BCMA-Targeted Therapies Take Multiple Approaches in Multiple Myeloma

In an interview with Pharmacy Times, Ryan Haumschild, PharmD, MS, MBA, discussed his presentation at the Oncology Pharmacists Connect meeting, taking place June 15 through 17 in Austin, Texas. Haumschild, who is also Chair of the meeting, discussed new BCMA-targeted approaches in multiple myeloma, including CAR T-cell therapies, bispecific antibodies, and antibody drug conjugates.

Q: Why are BCMA-targeted approaches so important and effective in multiple myeloma?

Ryan Haumschild, PharmD, MS, MBA: Yeah, I think, you know, BCMA is such a novel target. And I feel like there's a lot that we still have to discover from cellular therapy to the antibody drug conjugates to others. And so I think that's really what's going to drive innovation. It's a great target, it provides really good, durable responses within the space. And I think it's even interesting of how do we use it potentially in the future in earlier lines of therapy? And how do we use it in the relapsed refractory setting to give more durable responses?

Q: BCMA seems to be targeted in 3 approaches: CAR T-cell therapies, bispecific antibodies, and antibody drug conjugates. Does your session focus on any of these in particular, or are there key advancements in each that you’d like to highlight?

Ryan Haumschild, PharmD, MS, MBA: Yeah, I think our session is probably going to hit on the 3 advancements. Antibody drug conjugates—we had 1 on the market, it came off, but we know there's clinical trials that are even studying it in earlier lines of therapy. I think we've been utilizing cellular therapy and CAR T that are BCMA-targeted, and we're actually excited to start seeing greater utilization and greater manufacturing capabilities. And I think that's exciting for us for treatment experienced patients, BCMA-exposed patients, and nonexposed. And then I think really where innovation is occurring right now in practice is the utilization of bispecifics. How do we harbor those BCMA agents to provide great responses, those that might not be fit enough for cellular therapy, but might be a great fit for bispecifics? And then how do we see us utilizing that not only in the inpatient phase of care, but starting to become innovative, and then transitioning patients also to the outpatient phase of care, allowing for more timely treatment, more convenient treatment, but kind of still that wraparound safety and oversight.

Q: What CAR T-cell therapies are available for multiple myeloma treatment, and what are the opportunities and limitations of this approach?

Ryan Haumschild, PharmD, MS, MBA: Yeah, you have ide-cel which is Abecma, and cilta-cel which is Carvykti. And I think those are 2 that we've seen on the market. They're offering huge benefits to patients that are in the relapsed refractory multiple myeloma, some of the biggest benefits we've seen is really great overall response rates. It's something that I think will generally provide great progression-free survival for these patients, I think, overall, provide durable and deep responses. But some of the considerations are, you do have cytokine release syndrome. So that's something that we're really monitoring; how much tocilizumab are we going to have to give for these patients, how do we set them up for success to reduce that inpatient stay? And then again, I think the other concern is, can we get these patients scheduled? A big thing across industry is it's a great drug, offers great therapeutic benefit, but getting patients scheduled and getting enough doses to treat demand is something that I think we're ongoing going to be a challenge with. However, we do see relief in the future, and I know these manufacturers have been working hard to create increased capacity so that we can service more patients.

Q: How are bispecific antibodies being implemented in this space, and what are the limitations of them?

Ryan Haumschild, PharmD, MS, MBA: You know, bispecifics are coming, and we're excited about it. And I keep getting the question, you know, “Where do you see bispecifics landing between antibody drug conjugates and cellular therapies?” And I feel like there's a huge area for bispecifics, especially right now. One of the first is we do a risk stratification for our patients; so, are they fit enough for cellular therapy? Well, they may not always be, but can a bispecific be something that treats them where you have a lower incidence of grade 3, grade 4 cytokine release syndrome? And so we've gotten new ones in the market, tocilizumab and others that are being approved for lymphoma and some upcoming multiple myeloma again, and I think, how do we stratify patients to them, so that they are potentially treatment eligible for cellular therapy but can't get on the list or there's not enough manufacturing slots, or, you know, they wouldn't be able to handle cytokine release syndrome, but they can handle the lower grades that we see with bispecifics. And I think that's really where they fit in within the treatment algorithm. I think we have a waiting list right now for these patients, so we're welcoming these innovations in bispecific therapy. And then I think lastly, as we start to have more treatment experience or treatment exposure patients, we're seeing some of them designed to the clinical trial. And I think that's really going to make a difference too, as we introduce some upcoming bispecifics that are even novel therapeutics and targets that aren't even focused on BCMA.

Q: What are the key antibody drug conjugates for multiple myeloma, and what should pharmacists know about these options?

Ryan Haumschild, PharmD, MS, MBA: Yeah, so you know, antibody drug conjugates, I think are changing the way we treat patients. And so some of the ones that have been in the market is belantamab mafodotin, otherwise known as Blenrep, or tocilizumab and Tecvayli. Both are being, have been utilized, belantamab mafodotin was taken off the market, but there's been different additional studies that are being done such as DREAMM 7, so we may see it back in terms of its proven efficacy and overall survival. And then tocilizumab as we start to see antibody drug conjugates and bispecifics for the treatment of multiple myeloma, and really what pharmacists should know is it's a really unique and novel way to deliver medication, right.

So the antibody drug conjugates, I think of them as like guided missiles, where they contain 2 parts. One is the protein called the antibody, and it's attached to an anti-cancer drug, which is sometimes called the warhead or cytotoxic payload. And so that antibody seeks out, looks for that matching protein, an antigen on the surface of those myeloma cells, those plasma cells, and then once it's taken in, it provides that cytotoxic payload, which I think really kills the cancer cell and provides a really unique therapeutic delivery. Some of the great things about it is we're leveraging the power of the immune system, but we're also leveraging the power of cytotoxic to basically kill the cancer, bind to that BCMA if it is an antibody drug conjugate like belantamab mafodotin, and really allow your normal immune system to participate in the eradication of the cancer. And so hopefully this is a great new mechanism that destroys cancer without harming the nearby healthy cells. And I think that's ultimately the goal.

Q: Is there evidence for which approach might be optimal for different patients?

Ryan Haumschild, PharmD, MS, MBA: You know, the more therapeutics we have, it's a good thing, that we're saying, “Hey, do we have too many approaches?” I would say no, right now, it's good to have many approaches, you know, as we're treating patients in the relapsed refractory setting, a lot of times their triple-class-experienced already. And so at that point in time, we want to look towards maybe an antibody drug conjugate, like we just spoke about a little bit earlier that has the antibody and the cytotoxic payload. We might even look for a bispecific with two targeted agents and areas in terms of providing more deep and durable responses, but less side effects, less grade 3, grade 4 cytokine release syndromes that would allow patients to recover and potentially even receive it in the outpatient. And then lastly, we want those really significant overall response rates, those deep, durable responses, that's where the cellular therapies really come into play. And I think CAR-T with Carvykti and Abecma, I think are going to add extreme benefit to patients as long as they're fit enough. If we can get a durable response with that treatment, I think that's ultimately the goal for our patients, reducing any need to stay adherent to other medications or ongoing treatment. And then again, to live a really healthy life where we can make multiple myeloma more of something that might be chronic in their life, where they can live kind of a productive life, even with that disease.

Q: How are treatment decisions made given the expanding armamentarium of therapy options? What are some considerations?

Ryan Haumschild, PharmD, MS, MBA: Treatment decisions are changing rapidly in this environment. We're lucky that we can utilize treatment pathways, we have NCCN recommendations, but within multiple myeloma, there is a lot of resistance. And there's customized approaches to every patient, I mean, I think we initially start with is a patient transplant eligible or not? And then from there, we can stratify them based on their translocation, whether they should be high risk or standard. And I do think that we have some approaches there, we might start with a quadruple regimen, really leveraging the power of the IMiDs to produce some inhibitors, and dexamethasone, as well as some of the anti-CD-38 mechanisms. But then as patients develop different resistance, we will go through the monoclonal antibodies, then we might also go through some of the immune-modulating agents, maybe doing a step up from lenalidomide to pomalidomide.

And I think those changes with patients, I think, ultimately allow them to step through several different treatments. And we're still able to have additional treatments at the end. And that's really where I think in the relapsed refractory setting, we have more of the stronger agents such as the antibody drug conjugates, the bispecifics and the cellular therapies. And who knows in the future, we could have some innovative mechanism of actions that we haven't seen before, or we start to see some of the agents in the relapsed refractory setting getting pushed earlier and earlier in treatment and more durable responses. And then lastly, the exciting piece is really utilizing MRD as a determination of when a patient should go on maintenance and when they shouldn’t.

Q: Is there anything you’d like to add?

Ryan Haumschild, PharmD, MS, MBA: You know, I think the last thing is just how do we leverage and utilize MRD? And do we treat patients that are smoldering myeloma? Do we not? Or if they're asymptomatic, and I think those are areas that I think there's a lot of research coming out. And ultimately, we want to let the science guide us, that makes sure that we're making very efficacious decisions. And come up struggling with a decision, if a patient has minimal residual disease, do they still need to be treated? Can they have a treatment holiday? We can't answer that right now, we can't use MRD yet. But the exciting thing is MRD is being included in a lot of the clinical trials that we'll be discussing. And we can look at what is the future hold for MRD and how can we start to include that as pharmacists into our treatment recommendations?