Elotuzumab Misses Mark Again as Frontline Treatment for Multiple Myeloma

Elotuzumab (Empliciti) failed for a third time to improve progression-free survival (PFS) in newly diagnosed multiple myeloma when added to standard therapy, a large randomized trial showed.

After 4 years of follow-up, neither the median PFS nor the 3-year PFS differed significantly among four treatment groups who received lenalidomide (Revlimid) and bortezomib (Velcade) plus dexamethasone (RVd) with or without elotuzumab. The 3-year PFS ranged from 66% to 69% across the four groups. A preliminary analysis of 3-year overall survival (OS) also showed no significant differences between the groups.

Prespecified exploratory subgroup analyses did not identify any groups that benefited from the addition of elotuzumab, except for patients with elevated baseline serum lactate dehydrogenase, who had better PFS, reported Hartmut Goldschmidt, MD, of University Hospital Heidelberg in Germany, and co-authors in Lancet Haematology.

“[This trial] complements the existing evidence on the use of elotuzumab in patients with newly diagnosed multiple myeloma,” the authors wrote of the findings. “Addition of elotuzumab to RVd induction and consolidation, and lenalidomide maintenance did not improve survival outcomes in patients with newly diagnosed multiple myeloma who are eligible for an autologous HSCT [hematopoietic stem-cell transplant]. Long-term follow-up of the trial is ongoing.”

The results mirrored those of two previous trials of elotuzumab in newly diagnosed myeloma, ELOQUENT-1 and SWOG-1211. ELOQUENT-1 evaluated elotuzumab in patients who were not eligible for HSCT, and SWOG-1211 included high-risk patients who were or were not transplant eligible.

Collectively, the three trials represented a disappointment, given the favorable effect of elotuzumab in the relapsed/refractory setting, which led to FDA approval.

“With daratumumab (Darzalex) and isatuximab (Sarclisa) coming up front more often, there probably isn’t room up front for the use of elotuzumab, in terms of how it’s going to add or vary based on what we have,” Sagar Lonial, MD, of Emory University and Winship Cancer Institute in Atlanta, told MedPage Today. “I do think that as we use our CD38 antibodies up front, it does bring up the idea of how you can use it in later relapse. Certainly, I’ve had patients who progressed on daratumumab-based regimens that I’ve salvaged with an elotuzumab-IMiD [immunomodulator] combination that had pretty reasonable long-term results.”

Elotuzumab is a monoclonal antibody targeting SLAMF7, a glycoprotein that is expressed by myeloma cells but not healthy cells. The antibody has multiple mechanisms of action, including activation of natural killer cells, cell-mediated antibody-dependent cellular cytotoxicity, and macrophage-mediated antibody-dependent cellular phagocytosis, Goldschmidt and co-authors noted.

In two phase III randomized trials in relapsed/refractory myeloma, ELOQUENT-2 and ELOQUENT-3, the addition of elotuzumab to lenalidomide and dexamethasone or pomalidomide (Pomalyst) and dexamethasone significantly reduced the risk of disease progression or death. The promising results provided impetus for evaluating elotuzumab as part of initial treatment for newly diagnosed myeloma.

Goldschmidt and colleagues reported findings from the German-speaking Myeloma Multicenter Group (GMMG)-HD6 trial. Investigators at 69 sites throughout Germany randomized 564 patients with newly diagnosed multiple myeloma to four treatment regimens (induction, HSCT, and consolidation/maintenance):

• RVd/R
• RVd/E-R
• E-RVd/R
• E-RVd/E-R

The primary analysis showed no difference (P=0.86) in median PFS among the four treatment groups: not reached with RVd/R, 60.8 months with RVd/E-R, 56.6 months with E-RVd/R, and not reached with E-RVd/E-R. The 3% maximum absolute difference in 3-year PFS (range 0-3%) also did not differ significantly in intergroup comparisons. A prespecified per-protocol analysis also showed no difference in median PFS (P=0.87).

The median OS was not reached in any treatment group. The 3-year OS was 89% with RVd/R and RVd/E-R, 93% with E-RVd/R, and 90% with E-RVd/E-R.

A preplanned multivariable analysis of PFS, using RVd/R as the reference, showed no significant difference for any of the other three regimens. The only significant prognostic factors were International Staging System stage III vs stage I (HR 2.04, 95% CI 1.36-3.07, P=0.0006) and high-risk cytogenetics (HR 1.63, 95% CI 1.19-2.25, P=0.0026).

Grade ≥3 treatment-emergent adverse events (TEAEs) occurred in 76-84% of each treatment group. Infection was the most common grade ≥3 TEAE, occurring in 23-34% of each group. Rates of serious AEs ranged from 36-48% of patients across the four groups.

“The reasons for the lack of benefit regarding outcomes from the addition of elotuzumab in combination with current treatment approaches such as RVd for newly diagnosed multiple myeloma remain elusive and are likely multifactorial,” the authors concluded. “These factors include differences in patient immune system and microenvironment at first diagnosis compared with the time of relapse, tumor burden, and disease biology.”