Continuous administration of lenolidamide plus dexamethasone significantly extended progression-free survival in older patients with newly diagnosed multiple myeloma, compared with the standard, fixed regimen of melphalan and prednisone combined with thalidomide, in a phase III randomized trial reported online Sept. 4 in the New England Journal of Medicine.
The open-label study involved patients aged 65 years and older who weren’t eligible for stem-cell transplantation. A total of 35% of the participants were over age 75, and many had more advanced disease than has been allowed in previous clinical trials of melphalan/prednisone/thalidomide (MPT), said Dr. Lotfi Benboubker of the hematology and cellular therapy service, Central Regional University Hospital, Tours, France, and his associates.
The 1,623 patients were enrolled during a 3-year period at 246 medical centers in 18 countries in Europe, North America, and the Asia-Pacific region. They were randomly assigned to receive unlimited lenalidomide/dexamethasone in 28-day cycles until disease progression (535 patients), 18 rounds of lenalidomide/dexamethasone in 28-day cycles for 72 weeks (541 patients), or 12 rounds of MPT in 42-day cycles for 72 weeks (547 patients). All patients received antithrombotic prophylaxis as specified in the study protocol, as well as bisphosphonates and other supportive therapies at the investigator’s discretion.
The median duration of follow-up was 37.0 months (range, 0-56.7 months). A total of 39% of the patients in the continuous lenalidomide group received more than 2 years of treatment.
The primary efficacy endpoint, progression-free survival, was 25.5 months with continuous lenalidomide, which was significantly (28%) longer than the 20.7 months with fixed lenalidomide and 21.2 months with MPT, the investigators reported (N. Engl. J. Med. 2014;371:906-17).
Rates of overall survival in the three study groups were 70%, 66%, and 62% at 3 years and 59%, 56%, and 51% at 4 years, for continuous lenalidomide, fixed lenalidomide, and MPT, respectively. "Although the difference in overall survival did not cross the prespecified superiority boundary, continuous lenalidomide/dexamethasone reduced the risk of death, as compared with MPT (hazard ratio, 0.78)," they noted.
Secondary outcomes such as treatment response rates, rates of complete response, and durability of response all were higher with continuous lenalidomide than with fixed lenalidomide or MPT. Continuous lenalidomide also was superior regarding two exploratory outcomes: need for second-line therapy and time to second-line therapy. "This represents a clinically significant advantage, especially for elderly patients, in whom a response to rescue therapy at the time of first relapse may be difficult to achieve," Dr. Benboubker and his associates said.
As expected, both lenalidomide groups had lower rates of hematologic toxic events than the MPT group, but both also had higher rates of infection. The incidence of second primary cancers was higher with MPT than with lenalidomide.
This study was funded by Celgene, maker of lenolidamide, which also took part in study design, data collection, data analysis, and manuscript preparation. Dr. Benboubker reported ties to Celgene, Millennium, Onyx Therapeutics, and Lilly; his associates reported ties to numerous industry sources.