Final overall survival results of the phase 2 ELOQUENT-3 trial reveal benefit with elotuzumab plus pomalidomide, and dexamethasone in patients with relapsed/refractory multiple myeloma.
The combination of elotuzumab (Empliciti), pomalidomide (Pomalyst), and dexamethasone (EPd) demonstrated a statistically significant improvement in overall survival (OS) vs pomalidomide and dexamethasone (Pd) alone in patients with pretreated relapsed/refractory multiple myeloma.1
Results come from the final OS analysis of the phase 2 ELOQUENT-3 trial (NCT02654132), which evaluated patients with who were relapsed or refractory to prior lenalidomide (Revlimid) and a proteasome inhibitor (PI).
At a minimum follow-up of 9.1 months, the preliminary OS analysis of the ELOQUENT-3 trial revealed a trend toward improved OS with EPd vs Pd. During a subsequent unplanned interim analysis and at the minimum follow-up of 18.3 months, this benefit continued to be confirmed as the OS trend was in favor of EPd.
With a cutoff date of January 11, 2021, after a minimum follow-up of 45 months, the median OS was 29.8 months (95% CI, 22.9-45.7 months) with EPd vs 17.4 months (95% CI, 13.8-27.7 months) with Pd (HR, 0.59; 95% CI, 0.37-0.93; P =.0217), corresponding with a 41% reduction in the risk of death with EPd vs Pd. Although sample sizes were small, the OS benefit with EPd was seen across most patient subgroups.
EPd was approved in multiple regions including the United States, Japan, Switzerland, and the European Union, for adult patients with relapsed/refractory multiple myeloma who have received at least 2 prior therapies, including lenalidomide- and PI-based regimens.
“The primary analysis of ELOQUENT-3 showed EPd significantly improved PFS compared with Pd [HR, 0.54 [95% CI, 0.34 to 0.86]; two-sided stratified log-rank P = .008]. Additionally, grade 3 or 4 adverse events [AEs], serious AEs [SAEs], and AEs leading to discontinuation were less frequent with EPd than Pd,” wrote lead study author Meletios-Athanasios Dimopoulos, MD, professor, and chairman of the Department of Clinical Therapeutics at the National and Kapodistrian University of Athens School of Medicine in Athens, Greece, and colleagues, in a published report from ELOQUENT-3published in the Journal of Clinical Oncology.
The controlled, multicenter, open-label, phase 2 ELOQUENT-3 trial evaluated patients with relapsed/refractory multiple myeloma who had received at least 2 prior lines of therapy to determine if adding elotuzumab to pomalidomide and dexamethasone at a low dose is more effective in treating patients than pomalidomide and low-dose dexamethasone alone.2
Enrollment was open to patients aged 18 years and older who were disease refractory to their last therapy, which was defined as progressing while receiving treatment or within 60 days after treatment discontinuation, and those who were relapsed/refractory to lenalidomide and a PI, which was defined as progressing within 6 months after treatment discontinuation after achieving at least a partial response.1 Eligibility in the trial was also open to patients who had measurable disease at screening, 2 or more prior lines of therapy, and an ECOG performance status 0-2.
The primary end point of the trial was progression-free survival with secondary end points including overall response rate and OS.
A total of 117 patients were randomly assigned in a 1:1 ratio to receive EPd (n = 60) or Pd (n = 57) with random assignments stratified based on the number of prior lines of therapy (2 or 3 vs 4 or more) and International Staging System disease stage at enrollment (1, 2, or 3). Of those enrolled, 60 patients in the EPd group were treated along with 55 in the Pd group.
Patients were administered treatment in 28-day cycles until disease progression, unacceptable toxicity, or withdrawal of patient consent. Those enrolled in the EPd group received elotuzumab at 10 mg/kg intravenously (IV) on days 1, 8, 15, and 22 during cycles 1 and 2, and at 20 mg/kg once daily on day 1 of every subsequent cycle. In the EPd group, patients also received oral dexamethasone at a dose of 40 mg once a week, except on days they were receiving elotuzumab, where they received both oral and IV dexamethasone, at 28 mg (or 8 mg in patients older than 75 years) and 8 mg, respectively. In the Pd group, patients were administered oral dexamethasone at 40 mg once a week.
In both groups, patients who were older than 75 years received 20 mg of dexamethasone and patients in both groups received 4 mg of pomalidomide once a day on days 1 through 21 of each treatment cycle.
Regarding baseline demographics and disease characteristics, each was balanced between the 2 groups with the median ages at 68.5 years and 66.0 years in the EPd and Pd arms. In both groups, the median number of prior lines of therapy was 3. A total of 68.3% of patients in the EPd group and 71.9% in the Pd group were refractory to lenalidomide and a PI. Additionally, patients given EPd received a median of 9.0 (range, 1-53) treatment cycles while patients given Pd received a median of 5.0 (range, 1-50) treatment cycles.
Findings showed that the Kaplan-Meier curves for OS each of the 2 groups demonstrated early and sustained separation. This resulted in a statistically significant difference in OS between EPd and Pd (2-sided stratified log-rank P = .0217).
The OS rate at year 1 was 79% with EPd vs 68% with Pd. Then at 2 years, the OS rate was 63% for the EPd arm vs 44% for the Pd arm, and at 3 years, the OS rate was 39% with EPd vs 29% with Pd.
In the EPd group, the majority of patients (80.0%) achieved at least a 90% relative dose intensity of elotuzumab. Further, 51.7% of the EPd group and 49.1% of the Pd group achieved a relative dose intensity of at least 90% with pomalidomide. Then, patients aged 75 years and younger (n = 93), 40.8% of the EPd group and 45.5% of the Pd group achieved a dexamethasone relative dose intensity of at least 90%. For patients over the age of 75 (n = 22), 63.6% of those given EPd and 54.5% of those given Pd achieved a dexamethasone relative dose intensity of at least 90%.
In the subgroup analysis of OS, which included patients associated with poor outcomes, a trend toward improved OS was seen with EPd vs Pd in patients who were at least 75 years of age. The median OS was 34.4 vs 14.7 months, respectively (HR, 0.36; 95% CI, 0.13-1.01).
Among patients who had refractory disease to both lenalidomide and a PI, the median OS was 28.3 vs 17.4 months, respectively (HR, 0.74; 95% CI, 0.44-1.25. For those who received at least 4 prior lines of therapy, the median OS was 29.8 vs 16.0 months, respectively (HR, 0.42; 95% CI, 0.20-0.89). In the subgroup of patients who had received lenalidomide as their most recent previous line of therapy, the median OS was 32.0-20.8 months, respectively (HR, 0.55; 95% CI, 0.29-1.04). EPd was also associated with improved survival trends.
There was no OS benefit seen with EPd vs Pd in patients who received prior stem-cell transplant. However, investigators note that this observation could be cofounded by favorable risk characteristics of patients in this subgroup who received Pd as a higher proportion of the Pd group (81.8%) had normal baseline lactate dehydrogenase levels compared with the EPd group (61.3%). When this was adjusted using multivariate analysis, an improvement in OS was confirmed with EPd vs Pd in this patient population consisting of those who had underwent a prior stem cell transplant.
In both groups, the types and frequencies of subsequent therapies were similar with the most common being daratumumab (Darzalex; 43.3% in the EPd group and 43.9% in the Pd group), carfilzomib (Kyprolis; 30.0% in the EPd group and 28.1% in the Pd group), and cyclophosphamide (25.0% in the EPd group and 24.6% in the Pd group). Additionally, the OS benefit derived with EPd vs Pd continued to be numerically consistent with the overall study population among the patients who received subsequent daratumumab (median, 33.6 vs 26.5 months; HR, 0.76; 95% CI, 0.39-1.48).
Regarding safety, the safety profile of EPd was consistent with prior data, and no new safety signals were reported. The most common AEs of any grade included anemia (EPd, 28.3%; Pd, 38.2%) and neutropenia (EPd, 26.7%; Pd, 30.9%), and the most common grade 3 or 4 AEs consisted of neutropenia (EPd, 15.0%; Pd, 27.3%) and anemia (EPd, 11.7%; Pd, 21.8%).
SAEs of any grade were found in 70.0% of patients in the EPd group and 60.0% of those in the Pd group. The most common SAEs were respiratory tract infection (EPd, 8.3%; Pd, 5.5%) and pneumonia (EPd, 6.7%; Pd, 9.1%). Further, infections occurred in 70.0% of patients treated with EPd and 65.5% of patients treated with Pd, with 25.0% in the EPd group and 21.8% in the Pd group being grade 3/4.
For any-grade treatment-related AEs, the most common included neutropenia (EPd, 20%; Pd, 21.8%) and hyperglycemia (EPd, 20%; Pd, 12.7%). In the EPd group, second primary malignancies were seen in 6.7% (n = 4) with prostate cancer occurring in 2 patients, pancreatic adenocarcinoma occurring in 1 patient, and basal cell carcinoma occurring in 1 patient. In the Pd group, second primary malignancies were seen in 3.6% (n = 2) with cholangiocarcinoma and invasive breast carcinoma occurring in 1 patient each. Then in the EPd group, 2 patients experienced infusion-related reactions during the first treatment cycle, 1 of which was a grade-1 reaction and 1 which was a grade-2 reaction.
Overall, AEs led to treatment discontinuation in 18.3% of patients in the EPd group and 23.6% of those in the Pd group. Grade 3/4 AEs led to discontinuation of treatment in 11.7% and 10.9%, respectively with infections leading to treatment discontinuation in 5 patients (8.3%) in the EPd group and 1 patient (1.8%) in the Pd group.
Treatment was discontinued in 96.7% (n = 58) of patients in the EPd group and 98.2% (n = 54) of patients in the Pd group. The most common reason for discontinuation of treatment was due to disease progression, which was observed in 70.0% (n = 42) of the EPd group and 70.9% (n = 39) of the Pd group.
Of the treated patients, 37 (61.7%) deaths occurred in the EPd group and 41 (74.5%) in the Pd group with 41.7% in the EPd group and 49.1% in the Pd group as a result of disease progression. No treatment-related deaths were observed in this study.
“In this final analysis of OS from ELOQUENT-3 (minimum follow-up of 45 months), OS was significantly improved with EPd versus Pd in patients with RRMM who received at least two prior therapies including lenalidomide and a PI. The median OS was prolonged by over 12 months, and the risk of death was reduced by 41% with EPd vs Pd. Additionally, the safety profile of EPd was consistent with previous reports, and no new safety signals were detected,” concluded the study authors.