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Results of Phase III OPTIMISMM Study Presented at ASCO 2018 Showed the PVd Triplet Improved PFS in Early Lines of Relapsed or Refractory Multiple Myeloma

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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.
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results or outcomes may differ materially from those implied by the
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