Elotuzumab Plus Pomalidomide and Dexamethasone Displays Sustained OS Benefit in Relapsed/Refractory Multiple Myeloma

Meletios-Athanasios Dimopoulos, MD

Elotuzumab (Empliciti) plus pomalidomide (Pomalyst) and dexamethasone (EPd) demonstrated a significant improvement in overall survival (OS) compared with pomalidomide and dexamethasone (Pd) alone in patients with relapsed/refractory multiple myeloma who previously received treatment with lenalidomide (Revlimid) and a proteasome inhibitor (PI), according to final OS results from the phase 2 ELOQUENT-3 trial (NCT02654132).

At a minimum follow-up of 9.1 months, the preliminary OS analysis showed a trend toward OS improvement with EPd vs Pd. An interim analysis at a minimum follow-up of 18.3 months continued to confirm this benefit.

In the final analysis conducted at the January 11, 2021, data cutoff, a minimum follow-up of 45 months, the median OS was 29.8 months (range, 22.9-45.7 months) with EPd vs 17.4 months (range, 13.8-27.7 months) with Pd (HR, 0.59; 95% CI, 0.37-0.93; P = .0217). These data corresponded with a 41% reduction in the risk of death with EPd vs Pd. This OS benefit with EPd was seen across most patient subgroups, although sample sizes were small.

“EPd demonstrated a statistically significant improvement in OS vs Pd in patients with relapsed/refractory multiple myeloma previously treated with lenalidomide and a PI who had disease refractory to last therapy. In this setting, ELOQUENT-3 is the first randomized study of a triplet regimen incorporating a monoclonal antibody and Pd to improve both [progression-free survival] PFS and OS significantly,” 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 wrote in a discussion of the data published in the Journal of Clinical Oncology.

EPd displayed improved PFS compared with Pd in this population (HR, 0.54; 95% CI, 0.34-0.86; 2-sided stratified log-rank P = .008). Regarding safety, grade 3 or 4 adverse effects (AEs), serious AEs, and AEs leading to treatment discontinuation were less frequent with EPd than with Pd.

Based on these results, EPd was approved in regions such as 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 a PI.

ELOQUENT-3 is a controlled, multicenter, open-label trial. Eligible patients included those with relapsed/refractory multiple myeloma who had received at least 2 prior lines of therapy; those who were disease refractory to their last therapy (defined as progressing while receiving treatment or within 60 days after treatment discontinuation); or those who relapsed or were refractory to lenalidomide and a PI (defined as progressing within 6 months after treatment discontinuation after achieving at least a partial response). Patients were excluded if they had active plasma cell leukemia, a creatine clearance of less than 45 mL/min, or prior treatment with pomalidomide.

From March 2016 to April 2017, 117 patients were randomly assigned to EPd (n = 60) or Pd (n = 57). Random assignments were 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). In total, 60 patients in the EPd group and 55 in the Pd group were treated.

Baseline demographics and disease characteristics were balanced between the 2 groups. The median ages were 68.5 years and 66.0 years in the EPd and Pd arms, respectively. In both groups, the median number of prior lines of therapy was 3. In total, 68.3% of patients in the EPd group and 71.9% of patients in the Pd group were refractory to lenalidomide and a PI.

Treatment was given in 28-day cycles until disease progression, unacceptable toxicity, or withdrawal of patient consent. Patients in the EPd group received elotuzumab at a dose of 10 mg/kg intravenously (IV) on days 1, 8, 15, and 22 during cycles 1 and 2, and at a dose of 20 mg/kg once daily on day 1 of every subsequent cycle. Patients in the EPd group also received oral dexamethasone at 40 mg once a week, except on days of elotuzumab administration, where they received both oral and IV dexamethasone, at 28 mg (or 8 mg in patients older than 75 years) and 8 mg, respectively. Patients in the Pd group received oral dexamethasone at 40 mg once weekly.

Patients in both groups who were older than 75 years instead received 20 mg of dexamethasone. Patients in both groups received 4 mg of pomalidomide once daily on days 1 through 21 of each treatment cycle.

Patients in the EPd group received a median of 9.0 (range, 1-53) treatment cycles, and patients in the Pd group received a median of 5.0 (range, 1-50) treatment cycles.

The primary end point of this trial was investigator-assessed PFS per International Myeloma Working Group consensus criteria. Secondary end points were overall response rate (ORR) and OS. End points were tested hierarchically in the sequence: PFS, ORR, OS.

Kaplan-Meier curves for OS in the 2 groups demonstrated early and sustained separation, showing a statistically significant difference in OS between EPd and Pd (2-sided stratified log-rank P = .0217). At 1 year, the OS rate was 79% with EPd vs 68% with Pd; at 2 years, the OS rate was 63% with EPd vs 44% with Pd; and at 3 years, the OS rate was 39% with EPd vs 29% with Pd.

A total of 80.0% of patients in the EPd group achieved at least a 90% relative dose intensity of elotuzumab. A total of 51.7% of the EPd group and 49.1% of the Pd group achieved a relative dose intensity of at least 90% with pomalidomide.

In patients 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%. In patients over the age of 75 (n = 22), 63.6% of the EPd group and 54.5% of the Pd group achieved a dexamethasone relative dose intensity of at least 90%.

Regarding subgroups typically associated with poor outcomes, investigators observed a trend improved OS with EPd vs Pd in patients who were at least 75 years of age (median, 34.4 vs 14.7 months; HR, 0.36; 95% CI, 0.13-1.01). EPd was also associated with improved survival trends in patients who had refractory disease to both lenalidomide and a PI (median, 28.3 vs 17.4 months; HR, 0.74; 95% CI, 0.44-1.25), received at least 4 prior lines of therapy (median, 29.8 vs 16.0 months; HR, 0.42; 95% CI, 0.20-0.89), and who had received lenalidomide as their most recent prior line of therapy (median, 32.0-20.8 months; HR, 0.55; 95% CI, 0.29-1.04).

Investigators did not see an OS benefit with EPd vs Pd for patients who received prior stem-cell transplant, although this observation may have been confounded by favorable risk characteristics of patients in this subgroup who received Pd. A higher proportion of the Pd group (81.8%) displayed normal baseline lactate dehydrogenase levels than the EPd group (61.3%). An EPd OS benefit among patients who had received prior stem-cell transplant was confirmed when these data were adjusted using multivariate analysis.

Both groups received similar types and frequencies of subsequent therapies, 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). The OS benefit with EPd vs Pd remained 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).

The safety profile of EPd was consistent with prior data, and investigators recorded no new safety signals. The most common any-grade AEs were anemia (EPd, 28.3%; Pd, 38.2%) and neutropenia (EPd, 26.7%; Pd, 30.9%). The most common grade 3/4 AEs were neutropenia (EPd, 15.0%; Pd, 27.3%) and anemia (EPd, 11.7%; Pd, 21.8%).

Any-grade serious AEs were seen in 70.0% of the EPd group and 60.0% of the Pd group, the most common being respiratory tract infection (EPd, 8.3%; Pd, 5.5%) and pneumonia (EPd, 6.7%; Pd, 9.1%). A total of 70.0% and 65.5% of patients treated with EPd and Pd, respectively, experienced infections, with 25.0% in the EPd group and 21.8% in the Pd group being grade 3/4.

The most common any-grade treatment-related AEs were neutropenia (EPd, 20%; Pd, 21.8%) and hyperglycemia (EPd, 20%; Pd, 12.7%). Second primary malignancies were seen in 6.7% (n = 4) of the EPd group, with prostate cancer occurring in 2 patients, pancreatic adenocarcinoma occurring in 1 patient, and basal cell carcinoma occurring in 1 patient.

Second primary malignancies were seen in 3.6% (n = 2) of the Pd group, with cholangiocarcinoma and invasive breast carcinoma occurring in 1 patient each. In the EPd group, 2 patients experienced infusion-related reactions during the first treatment cycle: 1 grade-1 reaction and 1 grade-2 reaction.

In total, 18.3% of the EPd group and 23.6% of the Pd group experienced AEs leading to treatment discontinuation. Grade 3/4 AEs leading to treatment discontinuation were seen in 11.7% of the EPd group and 10.9% of the Pd group. Infections leading to treatment discontinuation were observed in 8.3% (n = 5) of the EPd group and 1.8% (n = 1) of the Pd group.

A total of 96.7% (n = 58) of patients in the EPd group and 98.2% (n = 54) of patients in the Pd group discontinued treatment. The most common reason for discontinuation was disease progression, which was observed in 70.0% (n = 42) of the EPd group and 70.9% (n = 39) of the Pd group.

Among treated patients, there were 37 (61.7%) deaths in the EPd group and 41 (74.5%) in the Pd group. Of these deaths, 41.7% in the EPd group and 49.1% in the Pd group were because of disease progression. No treatment-related deaths were observed in this study.

“Overall, the findings in ELOQUENT-3 complemented the final OS results from ELOQUENT-2 [NCT01239797], which showed that [elotuzumab plus lenalidomide/dexamethasone] significantly improved OS compared with [lenalidomide/dexamethasone] in patients with 1 to 3 prior lines of therapy,” the study authors concluded.

Reference

Dimopoulos MA, Dytfeld D, Grosicki S, et al. Elotuzumab plus pomalidomide and dexamethasone for relapsed/refractory multiple myeloma: final overall survival analysis from the randomized phase II ELOQUENT-3 trial. J Clin Oncol. Published online August 12, 2022. doi:10.1200/JCO.21.02815