Transcript:James R. Berenson, MD: The goal of therapy should be to give our patients the longest life possible with not only the impact of the disease, but the impact of the treatment, which we often forget. And the beauty of some of the new treatments is they have really little impact on the patient’s quality of life. These targeted antibody therapies particularly, besides the early infusion reaction, seem to show little other untoward effects, which is great news for patients. In terms of the types of relapses our patients experience, they can be quite aggressive in which the disease explodes, and those patients you have to go off and treat with many drugs because you don’t want to blow it. For example, these are patients who come in and develop acute renal failure, like a patient I saw in the last few days. I have to make sure I get a great response because if I don’t, I’ve made that patient go on permanent dialysis. So, if you will, a 90% chance of responding is not good enough.
But a lot of patients simply have a biochemical relapse, an asymptomatic relapse, in which they’re not becoming more anemic, they don’t have more bone symptoms, they don’t have high calcium, they don’t have kidney problems, and their blood counts aren’t going down, but their myeloma markers are going up. We want to shoot it down, but we don’t want to shoot it down with drugs that make them sick. We want to make sure their quality of life is not actually taken into the dumper, if you will, because of the treatment. Therefore, we want to use drugs like antibodies, which are very well tolerated, and you have time to watch them. If you blow it and it doesn’t work, you can add something in, you can try something else, and you can take your time. I say a lot of times in myeloma that it’s a better philosophy: don’t just do something, sit there is what we should be doing a lot of times. And a lot of times we do a lot when we could do a little and really allow that patient to have a better quality of life and a really longer life.
Aggressive relapse is characterized by a rapid rise in the M protein marker, usually accompanied by “I feel lousy, I’m tired, I have more bone pain, I just don’t feel right.” And then in terms of objective findings, one can see rises in the creatinine, worsening of renal function. In other words, worsening of blood counts, usually anemia, but it may be white blood cells and platelet counts, as well. Calcium levels can rise, as well. And then on x-rays, one can see new holes in bones or on MRIs, masses that weren’t there before. So, those patients need to be gotten after pretty quickly.
Jatin P. Shah, MD: The goals of therapy for aggressive and nonregressive relapse, I think are actually quite similar. At the end of the day, we, as treating physicians, and our patients want to have an active regimen that gives good disease control. So, you’re looking for a combination that’s highly active, well tolerated, and, importantly, has long-term disease control.
When we think about an aggressive relapse or a nonaggressive relapse, we may think of the other goal of therapy, which is really getting rapid disease control. For an aggressive relapse where you have some end-organ damage, you may want to use a combination that gives you more rapid disease control to reverse some of that end-organ damage. But, ultimately, the goal of both an aggressive or nonaggressive relapse is to get good disease control with a good, well-tolerated combination. But, importantly, one of the things that we need to start thinking about is also long-term disease control, as well. I think that’s the key message here. Historically, when we thought about aggressive or nonaggressive relapse, we’d think about using a three-drug versus a two-drug regimen. So, for example, in an aggressive relapse, we may consider a three-drug regimen; in a nonaggressive relapse, we think of a two-drug regimen, and that’s been the treatment paradigm that we’ve always thought about. I think that’s still important to an extent.
When you think about an aggressive relapse, you want to think about a combination that’s going to be rapid disease control and start your therapy right away, as opposed to a nonaggressive relapse where maybe you can watch that or observe that or give a little more less intensive therapy. But I think that’s changing now because what we’ve seen with multiple trials is that the three-drug combination is superior to two-drug combinations and that includes if we look at a PI (proteasome inhibitor) plus an IMiD. If we look at the TOURMALINE study or the ASPIRE study, where we looked at carfilzomib and Revlimid or ixazomib and Velcade/Revlimid, both were superior to Revlimid and dexamethasone.
If we look at our new monoclonal antibodies with elotuzumab with lenalidomide/dexamethasone, and soon to be daratumumab, you’ll see consistently that three drugs are better than two drugs in progression-free survival and overall response rates. So, using aggressive and nonaggressive relapse to define if you’re going to use a three-drug versus a two-drug regimen has shifted. We still think of aggressive relapse to get rapid disease control. But I think importantly now, regardless of the type of relapse that we see, we’re seeing that a three-drug regimen is probably the best option for all of our patients. It’s no longer using a three- versus a two-drug that we need to think about when we think about the type of relapse and the type of therapy we choose; but now, we need to start shifting in terms of thinking about long-term disease control.
Importantly, with all of our three-drug options, they all have high response rates globally; they have a nice PFS that we see. And sometimes it’s difficult to compare across trials. But now we need to start shifting our mentality since we have lots of active regimens. And it’s no longer about the immediate disease control, but it’s also about long-term disease control, and that’s what our patients really want. Our patients want to say, “What can I do now to control the disease? What can I do to maximize my chance of being still in remission not 6 months or 8 months from down the road, which I think is important, but what am I going to do to maximize my chance of still being in a remission in a nice combination, 2, 3, 4 years down the road?” And I think that’s where we need to start shifting our mentality when we think about aggressive and nonaggressive relapse. It’s no longer about three drugs versus two drugs; it’s also about adding in this other thought process of saying, “Let’s think about long-term disease control, as well, in addition to the early disease control that we see, as well.”
Transcript Edited for Clarity