Dimopoulos Highlights Benefit of Elotuzumab Triplet in Relapsed/Refractory Myeloma

Meletios A. Dimopoulos, MD

The 3-drug regimen of elotuzumab (Empliciti), pomalidomide (Pomalyst), and low-dose dexamethasone is a promising option for patients with relapsed/refractory myeloma who are resistant to a lenalidomide (Revlimid)-based combination, said Meletios A. Dimopoulos, MD.

Updated data from the phase II ELOQUENT-3 study presented at the 2019 European Hematology Association (EHA) Congress showed that treatment with the triplet regimen reduced the risk of death by 46% compared with pomalidomide and low-dose dexamethasone alone.

At a median follow-up ≥18.3 months, the median overall survival (OS) was not reached with the triplet (95% CI, 24.9—not estimable [NE]) compared with 17.4 months (95% CI, 13.8–NE) with pomalidomide and dexamethasone (HR, 0.54; 95% CI, 0.30-0.9). Moreover, the 18-month progression-free survival (PFS) rates were 34% in the triplet arm compared with 11% in those treated with the standard doublet. The 18-month OS rates were 68% and 49% in favor of the elotuzumab combination.

Notably, the triplet combination had a better tolerability profile compared with the doublet, said Dimopoulos, lead study author and professor and chairman of the Department of Clinical Therapeutics at Kapodistrian University of Athens School of Medicine in Athens, Greece.

“I should mention we were pleasantly surprised to see that this combination was associated with less frequent neutropenia and less infection than the combination of pomalidomide and low-dose dexamethasone in the context of the trial,” noted Dimopoulos. “We don't have a clear explanation why this occurred; however, it was very rewarding to see that this combination was very tolerable.”

Based on the initial ELOQUENT-3 findings, the FDA approved elotuzumab in November 2018 for use in combination with pomalidomide and low-dose dexamethasone for the treatment of patients with relapsed/refractory multiple myeloma following ≥2 prior therapies, including lenalidomide and a proteasome inhibitor

In an interview with OncLive, Dimopoulos discussed where this triplet combination fits into the treatment paradigm and shared unanswered questions that remain in the relapsed/refractory myeloma space.

OncLive: What was the rationale to explore this combination?

Dimopoulos: This is a prospective, randomized phase II trial which was powered to detect a potential difference between the standard of care for patients with relapsed/refractory myeloma, which consists of oral pomalidomide with low-dose dexamethasone, versus the same regimen with the addition of elotuzumab, an immunostimulatory monoclonal antibody targeting SLAMF-7. This trial was first reported and published in 2018, and it showed that there was a PFS advantage in favor of the triplet combination in approximately 110 patients with relapsed/refractory myeloma; they were refractory to lenalidomide or a proteasome inhibitor with 2 or more prior lines of therapy.

In [these updated data], which were presented at the 2019 EHA Congress, there was an OS analysis. The results showed an OS advantage in the patients [treated with the triplet].

Where do you see this combination fitting into the treatment paradigm?

This is an important question because many patients, especially in the United States, receive a combination of bortezomib (Velcade), lenalidomide, and dexamethasone in the frontline setting. This is true for elderly patients who are continuing therapy or younger patients who are receiving this regimen as part of their induction before high-dose therapy. Thus, there is an increasing number of patients who develop resistance to lenalidomide and who have also been exposed to bortezomib or have residual peripheral neuropathy, which may prevent further treatment with bortezomib. I believe that for this particular patient population, especially after 2 lines of therapy, this is a combination that may induce significant responses with a rewarding PFS. Now, we also have OS data showing a 46% in the risk of death with the combination of elotuzumab, pomalidomide, and low-dose dexamethasone.

Furthermore, as we know, there will be an increasing number of patients who will be getting an anti-CD38 monoclonal antibody such as daratumumab (Darzalex) or isatuximab either in the frontline setting or later in the course of the disease. Although the ELOQUENT-3 trial did not include many patients who have been pretreated with daratumumab, I believe this type of population may be suitable for treatment with a combination of an alternative monoclonal antibody.

What is the tolerability of this triplet regimen?

We had the usual adverse events (AEs) of pomalidomide and low-dose dexamethasone, mainly neutropenia, but at a lower rate. Therefore, I believe that this is a suitable combination even for older patients with myeloma. There was no evidence whatsoever suggesting that the addition of elotuzumab to pomalidomide and low-dose dexamethasone increased AEs.

What are the next steps with this combination?

There should be a formal study evaluating this combination in patients who are progressing on an anti-CD38 monoclonal antibody. Of course, this would be for patients not previously exposed to pomalidomide and low-dose dexamethasone. Another approach would be a daratumumab plus pomalidomide/dexamethasone combination—since we have the data from the OPTIMISMM study—with the addition of elotuzumab, making it a 4-drug regimen.

Will it be challenging to distinguish between all of the available combinations and treatment strategies in this space?

Definitely. The field is moving towards having VRd (bortezomib, lenalidomide, and dexamethasone) or KRd (carfilzomib [Kyprolis], lenalidomide, and dexamethasone) in the frontline setting, and more and more patients will be receiving an additional CD38-directed monoclonal antibody. Thus, we will need regimens that could address patients who fail on this type of combination.

Dimopoulos M, Dytfeld D, Grosicki S, et al. Elotuzumab plus pomalidomide and dexamethasone for relapsed/refractory multiple myeloma: efficacy results after additional follow-up of the phase 2, randomized ELOQUENT-3 study. Presented at: 2019 EHA Congress; June 13-16, 2019; Amsterdam, The Netherlands. Abstract PS1370. http://bit.ly/2WW6D84.