A triplet of elotuzumab, lenalidomide, and dexamethasone produced sustained improvements in both progression-free survival and overall survival in patients with relapsed/refractory multiple myeloma, according to a 3-year analysis of the phase III ELOQUENT-2 trial.
Paul G. Richardson, MD
A triplet of elotuzumab (Empliciti), lenalidomide (Revlimid), and dexamethasone produced sustained improvements in both progression-free survival (PFS) and overall survival (OS) in patients with relapsed/refractory multiple myeloma, according to a 3-year analysis of the phase III ELOQUENT-2 trial.
In updated data from the study, adding the SLAMF7 antibody elotuzumab dropped the risk of progression or death by 27% and OS was improved by 4.1 months versus lenalidomide and dexamethasone alone. Additionally, the minimal incremental toxicity observed with elotuzumab remained consistent.
“Elotuzumab, a novel first-in-class immunostimulatory monoclonal antibody, in combination with lenalidomide and dexamethasone demonstrated a durable and clinically relevant improvement in both progression-free survival and overall response rate,” senior investigator Paul G. Richardson, MD, from the Dana-Farber Cancer Institute, said during a presentation of the data at the 2015 ASH Annual Meeting. “I'm very please to see that this benefit was sustained. Very importantly, we see a delay in next therapy, which is very relevant.”
On November 30, the FDA approved elotuzumab in combination with lenalidomide and dexamethasone for patients with multiple myeloma following progression on 1 to 3 prior therapies. This decision was based on a 2-year analysis of the ELOQUENT-2 trial, which showed a 30% improvement in PFS with the addition of elotuzumab compared with lenalidomide/dexamethasone alone.
In the study, 646 patients at a median age of 66 years were randomized in a 1:1 ratio to elotuzumab plus lenalidomide and dexamethasone (n = 321) or lenalidomide and dexamethasone alone (n = 325). Patients had received a median of 2 prior therapies before entering the trial and 35% were refractory to their last therapy.
The dual primary endpoints of the study were PFS and objective response rate (ORR). Key secondary endpoints focused on OS and safety. Additionally, post-hoc analyses were conducted for pain assessment using the Brief Pain Inventory-Short Form (BPI-SF). A sustained improvement in pain was defined as a ≥3-point decline for ≥2 consecutive 28-day treatment cycles.
In the elotuzumab arm, the antibody was administered intravenously at 10 mg/kg once a week for the first 2 cycles followed by biweekly. Dexamethasone was administered intravenously at 8 mg prior to infusion of elotuzumab and orally at 28 mg. In the control arm and for weeks without elotuzumab, dexamethasone was administered orally at 40 mg. Lenalidomide was administered at 25 mg orally on days 1 to 21 of each cycle for both groups.
Median PFS with elotuzumab was 19.4 versus 14.9 months with lenalidomide and dexamethasone alone (HR, 0.73; 95% CI, 0.60-0.89;P= .0014). The 3-year PFS rate was 26% with elotuzumab versus 18% with the doublet alone, representing a relative improvement of 44% at 3 years.
The ORR with elotuzumab was 75% compared with 66% in the control arm. The complete response (CR) and very good complete response rate with elotuzumab was 34% versus 29% for lenalidomide and dexamethasone alone. The CR rate was 5% versus 9%, with and without elotuzumab, respectively.
The time to next treatment was 12 months longer with elotuzumab (33 vs 21 months). Overall, 38% fewer patients started subsequent therapy during the follow-up period with elotuzumab, representing a substantial clinical benefit for patients, according to Richardson.
The median OS at 3-years was 43.7 months compared with a median of 39.6 months with the doublet (HR, 0.77; 95% CI, 0.63-0.97P= .0257). At the 3-year interim analysis for OS, 47.3% of patients remained alive in the elotuzumab arm versus 41.2% in the control group. The OS advantage held up across subgroups, particularly for those with high-risk cytogenetics.
In the 2-year data that were the basis for the FDA approval, the ORR was 79% with elotuzumab versus 66% with lenalidomide/dexamethasone alone (P= .0002). Median PFS with elotuzumab was 19.4 versus 14.9 months with lenalidomide and dexamethasone alone (HR, 0.70; 95% CI, 0.57-0.85;P<.001). At this point, OS data were not yet mature.
In patients who experienced a response, there was a sustained improvement in BPI-SF scores that favored the elotuzumab arm. An improvement in patient-reported pain was experienced by 74 patients treated with elotuzumab and for 56 patients in the lenalidomide/dexamethasone arm.
At the analysis, 26% of patients continued to receive elotuzumab versus 14% in the control arm. Treatment discontinuation was primary due to progression in both arms. The most frequently reported grade 3/4 adverse events (AEs) with and without elotuzumab, respectively, were anemia (15% vs 16%) and neutropenia (15% vs 16%).
The most common all-grade non-hematologic AEs with and without elotuzumab, respectively, were fatigue (48% vs 40%), diarrhea (48% vs 37%), pyrexia (38% vs 28%), constipation (36% vs 28%), cough (33% vs 19%), and muscle spasms (30% vs 27%).
Infections of any grade were seen in 83% of patients in the elotuzumab arm compared with 75% with lenalidomide and dexamethasone alone. Once adjusting for treatment exposure, the rates were similar between the two arms. Infusion reactions, which were mostly grade 1/2, occurred in 10% of patients in the elotuzumab arm.
"Updated safety and tolerability data are consistent with previous findings, confirming that there is minimal incremental toxicity associated with the addition of elotuzumab to lenalidomide/dexamethasone," said Richardson.
A number of clinical trials continue to assess elotuzumab for patients with multiple myeloma. The ELOQUENT-1 trial is looking at elotuzumab in combination with lenalidomide and dexamethasone in newly diagnosed patients. Additionally, in the relapsed/refractory setting, elotuzumab is being assessed in combination with pomalidomide and dexamethasone and with the PD-1 inhibitor nivolumab.
"There's some very exciting trials going forward combining elotuzumab with other immuno-oncology agents, such as nivolumab, in the future," concluded Richardson.