Celgene Receives CHMP Positive Opinions for Both REVLIMID® (lenalidomide) and IMNOVID® (pomalidomide)-Based Triplet Combination Regimens for Patients with Multiple Myeloma
March 29, 2019
The CHMP adopted two positive opinions recommending European
Commission approval of:
-
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), for
adult patients with multiple myeloma, who have received at least one
prior treatment regimen including lenalidomide
SUMMIT, N.J.–(BUSINESS WIRE)–Celgene Corporation (NASDAQ:CELG), today announced that the European
Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use
(CHMP) has adopted positive opinions for two triplet regimens based on
Celgene’s proprietary IMiD® medications, REVLIMID
(lenalidomide) and IMNOVID (pomalidomide).
The CHMP recommended approval of an expanded indication of REVLIMID as
combination therapy with bortezomib and dexamethasone (RVd) for the
treatment of adult patients with previously untreated multiple myeloma
who are not eligible for transplant.
The committee also recommended approval of IMNOVID in combination with
bortezomib and dexamethasone (PVd), for the treatment of adult patients
with multiple myeloma who have received at least one prior treatment
regimen including lenalidomide.
The European Commission, which generally follows the recommendation of
the CHMP, is expected to make its final decision in approximately two
months.
“The CHMP positive opinions for our IMiD combinations, RVd and PVd
represent very good news for patients with multiple myeloma in Europe,”
said Nadim Ahmed, President, Hematology/Oncology for Celgene. “We look
forward to potential EMA approvals, which would make these new triplet
regimens available to patients, as we aim to improve patient outcomes
across multiple stages of their disease.”
The CHMP positive opinion for REVLIMID was based on the data from SWOG
S0777, a phase 3 trial evaluating the triplet combination of REVLIMID,
bortezomib and dexamethasone (RVd) in adult patients with previously
untreated multiple myeloma, without an intent for immediate autologous
stem cell transplant (ASCT).1 Results from SWOG S0777 showed
statistically significant progression-free (PFS) and overall survival
improvements in patients treated with RVd compared to those treated with
REVLIMID and dexamethasone alone (Rd). The choice of treatment in a
first-line therapy setting is important2 as patients
progressively become less responsive to therapy and experience shorter
periods of remission at later lines of treatment.3
The CHMP positive opinion for PVd was based on the data from OPTIMISMM,
the first prospective phase 3 trial to evaluate an IMNOVID-based triplet
regimen in patients who were previously treated with REVLIMID, and who
were, in the majority (70 percent), REVLIMID refractory.4
This patient population represents a growing unmet medical need for
which new treatment options are necessary. Results from OPTIMISMM showed
that patients receiving PVd achieved a significantly longer PFS than
those in the Vd treatment arm.
REVLIMID in combination with bortezomib and dexamethasone and IMNOVID in
combination with bortezomib and dexamethasone are not approved for any
use in any country.
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.
About Multiple Myeloma
Multiple myeloma is a life-threatening blood cancer that is
characterized by tumor proliferation and suppression of the immune
system.5 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.6 The typical multiple
myeloma disease course includes periods of symptomatic myeloma followed
by periods of remission, and eventually, the disease becomes refractory
(nonresponsive).
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 previously untreated multiple myeloma without an
intent for immediate autologous stem cell transplant (ASCT).
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). 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.
Results from SWOG S07771 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 safety of RVd
was also consistent with the well-established safety profiles of each
drug in the triplet therapy.7,8
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.
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.
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 percent in the PVd arm vs 69 percent in
the Vd arm) and 70 percent vs 66 percent, respectively, were refractory
to their last treatment. Median follow-up was 16 months.
Results from OPTIMISMM4 showed that patients receiving PVd
achieved a significantly longer PFS than those in the Vd treatment arm
(11.20 months vs. 7.10 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 20.73 months vs 11.63 months with Vd (HR 0.54; p=0·0027). In
these patients, the benefit of PVd was independent of whether they were
refractory or non-refractory to prior therapy with lenalidomide. The
safety of PVd was consistent with the well-established safety profiles
of each drug in the triplet therapy.7
Patients were stratified based on age (≤ 75 years old vs > 75 years
old), number of prior anti-myeloma regimens (1 vs. > 1), and
β2-microglobulin levels (< 3.5 mg/L vs ≥ 3.5 to ≤ 5.5 mg/L vs > 5.5
mg/L). Patients were randomized 1:1 to receive PVd or Vd. 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.
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.
Contacts
Celgene Corporation
Investors:
+1-908-673-9628
[email protected]
or
Media:
+1-908-673-2275
[email protected]
