New Data and Approvals Shape Treatment Strategies in Multiple Myeloma

Jeffrey R. Schriber, MD

The treatment landscape for multiple myeloma has undergone significant changes, broadening from what was once only treatment with chemotherapy to now an array of options, including combination regimens.

Most recently, 2 therapies were approved by the FDA for the treatment of patients with multiple myeloma: Erlanatamab-bcmm (Elrexfio) and talquetamab-tgvs (Talvey).

Even with these promising updates and new approvals, research continues to explore innovative avenues for the treatment of this disease. According to Jeffrey R. Schriber, MD, the integration of chimeric antigen receptor (CAR) T-cell therapies and bispecific T-cell engager (BiTE) cells are 2 exciting efforts being researched further.

“The field is ripe, moving forward, and continuing to evolve. In almost every hematology malignancy that we've been dealing with, for long periods of time, there weren't advances. Now they're happening at a rapid speed, which is incredibly exciting,” Schriber, director of Hematologic Malignancies, City of Hope Phoenix, told Targeted Oncology^TM, in an interview.

In the interview, Schriber highlighted some of the most recent updates in the field of multiple myeloma, and discussed emerging therapies that show promise.

Targeted Oncology: Can you talk about some of the most recent therapies introduced in multiple myeloma?

Schriber: At recent meetings like ASH and ASCO, there haven't been any, at least from my perspective, major breakthroughs that are just going to change everything. What there has been is more scaffolding that tells us about therapies that are coming. A lot of the buzz of information is about CAR T cells, and about BiTE cells. Both therapies utilize the immune system to go after the particular tumor. There's now longer-term data with CAR T cells, and it's looking impressive. It looks like the numbers are holding up. Again, it still remains early, and you have to be cautious because we saw something like this a long time ago with the autologous stem cell transplant. The numbers looked fabulous, and then over time, they sort of dropped off. But these results have been very encouraging in terms of efficacy, and no new safety profiles, which is important. The beauty of the CAR T cell is its sort of a 1 and done thing. You get 1 therapy, and then you don't have to have a whole pile of additional therapies, at least related to the myeloma. We're seeing it used a little bit earlier on and used in different combinations with therapies in some cases. It looks like this is going to be an important therapy for us.

Now, there remains some real issues in terms of the availability. It's still a little bit hard to get, it's still a little clunky. You have to get the cells collected, and you've got to wait for the cells to be produced, and sometimes they're not able to be produced. There have been some issues getting the raw materials to be able to do this, but we're getting better at all of that. The biggest common complication, and it's less of a problem with myeloma typically, is that you have to be able to do something while you're waiting for the cells to be improved. You have to be able to get the disease, so it remains under control. That is more of a problem with lymphoma to be truthful that it is with myeloma. I think the results continue to look positive that people are excited about this.

What can you discuss about the emergence of BiTE therapies?

The next big thing is BiTE cell therapy. Personally, that is 1 of the things that I'm most excited about. We have 1 available now, teclicstamab (Tecvayli), which is looking promising. Again, the toxicity profile is terrific. It still has to be done at more of a specialized center because for the first eight days, as you ramp the dose up, that's when, if you're going to have the complications that are unique to CAR T and BiTE cells, that's when [they occur]. That's typically done in the hospital or in a closely monitored outpatient type setting. But the long-term results look like they are holding up the progression-free survival in patients who have done terribly, so very promising. We're now seeing that we can switch these from every week, to every other week, or every month, and that is critical for these patients who've been through a lot of different myeloma therapies. Many of them have had stem cell transplants, many of them have gone through each of the major drug areas, and they're tired, so this is huge for these patients.

There's also data on combining different BiTE cell therapies that target different agents, and that is exciting moving forward. There's also data that shows that BiTE cells can be effective post-CAR T-cell therapy. What it gives us is a variety of different options that we'll be able to use. What it doesn't tell us is, okay, you fail this, do this. We have a whole menu, not 1 choice alone. There are many choices, all of which will be very good, but we still don't have [all the answers], and that's okay. It means we're continuing to move forward, continuing to find things that will improve, help balance the efficacy with the toxicity that we may be facing, the expense for the patients, the time for the patients when you talk about toxicity. We have to think about financial toxicity, not just as a question of, what does it take for them to come to the clinic? Someone has to bring them in there. If they're working, they have to do that, and what does it do to their quality of life? Those are things that I think we're starting to address.

What are your expectations with these types of therapies moving forward?

I think it's incredibly exciting that we have combination therapies, utilization, and we are determining where things fit. Three years from now, we'll have a better idea of what the long-term data looks like, what combinations we should be using, and we will have other options. Initially, the BiTE cells targeted the same thing, the BCMA region, which is exactly the same area that the CAR Ts are going after. It makes sense logically that if we have different targets that might be good, but they're not quite ready to be released.

My expectation is a number of these are going to be FDA-approved in the not-too-distant future. It's going to expand dramatically. One of the studies used the combination of 2 different BiTE cells that had different targets. One could imagine how effective that could be, and the data looked interesting. Importantly, no new safety signals. What that means is you can give these, and not add to the [adverse] effect profile. It's early understanding where everything fits in, but clearly, there's a role for all these therapies. The challenge over the next few years is going to be to try and find out, what's the role? Do they move earlier? If they move earlier, what do they replace? Do they work in combination? All of these are critical things that we can look at, and it makes it an exciting time to be dealing with patients with myeloma.

Soon, we expect a response from the FDA on the application for idecabtagene vicleucel ide-cel [ide-cel; Abecma] for triple-class, relapsed/refractory disease. What are your thoughts on a potential approval?

Moving these therapies earlier will be very exciting. The data is very good for this, so we are excited, and I think this is where the field is moving. In myeloma, we have a good concept of how to start, and those patients are doing well. But it gets complicated when we talk about lines of therapy. First-line of therapy is induction, maybe with quadruplets. Now we've used 3 of the critical drugs, along with steroids, often with a transplant. Having something that's different given earlier is going to be important, because otherwise, what we're doing is largely shuffling things around. But if we're able to advance things for those patients who failed everything else, especially if we use it in some combinations, which are now being looked at, like post-CAR T with other agents. I think that has the opportunity to change them.

What we've seen traditionally is if a patient fails initial therapy, the next round of therapy just doesn't work as well. But imagine if we had a second option? I think there's potential there. What's exciting about this is that the median age for patients with myeloma is 70. We also have data that says you can use these in older patients. If we can do these techniques in someone who's 70, our initial therapy does well, and with our next therapy, we are going to be looking at patients who are much older.

Can you discuss some of the interesting CLL data presented at ASCO 2023?

CLL continues to move forward. I think there were a couple of things that were exciting, and 1 thing that was a little bit disappointing. One of the things that is exciting are the noncovalent BTK inhibitors. The 1 that's approved and available is pirtobrutinib. Pirtobrutinib [Jaypirca] works in a different way than our regular BTKs. It appears that this can be an effective therapy in patients that have failed more standard therapy. The binding works in different ways. That's exciting, and the safety profile is amazing. It is well-tolerated, and I think the data from the BRUIN study [NCT04662255] is 1 that looks great.

Now, there was the first read out, and an early read out, on a trial that looked at ibrutinib and obinutuzumab vs adding ibrutinib [Imbruvica]/venetoclax [Venclexta] to obinutuzumab [Gazyva]. Right now, the treatment of CLL is typically 1 or the other. You use a BTK or venetoclax. What people are excited about is the combination of the 2. That was done in a study. It's early follow-up, but it didn't show improvement in progression-free survival or overall survival. In fact, it did slightly worse. The reason for this was in patients who were a little bit older, they had more COVID deaths. There are a number of other studies that are coming out with younger patients at different times. It did appear that there was a higher [minimal residual disease] seen in the triplet combination, and we hope that will translate into patients doing well, but it was a little bit disappointing. We have many more studies, and as we learn about this, we have to understand these do have toxicities, too. While COVID was a unique circumstance, what it suggests potentially is that this is a harder therapy to give to those with more immunosuppression. I don't know that it was just a fluke, per se, but infectious complications are real. I think the follow-up is early.

Often in these studies, when you follow patients too early and look too early, you don't see the benefits. The curves don't begin to split until later. We see this all the time with autologous transplant where the curves start to split a little later. We're all impatient, [and we] want things to happen right away, and when they don't, we get a little disappointed. But I think this is something that remains to be seen. I think we have to look forward to it, but pirtobrutinib is a good story.

What other data has caught your eye in this space?

The other thing we've seen is the shift in patients who have relapsed/refractory disease to the second generation BTKs. There is a shift away from ibrutinib. The data with zanubrutinib [Brukinsa] in the ALPINE trial [NCT03734016] showed that they had a superior progression-free survival, which was exciting. Again, the follow-up is very short, so we'll have to wait and see what happens with that. But importantly, the toxicity profile was much better than in the ELEVATE TN trial [NCT02475681] looking at acalabrutinib [Calquence] which didn't show a survival advantage or a progression-free survival advantage, but significantly improved toxicity. Most of us have switched from the first generation to the second generation for these patients. I think that is a new way of moving forward with this.

There was a little bit of data on CAR Ts and when they were their role might be. It's effective, for sure. The problem is these other agents are way easier to give. I think CAR Ts can work in virtually everything, it's just the current integration with the sort of clunkiness of it is a little bit harder. I can't say I'm super excited about this disease just yet, but I think in the future, it may play a role, particularly in patients who are much younger.

What are your key takeaways regarding the evolution of treatment options for multiple myeloma?

The field is ripe, moving forward, and continuing to evolve. In almost every hematology malignancy that we've been dealing with, for long periods of time, there weren't advances. Now they're happening at a rapid speed, which is incredibly exciting. It wasn't long ago CLL was treated with chemotherapy, and that just doesn't happen anymore, nor should it now that we have pills that are well-tolerated and that patients do exceedingly well on. I think it's a tremendously exciting time in myeloma. We are getting better and better at our upfront care, which hopefully means patients don't even get to that point where they have their disease come back. But when they do, we now have incredibly effective therapies. It's truly exciting.