Multiple Myeloma Bispecific Agents in Special Populations: A Case-Based Approach

Kevin Brigle:

Hi, and welcome to our final installment of JADPRO's Roundtable discussion on Multiple Myeloma Bispecific Agents in Special Populations: A Case-Based Approach. I'm Kevin Brigle. I'm a nurse practitioner at the Massey Comprehensive Cancer Center in the Virginia Commonwealth University in Richmond, Virginia. And I'm joined by my two colleagues, Mary Steinbach and Kelley Julian, who are both at Huntsman, and I'll let them introduce themselves. Mary.

Mary Steinbach:

Great. Thank you, Kevin. So happy to be here with you again. I practice at Huntsman Cancer Hospital, which is located in Salt Lake City, Utah.

Kelley Julian:

And hi guys, it's Kelley Julian here. I'm a clinical pharmacist practicing alongside Mary, like she said, at Huntsman in Salt Lake City, Utah. I've been in the myeloma space since 2018, and I'm thrilled to be here to chat with you guys further today about some interesting cases.

Kevin Brigle:

Okay. Well I hope this is an interesting case. We have been talking about special populations. And what I'm going to talk about today is extramedullary disease, which we all know is a really hard-to-treat aspect of multiple myeloma. I'm going to start out here with basically definitions of when we think of bone or osteo disease. Most patients have some site of bone disease even at diagnosis. And then there's paramedullary or paraskeletal disease, and that's basically plasma cell tumors that are contiguous with the bone lesion. So they extend from the bone then as well. And if we want to talk about true extramedullary disease, which involves actual visceral organs and skin, musculoskeletal, soft tissue, lymph nodes, and probably the worst of all would be CNS involvement as well.

And so, we think of these things as being really aggressive. At diagnosis, the population is thought to be anywhere from 0.1% to 5%, and it kind of depends on how you define extramedullary disease. But obviously, these are plasma cells that can grow independent of the bone marrow environment from where they came, and so that's what really makes them very aggressive.

So I'm going to talk about our first patient, my first patient here. He's a really interesting gentleman, and he doesn't have extramedullary at diagnosis, but he develops it as he goes on. And again, I think we see that as well. If we look as patients go on, the actual presence of extramedullary disease actually increases as patients have more and more relapses. So this first patient at diagnosis, he was a 53-year-old male. He had shortness of breath, found out that he had hemoglobin of 7.2. He had a colonoscopy, they were all negative. And so, he was sent to a hematologist in the community. Bone marrow then showed 89-90% lambda-restricted plasma cells. He had some abnormalities on FISH. And also, cytogenetics noted an interesting monosomy 7, which is typically what you see in bone marrow failure or MDS.

And so anyway, he's considered to have a complex cytogenic stage III disease and you can see his PET scan shown here on this particular slide. Very interesting as well from that presentation of this left tibia lesion, 7.3, and he had a femur lesion in the pubic ramus as well. But the only thing that was symptomatic was that tibial lesion very interestingly. Another thing I'll point out, very interesting about this gentleman, is that his father had multiple myeloma and died at a young age.

Mary Steinbach:

Oh, wow.

Kevin Brigle:

This is kind of a familial thing. And so, when we think of that, then as well, this hereditary type of thing then as well.

So his treatment history, then he got radiation to that tibia lesion. Zometa was started. And at the time, then, he got the triplet 6 cycles of RVD, and then followed by a tandem transplant in November [2018] and March of 2019. Came out of that transplant bone marrow negative, there you can see. Completely fine. His PET was fine then as well. Started on maintenance Revlimid as we all did back at that time. And that was in July 2019. And about a year later, March 2020 then, a PET scan showed a single symptomatic lesion in the sternum. And you could see that up there on the top, that single lesion there. He wasn't terribly symptomatic at that time. Bone marrow biopsy showed 5% lambda-restricted plasma cells. His FISH and cytogenetics were then negative.

And so, the decision was made at that time to change therapies, especially since he'd been on maintenance, clearly having something going on. So he was started on a quad then at that time, and that continued for a year. And again, he had slowly rising serological markers, had a PET scan due to that. And so, that sternal lesion was stable, but now that was hurting and was fairly symptomatic, and he had new vertebral lytic lesions. Interestingly, bone marrow biopsy, negative. Now we got a guy who's now just having osseous lesions and no bone marrow disease. The idea then was, okay, let's radiate that sternal lesion then for starters, that would be the good thing to do. And so, I don't know, my experience with people who start to have osseous lesions only with no bone marrow disease, Mary, have you seen those patients then as well?

Mary Steinbach:

Yes, we do see these patients, and I think these tend to be people who had transplant and were on maintenance for a period of time, and then it's maybe third or fourth relapse and it tends to, you can have more of an oligo-secretory clone. It's hard because you're not sure exactly what to do at that point, because maybe this is just one spot in the bone. And for instance, as he relapsed just in that sternal lesion, very reasonable to give radiation, keep systemic therapy as it is. And there are cases where we do that, but I think in someone who is younger and already proven to have aggressive disease and they have that sort of relapse or progression picture, then you do just have to change systemic therapy and be aggressive.

Kevin Brigle:

Exactly. So he was young, and so that's kind of the plan that we made then as well. So you can see in our decision points, he had aggressive, obvious osseous disease. We had a clinical trial for talquetamab/dara/pom, he’s ineligible for that because he'd just been on pom. And CAR-T at that time, we had to wait 6 months to get anyone going. We were pre-bispecifics and there was a long wait there. Talquetamab, we said, "Okay, due in August of 2022, it was supposed to be approved." Unfortunately, that didn't happen until October, late October of 2022. And again, he had aggressive disease and his initial relapse was pretty early. So the decision then was to start him on isatuximab KPD. Not optimal, but then he had these slowly rising serological markers. And so again, we said, "Okay, let's go here."

We did not start him on teclistamab immediately, still thinking we might be able to get into the clinical trial. Bone marrow biopsy, as you can see here, basically almost MRD negative, 13 and 10^-6. But look at that PET scan now. Widespread bony lesions, extensive extramedullary disease. Look at those hepatic lesions, too. So he has got true extramedullary disease then as well. So, that really became a big thing. And we say, "Okay, now this guy has to go in for some type of treatment." The question was, "Are these going to work?"

And there's a lot of data we didn't really have at the time and we can see this in the next slide. If we look at some of the patients who got bispecifics in some of the clinical trials, and we can parse out all that data. In the teclistamab clinical trial, 17% of patients had extramedullary disease. Their response rate was less. And that's a little bit what we expected, too. In the elranatamab studies, same thing, 32% with EMD. And they defined it differently. That's a little bit of a problem with some of these clinical trials. And again, 38% overall response rate, 71% without. The LINKER trial, small population of extramedullary disease, those patients tend to do a little bit better. And then looking at talquetamab, at least where we parse out from that data then as well, didn't seem to do quite as well as with the BCMA-targeted therapy.

And so, if we look at the real-world data, there are a couple of published, at least retrospective studies as well. A really large one from the Myeloma Immunotherapy Consortium looked at 382 patients treated at 13 academic centers. And you say, "Okay, how did these patients do?"

And so overall rate, 42% with extramedullary disease, 64% without. So that looks pretty reasonable. But when you start to look at progression-free survival, a lot less, 1.8 months vs 8.9. And overall survival, certainly less than as well. Another retrospective analysis, it was 661 patients, again about 63% overall response rate. But if you look at the overall response rate and parse that out with patients with extramedullary disease and those without, again, they do a lot worse than those patients.

So fortunately, not knowing any of this information at the time, and it is all we really had at the time to get him admitted, and he was starting to become symptomatic from some of those lesions as well. And so, what I would ask, Kelley, in your experience, if you would go back to where we were in August 2022, we didn't have anything going, now would be a different picture, right? And thinking about sequencing of these things, where would you go with this patient in today's world back in August 2022 when we had to make a decision?

Kelley Julian:

Great question. This is an interesting case, and I think depending upon how you're counting lines of therapy, I was sitting here doing the math while you were talking and it's like is he at three lines? Is yet four lines? The radiation was there. So I think especially because you mentioned he was symptomatic from some of the lesions, we would've considered a chemo-debulk as a line of therapy in a young person and dealt with the cytopenias and the recovery and the supportive care to get that additional line if we needed it. I think we're like a K-DCEP center, but DPACE, you could do high dose cyclophosphamide, things like that.

Additionally, I was thinking, "Well, you could do dara, CyBorD, if he's not too symptomatic and you're not overly worried about this progression." But with extramedullary disease that's turned visceral, now, I don't know, that's maybe lower on the list.

You still have elo as an option. You still have selinexor as an option. But my preference would be to, in this young patient with a good performance status, to chemo debulk, and then hopefully that buys you a month or two, and then you can get the patient to a bispecific therapy of choice. I think it really depends on what your center's capability is there. But that's probably what I would've recommended if someone had asked me at the time.

Kevin Brigle:

Right. Unfortunately, talquetamab wasn't approved at the time, and so we didn't have that either. So anyway, so treatment history, we admitted him for teclistamab. Then he got CRS, got a dose of toci. We had concerns of tumor lysis, he had so much disease as well. And of course we started all the proper infectious prophylaxis. And Mary, I know you do a lot of outpatient step-up dosing. And so, would this be a person you'd consider for outpatient step-up dosing?

Mary Steinbach:

No, I think he's not on oxygen at this point any longer, right? That was just early in his case? So I think the truth of it is, it's always a little easier to admit the patient, especially if you've got a bed at the hospital and you just know that if something does go wrong, the right monitoring is always there. There's a bit of trust and good luck that happens in the outpatient setting. And so, if we're remotely worried or someone asks a second question about a case like this, then we're just going to admit them. So I think that sounds very reasonable.

Kevin Brigle:

All right. Well, how do you do, right? Because this guy isn't supposed to do so great with teclistamab. And so I'll show you right here. He admitted 6 months later, a PET scan September 2023, significant improvement in all those osseous lesions. We decreased to every other week. Six months later, then, he got another PET scan, continued improvement, everything continued to look a whole lot better then, as well. So at that point, then we continued the teclistamab every other week times 12 months. And I think we might do it a little bit differently now, perhaps. I'm not exactly sure, but 18 months total.

But you can see here, and then October 2024, he has the appearance and you can barely see it up there, but there's a right supraclavicular node. That node was actually present originally then as well. His light chain started to increase. Biopsy showed that to be plasma cells. So we repeat the bone marrow biopsy, he's MRD negative. And so again, now he has this recurrent extramedullary disease then.

And so what do we do? And Mary, I think you brought this up at one point then as well. So what are we worried about? Maybe T-cell exhaustion, a little bit unclear. So we added pomalidomide to him then as well to try and to stimulate those T-cells. Very quickly, another PET scan showed that that lymph node had decreased. Serological markers became undetectable. We did end up radiating that lymph node then as well. Obviously, it's been problematic, and so we radiated it probably just to make us feel better. And then in August 2025 and he's still serological marker-negative. He's due for PET scan next week, and so we'll find out how that does.

A really interesting thing, though, that popped up here, and this is one last thing I want to get to, is that in August '25, he was also admitted for a pacemaker. He had a slight left bundle branch block, and it progressed to a complete heart block.

Mary Steinbach:

Oh, wow.

Kevin Brigle:

And the cardiologist jumped all over us, says, "You know, this happens." And I really wasn't so much aware of it then as well. But I did end up looking at a couple of retrospective studies here, and this is a known side effect then as well. And there are two studies that are shown here. Both of them show interestingly about an 8.4% cardiovascular adverse event. They define them differently from bleeding and hypertension down to the second study, which has really been more specific to cardiovascular events as well, which include cardiac arrhythmias. And the arrhythmias in these things appear differently dependent upon which particular BCMA-targeted therapy that we're using. And so I'm curious, have you guys seen anything like this before in terms of cardiac arrhythmias? And I'll take it from both of you.

Kelley Julian:

Our main data collector announcement for the immunotherapy consortium that we take part in, of the 70 or so bispecific patients we've seen, three-quarters of those were for the anti-BCMA bispecifics. And we did not see any major signals that were anything to write home about. And there is an abstract that we've submitted to ASH, so a little bit of a precursor there, I won't spoil the surprise. But in our patients specifically, we had maybe minor QT prolongations, things like that. But nothing like what you're describing here. But I will also say we have seen some anecdotally with talquetamab. And so, we didn't collect on those patients yet. So I'm very curious to see the data there as well.

Kevin Brigle:

Okay, well very good. And Mary, do you have anything to add to that?

Mary Steinbach:

Well, I was just going to add, I can't add to that actual data answer, so thank you for it. But I've seen people on pomalidomide have arrhythmias and heart block. And so, it's not surprising, although I don't think it's very common. It is important, and I just want to say it's a good reminder, this patient obviously had an aggressive disease prior to bispecifics, may not have had a therapy that was going to work again. So we're extending people's lives and keeping them on treatment longer with the advent of bispecific antibodies and CAR-T therapies. And so I think unscientifically I will just say we will run into more and more odd adverse events that just happen to people who've had a lot of treatment over a long period of time.

Kevin Brigle:

Right. And I just want to wrap up then with at least a little on a positive side here. And there was what was the RedirecTT study, a phase II study. And so it was looking at talquetamab and teclistamab. And they looked specifically in patients with this extramedullary disease then as well. And so they used Q4 week dosing after 4 to 6 cycles. But you can see the overall response rate is 79%. And these were all patients with extramedullary disease, complete response rates of 52% then as well. So it looks like if we use combination bispecifics, maybe that'll provide some positive help in the future then as well.

So anyway, that brings us into the end of our discussion and I'd like to thank Mary, thank you so much. And Kelley, nice working with you again then as well, and taking time out of you guys' busy schedules to be with us. And so for more information, you can view other discussions and other parts of this program, visit JADPRO online at jadpro.com and thanks everybody for your time.