Expert Sheds Light on Role of Combinations, Transplant in Myeloma

Jayesh Mehta, MD

With a plethora of combinations available and being explored in the multiple myeloma landscape, researchers are assessing the right number of drugs to use in combination regimens.

While data have shown that triplet regimens are more beneficial than 2-drug combinations in the relapsed setting for patients not undergoing transplantation, Jayesh Mehta, MD, said that the added benefit of 4-drug regimens remains unclear.

During the 2017 OncLive^® State of the Science Summit^TM on Hematologic Malignancies, Mehta, professor of medicine (hematology and oncology), Feinberg School of Medicine at Northwestern University, discussed combination therapies in multiple myeloma, as well as the continued importance of stem cell transplant.

OncLive: Please provide an overview of your lecture on combination therapies in multiple myeloma.

In an interview during the meeting, Mehta shared his insight on the backbone of lenalidomide (Revlimid) and dexamethasone in combination therapies, the use of checkpoint inhibitors in multiple myeloma, and the stable role of stem cell transplantation in these patients.Mehta: We reviewed the role of combination therapies, and the fact that 3-drug combinations seem to be better than 2-drug combinations in relapsed myeloma. [It is unclear whether they are better] in patients who are not going to be transplanted. What is also unclear is whether 4-drug combinations are better than 3-drug combinations. Essentially, the whole point is, do we want to give multiple drugs at the same time, or give a small number of drugs first and then add in or substitute drugs later in the course of the disease? We don’t know the right answer to this.

What are the factors that you take into consideration when deciding between combination regimens for patients?

Will lenalidomide and dexamethasone remain an integral part of combinations for myeloma moving forward?

Are there any exciting newer combinations that are being studied?

What we do know is that when you have multiple new agents in the same combination, the cost becomes staggering. You have combinations that could cost as much as $400,000 a year. The health systems cannot survive such expenses.Patient age, what treatments they have had in the past, what their organ function—specifically kidneys—is like, what their blood counts are, whether they have undergone a stem cell transplant, and convenience for the patient. I am not sure that will be the case. The major reason that lenalidomide and dexamethasone is the backbone is because it is one of the major combinations in which data exist. The specific label was on lenalidomide and dexamethasone in the relapsed setting. However, there are other active combinations or active drugs that can be used. The attraction of lenalidomide is in the activity, but the proteasome inhibitors are also very active.Combinations that might include an element of immunotherapy might be interesting. Trying a drug such as elotuzumab (Empliciti) early in the course of the disease, when the immune system is not knocked out, may be interesting to use. Drugs such as lenalidomide and pomalidomide (Pomalyst) do not compromise the immune system, particularly T-cell—mediated immunity—the way that daratumumab (Darzalex) and the proteasome inhibitors do. Focusing on drugs that don't compromise the immune system that much would be quite fascinating. I'd love to explore the combinations of elotuzumab and lenalidomide in frontline myeloma.

There has been a lot of buzz about daratumumab. Could you share your insight on this agent?

There is some interesting stuff worth looking at. The problem is that the early pathway in myeloma is already pretty well established. By the time patients come in after relapse, I don't know that you have the luxury of time on your side to explore regimens that try to avoid immunosuppression by excluding drugs like proteasome inhibitors, steroids, and daratumumab. I have not been very impressed with daratumumab when it is used as a single agent as labeled. When we use it with high doses of steroids, the response rates have been better. When used in combination, the response rates have been better. It is a tough drug to use due to the fact that it causes myelosuppression.

It causes a lot of reactions and is associated with a lot of infections. However, we use a lot of daratumumab and all of these drugs because we have a very large population of patients to look after, and I see the kind of adverse effects that we used to never seen before.

There have been a few holds in multiple myeloma trials recently. What are your thoughts on the potential of pembrolizumab (Keytruda) and nivolumab (Opdivo) in these patients?

Your other lecture focused on stem cell transplant. What is important to highlight there?

Very few data have been released on what the causes of death were and what the toxicities were. We have used checkpoint inhibitors quite extensively in myeloma, particularly relapse after allogeneic transplantation. We have not seen any extraordinary toxicity at all; granted, we have stuck to nivolumab—which I believe is a much safer drug than pembrolizumab. However, we have used pembrolizumab in a couple of patients and we have not seen much [toxicity]. We need a close look at the data before we know what is going on. A lot of people don't like stem cell transplantation because it is perceived to be this brutal, old-school procedure where you give a massive dose of chemotherapy. Why do that when you have all these fancy drugs? You just give a little shot here or a pill there and life goes on. That is simply not true. Study after study has shown that when you eliminate transplantation from the algorithm of treatment, the person who pays the price is the patient—and they usually pay this price with their life.

In a curable disease with different pathways, it is acceptable to choose 1 versus the other. However, in an incurable disease, each treatment that you use makes a certain contribution to longevity. It is not appropriate to exclude 1 treatment for another. What some people don't like is that if you transplant the patient, the disease could actually be under control for many years, without requiring additional therapy or minimal therapy. Whereas, if you give combination therapies, that keeps the disease under control for a limited period of time; there is always some [disease] activity.

What do you hope community oncologists took away from your presentations?

If you were to do quality-of-life studies—which will never be done—you will find that quality-adjusted life years gained with transplantation is going to be far superior to the novel agents. We see this in real life all the time. One must keep their mind open and realize that transplantation has a place. I saw familiar faces in the audience; we work very closely with our community partners in the Chicago area and they know there is room for transplantation, and [they] have been absolutely terrific about making sure their patients get the right treatment at the right time. The physicians that we work with in this community provide exemplary care to their patients.