ELOQUENT-2: A PHASE 3, RANDOMIZED, OPEN-LABEL STUDY OF LENALIDOMIDE/DEXAMETHASONE WITH OR WITHOUT ELOTUZUMAB IN PATIENTS WITH RELAPSED/REFRACTORY MULTIPLE MYELOMA

Background
Elotuzumab, an immunotherapeutic monoclonal antibody (mAb), recognizes Signaling Lymphocytic Activation Molecule F7 (SLAMF7), a protein highly expressed on myeloma cells and natural killer cells. Elotuzumab targets and kills SLAMF7-expressing myeloma cells by direct activation of natural killer cells with minimal effect on normal tissues. Elotuzumab showed encouraging activity with lenalidomide/dexamethasone (Ld) in a Phase 1b/2 study in patients with relapsed/refractory multiple myeloma (RRMM).

Aims
ELOQUENT-2, a Phase 3 study (NCT01239797) compared efficacy and safety of elotuzumab plus lenalidomide/dexamethasone (ELd) vs Ld.

Methods
Patients with RRMM and 1–3 prior therapies were randomized 1:1 to ELd or Ld in 28-day cycles until disease progression or unacceptable toxicity: elotuzumab (10 mg/kg IV) was given weekly during Cycles 1 and 2 and then biweekly; lenalidomide (25 mg) was given on Days 1–21; dexamethasone was given weekly (40 mg or 28 mg PO + 8 mg IV on elotuzumab dosing weeks). Written informed consent was obtained for all patients. Response/progression was assessed by an independent review committee using European Group for Blood and Bone Marrow Transplant criteria. Primary endpoints were progression-free survival (PFS) and overall response rate (ORR). Results of a prespecified interim analysis are reported.

Results
646 RRMM patients were randomized (321 to ELd, 325 to Ld; median age 66 years [20% of patients ≥75 years old]; refractory to last therapy 35%). Median number of prior therapies was 2, including bortezomib 70%, thalidomide 48% and lenalidomide 6%. High-risk patients were included: del(17p) in 32%; t(4;14) in 9%. At the data cut-off (4 Nov 2014), 35% (ELd arm) and 21% (Ld arm) of patients remained on therapy; discontinuation was mainly due to disease progression (42% in the ELd arm, 47% in the Ld arm). Median number of cycles was 19 and 14 in the ELd and Ld arms, respectively. After a median follow-up of 24 months, PFS rate was superior in the ELd over the Ld arm: 68% vs 57% at 1 year and 41% vs 27% at 2 years. Hazard ratio for PFS was 0.70 (95% CI 0.57, 0.85; p=0.0004). Median (95% CI) PFS in the ELd arm was 19.4 (16.6, 22.2) months vs 14.9 (12.1, 17.2) months in the Ld arm (Figure). PFS benefit with ELd was consistent across key subgroups. ORR (95% CI) was 79% (74, 83) in the ELd arm vs 66% (60, 71) in the Ld arm (p=0.0002). Very good partial response or better was seen in 32.7% and 28.0% of patients in the ELd and Ld arms, respectively; partial response was seen in 45.8% and 37.5%, respectively. Grade 3–4 adverse events in ≥15% of patients include neutropenia (25% in the ELd arm, 33% in the Ld arm) and anemia (15% in the ELd arm, 16% in the Ld arm). Infections (any grade) occurred in 81% of patients in the ELd arm and 74% in the Ld arm. Exposure-adjusted infection rates were the same in both arms (incidence rate/100 person-years of exposure, 197). Infusion reactions occurred in 10% of patients with ELd (mostly Grade 1–2). There were 210 deaths (94 in the ELd arm, 116 in the Ld arm).

Summary
This is the first positive randomized Phase 3 trial with an immunotherapeutic mAb, assessing Ld with or without elotuzumab in RRMM. It showed a 30% reduction in risk of progression or death with ELd vs Ld. More patients remain on ELd vs Ld, and follow-up for long-term outcomes is ongoing. Infusion reactions were manageable. Elotuzumab, a mAb with a novel mechanism of action, showed improved PFS at 1 year and 2 years, with minimal added toxicity in combination with Ld vs Ld alone in patients with multiple myeloma.

†Equal contribution: M Dimopoulos and S Lonial

Keyword(s): Monoclonal antibody, Multiple myeloma, Refractory, Relapse

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