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Positive Phase III Results Reported for Lenalidomide Plus Dexamethasone in Multiple Myeloma Patients

Combo therapy submitted for FDA review in April

Positive data have been reported from an open-label phase III randomized study of continuous lenalidomide (Revlimid, Celgene Corporation) in combination with dexamethasone in patients with newly diagnosed multiple myeloma who were not candidates for stem-cell transplant.

The results were published September 4 in the New England Journal of Medicine.

In the FIRST (Frontline Investigation of Revlimid + Dexamethasone Versus Standard Thalidomide) trial, 1,623 patients ineligible for stem-cell transplant were randomly assigned to three treatment arms: lenalidomide plus low-dose dexamethasone in 28-day cycles until disease progression (continuous Rd); lenalidomide plus low-dose dexamethasone for 72 weeks (18 cycles, Rd18); or melphalan, prednisone, and thalidomide in 42-day cycles for 72 weeks (12 cycles, MPT). The primary endpoint was a comparison of progression-free survival for continuous Rd versus MPT.

In this study, the median progression-free survival was 25.5 months with continuous Rd; 20.7 months with Rd18; and 21.2 months with MPT. This represented a 28% reduction in the risk of progression or death in patients treated with continuous Rd compared with those treated with MPT (hazard ratio [HR], 0.72; P < 0.001) and a 30% reduction compared with Rd18 (HR, 0.70; P < 0.001).

A pre-planned interim analysis of overall survival demonstrated a 22% reduction in the risk of death with continuous Rd compared with MPT (HR, 0.78; P = 0.02), although the difference did not cross the pre-specified superiority boundary (P < 0.0096). At of the time of the analysis (May 24, 2013), 121 of 535 patients (23%) in the continuous Rd arm were still receiving therapy.

Additional secondary endpoints showed that response rates were also significantly better with continuous Rd and Rd18 than with MPT (75% and 73%, respectively, vs. 62%; P < 0.001 for both comparisons). More patients achieved a very good partial response or better in the continuous Rd (44%) or Rd18 arms (43%) compared with the MPT arm (28%).

The complete response rates were 15%, 14%, and 9% for continuous Rd, Rd18, and MPT, respectively. The median duration of response was 35.0 months with continuous Rd compared with 22.3 months with MPT (HR, 0.63; P < 0.001) and 22.1 months with Rd18 (HR, 0.60; P < 0.001). The median time to disease progression was 32.5 months for patients receiving continuous Rd compared with 23.9 months for those receiving MPT (HR, 0.68; P < 0.001) and 21.9 months for those receiving Rd18 (HR, 0.62; P < 0.001).

Grade-3/4 adverse events occurring in at least 8% of patients in the continuous Rd arm, Rd18 arm, or MPT arm included neutropenia (28%, 26%, 45%, respectively), anemia (18%, 16%, 19%), thrombocytopenia (8%, 8%, 11%), febrile neutropenia (1%, 3%, 3%), leukopenia (5%, 6%, 10%), infection (29%, 22%, 17%), pneumonia (8%, 8%, 6%), deep-vein thrombosis and/or pulmonary embolism (8%, 6%, 5%), asthenia (8%, 6%, 6%), fatigue (7%, 9%, 6%), and peripheral sensory neuropathy (1%, <1%, 9%). Rates of grade-3/4 cardiac disorders for patients in the continuous Rd, Rd18, and MPT arms were 12%, 7% and 9%, respectively. The incidence of invasive second primary malignancies was 3% in patients treated with continuous Rd, 6% in patients treated with Rd18, and 5% in patients treated with MPT; the overall incidence of solid tumors was identical in the continuous Rd and MPT arms (3%) and was 5% in the Rd18 arm.

Based on these results, lenalidomide in combination with dexamethasone was submitted to the FDA for the treatment of newly diagnosed multiple myeloma patients in April 2014.

In the U.S., lenalidomide (Revlimid) in combination with dexamethasone is indicated for the treatment of patients with multiple myeloma who have received at least one prior therapy. In addition, lenalidomide alone is indicated for the treatment of 1) patients with transfusion-dependent anemia due to low- or intermediate-risk myelodysplastic syndromes associated with a deletion 5q cytogenetic abnormality with or without additional cytogenetic abnormalities; and 2) patients with mantle cell lymphoma whose disease has relapsed or progressed after two prior therapies, one of which included bortezomib.

Lenalidomide is not indicated for use in patients with newly diagnosed multiple myeloma in any country.

Source: Celgene Corporation; September 4, 2014.

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