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Newly diagnosed multiple myeloma: continuous Lenalidomide plus Dexamethasone linked to significant progression-free survival benefit


Data from FIRST, an open-label phase III randomized study of continuous Lenalidomide ( Revlimid ) in combination with Dexamethasone in patients newly diagnosed with multiple myeloma ( NDMM ) who are not candidates for stem cell transplant, have been published in the New England Journal of Medicine.

The findings have demonstrated that at a median follow-up of 37 months among surviving patients, the median progression-free survival was 25.5 months with continuous oral Lenalidomide plus low-dose Dexamethasone ( Rd ), 20.7 months with a fixed course of oral Lenalidomide plus low-dose Dexamethasone ( Rd18 ) and 21.2 months with Melphalan, Prednisone and Thalidomide ( MPT ).
This resulted in a 28% reduction in risk of progression or death for patients treated with continuous Rd compared with those treated with MPT ( hazard ratio, HR=0.72; 95% CI, 0.61 to 0.85; P less than 0.001 ) and a 30% reduction compared with Rd18 ( HR=0.70; 95% CI, 0.60 to 0.82; P less than 0.001 ) in the study.

The pre-planned interim analysis of overall survival demonstrated a 22% reduction in risk of death for continuous Rd versus MPT ( HR=0.78; 95% CI, 0.64 to 0.96; P=0.02 ), although the difference did not cross the pre-specified superiority boundary (P less than 0.0096 ).
As of the time of the analysis ( May 24, 2013 ), 121 of 535 ( 23% ) patients in the continuous Rd arm were still on therapy.

Additional secondary endpoints showed response rates were also significantly better with continuous Rd ( 75% ) and with Rd18 ( 73% ) than with MPT ( 62%; P less than 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 MPT ( 28% ).

Complete response rates were 15%, 14% and 9% for continuous Rd, Rd18 and MPT, respectively. Median duration of response was 35.0 months with continuous Rd compared with 22.3 months for MPT ( HR=0.63; P less than 0.001 ) and 22.1 months for Rd18 ( HR=0.60; P less than 0.001 ).

Median time to disease progression was 32.5 months for patients receiving continuous Rd compared with 23.9 months ( HR=0.68; P less than 0.001 ) for MPT and 21.9 months ( HR=0.62; P less than 0.001 ) for Rd18.

Safety results showed that grade 3/4 adverse events that occurred 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%, less than 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 taking continuous Rd, 6% in patients taking Rd18 and 5% in those taking MPT; the overall incidence of solid tumors was identical in the continuous Rd and MPT arms ( 3% ) and 5% in the Rd18 arm.

In the FIRST ( Frontline Investigation of Revlimid + dexamethasone versus Standard Thalidomide ) trial, 1,623 patients from 18 countries either greater than or equal to 65 or less than 65 years of age and ineligible for stem cell transplant were randomized 1:1:1 into three 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 ). ( Xagena )

Source: Celgene, 2014

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