On December 9, 2024 Bristol Myers Squibb (NYSE: BMY) reported results from 18 presentations reinforcing its leadership in cell therapy, with data demonstrating efficacy, durability and safety of currently available therapies in blood cancers and highlighting the potential of its pipeline for future indications including autoimmune diseases (Press release, Bristol-Myers Squibb, DEC 9, 2024, View Source [SID1234648893]). These results, covering a breadth of potential targets within an expanding range of disease areas, were presented at the 66 th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition in San Diego, California.
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"Cell therapy is one of the fastest-growing modalities across our industry, and we’re committed to unlocking its full potential to deliver transformative treatments to patients with cancer and beyond," said Anne Kerber, senior vice president, head of late clinical development, Hematology, Oncology and Cell Therapy (HOCT), Bristol Myers Squibb. "Our data on Breyanzi and Abecma at ASH (Free ASH Whitepaper) reaffirm how our approved CAR T cell therapies continue to demonstrate favorable long-term outcomes, while results from our pipeline offer potential to address the unmet needs of patients with relapsed or refractory multiple myeloma and severe refractory autoimmune diseases."
Key presentations include:
Long-term analyses reinforcing the durable efficacy and well-established safety profile of Breyanzi (lisocabtagene maraleucel; liso-cel) in large B-cell lymphoma (LBCL), follicular lymphoma (FL) and chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL)
New circulating tumor DNA (ctDNA) data from the Phase 3 TRANSFORM study supporting the superiority of Breyanzi to achieve deeper responses over the former standard of care in second-line LBCL
New analysis highlighting global manufacturing capability, reliability and timely delivery for Abecma (idecabtagene vicleucel; ide-cel) in relapsed or refractory multiple myeloma (RRMM)
First overall and progression-free survival data for arlocabtagene autoleucel (arlo-cel; BMS-986393), a GPRC5D-directed CAR T cell therapy in RRMM
Updated Phase 1 data for CD19 NEX-T CAR T cell therapy (BMS-986353/CC-97540), highlighting its potential to make a meaningful impact for patients with severe, refractory autoimmune diseases including systemic lupus erythematosus, systemic sclerosis, idiopathic inflammatory myopathies, and multiple sclerosis
"We’re excited to disclose the progress of our robust pipeline, with promising early survival results for our GPRC5D-targeted cell therapy underscoring the first-in-class potential of arlocabtagene autoleucel for patients with relapsed or refractory multiple myeloma," said Bryan Campbell, senior vice president, Head of Global Program Leaders, HOCT, Bristol Myers Squibb. "Beyond blood cancers, we’re encouraged by the continued results we are seeing with CD19 NEX-T in autoimmune diseases, like severe lupus, highlighting its possibility as a one-time treatment to provide sustained and treatment-free remission."
Breyanzi Phase 1 TRANSCEND NHL Study Results: Abstract #3125
Five-year overall survival (OS) data from the Phase 1 TRANSCEND NHL 001 study support the deep and durable responses of Breyanzi in patients with relapsed or refractory LBCL (R/R LBCL) with median OS of 27.5 months (95% CI: 16.2–47.3) and an estimated OS rate at 5 years of 38% (95% CI: 32-45), with patients who achieved a complete response (CR) having the longest OS. The median disease-specific survival (DSS) was 67.8 months (95% CI: 23.5 – not reached) and estimated DSS rate at 5 years was 52% (95% CI: 45-59). Breyanzi continued to demonstrate an established safety profile with no new safety signals.
Breyanzi Phase 3 TRANSFORM Study Results: Abstract #72
New ctDNA data from the Phase 3 TRANSFORM study support ctDNA as an early predictor of durable clinical benefit after second-line LBCL treatment with Breyanzi . Patients with undetectable ctDNA in the Breyanzi vs standard of care (SOC) arm had longer event-free survival (EFS) at all predefined time points and had statistically longer EFS at Day 126 which corresponds to post-transplant visit for SOC arm (SOC vs Breyanzi : HR, 3.89 [95% CI: 1.43–10.58]). Among patients who achieved both CR and undetectable ctDNA at Day 126 in the study, Breyanzi provided significantly greater EFS benefit vs SOC (SOC vs Breyanzi in patients with CR and undetectable ctDNA: HR, 6.68 [95% CI: 2.11‒21.19]), supporting a deeper and more durable response with Breyanzi vs SOC. These data underscore the role of ctDNA as a biomarker of response in LBCL and support the superiority of Breyanzi to achieve deeper responses over SOC in second-line LBCL.
Breyanzi Real-World Outcomes in Second-Line LBCL: Abstract #470 and Abstract #472
Real-world data from the Center for International Blood and Marrow Transplant Research (CIBMTR) Registry supported the use of Breyanzi as a second-line salvage therapy and autologous stem cell transplant in R/R LBCL regardless of age, including for younger (under 70 years) and older patients (70 years and older). At a median follow-up of 6.4 months (95% CI: 6.1-6.5; range, 0.2-14.8), overall response rate (ORR) and CR rate in the overall cohort (n=156) were 84% (95% CI: 77–89) and 70% (95% CI: 62-77), respectively. TRANSFORM-ineligible patients (n=105) had an ORR of 84% (95% CI: 75-90) and CR rate of 68% (95% CI: 58–76), while those who might have been eligible (n=51) had an ORR of 84% (95% CI: 71–93) and CR rate of 75% (95% CI: 60-86). Median duration of response (DOR), progression-free survival (PFS), and OS were not reached. The safety profile remained predictable, with cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS) reported in 45% and 20% of patients, respectively.
Additionally, real-world data from the CIBMTR Registry supported the use of Breyanzi as a feasible and effective therapeutic option in real-world patients with R/R LBCL and secondary Central Nervous System (sCNS) involvement. At a median follow up of 12 months (95% CI: 1-24), ORR was 73% (95% CI: 60%–84%) and the CR rate was 64% (95% CI: 50%–77%). The CR rate in this population was similar to that observed in the overall population in the TRANSCEND NHL 001 (NCT02631044) study despite all patients in this study having sCNS involvement. The safety profile of Breyanzi in patients with sCNS was manageable and consistent with pivotal trials and prior real-world reports. CRS, mostly low grade, was reported in 60% of patients, and 58% did not experience any ICANS.
Breyanzi Phase 2 TRANSCEND FL Study Results: Abstract #4387
After two years of follow-up, patients with third-line-plus and second-line high-risk relapsed or refractory follicular lymphoma (R/R FL) who received a single administration of Breyanzi had ORR and CR rates above 94%. For third-line-plus patients, 24-month DOR, PFS and OS were 74.6% (95% CI: 64.8-82.1), 72.5% (95% CI: 62.7-80.1), and 88.2% (95% CI: 80.1-93.1), respectively. For 2L patients, 24-month DOR, PFS and OS were 86.4% (95% CI: 63.4-95.4), 82.6% (95% CI: 60.1-90.3), and 95.7% (95% CI: 72.9-99.4), respectively. Breyanzi continued to demonstrate a safety profile consistent with the primary analysis, with no new safety signals. These data support Breyanzi as a durable and safe treatment option for patients with R/R FL.
Breyanzi Phase 1/2 TRANSCEND CLL 004 Study Results: Abstract #887
Primary analysis results from the Breyanzi plus ibrutinib combination cohort of the Phase 1/2 TRANSCEND CLL 004 trial showed that treatment with Breyanzi plus ibrutinib, a Bruton tyrosine kinase inhibitor (BTKi), resulted in deep remissions (86% ORR [95% CI: 74-94], 45% CR [95% CI: 31-60] rate, and 86% undetectable measurable residual disease (MRD) [95% CI: 74-94] rate in blood), as well as an established safety profile in patients with R/R CLL/SLL. Grade ≥ 3 treatment emergent adverse events (TEAEs) occurred in 48 (86%) of patients, most commonly neutropenia (52%) and anemia (41%), with no Grade 5 TEAEs. The data support this novel combination as a promising therapeutic strategy for patients with R/R CLL/SLL.
Global Manufacturing Results for Abecma : Abstract #3476
A new analysis of 4,117 RRMM patients who underwent leukapheresis for commercial Abecma between February 23, 2021, and May 1, 2024, as captured on the Cell Therapy 360 portal, found that the overall manufacturing success rate (MSR) for Abecma was 96.8% and that the MSR rate improved over 3 years (95.8%, 96.4%, 97.2%, and 98.0% in 2021, 2022, 2023 and 2024, respectively). In addition, the analysis showed consistency in commercial MSR across geographies in 2024 (97.7%, 98.3% and 98.0% in the US, EU and Japan, respectively). These results reinforce the commercial manufacturing reliability for Abecma and ability to meet the increasing global patient demand.
First Disclosure of Phase 1 Efficacy and Safety Results of arlocabtagene autoleucel (BMS-986393): Abstract #922
In an oral presentation, BMS showcased the first OS and progression-free survival (PFS) data for arlo-cel, a GPRC5D-targeted CAR T therapy. In the Phase 1 study, patients had three or more prior anti-multiple myeloma regimens including a proteasome inhibitor, an immunomodulatory agent, and anti-CD38 therapy. After a median follow-up of 16.1 months (range, 2.8-25.2) in efficacy-evaluable patients (n= 79), arlo-cel demonstrated durable responses, with ORR maintained at 87%. MRD was evaluated as an exploratory endpoint, and 57% (48/84) of patients were MRD-evaluable. Results showed that 46% (22/48) of patients were MRD-negative and had a CR/stringent CR (sCR). In all treated patients, 27% (23/84) were MRD-negative and achieved a CR. Median PFS was 18.3 months (95% CI: 11.8-21.9) and median OS was not reached. Treatment-related adverse events (TRAEs), specifically hematological adverse events (AEs), were most common in patients, with neutropenia occurring in 62 (74%) patients. Overall, 69 patients (82%) had CRS. Three patients had macrophage activation syndrome/hemophagocytic lymphohistiocytosis, and ICANS occurred in eight patients. Safety data showed on-target/off-tumor AEs were low frequency, low severity, and mostly self-resolving.
These data support arlo-cel being investigated as a potential first-in-class treatment for heavily pretreated RRMM and its ongoing evaluation in the Phase 2 QUINTESSENTIAL study (NCT06297226).
Updated Data of Phase 1 Study of CD19-Directed CAR T BMS-986353: Abstract #2088
Updated data were presented from a Phase 1 study of CD19 NEX-T (BMS-986353) highlighting the promising efficacy and safety in patients with severe, refractory autoimmune diseases. Safety results were presented for 17 patients, including 2 patients with relapsing-remitting multiple sclerosis (MS), 3 patients with system sclerosis (SSc), 1 patient with idiopathic inflammatory myopathies (IIM), and 11 patients with systemic lupus erythematosus (SLE). In efficacy-evaluable patients with SLE (n=7), significant improvements in Systemic Lupus Erythematosus Disease Activity Index (median score reduction of 10 points at 1 month following BMS-986353 infusion) and Physician Global Assessment (median score reduction of 82% at 1 month following BMS-986353 infusion) were observed, and all patients remained off all autoimmune-directed therapies without evidence of disease flare. Results showed manageable initial safety in patients with autoimmune diseases. CRS was reported in 1 patient with SLE (Grade 1) and 1 patient with SSc (Grade 2), for a duration of one day. ICANS was reported in 1 patient with SSC (Grade 1) and 1 patient with SLE (Grade 3), with a median duration of 3 days. There were no prolonged Grade ≥3 cytopenias or dose-limiting toxicities reported.
These results highlight the potential of BMS-986353 as a one-time infusion of CD19-directed CAR T cell therapy to reset the immune systems of patients with autoimmune diseases, which may provide treatment-free sustained remission.
Bristol Myers Squibb thanks the patients and investigators participating in these cell therapy clinical trials.
Please see the Important Safety Information section below, including Boxed WARNINGS for Breyanzi and Abecma .
About TRANSCEND NHL 001
TRANSCEND NHL 001 (NCT02631044) is an open-label, multicenter, pivotal, Phase 1, single-arm, seamless-design study to determine the safety, pharmacokinetics and antitumor activity of Breyanzi in patients with relapsed or refractory B-cell non-Hodgkin lymphoma, including diffuse large B-cell lymphoma, high-grade B-cell lymphoma, primary mediastinal B-cell lymphoma, follicular lymphoma Grade 3B and mantle cell lymphoma. The primary outcome measures are treatment-related adverse events, dose-limiting toxicities and overall response rate. Secondary outcome measures include complete response rate, duration of response, and progression-free survival.
About TRANSFORM
TRANSFORM (NCT03575351) is a pivotal, global, randomized, multicenter Phase 3 trial evaluating Breyanzi compared to current standard therapy regimens (platinum-based salvage chemotherapy followed by high-dose chemotherapy and HSCT in patients responding to salvage chemotherapy) in patients with large B-cell lymphoma (LBCL) that was primary refractory or relapsed within 12 months after CD20-antibody and anthracycline containing first-line therapy. Patients were randomized to receive Breyanzi or standard of care salvage therapy, including rituximab plus dexamethasone, high-dose cytarabine, and cisplatin (R-DHAP), rituximab plus ifosfamide, carboplatin and etoposide (R-ICE), or rituximab plus gemcitabine, dexamethasone and cisplatin (R-GDP) per the investigators’ choice before proceeding to high-dose chemotherapy (HDCT) and hematopoietic stem cell transplant (HSCT). The primary endpoint of the study was event-free survival (EFS), defined as time from randomization to death from any cause, progressive disease, failure to achieve complete response or partial response, or start of new antineoplastic therapy due to efficacy concerns, whichever occurs first. Complete response (CR) rate was a key secondary endpoint. Other efficacy endpoints included progression-free survival (PFS), overall survival (OS), overall response rate (ORR) and duration of response (DOR).
About TRANSCEND CLL 004
TRANSCEND CLL 004 (NCT03331198) is a Phase 1/2 open-label, single-arm, multicenter study evaluating Breyanzi in patients with relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma. The Phase 1 dose escalation portion of the study assessed the safety and recommended dose for the subsequent Phase 2 expansion cohort. The phase 1 dose-escalation portion includes cohorts assessing liso-cel monotherapy and liso-cel combined with ibrutinib. The Phase 2 portion of the study is evaluating Breyanzi at the recommended dose from the Phase 1 monotherapy arm. The primary endpoint of the Phase 2 portion of the study is complete response rate, including complete remission with incomplete bone marrow recovery, based on independent review committee according to the International Workshop on Chronic Lymphocytic Leukemia (iwCLL) 2018 guidelines.
About Breyanzi
Breyanzi is a CD19-directed CAR T cell therapy with a 4-1BB costimulatory domain, which enhances the expansion and persistence of the CAR T cells. Breyanzi is made from a patient’s own T cells, which are collected and genetically reengineered to become CAR T cells that are then delivered via infusion as a one-time treatment.
Breyanzi is approved in the U.S. for the treatment of relapsed or refractory large B-cell lymphoma (LBCL) after at least one prior line of therapy, and for the treatment of relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma after at least two prior lines of therapy, and for the treatment of relapsed or refractory follicular lymphoma in adult patients who have received two or more prior lines of systemic therapy, and for the treatment of relapsed or refractory mantle cell lymphoma in patients who have received at least two prior lines of systemic therapy, including a Bruton tyrosine kinase (BTK) inhibitor. Breyanzi is also approved in Japan and Europe for the second-line treatment of relapsed or refractory LBCL, and in Japan, Europe, Switzerland and Canada for relapsed and refractory LBCL after two or more lines of systemic therapy.
Bristol Myers Squibb’s clinical development program for Breyanzi includes clinical studies in other types of lymphoma. For more information, visit clinicaltrials.gov.
Indications
BREYANZI is a CD19-directed genetically modified autologous T cell immunotherapy indicated for the treatment of:
adult patients with large B-cell lymphoma (LBCL), including diffuse large B-cell lymphoma (DLBCL) not otherwise specified (including DLBCL arising from indolent lymphoma), high-grade B cell lymphoma, primary mediastinal large B-cell lymphoma, and follicular lymphoma grade 3B, who have:
refractory disease to first-line chemoimmunotherapy or relapse within 12 months of first-line chemoimmunotherapy; or
refractory disease to first-line chemoimmunotherapy or relapse after first-line chemoimmunotherapy and are not eligible for hematopoietic stem cell transplantation (HSCT) due to comorbidities or age; or
relapsed or refractory disease after two or more lines of systemic therapy.
Limitations of Use : BREYANZI is not indicated for the treatment of patients with primary central nervous system lymphoma.
adult patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) who have received at least 2 prior lines of therapy, including a Bruton tyrosine kinase (BTK) inhibitor and a B-cell lymphoma 2 (BCL-2) inhibitor. This indication is approved under accelerated approval based on response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s).
adult patients with relapsed or refractory follicular lymphoma (FL) who have received 2 or more prior lines of systemic therapy. This indication is approved under accelerated approval based on response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s).
adult patients with relapsed or refractory mantle cell lymphoma (MCL) who have received at least 2 prior lines of systemic therapy, including a Bruton tyrosine kinase (BTK) inhibitor.
Important Safety Information
WARNING: CYTOKINE RELEASE SYNDROME, NEUROLOGIC TOXICITIES, AND SECONDARY HEMATOLOGICAL MALIGNANCIES
Cytokine Release Syndrome (CRS), including fatal or life-threatening reactions, occurred in patients receiving BREYANZI. Do not administer BREYANZI to patients with active infection or inflammatory disorders. Treat severe or life-threatening CRS with tocilizumab with or without corticosteroids.
Neurologic toxicities, including fatal or life-threatening reactions, occurred in patients receiving BREYANZI, including concurrently with CRS, after CRS resolution, or in the absence of CRS. Monitor for neurologic events after treatment with BREYANZI. Provide supportive care and/or corticosteroids as needed.
T cell malignancies have occurred following treatment of hematologic malignancies with BCMA- and CD19-directed genetically modified autologous T cell immunotherapies, including BREYANZI.
BREYANZI is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the BREYANZI REMS.
Cytokine Release Syndrome
Cytokine release syndrome (CRS), including fatal or life-threatening reactions, occurred following treatment with BREYANZI. In clinical trials of BREYANZI, which enrolled a total of 702 patients with non-Hodgkin lymphoma (NHL), CRS occurred in 54% of patients, including ≥ Grade 3 CRS in 3.2% of patients. The median time to onset was 5 days (range: 1 to 63 days). CRS resolved in 98% of patients with a median duration of 5 days (range: 1 to 37 days). One patient had fatal CRS and 5 patients had ongoing CRS at the time of death. The most common manifestations of CRS (≥10%) were fever, hypotension, tachycardia, chills, hypoxia, and headache.
Serious events that may be associated with CRS include cardiac arrhythmias (including atrial fibrillation and ventricular tachycardia), cardiac arrest, cardiac failure, diffuse alveolar damage, renal insufficiency, capillary leak syndrome, hypotension, hypoxia, and hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS).
Ensure that 2 doses of tocilizumab are available prior to infusion of BREYANZI.
Neurologic Toxicities
Neurologic toxicities that were fatal or life-threatening, including immune effector cell-associated neurotoxicity syndrome (ICANS), occurred following treatment with BREYANZI. Serious events including cerebral edema and seizures occurred with BREYANZI. Fatal and serious cases of leukoencephalopathy, some attributable to fludarabine, also occurred.
In clinical trials of BREYANZI, CAR T cell-associated neurologic toxicities occurred in 31% of patients, including ≥ Grade 3 cases in 10% of patients. The median time to onset of neurotoxicity was 8 days (range: 1 to 63 days). Neurologic toxicities resolved in 88% of patients with a median duration of 7 days (range: 1 to 119 days). Of patients developing neurotoxicity, 82% also developed CRS.
The most common neurologic toxicities (≥5%) included encephalopathy, tremor, aphasia, headache, dizziness, and delirium.
CRS and Neurologic Toxicities Monitoring
Monitor patients daily for at least 7 days following BREYANZI infusion at a REMS-certified healthcare facility for signs and symptoms of CRS and neurologic toxicities and assess for other causes of neurological symptoms. Monitor patients for signs and symptoms of CRS and neurologic toxicities for at least 4 weeks after infusion and treat promptly. At the first sign of CRS, institute treatment with supportive care, tocilizumab, or tocilizumab and corticosteroids as indicated. Manage neurologic toxicity with supportive care and/or corticosteroid as needed. Counsel patients to seek immediate medical attention should signs or symptoms of CRS or neurologic toxicity occur at any time.
BREYANZI REMS
Because of the risk of CRS and neurologic toxicities, BREYANZI is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the BREYANZI REMS. The required components of the BREYANZI REMS are:
Healthcare facilities that dispense and administer BREYANZI must be enrolled and comply with the REMS requirements.
Certified healthcare facilities must have on-site, immediate access to tocilizumab.
Ensure that a minimum of 2 doses of tocilizumab are available for each patient for infusion within 2 hours after BREYANZI infusion, if needed for treatment of CRS.
Further information is available at www.BreyanziREMS.com, or contact Bristol Myers Squibb at 1-866-340-7332.
Hypersensitivity Reactions
Allergic reactions may occur with the infusion of BREYANZI. Serious hypersensitivity reactions, including anaphylaxis, may be due to dimethyl sulfoxide (DMSO).
Serious Infections
Severe infections, including life-threatening or fatal infections, have occurred in patients after BREYANZI infusion. In clinical trials of BREYANZI, infections of any grade occurred in 34% of patients, with Grade 3 or higher infections occurring in 12% of all patients. Grade 3 or higher infections with an unspecified pathogen occurred in 7%, bacterial infections in 3.7%, viral infections in 2%, and fungal infections in 0.7% of patients. One patient who received 4 prior lines of therapy developed a fatal case of John Cunningham (JC) virus progressive multifocal leukoencephalopathy 4 months after treatment with BREYANZI. One patient who received 3 prior lines of therapy developed a fatal case of cryptococcal meningoencephalitis 35 days after treatment with BREYANZI.
Febrile neutropenia developed after BREYANZI infusion in 8% of patients. Febrile neutropenia 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.
Monitor patients for signs and symptoms of infection before and after BREYANZI administration and treat appropriately. Administer prophylactic antimicrobials according to standard institutional guidelines. Avoid administration of BREYANZI in patients with clinically significant, active systemic infections.
Viral reactivation: 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 B cells. In clinical trials of BREYANZI, 35 of 38 patients with a prior history of HBV were treated with concurrent antiviral suppressive therapy. Perform screening for HBV, HCV, and HIV in accordance with clinical guidelines before collection of cells for manufacturing. In patients with prior history of HBV, consider concurrent antiviral suppressive therapy to prevent HBV reactivation per standard guidelines.
Prolonged Cytopenias
Patients may exhibit cytopenias not resolved for several weeks following lymphodepleting chemotherapy and BREYANZI infusion. In clinical trials of BREYANZI, Grade 3 or higher cytopenias persisted at Day 29 following BREYANZI infusion in 35% of patients, and included thrombocytopenia in 25%, neutropenia in 22%, and anemia in 6% of patients. Monitor complete blood counts prior to and after BREYANZI administration.
Hypogammaglobulinemia
B-cell aplasia and hypogammaglobulinemia can occur in patients receiving BREYANZI. In clinical trials of BREYANZI, hypogammaglobulinemia was reported as an adverse reaction in 10% of patients. Hypogammaglobulinemia, either as an adverse reaction or laboratory IgG level below 500 mg/dL after infusion, was reported in 30% of patients. Monitor immunoglobulin levels after treatment with BREYANZI and manage using infection precautions, antibiotic prophylaxis, and immunoglobulin replacement as clinically indicated.
Live vaccines: The safety of immunization with live viral vaccines during or following BREYANZI treatment has not been studied. Vaccination with live virus vaccines is not recommended for at least 6 weeks prior to the start of lymphodepleting chemotherapy, during BREYANZI treatment, and until immune recovery following treatment with BREYANZI.
Secondary Malignancies
Patients treated with BREYANZI may develop secondary malignancies. T cell malignancies have occurred following treatment of hematologic malignancies with BCMA- and CD19-directed genetically modified autologous T cell immunotherapies, including BREYANZI. Mature T cell malignancies, including CAR-positive tumors, may present as soon as weeks following infusion, and may include fatal outcomes. Monitor lifelong 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.
Effects on Ability to Drive and Use Machines
Due to the potential for neurologic events, including altered mental status or seizures, patients receiving BREYANZI are at risk for developing altered or decreased consciousness or impaired coordination in the 8 weeks following BREYANZI administration. Advise patients to refrain from driving and engaging in hazardous occupations or activities, such as operating heavy or potentially dangerous machinery, for at least 8 weeks.
Immune Effector Cell-Associated Hemophagocytic Lymphohistiocytosis-Like Syndrome (IEC-HS)
Immune Effector Cell-Associated Hemophagocytic Lymphohistiocytosis-Like Syndrome (IEC-HS), including fatal or life-threatening reactions, occurred following treatment with BREYANZI. Three of 89 (3%) safety evaluable patients with R/R CLL/SLL developed IEC-HS. Time to onset of IEC-HS ranged from 7 to 18 days. Two of the 3 patients developed IEC-HS in the setting of ongoing CRS and 1 in the setting of ongoing neurotoxicity. IEC-HS was fatal in 2 of 3 patients. One patient had fatal IEC-HS and one had ongoing IEC-HS at time of death. IEC-HS is a life-threatening condition with a high mortality rate if not recognized and treated early. Treatment of IEC-HS should be administered per current practice guidelines.
Adverse Reactions
The most common adverse reaction(s) (incidence ≥30%) in:
LBCL are fever, cytokine release syndrome, fatigue, musculoskeletal pain, and nausea. The most common Grade 3-4 laboratory abnormalities include lymphocyte count decrease, neutrophil count decrease, platelet count decrease, and hemoglobin decrease.
CLL/SLL are cytokine release syndrome, encephalopathy, fatigue, musculoskeletal pain, nausea, edema, and diarrhea. The most common Grade 3-4 laboratory abnormalities include neutrophil count decrease, white blood cell decrease, hemoglobin decrease, platelet count decrease, and lymphocyte count decrease.
FL is cytokine release syndrome. The most common Grade 3-4 laboratory abnormalities include lymphocyte count decrease, neutrophil count decrease, and white blood cell decrease.
MCL are cytokine release syndrome, fatigue, musculoskeletal pain, and encephalopathy. The most common Grade 3-4 laboratory abnormalities include neutrophil count decrease, white blood cell decrease, and platelet count decrease.
Please see full Prescribing Information , including Boxed WARNINGS and Medication Guide .
About Abecma
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. Abecma is being jointly developed and commercialized in the U.S. as part of a Co-Development, Co-Promotion, and Profit Share Agreement between Bristol Myers Squibb and 2seventy bio.
Abecma U.S. Indication
ABECMA (idecabtagene vicleucel) 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.
U.S. Important Safety Information
WARNING: CYTOKINE RELEASE SYNDROME, NEUROLOGIC TOXICITIES, HLH/MAS, PROLONGED CYTOPENIA and SECONDARY HEMATOLOGICAL MALIGNANCIES
Cytokine Release Syndrome (CRS), including fatal or life-threatening reactions, occurred in patients following treatment with ABECMA. Do not administer ABECMA to patients with active infection or inflammatory disorders. Treat severe or life-threatening CRS with tocilizumab or tocilizumab and corticosteroids.
Neurologic Toxicities, which may be severe or life-threatening, occurred following treatment with ABECMA, including concurrently with CRS, after CRS resolution, or in the absence of CRS. Monitor for neurologic events after treatment with ABECMA. Provide supportive care and/or corticosteroids as needed.
Hemophagocytic Lymphohistiocytosis/Macrophage Activation Syndrome (HLH/MAS) including fatal and life-threatening reactions, occurred in patients following treatment with ABECMA. HLH/MAS can occur with CRS or neurologic toxicities.
Prolonged Cytopenia with bleeding and infection, including fatal outcomes following stem cell transplantation for hematopoietic recovery, occurred following treatment with ABECMA.
T cell malignancies have occurred following treatment of hematologic malignancies with BCMA- and CD19-directed genetically modified autologous T cell immunotherapies, including ABECMA.
ABECMA is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the ABECMA REMS.
Warnings and Precautions:
Early Death: In KarMMa-3, a randomized (2:1), controlled trial, a higher proportion of patients experienced death within 9 months after randomization in the ABECMA arm (45/254; 18%) compared to the standard regimens arm (15/132; 11%). 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.
Cytokine Release Syndrome (CRS): CRS, including fatal or life-threatening reactions, occurred following treatment with ABECMA. Among patients receiving ABECMA for relapsed refractory multiple myeloma in the KarMMa and KarMMa-3 studies (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 x 10 6 CAR-positive T cells and 5.4% (13/241) for patients treated in dose range of 300 to 460 x 10 6 CAR-positive T cells.
The most common manifestations of CRS (greater than or equal to 10%) included pyrexia (87%), hypotension (30%), tachycardia (26%), chills (19%), 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 HLH/MAS.
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.
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 x 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 x 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.
Monitor patients at least daily for 7 days following ABECMA infusion at the REMS-certified healthcare facility for signs or symptoms of CRS and monitor patients for signs or symptoms of CRS for at least 4 weeks after ABECMA infusion. At the first sign of CRS, institute treatment with supportive care, tocilizumab and/or corticosteroids as indicated. Ensure that a minimum of 2 doses of tocilizumab are available prior to infusion of ABECMA. Counsel patients to seek immediate medical attention should signs or symptoms of CRS occur at any time.
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 the KarMMa and KarMMa-3 studies, 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 x 10 6 CAR-positive T cells and 300 to 460 x 10 6 CAR-positive T cells, respectively. The most frequent (greater than or equal to 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 KarMMa-3 study, one patient developed fatal neurotoxicity 43 days after ABECMA. In KarMMa, 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 7 days following ABECMA infusion at the REMS-certified healthcare facility for signs or symptoms of neurologic toxicities and monitor patients for signs or symptoms of neurologic toxicities for at least 4 weeks after ABECMA infusion and treat promptly. Rule out other causes of neurologic symptoms. Neurologic toxicity should be managed with supportive care and/or corticosteroids as needed. Counsel patients to seek immediate medical attention should signs or symptoms occur at any time.
Hemophagocytic Lymphohistiocytosis (HLH)/Macrophage Activation Syndrome (MAS): In patients receiving ABECMA in the KarMMa and KarMMa-3 studies, 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 KarMMa-3, 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 KarMMa, one patient treated in the 300 x 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 guidelines.
ABECMA REMS: Due to the risk of CRS and neurologic toxicities, ABECMA is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the ABECMA REMS. Further information is available at www.AbecmaREMS.com or contact Bristol Myers Squibb at 1-866-340-7332.
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.
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 the KarMMa and KarMMa-3 studies, 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.
Prolonged Cytopenias: In patients receiving ABECMA in the KarMMa and KarMMa-3 studies, 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 x 10 6 CAR-positive T cells and 300 to 460 x 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.
Hypogammaglobulinemia: In all patients receiving ABECMA in the KarMMa and KarMMa-3 studies, 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 <400 mg/dL.
Monitor immunoglobulin levels after treatment with ABECMA and administer IVIG for IgG <400 mg/dl. Manage appropriately 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 after ABECMA treatment has not been studied. Vaccination with live virus vaccines is not recommended for at least 6 weeks prior to the start of lymphodepleting chemotherapy, during ABECMA treatment, and until immune recovery following treatment with ABECMA.
Secondary Malignancies: Patients treated with ABECMA may develop secondary malignancies. In KarMMa-3, 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 ide-cel 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.
Monitor life-long for secondary malignancies. In the event that a secondary malignancy occurs, contact Bristol Myers Squibb at 18888054555 for reporting and to obtain instructions on collection of patient samples for testing of secondary malignancy.
Effects on Ability to Drive and Operate Machinery: Due to the potential for neurologic events, including altered mental status or seizures, patients receiving ABECMA are at risk for altered or decreased consciousness or coordination in the 8 weeks following ABECMA infusion. Advise patients to refrain from driving and engaging in hazardous occupations or activities, such as operating heavy or potentially dangerous machinery, during this initial period.
Adverse Reactions: The most common nonlaboratory adverse reactions (incidence greater than or equal to 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.
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