For patients treated in dose range of 460 to 510 × 10 6 CAR-positive T cells, 76% (54/71) of patients received tocilizumab and 35% (25/71) received at least 1 dose of corticosteroids for treatment of CRS. For patients treated in dose range of 300 to 460 × 10 6 CAR-positive T cells, 63% (152/241) of patients received tocilizumab and 20% (49/241) received at least 1 dose of corticosteroid for treatment of CRS. Ensure that a minimum of two doses of tocilizumab are available prior to infusion of ABECMA. Monitor patients at least daily for seven days following ABECMA infusion for signs and symptoms of CRS. Continue to monitor patients for signs or symptoms of CRS for at least one week after infusion. At the first sign of CRS, institute treatment with supportive care, tocilizumab and/or corticosteroids as indicated [see Dosage and Administration (2.2) , (2.3) ]. Counsel patients to seek immediate medical attention should signs or symptoms of CRS occur at any time [see Patient Counseling Information (17) ] .

5.3 Neurologic Toxicities Neurologic toxicities, including immune-effector cell-associated neurotoxicity (ICANS), which may be severe or life-threatening, occurred concurrently with CRS, after CRS resolution, or in the absence of CRS following treatment with ABECMA. In patients receiving ABECMA in Study 1 and Study 2, CAR T cell-associated neurotoxicity occurred in 40% (139/349), including Grade 3 in 4% (14/349) and Grade 4 in 0.6% (2/349) of patients. The median time to onset of neurotoxicity was 2 days (range: 1 to 148 days). The median duration of CAR T cell-associated neurotoxicity was 8 days (range: 1 to 720 days) in all patients including those with ongoing neurologic events at the time of death or data cut off. CAR T cell-associated neurotoxicity resolved in 123 of 139 (88%) patients and median time to resolution was 5 days (range: 1 to 245 days). One-hundred and thirty four out of 349 (38%) patients with neurotoxicity had CRS. The onset of neurotoxicity during CRS was observed in 93 patients, before the onset of CRS in 12 patients, and after the CRS event in 29 patients. The rate of Grade 3 or 4 CAR T cell-associated neurotoxicity was 5.6% (4/71) and 3.7% (9/241) for patients treated in dose range of 460 to 510 × 10 6 CAR-positive T cells and 300 to 460 × 10 6 CAR-positive T cells, respectively. The most frequent (≥5%) manifestations of CAR T cell-associated neurotoxicity include encephalopathy (21%), headache (15%), dizziness (8%), delirium (6%), and tremor (6%). At the safety update for Study 1, one patient developed fatal neurotoxicity 43 days after ABECMA.

In Study

2, one patient had ongoing Grade 2 neurotoxicity at the time of death. Two patients had ongoing Grade 1 tremor at the time of data cutoff. Cerebral edema has been associated with ABECMA in a patient in another study in multiple myeloma.

Grade

3 myelitis and Grade 3 parkinsonism have occurred after treatment with ABECMA in another study in multiple myeloma. Monitor patients at least daily for seven days following ABECMA infusion for signs and symptoms of neurologic toxicities. Rule out other causes of neurologic symptoms. Continue to monitor patients for signs or symptoms of neurologic toxicities for at least one week after infusion and treat promptly. Neurologic toxicity should be managed with supportive care and/or corticosteroids as needed [see Dosage and Administration (2.2) , (2.3) ] . Advise patients to avoid driving for at least one week following infusion. Counsel patients to seek immediate medical attention should signs or symptoms of neurologic toxicity occur at any time [see Patient Counseling Information (17) ] .

5.4 Hemophagocytic Lymphohistiocytosis (HLH)/Macrophage Activation Syndrome (MAS) In patients receiving ABECMA in Study 1 and Study 2, HLH/MAS occurred in 2.9% (10/349) of patients. All events of HLH/MAS had onset within 10 days of receiving ABECMA, with a median onset of 6.5 days (range: 4 to 10 days) and occurred in the setting of ongoing or worsening CRS. Five patients with HLH/MAS had overlapping neurotoxicity. The manifestations of HLH/MAS include hypotension, hypoxia, multiple organ dysfunction, renal dysfunction, and cytopenia.

In Study

1, one patient had Grade 5, two patients had Grade 4 and two patients had Grade 3 HLH/MAS. The patient with Grade 5 HLH/MAS also had Grade 5 candida sepsis and Grade 5 CRS. In another patient who died due to stroke, the Grade 4 HLH/MAS had resolved prior to death. Two cases of Grade 3 and one case of Grade 4 HLH/MAS had resolved.

In Study

2, one patient treated in the 300 × 10 6 CAR-positive T cells dose cohort developed fatal multi-organ HLH/MAS with CRS. In another patient with fatal bronchopulmonary aspergillosis, HLH/MAS was contributory to the fatal outcome. Three cases of Grade 2 HLH/MAS resolved. HLH/MAS is a potentially life-threatening condition with a high mortality rate if not recognized early and treated. Treatment of HLH/MAS should be administered per institutional standards.

5.5 Hypersensitivity Reactions Allergic reactions may occur with the infusion of ABECMA. Serious hypersensitivity reactions, including anaphylaxis, may be due to dimethyl sulfoxide (DMSO) in ABECMA.

5.6 Infections ABECMA should not be administered to patients with active infections or inflammatory disorders. Severe, life‑threatening, or fatal infections occurred in patients after ABECMA infusion. In all patients receiving ABECMA in Study 1 and Study 2, infections (all grades) occurred in 61% of patients.

Grade

3 or 4 infections occurred in 21% of patients.

Grade

3 or 4 infections with an unspecified pathogen occurred in 12%, viral infections in 7%, bacterial infections in 4.3%, and fungal infections in 1.4% of patients. Overall, 15 patients had Grade 5 infections (4.3%); 8 patients (2.3%) with infections of pathogen unspecified, 3 patients (0.9%) with fungal infections, 3 patients (0.9%) with viral infections, and 1 patient (0.3%) with bacterial infection. Monitor patients for signs and symptoms of infection before and after ABECMA infusion and treat appropriately. Administer prophylactic, pre-emptive, and/or therapeutic antimicrobials according to standard institutional guidelines. Febrile neutropenia was observed in 38% (133/349) of patients after ABECMA infusion and may be concurrent with CRS. In the event of febrile neutropenia, evaluate for infection and manage with broad-spectrum antibiotics, fluids, and other supportive care as medically indicated.

Viral Reactivation

Cytomegalovirus (CMV) infection resulting in pneumonia and death has occurred following ABECMA administration. Monitor and treat for CMV reactivation in accordance with clinical guidelines. Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, can occur in patients treated with drugs directed against plasma cells. Perform screening for CMV, HBV, hepatitis C virus (HCV), and human immunodeficiency virus (HIV) in accordance with clinical guidelines before collection of cells for manufacturing. Consider antiviral therapy to prevent viral reactivation per local institutional guidelines/clinical practice.

5.7 Prolonged Cytopenias Patients may exhibit prolonged cytopenias following lymphodepleting chemotherapy and ABECMA infusion. In patients receiving ABECMA in Study 1 and Study 2, 40% of patients (139/349) experienced prolonged Grade 3 or 4 neutropenia and 42% (145/349) experienced prolonged Grade 3 or 4 thrombocytopenia that had not resolved by Month 1 following ABECMA infusion.

In

89% (123/139) of patients who recovered from Grade 3 or 4 neutropenia after Month 1, the median time to recovery from ABECMA infusion was 1.9 months.

In

76% (110/145) of patients who recovered from Grade 3 or 4 thrombocytopenia, the median time to recovery was 1.9 months. Five patients underwent stem cell therapy for hematopoietic reconstitution due to prolonged cytopenia. The rate of Grade 3 or 4 thrombocytopenia was 62% (44/71) and 56% (135/241) for patients treated in dose range of 460 to 510 × 10 6 CAR-positive T cells and 300 to 460 × 10 6 CAR-positive T cells, respectively. Monitor blood counts prior to and after ABECMA infusion. Manage cytopenia with myeloid growth factor and blood product transfusion support according to local institutional guidelines.

5.8 Hypogammaglobulinemia Plasma cell aplasia and hypogammaglobulinemia can occur in patients receiving treatment with ABECMA. In all patients receiving ABECMA in Study 1 and Study 2, hypogammaglobulinemia was reported as an adverse event in 13% (46/349) of patients; laboratory IgG levels fell below 500 mg/dL after infusion in 37% (130/349) of patients treated with ABECMA. Hypogammaglobulinemia either as an adverse reaction or laboratory IgG level below 500 mg/dL after infusion occurred in 45% (158/349) of patients treated with ABECMA. Forty-one percent of patients received intravenous immunoglobulin (IVIG) post-ABECMA for serum IgG &lt;400 mg/dL. Monitor immunoglobulin levels after treatment with ABECMA and administer IVIG for IgG &lt;400 mg/dL. Manage per local institutional guidelines, including infection precautions and antibiotic or antiviral prophylaxis. Use of Live Vaccines The safety of immunization with live viral vaccines during or following ABECMA treatment has not been studied. Vaccination with live virus vaccines is not recommended for at least six weeks prior to the start of lymphodepleting chemotherapy, during ABECMA treatment, and until immune recovery following treatment with ABECMA.

5.9 Secondary Malignancies Patients treated with ABECMA may develop secondary malignancies.

In Study

1, myeloid neoplasms (four cases of myelodysplastic syndrome and one case of acute myeloid leukemia) occurred in 2.2% (5/222) of patients following treatment with ABECMA compared to none in the standard regimens arm at the time of the safety update. The median time to onset of myeloid neoplasm from ABECMA infusion was 338 days (Range: 277 to 794 days). Three of these five patients have died following the development of myeloid neoplasm. One out of the five cases of myeloid neoplasm occurred after initiation of subsequent antimyeloma therapy. T cell malignancies have occurred following treatment of hematologic malignancies with BCMA- and CD19‑directed genetically modified autologous T cell immunotherapies, including ABECMA. Mature T cell malignancies, including CAR-positive tumors, may present as soon as weeks following infusion, and may include fatal outcomes [see Boxed Warning , Adverse Reactions (6.3) , Patient Counseling Information (17) ] . Monitor life-long for secondary malignancies. In the event that a secondary malignancy occurs, contact Bristol-Myers Squibb at 1‑888‑805‑4555 for reporting and to obtain instructions on collection of patient samples for testing of secondary malignancy.