Statistically sig­nif­i­cant im­prove­ment in pro­gres­sion-free survival dem­onstrated

{{image}}Boudry, Switzerland (Press Release) - Celgene Inter­na­tional Sàrl, a wholly-owned sub­sid­i­ary of Celgene Corpo­ra­tion (NASDAQ: CELG), today announced that its phase III study (MM-020/IFM 07-01) of REVLIMID^® (lena­lido­mide) in com­bi­na­tion with dexa­meth­a­sone in patients newly diag­nosed with multiple myeloma met its pri­mary end­point of pro­gres­sion-free survival (PFS). In the study, a doublet regi­men of continuous oral lena­lido­mide in com­bi­na­tion with low-dose dexa­meth­a­sone (Rd) dem­onstrated a statistically sig­nif­i­cant im­prove­ment in PFS compared to patients receiving a comparator arm with a triplet regi­men consisting of mel­phalan, pred­ni­sone and thalido­mide (MPT).

One of the largest phase III ran­dom­ized, inter­na­tional studies ever conducted in newly-diagnosed multiple myeloma, MM-020/IFM 07-01 is also known as the FIRST^® (Front-Line Investigation of REVLIMID/​Dexa­metha­sone vs. Standard Thalidomide) trial. The inter­na­tional study ran­dom­ized 1,623 patients who were in­eli­gible for au­tol­o­gous stem cell trans­plan­ta­tion to receive continuous oral lena­lido­mide plus low-dose dexa­metha­sone until disease pro­gres­sion; lena­lido­mide plus low-dose dexa­metha­sone for eighteen 28-day cycles (72 weeks); or mel­phalan, pred­ni­sone and thalido­mide for up to twelve 42-day cycles (72 weeks).

The pri­mary end­point for the study was PFS. Secondary end­points in­clude over­all survival, response rate, quality of life and safety.

The evaluation of safety and efficacy in the treat­ment arms is ongoing and the results of the study are planned to be presented at an upcoming medical meeting.

Based on the results of the FIRST^® study, the Company will commence discussions with regu­la­tory au­thor­i­ties and plans to submit dossiers for registration in the US, Europe and other markets.

These results are from an inves­ti­ga­tional phase III study. REVLIMID is not approved for the treat­ment of pa­tients with newly-diagnosed multiple myeloma in any country.

About REVLIMID^®

REVLIMID is approved in com­bi­na­tion with dexa­meth­a­sone for the treat­ment of patients with multiple mye­loma who have received at least one prior ther­apy, in nearly 70 countries, encompassing Europe, the Americas, the Middle-East and Asia, and in com­bi­na­tion with dexa­meth­a­sone for the treat­ment of patients whose disease has progressed after one ther­apy in Australia and New Zealand.

REVLIMID is approved in the United States, Canada, Switzerland, Australia, New Zealandand several Latin American countries, as well as Malaysia and Israel, for transfusion-dependent anaemia due to low- or intermediate-1-risk MDS asso­ci­ated with a deletion 5q cytogenetic ab­nor­mal­ity with or without addi­tional cytogenetic ab­nor­mali­ties and in Europe for the treat­ment of patients with transfusion-dependent anaemia due to low-or intermediate-1-risk myelo­dys­plastic syn­dromes asso­ci­ated with an isolated deletion 5q cytogenetic ab­nor­mal­ity when other thera­peutic options are insufficient or inadequate.

REVLIMID is approved in the United States 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.

U.S. Regulatory Information for Revlimid

REVLIMID^® (lena­lido­mide) in com­bi­na­tion with dexa­meth­a­sone is indicated for the treat­ment of patients with multiple myeloma (MM) who have received at least one prior ther­apy

REVLIMID^® (lena­lido­mide) 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^® (lena­lido­mide) 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

Important Safety Information

WARNING: EMBRYO-FETAL TOXICITY, HEMATOLOGIC TOXICITY, and VENOUS 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 Thromboembolism

REVLIMID has dem­onstrated a sig­nif­i­cantly in­­creased risk of deep vein thrombosis (DVT) and pul­mo­nary embolism (PE) in patients with MM who were treated with REVLIMID and dexa­meth­a­sone ther­apy. Pa­tients and physicians are advised to be observant for the signs and symp­toms of thromboembolism. Pa­tients should be instructed to seek medical care if they develop symp­toms such as shortness of breath, chest pain, or arm or leg swelling. It is not known whether pro­phy­lactic anticoagulation or anti­plate­let ther­apy prescribed in conjunction with REVLIMID may lessen the poten­tial for venous thromboembolism. The de­ci­sion to take pro­phy­lactic measures should be done carefully after an assess­ment of an individual patient’s under­lying risk factors.

CONTRAINDICATIONS

Pregnancy:

• REVLIMID can cause fetal harm when administered to a pregnant female. Lenalidomide 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:

• REVLIMID is an analogue of thalidomide, a known human teratogen that causes life-threatening human birth defects or embryo-fetal death. An embryo-fetal development study in monkeys indicates that lenalidomide produced malformations in the offspring of female monkeys who received the drug during pregnancy, similar to birth defects observed in humans following exposure to thalidomide during pregnancy
• Females of Reproductive Potential: Must avoid pregnancy for at least 4 weeks before beginning REVLIMID therapy, during therapy, during dose interruptions and for at least 4 weeks after completing therapy. Must commit either to abstain continuously from heterosexual sexual intercourse or to use two methods of reliable birth control beginning 4 weeks prior to initiating treatment with REVLIMID, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of REVLIMID therapy. Must obtain 2 negative pregnancy tests prior to initiating therapy
• 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

Because of embryo-fetal risk, REVLIMID is avail­able only through a restricted pro­gram under a Risk Eval­ua­tion and Mitigation Strategy (REMS) the REVLIMID REMS Program (formerly known as the “RevAssist^®” Program). Prescribers and pharmacies must be certified with the pro­gram and patients must sign an agree­ment form and comply with the require­ments. Further in­­for­ma­tion about the REVLIMID REMS program is avail­able at www.celgeneriskmanagement.com or by telephone at 1-888-423-5436

Hematologic Toxicity: REVLIMID can cause sig­nif­i­cant neu­tro­penia and thrombo­cytopenia. MM: Patients taking REVLIMID for MM should have their com­plete blood counts monitored every 2 weeks for the first 12 weeks and then monthly there­after. In the pooled MM trials Grade 3 and 4 hema­to­logic toxicities were more frequent in patients treated with the com­bi­na­tion of REVLIMID and dexa­meth­a­sone than in patients treated with dexa­meth­a­sone alone. MCL: Patients taking REVLIMID for MCL should have their com­plete blood counts monitored weekly for the first cycle (28 days), every 2 weeks during cycles 2-4, and then monthly there­after. In the MCL trial, Grade 3 or 4 neu­tro­penia was reported in 43% of the patients. Grade 3 or 4 throm­bo­cyto­penia was reported in 28% of the patients. Patients may require dose inter­rup­tion and/or dose reduction

Venous Thromboembolism: Venous thrombo­embolic events (predominantly deep venous thrombosis and pul­mo­nary embolism) have occurred in patients with MM treated with lena­lido­mide com­bi­na­tion ther­apy and patients with MDS or MCL treated with lena­lido­mide mono­therapy. It is not known whether pro­phy­lactic anti­coag­ulation or antiplatelet ther­apy prescribed in conjunction with REVLIMID may lessen the poten­tial for venous thromboembolism. The de­ci­sion to take pro­phy­lactic measures should be done carefully after assess­ment of the individual patient’s under­lying risk factors

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 REVLIMID treat­ment should be eval­u­ated in patients with lactose intolerance

Tumor Lysis Syndrome: Fatal instances of tumor lysis syn­drome (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: Tumor flare reac­tion (TFR) has occurred during inves­ti­ga­tional use of lena­lido­mide for chronic lym­pho­cytic leukemia (CLL) and lym­phoma, and is char­ac­ter­ized by tender lymph node swelling, low grade fever, pain and rash. Treatment of CLL with lena­lido­mide outside of a well-monitored clin­i­cal trial is discouraged

Monitoring and evaluation for 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 lena­lido­mide until TFR resolves to ≤ Grade 1. In the MCL trial, approx­i­mately 10% of subjects experi­enced TFR; all reports were Grade 1 or 2 in severity. All of the events occurred in cycle 1 and one patient developed TFR again in cycle 11. Lena­lido­mide may be con­tinued in patients with Grade 1 and 2 TFR without inter­rup­tion or modification, at the physician’s discretion. Patients with Grade 1 or 2 TFR may also be treated with corticosteroids, non-steroidal anti-inflammatory drugs (NSAIDs) and/or narcotic analgesics for man­age­ment of TFR symp­toms. Patients with Grade 3 or 4 TFR may be treated for man­age­ment of symp­toms per the guidance for treat­ment of Grade 1 and 2 TFR

Hepatotoxicity: Hepatic failure, in­­clud­ing fatal cases, has occurred in patients treated with lena­lido­mide in com­bi­na­tion with dexa­meth­a­sone. The mech­a­nism of drug-induced hepato­tox­ic­ity is unknown. 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

Second Primary Malignancies: Patients with MM treated with lena­lido­mide in studies in­­clud­ing mel­phalan and stem cell trans­plan­ta­tion had a higher incidence of second pri­mary malig­nan­cies, particularly acute mye­log­e­nous leukemia (AML) and Hodgkin lym­phoma, compared to patients in the control arms who received similar ther­apy but did not receive lena­lido­mide. Monitor patients for the devel­op­ment of second malig­nan­cies. Take into account both the poten­tial benefit of lena­lido­mide and the risk of second pri­mary malig­nan­cies when con­sidering treat­ment with lena­lido­mide

ADVERSE REACTIONS

Multiple Myeloma

• In the REVLIMID/dexamethasone treatment group, 269 patients (76%) underwent at least one dose interruption with or without a dose reduction of REVLIMID compared to 199 patients (57%) in the placebo/​dexa­metha­sone treatment group
• Of these patients who had one dose interruption with or without a dose reduction, 76% (269/353) vs 57% (199/350), 50% in the REVLIMID/​dexa­metha­sone treatment group underwent at least one addi­tional dose interruption with or without a dose reduction compared to 21% in the placebo/​dexa­metha­sone treatment group
• Most adverse events and Grade 3/4 adverse events were more frequent in MM patients who received the combination of REVLIMID/​dexa­metha­sone compared to placebo/​dexa­metha­sone
• Grade 3/4 neutropenia occurred in 33.4% vs 3.4%; 2.3% experienced Grade 3/4 febrile neutropenia vs 0%
• Deep vein thrombosis (DVT) was reported as a serious adverse drug reaction (7.4%) or Grade 3/4 (8.2%) compared to 3.1% and 3.4%. Discontinuations due to DVT were reported at comparable rates between groups
• Pulmonary embolism (PE) was reported as a serious adverse drug reaction (3.7%) or Grade 3/4 (4.0%) compared to 0.9% and 0.9%. Discontinuations due to PE were reported at comparable rates between groups
• Adverse reactions reported in ≥15% of MM patients (REVLIMID/dexamethasone vs dexa­metha­sone/​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%), weight decreased (20% vs 15%), nasopharyngitis (18% vs 9%), blurred vision (17% vs 11%), anorexia (16% vs 10%), and dysgeusia (15% vs 10%)

Myelodysplastic Syndromes

• Thrombocytopenia (61.5%; 91/148) and neutropenia (58.8%; 87/148) were the most frequently re­ported adverse events observed in the del 5q MDS population
• Grade 3 and 4 adverse events reported in ≥ 5% of patients with del 5q MDS were neutropenia (53%), thrombo­cyto­penia (50%), pneumonia (7%), rash (7%), anemia (6%), leukopenia (5%), fatigue (5%), dyspnea (5%), and back pain (5%)
• Other adverse events reported in ≥15% of del 5q MDS patients (REVLIMID): diarrhea (49%), pruritus (42%), rash (36%), fatigue (31%), constipation (24%), nausea (24%), nasopharyngitis (23%), arthralgia (22%), pyrexia (21%), back pain (21%), peripheral edema (20%), cough (20%), dizziness (20%), headache (20%), muscle cramp (18%), dyspnea (17%), pharyngitis (16%), epistaxis (15%), asthenia (15%), upper respiratory tract infection (15%)

Mantle Cell Lymphoma

• Grade 3 and 4 adverse events reported in ≥5% of patients treated with REVLIMID in the MCL trial (N=134) included neutro­penia (43%), thrombo­cyto­penia (28%), anemia (11%), pneumonia (9%), leu­ko­penia (7%), fatigue (7%), diarrhea (6%), dyspnea (6%), and febrile neutropenia (6%)
• Serious adverse events reported in ≥2 patients treated with REVLIMID monotherapy for MCL included chronic obstructive pulmonary disease, clostridium difficile colitis, sepsis, basal cell carcinoma, and supraventricular tachycardia
• Adverse events reported in ≥15% of patients treated with REVLIMID in the MCL trial included neutro­penia (49%), thrombo­cyto­penia (36%), fatigue (34%), anemia (31%), diarrhea (31%), nausea (30%), cough (28%), pyrexia (23%), rash (22%), dyspnea (18%), pruritus (17%), peripheral edema (16%), constipation (16%), and leukopenia (15%)
• Adverse events occurring in patients treated with REVLIMID in the MCL trial resulted in at least one dose interruption in 76 (57%) patients, at least one dose reduction in 51 (38%) patients, and dis­con­tinua­tion of treatment in 26 (19%) patients

DRUG INTERACTIONS

Periodic monitoring of digoxin plasma levels, in accordance with clin­i­cal judgment and based on standard clin­i­cal practice in patients receiving this medication, is recommended during admin­istra­tion of REVLIMID. It is not known whether there is an inter­action be­tween dexa­meth­a­sone and warfarin. Close monitoring of PT and INR is recommended in MM patients taking concomitant warfarin. Erythropoietic agents, or other agents, that may in­­crease the risk of thrombosis, such as estrogen con­taining ther­a­pies, should be used with cau­tion in MM patients receiving lena­lido­mide with dexa­meth­a­sone

USE IN SPECIFIC POPULATIONS

Pregnancy: If pregnancy does occur during treat­ment, im­medi­ately dis­con­tinue the drug. Under these con­di­tions, refer patient to an obstetrician/gynecologist ex­peri­enced in reproductive toxicity for further evalua­tion and counseling. Any sus­pected fetal exposure to REVLIMID must be reported to the FDA via the MedWatch pro­gram at 1-800-332-1088 and also to Celgene Corpo­ra­tion at 1-888-423-5436

Nursing Mothers: It is not known whether REVLIMID is excreted in human milk. Because many drugs are excreted in human milk and because of the poten­tial for adverse reac­tions in nursing infants, a de­ci­sion should be made whether to dis­con­tinue nursing or the drug, taking into account the importance of the drug to the mother

Pediatric Use: Safety and effectiveness in pediatric patients below the age of 18 have not been estab­lish­ed

Geriatric Use: Since elderly patients are more likely to have de­creased renal function, care should be taken in dose selection. Monitor renal function

Renal Impairment: Since REVLIMID is primarily excreted unchanged by the kidney, ad­just­ments to the start­ing dose of REVLIMID are recommended to provide appro­pri­ate drug exposure in patients with moder­ate (CLcr 30-60 mL/min) or severe renal im­pair­ment (CLcr < 30 mL/min) and in patients on dialysis

Please see full Prescribing Information, in­­clud­ing Boxed WARNINGS, CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and ADVERSE REACTIONS.

About Celgene

Celgene Inter­na­tional Sàrl, located in Boudry, in the Canton of Neuchâtel, Switzerland, is a wholly-owned sub­sid­i­ary and inter­na­tional headquarters of Celgene Corpo­ra­tion.Celgene Corpo­ra­tion, headquartered in Summit, New Jersey, is an integrated global pharma­ceu­tical com­pany engaged primarily in the discovery, devel­op­ment and com­mer­cial­iza­tion of inno­va­tive ther­a­pies for the treat­ment of cancer and inflammatory diseases through gene and protein reg­u­la­tion. For more in­­for­ma­tion, please visit the Company's website at www.celgene.com.

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.

Source: Celgene Inter­na­tional Sàrl.