The long wait for monoclonal antibodies for the treatment of multiple myeloma is over. In the landmark ELOQUENT-2 study, reviewed in this issue of The ASCO Post, Lonial and colleagues convincingly demonstrate the effectiveness of elotuzumab, a monoclonal antibody directed against SLAMF7, in the treatment of relapsed multiple myeloma.¹

The key findings of this randomized trial are straightforward: An absolute improvement in response rate of 15%, a median improvement in progression-free survival of 4.5 months, and no significant added toxicity were noted with the addition of elotuzumab to standard therapy. The results are clear and compelling. I believe that elotuzumab will be approved for the treatment of myeloma within the next several months and will usher in a new era in myeloma therapy.

Key Points From ELOQUENT-2

There are some key points from ELOQUENT-2 worthy of highlighting. First, elotuzumab does not possess significant single-agent activity in myeloma but yet appears to provide a meaningful therapeutic benefit in this trial when combined with lenalidomide [Revlimid]/low-dose dexamethasone. This finding raises the blinds on the increasing complexity of developing myeloma treatments. The demonstration of the clinical activity of drugs like elotuzumab, which need partner drugs to deliver synergistic benefit, requires large phase III trials and considerable risk of failure. This is in contrast to drugs like carfilzomib (Kyprolis), which have clear single-agent activity that can garner accelerated approval based on single-arm phase II trials.

Second, the trial illustrates the limitations of using median time-to-event estimates to assess the value of a new drug in the relapsed/refractory myeloma setting. Although the median improvement in progression-free survival is modest, the true benefit of elotuzumab is best appreciated in the proportion of patients who are progression free at 2 years, where the difference is much more striking: 27% (control) vs 41% (elotuzumab).

Third, I applaud the study team for designing a control arm (lenalidomide and low-dose dexamethasone) that is more in line with actual clinical practice rather than simply playing it safe and using a control arm that is unnecessarily more toxic. Thus, although the full approval of lenalidomide in relapsed myeloma was in combination with high-dose dexamethasone, the elotuzumab trial used low-dose dexamethasone based on data from a nonregulatory cooperative group trial showing that lowering the dose of dexamethasone reduced morbidity and mortality.

This approach is also in contrast to the trial supporting approval of panobinostat (Farydak), in which use of the approved dose of bortezomib (Velcade) rather than the less-toxic once-weekly schedule resulted in grade 3 or 4 neuropathy in approximately 25% of patients. The moral of the story is that the control arm for a regulatory study does not need to be an approved regimen: It just needs to be one that is considered by investigators in the field to be a reasonable standard.

Study Caveats

There are a few important caveats in interpreting this study. The trial was not blinded, which raises some uncertainty in the progression-free survival estimates. There was no improvement in quality of life. Merely demonstrating that a drug did not worsen quality of life is simply not enough; after all, we are hoping that delaying disease progression is associated with at least some improvement in patients’ perceived quality of life. Finally, there is no evidence that patients lived longer as a result of the therapy, since no overall survival benefit has been shown so far; survival estimates are “immature”—we shall wait and see.

So, what then is the value of a new drug that appears to have benefit based solely on surrogate endpoints, with no real clinical benefit having been shown yet in terms of either quality of life or overall survival? It depends on the setting. In this case, we have a new drug that is well tolerated in the treatment of relapsed myeloma. In this setting, progression-free survival has been consistently shown to be an excellent surrogate of clinical benefit in myeloma.

Therefore, I have no reservation in stating that the results of this trial are sufficient proof of the effectiveness of elotuzumab in relapsed myeloma. Had this study been in the front-line or maintenance setting with an approved drug, we would need to see evidence of true clinical benefit to be enthusiastic. Thus, the front-line elotuzumab study will be subject to greater scrutiny.

Real-World Implications

What are the real-world implications of this study once the drug is approved? Strangely, how well elotuzumab is used in the clinic may depend largely on how another monoclonal antibody, daratumumab, fares in the approval process.

Daratumumab targets CD38 and, unlike elotuzumab, has substantial single-agent activity (approximately 30% in heavily pretreated patients). This means it may secure accelerated approval based on phase II data and may be on the market at nearly the same time as elotuzumab. Time will tell. I expect that there will be competition between the two drugs. Since myeloma is incurable, I would try elotuzumab if daratumumab does not work and vice versa. It is also likely that these antibodies will be added not just to the regimens that were used in regulatory trials but to all manner of myeloma treatments, analogous to the way rituximab (Rituxan) is used in lymphoma. However, the complicating twist in myeloma is that we may have to adjudicate the clinical value of two antibodies simultaneously.

I do expect new monoclonal antibodies in myeloma to be pricey, similar to other new myeloma drugs. The cost will pose an enormous financial dilemma in the United States and elsewhere in the world, especially if it comes to pass that we wind up combining two monoclonal antibodies with carfilzomib (Kyprolis), pomalidomide (Pomalyst), and dexamethasone. ■

Disclosure: Dr. Rajkumar reported no potential conflicts of interest.

Reference

1. Lonial S, Dimopoulos M, Palumbo A, et al: Elotuzumab therapy for relapsed or refractory multiple myeloma. N Engl J Med 373:621-631, 2015.