FDA Approval Summary: Lenalidomide as Maintenance Therapy After Autologous Stem Cell Transplant in Newly Diagnosed Multiple Myeloma.

On February 22, 2017, the U.S. Food and Drug Administration (FDA) granted approval for the use of lenalidomide as maintenance therapy after autologous hematopoietic stem cell transplantation (auto-HSCT) for patients with multiple myeloma. The approval was based on evidence from two randomized, blinded trials of maintenance lenalidomide versus placebo in patients with myeloma who had undergone auto-HSCT along with a third trial of lenalidomide versus no therapy. Each of the trials demonstrated superior progression-free survival for the patients treated with lenalidomide. The effect on overall survival was mixed, with one trial showing longer overall survival and another showing no effect. Subgroup analysis suggested better results for patients with International Staging System stage I or II disease compared with stage III disease. Safety evaluation did not reveal any new safety concerns. More second primary malignancies were observed in the lenalidomide arm compared with the placebo arm. The FDA concluded that lenalidomide maintenance showed a favorable benefit-to-risk ratio when used as maintenance therapy after auto-HSCT. IMPLICATIONS FOR PRACTICE: Prior to this approval, there were no U.S. Food and Drug Administration-approved maintenance therapies for patients with multiple myeloma (MM) who have undergone autologous hematopoietic stem cell transplantation (auto-HSCT). Maintenance therapy with lenalidomide after auto-HSCT in patients with MM demonstrated an approximately 15- to 18-month advantage in progression-free survival compared with placebo at the time of the primary analysis. Patients treated with lenalidomide also appeared to have a survival advantage compared with patients treated with placebo. Because of the high rate of relapse of MM in patients following auto-HSCT and because MM is a serious and often fatal disease, these results appear to be clinically meaningful.

Eltrombopag for the treatment of chronic immune (idiopathic) thrombocytopenic purpura.

PURPOSE: On November 20, 2008, eltrombopag (Promacta) received approval from the US Food and Drug Administration (FDA) for the treatment of thrombocytopenia in patients with chronic immune thrombocytopenic purpura (ITP) who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy. This report summarizes the FDA analyses of the clinical data supporting this approval. EXPERIMENTAL DESIGN: The FDA reviewed data from two double-blind, placebo-controlled clinical studies, an uncontrolled extension study, and exploratory supportive studies. One study randomized patients among placebo or one of three daily doses of eltrombopag (30, 50, or 75 mg). The other study randomized patients between placebo or eltrombopag, 50 mg daily. Study drugs were administered for 6 weeks. The primary endpoint was response rate. Patients who completed these and other studies were eligible to enroll in the extension study. RESULTS: Overall, 231 patients were randomized within the two controlled studies (67 to placebo; 164 to eltrombopag). A platelet response was observed among 59% and 70% of the patients receiving eltrombopag, 50 mg daily. Corresponding placebo response rates were 16% and 11%, respectively. Serious hemorrhages occurred among two patients receiving eltrombopag and one patient receiving placebo, and among five patients following discontinuation of eltrombopag. In the extension study, eltrombopag was administered to 109 patients; median platelet counts were > 50 x 10(9)/L throughout the study's quarterly follow-up points. Major safety findings pertained to a risk for hepatotoxicity, worsened thrombocytopenia with hemorrhage following eltrombopag discontinuation, and bone marrow reticulin formation. CONCLUSIONS: The US FDA approved eltrombopag for use among certain patients with chronic ITP based upon demonstration of a favorable risk-to-benefit profile, where the major benefit pertained to demonstration of a clinically important increase in blood platelets among a population of patients relatively refractory to prior therapies.

FDA report: eculizumab (Soliris) for the treatment of patients with paroxysmal nocturnal hemoglobinuria.

On March 16, 2007, eculizumab (Soliris; Alexion Pharmaceuticals, Inc. Cheshire, CT), a humanized monoclonal antibody that binds to the human C5 complement protein, received accelerated approval by the U.S. Food and Drug Administration for the treatment of patients with paroxysmal nocturnal hemoglobinuria (PNH) to reduce hemolysis. Eculizumab was studied in a randomized, double-blind, placebo-controlled clinical trial in 87 RBC transfusion-dependent adult PNH patients and in a supportive single-arm study in 96 patients. The eculizumab dose was 600 mg as a 35-minute i.v. infusion administered weekly for the first 4 weeks followed by 900 mg (week 5) then 900 mg every 14 days thereafter. Hemoglobin stabilized in 21 of 43 (48.8%) eculizumab-treated patients, compared with none of 44 placebo-treated patients. Eculizumab-treated patients required significantly fewer RBC transfusions than placebo-treated patients (median, 0 versus 10 units). There was also a significant reduction in the serum lactate dehydrogenase area under the curve with eculizumab compared with placebo treatment. Results of the phase II supportive study were similar to those of the phase III study. The safety database included 196 adult patients with PNH. Significant findings included the development of human anti-human antibody responses in three patients and serious meningococcal infections in three patients. Patients should undergo meningococcal vaccination at least 2 weeks prior to receiving the first eculizumab treatment and have revaccination according to current medical guidelines. Patients must be monitored and evaluated immediately for early signs of meningococcal infections and treated with antibiotics as indicated.