The European Com­mis­sion has approved two of Celgene’s IMiD®-based com­bi­na­tion regi­mens:

• REVLIMID in combi­nation with bor­tez­o­mib and dexa­meth­a­sone (RVd) in adult patients with pre­vi­ously untreated multiple myeloma who are not eli­gible for trans­plant
• IMNOVID in com­bi­na­tion with bor­tez­o­mib and dexa­meth­a­sone (PVd), in adult patients with multiple myeloma, who have received at least one prior treat­ment regi­men in­­clud­ing REVLIMID.

{{image}}Boudry, Switzerland (Press Release) – Celgene Corpo­ra­tion (NASDAQ:CELG), today announced that the European Com­mis­sion (EC) has approved two new triplet regi­mens based on Celgene’s pro­pri­e­tary IMiD treat­ments, REVLIMID (lena­lido­mide) and IMNOVID (poma­lido­mide).

REVLIMID in com­bi­na­tion with bor­tez­o­mib and dexa­meth­a­sone (RVd), is now indicated for the treat­ment of adult patients with pre­vi­ously untreated multiple myeloma who are not eli­gible for trans­plant. In addi­tion, IMNOVID, in com­bi­na­tion with bor­tez­o­mib and dexa­meth­a­sone (PVd), is now indicated for the treat­ment of adult patients with multiple myeloma who have received at least one prior treat­ment regi­men in­­clud­ing lena­lido­mide.

“The approval of these com­bi­na­tion ther­a­pies marks a sig­nif­i­cant mile­stone for patients with multiple myeloma in Europe,” said Nadim Ahmed, Pres­i­dent of Hematology/Oncology for Celgene. “With these new triplet regi­mens we hope to im­prove out­comes for both newly diag­nosed patients as well as those who have re­lapsed or be­come refractory to first-line ther­apy. IMiD agents have brought sig­nif­i­cant benefit to multiple myeloma patients and we are committed to ad­vanc­ing our pipe­line of novel myeloma treat­ments in order to ensure physicians and patients con­tinue to have new treat­ment options avail­able to fight this disease.”

The choice of treat­ment in a first-line ther­apy setting is im­por­tant¹ as patients progressively be­come less re­spon­sive­ to ther­apy, and ex­peri­ence shorter periods of remission at later lines of treat­ment.² Studies have shown that RVd can provide newly diag­nosed patients that are not eli­gible for a trans­plant with a treat­ment option that sig­nif­i­cantly prolongs the first remission.³

“Determining first-line ther­apy is an im­por­tant con­sid­er­a­tion in the over­all treat­ment plan for patients with multiple myeloma,” said Prof. Thierry Facon, Pro­fessor of Haematology in the Department of Haematology, Lille University Hospital, France. “Since REVLIMID in com­bi­na­tion with dexa­meth­a­sone is already a standard of care in multiple myeloma, we’re excited by the pros­pect­ of a new REVLIMID-based triplet option for pre­vi­ously untreated patients who are not eli­gible for trans­plant.”

The approval for the REVLIMID triplet (RVd) was sup­ported by data from SWOG S0777³, a phase 3 trial eval­u­ating the triplet com­bi­na­tion, RVd, in adult patients with pre­vi­ously untreated multiple myeloma.

“Today’s approval for use of the IMNOVID-containing triplet, PVd, as early as first relapse, underscores the poten­tial clin­i­cal benefit this regi­men can provide to patients fol­low­ing a prior treat­ment in­­clud­ing REVLIMID,” said Prof. Meletios Dimopoulos, Pro­fessor and Chairman of the Department of Clinical Therapeutics at the University Athens School of Medicine, Athens, Greece. “REVLIMID-based regi­mens are often used as a standard of care in newly diag­nosed multiple myeloma patients, and there is a growing patient pop­u­la­tion who be­come refractory to REVLIMID and need proven treat­ment options.”

The approval of the IMNOVID triplet (PVd) was sup­ported by data from OPTIMISMM⁴, the first pro­spec­tive­ phase 3 trial to eval­u­ate an IMNOVID-based triplet regi­men in patients who were all pre­vi­ously treated with REVLIMID, and the majority (70%) of patients were REVLIMID refractory. Results from OPTIMISMM were recently published in The Lancet Oncology.

Pomalidomide in com­bi­na­tion with bor­tez­o­mib and dexa­meth­a­sone (PVd) is not approved for any use in the United States

Lenalidomide in com­bi­na­tion with bor­tez­o­mib and dexa­meth­a­sone (RVd) is not approved for any use in the United States.

About Multiple Myeloma

Multiple myeloma is a life-threatening blood cancer that is char­ac­ter­ized by tumor proliferation and sup­pres­sion of the immune sys­tem.^5,6 It is a rare but deadly disease – around 42,000 people are diag­nosed with multiple myeloma in Europe, and approx­i­mately 26,000 people die from the disease each year.⁷ The typical multiple myeloma disease course in­cludes periods of symp­tomatic myeloma followed by periods of remission, and eventually, the disease be­comes refractory (nonresponsive).⁸

About SWOG S0777

SWOG S0777 is a ran­dom­ized, open-label, multicentre, phase 3 study aiming to eval­u­ate the efficacy and safety of RVd com­pared to Rd in treating patients with newly diag­nosed multiple myeloma (ndMM) who were not in­tending on im­medi­ately receiving ASCT.³

SWOG S0777 recruited 525 patients with symp­tomatic and measurable ndMM aged 18 years and older. Patients were ran­domly assigned (1:1) to receive either an initial treat­ment of lena­lido­mide with bor­tez­o­mib and dexa­meth­a­sone (RVd group) or lena­lido­mide and dexa­meth­a­sone alone (Rd group) both followed by standard Rd until disease pro­gres­sion. Randomization was stratified based on Inter­na­tional Staging System stage (I, II, or III) and intent to trans­plant (yes versus no). The RVd regi­men was given as eight 21-day cycles. Bortezomib was given at 1.3 mg/m2 in­tra­venously on days 1, 4, 8, and 11, com­bined with oral lena­lido­mide 25 mg daily on days 1-14 plus oral dexa­meth­a­sone 20 mg daily on days 1, 2, 4, 5, 8, 9, 11, and 12. The Rd regi­men was given as six 28-day cycles. The standard Rd regi­men consisted of 25 mg oral lena­lido­mide once a day for days 1-21 plus 40 mg oral dexa­meth­a­sone once a day on days 1, 8, 15, and 22.³

Results from SWOG S07773 showed that median pro­gres­sion-free survival (PFS) was sig­nif­i­cantly im­proved in patients receiving RVd com­pared to those receiving REVLIMID and dexa­meth­a­sone (Rd) alone (42 months versus 30 months; HR 0.76, 95% CI 0.62-0.94; P=0.01). Median over­all survival was also sig­nif­i­cantly im­proved in patients receiving RVd com­pared to those receiving Rd (89 months versus 67 months; HR 0.72, 95% CI 0.56–0.94; P=0.013). The rates of over­all and com­plete response were higher in those receiving RVd com­pared to Rd (overall response: 82% RVd vs 72% Rd; com­plete response: 16% RVd vs 8% Rd) the duration of response was also sig­nif­i­cantly longer in those receiving RVd com­pared to Rd (52 months vs 38 months, re­spec­tive­ly).3 The safety of RVd was also con­sis­tent with the well-established safety profiles of each drug in the triplet regi­men.³

Upon completion of induction, all patients received ongoing main­te­nance with 25 mg oral lena­lido­mide once a day for 21 days plus 40 mg oral dexa­meth­a­sone once a day for days 1, 8, 15, and 22 of each 28-day cycle.³

About OPTIMISMM

OPTIMISMM is the first phase 3 trial designed to compare the safety and efficacy of PVd versus Vd, as an early line of ther­apy in patients with re­lapsed and refractory multiple myeloma (with 1-3 prior regi­mens of ther­apy) and prior REVLIMID-exposure, in­­clud­ing REVLIMID-refractory patients.⁴

The multi-center, inter­na­tional, open-label, ran­dom­ized phase 3 clin­i­cal trial in­cluded 559 patients (281 patients in the PVd arm and 278 in the Vd arm). Demographic, base­line, and prior disease char­ac­ter­istics were generally well bal­anced be­tween the two treat­ment arms. The median number of prior lines of ther­apy was two, while more than one third had one prior line of treat­ment (40% across both treat­ment arms). All patients had prior treat­ment with REVLIMID with the majority being REVLIMID refractory (71%in the PVd arm vs 69% in the Vd arm) and 70% vs 66%, re­spec­tive­ly, were refractory to their last treat­ment. Median follow-up was 16 months.⁴

Patients were stratified based on age, number of prior anti-myeloma regi­mens, and β2-microglobulin levels. Patients were ran­dom­ized 1:1 to receive PVd or Vd until disease pro­gres­sion. In 21-day cycles, patients received IMNOVID 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.⁴

Results from OPTIMISMM4 showed that patients receiving PVd achieved a sig­nif­i­cantly longer PFS than those in the Vd treat­ment arm (median PFS 11.2 months vs. 7.1 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. In an exploratory sub-group analysis of patients with one prior line of ther­apy, median pro­gres­sion-free survival with PVd was 20.7 months vs 11.6 months with Vd (95% CI: 7.52, 15.74). In these patients, the benefit of PVd was observed independent of whether they were refractory or non-refractory to prior ther­apy with lena­lido­mide. Neutropenia (PVd 42% vs Vd 9%), in­fec­tions (PVd 31% vs Vd 18%), and thrombo­cyto­penia (PVd 27% vs Vd 29%) were among the most frequently reported grade 3/4 treat­ment-emergent adverse events. Rates of grade 3/4 deep vein thrombosis (PVd: 0.7% versus Vd: 0.4%) and pul­mo­nary embolism (PVd: 4.0% versus Vd: 0.4%) were low, and no events were fatal. Second pri­mary malig­nan­cies occurred in 3.2% of patients treated with PVd and 1.5% of patients treated with Vd. The most common reason for treat­ment dis­con­tinu­a­tion was progressive disease. Patients discontinuing treat­ment due to adverse events were 10.7% for PVd versus 17.6% for Vd. The safety of PVd was con­sis­tent with the well-established safety profiles of each drug in the triplet ther­apy.⁴

About Celgene’s Immunomodulatory Drugs

IMiD® agents 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.

U.S. Safety Information

ABOUT POMALYST/IMNOVID

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

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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.

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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 inpedi­atric 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.

Please see full SmPC for more in­for­ma­tion.

About REVLIMID®

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

REVLIMID is indicated as main­te­nance ther­apy in patients with MM fol­low­ing au­tol­o­gous hema­to­poietic stem cell trans­plan­ta­tion (auto-HSCT)

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

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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.

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.

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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 risk to the fetus

Severe Hypersensitivity Reactions: REVLIMID is con­tra­in­di­cated in patients who have dem­onstrated severe 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 4 weeks 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 4 weeks 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 or REVLIMID as main­te­nance ther­apy 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 the regi­men should be based on patient’s 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 hema­to­logic plus solid tumor SPM, notably AML and MDS, have been observed. Monitor patients for the devel­op­ment of SPM. Take into account both the poten­tial benefit of REVLIMID and risk of SPM when con­sidering treat­ment

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

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

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. 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, TEN, or DRESS is sus­pected and should not be resumed fol­low­ing dis­con­tinu­a­tion for these reac­tions

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 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 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

Thyroid Disorders: Both hypo­thy­roid­ism and hyperthyroidism have been reported. Measure thyroid function before start of REVLIMID treat­ment and during ther­apy

Early Mortality in Patients with MCL: In another MCL study, there was an in­­crease in early deaths (within 20 weeks), 12.9% in the REVLIMID arm versus 7.1% in the control arm. Risk factors for early deaths in­clude high tumor burden, MIPI score at diag­nosis, and high WBC at base­line (≥10 x 109/L)

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%)
• Maintenance Therapy Post Auto-HSCT: The most frequently reported Grade 3 or 4 reac­tions in ≥20% (REVLIMID arm) in­cluded neu­tro­penia, thrombo­cyto­penia, and leu­ko­penia. The serious adverse reac­tions of lung in­fec­tion and neu­tro­penia (more than 4.5%) occurred in the REVLIMID arm
• The most frequently reported adverse reac­tions in ≥20% (REVLIMID arm) across both main­te­nance studies (Study 1, Study 2) were neu­tro­penia (79%, 61%), thrombo­cyto­penia (72%, 24%), leu­ko­penia (23%, 32%), anemia (21%, 9%), upper res­pira­tory tract in­fec­tion (27%, 11%), bronchitis (5%, 47%), nasopharyngitis (2%, 35%), cough (10%, 27%), gastroenteritis (0%, 23%), diarrhea (55%, 39%), rash (32%, 8%), fatigue (23%, 11%), asthenia (0%, 30%), muscle spasm (0%, 33%), and pyrexia (8%, 21%)
• 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%)

Myelodysplastic Syndromes

• 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%)
• Adverse events reported in ≥15% of del 5q MDS patients (REVLIMID): thrombo­cyto­penia (61.5%), neu­tro­penia (58.8%), 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%)
• 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%)

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 patients with MM taking concomitant warfarin

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 REVLIMID pregnancy exposure registry that monitors pregnancy out­comes in females exposed to REVLIMID during pregnancy as well as female partners of male patients who are exposed to REVLIMID. This registry is also used to under­stand the root cause for the pregnancy. Report any sus­pected fetal exposure to REVLIMID 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 lena­lido­mide in human milk, the effects of REVLIMID on the breastfed infant, or the effects of REVLIMID on milk pro­duc­tion. Because many drugs are excreted in human milk and because of the poten­tial for adverse reac­tions in breastfed infants from REVLIMID, advise female patients not to breastfeed during treat­ment with REVLIMID
• PEDIATRIC USE: Safety and effectiveness have not been estab­lish­ed inpedi­atric patients
• RENAL IMPAIRMENT: Adjust the starting dose of REVLIMID based on the creatinine clearance value and in patients on dialysis

Please see full Prescribing Information, in­­clud­ing Boxed WARNINGS.

Please see full SmPC for further in­for­ma­tion.

About Celgene

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. Follow Celgene on Social Media: @Celgene, Pinterest, LinkedIn, Facebook 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. Celgene under­takes 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 other reports filed with the Securities and Exchange Com­mis­sion, in­­clud­ing factors related to the proposed trans­­action be­tween Bristol-Myers Squibb and Celgene, such as, but not limited to, the risks that: man­agement’s time and attention is diverted on trans­­action related issues; disruption from the trans­­action makes it more dif­fi­cult to main­tain business, contractual and operational rela­tion­ships; legal proceedings are instituted against Bristol-Myers Squibb, Celgene or the com­bined com­pany could delay or prevent the proposed trans­­action; and Bristol-Myers Squibb, Celgene or the com­bined com­pany is unable to retain key per­son­nel.

References

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2. Kumar SK et al. Mayo Clin Proc 2004; 79(7): 867–874.
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4. Richardson P et al. OPTIMISMM: Phase 3 trial of poma­lido­mide, bor­tez­o­mib, and low‐dose dexa­meth­a­sone vs bor­tez­o­mib and low-dose dexa­meth­a­sone in lena­lido­mide-exposed patients with re­lapsed or refractory multiple myeloma (Abstract)
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7. European Cancer Information System. Estimates of cancer in­ci­dence and mortality in 2018, for all countries. Available at: https://ecis.jrc.ec.europa.eu/explorer.php Last accessed: March 2018
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Source: Celgene.