• REVLIMID® is the first and only medicine granted positive CHMP opinion for post-Autologous Stem Cell Transplantation (ASCT) main­te­nance ther­apy in MM
• The new indi­ca­tion expands the avail­a­bil­ity of REVLIMID® across the disease con­tin­uum of MM

Boudry, Switzerland (Press Release) – Celgene Inter­na­tional Sàrl, a wholly owned sub­sid­i­ary of Celgene Corpo­ra­tion (NASDAQ:CELG), today announced that the European Medicines Agency's (EMA) Committee for Medicinal Products for Human Use (CHMP) has adopted a positive opinion for the use of REVLIMID® as mono­therapy for the main­te­nance treat­ment of adult patients with newly diag­nosed multiple myeloma (MM) who have undergone au­tol­o­gous stem cell trans­plan­ta­tion (ASCT). Once approved by the European Com­mis­sion, REVLIMID® will be the first and only licensed main­te­nance treat­ment avail­able to these patients.

Multiple myeloma is an incurable and life-threatening blood cancer that is char­ac­ter­ised by tumour proliferation and sup­pres­sion of the immune system.¹ It is a rare but deadly disease—around 39,000 people are diag­nosed with MM in Europe, and around 24,000 people die from the disease each year.² The median age at diag­nosis in Europe is be­tween 65 and 70 years.³ In Europe, patients who are under 65 years, fit and in good clin­i­cal con­di­tion are typically con­sidered eli­gible for ASCT.⁴

For newly diag­nosed, trans­plant-eligible MM patients, key treat­ment goals are to obtain and to main­tain a deep response to ther­apy, with the ultimate objective of delaying disease pro­gres­sion.^5,6 These patients typically receive induction ther­apy and high-dose chemo­ther­apy with mel­phalan followed by ASCT. This treat­ment ap­proach has been an estab­lish­ed standard of care for over 20 years.⁷ Considering that over half of patients relapse within 2 to 3 years after ASCT,^8,9 trials have been conducted to assess whether main­te­nance ther­apy fol­low­ing ASCT could enable more durable remissions.

“Studies show that main­te­nance treat­ment after ASCT with REVLIMID® may help control residual malignant cells and delay tumour growth by enhancing immune function,” says Pro­fessor Michel Attal, Executive Director of the Institut Universitaire du Cancer Toulouse Oncopole and Institut Claudius Regaud, France. “Our pri­mary goal is to delay disease pro­gres­sion for as long as possible, and we have seen in several independent studies, that REVLIMID® main­te­nance after ASCT can halve the risk of disease pro­gres­sion by sustaining the response.”

The CHMP recom­men­da­tion was based on the results of two cooperative group-led studies, CALGB 100104¹⁰ and IFM 2005-02¹¹:

• CALGB 100104 was a phase III, controlled, double-blind, multi-centre study of 460 patients with newly diagnosed MM undergoing ASCT who received continuous daily treatment with REVLIMID® or placebo until relapse.
• IFM 2005-02 was an international, phase III, controlled, double-blind, multi-centre study of 614 patients newly diagnosed with MM who were randomized to receive a 2-month consolidation regimen post-ASCT of REVLIMID® monotherapy, followed by continuous daily treatment with either REVLIMID® or placebo until relapse.

In the two phase III studies, REVLIMID® mono­therapy as main­te­nance treat­ment post-ASCT sig­nif­i­cantly reduced the risk of disease pro­gres­sion or death in patients with MM, leading to the studies being unblinded based on passing their pre-specified boundary for superiority at interim analysis.

In these studies, the safety profile was in line with other clin­i­cal data in newly diag­nosed non-stem cell trans­plant (NSCT) and post-approval safety study in re­lapsed/refractory MM (rrMM). Across both phase III clin­i­cal studies, the most commonly reported adverse events (AE) were haematological and in­cluded neu­tro­penia and thrombo­cytopenia. The most commonly reported non-haematological AE were in­fec­tions. In both trials, an in­­creased incidence rate of haematologic second pri­mary malig­nan­cies (SPMs) has been observed in the REVLIMID® group compared with the placebo group. However, the CHMP positive opinion con­firms that the benefit-risk ratio for REVLIMID® is positive in this expanded indi­ca­tion.

Tuomo Pätsi, Pres­i­dent of Celgene in Europe, the Middle East and Africa (EMEA), said, “Despite sub­stan­tial progress made so far in multiple myeloma treat­ment, it remains an incurable disease. We welcome this CHMP opinion as it con­firms the im­por­tant role that REVLIMID® plays in treating multiple myeloma, extending the use of REVLIMID® across the disease con­tin­uum. At Celgene, we aspire to turn some of the most chal­leng­ing diseases, like multiple myeloma, into man­ageable con­di­tions. Therefore, we will con­tinue to invest more than one-third of our revenues back into research and devel­op­ment.”

The CHMP reviews appli­ca­tions for all 28 member states in the European Union (EU), as well as Norway, Liechtenstein and Iceland. The European Com­mis­sion, which generally follows the recom­men­da­tion of the CHMP, is ex­pec­ted to make its final de­ci­sion in approx­i­mately two months. If approval is granted, detailed con­di­tions for the use of this prod­uct will be described in the Summary of Product Characteristics (SmPC), which will be published in the revised European Public Assessment Report (EPAR).

About CALGB 100104

CALGB 100104 was a phase III, ran­domised, controlled, double-blind, multi-centre study conducted in 47 centres in the United States. 460 newly diag­nosed multiple myeloma patients – aged be­tween 18 and 70 years - who achieved at least stable disease (SD) or better 100 days after undergoing au­tol­o­gous stem cell trans­plant (ASCT), were ran­domised to receive either REVLIMID® main­te­nance (10 mg/day for 3 months, then 15 mg/day) or placebo until disease pro­gres­sion, intolerable side effects or death.

About IFM 2005-02

IFM 2005-02 was a phase III, controlled, double-blind, multi-centre study conducted in 77 centres across 3 countries in Europe. 614 newly diag­nosed multiple myeloma patients younger than 65 years without signs of disease pro­gres­sion within 6 months of undergoing ASCT, were then ran­domised to receive a two-month consolidation regi­men of REVLIMID® mono­therapy 25 mg per day on 21/28 days, followed by either REVLIMID® main­te­nance (10 mg/day for 3 months, then 15 mg/day) or placebo until disease pro­gres­sion, intolerable side effects or death.

About REVLIMID®

REVLIMID® in com­bi­na­tion with dexa­meth­a­sone is approved in Europe, in the United States, in Japan and in around 25 other countries for the treat­ment of adult patients with pre­vi­ously untreated multiple myeloma (MM) who are not eli­gible for trans­plant. REVLIMID® is also approved in com­bi­na­tion with dexa­meth­a­sone for the treat­ment of patients with MM 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 also approved in the United States, Canada, Switzerland, Australia, New Zealand and several Latin American countries, as well as Malaysia and Israel, for transfusion-dependent anaemia due to low- or intermediate-1-risk myelo­dys­plastic syn­dromes (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 anemia due to low- or intermediate-1-risk MDS asso­ci­ated with an isolated deletion 5q cytogenetic ab­nor­mal­ity when other thera­peutic options are insufficient or inadequate.

In addi­tion, REVLIMID® is approved in Europe and 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. In Switzerland, REVLIMID is indicated for the treat­ment of patients with re­lapsed or refractory MCL after prior ther­apy that in­cluded bor­tez­o­mib and chemo­ther­apy/rituximab.

ADDITIONAL IMPORTANT SAFETY INFORMATION based on EU SmPC

Contraindications

REVLIMID® (lena­lido­mide) is con­tra­in­di­cated in patients with known hypersensitivity to the active substance or to any of the excipients in the formulation.

REVLIMID® (lena­lido­mide) is con­tra­in­di­cated during pregnancy, and also in women of childbearing poten­tial unless all of the con­di­tions of the Pregnancy Prevention Programme are met.

Warnings and precautions

Pregnancy: the con­di­tions of the Pregnancy Prevention Programme must be fulfilled for all patients unless there is reliable evi­dence that the patient does not have childbearing poten­tial.

Cardiovascular disorders: patients with known risk factors for myo­cardial infarction or thromboembolism should be closely monitored.

Neutropenia and thrombo­cytopenia: com­plete blood cell counts should be per­formed every week for the first 8 weeks of treat­ment and monthly there­after to monitor for cytopenias. A dose reduction may be required.

Infection with or without neu­tro­penia: all patients should be advised to seek medical attention promptly at the first sign of in­fec­tion.

Renal im­pair­ment: monitoring of renal function is advised in patients with renal im­pair­ment.

Thyroid disorders: optimal control of co-morbid con­di­tions influencing thyroid function is recommended before start of treat­ment. Baseline and ongoing monitoring of thyroid function is recommended.

Tumour lysis syn­drome: patients with high tumour burden prior to treat­ment should be monitored closely and appro­pri­ate precautions taken.

Allergic reac­tions: patients who had pre­vi­ous allergic reac­tions while treated with thalido­mide should be monitored closely.

Severe skin reac­tions: REVLIMID® (lena­lido­mide) must be dis­con­tinued for exfoliative or bullous rash, or if SJS or TEN is sus­pected, and should not be resumed fol­low­ing dis­con­tinu­a­tion for these reac­tions. Interruption or dis­con­tinu­a­tion of lena­lido­mide should be con­sidered for other forms of skin reac­tion depending on severity. Patients with a history of severe rash asso­ci­ated with thalido­mide treat­ment should not receive lena­lido­mide.

Lactose intolerance: patients with rare hereditary problems of galactose intolerance, lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal prod­uct.

Second pri­mary malig­nan­cies (SPM): the risk of occurrence of hema­to­logic SPM must be taken into account before initiating treat­ment with REVLIMID® (lena­lido­mide) either in com­bi­na­tion with mel­phalan or im­medi­ately fol­low­ing high-dose mel­phalan and au­tol­o­gous stem cell trans­plant (ASCT). Physicians should carefully eval­u­ate patients before and during treat­ment using standard cancer screen­ing for occurrence of SPM and institute treat­ment as indicated.

Hepatic disorders: dose ad­just­ments should be made in patients with renal im­pair­ment. Monitoring of liver function is recommended, particularly when there is a history of or concurrent viral liver in­fec­tion or when REVLIMID® (lena­lido­mide) is com­bined with medicinal prod­ucts known to be asso­ci­ated with liver dysfunction.

Newly diag­nosed multiple myeloma patients: patients should be carefully assessed for their ability to tolerate REVLIMID® (lena­lido­mide) in com­bi­na­tion, with con­sid­er­a­tion to age, ISS stage III, ECOG PS≤2 or CLcr

Cataract: regular monitoring of visual ability is recommended.

Summary of the safety profile in multiple myeloma

Newly diag­nosed multiple myeloma in patients treated with REVLIMID® (lena­lido­mide) in com­bi­na­tion with low dose dexa­meth­a­sone:

• The serious adverse reactions observed more frequently (≥5%) with REVLIMID® (lenalidomide) in combination with low dose dexamethasone (Rd and Rd18) than with melphalan, prednisone and thalidomide (MPT) were pneumonia (9.8%) and renal failure (including acute) (6.3%).
• The adverse reactions observed more frequently with Rd or Rd18 than MPT were: diarrhoea (45.5%), fatigue (32.8%), back pain (32.0%), asthenia (28.2%), insomnia (27.6%), rash (24.3%), decreased appetite (23.1%), cough (22.7%), pyrexia (21.4%), and muscle spasms (20.5%).

Newly diag­nosed multiple myeloma patients treated with REVLIMID® (lena­lido­mide) in com­bi­na­tion with mel­phalan and pred­ni­sone:

• The serious adverse reactions observed more frequently (≥5%) with melphalan prednisone, and REVLIMID® (lenalidomide) followed by REVLIMID® (lenalidomide) maintenance (MPR+R) or melphalan prednisone, and REVLIMID® (lenalidomide) followed by placebo (MPR+p) than melphalan, prednisone and placebo followed by placebo (MPp+p) were febrile neutropenia (6.0%) and anaemia (5.3%).
• The adverse reactions observed more frequently with MPR+R or MPR+p than MPp+p were: neutropenia (83.3%), anaemia (70.7%), thrombocytopenia (70.0%), leukopenia (38.8%), constipation (34.0%), diarrhoea (33.3%), rash (28.9%), pyrexia (27.0%), peripheral oedema (25.0%), cough (24.0%), decreased appetite (23.7%), and asthenia (22.0%).

Patients with multiple myeloma who have received at least one prior ther­apy:

• The most serious adverse reactions observed more frequently with REVLIMID® (lenalidomide) and dexamethasone than with placebo and dexamethasone in combination were venous thromboembolism (deep vein thrombosis, pulmonary embolism) and grade 4 neutropenia.
• The observed adverse reactions which occurred more frequently with REVLIMID® (lenalidomide) and dexamethasone than placebo and dexamethasone in pooled multiple myeloma clinical trials (MM-009 and MM-010) were fatigue (43.9%), neutropenia (42.2%), constipation (40.5%), diarrhoea (38.5%), muscle cramp (33.4%), anaemia (31.4%), thrombocytopenia (21.5%), and rash (21.2%).

Special pop­u­la­tions

Paediatric pop­u­la­tion: REVLIMID® (lena­lido­mide) should not be used in children and adolescents from birth to less than 18 years.

Older people with newly diag­nosed multiple myeloma: for patients older than 75 years of age treated with REVLIMID® (lena­lido­mide) in com­bi­na­tion with dexa­meth­a­sone, the starting dose of dexa­meth­a­sone is 20 mg/day on Days 1, 8, 15 and 22 of each 28-day treat­ment cycle. No dose ad­just­ment is proposed for patients older than 75 years who are treated with REVLIMID® (lena­lido­mide) in com­bi­na­tion with mel­phalan and pred­ni­sone.

Older people with multiple myeloma who have received at least one prior ther­apy: care should be taken in dose selection and it would be prudent to monitor renal function.

Patients with renal im­pair­ment: care should be taken in dose selection and monitoring of renal function is advised. No dose ad­just­ments are required for patients with mild renal im­pair­ment and multiple myeloma. Dose ad­just­ments are recommended at the start of ther­apy and throughout treat­ment for patients with mod­er­ate or severe im­paired renal function or end stage renal disease.

Patients with hepatic im­pair­ment: REVLIMID® (lena­lido­mide) has not formally been studied in patients with im­paired hepatic function and there are no specific dose recom­men­da­tions.

Please refer to the Summary of Product Characteristics for full European Prescribing Information.

ABOUT CELGENE

Celgene Inter­na­tional Sàrl, located in Boudry, 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 next-generation solu­tions in protein homeo­stasis, immuno-oncology, epigenetics, immunology and neuro-inflammation. For more in­­for­ma­tion, please visit www.celgene.com. Follow Celgene on Social Media: @Celgene, Pinterest, LinkedIn, FaceBook and YouTube.

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 Celgene’s Annual Report on Form 10-K and other reports filed with the Securities and Exchange Com­mis­sion.

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References

1. Palumbo A, et al. N Engl J Med. 2011;364:1046–1060.
2. Ferlay J, et al. Eur J Cancer. 2013;49:1374–1403
3. Moreau P, et al. Ann Oncol. 2013; 24 (Suppl 6): vi133-vi137
4. Moreau P, et al. Ann Oncol. 2013; 24 (Suppl 6): vi133-vi137
5. Stewart AK, et al. Blood. 2009;114:5436-5443.
6. Hoering A, et al. Blood. 2009;114:1299-1305
7. Bird JM, et al. Br J Haematol. 2011;154:32-75
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9. Child JA, et al. N Engl J Med. 2003; 348:1875-1883
10. McCarthy PL, et al. N Engl J Med. 2012;366(19):1770-1781. CALGB is the cooperative group Cancer and Leukemia Group B (now known as Alliance).
11. Attal M, et al. N Engl J Med. 2012;366(19):1782-1791. IFM is the cooperative group Intergroupe Francophone du Myélome.

Source: Celgene Inter­na­tional Sàrl.