The European Commission has approved two of
Celgene’s IMiD®-based combination regimens:
- REVLIMID in combination with bortezomib
and dexamethasone (RVd) in adult patients with previously untreated
multiple myeloma who are not eligible for transplant
- IMNOVID in combination with bortezomib
and dexamethasone (PVd), in adult patients with multiple myeloma,
who have received at least one prior treatment regimen including
REVLIMID.
Celgene Corporation (NASDAQ:CELG), today announced that
the European Commission (EC) has approved two new triplet
regimens based on Celgene’s proprietary IMiD treatments, REVLIMID
(lenalidomide) and IMNOVID (pomalidomide).
REVLIMID in combination with bortezomib and dexamethasone (RVd),
is now indicated for the treatment of adult patients with
previously untreated multiple myeloma who are not eligible for
transplant. In addition, IMNOVID, in combination with bortezomib
and dexamethasone (PVd), is now indicated for the treatment of
adult patients with multiple myeloma who have received at least one
prior treatment regimen including lenalidomide.
“The approval of these combination therapies marks a significant
milestone for patients with multiple myeloma in Europe,” said Nadim
Ahmed, President of Hematology/Oncology for Celgene. “With these
new triplet regimens we hope to improve outcomes for both newly
diagnosed patients as well as those who have relapsed or become
refractory to first-line therapy. IMiD agents have brought
significant benefit to multiple myeloma patients and we are
committed to advancing our pipeline of novel myeloma treatments in
order to ensure physicians and patients continue to have new
treatment options available to fight this disease.”
The choice of treatment in a first-line therapy setting is
important1 as patients progressively become less responsive to
therapy, and experience shorter periods of remission at later lines
of treatment.2 Studies have shown that RVd can provide newly
diagnosed patients that are not eligible for a transplant with a
treatment option that significantly prolongs the first
remission.3
“Determining first-line therapy is an important consideration in
the overall treatment plan for patients with multiple myeloma,”
said Prof. Thierry Facon, Professor of Haematology in the
Department of Haematology, Lille University Hospital, France.
“Since REVLIMID in combination with dexamethasone is already a
standard of care in multiple myeloma, we’re excited by the prospect
of a new REVLIMID-based triplet option for previously untreated
patients who are not eligible for transplant.”
The approval for the REVLIMID triplet (RVd) was supported by
data from SWOG S07773, a phase 3 trial evaluating the triplet
combination, RVd, in adult patients with previously untreated
multiple myeloma.
“Today’s approval for use of the IMNOVID-containing triplet,
PVd, as early as first relapse, underscores the potential clinical
benefit this regimen can provide to patients following a prior
treatment including REVLIMID,” said Prof. Meletios Dimopoulos,
Professor and Chairman of the Department of Clinical Therapeutics
at the University Athens School of Medicine, Athens, Greece.
“REVLIMID-based regimens are often used as a standard of care in
newly diagnosed multiple myeloma patients, and there is a growing
patient population who become refractory to REVLIMID and need
proven treatment options.”
The approval of the IMNOVID triplet (PVd) was supported by data
from OPTIMISMM4, the first prospective phase 3 trial to evaluate an
IMNOVID-based triplet regimen in patients who were all previously
treated with REVLIMID, and the majority (70%) of patients were
REVLIMID refractory. Results from OPTIMISMM were recently published
in The Lancet Oncology.
Pomalidomide in combination with bortezomib and dexamethasone
(PVd) is not approved for any use in the United States
Lenalidomide in combination with bortezomib and dexamethasone
(RVd) is not approved for any use in the United States.
About Multiple Myeloma
Multiple myeloma is a life-threatening blood cancer that is
characterized by tumor proliferation and suppression of the immune
system.5,6 It is a rare but deadly disease - around 42,000
people are diagnosed with multiple myeloma in Europe, and
approximately 26,000 people die from the disease each year.7 The
typical multiple myeloma disease course includes periods of
symptomatic myeloma followed by periods of remission, and
eventually, the disease becomes refractory (nonresponsive).8
About SWOG S0777
SWOG S0777 is a randomized, open-label, multicentre, phase 3
study aiming to evaluate the efficacy and safety of RVd compared to
Rd in treating patients with newly diagnosed multiple myeloma
(ndMM) who were not intending on immediately receiving ASCT.3
SWOG S0777 recruited 525 patients with symptomatic and
measurable ndMM aged 18 years and older. Patients were randomly
assigned (1:1) to receive either an initial treatment of
lenalidomide with bortezomib and dexamethasone (RVd group) or
lenalidomide and dexamethasone alone (Rd group) both followed by
standard Rd until disease progression. Randomization was stratified
based on International Staging System stage (I, II, or III) and
intent to transplant (yes versus no). The RVd regimen was given as
eight 21-day cycles. Bortezomib was given at 1.3 mg/m2
intravenously on days 1, 4, 8, and 11, combined with oral
lenalidomide 25 mg daily on days 1-14 plus oral dexamethasone 20 mg
daily on days 1, 2, 4, 5, 8, 9, 11, and 12. The Rd regimen was
given as six 28-day cycles. The standard Rd regimen consisted of 25
mg oral lenalidomide once a day for days 1-21 plus 40 mg oral
dexamethasone once a day on days 1, 8, 15, and 22.3
Results from SWOG S07773 showed that median progression-free
survival (PFS) was significantly improved in patients receiving RVd
compared to those receiving REVLIMID and dexamethasone (Rd) alone
(42 months versus 30 months; HR 0.76, 95% CI 0.62-0.94; P=0.01).
Median overall survival was also significantly improved in patients
receiving RVd compared to those receiving Rd (89 months versus 67
months; HR 0.72, 95% CI 0.56–0.94; P=0.013). The rates of overall
and complete response were higher in those receiving RVd compared
to Rd (overall response: 82% RVd vs 72% Rd; complete response: 16%
RVd vs 8% Rd) the duration of response was also significantly
longer in those receiving RVd compared to Rd (52 months vs 38
months, respectively).3 The safety of RVd was also consistent with
the well-established safety profiles of each drug in the triplet
regimen.3
Upon completion of induction, all patients received ongoing
maintenance with 25 mg oral lenalidomide once a day for 21 days
plus 40 mg oral dexamethasone once a day for days 1, 8, 15, and 22
of each 28-day cycle.3
About OPTIMISMM
OPTIMISMM is the first phase 3 trial designed to compare the
safety and efficacy of PVd versus Vd, as an early line of therapy
in patients with relapsed and refractory multiple myeloma (with 1-3
prior regimens of therapy) and prior REVLIMID-exposure, including
REVLIMID-refractory patients.4
The multi-center, international, open-label, randomized phase 3
clinical trial included 559 patients (281 patients in the PVd arm
and 278 in the Vd arm). Demographic, baseline, and prior disease
characteristics were generally well balanced between the two
treatment arms. The median number of prior lines of therapy was
two, while more than one third had one prior line of treatment (40%
across both treatment arms). All patients had prior treatment with
REVLIMID with the majority being REVLIMID refractory (71%in the PVd
arm vs 69% in the Vd arm) and 70% vs 66%, respectively, were
refractory to their last treatment. Median follow-up was 16
months.4
Patients were stratified based on age, number of prior
anti-myeloma regimens, and β2-microglobulin levels. Patients were
randomized 1:1 to receive PVd or Vd until disease progression. In
21-day cycles, patients received IMNOVID 4 mg/d on days 1-14 (PVd
arm only); bortezomib 1.3 mg/m2 on days 1, 4, 8 and 11 of cycles
1-8 and on days 1 and 8 of cycles 9 and beyond; and dexamethasone
20 mg/d (10 mg if aged > 75 years) on the days of and after
receiving bortezomib treatment.4
Results from OPTIMISMM4 showed that patients receiving PVd
achieved a significantly longer PFS than those in the Vd treatment
arm (median PFS 11.2 months vs. 7.1 months, respectively [P= <
.0001, HR 0.61; 95% CI: (0.49-0.77)]), reducing the risk of disease
progression or death by 39% in the PVd arm. In an exploratory
sub-group analysis of patients with one prior line of therapy,
median progression-free survival with PVd was 20.7 months vs 11.6
months with Vd (95% CI: 7.52, 15.74). In these patients, the
benefit of PVd was observed independent of whether they were
refractory or non-refractory to prior therapy with
lenalidomide.
Neutropenia (PVd 42% vs Vd 9%), infections (PVd 31% vs Vd 18%),
and thrombocytopenia (PVd 27% vs Vd 29%) were among the most
frequently reported grade 3/4 treatment-emergent adverse events.
Rates of grade 3/4 deep vein thrombosis (PVd: 0.7% versus Vd: 0.4%)
and pulmonary embolism (PVd: 4.0% versus Vd: 0.4%) were low, and no
events were fatal. Second primary malignancies occurred in 3.2% of
patients treated with PVd and 1.5% of patients treated with Vd. The
most common reason for treatment discontinuation was progressive
disease. Patients discontinuing treatment due to adverse events
were 10.7% for PVd versus 17.6% for Vd. The safety of PVd was
consistent with the well-established safety profiles of each drug
in the triplet therapy.4
About Celgene’s Immunomodulatory
Drugs
IMiD® agents are Celgene’s proprietary small molecule, orally
available compounds for the treatment of some blood cancers. IMiD
agents are hypothesized to have multiple mechanisms of action. They
have been found to increase activation and proliferation of T
cells, and proliferation of the IL-2 protein and activity of CD8+
effector T cells. IMiD agents have also been found to affect the
stimulation and expression of natural killer (NK) cells, working
within the environment of the cell to stimulate the immune system
to attack the cancer cells, as well as attack the cancer cells
directly. In addition to immunomodulatory properties, IMiD agents
are hypothesized to have tumoricidal and antiangiogenic activity.
Celgene’s portfolio of IMiD agents have become a foundation of
multiple myeloma research, with a growing number of studies
exploring these compounds as combination partners across a range of
settings of the disease.
U.S. Safety Information
ABOUT POMALYST/IMNOVID
Indication
POMALYST® (pomalidomide) is a thalidomide analogue indicated, in
combination with dexamethasone, for patients with multiple myeloma
who have received at least two prior therapies including
lenalidomide and a proteasome inhibitor and have demonstrated
disease progression on or within 60 days of completion of the last
therapy.
Important Safety Information
WARNING: EMBRYO-FETAL TOXICITY and VENOUS AND ARTERIAL
THROMBOEMBOLISM
Embryo-Fetal Toxicity
- POMALYST is contraindicated in pregnancy. POMALYST is a
thalidomide analogue. Thalidomide is a known human teratogen that
causes severe birth defects or embryo-fetal death. In females of
reproductive potential, obtain 2 negative pregnancy tests before
starting POMALYST treatment.
- Females of reproductive potential must use 2 forms of
contraception or continuously abstain from heterosexual sex during
and for 4 weeks after stopping POMALYST treatment.
POMALYST is only available through a restricted distribution
program called POMALYST REMS®.
Venous and Arterial
Thromboembolism
- Deep venous thrombosis (DVT), pulmonary embolism (PE),
myocardial infarction, and stroke occur in patients with multiple
myeloma treated with POMALYST. Prophylactic antithrombotic measures
were employed in clinical trials. Thromboprophylaxis is
recommended, and the choice of regimen should be based on
assessment of the patient’s underlying risk factors.
CONTRAINDICATIONS
- Pregnancy: POMALYST can cause fetal
harm and is contraindicated in females who are pregnant. If
POMALYST is used during pregnancy or if the patient becomes
pregnant while taking this drug, the patient should be apprised of
the potential risk to a fetus.
WARNINGS AND PRECAUTIONS
- Embryo-Fetal
Toxicity & Females of Reproductive Potential: See Boxed
WARNINGS
- Males:
Pomalidomide 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
POMALYST and for up to 4 weeks after discontinuing POMALYST, even
if they have undergone a successful vasectomy. Males must not
donate sperm.
- Blood
Donation: Patients must not donate blood during treatment
with POMALYST and for 4 weeks following discontinuation of POMALYST
therapy because the blood might be given to a pregnant female
patient whose fetus must not be exposed to POMALYST.
- POMALYST
REMS® Program: See Boxed WARNINGS
- Prescribers and pharmacies must be
certified with the POMALYST REMS program by enrolling and
complying with the REMS requirements; pharmacies must only dispense
to patients who are authorized to receive POMALYST. 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.
- Further information about the
POMALYST REMS program is available at
www.CelgeneRiskManagement.com or by telephone at
1-888-423-5436.
- Venous and
Arterial Thromboembolism: See Boxed WARNINGS. 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 choice of regimen should
be based on assessment of the patient’s underlying risk
factors.
- Increased
Mortality with Pembrolizumab: In clinical trials
in patients with multiple myeloma, the addition of pembrolizumab to
a thalidomide analogue plus dexamethasone resulted in increased
mortality. Treatment of patients with multiple myeloma with a PD-1
or PD-L1 blocking antibody in combination with a thalidomide
analogue plus dexamethasone is not recommended outside of
controlled clinical trials.
- Hematologic
Toxicity: Neutropenia (46%) was the most
frequently reported Grade 3/4 adverse reaction in patients taking
POMALYST in clinical trials, followed by anemia and
thrombocytopenia. Monitor complete blood counts weekly for the
first 8 weeks and monthly thereafter. Patients may require dose
interruption and/or modification.
- Hepatotoxicity: Hepatic failure,
including fatal cases, has occurred in patients treated with
POMALYST. Elevated levels of alanine aminotransferase and bilirubin
have also been observed in patients treated with POMALYST. Monitor
liver function tests monthly. Stop POMALYST upon elevation of liver
enzymes. After return to baseline values, treatment at a lower dose
may be considered.
- Severe
Cutaneous Reactions Including Hypersensitivity
Reactions: Angioedema and severe cutaneous
reactions including Stevens-Johnson Syndrome (SJS), toxic epidermal
necrolysis (TEN), and drug reaction with eosinophilia and systemic
symptoms (DRESS) have been reported. DRESS may present with a
cutaneous reaction (such as rash or exfoliative dermatitis),
eosinophilia, fever, and/or lymphadenopathy with systemic
complications such as hepatitis, nephritis, pneumonitis,
myocarditis, and/or pericarditis. Discontinue POMALYST for
angioedema, skin exfoliation, bullae, or any other severe cutaneous
reactions such as SJS, TEN or DRESS, and do not resume
therapy.
- Dizziness and
Confusional State: In patients taking POMALYST in
clinical trials, 14% experienced dizziness (1% Grade 3 or 4) and 7%
a confusional state (3% Grade 3 or 4). Instruct patients to avoid
situations where dizziness or confusional state may be a problem
and not to take other medications that may cause dizziness or
confusional state without adequate medical advice.
- Neuropathy: In patients taking
POMALYST in clinical trials, 18% experienced neuropathy (2% Grade 3
in one trial) and 12% peripheral neuropathy.
- Second Primary
Malignancies: Cases of acute myelogenous leukemia
have been reported in patients receiving POMALYST as an
investigational therapy outside of multiple myeloma.
- Tumor Lysis
Syndrome (TLS): TLS may occur in patients treated
with POMALYST. Patients at risk are those with high tumor burden
prior to treatment. These patients should be monitored closely and
appropriate precautions taken.
ADVERSE REACTIONS
The most common adverse reactions for POMALYST (≥30%) included
fatigue and asthenia, neutropenia, anemia, constipation, nausea,
diarrhea, dyspnea, upper-respiratory tract infections, back pain,
and pyrexia.
In the phase III trial, nearly all patients treated with
POMALYST + low-dose dex experienced at least one adverse reaction
(99%). Adverse reactions (≥15% in the POMALYST + low-dose dex arm
and ≥2% higher than control) included neutropenia (51.3%), fatigue
and asthenia (46.7%), upper respiratory tract infection (31%),
thrombocytopenia (29.7%), pyrexia (26.7%), dyspnea (25.3%),
diarrhea (22%), constipation (21.7%), back pain (19.7%), cough
(20%), pneumonia (19.3%), bone pain (18%), edema peripheral
(17.3%), peripheral neuropathy (17.3%), muscle spasms (15.3%), and
nausea (15%). Grade 3 or 4 adverse reactions (≥15% in the POMALYST
+ low-dose dex arm and ≥1% higher than control) included
neutropenia (48.3%), thrombocytopenia (22%), and pneumonia
(15.7%).
DRUG INTERACTIONS
Avoid concomitant use of POMALYST with strong inhibitors of
CYP1A2. Consider alternative treatments. If a strong CYP1A2
inhibitor must be used, reduce POMALYST dose by 50%.
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 POMALYST pregnancy
exposure registry that monitors pregnancy outcomes in females
exposed to POMALYST during pregnancy as well as female partners of
male patients who are exposed to POMALYST. This registry is also
used to understand the root cause for the pregnancy. Report any
suspected fetal exposure to POMALYST 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 pomalidomide in human milk, the effects
of POMALYST on the breastfed child, or the effects of POMALYST on
milk production. Pomalidomide was excreted in the milk of lactating
rats. Because many drugs are excreted in human milk and because of
the potential for adverse reactions in a breastfed child from
POMALYST, advise women not to breastfeed during treatment with
POMALYST.
- Pediatric
Use: Safety and effectiveness have not been
established in pediatric patients.
- Geriatric
Use: No dosage adjustment is required for
POMALYST based on age. Patients >65 years of age were more
likely than patients ≤65 years of age to experience pneumonia.
- Renal
Impairment: Reduce POMALYST dose by 25% in
patients with severe renal impairment requiring dialysis. Take dose
of POMALYST following hemodialysis on hemodialysis days.
- Hepatic
Impairment: Reduce POMALYST dose by 25% in
patients with mild to moderate hepatic impairment and 50% in
patients with severe hepatic impairment.
- Smoking
Tobacco: Advise patients that smoking may reduce
the efficacy of POMALYST. Cigarette smoking reduces the AUC of
pomalidomide by 32% by CYP1A2 induction.
Please see full Prescribing Information, including
Boxed WARNINGS.
Please see full SmPC for more information.
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
Severe Hypersensitivity Reactions: REVLIMID is
contraindicated in patients who have demonstrated severe
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 as 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
Increased Mortality with Pembrolizumab: In clinical
trials in patients with multiple myeloma, the addition of
pembrolizumab to a thalidomide analogue plus dexamethasone resulted
in increased mortality. Treatment of patients with multiple myeloma
with a PD-1 or PD-L1 blocking antibody in combination with a
thalidomide analogue plus dexamethasone is not recommended outside
of controlled clinical trials
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
Severe Cutaneous Reactions Including Hypersensitivity
Reactions: Angioedema and severe cutaneous reactions including
Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN),
and drug reaction with eosinophilia and systemic symptoms (DRESS)
have been reported. DRESS may present with a cutaneous reaction
(such as rash, or exfoliative dermatitis), eosinophilia, fever,
and/or lymphadenopathy with systemic complications such as
hepatitis, nephritis, pneumonitis, myocarditis, and/or
pericarditis. 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, TEN, or DRESS is suspected
and should not be resumed following discontinuation for these
reactions
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
Early Mortality in Patients with MCL: In another MCL
study, there was an increase in early deaths (within 20 weeks),
12.9% in the REVLIMID arm versus 7.1% in the control arm. Risk
factors for early deaths include high tumor burden, MIPI score at
diagnosis, and high WBC at baseline (≥10 x 109/L)
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 in patients on dialysis
Please see full Prescribing Information,
including Boxed WARNINGS.
Please see full SmPC for further information.
About Celgene
Celgene Corporation, headquartered in Summit, New Jersey,
is an integrated global pharmaceutical company engaged primarily in
the discovery, development and commercialization of innovative
therapies for the treatment of cancer and inflammatory diseases
through gene and protein regulation. For more information, please
visit the Company's website at 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. Celgene undertakes 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 other reports filed with
the Securities and Exchange Commission, including factors
related to the proposed transaction between Bristol-Myers Squibb
and Celgene, such as, but not limited to, the risks that:
management’s time and attention is diverted on transaction related
issues; disruption from the transaction makes it more difficult to
maintain business, contractual and operational relationships; legal
proceedings are instituted against Bristol-Myers Squibb, Celgene or
the combined company could delay or prevent the proposed
transaction; and Bristol-Myers Squibb, Celgene or the combined
company is unable to retain key personnel.
References:
____________________________1 Liwing et al. Br J
Haematol. 2014; 164(5):684-93.2 Kumar SK et al. Mayo Clin Proc
2004; 79(7): 867–874.3 Durie B, et al. Lancet. 2017;389:519-527.4
Richardson P et al. OPTIMISMM: Phase 3 trial of pomalidomide,
bortezomib, and low‐dose dexamethasone vs bortezomib and low-dose
dexamethasone in lenalidomide-exposed patients with relapsed or
refractory multiple myeloma (Abstract)5 Palumbo A, et al. N
Engl J Med. 2011;364:1046-1060.6 Pratt G, et al. Br J Haematol.
2007; 38(5):563-79.7 European Cancer Information System. Estimates
of cancer incidence and mortality in 2018, for all countries.
Available at: https://ecis.jrc.ec.europa.eu/explorer.php Last
accessed: March 20188 Hulin C et al. Leuk Res. 2017; 59: 75–84.
2
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