Adding Isatuximab to Standard Backbone Prolongs PFS in Myeloma

Combining the anti-CD38 monoclonal antibody isatuximab (Sarclisa) with the standard backbone of bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone (VRd) significantly improved progression-free survival (PFS) in transplant-ineligible patients with newly diagnosed multiple myeloma, according to two phase III trials presented at the American Society of Clinical Oncology (ASCO) annual meeting.

MedPage Today brought together three expert leaders in the field: Moderator Joseph Mikhael, MD, is joined by Amrita Krishnan, MD, and Tulio Rodriguez, MD, all of City of Hope, for a virtual roundtable discussion. This first of four exclusive episodes focuses on the IMROZ and BENEFIT trials.

Following is a transcript of their remarks:

Mikhael: Hello and welcome to this roundtable discussion here at ASCO, the American Society of Clinical Oncology, where we are going to be discussing some of the key abstracts in multiple myeloma. These are amazing times in myeloma, lots to discuss, lots to think through, and I’m absolutely privileged to be joined by experts in the field. So my name is Dr. Joseph Mikhael. I’m a professor at the Translational Genomics Research Institute, part of the City of Hope family. And on the City of Hope family theme, I have two amazing friends and colleagues with me, Dr. Amrita Krishnan from the City of Hope in California, and Dr. Tulio Rodriguez, who is a little bit more local, but I’m going to let them introduce themselves more formally so we can know who they are. We’ll start with you Amrita.

Krishnan: Thanks so much, Joe. My name’s Amrita Krishnan. I’m director of the Judy and Bernard Briskin Center for Myeloma at the City of Hope, and also professor of hematology and hematopoietic cell transplantation and director of hematology for the City of Hope Irvine campus.

Mikhael: Did you fit that all onto the ASCO badge? [laughter] That’s fantastic. And Tulio.

Rodriguez: I’m Tulio Rodriguez. I’m the director of the division of Hematology, Bone Marrow Transplantation, and Cellular Therapy at City of Hope, Chicago. I’m thrilled to be here. Thank you for the invitation.

Mikhael: Oh, we’re delighted to have you here. It’s nice to have a local, it’s nice to have someone from sunny California, although it sort of feels like California here in Chicago with the sun and the heat that we’re experiencing.

Rodriguez: Today does, right.

Mikhael: So the plan today is to think through some of these key abstracts. Historically, ASCO was perhaps a meeting where we didn’t see a ton of myeloma, but we have just seen an inordinate amount of myeloma. We’re not even going to have time to talk about all the phase III trials alone, all of the abstracts in myeloma. But we’re going to start thinking about newly diagnosed multiple myeloma.

And maybe I’ll just set the stage initially to say that there has been this major shift over, in particular the last 1 to 2 years, based on the initial GRIFFIN study and then the PERSEUS study that looked at adding a fourth drug to our usual combination of bortezomib, lenalidomide, and dexamethasone, that fourth drug being daratumumab [Darzalex]. And so now that really has become the standard of care — quadruplets in patients who are planning to go to an autologous stem cell transplant. And you’re both transplanters, so I have to make sure that we include that discussion.

But here at ASCO, we now have two abstracts looking at transplant-ineligible patients. And I know that may be even part of your input here, should we really be making that distinction anymore, transplant eligible/ineligible? But for now that that distinction has been made in transplant-ineligible patients, we now have two abstracts that are looking at quadruplets. One of them is the IMROZ study where we’re seeing isatuximab added to VRd versus VRd. So a somewhat similar design to what we saw with adding daratumumab to VRd in transplant-eligible patients. And interestingly a second study — the BENEFIT study — looking at isatuximab Rd, so perhaps replicating the historical standard of care now in transplant-ineligible patients of giving daratumumab, lenalidomide, dexamethasone based on the MAIA study. But that’s the control arm. The intervention arm is now adding bortezomib to that isatuximab, lenalidomide, and dexamethasone.

So lots to discuss enough from Dr. Joe, let’s turn it to you. Maybe Amrita, let’s start with you and IMROZ. Tell me your thoughts about now moving to a quadruplet in patients who historically is transplant-ineligible. We were used to even be nervous giving a triplet.

Krishnan: So I think you nailed it, Joe, with the whole idea that we traditionally didn’t give triplets to older patients. And of course IMROZ only goes up to age 80. So there is some distinction to be made there in terms of the frail elderly patients still. So it’s still not a one size fits all, but I think it really cements, as you sort of very eloquently put it, in the non-transplant setting now, is there a benefit to using a quadruplet? And there seems to be pretty definitively from the IMROZ data. The answer is yes. So I think this is very practice-changing in that sense.

Mikhael: Tulio, do you feel the same way?

Rodriguez: Absolutely. I feel the same way. And something that impressed me about that study is the long-term progression-free survival. So we’re talking that median follow-up of almost 60 months, I mean we’re talking about 59 months. The median progression-free survival has not been reached for this drug quadruplet, which is very provocative. As Amrita just mentioned, we’re talking about patients who are fairly fit, those frail patients or older than 80 years old are not a participant of this study. But anyways it’s very provocative data.

Mikhael: I agree with you. So first of all, just as you’ve said, the gold standard as it were, what we typically use now with based on the MAIA study set a very high bar. I mean it has really revolutionized how we treat myeloma. That study using daratumumab-lenalidomide-dexamethasone versus lenalidomide-dexamethasone, in that intervention arm at 5 years, over half of patients still hadn’t progressed and over two-thirds of patients were still alive. And that median age going into MAIA was 73. So it was a pretty high bar to set.

So to see it now exceed that or obviously we’ll need even longer-term data is striking to me. And I guess what it speaks to is the value of those multi-mechanisms of action. I’d love to geek out and talk about the biology of myeloma now and its complexity, but to keep it simple, having those multiple mechanisms of action seems to exceed the worry and the risk we have of the potential toxicity of joining them.

And I think what we’re going to see out of this study, and I’d like you both to comment on this, is it’s conceptually now wonderful to say, “Okay, I want to give a four drug combination.” The pragmatic point is how do I deliver that in the clinic? I often say there is no drug in myeloma that we give now the way it was first given, right? We learn to maneuver these tools a bit better. Maybe we use a lower dose of lenalidomide, we use the bortezomib subcutaneously and once weekly, and sometimes even every other week in older and more frail patients. But I think what this study is showing us is that it is worth trying to get those multiple mechanisms of action together, even if we use lower doses or a less aggressive strategy than we may have done in the transplant-eligible population. Amrita, do you agree with that assessment or is that just Dr. Joe trying to make sense of it all?

Krishnan: No, I definitely agree with you because I think no one will be giving bortezomib twice a week and even the lenalidomide dose 25 mg, we don’t always start that dose in a older patient. Sometimes we start a little lower, assess tolerability, and then make a decision whether to escalate to full dose or not. So I think all those things will play into the real-world experience. It’s like cooking, right? We take the original recipe and then we tinker with it. So the same here.

Mikhael: Yeah, I think that that’s a perfect description. I always love your analogies by the way, but that tinkering becomes really important, doesn’t it? Because I think what happens is sometimes we may see it in this sort of idyllic world of a phase III clinical trial, but a community oncologist in Chicago that is referring you a patient says, “Listen, Tulio, come on, my patient has a bit of renal insufficiency,” or “my patient has diabetes, my patient is struggling with this. Can I really give this quad?” And what kind of advice do you give to that community oncologist who’s asking that question?

Rodriguez: Absolutely, Joe, even from the beginning, the designs, we started with the dexamethasone, remember that for elderly patients, we started just cutting down the dose from 40 to 20 and we did not see a big impact on outcomes. And that brings the point of when someone is transplant-ineligible, that is a moving target. So you start low and that patient, that performance most likely will improve over time as long as he continues responding to the therapy. And then you can start escalating the treatment. But certainly, absolutely adjusting and tailoring to the performance of that patient is completely necessary and make a lot of rationale.

Mikhael: And I think it’s important for all of us and for anyone in the audience listening, whether you are in an academic center already doing transplant and cellular therapy or out in the community, that tailoring is so fundamental because I would argue historically in myeloma, we haven’t been very good at doing frailty assessments and the like. We tend to bucket people, are you transplant-eligible or are you transplant-ineligible? And I think these kinds of studies help us.

And the second study that’s being presented, the BENEFIT study similarly, trying to look at that isa [isatuximab]-Rd versus now isa-VRd, obviously the intervention arm is the same as that in IMROZ. But again, looking at the multi approach that we can have that may not always be necessary to use that quadruplet depending, and as you mentioned in IMROZ, the age cutoff was at 80 as we see here with BENEFIT, that there may be opportunities, there may be individuals that you want to use that triplet, but there are different ways of approaching it.

And I think that becomes really important. It’s incumbent on us to not just look at the patient, say, “You’ll take it and you’ll like it and this is the way we give it.” And lastly, on your point, Tulio, I completely agree with you. As you may know, I’ve created this hashtag #downwithdex, and I think we have historically over “dex-ized” our patients. And in most of my patients now I’m planning that whatever initial dose, which very often in these transplant-ineligible patients shouldn’t be more than 20 mg, but only to give that for the first couple of months and then start to taper it down. Because I really do think patients and their partners are happy when we start to do that.

Rodriguez: And even the bortezomib dose, I mean it is kind of a weekly dose up to 18 months because interestingly, this trial endpoint is more response than progression-free survival. But the fact that they took in consideration, I mean the population that they were starting and they adjusted it simply instead of twice a week, once a week, and they were able to achieve those good responses, I think that is fascinating.

Mikhael: I think that’s critical. I think a lot of it’s even just preventing the potential neuropathy that can come and obviously having the conversation with the patient, right? I mean, I know it goes without saying, but we have to listen to our patients so carefully at the slightest hint of neuropathy. We need to make an adjustment, whether that’s reducing the frequency or sometimes having to discontinue it, because we don’t want to leave our patients with a long-term irreversible neuropathy because we’re trying to just follow a simple protocol. And I think that communication with the patient becomes really important. Because we’ve learned, unfortunately historically in some of our earlier transplant-ineligible patients, when we were aggressive with twice weekly and back in the day of SWOG, remember we started that study at IV bortezomib, people can really suffer. And so I think we have evolved in our thinking.

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