ASCO 2015: Phase III Randomised Trial Shows Superiority of Lenalidomide/Dexamethasone With Elotuzumab for Relapsed/Refractory Multiple Myeloma

  • Date: 04 Jun 2015

ELOQUENT-2 study: Compared lenalidomide & dexamethasone with/without elotuzumab

Results of an interim analysis of a phase III, randomised, open-label study of lenalidomide and dexamethasone with/without elotuzumab in patients with relapsed/refractory multiple myeloma showed a significantly relevant reduction in the risk of progression or death using the combination elotuzumab/lenalidomide/dexamethasone (ELd) versus lenalidomide/dexamethasone (Ld) alone. Elotuzumab is the first monoclonal antibody (mAb) demonstrating benefit in progression-free survival (PFS) in the context of a randomised phase III trial in this setting. The study results were presented in Chicago at the 2015 ASCO Annual Meeting and were simultaneously published in the New England Journal of Medicine by Dr Sagar Lonial and other ELOQUENT-2 investigators.

Elotuzumab, a novel immunostimulatory mAb with a dual mechanism of action elicited via natural killer cells, when given intravenously, targets Signaling Lymphocytic Activation Molecule F7 (SLAMF7), a glycoprotein highly expressed on myeloma and natural killer cells, but not on normal tissue cells; elotuzumab kills myeloma cells with minimal effect on normal tissue. Elotuzumab showed encouraging activity with Ld in an open-label phase Ib/II study in patients with relapsed/refractory multiple myeloma. Elotuzumab has FDA breakthrough therapy designation in multiple myeloma.

ELOQUENT-2 study

ELOQUENT-2 was a phase III trial in which 646 patients with 1-3 prior therapies for relapsed/refractory multiple myeloma were randomised 1:1 into two arms: ELd or Ld in 28-day cycles to disease progression/unacceptable toxicity level. 321 patients were included in the ELd arm, 325 patients in the Ld arm. All patients received premedication to mitigate infusion reactions prior to elotuzumab administration.

The primary endpoints were PFS and overall response rate (ORR). Response/progression was assessed by blinded independent review committee by response criteria of the European Group for Blood and Marrow Transplantation.

Of the 646 patients, of whom the median age was 66, 35% had refractory disease. The median range of prior therapies was two, including bortezomib in 70% of patients, thalidomide in 48%, and lenalidomide in 6%. Cytogenetic analysis showed that 32% of patients in each group had del(17p) deletion and 9% of patients in the ELd arm and 10% of patients in the Ld group had t(4;14) translocation.

At the data cut off, 35% (ELd) and 21% (Ld) of patients remained on therapy; discontinuation was mainly for disease progression (42% ELd, 47% Ld).

The median PFS for the ELd arm was 19.4 months, and for Ld 14.9 months (hazard ratio 0.70, p = 0.0004).

Patients treated with ELd regimen had a 30% reduction in the risk of disease progression or death. Estimated one year PFS was 68% ELd, 57% Ld; 2-year PFS: 41% ELd, 27% Ld. The benefit in PFS with ELd was consistent across key subgroups.

The ORR was 79% in the ELd arm, and 66% in the Ld arm (p = 0.0002). Patients achieving at least partial response showed improved PFS with ELd vs Ld alone.

In patients with del(17p) deletion, median PFS was 21,19 months in the ELd arm and 14,92 months in the Ld group. In patients with t(4;14) translocation, median PFS was 15,84 months in the ELd arm vs 5,55 months in the Ld arm.

Analysis of 2 years PFS rate according to age showed 42% in the ELd arm in patients who were at least 65 years old vs 25% in the Ld arm. In patients younger than 65 years, this rate was 40% in the ELd arm vs 30% in the Ld arm.

Common non-haematologic adverse events were fatigue, pyrexia, diarrhea, constipation, muscle spasm and cough. Grade 3 to 4 adverse events that occurred in 15% or above of patients (ELd vs Ld) were neutropenia (25%, 33%) and anaemia (15%, 16%). Exposure-adjusted infection rate was the same in both arms. There was no detriment to overall health-related quality of life with the addition of elotuzumab to Ld regimen.

Infusion reactions occurred in 10% of patients with ELd (mostly grade 1–2). No grade 4 or 5 infusion reactions were seen. Approximately 70% of infusion reactions occurred with the first dose. Elotuzumab infusion was interrupted in 5% of patients due to an infusion reaction. Median interruption duration was 25 minutes. Two patients discontinued the study due to an infusion reaction.

The overall survival data are not mature yet; there were 210 deaths (94 ELd, 116 Ld) at the time of analysis.

Dr Jeffrey Wolf, who discussed the study data in his talk entitled “Progress in the therapy of relapsed and refractory multiple myeloma – Contribution of big data”, said that factors in deciding the treatment in this setting are related to prior therapy and pace of relapse. Elotuzumab improves PFS when added to Ld and may result in a tail on the PFS curve, making it potentially also a good candidate for maintenance therapy. He questioned if elotuzumab's best use should actually be early in disease course, even in induction setting, given the need for an intact immune system.

Conclusions

A clinically-relevant 30% reduction in the risk of progression or death was seen with ELd vs Ld. In patients with relapsed/refractory multiple myeloma, ELd demonstrated a significant and clinically meaningful increase in PFS and ORR. Difference in PFS was greater at 2 years for ELd vs Ld. Benefit in PFS in elotuzumab group was consistent across key patient subgroups, including elderly and patients with high-risk disease. More patients remain on ELd vs Ld and follow-up for long-term outcomes, including survival, is ongoing.

Elotuzumab, a mAb with a novel immunotherapeutic mechanism of action, showed improved PFS, with minimal added toxicity in combination with Ld vs Ld alone, in patients with relapsed/refractory multiple myeloma.

The study sponsor was Bristol-Myers Squibb in collaboration with AbbVie.

 

References

Lonial S, Dimopoulos MA, Palumbo A, et al. Elotuzumab Therapy for Relapsed or Refractory Multiple Myeloma. NEJM 2015; Online first June 2. DOI: 10.1056/NEJMoa1505654.

Lonial S, Dimopoulos MA, Palumbo A, et al. ELOQUENT-2: A phase III, randomized, open-label study of lenalidomide (Len)/dexamethasone (dex) with/without elotuzumab (Elo) in patients (pts) with relapsed/refractory multiple myeloma (RRMM). J Clin Oncol 33, 2015 (suppl; abstr 8508)