Abecma Delivers Sustained Progression-Free Survival Versus Standard Regimens in Earlier Lines of Therapy for Relapsed and Refractory Multiple Myeloma Based on Longer-Term Follow-up from KarMMa-3

At median follow-up of more than 30 months, Abecma maintained a 51% reduction in risk of disease progression or death with median PFS of 13.8 months compared with 4.4 months for standard regimens

Responses were significantly improved with Abecma and continued to deepen over time with a complete response rate of 44% vs. 5% for standard regimens with consistent benefit observed across subgroups

In the KarMMa-3 study, the well-established safety profile of Abecma remained consistent with generally predictable and mostly low-grade occurrences of cytokine release syndrome and neurotoxicity

In newly-diagnosed multiple myeloma, Abecma demonstrated deep and durable responses with a 77% complete response rate and median PFS not reached with no new safety signals with extended follow-up from the KarMMa-2 study

PRINCETON, N.J., & CAMBRIDGE, Mass.--(BUSINESS WIRE)--$BMY #ASH--Bristol Myers Squibb (NYSE: BMY) and 2seventy bio, Inc. (Nasdaq: TSVT) today announced results from the preplanned final progression-free survival (PFS) analysis of KarMMa-3, the pivotal Phase 3, open-label, global, randomized controlled study evaluating Abecma (idecabtagene vicleucel) compared with standard combination regimens in adults with relapsed and refractory multiple myeloma after two to four prior lines of therapy, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody (triple-class exposed), who were refractory to their last regimen. At a median follow-up of 30.9 months (range: 12.7-47.8), representing the longest follow-up for a randomized Phase 3 CAR T cell therapy trial in this patient population, significantly improved PFS was maintained with Abecma compared to standard regimens (95% CI: 13.8 months vs. 4.4 months), with a 51% reduction in the risk of disease progression or death (HR: 0.49; 95% CI: 0.38-0.63). These data are being presented today in an oral presentation at the 65^th American Society of Hematology (ASH) Annual Meeting and Exposition (Oral Presentation #1028).

With extended follow-up, treatment with Abecma (n=254) continued to demonstrate higher overall response rates (ORR) and a deepening of responses versus standard regimens. The ORR with Abecma was 71% (95% CI: 66-77) with a complete response (CR) rate of 44% (95% CI: 38-50), which increased by 5% from the interim analysis. In comparison, the ORR for standard regimens was 41% (95% CI: 34-51), with a CR rate of 5% (95% CI: 2-9), which remained unchanged from the time of interim analysis. The PFS, ORR and CR rates observed in the KarMMa-3 trial in the standard regimens arm are consistent with those that have historically been observed in this heavily pre-treated triple-class exposed patient population, in which PFS is approximately four months and deep and durable responses are limited. With these data, Abecma is the first and only anti-BCMA CAR T cell therapy to demonstrate superiority over standard regimens in a randomized, controlled Phase 3 trial designed to evaluate patients with triple-class exposed relapsed and refractory multiple myeloma.

“With longer follow-up from the KarMMa-3 study, we continue to see the significant clinical benefit that Abecma delivers for triple-class exposed multiple myeloma, illustrating the potential of using Abecma for long-term disease control and remission when used earlier in the treatment paradigm,” said Paula Rodriguez-Otero, M.D., Ph.D., Department of Hematology, Clinica Universidad de Navarra, Pamplona, Spain. “As the CAR T therapy with the longest real-world experience in later lines of therapy, and with these latest data which demonstrate clinically meaningful benefit and a well-established and generally predictable safety profile, Abecma has the potential to be a transformative treatment option across lines of therapy for triple-class exposed relapsed and refractory multiple myeloma.”

“As the first-in-class anti-BCMA CAR T cell therapy, we have long believed in the clinical value Abecma can deliver across the treatment paradigm for multiple myeloma, transforming outcomes for patients with a relentless disease and continued unmet need,” said Anne Kerber, senior vice president, Head of Late Clinical Development, Hematology, Oncology, and Cell Therapy, Bristol Myers Squibb. “These longer-term results from the KarMMa-3 trial clearly demonstrate the potential of Abecma to be an important treatment option to provide improved progression-free survival and durable responses in patients with relapsed and refractory multiple myeloma after being treated with the three main classes of therapy. We are proud to share these data which further advance the use of cell therapies as a new standard of care for more patients in earlier lines of therapy for difficult-to-treat blood cancers.”

In the study, which included a patient-centric design that allowed for crossover from standard regimens to Abecma upon confirmed disease progression, overall survival (OS) was a key secondary endpoint. Due to the median PFS observed with standard regimens, more than half (56%) of patients in the standard regimens arm crossed over to receive Abecma as a subsequent therapy. The median OS was 41.4 months with Abecma (95% CI: 30.9-NR) and 37.9 months with standard regimens (95% CI: 23.4-NR) (95% CI: 0.73-1.40; HR: 1.01). However, the prespecified sensitivity analyses adjusting for crossover showed a median OS of 41.4 months for Abecma (95% CI: 30.9-NR) and 23.4 months (95% CI: 17.9-NR) for standard regimens (95% CI: 0.45-1.09; HR: 0.69), suggesting a positive trend in OS benefit for Abecma compared with standard regimens. Historically, based on real-world evidence, median OS for patients with triple-class exposed relapsed and refractory multiple myeloma is approximately 13 months.

“With the adjustments for crossover in the KarMMa-3 study, we clearly see the consistent trend in survival benefit that this anti-BCMA CAR T cell therapy delivers, introducing the potential for Abecma to be an important treatment option for these patients,” said Sergio Giralt, M.D., Division of Hematologic Malignancies, Memorial Sloan Kettering Cancer Center. “These results show remarkable and significantly improved durable outcomes for relapsing triple-class exposed multiple myeloma patients, which is a population that has had poor overall and progression-free survival and no established standard treatment approach that provides durable responses.”

“It’s important to bear in mind that management of relapsed refractory multiple myeloma remains challenging; patients are becoming triple-class exposed earlier in their treatment course and then developing disease that is resistant to existing therapies,” said Steve Bernstein, M.D., chief medical officer, 2seventy bio. “We are excited that these positive results from the KarMMa-3 study demonstrate a significant clinical benefit of Abecma across lines of care in triple-class exposed multiple myeloma and look forward to the potential of expanding the benefits of Abecma to these patients earlier in their treatment course.”

In the KarMMa-3 study, Abecma continued to exhibit a well-established and generally predictable safety profile, including no new safety signals, with mostly low-grade occurrences of cytokine release syndrome (CRS) and neurotoxicity. In patients treated with Abecma with extended follow-up, occurrences of CRS and neurologic toxicities remained consistent with the interim analysis with 88% of patients experiencing any grade CRS, and Grade 3/4 CRS events occurring in 4% of patients. Two patients (1%) experienced a Grade 5 CRS event. Any grade neurotoxicity occurred in 15% of patients, with Grade 3/4 neurotoxicity occurring in 3% of patients, and no Grade 5 events reported.

Abecma was recently approved in Japan for patients with relapsed or refractory multiple myeloma who have received at least two prior therapies, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 antibody based on the KarMMa-3 study, making it the first CAR T to receive regulatory approval for use in earlier lines of therapy for patients with relapsed or refractory multiple myeloma. A supplemental Biologics License Application for Abecma based on the KarMMa-3 results is currently under review with the U.S. Food and Drug Administration (FDA), and an Oncologic Drugs Advisory Committee meeting will be held to discuss the data. Regulatory applications for Abecma in earlier lines of therapy for triple-class exposed relapsed and refractory multiple myeloma are also under review with the European Medicines Agency and Swissmedic.

Results from Extended Follow-up for Cohort 2c of the KarMMa-2 Study

Results from extended follow-up for Cohort 2c of the multicohort, Phase 2, multicenter KarMMa-2 study, evaluating Abecma in patients with multiple myeloma who had an inadequate response to frontline therapy with autologous stem cell transplantation (ASCT) are also being presented in a poster presentation (Poster Presentation #2101) at the meeting. At data cutoff with a median follow-up of 39.4 months, the ORR in patients treated with Abecma (n=31) was 87.1% (95% CI: 70.2-96.4), with a CR rate of 77.4% (95% CI: 58.9-90.4). Median duration of response, median PFS and median OS were not reached, and all patients who received Abecma (n=31) remained alive at follow-up. Safety results were generally consistent with the well-established known safety profile of Abecma, with any grade CRS occurring in 58.1% of patients and no reports of Grade >3 CRS.

Abecma is the first-in-class B-cell maturation antigen (BCMA)-directed CAR T cell immunotherapy approved by the FDA for the treatment of adult patients with relapsed or refractory multiple myeloma after four or more prior lines of therapy, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody. Please see the Important Safety Information section below, including Boxed WARNINGS for Abecma regarding CRS, neurologic toxicities, Hemophagocytic Lymphohistiocytosis/Macrophage Activation Syndrome and Prolonged Cytopenia. Abecma is also approved in the European Union, Switzerland, Canada, the United Kingdom and Israel for adult patients with triple-class exposed relapsed or refractory multiple myeloma after three to four or more prior lines of therapy.

Memorial Sloan Kettering Cancer Center disclosures: Dr. Giralt and Memorial Sloan Kettering Cancer Center have financial interests associated with the research described in this release.

About KarMMa-3

KarMMa-3 (NCT03651128) is a pivotal, Phase 3, open-label, global, randomized, controlled trial evaluating Abecma compared to standard regimens in patients with relapsed and refractory multiple myeloma who have received two to four prior lines of treatment, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody, and were refractory to the last treatment regimen. Patients were randomized to receive Abecma or standard regimens that consisted of combinations that included daratumumab, pomalidomide, and dexamethasone (DPd), daratumumab, bortezomib, and dexamethasone (DVd), ixazomib, lenalidomide, and dexamethasone (IRd), carfilzomib and dexamethasone (Kd) or elotuzumab, pomalidomide and dexamethasone (EPd) chosen based on their most recent treatment regimen and investigator discretion. The primary endpoint evaluated in this study is progression-free survival (PFS), defined as time from randomization to the first documentation of progressive disease or death due to any cause, whichever occurs first. Key secondary endpoints include overall response rate (ORR) and overall survival (OS).

About KarMMa-2

KarMMa-2 (NCT03601078) is a Phase 2, open-label, multicohort, multicenter study evaluating the efficacy and safety of Abecma in patients with relapsed and refractory multiple myeloma (Cohort 1), patients with multiple myeloma that has progressed within 18 months of initial treatment including autologous stem cell transplantation (ASCT) (Cohort 2a), or without ASCT (Cohort 2b) or, in patients with inadequate response post-ASCT during initial treatment (Cohort 2c), and patients with newly diagnosed multiple myeloma with suboptimal response to ASCT (Cohort 3). The primary endpoints evaluated in this study are ORR in Cohort 1 and complete response (CR) rate in Cohorts 2a, b, c and Cohort 3. Key secondary endpoints include CR rate in Cohort 1, ORR in Cohorts 2a, b, c and Cohort 3, duration of response, PFS and OS.

About Abecma

Abecma recognizes and binds to BCMA on the surface of multiple myeloma cells leading to CAR T cell proliferation, cytokine secretion, and subsequent cytolytic killing of BCMA-expressing cells. 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.

The companies’ broad clinical development program for Abecma includes clinical studies (KarMMa-2, KarMMa-3, KarMMa-9) in earlier lines of treatment for patients with multiple myeloma. For more information visit clinicaltrials.gov.

Important Safety Information

BOXED WARNING: CYTOKINE RELEASE SYNDROME, NEUROLOGIC TOXICITIES, HLH/MAS, AND PROLONGED CYTOPENIA

• 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.
• ABECMA is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the ABECMA REMS

WARNINGS AND PRECAUTIONS:

Cytokine Release Syndrome (CRS): CRS, including fatal or life-threatening reactions, occurred following treatment with ABECMA in 85% (108/127) of patients. Grade 3 or higher CRS occurred in 9% (12/127) of patients, with Grade 5 CRS reported in one (0.8%) patient. The median time to onset of CRS, any grade, was 1 day (range: 1 - 23 days) and the median duration of CRS was 7 days (range: 1 - 63 days). The most common manifestations included pyrexia, hypotension, tachycardia, chills, hypoxia, fatigue, and headache. Grade 3 or higher events that may be associated with CRS include hypotension, hypoxia, hyperbilirubinemia, hypofibrinogenemia, acute respiratory distress syndrome (ARDS), atrial fibrillation, hepatocellular injury, metabolic acidosis, pulmonary edema, 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. In patients with progressive symptoms of CRS or refractory CRS despite treatment, evaluate for evidence of HLH/MAS.

Fifty four percent (68/127) of patients received tocilizumab (single dose: 35%; more than 1 dose: 18%). Overall, 15% (19/127) of patients received at least 1 dose of corticosteroids for treatment of CRS. All patients that received corticosteroids for CRS received tocilizumab. Ensure that a minimum of 2 doses of tocilizumab are available prior to infusion of ABECMA.

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.

Counsel patients to seek immediate medical attention should signs or symptoms of CRS occur at any time.

Neurologic Toxicities: Neurologic toxicities, which may be severe or life-threatening, occurred following treatment with ABECMA in 28% (36/127) of patients receiving ABECMA, including Grade 3 in 4% (5/127) of patients. 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. The median time to onset of neurotoxicity was 2 days (range: 1 - 42 days). CAR T cell-associated neurotoxicity resolved in 92% (33/36) of patients with a median time to resolution of 5 days (range: 1 - 61 days). The median duration of neurotoxicity was 6 days (range: 1 - 578) in all patients including 3 patients with ongoing neurotoxicity. Thirty-four patients with neurotoxicity had CRS with onset in 3 patients before, 29 patients during, and 2 patients after CRS. The most frequently reported manifestations of CAR T cell-associated neurotoxicity include encephalopathy, tremor, aphasia, and delirium. Grade 4 neurotoxicity and cerebral edema in 1 patient, Grade 3 myelitis, and Grade 3 parkinsonism have been reported 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): HLH/MAS occurred in 4% (5/127) of patients receiving ABECMA. One patient developed fatal multi-organ HLH/MAS with CRS and another patient developed fatal bronchopulmonary aspergillosis with contributory HLH/MAS. Three cases of Grade 2 HLH/MAS resolved. All events of HLH/MAS had onset within 10 days of receiving ABECMA with a median onset of 7 days (range: 4 - 9 days) and occurred in the setting of ongoing or worsening CRS. Two patients with HLH/MAS had overlapping neurotoxicity. The manifestations of HLH/MAS include hypotension, hypoxia, multiple organ dysfunction, renal dysfunction, and cytopenia. 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 1-888-423-5436.

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. Infections (all grades) occurred in 70% of patients. Grade 3 or 4 infections occurred in 23% of patients. Overall, 4 patients had Grade 5 infections (3%); 2 patients (1.6%) had Grade 5 events of pneumonia, 1 patient (0.8%) had Grade 5 bronchopulmonary aspergillosis, and 1 patient (0.8%) had cytomegalovirus (CMV) pneumonia associated with Pneumocystis jirovecii. 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 16% (20/127) 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.

Viral Reactivation: 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.

Prolonged Cytopenias: In the clinical study, 41% of patients (52/127) experienced prolonged Grade 3 or 4 neutropenia and 49% (62/127) experienced prolonged Grade 3 or 4 thrombocytopenia that had not resolved by Month 1 following ABECMA infusion. In 83% (43/52) 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 65% (40/62) of patients who recovered from Grade 3 or 4 thrombocytopenia, the median time to recovery was 2.1 months.

Three patients underwent stem cell therapy for hematopoietic reconstitution due to prolonged cytopenia. Two of the three patients died from complications of prolonged cytopenia. Monitor blood counts prior to and after ABECMA infusion. Manage cytopenia with myeloid growth factor and blood product transfusion support.

Hypogammaglobulinemia: Hypogammaglobulinemia was reported as an adverse event in 21% (27/127) of patients; laboratory IgG levels fell below 500 mg/dl after infusion in 25% (32/127) of patients treated with ABECMA.

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.

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. Monitor life-long for secondary malignancies. If a secondary malignancy occurs, contact Bristol-Myers Squibb at 1-888-805-4555 to obtain instructions on patient samples to collect for testing of secondary malignancy of T cell origin.

Effects on Ability to Drive and Operate Machinery: Due to the potential for neurologic events, 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 include CRS, infections – pathogen unspecified, fatigue, musculoskeletal pain, hypogammaglobulinemia, diarrhea, upper respiratory tract infection, nausea, viral infections, encephalopathy, edema, pyrexia, cough, headache, and decreased appetite.

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