Meletios A. Dimopoulos, MD

AS REPORTED in The New England Journal of Medicine by Meletios A. Dimopoulos, MD, of the National and Kapodistrian University of Athens, and colleagues, the phase II ELOQUENT-3 trial has shown that the addition of elotuzumab to pomalidomide and dexamethasone significantly prolonged progression-free survival in patients with refractory or relapsed and refractory multiple myeloma who previously received treatment with lenalidomide and a proteasome inhibitor.¹ The trial supported the approval of elotuzumab in combination with pomalidomide/dexamethasone in this setting.

Study Details

IN THE OPEN-LABEL trial, 117 patients from 43 sites in Europe, North America, Japan, and Australia were randomly assigned between March 2016 and April 2017 to receive elotuzumab, pomalidomide, and dexamethasone (n = 60) or pomalidomide and dexamethasone (n = 57). Treatment was given in 28-day cycles until disease progression, unacceptable toxicity, or withdrawal of consent.

Elotuzumab was given intravenously at 10 mg/kg on days 1, 8, 15, and 22 during cycles 1 and 2 and 20 mg/kg on day 1 of each cycle thereafter. All patients received oral pomalidomide at 4 mg/d on days 1 through 21 of each cycle. Patients received oral dexamethasone at 40 mg (patients aged ≤ 75 years) or 20 mg (patients aged > 75 years) per week, except on the days of elotuzumab administration, when patients in the elotuzumab group received dexamethasone both orally (28 mg in patients aged ≤ 75 years or 8 mg in patients aged > 75 years) and intravenously (8 mg).

Randomization was stratified by the number of previous lines of therapy and International Staging System disease stage at enrollment. The primary endpoint was investigator-assessed progression-free survival. For the elotuzumab vs control groups, the median age was 69 vs 66 years (63% vs 61% ≥ 65 years, 22% vs 21% ≥ 75 years); 53% vs 61% were male; 88% of both groups had stage I or II disease; 60% vs 63% had 2 or 3 prior lines of therapy and 40% vs 37% had ≥ 4; 90% vs 84% were refractory to lenalidomide and 8% vs 12% had relapse and were refractory to lenalidomide; 78% vs 82% were refractory to a proteasome inhibitor and 22% vs 14% had relapse and were refractory to a proteasome inhibitor; and 68% vs 72% were refractory to both lenalidomide and a proteasome inhibitor.

Progression-Free Survival

THE MINIMUM follow-up at database lock in February 2018 was 9.1 months. The median progression-free survival was 10.3 months in the elotuzumab group vs 4.7 months in the control group (hazard ratio [HR] = 0.54, P = .008). The benefit of elotuzumab was consistent across patient subgroups, including among patients with 2 to 3 prior lines of therapy (HR = 0.55, 95% confidence interval [CI] = 0.31–0.98), those with ≥ 4 prior lines of therapy (HR = 0.51, 95% CI = 0.24–1.08), those with disease stage I or II (HR = 0.54, 95% CI = 0.33–0.90), those with stage III disease (HR = 0.52, 95% CI =0.16–1.69), and those with disease refractory to both lenalidomide and a proteasome inhibitor (HR = 0.56, 95% CI = 0.33–0.97). On independent review committee assessment, the median progression-free survival was 10.3 months vs 4.7 months (HR = 0.51, 95% CI = 0.32–0.82).

The overall response rate on investigator assessment was 53% in the elotuzumab group vs 26% in the control group (odds ratio [OR] = 3.25, 95% CI = 1.49–7.11), with 20% vs 9% of patients having a very good partial response or better. The median time to response was 2.0 vs 1.9 months. The median duration of response was not reached vs 8.3 months. The overall response rate on independent review committee assessment was 58% vs 25% (OR = 4.62, 95% CI = 2.05–10.43).

Overall survival data were immature at the time of the analysis. At the time of the analysis, 22% of the elotuzumab group vs 32% of the control group had died (HR = 0.62, 95% CI = 0.30–1.28).

Adverse Events

“The risk of progression or death was significantly lower among those who received elotuzumab plus pomalidomide and dexamethasone than among those who received pomalidomide plus dexamethasone alone.”

— Meletios A. Dimopoulos, MD, and colleagues

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GRADE 3 or 4 adverse events were reported in 57% of the elotuzumab group vs 60% of the control group, with the most common in the elotuzumab group being neutropenia (13% vs 27%), anemia (10% vs 20%), hyperglycemia (8% vs 7%), thrombocytopenia (8% vs 5%), and lymphopenia (8% vs 2%). Infections of any grade were reported in 65% of both groups, with grade 3 or 4 infections occurring in 13% vs 22%. Serious adverse events occurred in 53% vs 55% of patients. Adverse events led to discontinuation of treatment in 18% vs 24% of patients, with causes including infection in 7% vs 5%. Infusion reactions occurred in 5% of the elotuzumab group. No deaths in either group were considered to be drug-related.

The investigators concluded: “Among patients with multiple myeloma in whom treatment with lenalidomide and a proteasome inhibitor had failed, the risk of progression or death was significantly lower among those who received elotuzumab plus pomalidomide and dexamethasone than among those who received pomalidomide plus dexamethasone alone.” ■

DISCLOSURE: The study was funded by Bristol-Myers Squibb and AbbVie Biotherapeutics. For full disclosures of the study authors, visit www.nejm.org.

REFERENCE

1. Dimopoulos MA, Dytfeld D, Grosicki S, et al: Elotuzumab plus pomalidomide and dexamethasone for multiple myeloma. N Engl J Med 379:1811-1822, 2018.