Beyond the Basics: Bispecific Antibodies and the Care of Patients with Relapsed/Refractory Multiple Myeloma

Kevin Brigle:

Hi, and welcome to JADPRO's Roundtable discussion on Beyond the Basics: Bispecific Antibodies and The Care of Patients with Relapsed/Refractory Multiple Myeloma. My name's Kevin Brigle and I'm a nurse practitioner in the Heme Malignancy at the Massey Comprehensive Cancer Center at Virginia Commonwealth University in Richmond, Virginia. And it's great to be here with my colleagues Mary Steinbach and Kelley Julian. Mary?

Mary Steinbach:

Hi Kevin. Thanks for having me. So happy to be here with you and Kelley as well. I am a nurse practitioner at Huntsman Cancer Hospital in Salt Lake City, Utah, and honored to be here, as I said.

Kevin Brigle:

Kelley?

Kelley Julian:

I am Kelley Julian. I'm a clinical pharmacist also working at Huntsman Cancer Institute. It's a privilege to be here with you both. Thank you for having me. And I will try to add what I can from the pharmacist perspective in relation to further topics about bispecifics.

Kevin Brigle:

In the first part of this series, we talked about bispecific antibodies and we compared and contrasted them a little bit with CAR-T. In the second part we talked about bispecific antibodies, specifically the BCMA-directed bispecific antibodies and when we might use them. And we looked at a case study. Now in this third part of the series then we are going to be talking about case studies and looking at the GPRC5D-directed bispecific antibodies. Mary, would you like to move ahead with that?

Mary Steinbach:

Sure, thank you. I'm happy to kick us off. You can talk about GPRC5D without talking about BCMA, but I think when we look at NCCN guidelines and then we think about the way we're treating relapsed patients now a lot of patients are going to have exposure to BCMA before GPRC5D. And the GPRC bispecific antibody is talquetamab. There is only one, and it is actually the only GPRC5D drug we have in the whole myeloma space. It's really revolutionary in that sense that for patients who have failed BCMA and failed all their other therapies, this drug is still very likely to work well for them. It holds a very important position I think. And again, just to review our sequencing a little bit, we talked early on about offering CAR-T to patients who are eligible for it and meet criteria for it, and improving access to that is super important.

But when that is not a possibility or patients have already relapsed or progressed after CAR-T because that is now in an earlier line, certainly using a GPRC5D, I've seen it just do wonderful things for a lot of patients. And I thought that what we should do is just talk about GPRC5D first because it is quite different for us in the myeloma space. This is an antigen that is expressed on the surface of malignant myeloma cells, but also on keratin cells. The side effects here are a little bit daunting, can certainly have people shy away from use of this drug. But again, I think once you have experience with it and you get to witness patients live for 2 to 3 years longer than anyone ever thought they did while on this treatment, hopefully you'll find it easier and easier to give. Because GPRC5D is expressed on keratin cells, most of the side effects are related to skin, hair, and nails.

Patients tend to get a very dry mouth and this happens quickly. They can get dry, brittle nails that crack, they can have skin rashes. The dry mouth leads to taste changes, taste changes can even occur outside of dry mouth though I've yet to meet a patient who didn't experience dry mouth while on the drug talquetamab. And then with that can come anorexia and weight loss. And it's really important to monitor patients closely. I thought we also would just take a look, I guess I'm backtracking a little bit here, but if we talk about sequencing of a bispecific in those who have had a prior BCMA exposure, talquetamab still has very good outcomes for these patients. Kelley, before we get into a patient case where we treat the patient with talquetamab, do you have anything to add from your perspective?

Kelley Julian:

Yes, thank you. I think this would be a good time to talk about a potential talquetamab bridge. I know that we're still working on getting CAR-T in earlier lines of therapy. We talked about that previously. But often these patients are coming to us and they're 4 prior lines in and they're just now gearing up for CAR-T, and they're having an extensive progression where we need to have a bridging therapy between their last line of therapy that they progressed on while the CAR-T cells are being manufactured, which can take anywhere from 2 to 4 weeks, potentially even longer. And where our CAR-Ts are anti-BCMA, it's like, "Talquetamab has a really niche unique mechanism here where we can target a different part of the malignant plasma cell and hopefully still not affect the efficacy of the CAR-T." And we've done this countless times in our practice at Huntsman.

I've collected data on a lot of these patients. And the bridge can be anywhere from 1 to 3 cycles, potentially even longer. We've also had patients who we thought we were putting on a bridge and then they did so well that we in fact didn't even end up going to CAR-T or we're waiting on CAR-T. And I think the sequencing question is an interesting one. Often we use it after a BCMA agent, but I would say that this mechanism is really beneficial for a lot of our patients who are in between a rock and a hard spot. And we may use this in place of other bridging strategies in the eligible patients. I really like it here. While the side effects are daunting, as you said, we've seen that in practice, if you use it as a bridging therapy, we can really work on mitigating those side effects up front and they get better after the bridge is over and then you take them to CAR-T, they're not long-lasting. And we can try to harness the patient's expectations in that setting.

Mary Steinbach:

Awesome, thank you. Kevin, are you seeing talquetamab used as bridging therapy prior to CAR-T?

Kevin Brigle:

We used it quite a bit. And again, I think it depends on how you limit the use of it up front too, where patients don't go into CAR-T with a lot of those toxicities. The one thing I would point out when we talk about use that as a bridge, again, you collect the cells for CAR-T prior to using the talquetamab. I think that's an important thing to bring up also, not to collect them after you started the CAR-T. But it's very, very, very effective and it's amazing how quickly you can get site reduction, and those patients get really good control of their disease, which is going to bode better for them in CAR-T then in the long run.

Mary Steinbach:

Absolutely. And it's so nice when you can approach the patient with the side effect profile and say, "But you're only going to get a few doses. It will be limited overall." Though, I still am always going to build the case for treating a patient for the long term on talquetamab and I think for a lot of people the symptoms do get better over time. Why don't we just jump into this patient case. This is a high-risk patient who is on the younger end, in her 50s, just diagnosed a little bit over 2 years ago and has blown through therapies. She did get Carvykti early though unfortunately remission was only about 12 months. And having blown through our more conventional myeloma drugs and the classes of proteasome inhibitor, immunomodulatory agent, anti-CD38 antibody, the patient received Carvykti, had 12 months of progression-free survival, and then unfortunately just slowly had a biochemical progression.

But as we discussed in our first round, in a high-risk patient, biochemical progression is something you should probably act on sooner rather than later. And knowing that, this patient was started on talquetamab, and as I mentioned talquetamab is on normal keratin cells and this is where the side effects come from. Like our other bispecific drugs, it's given in a step-up fashion, there's actually 2 dosing schemas for talquetamab. If you look at the FDA packaging, it can be given weekly or it can be given biweekly. I don't know anyone who is giving talquetamab weekly. The efficacy is about the same, side effects are about the same. And actually, in the biweekly dosing side effects are probably a little bit better. We do only biweekly. Kevin, do you have any experience with anyone getting it weekly?

Kevin Brigle:

I've never used it weekly, ever.

Mary Steinbach:

Perfect. And after the ramp-up, the ramp-up is really the longest ramp-up of all of the bispecifics that we have. Whether your institution is ramping up inpatient or outpatient it takes about 11 days to get through that. And there's probably a couple approaches to ramp-up, Kelley, because we tend to give the weekly ramp-up but then we jump right into the biweekly dosing. Did I say that correctly?

Kelley Julian:

Exactly. On the patients who we admit and do the ramp-up inpatient, we try to minimize the admission if we can as long as there are no major safety issues with CRS or neurotoxicity. We do the 1, 3, 5, monitor for the 48 hours. If there are no issues, then we can discharge and we give the full 0.8 mg/kg dose, the first full treatment dose outpatient, and then we go every 2 weeks from there. But out-patient, we keep it a little bit more spaced out. We do exactly as the package insert states just to give the patients a little bit more time since they're outpatient.

Mary Steinbach:

Awesome, thank you. And I think in terms of cytokine release syndrome and ICANS, I sort of package, as we mentioned before, all the bispecifics together in this space. They have pretty similar occurrences with ICANS being pretty rare overall for all of these drugs. But let's spend most of our time talking about symptom management with the dry mouth that patients can experience and the skin reactions and nail reactions. Kevin, do you feel like there's any one magic thing that helps all these people?

Kevin Brigle:

Education. It's probably the one drug I never minimize side effects on to begin with. We all have our drugs and we go, "This is really well tolerated and this, this, and this," but you rarely see it. But talquetamab is the one which I will tell patients the side effects because when it's bad, it's bad and I never minimize that and I'm always pleased if they don't get it quite as bad as I described, I guess is the best way to put that. Education up front that these things are going to happen and that things are going to taste bad and you're going to get a dry mouth and you're going to have skin issues without a doubt and here's some of the things we can do to help. Education, education, that's the big one right up front.

Mary Steinbach:

Perfect. Those oral toxicities are happening in almost everyone. And as you mentioned, and I think technically it's like 80% of patients and they tend to-

Kevin Brigle:

And it happened quickly.

Mary Steinbach:

That's exactly what I was going to say. Before this patient is done with ramp-up, they're most likely experiencing them already. And part of the supportive care that we do at Huntsman is to start dexamethasone, swish and spits, and alongside that some antifungal like nystatin swish and spit. If the patients can do that because of such a severe dry mouth patient's tongues can be quite tender, there can be pain. I have seen patients experience ulcers as well, although that is very rare. I think I always try to encourage people that these do resolve over time. We know with all these toxicities too that less frequent dosing is what makes a difference.

We tend to follow markers very closely and people were starting on talquetamab because once you see a response you really can back down on the dosing and really improve on patient symptoms. For this high-risk example that we're using with a progression after CAR-T, at Huntsman we will follow markers if they have a light chain or monoclonal protein that's measurable probably every week to at least every 2 weeks. And if we're pretty confident this patient's having a response and their symptoms are severe, then we'll back off of that Q2 week dosing to maybe once every 3 weeks. And then the majority of patients we have here at Huntsman who have been on talquetamab for 8-plus months and have really deep long-standing remissions, they're going to be on monthly dosing and I can think of more than a handful who are doing very well and have improvement in their dry mouth and taste changes over time with that monthly dosing. Kelley, do you want to talk about the table that we developed at Huntsman for the supportive care?

Kelley Julian:

I would love to. Shout out to Mary and one of our nursing colleagues, Carrie. They went to a meeting and we're taking frivolous notes and they came back and they said, "We should make a talquetamab table." I said, "Let me do that for you." We now have this reference, which is huge because as Kevin alluded to, you can experience these side effects super quickly even after the first dose of talquetamab. Having this resource for the inpatient team is extremely helpful. We've developed this and you can see that we've got dysgeusia, dysphasia, dry mouth, mucositis and thrush, rash, hand-foot syndrome, pruritus, and nail dystrophy and it's like, "What is the early prevention? What can we do even day 1 before the patient is technically even started or tell them to do that can support them through this and stave off some of these severe side effects before they're grade 1, grade 2, grade 3, and we're having to look at dose holds?"

You can see things listed here. The early prevention is we do that at the ready and we have these conversations. Like Mary and I had a conversation today, we've got a patient starting and we want to make sure we give her the benefit of the doubt and as far as tolerability goes, we're going to have the dex and the heavy moisturizers ready and potentially the nystatin. We'll have to circle back with that, Mary, just to make sure we take care of her. But you can see that a lot of this isn't even pharmacologic. And things like for dysphasia—smaller bites, sitting upright—having these discussions with the patients about what they can do on their own that isn't necessarily taking an additional pill goes a really long way. Then honestly having a dietician support because it feels like a majority of the patients I've looked back on and collected data on have had either moderate or significant weight loss.

And how do we support them through that and give them the tools they need? Getting them plugged in with a dietician upfront, at least at some point during cycle 1, is critical for them to maintain their weight. Some people are really happy about that at first, but then how do you stabilize that and prevent them from losing any extra? It goes a long way. And having a tool like this where you can grade things out and you're seeing these patients, especially if you're not quite sure if we can push out the frequency of dosing on somebody who their markers are moving but maybe not as fast as we want, to try to push them through and get them into a better place, really goes a long way for the providers taking care of the patient both inpatient and outpatient.

Mary Steinbach:

One of my favorite tricks to talk to patients about is using the food squeeze packets. The yogurt squeeze packets or, now for toddlers, you can basically get a full meal in one packet and it has your protein, vegetables, fruits, like all the servings, and sometimes they taste bad, but these patients don't taste that well. Often I'm recommending like the salmon one that has Omega-3s and has good fat in it and because Kelley, as you mentioned, weight loss, some people can appreciate that at times, but a lot of this weight loss is muscle mass loss. And we want to keep our patients as strong and mobile as possible. Talking to a nutritionist or dietitian can be helpful. And then those squeeze packets, you don't have to chew, you don't have to produce a lot of saliva to get it down. I've experienced a lot of patients similar to that acute post-transplant mucositis when they can't chew meat or chew bread because there's just not enough saliva production and things don't taste good. That can be a good trick to use. Kevin, do you guys have any tricks there at the Massey?

Kevin Brigle:

I don't think any tricks that really aren't either well published or things that you talk about at all. I think one thing to keep always in consideration as well is the social aspect of eating. Because meals are meals and sitting down at the table is an important thing and when patients can't participate in that for a lengthy period of time, that's not just a stressor on the patient but on the family as well. I think understanding that part of it as well, that you're not going to be able to sit down at a meal with everybody else and enjoy it and then hopefully you will. I try to prep for that as well.

Mary Steinbach:

That is a really good point because people do tend to just lose their appetite too and then not want to socialize because they know it's not going to go how they remember it going and have those sensual experiences that you can have with food and drink. I think also we should probably just touch on the role that us as APPs have alongside our PharmD colleagues in keeping patients on treatments like this that can be super helpful. The more we know about what the clinical trial tells us about these drugs, but then experiential knowledge can be super important. But as APPs and PharmDs, it's really us on the front line, talking to patients, educating them, educating the families, setting expectations. And thankfully when patients do respond to this drug, it tends to last a long time and you can space out that dosing and patients do much better.

And also on the flip side, there's not the severe infectious complications that we see occurring with our BCMA-treated bispecific patients, though in the future I think we will see more combinations of bispecifics given or even talquetamab in combination with some of our more historical myeloma drugs such as pomalidomide or daratumumab. These can really add efficacy is what we're seeing in some clinical trials that are out now. There's definitely more to come on this. And with that I think we're going to see these bispecifics moved into earlier lines of therapy and that's where discussions with your patients about what their goals are and what types of symptoms they're up for experiencing at what timepoints can be really important.

Kevin Brigle:

I think when that happens, the decisions get tougher because every mile on the drug we have will be second line at that point, a lot of treatments.

Mary Steinbach:

I know good problems to have, but it does complicate the conversations and complicate knowing what is next best.

Kevin Brigle:

That brings us to the end of this discussion. I'd like to thank my colleagues, Mary Steinbach and Kelley Julian, for taking the time on their busy days to talk with me. For more information and to view the other discussions, Part 1 and Part 2 on multiple myeloma, please visit JADPRO online at jadpro.com. Thank you so much and have a great day.