For older patients with multiple myeloma who are ineligible for stem cell transplantation, continuous therapy with lenalidomide(Revlimid, Celgene) and dexamethasone improves progression-free survival and risk for death, compared with the current standard of care of melphalan, prednisone, and thalidomide(MPT), a new study shows.
Results from the Frontline Investigation of Revlimid and Dexamethasone vs Standard Thalidomide (FIRST) study, an international phase 3 trial sponsored by Celgene, the manufacturer of lenalidomide and thalidomide, were publishedin the September 4 issue of the New England Journal of Medicine.
The findings show that continuous lenalidomide plus dexamethasone is "safe to give and effective," said Saad Usmani, MD, when the FIRST results were presented at the 2013 American Society of Hematology meeting. He is director of the plasma cell disorders program and director of clinical research in hematologic malignancies at the Levine Cancer Institute/Carolinas Healthcare System in Charlotte, North Carolina, and 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 better progression-free and overall survival, so don't treat until best response and then stop," Dr. Usmani explained.
Celgene submitted the results of this study to regulatory authorities (in Europe in February and in the United States in April) for the approval of lenalidomide plus dexamethasone in the treatment of newly diagnosed multiple myeloma. At the moment, it is approved for use as second-line therapy in myeloma patients who have used 1 previous therapy.
"This study will hopefully lead to registration and reimbursement [for first-line use] in many countries," said lead researcher Thierry Facon, professor of hematology at the University of Lille in France.
If approved, it will be the first nonalkylating-agent-based regimen in the United States.
Some Americans "have said that melphalan has been 'killed' by this study, and they consider this good news for patients," Dr. Facon told Medscape Medical News. In the United States, physicians already use lenalidomide as a first-line drug, but without formal approval from the US Food and Drug Administration, he noted.
In fact, Dr. Usmani, too, reported that "physicians practicing in the community [have] already started employing this regimen for this patient population."
In other countries, however, lenalidomide is not currently used as a first-line drug.
Addresses Question of Prolonged Therapy
"The important question that this study addresses is about the possibility for prolonged therapy," said Jacalyn Rosenblatt, MD, hematologist and assistant professor of medicine at the Beth Israel Deaconess Medical Center in Boston, who is coauthor of an accompanying editorial.
"What the study showed was that the regimen of lenalidomide and dexamethasone given until progression had a progression-free survival advantage and a modest improvement in overall survival at the interim analysis," Dr. Rosenblatt told Medscape Medical News.
For patients not eligible for transplantation, such as older patients and those unable to tolerate high-dose chemotherapy, the standard of care for a long time has been melphalan plus prednisone, she explained. The addition of proteasome inhibitors and immunomodulatory agents to the backbone of melphalan and prednisone has resulted in improved outcomes.
"The low-toxicity profile of these novel agents allows for long-term therapy, with the potential to further prolong survival," Dr. Rosenblatt explained. "This study demonstrates that treatment with lenalidomide and dexamethasone until the time of disease progression offers an advantage over a defined course of therapy."
Whether or not giving this regimen until progression ultimately leads to improved survival remains to be seen, according to Dr. Rosenblatt, who noted that longer follow-up is necessary.
"The overarching message is that we now have newer drugs and novel agents. Thinking about how to incorporate them into the care of myeloma patients is important," Dr. Rosenblatt emphasized. This study and one published in the same issue,as reported by Medscape Medical News (N Engl J Med. 2014;371:895-905), "are starting to address that," she added.
Details of the Results
The open-label FIRST study involved 1623 participants from 246 treatment centers in 18 countries in Europe, North America, and the Asia-Pacific region. All were newly diagnosed with multiple myeloma and ineligible for transplantation; 35% were older than 75 years, about 40% had stage III disease, and 9% had severe renal impairment but did not require dialysis.
Participants were randomly assigned to 1 of 3 treatment groups: lenalidomide plus dexamethasone administered continuously in 28-day cycles until disease progression (n = 535); lenalidomide plus dexamethasone for 18 cycles over 72 weeks (n = 541); or MPT for 12 cycles over 72 weeks (n = 547).
Median follow-up was 37 months.
Independent committees reviewed response and progression using the International Uniform Response Criteria for Multiple Myeloma, and monitored safety and efficacy. The researchers also assessed quality of life.
Progression-free survival was longer with continuous lenalidomide plus dexamethasone than with 18 cycles of lenalidomide plus dexamethasone or MPT (25.5 vs 20.7 vs 21.2 months).
Risk for progression or death was 28% lower with the continuous regimen than with MPT (hazard ratio [HR], 0.72; P < .001), and 30% lower with the continuous regimen than with the 18-cycle regimen (HR, 0.70; P < .001). Risk for progression or death was similar with the 18-cycle regimen and MPT (HR, 1.03;P = .70).
Overall survival at 4 years was 59% with the continuous regimen, 56% with the 18-cycle regimen, and 51% with MPT. Although this difference did not satisfy the prespecified criteria for superiority, the results suggest that the continuous regimen reduced the risk for death compared with MPT (HR, 0.78; P = .02), the researchers note.
Grade 3/4 adverse events were slightly less common with the continuous regimen than with MPT (70% vs. 78%). In addition, there were fewer hematologic, neurologic, and second primary hematologic cancers with the continuous regimen. However, infections were more common with the continuous regimen than with the 18-cycle regimen or with MPT (29% vs 22% vs 17%).
Still, quality of life "generally improved" in all groups, the researchers report.
The study was sponsored by Celgene. Dr. Facon reports financial relationships with Celgene, Millennium, Amgen, Novartis, Bristol-Myers Squibb, and Janssen. Several of his coauthors are employees of Celgene, and others report financial relationships with Celgene, sanofi-aventis, Gilead, Onyx, Millennium, Janssen, Lilly and Company, Ortho-Biotech, Pfizer, Amgen, Novartis, Bristol-Myers Squibb, Janssen-Cilag, Roche, Mundipharma, Teva, Takeda, and/or Otsuka. Dr. Rosenblatt reports receiving grant support from Millennium
Δεν υπάρχουν σχόλια:
Δημοσίευση σχολίου