Recommendation for approval based on Phase 3
KarMMa-3 study in which Abecma demonstrated superiority over
standard regimens, significantly improved progression-free survival
and a well-established safety profile with mostly low-grade
occurrences of cytokine release syndrome and neurotoxicity
This is the first positive CHMP opinion in
earlier lines of therapy for a chimeric antigen receptor (CAR) T
cell therapy in the treatment of relapsed and refractory multiple
myeloma
Approval by the European Commission would
expand Abecma’s indication, making it the first CAR T cell therapy
available in the European Union (EU) for patients with triple-class
exposed relapsed and refractory multiple myeloma earlier in the
treatment journey
Bristol Myers Squibb (NYSE: BMY) today announced the Committee
for Medicinal Products for Human Use (CHMP) of the European
Medicines Agency (EMA) has recommended marketing authorization
approval of Abecma® (idecabtagene vicleucel; ide-cel) for the
treatment of adult patients with relapsed and refractory multiple
myeloma who have received at least two prior therapies, including
an immunomodulatory agent (IMiD), a proteasome inhibitor (PI), and
an anti-CD38 monoclonal antibody. The European Commission (EC),
which has the authority to approve medicines for the European Union
(EU), will now review the CHMP recommendation.
“This positive CHMP opinion represents an important step toward
bringing our potentially transformative first-in-class anti-BCMA
CAR T cell therapy, Abecma, to more patients earlier in the
multiple myeloma treatment paradigm to improve outcomes,” said Anne
Kerber, M.D., senior vice president and head, Late Clinical
Development, Hematology, Oncology, Cell Therapy (HOCT), Bristol
Myers Squibb. “We look forward to working with the European
Commission with the shared goal of delivering innovative treatment
options to more patients with continued unmet need.”
The CHMP adopted a positive opinion based on the final
progression-free survival (PFS) analysis from the pivotal, Phase 3,
open-label, global, randomized, controlled KarMMa-3 study
evaluating Abecma compared with standard combination regimens in
adults with relapsed and refractory multiple myeloma after two to
four prior lines of therapy, including an IMiD, a PI, and an
anti-CD38 monoclonal antibody, which are the three main classes of
therapy (triple-class exposed) in multiple myeloma, and who were
refractory to their last regimen. Results recently presented at the
American Society of Hematology (ASH) Annual Meeting in December
2023 showed, at a median follow-up of 30.9 months (range:
12.7-47.8), Abecma significantly improved PFS compared with
standard regimens, with a median PFS of 13.8 months vs. 4.4 months
(HR:0.49; 95% CI: 0.38-0.63), representing a 51% reduction in the
risk of disease progression or death with Abecma.
Results for the key secondary endpoint of overall response rate
showed the majority of patients (71%; (95% CI: 66-77) treated with
Abecma achieved a response, with 44% (95% CI: 38-50) achieving a
complete response or stringent complete response. In comparison,
less than half of patients (41%; 95% CI: 34-51) who received
standard regimens achieved a response, with 5% (95% CI: 2-9)
experiencing a complete response or stringent complete
response.
Treatment with Abecma exhibited a well-established safety
profile, with mostly low-grade and transient occurrences of
cytokine release syndrome (CRS) and neurotoxicity. In patients
treated with Abecma, 88% experienced any grade CRS, with Grade 3/4
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.
In the EU, the EC delivers its final decision approximately two
months following receipt of the CHMP opinion. The decision will be
applicable to all EU member states and Iceland, Norway and
Liechtenstein.* Please see the Important Safety Information section
below, including Boxed WARNINGS for Abecma regarding
cytokine release syndrome, neurologic toxicities, Hemophagocytic
Lymphohistiocytosis/Macrophage Activation Syndrome and Prolonged
Cytopenia. A supplemental Biologics License Application for Abecma
in earlier lines of therapy for triple-class exposed relapsed and
refractory multiple myeloma is currently under review by the U.S.
Food and Drug Administration (FDA), and the Oncologic Drugs
Advisory Committee of the FDA will convene a meeting to review data
from KarMMa-3 supporting the application. Abecma is also approved
in Japan for adult patients with triple-class exposed relapsed or
refractory multiple myeloma after two prior lines of therapy, and
in the EU, Switzerland, the United Kingdom, Canada, and Israel for
adult patients with triple-class exposed relapsed and/or refractory
multiple myeloma after three to four or more prior lines of
therapy.
Bristol Myers Squibb thanks the patients and investigators
involved in the KarMMa-3 study.
*Centralized Marketing Authorization does not include approval
in Great Britain (England, Scotland and Wales).
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, 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 and overall survival.
About Abecma
Abecma is a CAR T cell therapy that 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. Bristol Myers Squibb assumes sole
responsibility for Abecma drug product manufacturing and
commercialization outside of the U.S.
The companies’ broad clinical development program for Abecma
includes ongoing clinical studies (KarMMa-2, KarMMa-3, KarMMa-9) in
early lines of treatment for patients with multiple myeloma. For
more information visit clinicaltrials.gov.
Full European Summary of Product Characteristics for Abecma is
available from the EMA website at www.ema.europa.eu.
Abecma U.S. FDA-Approved 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 four or more prior
lines of therapy, including an immunomodulatory agent, a proteasome
inhibitor, and an anti-CD38 monoclonal antibody.
U.S. 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, including
immune effector cell-associated neurotoxicity syndrome (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. Neurologic toxicities occurred 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.
Please see full Prescribing Information, including Boxed
WARNINGS and Medication Guide.
Bristol Myers Squibb: Creating a Better
Future for People with Cancer
Bristol Myers Squibb is inspired by a single vision —
transforming people’s lives through science. The goal of the
company’s cancer research is to deliver medicines that offer each
patient a better, healthier life and to make cure a possibility.
Building on a legacy across a broad range of cancers that have
changed survival expectations for many, Bristol Myers Squibb
researchers are exploring new frontiers in personalized medicine,
and through innovative digital platforms, are turning data into
insights that sharpen their focus. Deep scientific expertise,
cutting-edge capabilities and discovery platforms enable the
company to look at cancer from every angle. Cancer can have a
relentless grasp on many parts of a patient’s life, and Bristol
Myers Squibb is committed to taking actions to address all aspects
of care, from diagnosis to survivorship. Because as a leader in
cancer care, Bristol Myers Squibb is working to empower all people
with cancer to have a better future.
About Bristol Myers
Squibb
Bristol Myers Squibb is a global biopharmaceutical company whose
mission is to discover, develop and deliver innovative medicines
that help patients prevail over serious diseases. For more
information about Bristol Myers Squibb, visit us at BMS.com or
follow us on LinkedIn, Twitter, YouTube, Facebook and
Instagram.
Forward-Looking Statement of Bristol
Myers Squibb
This press release contains “forward-looking statements” within
the meaning of the Private Securities Litigation Reform Act of 1995
regarding, among other things, the research, development and
commercialization of pharmaceutical products. All statements that
are not statements of historical facts are, or may be deemed to be,
forward-looking statements. Such forward-looking statements are
based on current expectations and projections about our future
financial results, goals, plans and objectives and involve inherent
risks, assumptions and uncertainties, including internal or
external factors that could delay, divert or change any of them in
the next several years, that are difficult to predict, may be
beyond our control and could cause our future financial results,
goals, plans and objectives to differ materially from those
expressed in, or implied by, the statements. These risks,
assumptions, uncertainties and other factors include, among others,
that the CHMP opinion is not binding on the EC, that Abecma®
(idecabtagene vicleucel) may not receive regulatory approval for
the additional indication described in this release in the
currently anticipated timeline or at all, that any marketing
approvals, if granted, may have significant limitations on their
use, and if approved, whether such treatment for the additional
indication described in this release will be commercially
successful. Forward-looking statements in this press release should
be evaluated together with the many risks and uncertainties that
affect Bristol Myers Squibb’s business and market, particularly
those identified in the cautionary statement and risk factors
discussion in Bristol Myers Squibb’s Annual Report on Form 10-K for
the year ended December 31, 2022, as updated by our subsequent
Quarterly Reports on Form 10-Q, Current Reports on Form 8-K and
other filings with the Securities and Exchange Commission. The
forward-looking statements included in this document are made only
as of the date of this document and except as otherwise required by
applicable law, Bristol Myers Squibb undertakes no obligation to
publicly update or revise any forward-looking statement, whether as
a result of new information, future events, changed circumstances
or otherwise.
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