Lenalidomide and Dexamethasone for Older Patients With Multiple Myeloma: Less Is More

According to a study published in Blood, older patients with multiple myeloma (MM) who are taking continuous lenalidomide-dexamethasone (Rd) may be able to switch to reduced-dose lenalidomide maintenance without dexamethasone (Rd-R). Researchers, led by Alessandra Larocca, MD, PhD, of the University of Turin in Italy, noted that, among the intermediate-fit patients enrolled in this study, the Rd-R approach also was associated with similar responses and longer event-free survival (EFS).

“This type of dexamethasone-sparing strategy, combined with lenalidomide at a reduced post-induction maintenance dose, could be an adapted scheme to be evaluated in combination with new agents such as monoclonal antibodies in this subgroup of intermediate-fit patients,” Dr. Larocca told ASH Clinical News.

The multicenter Italian study enrolled 199 patients between the ages of 65 and 80 years with measurable and symptomatic MM who were considered ineligible for autologous hematopoietic cell transplantation. Patients were considered “intermediate-fit” if they were ages 76 to 80, or younger but with comorbidities or impairment in functional abilities as outlined by International Myeloma Working Group frailty score criteria.

Patients were randomized to receive either:

continuous Rd (n=98)
Rd-R (n=101)

In the continuous Rd arm, treatment consisted of 28-day induction cycles of lenalidomide 25 mg/day on days one through 21 plus dexamethasone 20 mg on days one, eight, 15, and 22, until disease progression or intolerance. In the Rd-R arm, patients received a total of nine 28-day induction cycles, followed by lenalidomide maintenance 10 mg/day for up to 21 days until either disease progression or intolerance. During lenalidomide therapy, patients were required to take antithrombotic prophylaxis.

The primary endpoint of the trial was EFS, with events defined as progression/death for any cause, lenalidomide discontinuation, or any hematologic grade 4 or nonhematologic grades 3 to 4 adverse events (AEs).

Secondary endpoints of the study included progression-free survival (PFS), overall survival (OS), response rate, and the incidence of dose reductions.

In the study group, the median age was 75 years in patients allocated to Rd-R and 76 years in patients randomized to Rd. A higher proportion of patients in the Rd-R arm was defined as intermediate-fit based on geriatric impairments rather than age (52% vs. 43%). After a median follow-up period of 37 months, the authors reported that median EFS was significantly longer in the Rd-R arm (10.4 vs. 6.9 months; hazard ratio [HR] = 0.70; p=0.02).

In terms of secondary endpoints, no significant difference in overall response (defined as a very good partial response or better) between treatment with Rd-R or continuous Rd (78% vs. 68%, respectively; p=0.15) was found. However, the three-year rate of OS was significantly greater in the Rd-R group (74% vs. 63%; HR=0.62; p=0.06).

The median PFS appeared to be extended in the Rd-R group (20.2 months vs. 18.3 months; HR=0.78; p=0.16), but there was no difference in median PFS between the two treatment regimens when looking at a subgroup of patients who remained on therapy after nine cycles (24.3 vs. 18.7 months; HR=0.73; p=0.19).

Dr. Larocca and colleagues also observed a trend toward a PFS benefit favoring Rd-R in patients classified as “standard risk” (HR=0.62; 95% CI 0.39-1.00), but not in patients classified as “high risk” (HR=1.10; 95% CI 0.47-2.55).

Fewer patients in the Rd-R group required at least one dose reduction for lenalidomide (45% vs. 62%) and dexamethasone (17% vs. 31%).

The most frequent grade ≥3 AEs in this study were neutropenia (21% vs. 18%), infections (10% vs. 12%), and dermatologic disorders (7% vs. 3%). The authors noted that a lower proportion of patients in the Rd-R group discontinued lenalidomide (24% vs. 30%) and dexamethasone (14% vs. 35%) because of AEs.

The researchers concluded that these findings suggest an adapted Rd-R treatment schedule is feasible and safe in older, transplant-ineligible people with MM, but noted some potential limitations. Given that the study used EFS as its primary endpoint, it was underpowered to identify a statistically significant difference between the two therapeutic approaches in terms of PFS. The trial was also limited by its lack of stratification according to prognostic variables or other factors at the time of randomization.

“In the future, new treatments and combinations including dose reduction or eliminating steroid use could be further explored in intermediate-fit and frail myeloma patients,” Dr. Larocca added.

Study authors report no relevant conflicts of interest.

Reference

Larocca A, Bonello F, Gaidano G, et al. Dose/schedule-adjusted Rd-R vs continuous Rd for elderly, intermediate-fit, newly diagnosed multiple myeloma patients. [published online ahead of print, 2021 Mar 19]. Blood. doi: 10.1182/blood.2020009507.