Market Overview

Celgene Announces Phase III 'AUGMENT' Study of REVLIMID® in Combination with Rituximab (R2) for the Treatment of Patients with Relapsed/Refractory Indolent Lymphoma Met Primary Endpoint


Final analysis showed highly statistically significant improvement in
progression-free survival for R
2 compared with
rituximab plus placebo

Global regulatory submissions planned in the first quarter of 2019

Celgene Corporation (NASDAQ:CELG) today announced results from a phase
III, randomized, double-blind, international clinical study (AUGMENT).
REVLIMID® (lenalidomide) plus rituximab (R2)
achieved a highly statistically significant improvement in the primary
endpoint of progression-free survival (PFS), compared to rituximab plus
placebo, in the final PFS analysis.

AUGMENT evaluated the efficacy and safety of the investigational
combination of R2 versus rituximab plus placebo in patients
(N=358) with relapsed/refractory follicular and marginal zone lymphoma.

In addition to achieving the primary endpoint of the study, a favorable
trend was observed for overall survival (OS) during this analysis and
follow-up will continue for the mature OS results. The safety profile of
R2 was consistent with the known safety profiles of the
individual medicines, and no new safety signals were identified with the

"Indolent non-Hodgkin lymphomas, such as follicular lymphoma and
marginal zone lymphoma, are diseases of underlying immune dysfunction
with a need for new options beyond currently available therapies," said
Jay Backstrom, M.D., Chief Medical Officer for Celgene. "We are
encouraged by the highly significant improvement in progression-free
survival observed in this study and look forward to engaging with
regulatory authorities as soon as possible. The R2 regimen
represents a potentially new chemotherapy-free option for these

Data from AUGMENT will be submitted to a future medical meeting and
Celgene plans to prepare global regulatory submissions in the first
quarter of 2019.

REVLIMID® alone or in combination is not approved for
use in follicular lymphoma or marginal zone lymphoma in any geography.


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




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


Information about the REVLIMID REMS®
program is available at
or by calling the manufacturer's toll-free number 1-888-423-5436.


Hematologic Toxicity (Neutropenia and

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.



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


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

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

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

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

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)


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

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%)


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


  • 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
, 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
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