Approaching Induction Therapy for Patients With Transplant-Ineligible MM
Switching their focus to transplant-ineligible multiple myeloma, panelists review available triplet therapy regimens for induction therapy.
Transcript:
Sagar Lonial, MD: Let’s talk a little bit about the frailer patient, the older patient. You can define that however you like; certainly, the transplant-ineligible group. Where are we [currently] with that patient population?
Samuel M. Rubinstein, MD: Certainly, it is a very exciting time to be taking care of patients with multiple myeloma. There has been a lot of excellent drug development in recent years, but it’s disproportionately in a population of patients that may not reflect the real-world population of patients with myeloma. The average patient in some of these frontline transplant trials are in their mid-50s, whereas the typical patient with newly diagnosed myeloma is nearly age 70 in the United States. Many patients are not eligible for autologous transplant frontline and the question is, has this drug development benefited that patient population? The historical standard of care for patients not eligible for transplant with newly diagnosed myeloma has been a doublet, lenalidomide and dexamethasone. In the last 5 to 7 years, we’ve shown good outcomes with triplet therapy. RVd [lenalidomide, bortezomib, dexamethasone], we all know the SWOG S077 study [NCT00644228], which included both transplant-eligible and transplant-ineligible patients, showed an overall survival advantage to adding bortezomib to induction in that patient population. Then more recently we have the MAIA trial [NCT02252172] looking at daratumumab, lenalidomide, and dexamethasone showing an impressive progression-free survival median of more than 5 years, then recently in multiple updates an overall survival advantage to adding daratumumab. We now have multiple options for triplet inductions that are shown to be effective and, increasingly, we have data showing that it’s safe and well tolerated even in a frail subgroup of transplant-ineligible population. We had data published recently looking at the relatively frail subgroup. To Sagar’s point, frailty is in the eye of the beholder. We have formal ways that we can categorize patients as frail or not frail. The International Myeloma Working Group has a simple metric based on age, performance status, and comorbidities that’s often used. Patients categorized as frail by that simple scoring system still derive overall survival advantage on dara-Rd [daratumumab and dexamethasone] and maybe more importantly, tolerate that therapy very well and preserve excellent quality of life. It’s an exciting time. These drug developments are benefiting all our patients.
Sagar Lonial, MD: One question that often comes up is this question about duration of therapy. I know, certainly in the community, there’s always a “Well, they’re doing fine and they’re older, can we stop?” How do you all approach that question?
Caitlin Costello, MD: I think we learned from the first study that continuous therapy matters, right? When the European studies compared a fixed duration of lenalidomide versus that of a continuous therapy until progression, we saw that those patients benefited from it. I think with dara-len-dex [daratumumab, lenalidomide, and dexamethasone] on the MAIA study, we’re seeing that continuous treatment matters there, too. That is a very tolerable combination. We all know our patients have trouble with lenalidomide. You can make dose modifications to make it more tolerable for the long run. Some patients want to get off of it and stay on daratumumab instead. Maybe, without any data, that’s not a wrong thing to do, either. I think with a good conversation with your patient to understand what the barriers are to continuous therapy, adjustments can be made to allow that to happen, because it does matter.
Samuel M. Rubinstein, MD: I totally agree.
Sandy Wong, MD: I am also a believer in continuous therapy. I think it’s important not to simply suppress the clone quickly and deeply to decrease clonal heterogeneity. Taking pressure off that clone allows it to increase the chances it will produce more clonal heterogeneity. The problem with taking pressure off the clone is that [if] you allow that to happen, the patient relapses. I do think any time you give…the myeloma a chance to relapse, it can be much cleverer. Then you move them to your second line of therapy. In an already transplant-ineligible patient, what if they have a fracture? That really is a big deal for patients who are already transplant-ineligible. The second point I’ll make is a bit of a pet peeve, but you talk about a lot of these great trials. Taking a step back, there’s such a big difference between transplant ineligibility and frailty. We do have an IMWG [International Myeloma Working Group] scoring system. We need to be using that more to better define these populations. Sometimes transplant ineligible doesn’t mean that they’re frail. That will help us delineate and better tailor our treatments to these populations that are frail. We’re really worried about those frail patients; they’re much more difficult to treat.
Samuel M. Rubinstein, MD: I agree, continuous therapy is very important. Many patients, though, feel the cumulative effects of continuing same exact regimen that they started off with. You get benefit in controlling myeloma initially and then in the long run, it’s the therapy that patients feel the effects of. We [recently] got excellent data on a way to cleverly deescalate therapy, particularly for patients who are not eligible for transplant, from France. As an American, it pains me that the Europeans tend to do these so much better than we do in some cases. But they had a nice, randomized trial, IFM 2017, comparing lenalidomide and dexamethasone to daratumumab and lenalidomide. So, no dexamethasone. Dexamethasone, we don’t often talk about it because it’s not the new hip drug, but [it’s]arguably the most toxic drug we’re still giving for myeloma in many cases. What they showed is response rates, MRD [minimal residual disease] negativity, progression-free survival, better in the steroid-free arm than in the RD arm. If we’re going to be deescalating therapy to improve quality of life, maybe we can drop dexamethasone and derive benefit [from] our modern therapies by continuing those in the long run.
Sandy Wong, MD: I have been a longtime hater of dex[amethasone]. It’s so great to actually see data that shows the harmful effects of dex. I love that study. That actually is really important for patients, because traditionally, dex has a very long history in myeloma. Now that we have all these better agents, we don’t need these more toxic drugs. Oftentimes, I think dex has been in the background—it’s always there—but now it’s time to just get rid of it with trials like this one.
Sagar Lonial, MD: The de-escalation question is important. I will say, I’m going to be a little old school, I remember when that paper came out about dex versus nothing for relapse in multiple myeloma in Annals of Internal Medicine. I think there’s value in the first few cycles to help speed and manage symptoms. But then, I agree, I think tapering off is really important. It’s important for everybody to realize that the premedication schema for dara doesn’t necessarily have to use continuous corticosteroids. Once you get past the first cycle or 2, you don’t need the steroids anymore. You actually don’t need the Tylenol [acetaminophen] or the Benadryl [diphenhydramine], either.
Timothy Schmidt, MD: Right, with subcutaneous administration, we’re not really seeing reactions at all.
Caitlin Costello, MD: Can I push back a little bit on the transplant-ineligibility concept? I think we needed a little bit more consistency in these patients when we’re studying them. You have the SWOG study, which looked at transplant-ineligible [patients], but also included a group of patients who chose to not go to transplant, so it’s a much younger population. We try to compare that to the MAIA study, which was an older population. Now seeing some subgroup analyses, we can see the difference between the frail and the super-frail in those groups. Seeing that the much frailer patients, even on dara-len-dex, didn’t do as well as those who were less frail. I think we really need to understand that there is this big spectrum of frailty and design trials that are specifically adapted to frailty, so we can really understand this is not transplant-ineligible. These are very well-defined subgroups of frailty that need to have the best treatments available.
Samuel M. Rubinstein, MD: To your point, who’s eligible for a transplant depends on where you are. Many of the patients who are transplant ineligible on MAIA could very well have gotten a transplant in any of our centers in the United States. They have very strict age criteria for [determining] who they’ll transplant and not transplant in some European countries. Here, we know age is nothing but a number. So, to your point, many of the trials that are done in a population that is transplant-ineligible probably includes several patients who would be eligible in our clinics.
Transcript edited for clarity.
