Twice Weekly, Biweekly, or Somewhere in Between? Updates on Dosing Schedules in Multiple Myeloma With Rahul Banerjee, MD, FACP, and Gurbakhash Kaur, MD

Rahul Banerjee, MD, FACP: Welcome to Oncology Data Advisor. My name is Rahul Banerjee. I'm Assistant Professor of Medicine at the Fred Hutchinson Cancer Center in Seattle. September is Blood Cancer Awareness Month and as a result, we're doing several episodes this month around multiple myeloma. Today, it is my honor to speak with Dr. Gurbakhash Kaur about dosing of medications in myeloma—twice-weekly, biweekly, or somewhere in between. Dr. Kaur is an Assistant Professor of Medicine at the University of Texas Southwestern Medical Center in Dallas. She specializes in multiple myeloma and amyloid light chain (AL) amyloidosis.

Dr. Kaur, Gurbakhash, it's a pleasure to host you today.

Gurbakhash Kaur, MD: Thank you for having me, Rahul.

Dr. Banerjee: Some of these things are topics that are near and dear to both of us, so let's jump right into it. So, in the title, I said twice-weekly versus biweekly. I always get confused. Apparently, biweekly is every other week. Twice-weekly is twice per week. It can be once-weekly. Let's talk about all of those or more with bortezomib. How do you dose bortezomib during induction in your practice, and how does this differ from how some of the trials were done?

Dr. Kaur: Well, historically, the trials were mostly done with 1, 4, 8, 11—so twice a week dosing, right? That's how the trials have been done, but in our clinical practice, we deviate from this, and it's for several reasons. So, I dose bortezomib on a weekly basis whenever I do induction, but even in the relapsed/refractory settings, if I end up using a bortezomib-based regimen, I prefer to keep bortezomib only once a week. This is to make it patient-friendly, number one, because myeloma is a chronic disease, and they spend a lot of time with us. And they don't need to be seeing us twice a week if they really don't need to be seeing us twice a week. That's a big motivation for me, actually.

The second is the side effects, and particularly, peripheral neuropathy. The rates are as high as 30% when you do twice a week. So, I feel that when somebody's living for 10 years and their myeloma's under control, but then it's the chronic debilitating neuropathy that's impacting their quality of life, I think there's an onus on us as providers to take responsibility and to be more mindful of how we schedule and give these drugs.

Dr. Banerjee: Absolutely, I think it's important to remember—and I've seen this, you've probably seen this even more—that some of these patients have neuropathy for years afterwards, even when they're on lenalidomide, like lenalidomide maintenance thereafter. With bortezomib, the neuropathy can really, as you said, be quite debilitating to them. It makes sense for us to deescalate as we can. Does that change whether someone's transplant-eligible or transplant-ineligible? Or for everybody, once-weekly bortezomib?

Dr. Kaur: Well, if somebody's transplant-ineligible, then I prefer to use the MAIA regimen: daratumumab plus lenalidomide plus dexamethasone.

Dr. Banerjee: Myself as well.

Dr. Kaur: If somebody is transplant-eligible, I tend to use a quadruplet—daratumumab, lenalidomide, bortezomib, and dexamethasone—in all comers irrespective of their high-risk status or not. So, that is my preference, and I still do once-a-week bortezomib.

Dr. Banerjee: Likewise. That's exactly what I do for both transplant-eligible and ineligible. This is very helpful. So then, let's move on; staying on the topic of bortezomib and now switching to the other side, let's say someone did undergo transplant, do you ever use bortezomib for maintenance either because of lenalidomide refractoriness or, I should rephrase, lenalidomide intolerance, or because they have higher cytogenetics? And if so, when you dose bortezomib in this setting, how do you dose bortezomib in terms of dosing and frequency?

Dr. Kaur: I very infrequently use bortezomib maintenance partially because many patients end up having peripheral neuropathy even with once-a-week dosing. It's mild. It might be grade 1, but I do not want them to progress to grade 2. So, keeping that in mind, I use it particularly in 4;14. I also use a second-generation proteasome inhibitor (PI) such as carfilzomib. I tend to not do a weekly regimen and not every week. I still do, say, once a week, but I might do it every two weeks just as a maintenance protocol.

Dr. Banerjee: Very helpful. So, now we're going from twice-weekly to biweekly in this setting and every two weeks, and I agree. So, it's worth noting to the audience listening to this to think—correct me if I'm wrong, Gurbakhash—the Emory group first presented some of this doublet maintenance, like bortezomib plus lenalidomide (V plus R) maintenance, and they had once-weekly bortezomib. I packed it very similar to you, that I'll space it out to every other week. And similarly, for carfilzomib, I'll do the same.

So, let's talk about carfilzomib. Each topic is going from one, by one, by one to the next topic. So, for carfilzomib, let's say someone does have relapse disease after they've been on lenalidomide maintenance, and let's say you're considering daratumumab/carfilzomib/dexamethasone (Dara-Kd) or isatuximab/carfilzomib/dexamethasone (Isa-Kd), how do you dose carfilzomib for your patients, and why?

Dr. Kaur: So, Rahul, before I even go into this, I think that this topic is very near and dear to your and my heart because, historically, we had a disease that really didn't have good treatment options. So, I think the trials—and it's always easy to be a Monday-morning quarterback and reflect and say, "Hey, this approach is wrong." That is essentially not the case over here. I think endeavors have been done by our colleagues who move these therapies into clinical practice. Back then, we didn't have good options. We didn't have a bispecific or a CAR T waiting. So, you wanted to get the biggest bang for your buck and that may have driven why scheduling practices were the way they were recommended. And now we are in a different era and we need to adapt.

So going from that into how I dose carfilzomib—and with carfilzomib, the dosing is everywhere. First of all, when it comes to the grams, is it 20/36 or 36/36? Day 1 and 2, 8, 9, 15, 16—is it 27 mg/m² every day? Or is it 56 mg/m² once a week? 56 mg/m² two days a week? Even 70 mg/m² once a week? So, we have such degree of variability in the doses of it, in how frequently we give it. And we don't have a unified approach and that is what it is right now.

Like I said, I do value quality of life. And I like my patients to spend as much time away from my office and my practice as they can, without compromising their efficacy. So, generally, the first dose is 20 mg/m² on Day 1. Subsequently, I will transition into a 56 mg/m² on the second week and the third week. So, it's a weekly dosing, but I don't do twice a week dosing here as well. Part of that is, obviously, quality of life and time away from the doctor's office. And the second is this fear of many patients who are wary of having the cardiac toxicity profile that comes with carfilzomib and such, as it can be as simple as chest pain, to shortness of breath, to actually having systolic dysfunction. And we know that it's higher when the doses are higher actually.

So, I tend to not utilize the 70 mg/m² unless I really need to. Somebody who's young and has very high-risk disease and has an explosive relapse, I think those are the settings where I do go for that. That's not to say I rule it out completely, but generally my go-to regimen is 56 mg/m² on a weekly basis.

Dr. Banerjee: And on a once-weekly basis. This is very elegant commentary. A couple of things you said I'll just to draw attention to. I just hadn't thought of it that way—you're right that there was a time when KRd, or Dara-Kd, more recently, that was kind of destination therapy for many of these patients. And there, it makes sense to hit the maximum tolerated dose of carfilzomib that you can. We have better options in later relapses for sure. And you're right, that heart failure risk, the hypertension risk—the heart failure more than hypertension obviously—that scares patients, especially some of our older patients who have more comorbidities at baseline. And you're right, all those studies that show this carfilzomib heart failure signal where typically 56 mgs/m² twice-weekly, it doesn't mean it doesn't happen at once-weekly. But I agree with you, I think the dose really makes a difference, how much intravenous (IV) fluids make a difference, and so forth. So, this is very, very helpful. Do you ever use 70 mgs/m² once per week the way that ARROW trial tried to do, or you do 50 mgs/m²?

Dr. Kaur: I have used 70 mg/m², like I said, for the patient who desperately needs it, the one who has very explosive disease and high-risk and I need to get really, really good responses. I think those are the patients I tend to reserve that for. Maybe for my older patients, I don't go for the 70 mg/m². My younger patients, I do, in the right context.

Dr. Banerjee: Absolutely. Makes sense. Right, this context makes a big difference on how we approach our patients. So, before we talked about these proteasome inhibitors (PIs) of bortezomib and carfilzomib in the setting of "we didn't have more advanced options." Now we do have advanced options. Chimeric antigen receptor T cells (CAR T) and bispecifics come to mind. Bispecifics are fascinating. Because I know you just said how carfilzomib dosing is all over the place, I would say bispecific dosing is also all over the place in terms of frequency. And as you know, we're filming this interview on September 15th, 2023, and we now have three bispecific antibodies that are approved, teclistamab, talquetamab, and elranatamab.

Let's talk about teclistamab because that's the one that I think you and I, maybe you, have the most experience with here as a BCMA-targeting bispecific antibody. How do you dose teclistamab? Not so much the step-up dosing period—let's forget about Cycle 1—from Cycle 2 onwards, how do you dose teclistamab? How would you like to dose teclistamab? What makes you change the frequency of dosing? How do you approach that for your patients?

Dr. Kaur: So, I think we're at an interesting juncture when it comes to bispecific therapy. We are finally at a point where our decision to whether somebody gets teclistamab or CAR T is not really driven by availability, but more so by patient preference and what their biological needs are in terms of disease.

My first preference is to go to CAR T for patients who I think are candidates for it. And then bispecific therapy is a second option because, again, like I said, the theme of my practice is time away from the doctor so you can enjoy your time away from my office and don't have to go there on a weekly basis. But not everybody is going to get CAR T because of a myriad of reasons that have been highlighted in every publication or podcast online. So, in that case, we have to be practical, and bispecific therapy becomes a very good option, a treatment that has really, really good response.

We do our step-up very differently. We don't do the full; we do it, I believe, on one, three, and five, and our patients are out by the seventh day just because hospital beds are always in crunch. So, we try to squeeze as much time out of that as we can.

Up until this point, the majority of my patients who needed teclistamab are the ones who needed it once a week, as in I didn't have the liberty to go to an every-two-week option or every-four-week option because their disease responded. They responded and they actually relapsed off of it, and I had to go to something else. And these were patients who were on the waiting list for CAR T and all that once it got approved.

Now we're going into a phase where I think that's going to change. And I think we have very little data that we can space out dosing. That's just the reality of it. What would I like to have happen? I think we need to have a response-driven approach when it comes to bispecifics, and that's partially driven by how good they are, how much they cost, and the significant side effects that they carry—infections not being understated.

So, I would love an approach and I might tailor my practice towards that, that if they achieve a stringent complete response (CR) or they achieve a minimal residual disease (MRD)–negative response. After a certain amount of time, I may stop or I may change the frequency of the bispecific. That's how I foresee myself going into in the coming months when it comes to teclistamab.

Dr. Banerjee: Agreed. This is very, very helpful. And I know what you're getting at is a response-driven paradigm more than a time-driven paradigm. Obviously, it's a little bit of a mix of both. But I think you're right, many of us are used to, "All right, six months of this, six months of this. So, if you achieve this in six months, then do this." And what you're getting at absolutely makes sense that that benefit-risk ratio, the benefit of this drug at weekly dosing versus the risks in terms of infections where you're talking about cytomegalovirus (CMV) reactivation, weird viral things that, kind of shifts over time. If someone's already in a CR, that benefit-risk is now going more towards a risk with weekly dosing. So, it makes sense.

I guess, maybe I'll go back to wrap things up. One of the themes you brought up throughout this whole podcast is the idea of time toxicity, or just the amount of time that people are stuck spending in clinic, whether it be for twice-weekly bortezomib, which you avoid for that reason, twice-weekly carfilzomib, or once-weekly teclistamab. Are there other strategies or things that you think can help with time toxicity? Or how do you spread the awareness to others in the community to start implementing this and not having patients come in so, so often in the clinic?

Dr. Kaur: I think we can think all we want and we can have theories all we want, but we need to produce the data to change minds to say, "Hey, this approach is equally effective if you do it this way, and still you will get the efficacy that you want", because all of us are well-intentioned and we don't want to compromise our patients' care and the response they're going to get from a therapy. So, one of the things that you and I are doing is, with our real-world project, we're doing the Flatiron real-world database analysis, where we've looked at patients who've gotten bortezomib-based regimens in terms of induction. And we've evaluated, well, how often did they get once-weekly? How often did they get—or, not even how often, but what are the patterns of prescribing bortezomib in the community, in the academic centers? And then compare the efficacy, assess the side effect profile when it comes to peripheral neuropathy, and make a case for it.

I think that sort of evidence needs to be out there because it is not sexy in today's day and world to do a study that's just going to say, "Hey, once-weekly bortezomib versus twice-weekly bortezomib." That's just not going to get funded. There are bigger questions to ask from a funding perspective. But I think the questions you and I are asking in this project will answer that, and we'll make a case for it. So, I think we need to generate data to convince minds that this approach is okay, and this approach is perfectly fine to pursue. And that's how we're going to make change.

Dr. Banerjee: I love that—very prescient words of wisdom there. Yes, for anyone who's listening—not anyone, lots of you who are listening to this podcast or reading it, stay tuned, Dr. Kaur and I are working on some ideas to change some hearts and minds in favor of once-weekly proteasome inhibitor dosing in terms of response or toxicity-guided de-escalation of bispecific antibody dosing, and so forth. So, stay tuned.

Gurbakhash, this has been awesome. I actually learned a lot even though we've already worked together on a bunch of projects already. So, thanks again, for your time. I really appreciate it.

Dr. Kaur: Thank you so much, Rahul. As always, you're wonderful. And thank you for having me.

Dr. Banerjee: Of course, and to all our readers, again, thanks again for listening in, or tuning in, or reading into this. This has been another episode of Oncology Data Advisor. Thank you all. Have a good day.

About Dr. Banerjee and Dr. Kaur

Rahul Banerjee, MD, FACP, is an Assistant Professor in the Division of Medical Oncology at the University of Washington, and he also holds a faculty appointment at the Fred Hutchinson Cancer Center. He previously completed his Hematology/Oncology Fellowship and Advanced BMT/CAR-T Fellowship at the University of California, San Francisco. His clinical interests are in multiple myeloma, amyloid light-chain (AL) amyloidosis, and chimeric antigen receptor (CAR) T-cell therapy. His research interests are in toxicity management, digital health, and the patient experience.

Gurbakhash Kaur, MD, is an Assistant Professor of Medicine in the Department of Internal Medicine at the University of Texas Southwestern Medical Center. Dr. Kaur's specialty and research expertise revolves around stem cell transplantation, immunotherapy, CAR T-cell therapy, and multiple myeloma. She actively participates in clinical trials for novel therapeutic options and quality of life improvements in treatment of multiple myeloma.

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Transcript edited for clarity. Any views expressed above are the speakers' own and do not necessarily reflect those of Oncology Data Advisor.