Selecting Treatment at First Relapse of Multiple Myeloma

Amrita Krishnan, MD, FACP: The first relapse of myeloma is really still a wide-open bucket for patients. There’s really a myriad of options, and so it becomes a question of patient factors—comorbidities, disease factors. Do they have high-risk disease? When did they relapse? We clearly know that patients who relapse within 12 months of autologous transplant have poor-risk disease. So, those are patients you would tend to be very aggressive about. Do patients have a biochemical relapse? Those are patients where you may take a different approach.

And as 1 of my colleagues, I think, put it very nicely, “My first intervention in a patient with a biochemical relapse is to just follow them more closely and repeat that number, because you want to get a sense of tempo.” And with someone whose numbers then continue to rise fairly quickly, you are going to act upon that. You don’t want to wait in a relapsed setting until someone gets organ toxicity. Clearly, we have drugs and the ability to intervene before that happens. Obviously, there are some patients whose disease is so aggressive that even in the best-case scenario of watching them closely, they still progress that quickly. And those are obviously patients who you’re going to be very aggressive about treating at relapse.

Generally, most of us, if we haven’t used daratumumab initially, we use daratumumab now in that first relapsed setting, given the recent approval. And we combine it, depending on what the patients had before, with either an IMiD or with a proteasome inhibitor. And, generally, if patients have been on lenalidomide maintenance, for example, I would tend to then, at first relapse, give daratumumab plus pomalidomide and dexamethasone. We have some phase II trials suggesting extremely high response rates with that combination. If patients are IMiD intolerant, for example, then I would give daratumumab plus bortezomib and dexamethasone at first relapse.

One of the questions I get a lot is, should you switch classes of drugs, or can you stay in the same class of drugs? At ASCO, we heard from the results of the OPTIMISMM trial, which was a trial looking at pomalidomide/bortezomib/dexamethasone, or PVd, in contrast with bortezomib/dexamethasone. Patients had to be lenalidomide exposed. And, in fact, they also included patients who were lenalidomide refractory, which was an important point, because then it does speak to this question of class of drugs. Patients could not be bortezomib refractory, because the control arm was bortezomib/dexamethasone. And what we saw was that if you received PVd, if you were lenalidomide refractory, you still did derive a benefit. The median PFS was on the order of 9 months—so about a 4-month improvement over the bortezomib/dexamethasone arm. If you were lenalidomide exposed but not refractory—so patients stopped lenalidomide for whatever other reason, be it toxicity, treatment fatigue, or other reasons—those patients obviously had even more benefit. Their median PFS was 22 months in the PVd arm compared with the bortezomib/dexamethasone arm, which was about 11 months. So, it suggests that yes, you can stay in the same class of drugs, but, as I said, switching from lenalidomide to pomalidomide is a reasonable option for patients.

The ARROW trial was presented at ASCO, and most of us were very excited with the results because, I think, it will be landscape changing—because it showed us that you can give weekly carfilzomib. So, the ARROW trial looked at escalating doses up to 70 mg/m² of carfilzomib weekly in comparison with our standard dosing, the 27 mg/m² twice a week. And what we were watching for, really, was toxicity. I don’t think we would be surprised by efficacy signals, but we were concerned about cardiac toxicity and hypertension. And it was gratifying to see in that trial that the incidence of cardiac toxicity was the same in both the biweekly and weekly dosing schedule and similarly with hypertension. Interestingly, there was a better PFS in the weekly dosing schedule. I don’t have a clear reason for that. But it was, I think, paradigm shifting that if you’re going to use carfilzomib as a doublet at least in this trial—so I would add that notion of caution right now—that you can give it safely as a weekly dosing schedule.

Similarly, the trial that Ajai Chari presented of carfilzomib plus daratumumab also gave the carfilzomib in a weekly dosing schedule and in combination with dexamethasone. So, here you do have 3 drugs giving carfilzomib weekly—cardiac toxicity, again, very tolerable with grade 3 events being about 6%. So, I think we’re getting more and more evidence that you can give carfilzomib safely as a weekly dosing schedule. I think some of that is also a caution that these are in clinical trials, so patients were very closely followed. And you do need to do that to monitor patients for hypertension, especially, and fluid challenges to allow you to do that very safely.