Deep and rapid responses with a dexamethasone-sparing combination of daratumumab and lenalidomide in elderly patients with multiple myeloma

Long term use of dexamethasone is known to have a detrimental impact on treatment tolerability and quality of life in elderly, or frail multiple myeloma (MM) patients. In this respect, interim results of a randomized phase III study show that a dexamethasone-sparing regimen with daratumumab and lenalidomide is associated with a high rate of rapid and deep responses in a cohort of frail newly-diagnosed MM patients (NDMM). Further follow-up of this trial is necessary to see whether this response benefit also leads to a delayed disease progression.

Introduction

MM is in essence a disease of the elderly, with about two thirds of patients being over the age of 65 at diagnosis. While a higher age is often associate with a reduced performance status, there still is considerable heterogeneity in the fitness of elderly patients, resulting in a variable tolerance to treatment. Overall, however, it is clear that frail MM patients have a shorter survival, with higher rates of non-hematological adverse events (AEs) and treatment discontinuation. In this respect, particularly the long-term use of dexamethasone is associated with multiple side effects in elderly patients. To address this, researchers of the IFM group set up the phase III IFM2017-03 trial comparing a dexamethasone-sparing treatment regimen consisting of daratumumab and lenalidomide (DR) to a combination of lenalidomide and dexamethasone (Rd) in a population of frail, NDMM patients.

Study design

The study at hand enrolled a total of 295 patients with NDMM over the age of 65 with an ECOG proxy frailty score ≥2 and randomized them (1:2) to receive 28-day cycles of lenalidomide (25mg/day, 21/28) plus dexamethasone (20mg qw) (Rd) or daratumumab (1800mg SC qw for 8 weeks, q2w for 16 weeks and q4w thereafter) in combination with lenalidomide (25mg/day, 21/28) and just 2 cycles of dexamethasone (20mg qw for 8 weeks) (DR). Patients in the study were treated with these regimens until disease progression or unacceptable toxicity. The primary endpoint of the trial is progression-free survival (PFS). The statistical design of the trial included an interim analysis after 12 months of therapy at which point the following endpoints were assessed: overall response rate (ORR), the rate of very good partial response or better (≥VGPR), the rate of minimal residual disease (MRD) measured using next-generation sequencing at a level of 10^-5, and the incidence of grade ≥3 AEs.

Results

After exclusion of two patients with an exclusion criteria violation, the intent to treat population of this trial was made up of 293 patients of whom 199 patients were treated with DR vs. 94 with Rd. The median age of patients in the trial was 81 years, with 84% and 61% of them being older than 75 or 80 years, respectively. Baseline demographics and disease characteristics were well balanced between arms.

The ORR was significantly higher with DR than with Rd at 96% and 85%, respectively (p= 0.001). The percentage of patients with a ≥VGPR as best response was 64% with DR, while this was only 43% with Rd. Interestingly, deeper responses were obtained with DR at all investigated timepoints. At 14 months, the rate of ≥VGPR was 41% with DR as compared to 26% with Rd. After 8 and 12 months, these rates were reported at 68% vs. 48% and 71% vs. 55%, respectively. Importantly, the treatment benefit with DR vs. Rd was consistent across all investigated subgroups, irrespective of age, ECOG performance status, IFM frailty score, Charlson index, ISS stage, cytogenetic profile and creatinine clearance. MRD was assessed for all patients with at least a VGPR at 12 months. From this analysis it became clear that the rate of MRD negativity at the 10^-5 was significantly higher with DR than with Rd at 10% and 3%, respectively (p= 0.012).

The incidence of grade ≥3 AEs was higher among patients treated with DR compared to Rd (82% vs. 68%, p= 0.010). However, this difference was mainly driven by a higher incidence of grade ≥3 hematological AEs which occurred in 55% and 26% of DR and Rd treated patients, respectively (neutropenia: 46% vs. 18%; anemia: 11% vs. 2%). In contrast, the rate of grade ≥3 infections was lower with DR than with Rd (13% vs. 18%). Importantly, the higher incidence of grade ≥3 AEs did not lead to a higher discontinuation rate (14% with DR vs. 16% with Rd). Interestingly, while the incidence of grade ≥3 serious AEs was similar between both groups in patients with an IFM frailty score of 2-3 (54% vs. 57%), far less serious AEs were seen with DR in patients with an IFM score of 4-5 (57% vs. 73%). In this respect, especially the higher rate of grade ≥3 pneumonia among IFM 4-5 patients treated with Rd is notable (5% with DR vs. 12% with Rd)

Conclusion

In this phase 3 trial dedicated to frail patients with NDMM, a dexamethasone-sparing regimen combining daratumumab and lenalidomide demonstrates deep and rapid responses and a favorable safety profile.

Reference

S. Manier, et al. A Dexamethasone Sparing-Regimen with Daratumumab and Lenalidomide in Frail Patients with Newly-Diagnosed Multiple Myeloma: Efficacy and Safety Analysis of the Phase 3 IFM2017-03 Trial. Presented at ASH 2022; Abstract 569.