On January 30, 2017 Exelixis, Inc. (NASDAQ:EXEL) and Takeda Pharmaceutical Company Limited (TSE:4502) reported an exclusive licensing agreement for the commercialization and further clinical development in Japan of cabozantinib, Exelixis’ lead oncology medicine (Press release, Exelixis, JAN 30, 2017, View Source [SID1234517596]). With the signing of the agreement, Takeda gains exclusive commercial rights for all potential future cabozantinib indications in Japan, including advanced renal cell carcinoma (RCC), for which cabozantinib is marketed in the United States and European Union as CABOMETYX tablets. The two companies will collaborate on the future clinical development of cabozantinib in Japan.

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Under the terms of the agreement, Exelixis will receive a $50 million upfront payment. Exelixis is eligible to receive development, regulatory, and first-sales milestones of $95 million for the first three planned indications. In addition,
Exelixis will be eligible to receive royalties on sales by Takeda.

"As an organization with a strong focus on oncology innovation, our agreement with Exelixis brings a promising and well-studied solid-tumor therapy to our pipeline that may help patients in Japan suffering from RCC and potentially other equally devastating cancers," said Tsudoi Miyoshi, Head of Japan Oncology Business Unit of Takeda. "We intend to pursue regulatory approval for RCC indications as soon as we’re able, and look forward to commencing the local clinical trial program to further strengthen the clinical profile of cabozantinib."

Exelixis and Takeda will partner on cabozantinib’s clinical development in Japan and on translating existing and forthcoming clinical data for potential regulatory filings in the country. In the METEOR pivotal trial, cabozantinib demonstrated statistically significant improvements in overall survival, progression-free survival and objective response rate, meaningfully differentiating it from other therapies to treat advanced renal cell carcinoma following prior therapy. In addition to advanced RCC, future indications could include advanced hepatocellular cancer (HCC), the subject of the CELESTIAL global pivotal trial for which results are anticipated in 2017. Additional earlier-stage studies are under way through Exelixis’ collaboration with the National Cancer Institute’s Cancer Therapy Evaluation Program, and its ongoing Investigator-Sponsored Trial program. Through these two programs, there are more than 45 ongoing or planned studies including trials in advanced RCC, bladder cancer, colorectal cancer, non-small cell lung cancer, and endometrial cancer.

"Takeda is the ideal partner to advance cabozantinib in Japan and deliver this important treatment option to Japanese patients with cancer," said Michael M. Morrissey, Ph.D., President and Chief Executive Officer of Exelixis. "Takeda is widely respected for both its clinical development and commercial expertise. We look forward to supporting our new partner as it pursues Japanese regulatory approval for cabozantinib, while simultaneously working together to plan the next steps for clinical development in the country. This agreement further propels the global progress for cabozantinib development and commercialization, which now includes the recent first commercial sale of
CABOMETYX in the United Kingdom, triggering a $10 million milestone payment from Ipsen to Exelixis."

Cabozantinib is not approved for use in Japan. Previously, Exelixis and its collaborators conducted early-stage clinical trials in Japan, including a phase 1 trial in advanced solid tumors. Data from this trial were presented at the European Society for Medical Oncology 2012 Congress and the 2015 AACR (Free AACR Whitepaper)-NCI-EORTC AACR-NCI-EORTC (Free AACR-NCI-EORTC Whitepaper) International Conference on Molecular Targets and Cancer Therapeutics (EORTC-NCI-AACR) (Free ASGCT Whitepaper) (Free EORTC-NCI-AACR Whitepaper).1,2

Exelixis maintains its exclusive rights to develop and commercialize cabozantinib in the United States, and its partner Ipsen maintains its exclusive commercialization rights for current and potential future cabozantinib indications outside of the United States and Japan.
About CABOMETYX (cabozantinib) Tablets
CABOMETYX is the tablet formulation of cabozantinib. Its targets include MET, AXL, and VEGFR-1, -2 and -3. In preclinical models, cabozantinib has been shown to inhibit the activity of these receptors, which are involved in normal cellular function and pathologic processes such as tumor angiogenesis, invasiveness, metastasis, and drug resistance.
CABOMETYX is available in 20 mg, 40 mg or 60 mg doses. The recommended dose is 60 mg orally, once daily.
On April 25, 2016, the FDA approved CABOMETYX tablets for the treatment of patients with advanced renal cell carcinoma who have received prior anti-angiogenic therapy. On September 9, 2016, the European Commission approved CABOMETYX tablets for the treatment of advanced renal cell carcinoma in adults who have received prior vascular endothelial growth factor (VEGF)-targeted therapy in the European Union, Norway and Iceland. On February 29, 2016, Exelixis and Ipsen jointly announced an exclusive licensing agreement for the commercialization and further development of cabozantinib indications outside of the United States, Canada and Japan. On December 21, 2016, Exelixis and Ipsen jointly announced an amendment to their exclusive licensing agreement for the commercialization and development of cabozantinib to include Canada.
U.S. Important Safety Information
Hemorrhage: Severe hemorrhage occurred with CABOMETYX. The incidence of Grade ≥3 hemorrhagic events was 2.1% in CABOMETYX-treated patients and 1.6% in everolimus-treated patients. Fatal hemorrhages also occurred in the cabozantinib clinical program. Do not administer CABOMETYX to patients that have or are at risk for severe hemorrhage.
Gastrointestinal (GI) Perforations and Fistulas: Fistulas were reported in 1.2% (including 0.6% anal fistula) of CABOMETYX-treated patients and 0% of everolimus-treated patients. GI perforations were reported in 0.9% of CABOMETYX-treated patients and 0.6% of everolimus-treated patients. Fatal perforations occurred in the cabozantinib clinical program. Monitor patients for symptoms of fistulas and perforations. Discontinue CABOMETYX in patients who experience a fistula that cannot be appropriately managed or a GI perforation.
Thrombotic Events: CABOMETYX treatment results in an increased incidence of thrombotic events. Venous thromboembolism was reported in 7.3% of CABOMETYX-treated patients and 2.5% of everolimus-treated patients. Pulmonary embolism occurred in 3.9% of CABOMETYX-treated patients and 0.3% of everolimus-treated patients. Events of arterial thromboembolism were reported in 0.9% of CABOMETYX-treated patients and 0.3% of everolimus-treated patients. Fatal thrombotic events occurred in the cabozantinib clinical program. Discontinue CABOMETYX in patients who develop an acute myocardial infarction or any other arterial thromboembolic complication.
Hypertension and Hypertensive Crisis: CABOMETYX treatment results in an increased incidence of treatment-emergent hypertension. Hypertension was reported in 37% (15% Grade ≥3) of CABOMETYX-treated patients and 7.1% (3.1% Grade ≥3) of everolimus-treated patients. Monitor blood pressure prior to initiation and regularly during CABOMETYX treatment. Withhold CABOMETYX for hypertension that is not adequately controlled with medical management; when controlled, resume CABOMETYX at a reduced dose. Discontinue CABOMETYX for severe hypertension that cannot be controlled with anti-hypertensive therapy. Discontinue CABOMETYX if there is evidence of hypertensive crisis or severe hypertension despite optimal medical management.
Diarrhea: Diarrhea occurred in 74% of patients treated with CABOMETYX and in 28% of patients treated with everolimus. Grade 3 diarrhea occurred in 11% of CABOMETYX-treated patients and in 2% of everolimus-treated patients. Withhold CABOMETYX in patients who develop intolerable Grade 2 diarrhea or Grade 3-4 diarrhea that cannot be managed with standard antidiarrheal treatments until improvement to Grade 1; resume CABOMETYX at a reduced dose. Dose modification due to diarrhea occurred in 26% of patients.
Palmar-Plantar Erythrodysesthesia Syndrome (PPES): Palmar-plantar erythrodysesthesia syndrome (PPES) occurred in 42% of patients treated with CABOMETYX and in 6% of patients treated with everolimus. Grade 3 PPES occurred in 8.2% of CABOMETYX-treated patients and in <1% of everolimus-treated patients. Withhold CABOMETYX in patients who develop intolerable Grade 2 PPES or Grade 3 PPES until improvement to Grade 1; resume CABOMETYX at a reduced dose. Dose modification due to PPES occurred in 16% of patients.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS): RPLS, a syndrome of subcortical vasogenic edema diagnosed by characteristic finding on MRI, occurred in the cabozantinib clinical program. Perform an evaluation for RPLS in any patient presenting with seizures, headache, visual disturbances, confusion, or altered mental function. Discontinue CABOMETYX in patients who develop RPLS.

Embryo-fetal Toxicity: CABOMETYX can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with CABOMETYX and for 4 months after the last dose.
Adverse Reactions: The most commonly reported (≥25%) adverse reactions are: diarrhea, fatigue, nausea, decreased appetite, PPES, hypertension, vomiting, weight decreased, and constipation.

Drug Interactions: Strong CYP3A4 inhibitors and inducers: Reduce the dosage of CABOMETYX if concomitant use with strong CYP3A4 inhibitors cannot be avoided. Increase the dosage of CABOMETYX if concomitant use with strong CYP3A4 inducers cannot be avoided.

Lactation: Advise a lactating woman not to breastfeed during treatment with CABOMETYX and for 4 months after the final dose.

Reproductive Potential: Contraception―Advise females of reproductive potential to use effective contraception during treatment with CABOMETYX and for 4 months after the final dose. Infertility ―CABOMETYX may impair fertility in females and males of reproductive potential.

Hepatic Impairment: Reduce the CABOMETYX dose in patients with mild (Child-Pugh score [C-P] A) or moderate (C-P B) hepatic impairment. CABOMETYX is not recommended for use in patients with severe hepatic impairment.
Please see full Prescribing Information at View Source

On Januar 30, 2017 Incyte Corporation (NASDAQ:INCY) and Calithera Biosciences, Inc. (NASDAQ:CALA) reported that the companies have entered into a global collaboration and license agreement for the research, development and commercialization of Calithera’s first-in-class, small molecule arginase inhibitor CB-1158 in hematology and oncology (Press release, Calithera Biosciences, JAN 30, 2017, View Source [SID1234517593]). CB-1158 is currently being studied in a monotherapy dose escalation trial and additional studies are expected to evaluate CB-1158 in combination with immuno-oncology agents, including anti-PD-1 therapy.

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"Arginase-expressing tumor-infiltrating myeloid cells have been shown to play an important role in orchestrating the immune suppressive microenvironment in cancer; but, to date, therapeutic targeting of the arginase enzyme has remained elusive," said Reid Huber, Ph.D., Incyte’s Chief Scientific Officer. "The addition of this first-in-class, small molecule arginase inhibitor, CB-1158, to our portfolio expands our innovative immuno-oncology pipeline and allows us to continue to advance our mission of discovering and developing immune-active combination therapies to treat patients with cancer."

"In this strategic partnership with Incyte, CB-1158 is expected to be evaluated in multiple trials of novel therapeutic combinations, accelerating its development across hematological and oncology indications," said Susan Molineaux, Ph.D., Calithera’s Chief Executive Officer.

Terms of the Collaboration

Under the terms of the collaboration and license agreement, Calithera will receive an up-front payment of $45 million from Incyte. In addition, Incyte will make an equity investment in Calithera of $8 million through the purchase of shares at a price of $4.65 per share.

Incyte will receive worldwide rights to develop and commercialize CB-1158 in hematology and oncology and Calithera will retain certain rights to research, develop and commercialize certain other arginase inhibitors in certain orphan indications.

Incyte and Calithera will jointly conduct and co-fund development of CB-1158, with Incyte leading global development activities. Incyte will fund 70 percent of global development and Calithera will be responsible for the remaining 30 percent. In the event of regulatory approvals and commercialization of CB-1158, Incyte and Calithera will share in any future U.S. profits and losses (receiving 60 percent and 40 percent, respectively) and Calithera will be eligible to receive over $430 million in potential development, regulatory and commercialization milestones from Incyte. Per the terms of the agreement, Calithera will have the right to co-detail CB-1158 in the U.S. and also be eligible to receive from Incyte tiered royalties based on future ex-U.S. sales, with rates ranging from low-to-mid double-digits.

The agreement also provides that Calithera may choose to opt out of its co-funding obligations. In this scenario, Calithera would no longer be eligible to receive future U.S. profits and losses but would be eligible to receive up to $750 million in potential development, regulatory and commercialization milestones from Incyte and, if the product is approved and commercialized, also be eligible to receive reimbursement based on previous development expenditures incurred by Calithera and tiered royalty payments on future global sales of CB-1158, with rates ranging from low-to-mid double-digits.

The transaction is expected to close in the first quarter of 2017, subject to customary closing conditions.

On January 30, 2017 Advaxis, Inc. (NASDAQ:ADXS), a clinical-stage biotechnology company developing cancer immunotherapies, reported that an abstract on data from the company’s Phase 2 GOG-0265 trial evaluating axalimogene filolisbac for metastatic cervical cancer has been accepted as a late-breaking presentation at the Society of Gynecologic Oncology’s (SGO) 48th Annual Meeting on Women’s Cancer in March (Press release, Advaxis, JAN 30, 2017, View Source [SID1234517591]).

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The poster, "A prospective phase 2 trial of the listeria-based HPV immunotherapy axalimogene filolisbac in second and third-line metastatic cervical cancer: A NRG oncology group trial," will be presented by investigator Charles A. Leath, III, M.D., associate professor of obstetrics and gynecology at the University of Alabama at Birmingham School of Medicine. It will highlight final data from the GOG-0265 study, which evaluated the safety and activity of axalimogene filolisbac in patients with persistent or recurrent metastatic (squamous or non-squamous cell) carcinoma of the cervix.

SGO accepts late-breaking abstracts that demonstrate timely findings of the highest scientific impact in the form of an oral presentation followed by a panel discussion at a scientific plenary session during the meeting. The data are selected on the basis of double-blinded peer review and relevance to current gynecologic cancer treatment challenges. Abstracts selected for scientific plenary will also be published in Gynecologic Oncology.

"Axalimogene filolisbac continues to gain validation for its potential as a therapy to treat women with this advanced cervical cancer who have no treatment options other than a repeat of chemotherapy and radiation," said Daniel J. O’Connor, President and Chief Executive Officer. "We look forward to sharing this data, which supports our plan to initiate a phase 3 study in metastatic cervical cancer later this year."

The SGO’s Annual Meeting on Women’s Cancer, the largest educational and scientific event for members of women’s cancer care teams which attracts more than 2,000 multi-disciplinary attendees, is March 12-15 at the Gaylord National Resort & Convention Center in National Harbor, MD.

On January 27, 2017 Celgene International Sàrl, a wholly owned subsidiary of Celgene Corporation (NASDAQ:CELG), reported 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) (Press release, Celgene, JAN 27, 2017, View Source [SID1234517580]). Once approved by the European Commission, REVLIMID will be the first and only licensed maintenance treatment available to these patients.

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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 < 60 mL/min.

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.