On February 24, 2017 Trillium Therapeutics Inc. (NASDAQ/TSX: TRIL), a clinical-stage immuno-oncology company developing innovative therapies for the treatment of cancer, reported new pharmacology data from its ongoing Phase 1 a/b trial of TTI-621, a SIRPaFc fusion protein targeting CD47 in patients with advanced hematologic malignancies (Press release, Trillium Therapeutics, FEB 24, 2017, View Source [SID1234517831]). The presentation took place at the ASCO (Free ASCO Whitepaper)-SITC Clinical Immuno-Oncology Symposium in Orlando, Florida.

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The company presented the following new information from the trial:

Receptor occupancy increases with multiple infusions of TTI-621, conferring robust CD47 blockade on circulating leukemic cells: Compared to the initial infusion, the extent and duration of CD47 occupancy on peripheral leukocytes was elevated following the sixth dose. Importantly, emerging data suggests increased receptor occupancy on circulating leukemic blast cells. The level of target engagement achieved is associated with strong phagocytosis activity of tumor cells in vitro.

Increases in cytokines associated with macrophage activation suggest rapid engagement of the innate immune system: Post-infusion elevations were observed in MIP-1a, MIP-1b and other cytokines associated with macrophage activation, supporting the proposed role of TTI-621 as an innate immune checkpoint inhibitor.

Transient thrombocytopenia due to target mediated clearance is attenuated subsequent to the first infusion of TTI-621: Additional data has clarified that the transient thrombocytopenia observed following TTI-621 exposure is often diminished after multiple infusions. This suggests that there may be an opportunity to increase TTI-621 exposure in patients after the initial dose.

Weekly infusions lead to a longer half-life and accumulation of circulating drug, overcoming the platelet antigen sink: After six infusions the terminal half-life of TTI-621 increased to 3.7 days with an attendant rise in circulating drug trough levels, which is consistent with the half-lives of many marketed Fc fusion proteins. Drug accumulation was accompanied by stable pre-dose platelet counts, suggesting that multiple infusions of TTI-621 overcome the platelet antigen sink.

"This recently expanded data set markedly advances our understanding of TTI-621’s pharmacological properties, and exemplifies the emerging nature of this exciting development program," said Dr. Niclas Stiernholm, Trillium’s Chief Executive Officer. "These latest results suggest that we overcome the antigen sink and achieve meaningful TTI-621 exposure while maintaining acceptable platelet counts. We are excited to continue the exploration of this unique checkpoint inhibitor in patients with multiple types of blood cancers, as well as in patients with solid tumors."

The ASCO (Free ASCO Whitepaper)-SITC poster presentation on TTI-621 can be found on the company’s website at www.trilliumtherapeutics.com. Additional information about this clinical trial of TTI-621 is available at www.clinicaltrials.gov using identifier: NCT02663518.

On February 24, 2017 Oxford BioMedica plc (LSE:OXB) ("Oxford BioMedica" or "the Group"), a leading gene and cell therapy group, reported the results from a Phase I/II clinical trial of MVA-5T4 immunotherapy (TroVax) and low dose cyclophosphamide (CPM) in patients with advanced colorectal cancer (TaCTiCC) (Press release, Oxford BioMedica, FEB 24, 2017, View Source [SID1234517827]). A poster was presented by the clinical investigators in a poster session at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) and Society for Imumunotherapy of Cancer (ASCO-SITC) Clinical Immuno-Oncology Symposium on 23 February 2017 in Orlando, USA.

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The poster described the open-label Phase I/II clinical trial involving 53 patients with inoperable, metastatic colorectal cancer who were randomised to receive either no treatment, low dose CPM, TroVax only or low dose CPM followed by TroVax. The primary study endpoint was to assess increased anti-5T4 responses after treatment on day 43 and the secondary endpoints were progression free /overall survival and anti-5T4 responses over the trial period.

The study findings demonstrated that significant anti-5T4 immune responses were generated at treatment day 43. Secondary analysis revealed that both CPM and TroVax independently induced highly beneficial anti-tumour immune responses, resulting in significant survival of end stage colorectal cancer patients, without any major toxicity. This was the first randomised study to show a benefit of immunotherapy in advanced colorectal cancer patients.

Commenting on the results, John Dawson, Chief Executive Officer of Oxford BioMedica, said: "The presentation by the Clinical Investigators of the Phase I/II TaCTiCC study at the ASCO (Free ASCO Whitepaper)-SITC Clinical Immuno-Oncology symposium showed the potential benefit that Oxford BioMedica’s immunotherapy (TroVax) treatment could give to patients with advanced colorectal cancer."

On February 24, 2017 Novartis reported the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion recommending approval of Tafinlar (dabrafenib) in combination with Mekinist (trametinib) to treat patients with advanced or metastatic non-small cell lung cancer (NSCLC) whose tumors express the BRAF V600 mutation (Press release, Novartis, FEB 24, 2017, View Source [SID1234517826]). If approved, Tafinlar + Mekinist will be the first targeted treatment available for patients with BRAF V600-positive NSCLC. Of the estimated 1.8 million new cases of lung cancer diagnosed worldwide each year[2], 1-3%, may be driven by the BRAF mutation[3].

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"At Novartis, we are committed to finding treatments for rare cancers with an unmet need. Today’s CHMP opinion marks a major milestone for NSCLC patients with the BRAF V600 mutation, who have very limited treatment options," said Bruno Strigini, CEO, Novartis Oncology. "We welcome the CHMP’s opinion as a first step towards that goal, and look forward to continuing to work with European health authorities to make Tafinlar + Mekinist available for appropriate NSCLC patients."

The positive CHMP opinion was based on safety and efficacy data from a Phase II study of Tafinlar + Mekinist in patients with BRAF V600-positive NSCLC (36 treatment-naïve and 57 previously treated with chemotherapy).

The 57 patients who had tumor progression on at least one platinum based chemotherapy, receiving 150 mg of Tafinlar twice daily and 2 mg of Mekinist once daily, demonstrated an overall response rate (ORR) of 63.2% (95% confidence interval [CI], 49.3%, 75.6%) and duration of response of 9.0 months (95% CI, 6.9, 18.3 months). The most common adverse events (incidence >20%) were pyrexia, nausea, vomiting, diarrhea, asthenia, decreased appetite, dry skin, chills, peripheral edema, cough and rash[1]. Updated data from the previously treated and treatment-naïve cohorts were included in the overall data package for EMA review and will also be presented at upcoming medical meetings.

The European Commission (EC) typically adheres to the recommendation of the CHMP and usually delivers its final decision within two months. The decision will be applicable to all 28 European Union (EU) member states plus Iceland and Norway. In Europe, Tafinlar and Mekinist is approved for the treatment of patients with unresectable or metastatic melanoma who have a BRAF V600 mutation.

The US Food and Drug Administration (FDA) granted Tafinlar + Mekinist Breakthrough Therapy Designation for advanced or metastatic BRAF V600-positive NSCLC patients in 2015 and Priority Review in November 2016. Combination use of Tafinlar + Mekinist is also approved in the US, Australia, Canada and additional countries for patients with unresectable or metastatic melanoma whose tumors tested positive for the BRAF V600 mutation.

Worldwide, lung cancer causes more deaths than colon, breast, and prostate cancer combined[4], and an estimated 1.8 million new cases of lung cancer are diagnosed each year[2]. Among patients with NSCLC, roughly 30% have an actionable mutation that may be targeted with available therapies[5],[6],[7],[8]. To determine that treatment, medical organizations recommend genetic testing for patients with lung cancer[9].

Novartis Commitment to Lung Cancer
Novartis Oncology’s research into targeted therapies has helped transform treatment approaches for patients living with mutation-driven types of lung cancer. Patients with a mutation-driven NSCLC may be candidates for treatment with targeted therapies[6].

Novartis continues its commitment to the global lung cancer community through ongoing studies, as well as the exploration of investigational compounds that target genetic biomarkers in NSCLC.

About Tafinlar + Mekinist Combination
Combination use of Tafinlar + Mekinist in patients with unresectable or metastatic melanoma who have a BRAF V600 mutation is approved in the US, EU, Australia, Canada and other countries.

Tafinlar and Mekinist target different kinases within the serine/threonine kinase family – BRAF and MEK1/2, respectively – in the RAS/RAF/MEK/ERK pathway, which is implicated in non-small cell lung cancer (NSCLC) and melanoma, among other cancers. When Tafinlar is used with Mekinist, the combination has been shown to slow tumor growth more than either drug alone. The combination of Tafinlar + Mekinist is currently being investigated in an ongoing clinical trial program across a range of tumor types conducted in study centers worldwide.
The safety and efficacy profile of the Tafinlar + Mekinist combination has not yet been established outside of the approved indications.

Tafinlar and Mekinist are also indicated in more than 40 countries worldwide, including the US and EU, as single agents to treat patients with unresectable or metastatic melanoma with a BRAF V600 mutation.

Tafinlar + Mekinist Combination Important Safety Information for Metastatic Melanoma

Tafinlar + Mekinist combination may cause serious side effects.

Tafinlar in combination with Mekinist should only be used to treat melanoma with a change (mutation) in the BRAF gene; therefore, doctors should test their patients before treatment, as patients without a BRAF mutation and with a RAS mutation can be at risk of increased cell proliferation in the presence of a BRAF inhibitor.

Doctors should also consider other treatment options for their patients if they had been previously treated with a BRAF inhibitor as single agent, as the limited data available have shown that the efficacy of Tafinlar + Mekinist is lower in these patients.

When Tafinlar is used in combination with Mekinist, or when Tafinlar is administered as monotherapy, it can cause new cancers (both skin cancer and non-skin cancer). Patients should be advised to contact their doctor immediately for any new lesions, changes to existing lesions on their skin, or signs and symptoms of other malignancies.

Tafinlar in combination with Mekinist, or Mekinist alone, can cause severe bleeding, and in some cases can lead to death. Patients should be advised to call their healthcare provider and get medical help right away if they have headaches, dizziness, or feel weak, cough up blood or blood clots, vomit blood or their vomit looks like "coffee grounds," have red or black stools that look like tar, or any unusual signs of bleeding.

Tafinlar in combination with Mekinist, or either drug alone, can cause severe eye problems that can lead to blindness. Patients should be advised to call their healthcare provider right away if they get these symptoms of eye problems: blurred vision, loss of vision, or other vision changes, seeing color dots, halo (seeing blurred outline around objects), eye pain, swelling, or redness.

Tafinlar in combination with Mekinist, or Tafinlar alone, can cause fever which may be serious. When taking Tafinlar in combination with Mekinist, fever may happen more often or may be more severe. In some cases, chills or shaking chills, too much fluid loss (dehydration), low blood pressure, dizziness, or kidney problems may happen with the fever. Patients should be advised to call their healthcare provider right away if they get a fever above 38.5oC (101.3oF) while taking Tafinlar.

Tafinlar in combination with Mekinist, or Mekinist alone, can affect how well the heart pumps blood. A patient’s heart function should be checked before and during treatment. Patients should be advised to call their healthcare provider right away if they have any of the following signs and symptoms of a heart problem: feeling like their heart is pounding or racing, shortness of breath, swelling of their ankles and feet, or feeling lightheaded.

Tafinlar in combination with Mekinist, or Tafinlar alone, can cause abnormal kidney function or inflammation of the kidney. Abnormal kidney function may happen more often for patients with fever or too much fluid loss. Patients should be advised to call their healthcare provider right away if they have a fever above 38.5oC (101.3oF), decreased urine, fatigue, loss of appetite or discomfort in lower abdomen or back. Tafinlar has not been studied in patients with renal insufficiency (defined as creatinine > 1.5 x ULN) therefore caution should be used in this setting.

Tafinlar in combination with Mekinist, or Mekinist alone, can cause abnormal liver function. A patient may feel tired, lose appetite, yellow skin, dark urine colour, or discomfort in abdomen. The liver function abnormality needs to be assessed by laboratory test of the blood. Patients should consult their healthcare provider if they have such experience. Administration of Tafinlar or Mekinist should be done with caution in patients with moderate to severe hepatic impairment.

Elevations in blood pressure have been reported in association with Mekinist in combination with Tafinlar, or with Mekinist alone, in patients with or without pre-existing hypertension. Patients should be advised to monitor blood pressure during treatment with Mekinist and control potential hypertension by standard therapy, as appropriate.

Tafinlar in combination with Mekinist, or Mekinist alone, can cause inflammation of the lung tissue. Patients should notify their doctor if they experience any new or worsening symptoms of lung or breathing problems, including shortness of breath or cough.

Rash is a common side effect of Tafinlar in combination with Mekinist, or with Mekinist alone. Tafinlar in combination with Mekinist, or Mekinist alone, can also cause other skin reactions which can be severe, and may need to be treated in a hospital. Patients should be advised to call their healthcare provider if they get any of the following symptoms: skin rash that bothers them or does not go away, acne, redness, swelling, peeling, or tenderness of hands or feet, skin redness.

Tafinlar in combination with Mekinist, or Mekinist alone, can cause muscle breakdown, a condition called Rhabdomyolysis. Patients experiencing muscle pain, tenderness, weakness or a swelling of their muscles should contact their healthcare provider immediately.

Tafinlar in combination with Mekinist, or Tafinlar alone, can uncommonly cause an inflammation of the pancreas (pancreatitis). Patients should be promptly investigated if they experience unexplained abdominal pain and closely monitored if they re-start Tafinlar after a prior episode of pancreatitis.

Tafinlar in combination with Mekinist, or Mekinist alone, can cause blood clots in the arms or legs, which can travel to the lungs and can lead to death. Patients should be advised to get medical help right away if they have the following symptoms: chest pain, sudden shortness of breath or trouble breathing, pain in their legs with or without swelling, swelling in their arms or legs, or a cool or pale arm or leg.

Mekinist, alone or in combination with Tafinlar, may increase the risk of developing holes in the stomach or intestine (gastrointestinal perforation). Treatment with Mekinist alone or in combination with Tafinlar should be used with caution in patients with risk factors for gastrointestinal perforation, including concomitant use of medications with a recognised risk of gastrointestinal perforation.

Tafinlar and Mekinist both can cause harm to an unborn baby when taken by a pregnant woman. Tafinlar can also render hormonal contraceptives ineffective.

The most common side effects of Tafinlar + Mekinist combination include fever, tiredness, nausea, headache, chills, diarrhea, rash, joint pain, high blood pressure, vomiting and cough. The incidence and severity of fever is increased when Mekinist is used in combination with Tafinlar. Patients should tell their doctor of any side effect that bothers them or does not go away. These are not all of the possible side effects of Tafinlar + Mekinist combination. For more information, patients should ask their doctor or pharmacist.

Patients should take Tafinlar + Mekinist combination exactly as their health care provider tells them. Patients should not change their dose or stop taking Tafinlar + Mekinist combination unless their health care provider advises them to. Mekinist should be taken only once daily (either in the morning or evening, at the same time as Tafinlar). The first and second doses of Tafinlar should be taken approximately 12 hours apart. Patients should take Tafinlar + Mekinist at least 1 hour before or 2 hours after a meal. Do not take a missed dose of Tafinlar within 6 hours of the next dose of Tafinlar. Do not open, crush, or break Tafinlar capsules. Do not take a missed dose of Mekinist within 12 hours of the next dose of Mekinist.

Please see full Prescribing Information for Tafinlar and Mekinist.

On February 24, 2017 Celgene International Sàrl, a wholly-owned subsidiary of Celgene Corporation (NASDAQ: CELG), reported 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) (Press release, Celgene, FEB 24, 2017, View Source [SID1234517823]). 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.