REVLIMID and IMNOVID for Multiple Myeloma

Transcription

1 REVLIMID and IMNOVID for Multiple Myeloma What is Multiple Myeloma? Multiple myeloma (MM) is a persistent and life-threatening blood cancer that is characterised by tumour proliferation and immune suppression. It is a rare but deadly disease. An estimated 38,000 people were newly diagnosed with multiple myeloma in Europe in 2012, with 24,300 people dying from the disease in the same year. 1 Many patients who are newly diagnosed with MM have progressed from related conditions such as monoclonal gammopathy of undetermined significance (MGUS) and/ or smouldering myeloma. 2 Patients with MM experience periods of relapse and remission, although underlying disease constantly remains throughout the disease course, regardless of how well they respond to therapy. 3 Before the introduction of stem cell therapies, melphalan plus prednisolone was the standard of care for patients with MM for around three decades. 4 For patients under the age of 65 years, induction followed by high-dose therapy with autologous stem cell transplantation is now the standard treatment. 2 However, with a median age at diagnosis of years, 2 many patients are ineligible for transplantation, so there is a need for effective treatments that can be tolerated by these patients. What is REVLIMID? REVLIMID is the first oral medicine for multiple myeloma to be approved for treatment until disease progression. It is an oral immunomodulatory therapy indicated by the European Commission for use: In combination with dexamethasone (dex) for the treatment of adult patients with previously untreated multiple myeloma who are not eligible for transplant, until their disease progresses, In combination with melphalan and prednisone followed by maintenance monotherapy for the treatment of adult patients with previously untreated multiple myeloma who are not eligible for transplant, In combination with dex for the treatment of adult patients with MM who have received at least one prior therapy.

2 The European Commission marketing authorisation applies to adult patients in the European Union, Iceland, Liechtenstein and Norway. REVLIMID is also indicated by the European Commission for the treatment of patients with transfusion-dependent anaemia due to low- or intermediate-1-risk MDS associated with an isolated deletion 5q cytogenetic abnormality when other therapeutic options are insufficient or inadequate. REVLIMID is also approved and/or under regulatory review in other regions/countries. Please refer to local agencies for more information. How does REVLIMID work? REVLIMID, an analogue of thalidomide, belongs to Celgene s class of cancer drugs called IMiDs. These small molecule, orally available therapies modulate the immune system and other biological targets through multiple mechanisms of action: REVLIMID targets MM cells in vitro via a dual mechanism of action: tumouricidal and immunomodulatory 5,6 Tumouricidal effects of REVLIMID may rapidly reduce MM tumour burden and immunomodulatory effects may enhance immune function. 7 What is IMNOVID? IMNOVID (pomalidomide) is another oral immunomodulatory therapy, used in patients with MM who are resistant to, or cannot tolerate, REVLIMID. In Europe, IMNOVID is approved in combination with dex to treat MM in adults who have received at least two prior therapies, including both REVLIMID and bortezomib, and whose disease progressed after the last treatment. IMNOVID is also approved and/or under regulatory review in other regions/countries. In the United States, pomalidomide is marketed under the brand name POMALYST. Please refer to local agencies for more information. How does IMNOVID work? Like REVLIMID, IMNOVID is also an analogue of thalidomide and an IMiD, which modulates the immune system and has anti-tumour activity. It has shown significant activity against myeloma cells, including those that are no longer responsive to other therapies. 8 In cell cultures, IMNOVID was shown to inhibit tumour cell growth and trigger tumour cell death. 9 IMNOVID also enhances the body s immune response to the tumour, specifically through T cells and natural killer (NK) cells and by reducing production of pro-inflammatory molecules made by the immune system. Date of Preparation: February 2015 INT-REV150004

3 ADDITIONAL IMPORTANT SAFETY INFORMATION FOR REVLIMID based on EU Summary of Product Characteristics 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.

4 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: abnormal liver function is generally reversible on dosing interruption. Once parameters have returned to baseline, treatment at a lower dose may be considered. It is important to dose-adjust patients with renal impairment in order to avoid plasma levels which may increase the risk for higher haematological adverse reactions or hepatotoxicity. Monitoring of liver function is recommended. 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%)

5 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 click here for Full Prescribing Information (EU Summary of Product Characteristics)

6 ADDITIONAL IMPORTANT SAFETY INFORMATION FOR IMNOVID based on EU Summary of Product Characteristics Contraindications IMNOVID (pomolidamide) is contraindicated during pregnancy, and also in women of childbearing potential, unless all the conditions of the Pregnancy Prevention Programme are met. It is also contraindicated in male patients unable to follow or comply with the required contraceptive measures. IMNOVID (pomolidamide) is contraindicated in patients with known hypersensitivity to the active substance or to any of the excipients in the formulation. 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. Haematological events: patients should be monitored for haematological adverse reactions, especially neutropenia. Patients should be advised to report febrile episodes promptly. Physicians should observe patients for signs of bleeding including epistaxes, especially with use of concomitant medicinal products known to increase the risk of bleeding. Complete blood counts should be monitored at baseline, weekly for the first 8 weeks and monthly thereafter. A dose modification may be required. Patients may require use of blood product support and /or growth factors. Thromboembolic events: patients with known risk factors for thromboembolism should be closely monitored. Peripheral neuropathy: patients with ongoing Grade 2 peripheral neuropathy were excluded from clinical studies with IMNOVID (pomalidomide). Appropriate caution should be exercised when considering the treatment of such patients with IMNOVID (pomalidomide). Significant cardiac dysfunction: patients with significant cardiac dysfunction were excluded from clinical studies with IMNOVID (pomalidomide). Appropriate caution should be exercised when considering the treatment of such patients with IMNOVID (pomalidomide). Tumour lysis syndrome: patients with high tumour burden prior to treatment should be monitored closely and appropriate precautions taken. Second primary malignancies (SPM): physicians should carefully evaluate patients before and during treatment using standard cancer screening for occurrence of SPM and institute treatment as indicated.

7 Allergic reactions: patients who had previous allergic reactions while treated with thalidomide should be monitored closely. Allergic reaction: patients with a prior history of serious allergic reactions associated with thalidomide or lenalidomide were excluded from clinical studies. Such patients may be at higher risk of hypersensitivity reactions and should not receive IMNOVID (pomalidomide). Dizziness and confusion: patients must avoid situations where dizziness or confusion may be a problem and not take other medicinal products that may cause dizziness or confusion without first seeking medical advice. Summary of the safety profile The most commonly reported adverse reactions in clinical studies have been blood and lymphatic system disorders including anaemia (45.7%), neutropenia (45.3%) and thrombocytopenia (27%); in general disorders and administration site conditions including fatigue (28.3%), pyrexia (21%) and oedema peripheral (13%); and in infections and infestations including pneumonia (10.7%). Peripheral neuropathy adverse reactions were reported in 12.3% of patients and venous embolic or thrombotic (VTE) adverse reactions were reported in 3.3% of patients. The most commonly reported Grade 3 or 4 adverse reactions were in the blood and lymphatic system disorders including neutropenia (41.7%), anaemia (27%) and thrombocytopenia (20.7%); in infections and infestations including pneumonia (9%); and in general disorders and administration site conditions including fatigue (4.7%), pyrexia (3%) and oedema peripheral (1.3%). The most commonly reported serious adverse reaction was pneumonia (9.3%). Other serious adverse reactions reported included febrile neutropenia (4.0%), neutropenia (2.0%), thrombocytopenia (1.7%) and VTE adverse reactions (1.7 %). Adverse reactions tended to occur more frequently within the first 2 cycles of treatment with IMNOVID (pomalidomide).

8 Special populations Paediatric population: there is no relevant use of IMNOVID (pomalidomide) in children aged 0 17 years in the indication of multiple myeloma. Older people: no dose adjustment is required for IMNOVID (pomalidomide). For patients >75 years of age, the starting dose of dexamethasone is 20 mg once daily on Days 1, 8, 15 and 22 of each 28-day treatment cycle. Renal impairment: a study in subjects with renal impairment has not been conducted with IMNOVID (pomalidomide). Patients with moderate or severe renal impairment (creatinine clearance <45 ml/min) were excluded from clinical studies. Patients with renal impairment should be carefully monitored for adverse reactions. Hepatic impairment: a study in subjects with hepatic impairment has not been conducted with IMNOVID (pomalidomide). Patients with serum total bilirubin >2.0 mg/dl were excluded from clinical studies. Patients with hepatic impairment should be carefully monitored for adverse reactions. Please click here for Full Prescribing Information (EU Summary of Product Characteristics) Please see full Prescribing Information, including CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and ADVERSE REACTIONS.

9 References 1. European Cancer Observatory. EUCAN Factsheet. Multiple myeloma and immunoproliferative diseases. eucancer.iarc.fr/eucan/cancer.aspx?cancer=39 [Accessed August 2013] 2. Moreau P et al. Multiple myeloma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Onc 2013;24 (Suppl 6):vi133 vi Martinez-Lopez J et al. Prognostic value of deep sequencing method for minimal residual disease detection in multiple myeloma. Blood 2014;123: Attal, M et al. A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. NEJM 1996;335(2): Chanan-Khan, AA & Cheson, BD. Lenalidomide for the treatment of B-cell malignancies. J Clin Oncol 2008;26(9): Davies, F and Baz, R. Lenalidomide mode of action: linking bench and clinical findings. Blood Rev 2010;4 (Suppl 1):S13 S19 7. Morgan, G. Future drug developments in multiple myeloma: an overview of novel lenalidomide-based combination therapies. Blood Rev 2010;4 (Suppl 1):S27 S32 8. Hideshima, T et al. Thalidomide and its analogs overcome drug resistance of human multiple myeloma cells to conventional therapy. Blood 2000;96: Mitsiades, N et al. Apoptotic signaling induced by immunomodulatory thalidomide analogs in human multiple myeloma cells: therapeutic implications. Blood 2002;99: