The OPTIMISMM study is the first Phase 3 Study
to report findings for a triplet combination regimen in which 100%
of patients have received prior lenalidomide therapy
Celgene Corporation (NASDAQ:CELG) today announced results from
the OPTIMISMM study, a phase III, randomized, open-label,
international clinical study of the investigational combination
regimen of POMALYST® (pomalidomide), bortezomib and dexamethasone
in patients with relapsed or refractory multiple myeloma (RRMM) who
had received at least one prior treatment including lenalidomide.
The results were presented at the 54th Annual American Society of
Clinical Oncology Scientific Sessions (ASCO) in Chicago, Illinois
on June 1-5, 2018.
OPTIMISMM evaluated the efficacy and safety of POMALYST/IMNOVID
(pomalidomide) plus bortezomib and low-dose dexamethasone (PVd)
versus bortezomib and low-dose dexamethasone (Vd) in patients with
early RRMM (1-3 prior lines of therapy). It is the only phase III
trial to report results with a triplet combination in patients who
have all received prior lenalidomide therapy. With lenalidomide
becoming a standard of care, this represents a patient population
for which there is a growing unmet medical need.
An analysis of the results found that the treatment with PVd
resulted in significantly improved progression-free survival (PFS)
and an earlier, deeper, more durable response in these patients
compared to Vd treatment. The study, which included a high
percentage of patients refractory to lenalidomide (71% in the PVd
arm, 69% in the Vd arm), met its primary endpoint of PFS. Those
receiving PVd achieved a statistically significant 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. The PFS benefit was observed in the following subgroups of
patients: LEN-refractory, LEN-nonrefractory, prior PI exposure or
high-risk cytogenetics. Overall response rate (ORR), one of the
study’s secondary endpoints, was also significantly higher in the
PVd treatment arm, compared to those receiving Vd (82.2% vs. 50.0%,
p<0.001). Additionally, time to treatment response was longer in
the PVd arm (0.9 months PVd vs. 1.4 months Vd), complete response
was higher in the PVd arm (15.7% PVd vs. 4.0% Vd) and those
receiving PVd experienced a longer duration of response than those
in the Vd arm (13.7 months PVd vs. 10.9 months Vd.)
In an exploratory sub-group analysis, patients who had received
one prior line of therapy reported longer PFS (20.73 months in PVd
arm (n=40) vs. 11.63 months in Vd arm (n=41)) and ORR (90.1% in PVd
arm vs. 54.8% in Vd arm) with a 46% reduction in the risk of
disease progression or death in the PVd treatment arm compared with
Vd. Other secondary endpoints included overall survival and
safety.
"In the early relapse setting, there remains a need for a deeper
understanding of potential treatment options, and in particular for
patients who have received prior lenalidomide-based therapy. These
are the first phase III clinical findings to report a significant
and clinically meaningful progression-free survival improvement in
patients who have previously received lenalidomide, a majority of
whom are lenalidomide refractory," said Paul Richardson, MD,
Clinical Program Leader and Director of Clinical Research, Jerome
Lipper Multiple Myeloma Center, Department of Medical Oncology,
Dana-Farber Cancer Institute.
The most common Grade 3/4 treatment-emergent adverse events
(TEAE) were neutropenia (PVd: 42% vs. Vd: 9%), infections (PVd: 31%
vs. Vd: 18%) and thrombocytopenia (PVd: 27% vs. Vd: 29%.) Rates of
grade 3 or 4 deep vein thrombosis in the PVd vs. Vd arms were 0.7%
vs. 0.4% and rates of grade 3 or 4 pulmonary embolism in PVd vs. Vd
were 4.0% vs. 0.4%. No events were fatal. SPMs occurred in 3.2%
(2.7 per 100 person years) of patients treated with PVd and 1.5%
(1.2 per 100 person years) of patients treated with Vd. The most
common reason for treatment discontinuation was progressive
disease.
"The results of the OPTIMISMM trial continue to bolster the
growing body of research into combination regimens based on the
foundation of our IMiD® therapies," said Nadim Ahmed, President of
Hematology and Oncology for Celgene. "We are excited by the
findings, as they illustrate the potential for a pomalidomide-based
triplet regimen to be used earlier in the treatment course. The
study also included patients who received PVd immediately following
progression after lenalidomide treatment, a growing and clinically
relevant patient population for which no phase III data were
available until now.”
Pomalyst plus dexamethasone in combination with bortezomib is
not approved in any country for any use.
ABOUT OPTIMISMM
OPTIMISMM is the first phase III trial to compare the efficacy
and safety of PVd vs. Vd as an early line of therapy in patients
with RRMM (with 1-3 prior lines of therapy) and prior lenalidomide
(LEN) exposure, including LEN-refractory patients. The study was a
multi-center, international, open-label, randomized phase III
clinical trial to compare the efficacy and safety of a POMALYST
(lenalidomide), bortezomib and low-dose dexamethasone (PVd)
treatment regimen to a bortezomib and low-dose dexamethasone (Vd)
treatment regimen in patients with relapsed or refractory multiple
myeloma.
This global study evaluated 559 patients with relapsed or
refractory multiple myeloma who had received up to three prior
lines of therapy, including two or more cycles of lenalidomide
treatment, who had an ECOG score of PS ≤ 2. Prior treatment with
bortezomib was allowed, except for patients whose disease
progressed while on a regimen containing bortezomib 1.3 mg/m2 twice
weekly dosing. Patients were stratified based on age (≤ 75 years
old vs > 75 years old), number of prior antimyeloma 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) at screening. The median age of the
patients was 67 years in the PVd group and 68 years in the Vd
group.
Patients were randomized 1:1 to receive PVd or Vd. In 21-day
cycles, patients received POMALYST 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 POMALYST
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.
About Celgene’s Immunomodulatory Drugs
Immunomodulatory Drugs (IMiDs®) 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 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: @Celgene, Pinterest, LinkedIn, Facebook and
YouTube.
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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. We undertake 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 our other reports filed with the Securities
and Exchange Commission.
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