For select older patients, it is safe to switch to a lower dose of lenalidomide maintenance therapy and discontinue dexamethasone after 9 months. The regimen is safe and yields outcomes similar to those of standard, continuous lenalidomide/dexamethasone (Rd), according to new findings.
At a median follow-up of 37 months, event-free survival was 10.4 months in the experimental arm in which dexamethasone therapy was stopped (Rd-R), vs 6.9 months for standard therapy. The tailored approach also resulted in fewer adverse effects.
The authors note that there was no difference in progression-free survival (PFS) and overall survival between the two groups.
“These results may be useful for the treatment of myeloma patients, since approximately one third of patients not eligible for stem cell transplantation are intermediate fit, the population in our study,” said lead author Alessandra Larocca, MD, PhD, from the Department of Hematology-Oncology of the University Hospital Città della Salute e della Scienza, Torino, Italy.
She told Medscape Medical News that they expect that these findings “may help to optimize the treatment of less fit elderly patients by reducing the occurrence of adverse events and thus improving outcomes and preserving quality of life of these patients.”
This approach is a viable option for clinicians to consider for some patient subgroups. “This steroid-sparing approach can also be used in other combinations,” she said. “Ongoing trials are now evaluating steroid sparing in combination with monoclonal antibodies or the role of frailty-guided treatment.”
The study was published March 19 in Blood.
Myeloma patients aged 75 years or older or who have comorbidities and functional impairments are an understudied population. They are more susceptible to adverse events that may negatively affect the duration of treatment and outcomes. Steroids are “scarcely tolerated” in the long term, even among younger patients, and “whether sparing dexamethasone is as effective as a prolonged steroid-exposure remains an open issue,” the authors write. There are still no clear data on the advantage of continuous steroid treatment as opposed to fixed-duration treatment for newly diagnosed patients.
In 2010, a study compared high-dose with low-dose dexamethasone. As expected, the rate of adverse events was lower among patients who received the low-dose steroid, but quite unexpectedly, deaths with high-dose dexamethasone were significantly higher than with low-dose dexamethasone.
One-year overall survival was 96% among patients who received the low dose of dexamethasone, vs 87% with the standard high dose.
S. Vincent Rajkumar, MD, of the Mayo Clinic, Rochester, Minnesota, who was the lead author of the 2010 study, spoke with Medscape Medical News about the current study. “This is an important and practice-changing study,” he said. “We have already changed our practice and recommendations based on this study.”
He explained that for transplant-ineligible patients, instead of initial therapy with bortezomib-lenalidomide-dexamethasone followed by Rd, they use lenalidomide alone without steroids.
“After 9 months of initial therapy, I now recommend we stop dexamethasone unless we are having problems controlling the myeloma, such as progressive disease,” Rajkumar said. “I congratulate the authors on a study that will improve the quality of life for our patients.”
Improved Event-Free Survival
In this study, Larocca and colleagues investigated the efficacy and feasibility of a dose- and schedule-adjusted Rd regimen that was followed by maintenance Rd-R 10 mg/d and compared the regimen to continuous Rd in elderly, intermediate-fit patients who were newly diagnosed with multiple myeloma.
The primary endpoint was event-free survival, defined as progression/death from any cause, lenalidomide discontinuation, and any hematologic grade 4 or nonhematologic grade 3–4 adverse events.
The cohort consisted of 199 patients who were randomly assigned to receive either Rd-R (n = 101) or continuous Rd (n = 98). The median age was 75 years in the Rd-R arm and 76 years in the Rd arm; 52% of patients in the Rd-R group and 43% in the Rd group were classified as being intermediate-fit not for age but for geriatric impairments.
With a median follow-up of 37 months, event-free survival was 10.4 months in the Rd-R arm vs 6.9 months in the Rd arm (hazard ratio [HR], 0.70; P = .02). This benefit was maintained beyond nine cycles (median: 19.8 vs 10.6 months for Rd-R vs Rd; HR, 0.55; P = .03)
The median PFS was 20.2 months with Rd-R and 18.3 months with Rd (HR, 0.78; P = .16). The median overall survival was not reached. The 3-year overall survival was 74% with Rd-R and 63% with continuous Rd (HR, 0.62; P = .06). Among patients remaining on therapy after nine cycles, no difference in median PFS was observed between the two groups (24.3 vs 18.7 months; HR, 0.73; P = .19).
Best response was similar for both groups, with an overall response rate of 78% vs 68% (P = .15). The very good partial response rate was 51% in the Rd-R arm, vs 39% in the continuous Rd arm (P = .09).
Toxicities were similar between the two groups. Grade ≥3 hematologic adverse events were reported in 26% of Rd-R patients, vs 20% of Rd patients (P = .40). In both groups, the most frequent grade ≥3 hematologic toxicity was neutropenia (21% vs 18%). The most frequent grade ≥3 toxicities were nonhematologic. They occurred in 33% of Rd-R patients and 43% of Rd patients (P = .15). The most frequent nonhematologic toxicities were infections (10% vs 12%), constitutional (3% vs 12%), dermatologic (7% vs 3%), and central nervous toxicities (2% vs 6%).
The study was sponsored by Fondazione EMN Italy Onlus. Larocca has received honoraria from Amgen, Bristol-Myers Squibb, Celgene, Janssen, and GSK and has served on the advisory boards for Bristol-Myers Squibb, Celgene, Janssen, and Takeda. Several coauthors also have disclosed relationships with industry. Kumar has disclosed no relevant financial relationships.
Blood. Published online March 19, 2021. Abstract