Multiple Myeloma: Frontline Daratumumab Combinations

Amrita Krishnan, MD, FACP: The ALCYONE trial, which was recently published in the New England Journal of Medicine, of daratumumab/bortezomib/melphalan/prednisone, or daratumumab/VMP, compared with VMP alone showed a significantly higher response rate, significantly higher progression-free survival for the daratumumab/VMP arm, and a favorable toxicity profile. Its implications in the United States are probably very different from its implications in the rest of the world, because the use of VMP in the United States is so low. And I don’t think that this trial is going to change that, and we’re going to suddenly switch to RVd even in our elderly transplant ineligible to suddenly using daratumumab/VMP. But it will just allow us to say that you can give 4 drugs in an elderly population in the frontline setting, and it can be tolerated.

Now, without going into the weeds of the study design, that study is not a perfect study design in regard to the experimental arm or the control arm. The control arm received a set number of courses of therapy because that, again, speaks to the way that you can give VMP. You can’t give it indefinitely until disease progression compared with daratumumab. But my other takeaway from that trial is the fact that in the daratumumab/VMP arm, patients continued on daratumumab and have been able to be maintained on daratumumab for long periods of time, suggesting that it’s a very attractive agent as a maintenance strategy, a once-a-month infusion, and as we see daratumumab ultimately become a subcutaneous drug, even more attractive as a long-term maintenance strategy in a transplant-ineligible population.

The MAIA study of daratumumab/lenalidomide/dexamethasone in comparison with lenalidomide/dexamethasone is an important study. I think it will very likely show that the daratumumab/Rd arm is going to be superior in terms of PFS and in terms of MRD-negative rates. We’ve already seen that in the relapsed setting with daratumumab/Rd versus Rd alone. I think it will allow us, for older patients who are not going to transplant, another option in the frontline setting that will be more commonly adopted in the United States, because clearly, we use a lot of our up-front therapies as our induction regimens.

Daratumumab/carfilzomib/dexamethasone was presented at ASCO this year, and it showed us a couple things. First, they used the carfilzomib on a weekly dosing schedule, escalated up to 70 mg/m². With the daratumumab, after initial safety run-in, they split the dosing over 2 days, which is a question we tend to get a lot because of the length of the first dose of daratumumab. So, it was a nice trial, because it addressed some of the concerns of giving 2 IV drugs, and it showed that split dosing was very feasible. It showed that the combination of daratumumab plus weekly carfilzomib had no new safety signals. The cardiac toxicity grade 3 was 6%, which was very much in keeping with our prior carfilzomib experience. So, that was very encouraging, and the response rates were very high. The response rates were about 90% in lenalidomide-exposed patients, and the high 80% for patients who were lenalidomide refractory. Now, having said that, 1 important point to keep in mind about that daratumumab/carfilzomib/dexamethasone trial is that those patients were carfilzomib-naïve. Nonetheless, it suggests that in patients who had other proteasome inhibitor exposure and who were lenalidomide refractory, for example, this is a good alternative regimen to consider.