The CHMP adopted two pos­i­tive opinions recommending European Com­mis­sion approval of:

• 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), for adult patients with multiple myeloma, who have received at least one prior treat­ment regi­men in­­clud­ing lena­lido­mide

Summit, NJ (Press Release) – Celgene Corpo­ra­tion (NASDAQ:CELG), today announced that the European Medicines Agency's (EMA) Committee for Medicinal Products for Human Use (CHMP) has adopted pos­i­tive opinions for two triplet regi­mens based on Celgene’s pro­pri­e­tary IMiD® medications, REVLIMID (lena­lido­mide) and IMNOVID (poma­lido­mide).

The CHMP recommended approval of an expanded indi­ca­tion of REVLIMID as com­bi­na­tion ther­apy with bor­tez­o­mib and dexa­meth­a­sone (RVd) for the treat­ment of adult patients with pre­vi­ously untreated multiple myeloma who are not eli­gible for trans­plant.

The committee also recommended approval of IMNOVID in com­bi­na­tion with bor­tez­o­mib and dexa­meth­a­sone (PVd), for the treat­ment of adult patients with multiple myeloma who have received at least one prior treat­ment regi­men in­­clud­ing lena­lido­mide.

The European Com­mis­sion, which generally follows the recom­men­da­tion of the CHMP, is ex­pec­ted to make its final de­ci­sion in approx­i­mately two months.

“The CHMP pos­i­tive opinions for our IMiD com­bi­na­tions, RVd and PVd rep­re­sent very good news for patients with multiple myeloma in Europe,” said Nadim Ahmed, Pres­i­dent, Hematology/Oncology for Celgene. “We look forward to poten­tial EMA approvals, which would make these new triplet regi­mens avail­able to patients, as we aim to im­prove patient out­comes across multiple stages of their disease.”

The CHMP pos­i­tive opinion for REVLIMID was based on the data from SWOG S0777, a phase 3 trial eval­u­ating the triplet com­bi­na­tion of REVLIMID, bor­tez­o­mib and dexa­meth­a­sone (RVd) in adult patients with pre­vi­ously untreated multiple myeloma, without an intent for im­medi­ate au­tol­o­gous stem cell trans­plant (ASCT).¹ Results from SWOG S0777 showed statistically sig­nif­i­cant pro­gres­sion-free (PFS) and over­all survival im­prove­ments in patients treated with RVd com­pared to those treated with REVLIMID and dexa­meth­a­sone alone (Rd). The choice of treat­ment in a first-line ther­apy setting is im­por­tant² as patients progressively become less re­spon­sive­ to ther­apy and ex­peri­ence shorter periods of remission at later lines of treat­ment.³

The CHMP pos­i­tive opinion for PVd was based on the data from OPTIMISMM, the first pro­spec­tive­ phase 3 trial to eval­u­ate an IMNOVID-based triplet regi­men in patients who were pre­vi­ously treated with REVLIMID, and who were, in the majority (70 per­cent), REVLIMID refractory.⁴ This patient pop­u­la­tion rep­re­sents a growing unmet medical need for which new treat­ment options are nec­es­sary. Results from OPTIMISMM showed that patients receiving PVd achieved a sig­nif­i­cantly longer PFS than those in the Vd treat­ment arm.

REVLIMID in com­bi­na­tion with bor­tez­o­mib and dexa­meth­a­sone and IMNOVID in com­bi­na­tion with bor­tez­o­mib and dexa­meth­a­sone are not approved for any use in any country.

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.

About Multiple Myeloma

Multiple myeloma is a life-threatening blood cancer that is char­ac­ter­ized by tumor proliferation and sup­pres­sion of the immune system.⁵ 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.⁶ The typical multiple myeloma disease course in­cludes periods of symp­tomatic myeloma followed by periods of remission, and eventually, the disease becomes refractory (nonresponsive).

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 pre­vi­ously untreated multiple myeloma without an intent for im­medi­ate au­tol­o­gous stem cell trans­plant (ASCT).

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). 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.

Results from SWOG S07771 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 safety of RVd was also con­sis­tent with the well-established safety profiles of each drug in the triplet ther­apy.^7,8

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.

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.

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 per­cent in the PVd arm vs 69 per­cent in the Vd arm) and 70 per­cent vs 66 per­cent, re­spec­tive­ly, were refractory to their last treat­ment. Median follow-up was 16 months.

Results from OPTIMISMM4 showed that patients receiving PVd achieved a sig­nif­i­cantly longer PFS than those in the Vd treat­ment arm (11.20 months vs. 7.10 months, re­spec­tive­ly [P= < .0001, HR 0.61; 95% CI: (0.49-0.77)]), reducing the risk of disease pro­gres­sion or death by 39% in the PVd arm. In an exploratory sub-group analysis of patients with one prior line of ther­apy, median pro­gres­sion-free survival with PVd was 20.73 months vs 11.63 months with Vd (HR 0.54; p=0·0027). In these patients, the benefit of PVd was independent of whether they were refractory or non-refractory to prior ther­apy with lena­lido­mide. The safety of PVd was con­sis­tent with the well-established safety profiles of each drug in the triplet ther­apy.⁷

Patients were stratified based on age (≤ 75 years old vs > 75 years old), number of prior anti-myeloma regi­mens (1 vs. > 1), and β2-microglobulin levels (< 3.5 mg/L vs ≥ 3.5 to ≤ 5.5 mg/L vs > 5.5 mg/L). Patients were ran­dom­ized 1:1 to receive PVd or Vd. 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.

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

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.

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 in pediatric 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.

About IMNOVID® (poma­lido­mide)

IMNOVID® in com­bi­na­tion with dexa­meth­a­sone is indicated in the treat­ment of adult patients with re­lapsed and refractory multiple myeloma who have received at least two prior treat­ment regi­mens, in­­clud­ing both lena­lido­mide and bor­tez­o­mib, and have dem­onstrated disease pro­gres­sion on the last ther­apy. It belongs to a group of drugs called immuno­modu­la­tory drugs (IMiDs®).

IMNOVID, which is marketed under trade name POMALYST® in the US, was first approved for use in the US in 2013 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.

Imnovid in com­bi­na­tion with bor­tez­o­mib and dexa­meth­a­sone is not approved for use in United States.

It was approved in the EU in 2013, in com­bi­na­tion with dexa­meth­a­sone for the treat­ment of adult patients with re­lapsed and refractory multiple myeloma who have received at least two prior treat­ment regi­mens, in­­clud­ing both lena­lido­mide and bor­tez­o­mib, and have dem­onstrated disease pro­gres­sion on the last ther­apy.

It is also approved in a total of 66 countries world­wide in­­clud­ing Australia, Canada, Japan and Switzerland for use in com­bi­na­tion with dexa­meth­a­sone for similar indi­ca­tions to US and EU.

About POMALYST

Indication

POMALYST® (poma­lido­mide) is a thalido­mide analogue indicated, in com­bi­na­tion with dexa­meth­a­sone, for patients with multiple myeloma who have received at least two prior ther­a­pies in­­clud­ing lena­lido­mide and a pro­te­a­some inhibitor and have dem­onstrated disease pro­gres­sion on or within 60 days of completion of the last ther­apy.

Important Safety Information

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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 in pediatric patients.
• Geriatric Use: No dosage ad­just­ment is required for POMALYST based on age. Patients >65 years of age were more likely than patients ≤65 years of age to ex­peri­ence pneu­monia.
• Renal Impairment: Reduce POMALYST dose by 25% in patients with severe renal im­pair­ment requiring dialysis. Take dose of POMALYST fol­low­ing hemodialysis on hemodialysis days.
• Hepatic Impairment: Reduce POMALYST dose by 25% in patients with mild to mod­er­ate hepatic im­pair­ment and 50% in patients with severe hepatic im­pair­ment.
• Smoking Tobacco: Advise patients that smoking may reduce the efficacy of POMALYST. Cigarette smoking reduces the AUC of poma­lido­mide by 32% by CYP1A2 induction.

Please see full Prescribing Information, in­­clud­ing Boxed WARNINGS.

ABOUT CELGENE

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; pending legal proceedings or any future litigation 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

1. Durie BG, Hoering A, Abidi MH, et al. Bortezomib with lena­lido­mide and dexa­meth­a­sone versus lena­lido­mide and dexa­meth­a­sone alone in patients with newly diag­nosed myeloma without intent for im­medi­ate au­tol­o­gous stem-cell trans­plant (SWOG S0777): a ran­domised, open-label, phase 3 trial. Lancet. 2017 Feb 4;389(10068):519-527.
2. Liwing J, Uttervall K, Lund J, et al. Improved survival in myeloma patients: starting to close in on the gap be­tween elderly patients and a matched normal pop­u­la­tion. Br J Haematol. 2014 Mar;164(5):684-93.
3. Kumar SK, Therneau TM, Gertz MA, et al. Clinical course of patients with re­lapsed multiple myeloma. Mayo Clin Proc. 2004 Jul;79(7):867–874.
4. Richardson P, Rocafiguera A, Beksac M, 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. Presented at: American Society of Clinical Oncology Annual Meeting; June 1, 2018; Chicago, IL.
5. Palumbo A and Anderson K. Multiple myeloma. N Engl J Med. 2011;364:1046-1060.
6. 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. Accessed March 2019.
7. Berenson JR, Jagannath S, Barologie B, et al. Safety of prolonged ther­apy with bor­tez­o­mib in re­lapsed or refractory multiple myeloma. Cancer. 2005:104(10):2141-8.
8. European Medicines Agency. REVLIMID summary of prod­uct char­ac­ter­istics, 2009. Updated 23/08/2018.

Source: Celgene.