Oral REVLIMID is approved for treat­ment until disease pro­gres­sion

Boudry, Switzerland (Press Release) – Celgene Inter­na­tional Sàrl, a wholly owned sub­sid­i­ary of Celgene Corpo­ra­tion (NASDAQ: CELG), today announced that the European Com­mis­sion (EC) has approved REVLIMID® (lena­lido­mide) for the treat­ment of adult patients with pre­vi­ously untreated multiple myeloma who are not eli­gible for trans­plant.

The REVLIMID Marketing Authorisation has been updated to in­clude this new indi­ca­tion in multiple myeloma, build­ing upon the already approved indi­ca­tion of REVLIMID in com­bi­na­tion with dexa­meth­a­sone for the treat­ment of multiple myeloma in adult patients who have received at least one prior ther­apy.

Multiple myeloma is a persistent 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 38,900 people were newly diag­nosed with multiple myeloma in Europe in 2012, and 24,300 people died from the disease in the same year.² On average, multiple myeloma is diag­nosed in people 65-74 years of age,³ and the majority of newly diag­nosed patients may not be eli­gible for more aggressive treat­ment options such as high-dose chemo­ther­apy with stem cell trans­plant.⁴

Professor Thierry Facon, Services des Maladies du Sang, Hôpital Claude Huriez, and CHRU Lille, France, says: "Having a new treat­ment option now avail­able for patients newly diag­nosed with multiple myeloma is a real step forward. Treating patients continuously until disease pro­gres­sion is sup­ported by several clin­i­cal studies, and will have an im­por­tant impact on how we man­age the disease over the long-term."

"We are very pleased that physicians can now offer their patients a new and dif­fer­en­t treat­ment option," said Tuomo Pätsi, Pres­i­dent of Celgene in Europe, the Middle East and Africa (EMEA). "Multiple myeloma is rare, but it is dev­as­tat­ing for those who have it, and it has a major impact on their friends and family too. We have seen sig­nif­i­cant progress in the treat­ment of the disease over the years, with an im­prove­ment of more than 50% in 5-year survival rates, but there con­tinues to be a need for inno­va­tive new ap­proaches to turn deadly diseases, like this one, into man­ageable, long-term, chronic con­di­tions."

The EC de­ci­sion in newly diag­nosed multiple myeloma was based on the results of two pivotal studies: MM-020 (also known as the FIRST trial) and MM-015.

• The FIRST study, MM-020,⁵ was one of the largest phase III, multi-centre, open-label, randomised studies in patients newly diagnosed with multiple myeloma and not eligible for stem cell transplantation, including 1,623 patients. It compared lenalidomide plus dexamethasone administered in 28-day cycles until disease progression (Rd), with Rd for 72 weeks (18 cycles; Rd18) and melphalan-prednisone-thalidomide (MPT) for 72 weeks. Progression-free survival (PFS; study primary endpoint) was significantly improved in patients treated continuously with Rd, compared with those receiving MPT (primary comparison, p < 0.0001) or Rd18 (p < 0.0001). Median overall survival (OS) in patients receiving Rd continuous therapy was 58.9 months, vs. 48.5 months for patients treated with MPT (HR 0.75; 95% CI 0.62, 0.90), based on a March 3, 2014 interim OS analysis. The numbers of patients experiencing any grade 3 or 4 adverse event were similar in each group. The most frequent grade 3 or 4 adverse events were neutropenia, anaemia and infections.
• MM-015⁵ was a multi-centre, randomised, double-blind, placebo-controlled phase III study of 459 patients that compared melphalan-prednisone-lenalidomide induction followed by lenalidomide maintenance (MPR-R) with melphalan-prednisone-lenalidomide (MPR) or melphalan-prednisone (MP) followed by placebo in patients ≥65 years or older with newly diagnosed multiple myeloma. Pro­gression-free survival (PFS; study primary endpoint) was significantly improved in patients treated with MPR-R when compared with MPR and MP (p < 0.001 for comparisons of MPR-R over MPR and MP). In the MM-015 study, overall survival was not significantly improved when compared across any treatment arm. During induction, the most frequent adverse events were hematologic (including neutropenia, thrombocytopenia, and anaemia). During the maintenance phase, the incidence of new or worsened grade 3 or 4 adverse events was low (0 to 6%).

The EC de­ci­sion for the use of REVLIMID in newly diag­nosed multiple myeloma in adult patients in­eli­gible for trans­plan­ta­tion follows the positive opinion issued by the Committee for Medicinal Products for Human Use (CHMP) in December 2014. It is the second European Com­mis­sion approval Celgene has received this year, fol­low­ing the approval of OTEZLA®, the first phosphodiesterase-4 (PDE-4) inhibitor for use in psoriasis and psoriatic arthritis, in January 2015. A CHMP positive opinion was also issued in January for use of the com­pany's on­col­ogy drug ABRAXANE®, in non-small cell lung cancer.

Celgene announced on 18 February 2015 that the U.S. Food and Drug Admin­istra­tion (FDA) has expanded the existing indi­ca­tion for REVLIMID (lena­lido­mide) in com­bi­na­tion with dexa­meth­a­sone to in­clude patients newly diag­nosed with multiple myeloma in the U.S.

About REVLIMID®

In the United States, REVLIMID is approved in com­bi­na­tion with dexa­meth­a­sone for the treat­ment of patients with multiple myeloma. In the European Union, REVLIMID is approved for the treat­ment of adult patients with pre­vi­ously untreated multiple myeloma who are not eli­gible for trans­plant. REVLIMID is approved in com­bi­na­tion with dexa­meth­a­sone for the treat­ment of patients with multiple myeloma who have received at least one prior ther­apy in nearly 70 countries, encompassing Europe, the Americas, the Middle-East and Asia, and in com­bi­na­tion with dexa­meth­a­sone for the treat­ment of patients whose disease has progressed after one ther­apy in Australia and New Zealand.

REVLIMID is 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 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 myelo­dys­plastic syn­dromes asso­ci­ated with an isolated deletion 5q cytogenetic ab­nor­mal­ity when other thera­peutic options are insufficient or inadequate.

In addi­tion, REVLIMID is approved in the United States for the treat­ment of patients with mantle cell lym­phoma (MCL) whose disease has re­lapsed or progressed after two prior ther­a­pies, one of which in­cluded bor­tez­o­mib. In Switzerland, REVLIMID is indicated for the treat­ment of patients with re­lapsed or refractory MCL after prior ther­apy that in­cluded bor­tez­o­mib and chemo­ther­apy/rituximab.

About Celgene

Celgene Inter­na­tional Sàrl, located in Boudry, in the Canton of Neuchâtel, Switzerland, is a wholly-owned sub­sid­i­ary and Inter­na­tional Headquarters of Celgene Corpo­ra­tion. Celgene Corpo­ra­tion, headquartered in Summit, New Jersey, is an integrated global pharma­ceu­tical com­pany engaged primarily in the discovery, devel­op­ment and com­mer­cial­iza­tion of inno­va­tive ther­a­pies for the treat­ment of cancer and inflammatory diseases through gene and protein reg­u­la­tion. For more in­­for­ma­tion, please visit www.celgene.com. Follow us on Twitter @Celgene, and on Pinterest and LinkedIn.

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 < 60 mL/min.

Cataract: regular monitoring of visual ability is recommended.

Summary of the safety profile in multiple myleloma

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.

Forward-Looking Statements

This press release con­tains forward-looking state­ments, which are generally state­ments that are not historical facts. Forward-looking state­ments can be identified by the words "expects," "antic­i­pates," "believes," "intends," "estimates," "plans," "will," "outlook" and similar ex­pres­sions. Forward-looking state­ments are based on man­agement's current plans, esti­mates, assump­tions and projections, and speak only as of the date they are made. We under­take no obli­ga­tion to update any forward-looking state­ment in light of new in­­for­ma­tion or future events, except as other­wise required by law. Forward-looking state­ments involve in­her­ent risks and un­cer­tain­ties, most of which are dif­fi­cult to predict and are generally beyond our control. Actual results or out­comes may differ ma­teri­ally from those implied by the forward-looking state­ments as a result of the impact of a number of factors, many of which are discussed in more detail in Celgene Corpo­ra­tion's Annual Report on Form 10-K and other reports filed with the Securities and Exchange Com­mis­sion.

All registered trademarks are owned by Celgene Corpo­ra­tion.

References

1. Palumbo A & Anderson K. Multiple myeloma. N Engl J Med 2011;364:1046-1060.

2. Ferlay J et al. Cancer incidence and mortality patterns in Europe: Estimates for 40 countries in 2012. Eur J Cancer 2013;49:1374-1403.

3. National Cancer Institute. SEER Stat Fact Sheets: Myeloma. http://seer.cancer.gov/statfacts/html/mulmy.html

4. Jagannath S. Treatment of myeloma in patients not eli­gible for trans­plan­ta­tion. Curr Treat Options Oncol 2005;6(3):241-53.

5. Summary of Product Characteristics, REVLIMID, February 2015.

Source: Celgene.