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FDA Expands Indication for REVLIMID® (lenalidomide) as a Maintenance Treatment for Patients with Multiple Myeloma Following Autologous Hematopoietic Stem Cell Transplant (auto-HSCT)

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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: @CelgenePinterestLinkedInFacebook and YouTube.

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