Individuals with newly diagnosed multiple myeloma who were ineligible for stem cell transplantation were 31% less likely to die or progress on continuous lenalidomide plus low-dose dexamethasone (Rd continuous) than were those on melphalan, prednisone, and thalidomide (MPT), according to an extended follow-up of patients from the FIRST trial.
In addition, Rd continuous was associated with a statistically significant 20% decrease in risk of death or disease progression, compared with MPT among patients older than 75 years, reported Dr. Cyrille Hulin of Bordeaux (France) Hospital University Center and associates. The finding “establishes continuous treatment with Rd until disease progression as a new standard of care for patients with newly diagnosed multiple myeloma who are ineligible for stem cell transplantation, regardless of age. With proper monitoring and dose adjustment, Rd continuous is an effective and tolerable treatment option for even the most elderly patients,” they wrote online June 20 in the Journal of Clinical Oncology.
FIRST (Frontline Investigation of Revlimid Plus Dexamethasone Versus Standard Thalidomide) was an international, randomized, phase III open-label study of patients with untreated symptomatic multiple myeloma enrolled between 2008 and 2011. Patients were randomly assigned to Rd continuous, 72 weeks/18 cycles of Rd (Rd18), or MPT. The primary endpoint was progression-free survival (PFS). In the original analysis, Rd continuous led to a 28% lower risk of progression or death, compared with MPT, for a statistically significant hazard ratio (HR) of 0.72. The current study involved longer follow-up, with an updated data cutoff that was 3 years after the end of recruitment, the researchers said (J Clin Oncol. 2016 Jun 20. doi: 10.1200/JCO.2016.66.7295).
The cohort included 1,623 patients, of whom 567 (35%) were older than 75 years. The intention-to-treat populations included 535 Rd continuous patients, 541 Rd18 patients, and 547 MPT patients. Survivors were followed for a median of 45.5 months. As in the earlier analysis of FIRST data, the PFS was longer with Rd continuous than with MPT. For the overall intention-to-treat group, the median PFS was 26 months with Rd continuous, and 21.9 months with MPT (HR, 0.69; 95% confidence interval, 0.59-0.80). Among patients aged 75 years and younger, the median PFS was 28.1 months and 22.4 months, respectively (HR, 0.64; 95% CI, 0.53-0.77). Among patients over age 75 years, the median PFS was 20.3 months and 19.8 months, respectively (HR, 0.80, 95% CI, 0.62-1.03). In addition, the 4-year PFS “was more than doubled with Rd continuous versus MPT, regardless of age,” the investigators said. In contrast, Rd18 and MPT led to a similar median PFS, regardless of age.
As in the prior FIRST analysis, MPT was more often linked to grade 3 and 4 neutropenia (40% and 47% of older and younger patients, respectively, versus about 28% of Rd continuous patients), while Rd more often led to grade 3 and 4 infections (about 30% of Rd continuous patients, about 22% of Rd18 patients, and 16%-20% of MPT patients).
A total of 40% of younger Rd patients remained at their starting lenalidomide dose at 72 weeks, while only 16% of MPT patients stayed at their starting thalidomide dose. Similarly, 30% of older Rd continuous patients remained on their starting dose at 72 weeks, compared with 19% of older MPT patients.
Older age was associated with International Staging System stage III disease, renal impairment, and more comorbidities, but not with high-risk cytogenetics (that is, del[17p] and t[4;14]). “Although chronologic age is not necessarily an indicator of frailty, FIRST trial results did show greater PFS and OS [overall survival] benefits with Rd continuous versus MPT therapy, regardless of age,” the researchers commented.
The study was funded by Intergroupe Francophone du Myélome and Celgene. Dr. Hulin disclosed honoraria from Celgene, Amgen, Bristol-Myers Squibb, and Novartis.