James Armitage: Hello. I am Jim Armitage from the University of Nebraska Medical Center. I want to welcome you to The ASCO Post Video Roundtable Series featuring the Appropriate Management of Challenging Cases in Myeloma and Lymphoma. This installment will focus on the current treatment options for patients with relapsed or refractory multiple myeloma. Now we did not just forget the role CAR T-cell therapy. It’s going to be discussed in a separate installment later. Today I am joined by two of my friends and colleagues and experts in the management of patients with hematological malignancies, and I will let them introduce themselves.
Sarah Holstein: Hello. My name is Sarah Holstein. I am an associate professor at the University of Nebraska Medical Center, and I specialize in the treatment of multiple myeloma and related plasma cell dyscrasias.
Matthew Lunning: Hello. I’m Matthew Lunning. I am an associate professor at the University of Nebraska Medical Center. I specialize in lymphoma and cellular therapy.
Dr. Armitage: Okay, Sarah. The patient for this session is going to be a 59-year-old man who had presented with symptomatic myeloma with bone pain and feeling unwell. He had bone lesions on images. He was anemic. This all happened two years ago. He was treated with RVD for six cycles and then an autotransplant and then lenalidomide maintenance. He came back to see you 2 years after the treatment started not feeling well, found to have a falling hemoglobin and a bone marrow biopsy that showed 50% plasma cells, and repeat bone imaging showed new lytic lesions. What do you tell him?
Dr. Holstein: So, one of the things I have to tell him is that this is characteristic of much more aggressive myeloma. Although you did not share with me the cytogenetics at diagnosis or relapse, my guess would be that he has high-risk cytogenetic features because the amount of time that he got out of his transplant with maintenance is far below what would be expected these days based on the data that we have from other randomized phase III studies that looked at lenalidomide maintenance post-transplant. Not only that but his relapse is not just biochemical in nature meaning that he has a slowly developing M spike, but clearly this is a symptomatic relapse. So we talk about the fact that unfortunately his disease has failed, what is his current standard of care, which is RVD induction, transplant, and maintenance, and then talk about how we move forward. The good news is that we have a lot of new therapies available for relapsed/refractory myeloma. The more difficult discussion is really talking about what the long-term strategy is going to be to keep his disease under control. In the short term, given how rapid his relapse was and his progression and especially that it occurred on lenalidomide maintenance, I would generally move away from the class of immunomodulatory drugs and move to a different class of agents. In this case, I would discuss with him the possibility of using a carfilzomib-based regimen.
For the most part these days, we talk about the use of triplets versus doublets. I think the one exception in wanting to use a triplet versus doublet is probably in the realm of carfilzomib now that we do have available to us the high-dose weekly regimen, but having said that, my preference would be to try to add another drug to that mix, whether it be cyclophosphamide or daratumumab. We recently have the results of a phase III study that compared daratumumab/carfilzomib/dexamethasone to carfilzomib/dexamethasone, and the triplet won out over the doublet. So again, short term, it is not too difficult to come up with a plan, but longer term, it is much more difficult because after he progresses on the daratumumab/carfilzomib/dex, then we are in all likelihood talking about a pomalidomide-based regimen, and you could envision perhaps using pomalidomide with elotuzumab, and after that, then we start getting into drugs which have probably very short progression-free survival rates such as selinexor or potentially newer therapies down the road, but either way, it is difficult to talk about long-term survival with the drugs that we currently have available.
Dr. Armitage: You pointed out that myeloma is not just one illness. Is there other certain genetic abnormalities or other things that you would measure about this patient’s myeloma that would make you treat them differently if they did not have those abnormalities?
Dr. Holstein: You know, so knowing the cytogenetic information, so knowing whether there is a deletion 17p abnormality or a translocation 14, 16, 4:14, it is certainly helpful, but honestly in this particular patient’s case, the speed at which he relapsed tells you more than anything you could learn from the textbook of doing the cytogenetic information. At this point, we really do not have cytogenetic-based treatment strategies. It is useful when you know it, and it does help you counsel patients about what the likelihood of benefit is from a particular regimen, but in this particular example that you gave, what is most striking is how quickly he relapsed and how active of a relapse it was after a transplant.
Dr. Armitage: What if the patient asked you, “well, the transplant was supposed to be such a good deal; can’t we just do it again after my chemotherapy?”
Dr. Holstein: So, I actually have that discussion quite often. It used to be that we kind of had the threshold of the three-year mark. If you got three years out of your transplant, there is at least some retrospective data suggesting that it was reasonable to do a second transplant. What I tell the patients now is that that bar has really changed in the era of lenalidomide maintenance. We know from studies such as CALGB100-104 and European studies that the average PFS or time to progression is well above four and a half years, so 53 to 56 months depending on which study you looked at. And so if somebody is relapsing 2 or even 3 years after transplant with lenalidomide maintenance, they are doing far below what was to be expected. And so from that perspective, these days my threshold is to really only consider a second transplant in patients who have gone beyond 5 years if they are on lenalidomide – and this happens not infrequently. Sometimes people were on lenalidomide maintenance and stopped it after 2 or 3 years, perhaps because their oncologist recommended it or perhaps because of side effects, and if they then relapsed a couple of years after that, then I think it would be reasonable to talk about a second transplant. But these days, I think it makes very little sense to offer a second transplant to somebody who relapsed very quickly after the first one on lenalidomide maintenance. And to complicate things even further, we have very little data to inform us as to what to do for maintenance after the second transplant. So we know lenalidomide is great, but if you have already progressed on lenalidomide, it does not make much sense to just do that again. But what we really need are good clinical trial data to tell us whether a pomalidomide maintenance strategy, a daratumumab maintenance strategy or something else could be used.
Dr. Armitage: There are a few cases that suggest that some patients with myeloma might be cured with an allotransplant. Would you bring that up with this person?
Dr. Holstein: I typically don’t or at least if I bring it up, I then talk about the data. It is true that to date some of the longest-lasting remissions and potentially even cures in myeloma appear to be in patients who underwent an allotransplant. But unfortunately the vast majority of patients who undergo allotransplant for the myeloma will either die of toxicity, related to the transplant itself, or will relapse from a myeloma perspective, and we really have no way to identify which patients might be those patients who benefit long-term from an allotransplant. Given emerging new treatment strategies, I think it is very difficult to justify the recommendation for allotransplant these days.
Dr. Armitage: In a patient in this situation, is there any reason that you would ever include radiotherapy in their treatment approach?
Dr. Holstein: I generally reserve radiation therapy for symptomatic lesions, particularly anything that is in the spine, but otherwise these days there is really not radio-labeled agents such as what you have for lymphoma available. There is some interesting anecdotal evidence that perhaps you could radiate a lesion and give an immune-modulating agent and get abscopal effects, but that’s really anecdotal at this point.
Dr. Armitage: When you first treated this patient, they probably have been receiving some bone-sparing agent – a whole bunch of choices but one of them, would you still keep doing that now?
Dr. Holstein: Yes. So, you know, for some patients that stopped after a couple of years after a transplant. Everybody is a little bit different still in terms of how long they could continue with the bone-strengthening agent. Now that we do have two classes available that have two different mechanisms of action, what I will sometimes do is switch classes if somebody is developing new lytic lesions while on the first class of bone agents.
Dr. Armitage: Alright: Thank you very much. I want to thank you all for watching Sarah and Matt and me on this session on relapsed/refractory myeloma. You stay tuned for more interesting installments of The ASCO Post Video Roundtable exploring other situations that pose clinical problems in patients with hematologic malignancies, and you can find these on ascopost.com.