LENALIDOMIDE-DEXAMETHASONE A NEW STANDARD FOR MYELOMA

NEW ORLEANS ― The combination of lenalidomide (Revlimid, Celgene Corporation) plus low-dose dexamethasone (LD) used first-line in the treatment of multiple myeloma significantly improved progression-free and overall survival when compared with standard therapy and should become the new standard of care, say experts here at the American Society of Hematology (ASH) 55th Annual Meeting.

Data presented during the plenary session showed that patients treated with LD were 28% less likely to experience disease progression or death when compared with patients treated with the standard triplet of melphalan, prednisone, and thalidomide (MPT).

In newly diagnosed patients with multiple myeloma who are ineligible for transplant, the FIRST trial establishes lenalidomide and low-dose dexamethasone as a new standard of care, commented lead study author Thierry Facon, MD, of Service des Maladies du Sang, Hôpital Claude Huriez, and CHRU Lille in France, who spoke during a press briefing.

The combination significantly extended progression-free survival, with an overall survival benefit, compared with MPT, he said. "There was a consistent benefit across most subgroups. The response rate was 75% with a median duration of 35 months."

In addition, LD was superior to MPT "across all other efficacy secondary endpoints," Dr. Facon added.

MPT and bortezomib (Velcade, Millennium Pharmaceuticals, Inc)-melphalan-prednisone (VMP) have both demonstrated superiority to melphalan and prednisone alone, Dr. Facon pointed out, in the population deemed ineligible for stem cell transplantation.

Therefore, MPT and VMP have been the preferred regimens recommended by the National Comprehensive Cancer Network, along with other national guidelines, for this group of multiple myeloma patients.

The authors also note that research shows that LD also increases overall survival, and with fewer side effects, compared with lenalidomide and high-dose dexamethasone in this population. This study strengthens the evidence for using this combination, noted Saad Usmani, MD, director of the plasma cell disorders program and director of clinical research in hematologic malignancies at the Levine Cancer Institute/Carolinas Healthcare System, Charlotte, North Carolina. "Physicians practicing in the community had already started employing this regimen for this patient population."

"One lesson is that it's safe to give, and effective," said Dr. Usmani, who was not involved in the study. "The other extremely important lesson is that if you achieve a certain response with this regimen, do not stop the treatment. If you continue the treatment, this will result in a better progression-free and overall survival. So don't treat until best response and then stop."

The dose may need to be reduced as time goes on to reduce toxicity, but one of the lessons learned during the past few years is to keep patients on the drug, regardless of whether they are transplant eligible or ineligible, he added. "We have evidence that this improves progression-free and overall survival. Based on these data, physicians will likely feel more comfortable using this regimen and recommending it to their patients."

Met Primary Endpoint

The FIRST was conducted at 246 center in 18 countries.

A total of 1623 patients with multipe myeloma who were not eligible for stem cell transplants were randomly assigned in a 1:1:1 ratio in 3 arms: LD in 28-day cycles until disease progression (Arm A); LD in 28-day cycles for 72 weeks (18 cycles, Arm B); or MPT in 42-day cycles for 72 weeks (12 cycles, Arm C).

However, all the results presented at the meeting were for Arm A (LD until progression) vs Arm C (MPT).

Treatment assessment followed International Myeloma Working Group criteria and was conducted after each cycle.

The median age of patients in this cohort was 73 years, and roughly a third (35% ) were aged 75 years or older. Additionally, 41% of patients had ISS stage 3 disease.

At the meeting, Dr. Facon presented the final preplanned analysis of independently adjudicated progressive disease events in Arm A vs Arm C, which were conducted after 960 events of death or progressive disease, along with an interim overall survival in 64% of survival events (574/896 events). Within the cohort, 121 patients continue to receive LD on study (Arm A).

After a median follow-up of 37 months, the trial met its primary endpoint of progression-free survival, showing that there was a 28% reduction in risk for progression or death in the LD group compared with MPT (hazard ratio [HR] = 0.72; P = .00006).

Trending Toward Overall Survival

The overall interim analysis (574 deaths or 35% of ITT) for overall survival also demonstrated superiority for LD, explained Dr. Facon. At 4 years, it was 59.4% for LD vs 51.4% for MPT.

All of the other secondary endpoints consistently showed improvement in favor of LD vs MPT; overall response rate was 75% vs 62% (P < .00001), duration of response (HR = 0.63; P < .00001), and second progression event or death (HR = 0.78; P = .0051).

Safety profiles of the 2 treatment regimens were similar, but those in the LD arm had fewer secondary hematologic malignancies than those treated with MPT. Relevant grade 3/4 adverse events in Arm A vs Arm C were neutropenia (28% vs 45%), thrombocytopenia (8% vs 11%), febrile neutropenia (1% vs 3%), infection (29% vs 17%), neuropathy (5% vs15%), and deep-vein thrombosis (5% vs 3%).

The incidence of secondary primary malignancies was also evaluated, and hematologic malignancies were 0.4% with LD vs 2.2% with MPT. The overall incidence of solid tumors was identical (2.8%).

The study was supported by Celgene in collaboration with the French Francophone Myeloma Intergroup (IFM).

American Society of Hematology (ASH) 55th Annual Meeting: Abstract 2, presented December 8, 2013.