Shaji Kumar: Results of the ENDURANCE Trial Support Standard of Care Treatment for Myeloma

Shaji Kumar, MD, consultant in the Division of Hematology and professor of medicine at Mayo Clinic Cancer Center in Rochester, Minnesota, talks about the ENDURANCE trial, which assessed carfilzomib versus bortezomib plus lenalidomide and dexamethasone for newly diagnosed multiple myeloma, and how quadruplet therapy may build on this standard of care.

Watch part one of the interview with Dr. Kumar where he discusses the first approved anti-BCMA therapy.

The results of the ENDURANCE trial were recently released demonstrating that carfilzomib, lenalidomide, and dexamethasone (KRd) did not improve outcomes in patients with newly diagnosed multiple myeloma compared with bortezomib plus lenalidomide and dexamethasone (VRd). So can you discuss the study design and some of the results?

Dr. Kumar: This study was designed because there was phase two data suggesting that the carfilzomib might be a better drug in terms of a proteasome inhibitor for combinations with newly diagnosed myeloma. VRd is a standard for right now, then that’s based on phase III trials showing improved survival. So the question was, can we actually demonstrate in a phase III trial that KRd is better than VRd. The trial was designed to incorporate mostly excluding a few high-risk patients, because there was another trial that was going on in parallel looking at only high-risk patients. We wanted to make sure we complement each other in terms of how we look at these patients. And there’s increasing interest in trying to look at the high-risk patients as an individual group, because those patients do have poor outcomes based on the current treatment, so we clearly need something better than what we are doing right now.

And the problem is if we clump them with all the myeloma patients, then we may never learn what could be done specifically for those. So that was the rationale for the design, excluding some of the high-risk patients. But nevertheless, it did include t(4;14) and 1q amplifications who are allowed, which probably represent a majority of the high-risk patients. So I think with the exception of the truly high-risk, like the t(14;16), t(14;20), del(17p), high LDH, everything else was included in this trial. Now, in terms of the results, we clearly, even though the KRd did give a higher very-good partial response rate compared to the VRd, that did not seem to make an impact on the progression-free survival. And we think that’s most likely related to the fact that the patients who are on the KRd had more cardiac, pulmonary, and renal toxicity, which may have negated some of the potential improved outcomes later to depth of response.

Now, one of the characteristics of this study is that we only included patients who are not going to use stem cell transplant as upfront therapy. So clearly, when you look at the data from the ENDURANCE trial, one could argue that maybe this does not tell you whether or not use KRd versus VRd in somebody who is getting four cycles of induction therapy, and then going to an autologous stem cell transplant, but even when we look at the subgroup of patients and look at the response overall at four cycles, that it was slightly higher than normal depth of response with KRd, but the differences seem unlikely that it would translate into a significantly better long-term outcome, but obviously that’s a result that they can’t really, truly derive out of the current data.

What does the trial tell us? I think one is obviously for the patients who are not going to an autologous stem cell transplant in the beginning, there’s no reason to use KRd instead of VRd. And based on the toxicity profile and the lack of improvement in progression-free survival, we think VRd still should remain the backbone for combination therapies going forward, because it is a safe, effective regimen that we are all very comfortable with. And bortezomib, especially the new subcutaneously once-weekly, typically does not cost the same degree of neuropathy that we have seen in the past.

This study found that bortezomib, lenalidomide, and dexamethasone remain the standard of care. How do you foresee a quadruplet therapy building upon this standard?

Dr. Kumar: We already have trials. Some of the trials that have reported on combining daratumumab with the currently used triplets, including VRd and VTd. We do have data from the CASSIOPEIA trial that looked at VTd data that progression-free survival can improve. We have data from GRIFFIN trial showing a similar increase in the depth of response improvement, adding daratumumab to VRd. Obviously, we don’t have longer-term outcomes from the GRIFFIN trial yet, but that, along with another large phase III trial called PERSEUS that’s going on in Europe, might better define how we’re going to be using the quadruplets in these patients. But the key question that needs to be addressed is if you’re going to treat someone with quadruplets, how long do we need to keep them on therapy? So those are things that are still being explored.