Celgene Corporation
Dec 6, 2016
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Phase III Studies Present Additional Evidence for REVLIMID® (lenalidomide) as Maintenance Therapy in Multiple Myeloma

SUMMIT, N.J.--(BUSINESS WIRE)-- Celgene Corporation (NASDAQ:CELG), today announced results from two studies (Abstracts #1143, LBA-1) evaluating the investigational use of REVLIMID® (lenalidomide) maintenance therapy in patients with multiple myeloma. These studies were presented at the 58th American Society of Hematology (ASH) Annual Meeting in San Diego, Calif.

Myeloma XI Study

The Myeloma XI trial is a UK-based, large, randomized, open-label phase III study that included a comparison of investigational lenalidomide maintenance treatment versus no maintenance for patients with newly diagnosed multiple myeloma. The study included both transplant-eligible (TE) and transplant non-eligible (TNE) patients. Patients received induction treatment in both segments with lenalidomide or thalidomide plus cyclophosphamide and dexamethasone. TE patients proceeded to a standard melphalan 200mg/m2 autologous stem cell transplant (ASCT). Patients were then randomized to either maintenance lenalidomide or observation after achieving maximum response (TNE) or at 100 days after transplant (TE). Lenalidomide maintenance was administered at a dose of 10mg daily in 21/28 day cycles until disease progression.

Overall, the primary endpoint of progression-free survival (PFS) was 36 months for patients receiving lenalidomide (n=857) and 18 months for observation (n=694) (HR:0.45 95% CI [0.39, 0.52] P < 0.0001) in the maintenance phase of the study.

"The Myeloma XI study provides important insights for the continued investigation of lenalidomide as a maintenance treatment for people living with multiple myeloma," said Gareth Morgan, M.D., Ph.D., Director of the Myeloma Institute at the University of Arkansas for Medical Sciences. "Building on previous studies, lenalidomide maintenance in this study delayed relapse in patients compared to no maintenance."

StaMINA Study

In the phase III BMT CTN 0702 StaMINA trial, TE patients were randomized following transplant between three arms to receive either 4 cycles of lenalidomide-bortezomib-dexamethasone (RVD) consolidation (ACM) (n=254), tandem melphalan 200mg/m2 autologous stem cell transplant (TAM) consolidation (n=247), or no consolidation (AM) (n=257). All arms included lenalidomide maintenance (at a starting dose of 10 mg daily in 28/28 day cycles until disease progression.

At a median follow-up of 38 months, all three arms demonstrated comparable PFS and OS. The addition of RVD consolidation or a second ASCT was not superior to a single ASCT followed by lenalidomide maintenance. The estimated PFS rates were 57% (95% CI: 50-63%), 56% (95% CI: 49-63%) and 52% (95% CI: 45-59%) for ACM, TAM and AM arms, respectively (ACM vs TAM p=0.75, ACM vs AM p=0.21, TAM vs AM p=0.37). The estimated overall survival (OS) rates were 86% (95% CI: 80-90%), 82% (95% CI: 76-87%) and 83% (95% CI: 78-88%). Median OS had not been reached.

There were 39 cases of SPM reported in 36 patients and the cumulative incidences for first SPM were 6.0% (95% CI: 3.4-9.6%), 5.9% (95% CI: 3.3-9.6%) and 4.0% (95% CI: 1.9-7.2%) for the ACM, TAM and AM arms, respectively.

"The StaMINA trial demonstrated that the addition of RVD consolidation or a second autologous stem cell transplant did not provide a superior outcome, on average, to a single autologous stem cell transplant followed immediately by lenalidomide maintenance," said Edward Stadtmauer, M.D., Section Chief, Hematologic Malignancies at the University of Pennsylvania School of Medicine. "As transplants continue to be an option for many myeloma patients, these are important insights for determining the path to subsequent maintenance therapy."

Health-Related Quality of Life Analysis

An additional analysis presented at ASH (Abstract #537) examined health related quality of life in post-transplant maintenance in patients from Celgene's CONNECT® MM registry.

The analysis evaluated data from patients newly-diagnosed with multiple myeloma (n=1493) registered between September 2009 and December 2011.

Quality of life was measured for those who received ASCT (n=540) using the EQ-5D quality of life index, Fact-MM total score and brief pain inventory (BPI), assessed at a median follow-up of 39.5 months. Patients who received any maintenance therapy (n=238) were compared with those receiving no maintenance therapy (n=138). Another analysis compared those receiving any maintenance therapy versus those who received lenalidomide maintenance (n=167).

In the analysis, patients on average did not report a decrease in quality of life measures with the use of maintenance therapy. The EQ-5D overall index score was 0.79 (0.14) across all patient groups. The Fact-MM total score was 117.7 for any maintenance, compared with 118.9 for lenalidomide maintenance and 114.8 for no maintenance. BPI was 4.0 for any maintenance and 3.9 for both lenalidomide maintenance and no maintenance.

REVLIMID is not approved as a maintenance treatment for post ASCT patients with multiple myeloma.

Celgene filed a supplemental New Drug Application (sNDA) with the U.S. Food and Drug Administration (FDA) for the expanded indication of REVLIMID as maintenance treatment in newly diagnosed multiple myeloma patients after receiving an ASCT based on separate studies. The sNDA was granted Priority Review and the Prescription Drug User Fee Act date of February 24, 2017.

In June, an application was submitted to the European Medicines Agency (EMA) for the review of REVLIMID as maintenance treatment in NDMM patients after receiving an ASCT. A decision on the European Union (EU) application is expected in the first half of 2017.

About REVLIMID

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

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 (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

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. 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 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

Myelodysplastic Syndromes

Mantle Cell Lymphoma

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 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: @CelgenePinterestLinkedInFacebook and YouTube.

Forward-Looking Statements

This press release contains forward-looking statements, which 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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