The Current Treatment Landscape for Relapsed/Refractory Multiple Myeloma: A Case-Based Approach

Rhonda Hewitt: Thank you for joining us today. Welcome to this virtual round table on relapse/refractory multiple myeloma. My name is Rhonda Hewitt and I'm a nurse practitioner at Stanford Health Care in the department of hematology. Joining me today are two of my colleagues, Kevin and Ann. Kevin and Ann, if you could introduce yourselves please.

Kevin Brigle: Thanks, Rhonda. My name is Kevin Brigle, and I'm a nurse practitioner in the heme-malignancy clinic at Virginia Commonwealth University, Massey Cancer Center.

Ann McNeill: My name is Ann McNeill. I'm a nurse practitioner in the myeloma division at the John Theurer Cancer Center at Hackensack, New Jersey.

Rhonda Hewitt: Thank you very much. So today we'll be discussing the utilization of bispecific antibody T-cell engager therapy in relapsed/refractory multiple myeloma. So Gary is a 56-year-old male with a history of IgG kappa multiple myeloma with standard risk cytogenetics. He was diagnosed with myeloma in November of 2019 when he presented with chest pain, shortness of breath with chills, was diagnosed with a pneumonia and was found to have elevated proteins as well as an acute kidney injury. His past medical history was significant for fatty liver, high lipids, hypertension, obesity. He had a right bundle branch block in 2015 and he has a history of tubular adenoma. He is a former smoker, he quit about 10 years ago, and he lives about 20 minutes from the hospital. Works as a radiology film librarian at a local community hospital. And he's married without children.

His labs at diagnosis. He had a normal hemoglobin at 14.8. His calcium was 9.2. His creatinine was a little elevated at 1.36. He did not have a LDH at diagnosis. And his beta-2 microglobulin was 2.4, LB1 little low at 3.2. He had an M spike,which was 3.6 grams. It was IgG kappa. His IgG level was 4,765. His free light chains showed that his kappa light chains were 68.7, lambda 11.3, which gave him a free light chain ratio of 6.19. And his bone marrow biopsy showed that he had 80% plasma cells. His cytogenetics were normal. He did have the presence of an IGH rearrangement, deletion 13Q and translocation 11;14. And his PET scan … So looking at his bones, he did not have any FDG avid plasmacytoma or lytic lesions. So he was induced with lenalidomide, bortezomib, and dexamethasone. He received this 2 weeks on, 1 week off.

So he was receiving that lenalidomide on a twice weekly schedule on days 1, 4, 8, and 11. And he received six cycles of that. And his best response that he achieved was a very good partial response. Adverse events due to therapy, he did develop a superficial venous thrombosis, and he did develop a Grade 1 peripheral neuropathy. So he proceeded to autologous transplant with N-Ethylmaleimide 200 prep and pre-stem cell collection. His bone marrow biopsy showed that he had less than 5% plasma cells. There was no detectable M spike, and his free light chain ratio had decreased to 0.5. Post-transplant now, we go ahead to the day 100 bone marrow biopsy and his plasma cells. Unfortunately, are up to 20%, and his M spike has increased from non-detectable up to 0.85 grams per deciliter. His free light chain ratio has also gone up a little bit to 1.2. Again, a bone skeletal imaging with his PET scan showed that he did not have any evidence of eclectic lesion.

And he was started on lenalidomide and bortezomib maintenance therapy. And I say maintenance like that because he had increased his plasma cells after transplant. His M spike was a little bit up. So rather than just putting him on traditional therapy, which in somebody with standard-risk myeloma, we would use single-agent lenalidomide in this situation. He was actually started on two drugs with the lenalidomide and the bortezomib. So that was the end of September, hoping that they would get disease control for him. Unfortunately, 2 months later, his M spike was up to 3.0, and his free light chains had actually increased to 15.9. So he was switched to daratumumab, carfilzomib, and dexamethasone. And initially he responded to therapy but unfortunately showed disease progression in the beginning of June. And then he was switched to venetoclax on clinical trial because he had this translocation 11;14. Do either of you guys have experience with utilizing venetoclax in your myeloma patients and any thoughts to share with the audience on that?

Ann McNeill: Yes. We definitely have a lot of experience with the venetoclax in our myeloma patients who are translocation 11;14 positive. I think in general, it's a very well tolerated treatment. Patients like it because it's oral. And so in general, I think it's a very viable treatment option for them, but we do use a lot. I think that it's interesting because the dosing that is used in myeloma is so much higher than the dosing used in the certain lymphomas and stuff like that. So it's a little bit ... Different patients are saying, "Oh my God, don't they have a pill that's bigger than a hundred milligram capsules?" But yeah, we do have a lot of experience. It's a very efficacious regimen.

Rhonda Hewitt: One of the questions that I often get from providers that haven't used venetoclax or even the nurses that haven't seen it used is, do you worry about tumor lysis syndrome? Do either of you want to comment on that?

Ann McNeill: So I used to also spend a lot of time working in the lymphoma outpatient, where the ramping of venetoclax is very strict. In myeloma, we can start at a lower dose before going to the standard dosing for myeloma of 800 milligrams daily. But we are concerned about tumor lysis syndrome, even though it's not as common in myeloma as in the lymphomas, especially with patients with high tumor burden. So we will monitor those labs. We will definitely hydrate patients appropriately, maybe put them on hyperuricemic agents but yeah, we are concerned about it. But each case is individual about how their clinical presentation is.

Kevin Brigle: And I would also point out too, that unlike leukemias and the lymphomas, that myeloma is not such a rapidly prolific disease as it is in there. So I think Ann you're right, we do concern ourselves with tumor lysis but it's much, much less common, even in patients with a high disease burden just for that period as well.

Rhonda Hewitt: Yeah. I think I tend to worry about it a little bit more if I maybe have a patient who has plasma cell leukemia. So they have plasma cells circulating. I don't know if that's correct, but I'm more concerned about it in that case. But otherwise, similarly to you guys, I don't worry about it that much. So he did do well for about 9 months on the venetoclax clinical trial, but in March of 2022, so just this past spring, he had disease progression and he was started on teclistamab clinical trial. Ann, I think you have experience with using teclistamab in clinical trial. Do you want to tell us a little bit about your experience and maybe a little bit about the mechanism of action for our audience? Because this is probably our newest therapy for myeloma.

Ann McNeill: Sure. So again, these patients at our institution are enrolled on a clinical trial. With teclistamab, it is a bispecific, so it targets BCMA-CD3. So BCMA on the plasma cell and then CD3 T-cell. So it's an engager of both to promote tumor kill. Very interestingly, it requires an inpatient dosing schedule initially. So that's a little bit different from the traditional myeloma regimens that we've used in the past. We have currently three bispecifics that we are in clinical trials with. There are three different agents that we're using. I have to tell you that in general, we're seeing very good responses. Again, the only hurdle, and not really a hurdle for us or the patients but difference I guess is a better word, is that inpatient dosing for the initial. For teclistamab, the patients are in the hospital for 11 days.

So they get dosing on days one, day three, day eight. Then they come out on day 11 and then they continue on day 15, 22 because it's weekly dosing. So that first 11 days ... Because we're worried about CRS, it's what I forgot to mention. So we are concerned about potential of cytokine release syndrome, which is a side effect we don't normally see with the traditional myeloma treatments except for eliminating [inaudible] transplant treatment option. The one thing I have to say is that we've been using the drug quite a long time. I think it's very important and we're used to this in the myeloma patient population to really look out for signs and symptoms of infection.

So because we're engaging those T-cells, we are seeing a little bit more infection, immunosuppression. So what we have been doing with some of our patients is using a little bit more IVIG as supportive care in these patients. But in general, like I said, we're seeing some very good responses, very manageable side effects. I have to tell you that the CRS, even though it is a potential side effect, it's not something that is profoundly common with ... at least from my experience from what I've seen so far. But again, it's a small patient population and we're still learning about the drug. We're still learning about this class of drugs.

Kevin Brigle: Can I ask a question? And so Ann, in your institution then, is that given inpatient, is that given in the same area or group of nurses where you do the CAR T, or is that a different group?

Ann McNeill: Wonderful question. Those patients who are admitted for bispecific administration infusions are admitted to the transplant floor, and the transplant nurses are the ones that take care of them. Absolutely. And then if they don't have CRS with day one, three or eight, then the likelihood of them getting it declines. So that's when we give it as an outpatient. But yes, the nursing staff who are so familiar ... because we've been doing CAR T for a very long time, they are very familiar with how to manage it. So they are being treated as inpatients on the transplant units. Very good.

Rhonda Hewitt: I have a related question. Now, this would be a therapy that's not for multiple myeloma, but another bispecific T-cell engager that we utilize in hematology for ALL, blinatumomab. Do you also give that therapy? But it's the same group of nurses?

Ann McNeill: So that drug, very commonly used in our leukemia division. So we also have in our institution, a specific unit for leukemia. So we have two transplant units. We have a whole area of the ninth floor that's just leukemia, because most of those regimens for leukemia are so heavily inpatient for  , they're in the hospital for a month. They're getting all that intense chemo. So those nurses are very familiar with that drug and the potential side effects. So they are familiar. So they don't go to a transplant floor, they stay on the leukemia floor.

Rhonda Hewitt: Yeah. Because I will say I have not personally used teclistamab in a patient, but when I read about teclistamab ... I've used a lot of blinatumomab in my ALL patient population. And the CRS that we see with blinatumomab is generally considerably less than we would see with CAR T. And when I read about teclistamab, I may be wrong but the way that I interpret it is that I'm going to experience something similar in intensity, but maybe I'm wrong.

Ann McNeill: No, that's definitely what we're seeing. From my experience again, smaller patient population because it's still on clinical trial. So we are seeing it not as significant as what we can potentially see in the CAR T-cell patient population. Absolutely. I agree.

Rhonda Hewitt: And so I'm guessing that there's dose adjustments and stuff and hold parameters for CRS. And for the CRS, what are you treating that with?

Ann McNeill: So we are using tocilizumab, the steroids ... the same way you would treat CRS in a CAR T patient, would be the way you treat CRS in a bispecific. It's the same reaction that hyper immune system stimulation. So just so you know that I'm an APN as well, but the transplant team takes over when they're in the hospital. Interestingly, we had a discussion in our institution that if and when or when and if the drug becomes FDA approved, the myeloma team will be in charge of that inpatient monitoring. So again, for some of the nurses it might be a little bit more education but again, nothing we're not familiar with. But again, it's when to use toci, when to use steroids, when to intervene, when not to intervene, that kind of thing.

Kevin Brigle: I think you bring a good point there, Ann. I think we're going to be [inaudible] a whole group of nurses to be using these drugs because it's going to be ...

Ann McNeill: I mean, we're getting ready. We have a lot of patients on the clinical trial. Like I said, we have three bispecifics that were in clinical trial right now, two different companies, three bispecifics, different ... With this teclistamab, it's a step up regimen. So on day one they get a dose, a small dose, day three they get a bigger dose and then day eight, they get the full dose and then that's a weekly dosing. So that's a good thing to reduce that CRS side effect. But like you said, Kevin, it's going to be a whole new educational endeavor because we're not used to patients being in the hospital for our traditional therapies. I mean, we do inpatient chemos for some of our myeloma patients, but not routinely.

Rhonda Hewitt: Yeah, I agree. You brought up one other point there, and I just have a question about the patient population on the clinical trial. So you had mentioned that many of these people, by the time they got to teclistamab, they were very immunosuppressed with getting frequent infections and they needed support with IVIG and we all know that-

Ann McNeill: So wait, wait, wait, Ronda, let me correct you. Not prior to teclistamab. They've multiply relapsed. The clinical trial is your penta-refractory. So you definitely have some elements of immunosuppression, but despite that immunosuppression, putting them on teclistamab I think can make that even more challenging.

Rhonda Hewitt: We also see that though. Even going back to prior discussions that we've had, where we've had patients who have been on daratumumab say for 5 plus years, they start to get frequent infections or even that myeloma patient who has received 13, 14 prior lines of therapy. I think over time, myeloma itself predisposes somebody to having a lower …

Ann McNeill: Yes. Just to interrupt you, I apologize Rhonda. But I think that once you start improving those T-cells, you run the risk of a very different kind of immunosuppression that can definitely be more problematic. So I'm just saying that we do see infections ... You're absolutely right. These patients are very refractory, multiple lines of therapy. Their bone marrow is traumatized, their immune system has had years of dex, years of whatever. So they're in a challenging position but then when you give them these BiTE therapies, you're now taking another cell population and altering it ... Doing a good thing to get disease control but at the same time, what are you doing to the immune system?

Rhonda Hewitt: Yeah. It's definitely something that we need to consider because these therapies are great at treating the myeloma …

Ann McNeill: Yeah, we've seen some great responses. But again, we're seeing a little bit more of the infection. So we are using a little bit more IVIG that I've seen just from my personal experience.

Rhonda Hewitt: I wonder if it'll be ... As we utilize more immunotherapy like these types of things in myeloma, if we will end up needing to vaccinate people like they do after allogeneic bone marrow transplant. Because when you're manipulating the immune system like that, what's the outcome down the road?

Ann McNeill: I think that's a very good point, but I can tell you that my guess ... And again, this is just the guess of an APN who's been working in myeloma for years. I think you will see an increased use of IVIG. And that's not a bad thing. I mean, it's not a chemo, it's an immune booster, and patients certainly don't have a problem with it, but I just personally think that we will see in the general population a little bit more use of that with the new bio therapies.

Rhonda Hewitt: Kevin, did you have any comments?

Kevin Brigle: I absolutely agree with Ann and the use of the IVIG. I think the only drawback with using more is, it is an expensive drug. So that will be an issue with that as well.

Ann McNeill: Unfortunately, yes. So you worry about insurance authorization and all that kind of thing.

Kevin Brigle: Absolutely.

Ann McNeill: And sometimes, I don't know if you remember, but not too far in the distant past, there was a very big shortage of IVIG. So it was very limited and you had to ... But these patients will meet criteria. A lot of them have had a transplant in the past, they have IgG levels that are less than a hundred, nevermind less than 400. So I think that's not the big issue, but the availability and the insurance is going to be our challenge.

Rhonda Hewitt: Well, I think that brings us to the end of this case discussion. So I would like to just mention to our audience that please see the other segments for further discussion on relapse/refractory multiple myeloma. And you can also visit advancedpractitioner.com if you would like to find these cases online. Thank you very much for your time today.