REVLIMID is the first and only treatment
approved for maintenance following auto-HSCT
Updated data from two large, randomized,
controlled studies demonstrated median progression-free survival
(PFS) advantages of 3.8 and 1.9 years, respectively, in favor of
patients receiving REVLIMID compared to no maintenance
Median overall survival (OS) for patients
receiving REVLIMID in each study was 9.3 years and 8.8 years,
respectively, compared to 7 and 7.3 years for no maintenance in a
descriptive analysis (studies not powered for OS)
Approval enables Celgene to provide patients
with treatment options across the multiple myeloma spectrum
Celgene Corporation (NASDAQ:CELG) today announced that the U.S.
Food and Drug Administration (FDA) has expanded the existing
indication for REVLIMID (lenalidomide) 10 mg capsules to include
use for patients with multiple myeloma as maintenance therapy
following autologous hematopoietic stem cell transplant
(auto-HSCT). The expanded indication makes REVLIMID the first and
only treatment to receive FDA approval for maintenance use
following auto-HSCT.
“Autologous stem cell transplant after induction therapy is part
of the continuum of care for transplant-eligible multiple myeloma
patients. However, most patients will still see their disease recur
or progress after this treatment,” said Philip McCarthy, M.D.,
Director, Blood and Marrow Transplant Center, Department of
Medicine at Roswell Park Cancer Institute. “Lenalidomide
maintenance therapy, which has been shown to increase
progression-free survival following autologous stem cell transplant
in clinical trials can be considered a standard of care for
these patients.”
The approval was based on two large studies including more than
1,000 patients comparing REVLIMID maintenance therapy given until
disease progression or unacceptable toxicity after auto-HSCT versus
no maintenance. In both studies, the primary efficacy endpoint was
progression-free survival (PFS) defined from randomization to the
date of progression or death, whichever occurred first. In the most
current PFS analysis, Study 1 (U.S.-based NCI sponsored cooperative
group study CALGB 100104) demonstrated a median PFS of 5.7 years
(95% CI: 4.4-not estimable) versus 1.9 years (95% CI: 1.6-2.5) for
no maintenance, a difference of 3.8 years (HR 0.38 [95% CI:
0.28-0.50]). Study 2 (European-based study IFM 2005-02) also showed
a benefit with a median PFS of 3.9 years (95% CI: 3.3-4.7) versus 2
years (95% CI: 1.8-2.3) for no maintenance, a difference of 1.9
years (HR 0.53 [95% CI: 0.44-0.64]). Individual studies were not
powered for an overall survival endpoint. A descriptive analysis
showed the median overall survival in Study 1 was 9.3 years (95%
CI: 8.5-not estimable) for patients who received REVLIMID versus 7
years (95% CI: 5.9-8.6) for no maintenance (HR 0.59 [95% CI:
0.44-0.78]). In Study 2, median overall survival was 8.8 years (95%
CI: 7.4-not estimable) for patients who received REVLIMID versus
7.3 years (95% CI: 6.7-9.0) for no maintenance (HR 0.90 [95% CI:
0.72-1.13]).
“In newly-diagnosed multiple myeloma, auto-HSCT remains a viable
option for many patients and often provides a strong response
against the disease,” said Michael Pehl, President, Global
Hematology and Oncology for Celgene. “By expanding the approval for
REVLIMID to include post-transplant maintenance, patients have the
potential to maintain those responses and, importantly, delay
progression of the disease.”
As described in the prescribing information, REVLIMID can cause
fetal harm and is contraindicated in females who are pregnant.
REVLIMID is only available through a restricted distribution
program, Revlimid REMS®. Deep vein thrombosis, pulmonary embolism,
myocardial infarction and stroke occur in patients with MM
treatment with REVLIMID and thromboprophylaxis is recommended. See
additional Important Safety Information below.
The most frequently reported adverse reactions in ≥20% (REVLIMID
arm) across both maintenance studies (Study 1, Study 2
respectively) were neutropenia (79%, 61%), thrombocytopenia (72%,
24%), leukopenia (23%, 32%), anemia (21%, 9%), upper respiratory
tract infection (27%, 11%), bronchitis (5%, 47%), nasopharyngitis
(2%, 35%), cough (10%, 27%), gastroenteritis (0%, 23%), diarrhea
(55%, 39%), rash (32%, 8%), fatigue (23%, 11%), asthenia (0%, 30%),
muscle spasm (0%, 33%) and pyrexia (8%, 21%). The most frequently
reported Grade 3 or 4 reactions (more than 20% in the REVLIMID arm)
included neutropenia, thrombocytopenia, and leukopenia.
The frequencies of onset of adverse reactions were generally
highest in the first six months of treatment and then the
frequencies decreased over time or remained stable throughout
treatment.
In patients receiving REVLIMID maintenance therapy, hematologic
second primary malignancies (SPM) occurred in 7.5% of patients
compared to 3.3% in patients receiving placebo. The incidence of
hematologic plus solid tumor (excluding squamous cell carcinoma and
basal cell carcinoma) SPM was 14.9%, compared to 8.8% in patients
receiving placebo with a median follow-up of 91.5 months.
Non-melanoma skin cancer SPM, including squamous cell carcinoma and
basal cell carcinoma, occurred in 3.9% of patients receiving
REVLIMID maintenance, compared to 2.6% in the placebo arm. Patients
should be monitored for the development of second primary
malignancies. Take into account both the potential benefit of
REVLIMID and the risk of second primary malignancies when
considering treatment with REVLIMID.
REVLIMID in combination with dexamethasone was previously
approved in June 2006 for use in patients with multiple myeloma who
have received at least one prior therapy, and the indication
expanded in February 2015 to include patients newly diagnosed with
multiple myeloma.
In June 2016, an application was submitted to the European
Medicines Agency (EMA) for the review of REVLIMID as maintenance
treatment in NDMM patients after receiving an autologous stem cell
transplant. In January 2017, the European Medicines Agency's (EMA)
Committee for Medicinal Products for Human Use (CHMP) adopted a
positive opinion for the use of REVLIMID as monotherapy for the
maintenance treatment of adult patients with newly diagnosed
multiple myeloma (MM) who have undergone autologous stem cell
transplantation.
About CALGB 100104 (Study 1)
CALGB 100104 was a phase III, randomized, controlled,
double-blind, multi-center study conducted in 47 centers by the
CALGB, which is now part of the Alliance for Clinical Trials in
Oncology, a US national oncology cooperative group. 460 newly
diagnosed multiple myeloma patients – aged between 18 and 70 years
(CLcr ≥ 30 mL/min) – who had undergone induction therapy within 12
months of diagnosis and achieved at least stable disease (SD) or
better 90-100 days following autologous stem cell transplant
(ASCT), were randomized to receive either REVLIMID maintenance or
placebo. The REVLIMID maintenance dose was 10 mg/day (after 3
months increased to 15 mg/day if tolerated) until disease
progression, intolerable side effects, patient withdrawal for
another reason, or death. The dose was reduced, or treatment was
temporarily interrupted or stopped, as needed to manage toxicity. A
dose increase to 15 mg once daily occurred in 135 patients
(58%).
About IFM 2005-02 (Study 2)
IFM 2005-02 was a phase III, controlled, double-blind,
multi-center study conducted by the University Hospital of Toulouse
in concert with the IFM, an independent French myeloma cooperative
group, at 78 centers in France, Belgium, and Switzerland. 614 newly
diagnosed multiple myeloma patients younger than 65 years (CLcr ≥
30 mL/min) who had undergone induction therapy and did not present
with signs of disease progression within 6 months of undergoing
ASCT. Patients were then randomized to receive a two-month
consolidation regimen of REVLIMID monotherapy 25 mg per day on
21/28 days, followed by either REVLIMID maintenance or placebo. The
REVLIMID dose was 10 mg/day (after 3 months increased to15 mg/day
if tolerated) until disease progression, intolerable side effects,
patient withdrawal for another reason or death. The dose was
reduced, or treatment was temporarily interrupted or stopped, as
needed to manage toxicity. A dose increase to 15 mg once daily
occurred in 185 patients (60%).
About REVLIMID®
REVLIMID® (lenalidomide) in combination with
dexamethasone (dex) is indicated for the treatment of patients with
multiple myeloma (MM)
REVLIMID is indicated as maintenance therapy in patients with
MM following autologous hematopoietic stem cell transplantation
(auto-HSCT)
REVLIMID® is indicated for the treatment of
patients with transfusion-dependent anemia due to low-or
intermediate-1–risk myelodysplastic syndromes (MDS) associated with
a deletion 5q cytogenetic abnormality with or without additional
cytogenetic abnormalities
REVLIMID® is indicated for the treatment of
patients with mantle cell lymphoma (MCL) whose disease has relapsed
or progressed after two prior therapies, one of which included
bortezomib
REVLIMID is not indicated and is not recommended for the
treatment of patients with chronic lymphocytic leukemia (CLL)
outside of controlled clinical trials
Important Safety Information
WARNING: EMBRYO-FETAL TOXICITY,
HEMATOLOGIC TOXICITY, and VENOUS and ARTERIAL
THROMBOEMBOLISM
Embryo-Fetal
Toxicity
Do not use REVLIMID during pregnancy.
Lenalidomide, a thalidomide analogue, caused limb abnormalities in
a developmental monkey study. Thalidomide is a known human
teratogen that causes severe life-threatening human birth defects.
If lenalidomide is used during pregnancy, it may cause birth
defects or embryo-fetal death. In females of reproductive
potential, obtain 2 negative pregnancy tests before starting
REVLIMID treatment. Females of reproductive potential must use 2
forms of contraception or continuously abstain from heterosexual
sex during and for 4 weeks after REVLIMID treatment. To avoid
embryo-fetal exposure to lenalidomide, REVLIMID is only available
through a restricted distribution program, the REVLIMID
REMS® program).
Information about the REVLIMID
REMS® program is available at
www.celgeneriskmanagement.com or by calling the
manufacturer’s toll-free number 1-888-423-5436.
Hematologic
Toxicity (Neutropenia and Thrombocytopenia)
REVLIMID can cause significant
neutropenia and thrombocytopenia. Eighty percent of patients with
del 5q MDS had to have a dose delay/reduction during the major
study. Thirty-four percent of patients had to have a second dose
delay/reduction. Grade 3 or 4 hematologic toxicity was seen in 80%
of patients enrolled in the study. Patients on therapy for del 5q
MDS should have their complete blood counts monitored weekly for
the first 8 weeks of therapy and at least monthly thereafter.
Patients may require dose interruption and/or reduction. Patients
may require use of blood product support and/or growth
factors.
Venous and
Arterial Thromboembolism
REVLIMID has demonstrated a
significantly increased risk of deep vein thrombosis (DVT) and
pulmonary embolism (PE), as well as risk of myocardial infarction
and stroke in patients with MM who were treated with REVLIMID and
dexamethasone therapy. Monitor for and advise patients about signs
and symptoms of thromboembolism. Advise patients to seek immediate
medical care if they develop symptoms such as shortness of breath,
chest pain, or arm or leg swelling. Thromboprophylaxis is
recommended and the choice of regimen should be based on an
assessment of the patient’s underlying risks.
CONTRAINDICATIONS
Pregnancy: REVLIMID can cause fetal harm when
administered to a pregnant female and is contraindicated in females
who are pregnant. If this drug is used during pregnancy or if the
patient becomes pregnant while taking this drug, the patient should
be apprised of the potential risk to the fetus
Allergic Reactions: REVLIMID is contraindicated in
patients who have demonstrated hypersensitivity (e.g., angioedema,
Stevens-Johnson syndrome, toxic epidermal necrolysis) to
lenalidomide
WARNINGS AND PRECAUTIONS
Embryo-Fetal Toxicity: See Boxed WARNINGS
- Females of
Reproductive Potential: See Boxed WARNINGS
- Males:
Lenalidomide is present in the semen of patients receiving the
drug. Males must always use a latex or synthetic condom during any
sexual contact with females of reproductive potential while taking
REVLIMID and for up to 4 weeks after discontinuing REVLIMID, even
if they have undergone a successful vasectomy. Male patients taking
REVLIMID must not donate sperm
- Blood
Donation: Patients must not donate blood during treatment
with REVLIMID and for 4 weeks following discontinuation of the drug
because the blood might be given to a pregnant female patient whose
fetus must not be exposed to REVLIMID
REVLIMID REMS® Program: See Boxed WARNINGS:
Prescribers and pharmacies must be certified with the REVLIMID REMS
program by enrolling and complying with the REMS requirements;
pharmacies must only dispense to patients who are authorized to
receive REVLIMID. Patients must sign a Patient-Physician Agreement
Form and comply with REMS requirements; female patients of
reproductive potential who are not pregnant must comply with the
pregnancy testing and contraception requirements and males must
comply with contraception requirements
Hematologic Toxicity: REVLIMID can cause significant
neutropenia and thrombocytopenia. Monitor patients with neutropenia
for signs of infection. Advise patients to observe for bleeding or
bruising, especially with use of concomitant medications that may
increase risk of bleeding. MM: Patients taking REVLIMID/dex or
REVLIMID maintenance therapy should have their complete blood
counts (CBC) assessed every 7 days for the first 2 cycles, on days
1 and 15 of cycle 3, and every 28 days thereafter. MDS: Patients on therapy for del 5q
MDS should have their complete blood counts monitored weekly for
the first 8 weeks of therapy and at least monthly thereafter.
Patients may require dose interruption and/or dose reduction.
Please see the Black Box WARNINGS for further information.
MCL: Patients taking
REVLIMID for MCL should have their CBCs monitored weekly for the
first cycle (28 days), every 2 weeks during cycles 2-4, and then
monthly thereafter. Patients may require dose interruption and/or
dose reduction
Venous and Arterial Thromboembolism: See Boxed WARNINGS:
Venous thromboembolic events (DVT and PE) and arterial thromboses
(MI and CVA) are increased in patients treated with REVLIMID.
Patients with known risk factors, including prior thrombosis, may
be at greater risk and actions should be taken to try to minimize
all modifiable factors (e.g., hyperlipidemia, hypertension,
smoking). Thromboprophylaxis is recommended and the regimen should
be based on patient’s underlying risks. ESAs and estrogens may
further increase the risk of thrombosis and their use should be
based on a benefit-risk decision
Increased Mortality in Patients with CLL: In a clinical
trial in the first-line treatment of patients with CLL, single
agent REVLIMID therapy increased the risk of death as compared to
single agent chlorambucil. Serious adverse cardiovascular
reactions, including atrial fibrillation, myocardial infarction,
and cardiac failure, occurred more frequently in the REVLIMID arm.
REVLIMID is not indicated and not recommended for use in CLL
outside of controlled clinical trials
Second Primary Malignancies (SPM): In clinical trials in
patients with MM receiving REVLIMID, an increase of hematologic
plus solid tumor SPM, notably AML and MDS, have been observed.
Monitor patients for the development of SPM. Take into account both
the potential benefit of REVLIMID and risk of SPM when considering
treatment
Hepatotoxicity: Hepatic failure, including fatal cases,
has occurred in patients treated with REVLIMID/dex. Pre-existing
viral liver disease, elevated baseline liver enzymes, and
concomitant medications may be risk factors. Monitor liver enzymes
periodically. Stop REVLIMID upon elevation of liver enzymes. After
return to baseline values, treatment at a lower dose may be
considered
Allergic Reactions: Angioedema and serious dermatologic
reactions including Stevens-Johnson syndrome (SJS) and toxic
epidermal necrolysis (TEN) have been reported. These events can be
fatal. Patients with a prior history of Grade 4 rash associated
with thalidomide treatment should not receive REVLIMID. REVLIMID
interruption or discontinuation should be considered for Grade 2-3
skin rash. REVLIMID must be discontinued for angioedema, Grade 4
rash, exfoliative or bullous rash, or if SJS or TEN is suspected
and should not be resumed following discontinuation for these
reactions. REVLIMID capsules contain lactose; risk-benefit of
treatment should be evaluated in patients with lactose
intolerance
Tumor Lysis Syndrome (TLS): Fatal instances of TLS have
been reported during treatment with lenalidomide. The patients at
risk of TLS are those with high tumor burden prior to treatment.
These patients should be monitored closely and appropriate
precautions taken
Tumor Flare Reaction (TFR): TFR has occurred during
investigational use of lenalidomide for CLL and lymphoma.
Monitoring and evaluation for TFR is recommended in patients with
MCL. Tumor flare may mimic the progression of disease (PD). In
patients with Grade 3 or 4 TFR, it is recommended to withhold
treatment with REVLIMID until TFR resolves to ≤ Grade 1. REVLIMID
may be continued in patients with Grade 1 and 2 TFR without
interruption or modification, at the physician’s discretion
Impaired Stem Cell Mobilization: A decrease in the number
of CD34+ cells collected after treatment (>4 cycles) with
REVLIMID has been reported. Consider early referral to transplant
center to optimize timing of the stem cell collection
Thyroid Disorders: Both hypothyroidism and
hyperthyroidism have been reported. Measure thyroid function before
start of REVLIMID treatment and during therapy
ADVERSE REACTIONS
Multiple Myeloma
- In newly diagnosed: The most
frequently reported Grade 3 or 4 reactions included neutropenia,
anemia, thrombocytopenia, pneumonia, asthenia, fatigue, back pain,
hypokalemia, rash, cataract, lymphopenia, dyspnea, DVT,
hyperglycemia, and leukopenia. The highest frequency of infections
occurred in Arm Rd Continuous (75%) compared to Arm MPT (56%).
There were more Grade 3 and 4 and serious adverse reactions of
infection in Arm Rd Continuous than either Arm MPT or Rd18
- The most common adverse reactions
reported in ≥20% (Arm Rd Continuous): diarrhea (46%), anemia (44%),
neutropenia (35%), fatigue (33%), back pain (32%), asthenia (28%),
insomnia (28%), rash (26%), decreased appetite (23%), cough (23%),
dyspnea (22%), pyrexia (21%), abdominal pain (21%), muscle spasms
(20%), and thrombocytopenia (20%)
- Maintenance Therapy Post
Auto-HSCT: The most frequently reported Grade 3 or 4 reactions
in ≥20% (REVLIMID arm) included neutropenia, thrombocytopenia, and
leukopenia. The serious adverse reactions of lung infection and
neutropenia (more than 4.5%) occurred in the REVLIMID arm
- The most frequently reported adverse
reactions in ≥20% (REVLIMID arm) across both maintenance studies
(Study 1, Study 2) were neutropenia (79%, 61%), thrombocytopenia
(72%, 24%), leukopenia (23%, 32%), anemia (21%, 9%), upper
respiratory tract infection (27%, 11%), bronchitis (5%, 47%),
nasopharyngitis (2%, 35%), cough (10%, 27%), gastroenteritis (0%,
23%), diarrhea (55%, 39%), rash (32%, 8%), fatigue (23%, 11%),
asthenia (0%, 30%), muscle spasm (0%, 33%), and pyrexia (8%,
21%)
- After at least one prior
therapy: The most common adverse reactions reported in ≥20%
(REVLIMID/dex vs dex/placebo): fatigue (44% vs 42%), neutropenia
(42% vs 6%), constipation (41% vs 21%), diarrhea (39% vs 27%),
muscle cramp (33% vs 21%), anemia (31% vs 24%), pyrexia (28% vs
23%), peripheral edema (26% vs 21%), nausea (26% vs 21%), back pain
(26% vs 19%), upper respiratory tract infection (25% vs 16%),
dyspnea (24% vs 17%), dizziness (23% vs 17%), thrombocytopenia (22%
vs 11%), rash (21% vs 9%), tremor (21% vs 7%), and weight decreased
(20% vs 15%)
Myelodysplastic
Syndromes
- Grade 3 and 4 adverse events reported
in ≥ 5% of patients with del 5q MDS were neutropenia (53%),
thrombocytopenia (50%), pneumonia (7%), rash (7%), anemia (6%),
leukopenia (5%), fatigue (5%), dyspnea (5%), and back pain
(5%)
- Adverse events reported in ≥15% of del
5q MDS patients (REVLIMID): thrombocytopenia (61.5%), neutropenia
(58.8%), diarrhea (49%), pruritus (42%), rash (36%), fatigue (31%),
constipation (24%), nausea (24%), nasopharyngitis (23%), arthralgia
(22%), pyrexia (21%), back pain (21%), peripheral edema (20%),
cough (20%), dizziness (20%), headache (20%), muscle cramp (18%),
dyspnea (17%), pharyngitis (16%), epistaxis (15%), asthenia (15%),
upper respiratory tract infection (15%)
Mantle Cell Lymphoma
- Grade 3 and 4 adverse events reported
in ≥5% of patients treated with REVLIMID in the MCL trial (N=134)
included neutropenia (43%), thrombocytopenia (28%), anemia (11%),
pneumonia (9%), leukopenia (7%), fatigue (7%), diarrhea (6%),
dyspnea (6%), and febrile neutropenia (6%)
- Adverse events reported in ≥15% of
patients treated with REVLIMID in the MCL trial included
neutropenia (49%), thrombocytopenia (36%), fatigue (34%), anemia
(31%), diarrhea (31%), nausea (30%), cough (28%), pyrexia (23%),
rash (22%), dyspnea (18%), pruritus (17%), peripheral edema (16%),
constipation (16%), and leukopenia (15%)
DRUG INTERACTIONS
Periodic monitoring of digoxin plasma levels is recommended due
to increased Cmax and AUC with concomitant REVLIMID therapy.
Patients taking concomitant therapies such as erythropoietin
stimulating agents or estrogen containing therapies may have an
increased risk of thrombosis. It is not known whether there is an
interaction between dex and warfarin. Close monitoring of PT and
INR is recommended in patients with MM taking concomitant
warfarin
USE IN SPECIFIC POPULATIONS:
- PREGNANCY: See Boxed WARNINGS:
If pregnancy does occur during treatment, immediately discontinue
the drug and refer patient to an obstetrician/gynecologist
experienced in reproductive toxicity for further evaluation and
counseling. There is a REVLIMID pregnancy exposure registry that
monitors pregnancy outcomes in females exposed to REVLIMID during
pregnancy as well as female partners of male patients who are
exposed to REVLIMID. This registry is also used to understand the
root cause for the pregnancy. Report any suspected fetal exposure
to REVLIMID to the FDA via the MedWatch program at 1-800-FDA-1088
and also to Celgene Corporation at 1-888-423-5436
- LACTATION: There is no
information regarding the presence of lenalidomide in human milk,
the effects of REVLIMID on the breastfed infant, or the effects of
REVLIMID on milk production. Because many drugs are excreted in
human milk and because of the potential for adverse reactions in
breastfed infants from REVLIMID, advise female patients not to
breastfeed during treatment with REVLIMID
- PEDIATRIC USE: Safety and
effectiveness have not been established in pediatric patients
- RENAL IMPAIRMENT: Adjust the
starting dose of REVLIMID based on the creatinine clearance value
and for patients on dialysis
Please see full Prescribing Information,
including Boxed WARNINGS.
About Celgene
Celgene Corporation, headquartered in Summit, New
Jersey, is an integrated global biopharmaceutical company engaged
primarily in the discovery, development and commercialization of
innovative therapies for the treatment of cancer and inflammatory
diseases through next-generation solutions in protein homeostasis,
immuno-oncology, epigenetics, immunology and neuro-inflammation.
For more information, please visit www.celgene.com. Follow
Celgene on Social
Media: @Celgene, Pinterest, LinkedIn, Facebook and YouTube.
Forward-Looking Statements
This press release contains forward-looking statements, which
are generally statements that are not historical facts.
Forward-looking statements can be identified by the words
"expects," "anticipates," "believes," "intends," "estimates,"
"plans," "will," “outlook” and similar expressions. Forward-looking
statements are based on management’s current plans, estimates,
assumptions and projections, and speak only as of the date they are
made. We undertake no obligation to update any forward-looking
statement in light of new information or future events, except as
otherwise required by law. Forward-looking statements involve
inherent risks and uncertainties, most of which are difficult to
predict and are generally beyond our control. Actual results or
outcomes may differ materially from those implied by the
forward-looking statements as a result of the impact of a number of
factors, many of which are discussed in more detail in our Annual
Report on Form 10-K and our other reports filed with the Securities
and Exchange Commission.
All registered trademarks are owned by Celgene Corporation.
View source
version on businesswire.com: http://www.businesswire.com/news/home/20170222006533/en/
Celgene
CorporationInvestors:+1-908-673-9628ir@celgene.comorMedia:+1-908-673-2275media@celgene.com
Celgene (NASDAQ:CELG)
Historical Stock Chart
From Mar 2024 to Apr 2024
Celgene (NASDAQ:CELG)
Historical Stock Chart
From Apr 2023 to Apr 2024