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.
BOUDRY, Switzerland–(BUSINESS WIRE)–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 only available through a restricted distribution Venous and Arterial Thromboembolism
|
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
Embryo-Fetal Toxicity
Do not use REVLIMID during pregnancy. Lenalidomide, a
Information about the REVLIMID REMS® program
Hematologic Toxicity (Neutropenia and
REVLIMID can cause significant neutropenia and
Venous and Arterial Thromboembolism
REVLIMID has demonstrated a significantly increased risk of |
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
Contacts
Celgene Corporation
Investors:
+1-908-673-9628
ir@celgene.com
or
Media:
+1-908-673-2275
media@celgene.com