New England Journal of Medicine Reports on Three Phase III Revlimid (Lenalidomide) Trials in Patients With Newly Diagnosed Multiple Myeloma
Consistent progression-free survival improvement shown with continuous lenalidomide therapy in elderly patients not eligible for transplant and as maintenance therapy in patients following autologous stem cell transplant
BOUDRY, Switzerland--(BUSINESS WIRE)--May. 10, 2012-- Celgene International Sàrl, a subsidiary of Celgene Corporation (NASDAQ: CELG), today announced that results from three phase III studies evaluating the use of continuous REVLIMID® (lenalidomide) treatment in newly diagnosed multiple myeloma (MM) patients or maintenance treatment with lenalidomide following autologous stem cell transplant were published online in the May 10, 2012 edition of the New England Journal of Medicine. All three publications highlight the expanding body of clinical evidence supporting lenalidomide treatment in these areas.
Continuous Lenalidomide Therapy (non-transplant eligible population):
The first article highlights a Celgene-sponsored study of continuous lenalidomide treatment in elderly patients newly diagnosed with multiple myeloma.
Continuous Lenalidomide Treatment for Newly Diagnosed Multiple Myeloma (MM-015)
This double-blind, phase III, multicenter, randomized study conducted by Celgene compared melphalan–prednisone–lenalidomide induction followed by lenalidomide maintenance (MPR-R), with melphalan–prednisone–lenalidomide (MPR), or melphalan–prednisone (MP) followed by placebo in 459 patients aged ≥65 years with newly-diagnosed myeloma who were not eligible for autologous stem-cell transplant.
The two additional articles published in the edition highlighted cooperative group studies that evaluated the use of lenalidomide maintenance following autologous stem cell transplant (ASCT).
In each of the studies, one funded by the National Cancer Institute and conducted by the Cancer and Leukemia Group B (CALGB) and one by the Intergroupe Francophone du Myelome (IFM), maintenance treatment with lenalidomide following ASCT resulted in delayed time to disease progression or death compared to placebo.
Lenalidomide after Stem-Cell Transplantation for Multiple Myeloma (CALGB 100104)
The phase III CALGB study assessed 460 newly-diagnosed patients who received either lenalidomide or placebo following ASCT until disease progression.
Lenalidomide Maintenance after Stem-Cell Transplantation for Multiple Myeloma (IFM 2005-02)
IFM 2005-02 is a phase III, placebo-controlled trial investigating the efficacy of lenalidomide maintenance after transplantation in 614 myeloma patients.
REVLIMID® is not approved for use in newly diagnosed multiple myeloma.
REVLIMID is approved in combination with dexamethasone for the treatment of patients with multiple myeloma who have received at least one prior therapy in nearly 70 countries, encompassing Europe, the Americas, the Middle-East and Asia, and in combination with dexamethasone for the treatment of patients whose disease has progressed after one therapy in Australia and New Zealand.
REVLIMID is also approved in the United States, Canada, Switzerland, Australia, New Zealand and several Latin American countries, as well as Malaysia and Israel, for transfusion-dependent anaemia due to low- or intermediate-1-risk MDS associated with a deletion 5q cytogenetic abnormality with or without additional cytogenetic abnormalities. Marketing Authorization Applications are currently being evaluated in a number of other countries.
Since 1998, Celgene continues to be a pioneer in creating environments in which patients can benefit from our disease-altering therapies safely. As a result, hundreds of thousands of patients worldwide have accessed the clinical benefits of our therapies through our performance-based risk management programs including, S.T.E.P.S.®, RevAssist® and RevMate®, which form the foundation of our commitment to patient safety.
U.S. Regulatory Information for Revlimid
REVLIMID® (lenalidomide) in combination with dexamethasone is indicated for the treatment of multiple myeloma (MM) patients who have received at least one prior therapy.
REVLIMID® (lenalidomide) is indicated for patients with transfusion-dependent anemia due to Low- or Intermediate-1–risk myelodysplastic syndromes (MDS) associated with a deletion 5q cytogenetic abnormality with or without additional cytogenetic abnormalities.
Important Safety Information
WARNING: FETAL RISK, HEMATOLOGIC TOXICITY, and DEEP VEIN THROMBOSIS AND PULMONARY EMBOLISM
Do not use REVLIMID during pregnancy. Lenalidomide, a thalidomide analogue, caused limb abnormalities in a developmental monkey study. Thalidomide is a known human teratogen that causes severe life-threatening human birth defects. If lenalidomide is used during pregnancy, it may cause birth defects or death to a developing baby. In women of childbearing potential, obtain 2 negative pregnancy tests before starting REVLIMID treatment. Women of childbearing potential must use 2 forms of contraception or continuously abstain from heterosexual sex during and for 4 weeks after REVLIMID treatment. To avoid fetal exposure to lenalidomide, REVLIMID is only available in the United States under a restricted distribution program called “RevAssist®.”
Information about the RevAssist program is available at www.REVLIMID.com or by calling the manufacturer’s toll-free number 1-888-423-5436.
HEMATOLOGIC TOXICITY (NEUTROPENIA AND THROMBOCYTOPENIA)
REVLIMID can cause significant neutropenia and thrombocytopenia. Eighty percent of patients with del 5q MDS had to have a dose delay/reduction during the major study. Thirty-four percent of patients had to have a second dose delay/reduction. Grade 3 or 4 hematologic toxicity was seen in 80% of patients enrolled in the study. Patients on therapy for del 5q MDS should have their complete blood counts monitored weekly for the first 8 weeks of therapy and at least monthly thereafter. Patients may require dose interruption and/or reduction. Patients may require use of blood product support and/or growth factors. (see DOSAGE and ADMINISTRATION)
DEEP VEIN THROMBOSIS AND PULMONARY EMBOLISM
REVLIMID has demonstrated a significantly increased risk of deep vein thrombosis (DVT) and pulmonary embolism (PE) in patients with MM who were treated with REVLIMID and dexamethasone therapy. Patients and physicians are advised to be observant for the signs and symptoms of thromboembolism. Patients should be instructed to seek medical care if they develop symptoms such as shortness of breath, chest pain, or arm or leg swelling. It is not known whether prophylactic anticoagulation or antiplatelet therapy prescribed in conjunction with REVLIMID may lessen the potential for venous thromboembolic events. The decision to take prophylactic measures should be done carefully after an assessment of an individual patient’s underlying risk factors.
Pregnancy Category X:
•Lenalidomide is contraindicated in pregnant women and
women capable of becoming pregnant. Females of childbearing
potential may be treated with lenalidomide provided adequate
precautions are taken to avoid pregnancy
•REVLIMID is contraindicated in patients who have
demonstrated hypersensitivity (e.g., angioedema, Stevens-Johnson
syndrome, toxic epidermal necrolysis) to lenalidomide
WARNINGS AND PRECAUTIONS:
•REVLIMID is an analogue of thalidomide, a known human
teratogen that causes life-threatening human birth defects. An
embryofetal development study in non-human primates indicates that
lenalidomide produced malformations in the offspring of female
monkeys who received the drug during pregnancy, similar to birth
defects observed in humans following exposure to thalidomide during
pregnancy. If REVLIMID is used during pregnancy, it may cause birth
defects or death to a developing baby
•Females of childbearing potential must be advised to avoid pregnancy while on REVLIMID. Two effective contraceptive methods should be used during therapy, during dose interruptions, and for at least 4 weeks after completing therapy
•Male Patients: Clinical data has demonstrated the presence of lenalidomide in human semen. Male patients taking REVLIMID should not donate sperm. Males receiving REVLIMID must always use a latex condom during any sexual contact with females of childbearing potential, even if they have undergone a successful vasectomy
Reproductive Risk and Special Prescribing Requirements (RevAssist Program):
•Because of this potential toxicity and to avoid fetal
exposure, REVLIMID is only available under a special restricted
distribution program called “RevAssist.” Prescribers
and pharmacists registered with the program can prescribe and
dispense the product to patients who are registered and meet all
the conditions of the RevAssist program
Hematologic Toxicity—Multiple Myeloma:
•REVLIMID can cause significant neutropenia and
•Patients taking REVLIMID for MM should have their complete blood counts monitored every 2 weeks for the first 12 weeks and then monthly thereafter
•In the pooled MM studies Grade 3 and 4 hematologic toxicities were more frequent in patients treated with the combination of REVLIMID and dexamethasone than in patients treated with dexamethasone alone
•Patients may require dose interruption and/or dose reduction
Deep Vein Thrombosis and Pulmonary Embolism:
•Venous thromboembolic events (predominantly deep venous
thrombosis and pulmonary embolism) have occurred in patients with
MM treated with lenalidomide combination therapy and patients with
MDS treated with lenalidomide monotherapy
•Angioedema and serious dermatologic reactions including
Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN)
have been reported. These events can be fatal. Patients with a
prior history of Grade 4 rash associated with thalidomide treatment
should not receive REVLIMID. REVLIMID interruption or
discontinuation should be considered for Grade 2-3 skin rash.
REVLIMID must be discontinued for angioedema, Grade 4 rash,
exfoliative or bullous rash, or if SJS or TEN is suspected, and
should not be resumed following discontinuation for these
•REVLIMID capsules contain lactose. Risk-benefit of REVLIMID treatment should be evaluated in patients with lactose intolerance
Tumor Lysis Syndrome:
•Fatal instances of tumor lysis syndrome have been reported
during treatment with lenalidomide. The patients at risk of tumor
lysis syndrome are those with high tumor burden prior to treatment.
These patients should be monitored closely and appropriate
Tumor Flare Reaction:
•Tumor flare reaction has occurred during investigational
use of lenalidomide for chronic lymphocytic leukemia (CLL) and
lymphoma, and is characterized by tender lymph node swelling, low
grade fever, pain and rash. Treatment of CLL or lymphoma with
lenalidomide outside of a well-monitored clinical trial is
•Cases of transient liver laboratory abnormalities
(predominantly transaminases) were reported in patients treated
with lenalidomide. Treatment with lenalidomide should be
interrupted and restarted once the levels return to baseline.
Successful re-challenge without recurrence of liver laboratory
elevation was reported in some patients
Second Primary Malignancies
•Patients with MM treated with lenalidomide in studies
including melphalan and stem cell transplantation had a higher
incidence of second primary malignancies, particularly acute
myelogenous leukemia (AML) and Hodgkin lymphoma, compared to
patients in the control arms who received similar therapy but did
not receive lenalidomide. Monitor patients for the development of
second malignancies. Take into account both the potential benefit
of lenalidomide and the risk of second primary malignancies when
considering treatment with lenalidomide
•Periodic monitoring of digoxin plasma levels, in
accordance with clinical judgment and based on standard clinical
practice in patients receiving this medication, is recommended
during administration of REVLIMID
•It is not known whether there is an interaction between dexamethasone and warfarin. Close monitoring of PT and INR is recommended in MM patients taking concomitant warfarin
•Erythropoietic agents, or other agents, that may increase the risk of thrombosis, such as estrogen containing therapies, should be used with caution in MM patients receiving lenalidomide with dexamethasone
USE IN SPECIFIC POPULATIONS:
•It is not known whether REVLIMID is excreted in human
•Because of the potential for adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the mother
•Since elderly patients are more likely to have decreased
renal function, care should be taken in dose selection. Monitor
•Since REVLIMID is primarily excreted unchanged by the
kidney, adjustments to the starting dose of REVLIMID are
recommended to provide appropriate drug exposure in patients with
moderate (CLcr 30-60 mL/min) or severe renal impairment (CLcr <
30 mL/min) and in patients on dialysis
•In the REVLIMID/dexamethasone treatment group, 269
patients (76%) underwent at least one dose interruption with or
without a dose reduction of REVLIMID compared to 199 patients (57%)
in the placebo/dexamethasone treatment group
•Of these patients who had one dose interruption with or without a dose reduction, 50% in the REVLIMID/dexamethasone treatment group underwent at least one additional dose interruption with or without a dose reduction compared to 21% in the placebo/dexamethasone treatment group
•Most adverse events and Grade 3/4 adverse events were more frequent in MM patients who received the combination of REVLIMID/dexamethasone compared to placebo/dexamethasone
•Adverse reactions reported in ≥15% of MM patients (REVLIMID/dexamethasone vs dexamethasone/placebo): fatigue (44% vs 42%), neutropenia (42% vs 6%), constipation (41% vs 21%), diarrhea (39% vs 27%), muscle cramp (33% vs 21%), anemia (31% vs 24%), pyrexia (28% vs 23%), peripheral edema (26% vs 21%), nausea (26% vs 21%), back pain (26% vs 19%), upper respiratory tract infection (25% vs 16%), dyspnea (24% vs 17%), dizziness (23% vs 17%), thrombocytopenia (22% vs 11%), rash (21% vs 9%), tremor (21% vs 7%), weight decreased (20% vs 15%), nasopharyngitis (18% vs 9%), blurred vision (17% vs 11%), anorexia (16% vs 10%), and dysgeusia (15% vs 10%)
•Thrombocytopenia (61.5%; 91/148) and neutropenia (58.8%;
87/148) were the most frequently reported adverse events observed
in the del 5q MDS population
•Other adverse events reported in ≥15% of del 5q MDS patients (REVLIMID): diarrhea (49%), pruritus (42%), rash (36%), fatigue (31%), constipation (24%), nausea (24%), nasopharyngitis (23%), arthralgia (22%), pyrexia (21%), back pain (21%), peripheral edema (20%), cough (20%), dizziness (20%), headache (20%), muscle cramp (18%), dyspnea (17%), pharyngitis (16%), epistaxis (15%), asthenia (15%), upper respiratory tract infection (15%)
DOSAGE AND ADMINISTRATION:
•Treatment is continued or modified based upon clinical and laboratory findings. Dosing modifications are recommended to manage Grade 3 or 4 neutropenia or thrombocytopenia or other Grade 3 or 4 toxicity judged to be related to REVLIMID
•For other Grade 3 or 4 toxicities judged to be related to
REVLIMID, hold treatment and restart at next lower dose level when
toxicity has resolved to ≤Grade 2
Please see full Prescribing Information, including Boxed WARNINGS, CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and ADVERSE REACTIONS.
About Celgene International Sàrl
Celgene International Sàrl, located in Boudry, in the Canton of Neuchâtel, Switzerland, is a wholly owned subsidiary and international headquarters of Celgene Corporation. Celgene Corporation, headquartered in Summit, New Jersey, is an integrated global pharmaceutical company engaged primarily in the discovery, development and commercialization of innovative therapies for the treatment of cancer and inflammatory diseases through gene and protein regulation. For more information, please visit the Company's website at www.celgene.com.
This press release contains forward-looking statements, which are generally statements that are not historical facts. Forward-looking statements can be identified by the words "expects," "anticipates," "believes," "intends," "estimates," "plans," "will," “outlook” and similar expressions. Forward-looking statements are based on management’s current plans, estimates, assumptions and projections, and speak only as of the date they are made. We undertake no obligation to update any forward-looking statement in light of new information or future events, except as otherwise required by law. Forward-looking statements involve inherent risks and uncertainties, most of which are difficult to predict and are generally beyond our control. Actual results or outcomes may differ materially from those implied by the forward-looking statements as a result of the impact of a number of factors, many of which are discussed in more detail in our Annual Report on Form 10-K and our other reports filed with the Securities and Exchange Commission.
Source: Celgene Corporation
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Posted: May 2012