Advent of Combination Strategies in Multiple Myeloma

Amrita Krishnan, MD, FACP: Combination chemotherapy for myeloma has really changed the paradigm, as well as responses, in myeloma. We recognize that each myeloma patient has multiple clones of the disease, so single-agent therapy is not adequate, and really, combinations are what lead us to deep responses.

Immunomodulatory drugs have formed a foundation of our therapy for myeloma, both in the frontline setting and the relapsed setting. And we have randomized trials—for example, a French trial looking at the combination of bortezomib/thalidomide/Decadron (dexamethasone) compared with a non—IMiD based regimen of bortezomib/cyclophosphamide/dexamethasone. And it shows us that the IMiD/PI combination really leads to deeper responses. And one of the tenets now of our myeloma therapy is really getting the deepest response we can, because we think that deep responses lead to sustained remissions.

Cost of therapy has always been a challenge in myeloma, certainly, as we add new drugs. We started with doublet regimens, which were already relatively expensive. We made it triplet regimens, and now, in fact, we’re talking about quadruplet regimens. Now, having said that, part of the paradigm, I think, is getting that deep response early, and then obviously you can back down. You’re not going to keep a person on a quadruplet regimen indefinitely. Ultimately, the hope is that you have a regimen that you can get such a deep response, MRD-negative, and sustain it so that you are able to stop therapy. So, really front-loading, hopefully will, in the future, allow us to also maximize efficacy and ultimately reduce the cost downstream of therapy.

I think most patients, when they come to you with myeloma, are understandably very frightened. First of all, I try to provide them hope—and hope is with all these new therapies—and balance this discussion about efficacy, toxicity, and cost in the fashion or framing of trying to individualize it for each patient. But ultimately, for most patients, certainly we will use a multidrug combination and minimize toxicity from it.

Autologous transplant has been around for myeloma since the 1980s. When the “novel” drugs such as bortezomib came on board, there was a big buzz—is transplant going to go away? What is the role of transplant in the era of novel agents? What we’ve seen is that transplant still remains a backbone of therapy for myeloma. And as a myeloma transplant doctor, how I generally frame it to patients is, the new drugs allow us to make transplant better. So, we’ve made transplant safer, and now we can use new drugs to induce deep responses prior to transplant, use transplant to consolidate those responses, and then maintain patients post transplant.

So, if we look at the trial that was published by the French—the IFM trial that was published in the New England Journal of Medicine that looked at RVd followed by transplant or RVd alone in 1 arm—I really look at that as an early versus delayed transplant. All patients had stem cells collected. The group that went to early transplant had better PFS. They had a higher rate of MRD negativity, as well, suggesting to me, again, that transplant can consolidate your responses and get you to deeper remission. Having said that, many people point to that trial and say that overall survival was the same in both arms.

But first, the good news is, overall survival was the same, and it was also very, very high, over 80%. If you look at the arm that was randomized to no transplant, it wasn’t really no transplant—80% of them at the time of relapse got a transplant. So, in my mind, it really becomes more a conversation of transplant now or transplant later. I tend to favor, of all things being equal, doing it early in the course of disease, as I mentioned, to try to consolidate that response up front. But I do have a conversation with patients that this is not always the best time for you to get a transplant, depending on their social situation. So that at the very least, collecting and storing stem cells is important to give them the option of transplant.