Treating Multiple Myeloma at First Relapse

Sagar Lonial, MD, FACP: When we begin to talk about relapsed myeloma, there are a number of regimens that come to mind for use in that situation. Almost all trials that have been done looking at triplets versus doublets have established the benefit of a triplet-based approach, both in terms of progression-free and overall survival. The regimens that we clearly have data on and that are supported by the NCCN [National Comprehensive Cancer Network] include things like KRd, or carfilzomib, lenalidomide, dexamethasone; ERd, or elotuzumab, lenalidomide, dexamethasone; DRd, or daratumumab with lenalidomide, dexamethasone; DVd, or daratumumab with bortezomib and dexamethasone; as well as PVd, which is panobinostat in combination with bortezomib and dexamethasone. And most recently, now we have new data on a different “P,” pomalidomide, in combination with bortezomib and dexamethasone, based on the OPTIMISMM study.

As we think about the types of relapse, I think it’s important to use that to make decisions about when to initiate salvage therapy. For patients who have pure biochemical relapse and are standard risk, I don’t jump in to treat them immediately. I watch them, try to get a sense for the tempo of their relapse, and what I do now that I didn’t used to do before is get a PET/CT [positron emission tomography/computed tomography] scan to understand whether or not even though they look indolent and biochemical, do they have new bone lesions? Because if they do, then that to me hastens the decision about when to start treatment.

On the other hand, patients with symptomatic relapse clearly need treatment. If they’re a high-risk patient with biochemical relapse, I’m probably going to initiate therapy sooner rather than later. So I think taking into account how long they were in remission, what is their original genetics, and what’s the tempo of their relapse factors into how you decide when to treat them.

When we think about how to sequence agents in the context of relapsed disease, I think it’s important to realize that most patients will have had VRd [bortezomib, lenalidomide, dexamethasone] up front now. They may or may not have had a transplant, and they will likely have had lenalidomide maintenance. And what the lenalidomide maintenance in my mind really does is make many of those randomized phase 3 trials—KRd vs Rd [lenalidomide, dexamethasone]; DRd versus Rd; ERd versus d [dexamethasone]—less relevant for me. And so what I’m really thinking about is going back to a proteasome inhibitor—so something like daratumumab, bortezomib, dexamethasone—or going to the second-generation IMiD [immunomodulatory drug] like pomalidomide. And so what we have tended to use at our center is pomalidomide in combination with daratumumab based on the MMY1001 study, where there were over 100 patients treated with daratumumab/pomalidomide/dexamethasone, clearly an active regimen, and this led to the FDA approval of daratumumab/pomalidomide/dexamethasone in the relapsed myeloma setting.

More recently, we have data from the OPTIMISMM trial that suggest pomalidomide can be partnered with bortezomib. That clearly is a very active regimen and, in a phase 3 trial, demonstrated significant improvement in progression-free survival and overall survival, and there are emerging data on ixazomib with pomalidomide and dexamethasone, as well, an all-oral regimen in the salvage setting. Figuring out which of those is best for your patient in addition to carfilzomib-based approaches, I think, is an important part of the discussion.

When we think about carfilzomib in the context of relapsed myeloma, there certainly are a number of partners we can talk about. There are data combining with cyclophosphamide, there are data combining with pomalidomide, and there are data combining with daratumumab as well. So any of those are potentially viable salvage regimens in the first- or second-relapse setting.

What we have seen more recently is a randomized phase 3 trial comparing once-a-week versus twice-a-week dosing of carfilzomib in the ARROW study. And what’s really interesting about that is that the once-a-week dosing did not appear to have more adverse effects or toxicity but clearly appeared to have a longer progression-free survival than the twice-a-week dosing.

Now, the important thing to remember about this is that the twice-a-week dosing used the 20/27 dosing of carfilzomib; it didn’t use the 56 mg/m² that the ENDEAVOR trial gave us. The once-a-week dosing used 70 mg/m² once a week. So we’d seen hints about that from a phase 1/2 trial, but this is a phase 3 trial really establishing that dose in the context of myeloma.

One of the challenges in dealing with relapsed myeloma is overcoming drug resistance. And we know, for instance, that cells can become resistant to proteasome inhibitors, cells can become resistant to IMiDs. We see that with lenalidomide, we see that with pomalidomide, we see that with thalidomide, bortezomib as well. So the second-generation agents clearly are more potent than the first-generation agents and may help to overcome some of that resistance. We know that HDAC [histone deacetylase] inhibitors such as panobinostat can overcome proteasome inhibitor resistance. We saw that with bortezomib in the PANORAMA trial. We’ve also seen it with carfilzomib in a number of phase 2 trials that have been published and presented as well. The antibodies really bring in a different flavor, and what they really allow us to do is to potentially overcome resistance, not through intracellular signaling but through extracellular immune modulation. And that’s really an important new mechanism that we’ve not been able to do up until the past few years.