Impact of Elotuzumab on Multiple Myeloma Patients

The addition of elotuzumab to pomalidomide and dexamethasone resulted in significantly improved risk for progression and death in patients with relapsed/refractory multiple myeloma who had failed on treatment with lenalidomide and a proteasome inhibitor, according to results of the ELOQUENT-3 trial published in The New England Journal of Medicine.

A prior trial, ELOQUENT-2, had shown that elotuzumab plus lenalidomide and dexamethasone reduced the risk for progression or death compared with lenalidomide and dexamethasone alone. Pomalidomide is already approved in combination with dexamethasone in patients with myeloma who have failed on two prior treatments.

In ELOQUENT-3 researchers led by Meletios A. Dimopoulous, MD, of the National and Kapodistrian University of Athens, Greece, thought that “the combination of elotuzumab and pomalidomide may have synergistic clinical effects in patients with multiple myeloma that relapsed after treatment with lenalidomide or are refractory to lenalidomide.”

To test that theory, the study enrolled 117 patients and randomly assigned them to elotuzumab plus pomalidomide and dexamethasone or to pomalidomide and dexamethasone alone (control).

After a minimum follow-up of 9.1 months, the median progression-free survival (PFS) was more than double in the elotuzumab group compared with the control group (10.3 vs 4.7 months). There was a 46% decreased risk for progression or death in the elotuzumab group compared with the control group (hazard ratio [HR], 0.54; 95% CI, 0.34–0.86; P = .008).

More than half of patients (53%) assigned to elotuzumab responded to treatment compared with 26% of patients in the control group (overall response [OR], 3.25; 95% CI, 1.49–7.11).

Grade III/IV neutropenia occurred in 27% of patients in the control group compared with 13% of patients in the elotuzumab group. Additional grade III/IV events were anemia (10% vs 20%), and hyperglycemia (8% vs 7%).

In 2017, the US Food and Drug Administration put a clinical hold on two trials of pembrolizumab plus an immunomodulatory agent in patients with relapsed or refractory myeloma (KEYNOTE 183 and KEYNOTE 185) because of worse overall survival (OS) in the pembrolizumab arms. Both trials looked at pembrolizumab at the same dose and schedule, making it unclear whether similar OS results would be seen with other PD-1 or PD-L1 drugs would occur.

After this decision, one question raised was related to a lack of trials of single agent pembrolizumab in multiple myeloma before its combination use, Nicole J. Gormley, MD, and Richard Pazdur, MD, of the FDA, wrote in an accompanying editorial.

The “unexpected” findings of the ELOQUENT-3 trial “underscore the importance of evaluating new immuno-oncology combinations in randomized trials assessing overall survival.”

This experience shows that combining different immunotherapy drugs in patients with multiple myeloma, or with solid tumors, may not follow the same path as the combination use of cytotoxic drugs over the last few decades.

In fact, Gormley and Pazdur wrote that although many “oncology approvals of single-agent PD-1 and PD-L1 dugs have been based on durable response rates in single-arm trials, it’s difficult to adequately evaluate efficacy and safety of drug combinations without a control group.”

“How a combination’s components interact in a complex immunologic tumor microenvironment will need to be thoroughly investigated,” they wrote. “Developers of PD-1 agents for multiple myeloma should be cognizant of these considerations. Further investigations of PD-1 agents in this disease should ensure appropriate patient selection, and examination of a combination’s safety and the effect on mortality should be considered early in its development.”