Evolving Care for Relapsed Multiple Myeloma

Podcast Transcript

Dale Shepard, MD, PhD: Cancer Advances, a Cleveland Clinic podcast for medical professionals exploring the latest innovative research and clinical advances in the field of oncology.

Thank you for joining us for another episode of Cancer Advances. I'm your host, Dr. Dale Shepard, a medical oncologist, Director of International Programs for the Cancer Institute, and Co-Director of the Sarcoma Program here at Cleveland Clinic. Today I'm happy to be joined by Dr. Beth Faiman, a Nurse Practitioner and Clinical Researcher here in the Department of Hematology and Medical Oncology at Cleveland Clinic specializing in multiple myeloma. She's here today to talk to us about updates in the management of relapsed and refractory multiple myeloma.

So welcome, Beth.

Beth Faiman, PhD, CNP: Thank you Dr. Shepard for having me.

Dale Shepard, MD, PhD: Absolutely. Give us a little bit of an idea. I kind of summarize, but what do you do here at Cleveland Clinic?

Beth Faiman, PhD, CNP: My career began in 1994 in the inpatient environment, and I've just gravitated to hematology at an early age. I've been involved in the care of patients with multiple myeloma and plasma cell disorders pretty much my whole career, over 25 years. And so I work as a nurse practitioner in the Outpatient Cancer Institute and I see patients, I diagnose and manage them.

I see my own consults independently, but fortunately I have a great team to collaborate with this great multidisciplinary team in the plasma cell disorders environment that I get to work with on a daily basis.

Dale Shepard, MD, PhD: That's great. Well, we're going to talk about some of the new things that are coming along in terms of management of patients with multiple myeloma, but a lot of different people might be listening. Give us an idea. Big picture, what's the current landscape of how we treat this disease?

Beth Faiman, PhD, CNP: Yeah, absolutely. So as you probably know, multiple myeloma is a cancer of the bone marrow plasma cells, which are responsible for your humoral immunity. And so they're programmed to survive, and they secrete immunoglobulins, which are detected in the serum and urine.

About I think 30,000 cases were diagnosed this year, and the survival has vastly increased over the last two decades. We now have very many classes of drugs. We have proteasome inhibitors, anti-CD38 monoclonal antibodies, immunomodulatory drugs, corticosteroids. And now we have these new classes of drugs such as XPO inhibitors, which are oral small, molecule drugs as well as bispecific antibodies and CAR T-cell.

Now I just got back from this exciting meeting in Rio of the International Myeloma Society, and I'm just so excited to share that we have now four drugs is the current standard of care, proteasome inhibitor, CD38 monoclonal antibody, corticosteroid, and an IMiD, or whether or not the patients are transplant eligible or transplant ineligible. We used to have two drugs, three drugs, now there's four drugs to treat myeloma. There are amazing response rates, deep durable responses for these patients, which has translated to an improved overall survival.

And so mostly patients will have standard risk myeloma, but when all are offered these standard therapies, they can have now an improved overall survival.

Dale Shepard, MD, PhD: Oftentimes in the solid tumor world as you add drugs, you significantly impact toxicity. You might get a little bit of an efficacy benefit, but a lot more toxicity. Now we're talking four drugs as therapy. What does that look like in terms of tolerability?

Beth Faiman, PhD, CNP: Yeah, I'm so glad that you asked that question because there were actually earlier studies in the early 2000s, where we added four drugs with alkylating agent and a corticosteroids. The chemotherapy like drugs tended to add more toxicity with little benefit and so those drugs didn't go.

Now we have these very well-tolerated immune therapies, where you're balancing and adding low doses of medications to provide synergy. The different mechanisms of action don't add to increased toxicity. In the comparator trials, the phase three randomized trials for example, MRAS study which used isatuximab, lenalidomide, bortezomib, and dexamethasone, which was just published and is now an FDA-approved regimen as of August of 2024, for newly diagnosed patients who are transplant ineligible, there was not an increased toxicity or earlier discontinuation of treatment in the four-drug arm versus the three-drug arm. What you're doing is controlling the disease better, having a deeper response to therapy, which is translating to what looks like in some early reports improved quality and quantity of life for these patients.

Dale Shepard, MD, PhD: You've mentioned something a couple of times about transplant eligible. And so I have not treated anyone with multiple myeloma for a while, but I do remember there's this sort of transplant eligible, ineligible. As we've developed new drugs, what has changed, if anything, about how we first off even think that's important, and secondly how we view transplant eligibility?

Beth Faiman, PhD, CNP: Absolutely.

This transplant eligibility concept emerged because melphalan and prednisone was the gold standard of care, these two oral drugs, from the 1960s until the early 2000s. For newly diagnosed patients with myeloma, that was the standard of care. Melphalan as an alkylating agent is toxic to stem cells. Therefore, if patients had MP regimen, they were not able to harvest enough pluripotent stem cells to then have an autologous stem cell transplantation. That's really where that distinction came was from not giving those patients melphalan and prednisone.

Now fast-forward to 2024, and we don't in the United States give MP or melphalan and prednisone as a standard induction or a backbone in our country, but we still divide the patients out. The reason being we have studies like this DETERMINATION study, which was reported out about 2018, and then we have the newer studies.

When you think about treatment of myeloma, I think of it in buckets. There's this induction regimen much like any other cancers, where you get three or four drugs generally to induce a remission. And then after four to six cycles of chemotherapy for those patients that are fit and not frail, that don't have many comorbid conditions, they have social support and desire, we offer those patients a stem cell transplant based on 20 years of experience that tell us stem cell transplants can lead to deeper responses and hopefully translate to overall survival benefit. Now after that person receives that autologous stem cell transplant, then they're placed on a maintenance regimen. That's pretty much the standard of care. For patients that can't undergo a stem cell transplant, lack of desire is really a big one or they have comorbid conditions, organ function prevents such as cardiac or renal function prevents transplant, those patients will be on the same often four drugs that I just mentioned. And then therapy will be deescalated.

We think of multiple myeloma in 2024, or maybe if you're listening to this in 2025, we think of multiple myeloma as not curable for most but highly treatable. This has been transformed into a chronic condition with many patients living in excess of 10 years. The five-year survival for myeloma if you're diagnosed now is at least 62% as of the SEER database. At any rate, that four-month induction with four drugs, transplant if you're eligible is our gold standard of care as of this recording. Now, ask me in five years and that might change.

Dale Shepard, MD, PhD: Okay, we'll go ahead and pencil that in. Tell us a little bit about how bispecific antibodies have changed how we treat this disease.

Beth Faiman, PhD, CNP: Bispecific antibodies are an important class of drugs that are used in the treatment of patients with multiple myeloma. Now, they're FDA approved after four prior lines of therapy. If you think of that transplant eligible patient who goes through induction, consolidation with a transplant, then maintenance, that's one line of therapy. Patients have to have had four prior lines of therapy to qualify for this drug.

Now, there's two different types or two different targets that are approved. The bispecific antibodies have two arms that bind into CD3 on the one side and then bind to the myeloma cell cause cell death. And so at any rate, their BCMA, which is the B-cell maturation antigen, that's the first target. That's a member of the TNF super family. It's expressed on late memory B-cells, which are committed to plasma cell development but less often on healthy cells. It's a very attractive target. Our two CAR T-cell therapies are BCMA directed molecules as well as the two approved bispecifics teclistamab and elranatamab.

I think it's important to distinguish the mechanism of action with BCMA from the third approved bispecific antibody, which is talquetamab. That targets GPRC5D, again CD3 binding this GPRC5D and attaching to the myeloma cell. The difference between the two of them mostly is that GPRC5D is expressed on carotenized cells causes a lot of oral, dermato side effects that you don't see with the BCMA agents.

Another important distinction is if patients have had a CAR T-cell therapy, because you can have a CAR T before bispecific antibody in theory and we can talk about that later if you want, but the BCMA to BCMA in studies that still are not very mature with not very large series. But it looks like you want to try not to go towards that same target of BCMA. If you had a BCMA CAR T or BCMA bispecific, you could switch the target to talquetamab, which is a little different way of thinking in myeloma than we've thought about before because we have lots of different classes of drugs that we can mix and match. But there seems to be a difference with these immunotherapies.

Dale Shepard, MD, PhD: When you see a patient, of course they may come to see you after having a number of different lines. How do you make the choice of where to go? Which type of therapy is it about, patient characteristics, tumor characteristics? What are the factors you typically use?

Beth Faiman, PhD, CNP: That's an excellent question because we are still figuring this out, so the bispecific antibodies and CAR T-cell therapies have only been approved for the last couple of years, and there still are many in development.

But based on the approvals that we have currently with the three bispecific antibodies and the two BCMA directed CAR T-cell therapies, first of all, I think about three main factors pretty much. First of all, we consider the lines of therapy. As I mentioned, you can't get a bispecific antibody outside of the context of a well-designed clinical trial unless you've had four prior lines of therapy. CAR T-cell therapy in contrast is actually FDA approved for cilta-cel, which is based on this CARTITUDE-4 study after one prior line of therapy or ide-cel, which is based on the KarMMa-3 study after two prior lines of therapy. You actually could have gotten a CAR T ahead of time. When you're thinking of the lines of therapy as important and then what worked, what didn't work, are they refractory?

And then the disease relapse tempo. CAR T is a process where you have to harvest T-cells, store them, manufacture them with a viral vector, re-infuse after eight weeks. That takes time. For many of our patients who've been pretreated with myeloma or have aggressive disease, the tempo of the disease does not allow us to harvest and store and manufacture those T-cells. For those patients, a bispecific antibody would be more attractive.

I think that there's a lot to consider. There's still some really great approved mixing and matching. Think of that patient that had four drugs, induction therapy, and then now they're on maybe a two-drug maintenance and they're progressing. You can still give them like a carfilzomid-based regimen with pomalidomide, for example, if they're progressing on pomalidomide. There's different algorithmic approaches and recommendations from the International Myeloma Working Group and other expert opinion that guide that decision.

Before I forget, one of the third things is so important is shared decision-making, so sharing mutually between the patients, the provider, that healthcare team to make that decision because CAR T-cell therapy requires a lot more intensive work coming into the hospital. They can't drive for 30 days. They need a caregiver to support them. It's a big burden to the patient, but it might translate into a one-and-done where that living drug is going through their body and not having to take anti-myeloma therapy on a regular basis. Again, discussing the risks and benefits, and that's where the multidisciplinary team is so important with the social workers, pharmacists, advanced practitioners and the physicians to all work together to mutually meet the needs of the patient.

Dale Shepard, MD, PhD: We've talked about some exciting new therapies. Tell us about what we might be learning about the ability to use older drugs and maybe some different combinations.

Beth Faiman, PhD, CNP: Yeah, so daratumumab for example is an anti-CD38 monoclonal antibody that was approved in 2015 in heavily pre-treated relapsed myeloma after four prior lines of therapy. Isatuximab is also an anti-CD38 monoclonal antibody that was approved in 2020 March for patients with heavily pre-treated myeloma.

I give these two examples because now through many years of clinical research and now we've have these phase three randomized control, well-designed large scale trials that now have recommended to move these drugs into the upfront setting for patients with newly diagnosed myeloma. Those are those quad drugs that I mentioned at diagnosis, that four-drug therapy.

What's exciting to me is not only the different mechanisms of action, understanding the biology of myeloma, having MRD testing available to detect one in a million [inaudible 00:14:51] cells in the bone marrow. All of these better diagnostic techniques, better drugs to treat that now are moving forward in the disease trajectory. I can't imagine where bispecific antibodies and CAR T-cell therapies are going to be in the next few years.

But we are learning better ways to mix and match. Giving them sub-cu weekly or every three weeks is what we used to do. And then now we're giving them very intermittently depending on the therapy. And so understanding better how to give those drugs, also understanding better supportive care. Knowing the importance of antibiotic, antiviral, and IVIG prophylaxis for patients that are on bispecific antibodies and CAR T-cell therapies, that's really changed in the last two years. We know infection is the number one cause of death in myeloma because of B-cell aplasia or hypoplasia based on the biology of the disease and based on the drugs that we're using.

Giving antiviral therapies such as acyclovir, valacyclovir, antibacterial for PJP prophylaxis, which used to not be a thing for many years in myeloma, and then IVIG for IgG levels of less than 400. These are now recommended in the NCCN guidelines as well as the International Myeloma Working Group guidelines to protect our patients. And then finally, of course having the discussion of adherence with the patient and their caregiver. Just because we're prescribing these drugs or recommending them to take these drugs doesn't mean they're going to take them. What is it [inaudible 00:16:26] said, "Drugs don't work if people don't take them," and I always think about that with each encounter at each office visit. I try to go over the medications, make sure they know why we're recommending these drugs to be taken, and make sure that they have these drugs on hand and can afford them.

Dale Shepard, MD, PhD: So much like the treatments themselves, the supportive care, with these newer therapies, are patients more likely to have treatment-free intervals and for longer periods of time? How do things like survivorship come into play?

Beth Faiman, PhD, CNP: Yeah, so treatment-free intervals are something you see more often with CAR T-cell therapies. That's considered a "one-and-done therapy" when people have these T-cells manufactured and then re-infused. Depending on the product, like for example in the KarMMa study with the ide-cel, that was the one that was randomized two-to-one fashion to an earlier CAR T versus many different arms for the standard of care. The progression-free survival in the CAR T group was 13.3 months versus 4.4 months in the standard of care group.

Now cilta-cel with greater than one prior line of therapy, that's FDA approved, that progression-free survival so far has still not been reached with standard care at 11.8 months. Again, moving these drugs a little bit earlier line of therapy will translate into more of a longer survival. You can get patients two, three years off of anti-myeloma therapy with CAR T if they have good standard risk disease and a nice response, and especially if we're moving it earlier.

I will caution though that at least at our institution, we are not routinely recommending early CAR T-cell therapy according to the label yet because we still don't fully understand the immune risks. There's also an increased second risk of cancer. There's some weird neurotoxicity, Parkinsonian and Bell's palsy type things that can be seen with some of these products as well. And so we have to be careful to be early adopters with early CAR T just because it's approved.

But if this is a community person that's watching this podcast, try to form that relationship with the academic center who might have CAR T. Refer the patients early. Because maybe CAR T isn't available for them now according to the label, but we also have clinical trials that they might be a candidate for. And so that partnership is important, coordination of care is important, and getting patients access to clinical trials and drugs that might be of benefit to them is also important.

Dale Shepard, MD, PhD: Here at the Clinic we have a really robust myeloma program. What's an ideal patient that should be seen at a center with a solid program?

Beth Faiman, PhD, CNP: That's a great question.

I do a lot of volunteerism also with the International Myeloma Foundation, and my message is that anybody with a diagnosis of multiple myeloma should be referred to an academic center. It's okay for patients to not want to come and it's okay for physicians to not want to refer, but there's so many nuances with the diagnosis. There's different diagnostic algorithms. For example, the fish testing for the disease, risk status to understand, ruling out concurrent AL amyloidosis, which can be 10 to 15% of patients with myeloma. That might be an occult diagnosis that the academic center might pick up on, and then we would tailor treatment strategies a little bit differently.

And so getting that second opinion at an earlier diagnosis will also get people in the system. One of my passions is the survivorship aspect. Survivorship is supposed to be when you finish treatment, but for patients with myeloma, they never finish treatment. My opinion is that it starts a diagnosis. And so what we're trying to do at Cleveland Clinic is link in every patient, whether they come for transplant, they go back into the community, link them in with an advanced provider so that they can stay monitored. And so it's knowing who's monitoring the disease remission status and watching for relapse and knowing what drugs to give at that relapse.

Because there's many new therapies, if you have to deal with all these different cancers like breast, prostate, lung, how can you know what is on the cutting edge with myeloma? And so then forming that partnership will allow earlier access or equal access even to these newer bispecific CAR T or other drugs that are currently available.

Dale Shepard, MD, PhD: Certainly lots of things that are coming around in terms of new therapies.

You're at the forefront of seeing these. What excites you most right now? What do you think is going to be the next big break?

Beth Faiman, PhD, CNP: Oh my gosh, I can't even tell you how excited I am about the pipeline of drugs. There are these different target bispecific antibodies. There's one called cevostamab, which has a slightly different target as well as the allo CAR T-cell therapies. We discussed about how there's a process in manufacturing one's own T-cells to be fighters, and now we have this concept of T-cell fatigue. After numerous prior lines of therapy, the T-cell are just tired and can't work as well and they can't be manufactured with a viral vector or another vector into become fighters. And so having an allo CAR T is an option with different targets is important.

We circled back and said not everybody can get a bispecific antibody. Not everybody can have a CAR T-cell therapy, but mixing and matching of existing drugs with newer agents. We have newer drugs called CELMoDs, which are oral drugs like lenalidomide and pomalidomide or immunomodulatory drugs, but the newer generations are called CELMoDs, so these are pills patients can take at home.

Also, we have B-cell two inhibitors, which are typically given for CLL and other malignancies. We have one called lisaftoclax, which is particularly exciting.

I can go on and on and on. But in the interest of time, I'll stop right there and say that any patient with multiple myeloma now can enjoy hopefully many years of living well if they eat right and stay active, up to date in health maintenance, good supportive care, get part of that multidisciplinary team. And then hopefully they'll be fit for the next therapy, and hopefully they'll be able to have access to well-designed clinical trials because we haven't gotten to where we are in 2024 with myeloma by still giving melphalan and prednisone.

Dale Shepard, MD, PhD: Well, you have provided some great enthusiasm for the road ahead and some great insights. Thanks for being with us.

Beth Faiman, PhD, CNP: Thank you, Dr. Shepard. The pleasure is all mine.

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