Introduction

Stephanie Chuang, The Patient Story: I’m the founder of The Patient Story and I’m also a cancer survivor [of] lymphoma.

The Patient Story is co-hosting this program with The Leukemia and Lymphoma Society or LLS, which, as many of you already know, is an incredible organization with top resources to help guide you through myeloma — diagnosis, treatment, and everything in between.

We also want to thank Karyopharm Therapeutics for its support of our educational program. We do want to stress that The Patient Story and the LLS retain full editorial control.

Many of you are probably very familiar with Jack Aiello. He’s been living with myeloma for almost 30 years and even more incredible than that alone is for a lot of this time, Jack has dedicated himself to the research of the latest and greatest — what’s coming out in terms of the developments in therapies and the knowledge in terms of how to deal with myeloma — and he does this not just for himself but for those of you out there as well.

Two things I did right. I found that we had a myeloma support group in the San Francisco Bay Area, where I live, and they helped educate me about myeloma and [the] questions I should be asking. The second thing I did that really made a difference was seek out expert opinions. Ultimately, I went to Little Rock, Arkansas, to go through most of these treatments. Back then and still today, Little Rock [is] a premiere center for treating myeloma patients so that made a huge difference for me.

Today, whenever I talk with myeloma patients, I always suggest that they get a second opinion from expert doctors and there are so many more available these days from around the world. I’m fortunate enough to be pretty knowledgeable about myeloma these days.

The top doctors and researchers from around the world meet [at ASH] to discuss the latest in blood cancers, specifically myeloma. Two of those doctors are joining our conversation today: myeloma specialists Dr. Josh Richter and Dr. Muhamed Baljević. Both are committed to seeing myeloma patients in their clinics and also furthering research to get us those next improvements in treatments.

We will be highlighting the summary of top takeaways in myeloma from the ASH conference for first-line therapy patients all the way through later relapse. The big buzz at ASH for myeloma patients was the word bispecifics. But before we go there, there was some update that could actually change treatment for some myeloma patients today. And it has to do with steroids.

What are bispecific antibodies?

Jack: Let’s go now into the big area of buzz — bispecific antibodies. Dr. Richter, can you help us understand what bispecifics are? We actually know about monoclonal antibodies like daratumumab. But what’s a bispecific antibody?

Dr. Josh Richter: People may be familiar with monoclonal antibodies like Rituxan or Darzalex. It’s got one arm, grabs onto the cancer cell, and kills it. Bispecifics have two arms and classically, right now, each of those arms does this one thing: one arm grabs onto our T-cells and activates them to attack the cancer [and] the other grabs onto the cancer cell. This arm that attaches to the T-cell attaches to something called CD3. It’s on all T-cells. That, for the most part right now, is the same. But the arm that grabs onto the cancer cell is different.

At ASH, we’re seeing presentations from four different other arms. BCMA, some people may have heard of. It’s the target of many CAR T therapies and a drug called Blenrep. Talquetamab targets something called GPRC5D. There’s another drug called cevostamab that targets FcRH5. There’s another drug that targets CD38, the same marker that’s attacked for Darzalex, but also using the T-cells, and that drug goes by the name ISB 1342.

Really excited about talquetamab because right now, the majority of our T-cell redirecting therapies [have] all been BCMA. We have two FDA-approved CAR T-cells. They both attack BCMA. We have one FDA-approved bispecific. It attacks BCMA. We had an antibody-drug conjugate called Blenrep. It was taken off the market, but there are two ongoing phase 3 studies — the DREAMM-7 and DREAMM-8 study — which will hopefully bring the drug back within the next year, year and a half. Fingers crossed.

When will bispecifics be available in Community Cancer Centers?

Jack: How about true availability? For instance, CAR T has been limited to certain sites, mostly bigger and academic hospitals. Will bispecifics be available for those of us getting care in the community?

Dr. Richter: That’s a really, really great point. The short answer is yes. Yes, it is, but it’s not going to be given in the community just yet. There [are] still pretty high rates of CRS. It involves admission. It involves some of the management strategies that a lot of these doctors are not as familiar with.

A lot of hematologist-oncologists out there are used to dealing with [the] side effects of classical chemo. Then they got used to dealing with the side effects of checkpoint inhibitors. It’s going to be a learning curve.

We’re willing to partner with the community. You come to us, you get that first inpatient dosing, get you through the risky part, and then get you back to your community to get your regular treatment.

Will bispecifics be given in the outpatient setting?

Jack: With that in mind, will bispecifics be able to be given in the outpatient setting?

Dr. Richter: There are already a number of people starting to give these completely outpatient. There are certain risk factors for higher-grade CRS. If you have a very high tumor burden, we know you’re more likely. If certain markers like your LDH are already cranked up or circulating plasma cells, we know you’re more likely to have it. If we have someone that doesn’t have all those risk factors, we could give it as an outpatient.

But there’s actually some data from another bispecific being presented at ASH that is going to make it more applicable to the outpatient.

Dr. Richter: Cevostamab is another one of those bispecifics — CD3 to grab onto the T cells, something called FcRH5 that’s on all the myeloma cells. There [are] two presentations at ASH that I think in and of themselves wrap into a nutshell how we are likely to approach all bispecifics in the future. If you put them together, this is the blueprint.

We’re talking about CRS. We recognize that some people [are] going to end up in the hospital, have high grade, or get sicker. When you develop CRS, we give a drug like tociluzimab. What happens if you use it as a pre-medication? What happens if you give it before you even give the first dose? Can you mitigate or prevent CRS? And that’s exactly what they did for cevostamab. They took patients and they gave them a prophylactic dose of tocilizumab and it took the overall all-grade CRS rates from over 90% down to the 30th percentile. And that’s just the beginning.

People will just say, “Well, wait a minute. If we give toci, are we going to affect the efficacy?” For cevostamab? Absolutely not. We have not affected efficacy, but we’ve markedly reduced the incidence of CRS.

We’re all starting to talk about how we’re going to approach this. Should we consider giving people tocilizumab before we give them bispecifics, particularly for the people we worry may not tolerate it? 40-year-old, no medical problems? Not as worried. 80-year-old, [with] multiple comorbidities, may not be able to tolerate that grade 2 to 3? Consider giving them tocilizumab.

Dr. Baljević: I think that’s really interesting because we may yet use the findings of that cevostamab study to try to plan how we can reduce the incidence of CRS in other bispecifics and maybe even in the CAR Ts. A lot of interesting data [was] presented.

Dr. Baljević: [A] deeper understanding of T-cell function, T-cell exhaustion, and resistant mechanisms is needed and that’s where some of these other agents that have [a] positive impact in those situations can lend themselves even more useful. For example, selinexor is such an agent where some of the preclinical data has already been published and demonstrated maybe some of these roles.

Jack: Is the hope that other bispecific can also test this finite duration?

Dr. Richter: Absolutely. That is the big buzz when you talk with all of the pharma companies [at ASH]. Because why did cevostamab choose a year? We even asked them and they couldn’t give an answer, but I’ll give the answer. One year is a nice round number. It’s not a biological thing. It’s a nice round number. But what this is becoming thought-provoking for all the other bispecific manufacturers is to say, “We need to do this, but with a biological endpoint.”

For example, complete remission and then two more cycles and then stop or MRD negative and three more cycles. But right now, the big discussion is to not just pick a random number but to have a biological response. Right now, these are the big discussions in the halls of ASH: how do we design the next series of trials?

Dara had a response rate of 30% in the end and when you give it upfront, in combination, it’s 100%. What happens when you take a drug that [has a] 70, 80% response rate in someone who’s had an average of six prior lines? If you move it upfront, do you cure some people? Do you get remissions that are so long [that] it’s a functional cure?

That’s why the myeloma world couldn’t be more excited right now. There is a combination out there and there are actually several discussions right now of cure protocols and cure goals.

What is the overall takeaway from CAR T-cell therapy?

Jack: Dr. Richter, what’s the overall takeaway so far on the CAR T-cell therapy front?

Dr. Richter: The CAR T front is that they work well in the later lines. If you move those further up, initially we were worried about more side effects because it’s all about the T-cells again. As you go through your therapy, those T-cells get tired. And when you give a CAR T or collect T-cells in someone who’s had a whole bunch of therapy, you’re collecting tired T-cells.

What we were worried about is if we collect early on T-cells that are more robust, maybe they’re going to give you more side effects, more CRS, [and] more neurotoxicity. That is not happening. That’s not the case. So we know that we can give these drugs early on, but some of the early data has been extremely encouraging.

Personally, if I have a patient that can receive CAR T therapy and I’m in a position to give them CAR T therapy, preferentially, I probably will do that. Though we now have a first agent that’s bispecific and off the shelf by definition. We are expecting another number of agents in 2023, maybe Q2 — maybe one targeting BCMA or another one targeting GPRC5D for the first time. I think that both are associated with some of the serious side effects.

Autologous CAR Ts are associated with some requirements for generation and synthesis. Patients that are relapsing and have diseases with velocities that are pretty aggressive and whose proteins are rising rapidly, whose counts may be changing, or whose kidney functions, mineral levels, and calcium levels might be threatened, may not be the best candidates for those types of therapies. They’re better candidates for off-the-shelf therapy. That doesn’t only include BiTEs, but it may also include allo-based CAR T cells off the shelf.

Updates on CELMoDs

Jack: Were there any updates on CELMoDs?

Dr. Richter: These drugs, just like Revlimid, worked in people who had thalidomide and pomalidomide worked in people who had Revlimid. These drugs work really, really well in people who’ve had the others.

Iberdomide, for example, is one of the most potent ones and it has a lot less in terms of what we call myelotoxicity — it doesn’t lower your blood counts as much. If you wanted to strategize an optimal maintenance drug, it’d be a drug that someone’s going to tolerate very well and not lower their blood counts, especially after something like a CAR T where your counts may be lower.

These CELMoDs are really going to be a big part of our therapy. We probably have to wait till 2025 [or] 2026 for regimens like Velcade-iber-dex and dara-iber-dex. But some push to consider those drugs in earlier lines. There [are] a number of great drugs on the horizon.

Understanding what dose is best for selinexor

Jack: Dr. Baljević, speaking of selinexor, you presented additional details on using this drug weekly instead of twice a week, providing efficacy with fewer side effects. Both the STOMP and BOSTON trials used this lower selinexor dosage in combination with carfilzomib and Velcade respectively. Can you expand on this topic?

Dr. Baljević: We are shown the value of selinexor as an agent in this difficult-to-treat population. Earlier, we were talking about the outcomes of high-risk patients. Anybody who is triple-class refractory, even if they’re not harboring high-risk cytogenetic features, they are, biologically, already in a place where they have progressed on multiple good therapies. We know from previous large-scale analyses that these patients have short, medium progression-free survivals and survivals that are measured in single-digit outcome endpoints.

What we did is looked at the patients that were exposed — and some of which were actually refractory to CD38-based therapy as well — and we looked at what type of outcomes they can have with selinexor-based, importantly, weekly treatments. A lot of investigators still have angst using selinexor twice a week. I agree with that. I have never given anybody selinexor 80 mg twice a week. These are active triplets with Kyprolis and dex, with Pomalyst and dex, [and] even with Velcade and dex so BOSTON data phase III was [a] positive report. But particularly with the second-generation PIs (proteasome inhibitors), and IMiDs, Pom, and Kyprolis, these are powerful triplets that are effective in this difficult-to-treat population.

For example, [the] African-American population is still being accrued in the single digits on clinical trials so that’s a problem. And some of the other disparity populations as well. Where I practice and where I am in charge of the program, that’s really a programmatic goal for us to try to do better and increase disparity accruals on clinical trials.

In fact, we have a grant with LLS. [The Leukemia & Lymphoma Society^®] is really an amazing partner in so many areas and they’re supporting [the] increase of awareness and access of patients from the community areas, especially those that are underserved geographically. We are partnering successfully with colleagues in the community, trying to bring patients, and increase access to good quality clinical trials for hematologic malignancies in general, including myeloma.

We need to do a better job. That really needs to be a goal of every single myeloma physician. Hopefully, in the future, we’re going to see more trials that have more balanced accruals in terms of different ethnicities [and] different disparity populations in particular.