• Oral REVLIMID® is the first and only medicine licensed in Europe for use as post-autologous stem cell trans­plan­ta­tion main­te­nance ther­apy in multiple myeloma
• The new indi­ca­tion expands the avail­a­bil­ity of REVLIMID® across the disease con­tin­uum of multiple myeloma

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) as mono­therapy for the main­te­nance treat­ment of adult patients with newly diag­nosed multiple myeloma who have undergone au­tol­o­gous stem cell trans­plan­ta­tion (ASCT). REVLIMID® is the first and only licensed main­te­nance treat­ment avail­able to these patients.

The REVLIMID® Marketing Authorisation has been updated to in­clude this new indi­ca­tion, which expands on the existing multiple myeloma indi­ca­tions as com­bi­na­tion ther­apy for the treat­ment of those not eli­gible for trans­plant who are newly diag­nosed, or have received at least one prior ther­apy.

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 multiple myeloma 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 fit and in good clin­i­cal con­di­tion are typically con­sidered eli­gible for ASCT.⁴

For patients who are newly diag­nosed with multiple myeloma and eli­gible for ASCT, key treat­ment goals are to delay disease pro­gres­sion and ultimately achieve long-term control over multiple myeloma.⁵ 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.⁶ Considering that over half of those patients who relapse do so within 2 to 3 years of ASCT,⁷,⁸ the approval of a main­te­nance ther­apy for use after ASCT that may delay disease pro­gres­sion rep­re­sents a major ad­vance for these patients.

"After ASCT, most patients will still see their disease recur or progress. We now have an oppor­tu­ni­ty to en­hance immune function and delay disease pro­gres­sion by controlling residual malignant cells and slowing tumour growth. REVLIMID® has been shown to in­­crease pro­gres­sion-free survival after ASCT in clin­i­cal trials. Having a licensed ther­apy for use in this very im­por­tant setting means we now have the oppor­tu­ni­ty to delay disease pro­gres­sion by sustaining the response," says Pro­fessor Michel Attal, Executive Director of the Institut Universitaire du Cancer Toulouse Oncopole and Institut Claudius Regaud, France.

The EC de­ci­sion to approve REVLIMID® as mono­therapy for multiple myeloma in the post-ASCT setting was based on the results of two cooperative group-led studies, CALGB 100104⁹ and IFM 2005-02.¹⁰

• CALGB 100104 was a phase III, controlled, double-blind, multi-centre study of 460 patients with newly diagnosed multiple myeloma undergoing ASCT who were randomized to receive continuous daily treatment with REVLIMID® or placebo until relapse or intolerance.
• IFM 2005-02 was an international, phase III, controlled, double-blind, multi-centre study of 614 patients newly diagnosed with multiple myeloma 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 or intolerance.

In both studies, the pri­mary efficacy end­point in the study was pro­gres­sion-free survival (PFS) from trans­plant to the date of disease pro­gres­sion or death, whichever occurred first. REVLIMID® mono­therapy as main­te­nance treat­ment post-ASCT sig­nif­i­cantly reduced the risk of disease pro­gres­sion or death in patients with multiple myeloma, leading to the studies being unblinded based on passing their pre-specified boundary for superiority at interim analysis. The updated PFS, using a cut-off of 1 February 2016 con­tinues to show a PFS advantage:

• CALGB 100104: after 81.6 months of follow up, median PFS was 56.9 months (95% CI 41.9, 71.7) in the REVLIMID® arm versus 29.4 months (95% CI 20.7, 35.5) in the placebo arm (HR=0.61; 95% CI 0.48, 0.76; p < 0.001).
• IFM 2005-02: after 96.7 months of follow up, median PFS was 44.4 months (95% CI 39.6, 52.0) in the REVLIMID® arm versus 23.8 months (95% CI 21.2, 27.3) in the placebo arm (HR=0.57; 95% CI 0.47, 0.68; p < 0.001).

Individual studies were not powered for an over­all survival (OS) end­point. Using a cut-off of 1 February 2016, a descriptive analysis showed that the median over­all survival in the CALGB 100104 was 111.0 months (95% CI, 101.8, not estimable) for patients who received REVLIMID versus 84.2 (95% CI 71.0, 102.7) in the placebo arm (HR=0.61; 95% CI 0.46, 0.81; p < 0.001). In the IFM 2005-02 study, median over­all survival was 105.9 months (95% CI, 88.8, not estimable) for patients who received REVLIMID versus 88.1 (95% CI 80.7, 108.4) in the placebo arm (HR=0.90; 95% CI 0.72, 1.13; p=0.355, not sig­nif­i­cant).

In both of these phase III studies, the safety profile was in line with other clin­i­cal data in newly diag­nosed non-stem cell trans­plant and a post-approval safety study in re­lapsed/refractory multiple myeloma. The most commonly reported adverse events in these two studies were haematological, and in­cluded neu­tro­penia and thrombo­cytopenia. The most commonly reported non-haematological adverse events were in­fec­tions. An in­­creased incidence rate of haematological second pri­mary malig­nan­cies (SPMs) was also observed in the REVLIMID® group compared with the placebo group in both studies. However, the EC de­ci­sion con­firms that the benefit-risk ratio for REVLIMID® is positive in this expanded indi­ca­tion.

Tuomo Pätsi, Pres­i­dent of Celgene European and Inter­na­tional Operations, said, "We are glad to provide a treat­ment option for these patients with multiple myeloma, who have pre­vi­ously had no licensed medicine avail­able to them for main­te­nance treat­ment fol­low­ing ASCT. This latest approval underlines the im­por­tant role of REVLIMID® in the treat­ment of multiple myeloma, extending its use across the disease spectrum, and demonstrating our commitment to multiple myeloma patients. We con­tinue to invest in research and devel­op­ment as we strive to turn multiple myeloma - and other cur­rently incurable diseases - into man­ageable con­di­tions."

The EC de­ci­sion for the use of REVLIMID® as mono­therapy for the main­te­nance treat­ment of adult patients with newly diag­nosed multiple myeloma who have undergone ASCT follows the positive opinion issued by the Committee for Medicinal Products for Human Use (CHMP) in January 2017.

Celgene announced on 22 February 2017 that the U.S. Food and Drug Admin­istra­tion (FDA) has expanded the existing indi­ca­tion for REVLIMID® to in­clude use for patients with multiple myeloma as main­te­nance ther­apy fol­low­ing au­tol­o­gous hema­to­poietic stem cell trans­plant in the U.S.

About CALGB 100104

CALGB 100104 was a phase III, ran­domised, controlled, double-blind, multi-centre study conducted in 47 centres in the United States. A total of 460 patients newly diag­nosed with multiple myeloma - aged be­tween 18 and 70 years - who achieved at least stable disease or better 100 days after undergoing au­tol­o­gous stem cell trans­plant, 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. A total of 614 patients newly diag­nosed with multiple myeloma, who were younger than 65 years without signs of disease pro­gres­sion within 6 months of undergoing au­tol­o­gous stem cell trans­plant, were then ran­domised to receive a 2-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® as com­bi­na­tion ther­apy 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.

REVLIMID is not indicated and is not recommended for the treat­ment of patients with chronic lym­pho­cytic leukemia (CLL) outside of controlled clin­i­cal trials.

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 myeloma

Newly diag­nosed multiple myeloma: patients who have undergone ASCT treated with REVLIMID® (lena­lido­mide) main­te­nance:

• The serious adverse reactions observed more frequently (≥5%) with REVLIMID® (lenalidomide) maintenance than placebo were pneumonias (10.6%) and lung infection (9.4%)
• The adverse reactions observed more frequently with REVLIMID® (lenalidomide) maintenance than placebo were neutropenia (79.0%), thrombocytopenia (72.3%), diarrhoea (54.5%), bronchitis (47.4%), nasopharyngitis (34.8%), muscle spasms (33.4%), leucopenia (31.7%), rash (31.7%), asthenia (29.7%), cough (27.3%), upper respiratory tract infection (26.8%), fatigue (22.8%), gastroenteritis (22.5%), anaemia (21.0%), and pyrexia (20.5%).

Newly diag­nosed multiple myeloma: patients who are not eli­gible for trans­plant 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 who are not eli­gible for ASCT 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 Celgene's 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. Bird JM, et al. Br J Haematol. 2011;154:32-75
7. Attal M, et al. Blood. 2006 Nov 15;108(10):3289-94
8. Child JA, et al. N Engl J Med. 2003; 348:1875-1883
9. 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).
10. Attal M, et al. N Engl J Med. 2012;366(19):1782-1791. IFM is the cooperative group Intergroupe Francophone du Myélome.

Source: Celgene.