The study compared oral pomalidomide plus low-dose dexamethasone with high-dose dexamethasone in patients with refractory or relapsed and refractory multiple myeloma who have failed at least two prior therapies with both bortezomib and lenalidomide, administered alone or in combination.
At the interim analysis (ASH 2012, median follow-up 4.2 months), the study met its primary endpoint as pomalidomide plus low-dose dexamethasone demonstrated a significant improvement in progression-free survival (PFS) (3.8 months vs 1.9 months HR 0.41 p<0.0001) compared with high-dose dexamethasone. There was also a significant improvement in the key secondary endpoint of overall survival (OS) (11.9 months vs 7.8 months HR 0.53 p<0.0002) compared with high-dose dexamethasone even though 45 patients in the high-dose dexamethasone arm crossed over and received pomalidomide.
Additionally, the Data Monitoring Committee recommended that patients who had not yet progressed in the high-dose dexamethasone arm should have access to pomalidomide with or without low-dose dexamethasone.
At a median follow-up of 10.0 months, an updated PFS analysis and final OS analysis were conducted. Pomalidomide plus low-dose dexamethasone continued to demonstrate significantly longer PFS, the primary endpoint, compared with high-dose dexamethasone (4.0 months vs. 1.9 months, HR=0.48, p<0.0001). Additionally, pomalidomide plus low-dose dexamethasone demonstrated a significant improvement in OS compared with high-dose dexamethasone (12.7 months vs. 8.1 months, HR=0.74, p=0.0285). Overall response rate for patients receiving pomalidomide plus low-dose dexamethasone was 31% compared with 10% for patients receiving high-dose dexamethasone (p<0.0001).
The most common grade 3-4 hematological adverse events in the pomalidomide plus low-dose dexamethasone and high-dose dexamethasone arms, respectively, were: neutropenia (48% 143/300 vs. 16% 24/150), anemia (33% 99/300 vs. 37% 55/150) and thrombocytopenia (22% 67/300 vs. 26% 39/150). Grade 3-4 non-hematological adverse events in the pomalidomide plus low-dose dexamethasone and high-dose dexamethasone arms, respectively, included: pneumonia (13% 38/300 vs. 8% 12/150), bone pain (7% 21/300 vs. 5% 7/150) and fatigue (5% 16/300 vs. 6% 9/150). Four patients in the pomalidomide plus low-dose dexamethasone arm and one patient in the high-dose dexamethasone arm developed second primary malignancies. Of these, two patients in the pomalidomide plus low-dose dexamethasone arm had invasive solid tumor cancers and two patients in this group and the one in the high-dose dexamethasone group had non-invasive cancers (basal-cell skin cancers). Treatment-related adverse events led to treatment discontinuation in 4% of patients in the pomalidomide plus low-dose dexamethasone arm and 6% of patients in the high-dose dexamethasone arm.
Patients in the pomalidomide plus low-dose dexamethasone arm received 4 mg of oral pomalidomide on days 1-21 of each 28-day cycle. Oral dexamethasone was given at 40 mg on days 1, 8, 15, and 22); for patients older than 75 years, dexamethasone was administered at 20 mg weekly.
Patients in the comparator arm were treated with 40 mg oral high-dose dexamethasone on days 1-4, 9-12 and 17-20 of each 28-day cycle, until disease progression; patients older than 75 years received 20 mg oral dexamethasone on the same schedule.
Results of the MM-003 trial formed the basis of an August 2013 approval
For more information, visit http://www.thelancet.com/journals/lanonc/onlinefirst
Important Safety Information based on approved U.S. Label for Pomalyst (Trade name for Pomalidomide Celgene in the U.S.)
WARNING: EMBRYO-FETAL TOXICITY and VENOUS THROMBOEMBOLISM
POMALYST is only available through a restricted distribution program called POMALYST REMSTM.
WARNINGS AND PRECAUTIONS
POMALYST REMS Program
Because of the embryo-fetal risk, POMALYST is available only through a restricted distribution program under a Risk Evaluation and Mitigation Strategy (REMS) called “POMALYST REMS.” Prescribers and pharmacists must be certified with the program; patients must sign an agreement form and comply with the requirements. Further information about the POMALYST REMS program is available at [celgeneriskmanagement.com] or by telephone at 1-888-423-5436.
Venous Thromboembolism: Patients receiving POMALYST have developed venous thromboembolic events reported as serious adverse reactions. In the trial, all patients were required to receive prophylaxis or antithrombotic treatment. The rate of DVT or PE was 3%. Consider anticoagulation prophylaxis after an assessment of each patient’s underlying risk factors.
Hematologic Toxicity: Neutropenia of any grade was reported in 50% of patients and was the most frequently reported Grade 3/4 adverse event, followed by anemia and thrombocytopenia. Monitor patients for hematologic toxicities, especially neutropenia, with complete blood counts weekly for the first 8 weeks and monthly thereafter. Treatment is continued or modified for Grade 3 or 4 hematologic toxicities based upon clinical and laboratory findings. Dosing interruptions and/or modifications are recommended to manage neutropenia and thrombocytopenia.
Hypersensitivity Reactions: Patients with a prior history of serious hypersensitivity associated with thalidomide or lenalidomide were excluded from studies and may be at higher risk of hypersensitivity.
Dizziness and Confusional State: 18% of patients experienced dizziness and 12% of patients experienced a confusional state; 1% of patients experienced grade 3/4 dizziness, and 3% of patients experienced grade 3/4 confusional state. Instruct patients to avoid situations where dizziness or confusion may be a problem and not to take other medications that may cause dizziness or confusion without adequate medical advice.
Neuropathy: 18% of patients experienced neuropathy (approximately 9% peripheral neuropathy). There were no cases of grade 3 or higher neuropathy adverse reactions reported.
Risk of Second Primary Malignancies: Cases of acute myelogenous leukemia have been reported in patients receiving POMALYST as an investigational therapy outside of multiple myeloma.
In the clinical trial MM-002 of 219 patients who received POMALYST alone (n=107) or POMALYST + low-dose dexamethasone (low-dose dex) (n=112), all patients had at least one treatment-emergent adverse reaction.
No formal drug interaction studies have been conducted with POMALYST. Pomalidomide is primarily metabolized by CYP1A2 and CYP3A. Pomalidomide is also a substrate for P-glycoprotein (P-gp). Coadministration of POMALYST with drugs that are strong inhibitors or inducers of CYP1A2, CYP3A, or P-gp should be avoided. Cigarette smoking may reduce pomalidomide exposure due to CYP1A2 induction. Patients should be advised that smoking may reduce the efficacy of pomalidomide.
USE IN SPECIFIC POPULATIONS
Pregnancy: If pregnancy does occur during treatment, immediately
discontinue the drug and refer patient to an obstetrician/gynecologist
experienced in reproductive toxicity for further evaluation and
counseling. Report any suspected fetal exposure to POMALYST to the
Nursing Mothers: It is not known if pomalidomide is excreted in human milk. Pomalidomide was excreted in the milk of lactating rats. Because many drugs are excreted in human milk and because of the potential for adverse reactions in nursing infants from POMALYST, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Pediatric Use: Safety and effectiveness of POMALYST in patients under the age of 18 have not been established.
Geriatric Use: No dosage adjustment is required for POMALYST based on age. Patients greater than or equal to 65 years of age were more likely than patients less than or equal to 65 years of age to experience pneumonia.
Renal and Hepatic Impairment: Pomalidomide is metabolized in the liver. Pomalidomide and its metabolites are primarily excreted by the kidneys. The influence of renal and hepatic impairment on the safety, efficacy, and pharmacokinetics of pomalidomide has not been evaluated. Avoid POMALYST in patients with a serum creatinine >3.0 mg/dL. Avoid POMALYST in patients with serum bilirubin >2.0 mg/dL and AST/ALT >3.0 x ULN.
Please see full U.S. Prescribing Information, including Boxed WARNINGS, CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and ADVERSE REACTIONS.
Pomalidomide is an oral immunomodulatory drug (IMiD®) with a multimodal mechanism of action consisting of three main effects demonstrated in vitro: direct antimyeloma, stromal inhibitory effects and immunomodulatory effects. Pomalidomide in combination with dexamethasone has been approved in the EU for the treatment of adult patients with relapsed and refractory multiple myeloma who have received at least two prior therapies including lenalidomide and bortezomib and have demonstrated disease progression on the last therapy.
In addition to the EC decision for the EU, pomalidomide is approved in
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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
Source: Celgene International Sàrl