Pooled Data from Meta-Analysis Suggest Significant Overall Survival Benefit of Investigational REVLIMID® Maintenance Following Autologous Stem Cell Transplant in Multiple Myeloma

Celgene Corporation (NASDAQ:CELG) today announced data from a meta-analysis of overall survival in multiple myeloma (MM) patients receiving investigational maintenance treatment with REVLIMID^® (lenalidomide) capsules following high-dose melphalan and autologous stem cell transplant (ASCT) were presented during the 52^nd ASCO Annual Meeting in Chicago, Illinois. The analysis, based on data from studies conducted by the Alliance for Clinical Trials in Oncology (formerly Cancer and Leukemia Group B) with support from the National Cancer Institute, Intergroupe Francophone du Myélome (IFM) and the Gruppo Italiano Malattie EMatologiche dell’Adulto (GIMEMA), was presented by Dr. Philip McCarthy of Roswell Park Cancer Institute and lead investigator of the CALGB (Alliance) 100104 study. The findings demonstrated significantly prolonged overall survival (OS) compared to the control arm of placebo or no maintenance.

A meta-analysis of patient-level data from 1,209 patients in three randomized, controlled phase III studies (CALGB (Alliance) 100104, IFM 2005-02, GIMEMA-RVMM-PI-209) was conducted comparing lenalidomide maintenance (n=605) to either placebo or no maintenance (n=604). Each of these studies had individually shown that investigational lenalidomide maintenance treatment following autologous stem cell transplant reduced the risk of disease progression or death (PFS), the primary endpoint, by approximately 50% (McCarthy NEJM 2012; Attal NEJM 2012; Palumbo NEJM 2014).

Results of this analysis showed that at a median follow-up of 80 months, the median overall survival had not been reached for patients receiving lenalidomide maintenance compared with 86 months for the control arm [95% CI: HR 0.74 (0.62-0.89); p=0.001], representing an estimated 2.5-year benefit in favor of lenalidomide maintenance. Hazard ratios for each of the three studies favored maintenance treatment with lenalidomide. While not individually powered to evaluate this endpoint, each study contributed to the pooled OS benefit observed in the meta-analysis.

The risk of developing a hematologic second primary malignancy (SPM) in the lenalidomide arm in the pooled analysis had a hazard ratio of 2.03 (95% CI: 1.14-3.61). The risk of developing a solid tumor SPM in the lenalidomide arm had a hazard ratio of 1.71 (95% CI: 1.04-2.79). Hematologic SPMs observed in the studies totaled 15 for the lenalidomide arm and eight for the control arm in CALGB (Alliance) 100104, 21 for lenalidomide and nine for control in IFM 2005-02, and none for either arm in the GIMEMA-RVMM-PI-209 study. Solid tumor SPMs observed in the studies totaled 17 for the lenalidomide arm and 10 for the control arm in CALGB (Alliance) 100104, 21 for lenalidomide and 13 for control in IFM 2005-02, and five for lenalidomide and two for the control arm in the GIMEMA-RVMM-PI-209 study.

“The results of this meta-analysis reinforce the long-term benefit that lenalidomide maintenance therapy has demonstrated in myeloma patients who receive an autologous stem cell transplant within the large, phase III studies individually,” said Dr. Antonio Palumbo of the University of Torino and the lead investigator of the GIMEMA study.

“Lenalidomide has consistently demonstrated improvement in progression-free survival in this setting,” said Prof. Michel Attal of the University of Toulouse and the lead investigator of the IFM study. “The improved overall survival shown by this meta-analysis further supports the positive benefit-risk ratio observed in the individual phase III studies.”

REVLIMID is not indicated for maintenance treatment following ASCT.

About the studies

CALGB (Alliance) 100104

The study is a phase III, multicenter, randomized, double-blind, placebo-controlled trial in the first-line setting of MM that was conducted at 47 centers in the U.S. The study was sponsored and conducted by the CALGB, which is now part of the Alliance for Clinical Trials in Oncology, a U.S. national oncology cooperative group. The primary objective was to determine if maintenance treatment with lenalidomide would prolong time to tumor progression. Subjects were registered after completion of induction therapy and before ASCT. The starting dosage of lenalidomide was 10 mg/day (to be increased to 15 mg/day after three months for subjects who tolerated maintenance therapy).

IFM 2005-02

This study is a phase III, multicenter, randomized, double-blind, placebo-controlled trial that was conducted in the first-line setting of MM by the IFM, an independent French myeloma cooperative group, at 78 centers in France, Belgium and Switzerland. The primary objective of the IFM study was to evaluate the efficacy of maintenance treatment with lenalidomide following ASCT in extending post-transplant PFS, the primary endpoint. Subjects underwent induction chemotherapy and ASCT before inclusion in the study.

Patients were randomly assigned in a 1:1 ratio to receive either consolidation treatment with lenalidomide (at a dose of 25 mg/day, on days 1 to 21 of each 28-day cycle, for two cycles), followed by maintenance therapy with lenalidomide at a starting dose of 10 mg/day (to be increased up to 15 mg/day after three months in absence of dose-limiting toxicity), or the same consolidation treatment with lenalidomide, followed by maintenance therapy with placebo.

GIMEMA-RVMM-PI-209

This study is a phase III, multicenter, open-label, 2 x 2 factorial, controlled study conducted by Fondazione Neoplasie Sangue Onlus (FO.NE.SA Onlus), an independent Italian cooperative group, in the first-line setting of transplant-eligible newly diagnosed MM (NDMM). The study was conducted at 62 centers in Italy and Israel. The primary objective was to determine (after induction treatment with a standard Rd regimen) the efficacy and safety of treatment with melphalan, prednisone, REVLIMID versus high-dose melphalan (200 mg/m²) followed by ASCT in NDMM subjects in extending PFS, the primary endpoint. As a secondary objective, the efficacy and safety of lenalidomide as maintenance treatment were evaluated.

About REVLIMID ^®

REVLIMID ^® (lenalidomide) in combination with dexamethasone (dex) is indicated for the treatment of patients with multiple myeloma (MM)

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 (formerly known as the “RevAssist ® ” 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 hazard to the fetus

Allergic Reactions: REVLIMID is contraindicated in patients who have demonstrated 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 28 days 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 1 month 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 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

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 regimen is based on patients 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 invasive SPM notably AML and MDS have been observed. Monitor patients for the development of SPMs. Take into account both the potential benefit of REVLIMID and risk of SPMs when considering treatment

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

Allergic Reactions: Angioedema and serious dermatologic reactions including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported. 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 or TEN is suspected and should not be resumed following discontinuation for these reactions. REVLIMID capsules contain lactose; risk-benefit of treatment should be evaluated in patients with lactose intolerance

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 of 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

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%)
• 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%)

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. It is not known whether there is an interaction between dex and warfarin. Close monitoring of PT and INR is recommended in MM patients taking concomitant warfarin

NURSING MOTHERS

Discontinue drug or nursing taking into consideration the importance of the drug to the mother

PEDIATRIC USE

Safety and effectiveness in patients below the age of 18 have not been established

RENAL IMPAIRMENT

REVLIMID is primarily excreted unchanged by the kidneys; adjustments to the starting dose are recommended to provide appropriate drug exposure in patients with moderate or severe renal impairment and in patients on dialysis

Please see accompanying full Prescribing Information, 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 www.celgene.com. Follow Celgene on Social Media: @Celgene, Pinterest, LinkedIn, FaceBook and YouTube.

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