Abstract LBA3 reported the results of the phase 3 ENDURANCE trial, which was designed to examine whether initial therapy with KRd improves outcomes compared with VRd, the latter of which is the most widely used regimen in the treatment of newly diagnosed patients with multiple myeloma. We had seen some early data suggesting that carfilzomib might be more potent than bortezomib, and this was a trial designed to compare these 2 regimens. It is an investigator-initiated, National Institutes of Health–funded trial, and 1 of its key features is the head-to-head comparison of 2 triplets (ie, in contrast to triplet vs doublet trials, which often show advantages for the triplet). It was a large trial (N=1087) in newly diagnosed patients with standard- to intermediate-risk multiple myeloma. Those with high-risk cytogenetic features at diagnosis, such as 17p deletion, t(14;16), and t(14;20), were not eligible, while patients with t(4;14) were allowed to participate. The study found that there was no benefit of KRd over VRd in terms of overall response rate, progression-free survival, or 3-year overall survival. KRd was associated with a significantly higher rate of total composite cardiac, pulmonary, and renal adverse events, with 16.1% in the KRd arm compared with 4.8% in the VRd arm, while a higher rate of peripheral neuropathy was seen with VRd than with KRd (8% vs 1%, respectively). Our conclusion was that KRd has no significant benefit over VRd, at least in standard- and intermediate-risk patients with newly diagnosed multiple myeloma. Thus, VRd remains the backbone that we will build upon in the future, particularly when adding monoclonal antibodies. This trial emphasizes that if you are going to use a more toxic regimen, you must have clear evidence of benefit.

The ENDURANCE trial highlights the importance of phase 3 studies. Based on the preliminary data from single-arm studies, many of us would have predicted that patients in the KRd arm would do better than those receiving VRd. I would note that this trial was for patients who were not intending to proceed with autologous stem cell transplantation (ASCT) or who were ineligible for ASCT. Because this study specifically focused on standard-risk patients and the only molecularly high-risk patients who were included were those with t(4;14), there is still a possibility that KRd could have a role in treating high-risk individuals. Also, the KRd arm delivered more proteasome inhibitor per cycle than did the VRd arm, and if KRd could achieve a deeper response over a period of 4 cycles vs 4 cycles of VRd, one could still consider KRd induction in the ASCT setting. However, the increased toxicity of KRd needs to be considered, and patients with cardiac comorbidities or those who are frail should not be getting the KRd-based triplet.

In some ways, the ENDURANCE study reminds me of the SWOG-1211 trial, which was also presented at ASCO20 Virtual (abstract 8507). Led by Saad Zafar Usmani, MD, the SWOG-1211 trial looked at integrating elotuzumab into lenalidomide, bortezomib, and dexamethasone (RVd) as induction and maintenance for newly diagnosed, high-risk patients. The authors found no differences in progression-free survival or overall survival with the addition of elotuzumab to RVd induction and maintenance, a finding that was also unexpected. In contrast, the ELOQUENT-2 trial in the relapsed/refractory setting found that elotuzumab plus lenalidomide and dexamethasone was superior to lenalidomide and dexamethasone alone. It seems as if there may be differences in response to elotuzumab in the frontline vs the relapsed/refractory settings, and it would be interesting to better understand why this is the case.

With regard to elotuzumab performing better in the relapsed/refractory setting, it is important to note that, while we did see a positive signal in ELOQUENT-2 with elotuzumab when paired with lenalidomide and dexamethasone, the more striking difference was seen with the combination of elotuzumab plus pomalidomide and dexamethasone in ELOQUENT-3, albeit a smaller trial and caution is therefore needed in making cross-trial comparisons. However, that difference was striking in my view, and I think that there may be something about the pairing of elotuzumab with a particular immunomodulatory drug that could have clinical relevance in terms of its performance. Elotuzumab is a very selective antibody for natural killer cell activation, and that may be part of the challenge it faces as compared with something like CD38 targeting, which is more powerful overall but is less NK cell specific.

As relates to the ENDURANCE trial, the higher incidence of cardiac, pulmonary, and renal toxicity with KRd—as well as the underlining vascular toxicity, which is the basics of this, —is both apparent and potentially particularly significant. In my view, these findings may help us understand how we might think about strategically placing carfilzomib, recognizing its potency and its clear efficacy in other settings (eg, salvage after RVd). Additionally, although limited, the vascular toxicity with KRd may be an important consideration in the post–COVID-19 era, given that SARS-CoV-2 causes endotheliitis, which in turn causes its own significant and lethal vascular injury. It is also important to note that the mortality rate from COVID-19 in patients with multiple myeloma is high, and the known cardiovascular risk from the virus now has to be weighed, along with the relative toxicities of our other drugs, in the post–COVID-19 world.