Selecting and Sequencing Bispecifics and CAR-T Therapies in R/R MM


A review of novel treatment modalities for relapsed/refractory multiple myeloma, with a focus on selecting and sequencing bispecific antibodies and CAR T-cell therapies.

Beth Faiman, PhD, MSN, APN-BC:
Talking about the different available therapies, let’s say this individual was in a nice remission and starts this slow biochemical disease progression. There are numerous therapies that are FDA approved at first, second, third, and fourth lines. We can mix and match these therapies with a proteosome inhibitor, an immunomodulatory drug, and a monoclonal antibody. The list goes on and on. Unfortunately, we don’t have a great strategy for sequencing therapies. We have many algorithms and guidelines that recommend what to do next, but we individualize the initial treatment. Dr Mazzoni, how do you decide the next therapy you recommend on relapse?

Sandra Mazzoni, MD: The biggest thing is what adverse effects, if any, they had with the first line of therapy, [so we can] try to avoid that with the next line. Where do they live? Are they coming in? Do they get transplanted? What have they been exposed to? What comorbidities do they have? We can always come up with several options. We talk about what makes the most sense for each individual and then look at the data. It’s always an individualized discussion with the patients.

Beth Faiman, PhD, MSN, APN-BC: Absolutely.

Jack Khouri, MD: I highly favor daratumumab-based regimens in the first line.

Beth Faiman, PhD, MSN, APN-BC: In the first relapse.

Jack Khouri, MD: Yes, in the first-relapse setting, given the good hazard ratios in PFS [progression-free survival] data. I tend to use daratumumab in a triplet. If they live far, that’s a different situation, but I tend to favor daratumumab in general.

Sandra Mazzoni, MD: What about the ones who got the GRIFFIN [regimen] up front?

Jack Khouri, MD: Well, that’s another discussion.

Beth Faiman, PhD, MSN, APN-BC: What would you do if they had that up front?

Jack Khouri, MD: That’s another discussion. I tend to favor a carfilzomib base…. That would be my go-to.

Sandra Mazzoni, MD: That’s the big question with those high-risk patients you induce: care vs a GRIFFIN approach? No one knows.

Beth Faiman, PhD, MSN, APN-BC: [Is there] an early BCMA clinical trial?

Louis Williams, MD: Clinical trials are an option. Early line clinical trial, absolutely.

Beth Faiman, PhD, MSN, APN-BC: Yes, always. This individual ended up going onto a second-line therapy. Remember, they were off therapy for quite some time, and then they initially progressed. After 5 years, all they had was VRd [bortezomib, lenalidomide, dexamethasone], no transplant, no maintenance or continuous therapy. She ended up going into therapy A, B, or C—it’s dealer’s choice—and then eventually progressed. Now we have CAR [chimeric antigen receptor] T-cell therapies, bispecific antibodies. How do you and the patient decide? Because it’s patient specific. She didn’t have a transplant, so would you recommend a transplant before the bispecific? Dr Williams, what are your thoughts for CAR T cell vs a bispecific therapy? How would you decide? [Would you] start with mechanism of action of teclistamab or 1 of CAR T? Do you do CAR T and then bispecifics?

Louis Williams, MD: There’s a lot there. We talked about transplant, and I don’t think transplant is necessarily off the table in these situations. If the patient is still fit 4 lines in, that’s a little late to do that. If we’re looking at an anti-BCMA bispecific, the ones that we have available to us are anti-CD3. Those are antibodies that have dual specificity for CD3 and BCMA, and they’re given on a weekly basis continually. They rely on the patient’s T-cell population and adaptive immunity. That gets to be a concern after a number of lines of therapy. CAR T cells—and we can go into the construction—are essentially modified. They’re T cells that are taken from the patient, infected with lentiviral vectors to express a…region specific to BCMA. They’re onetime infusions, at least for now. We’re giving them a single time after lymphodepletion and then monitoring patients.

One thing I consider is how quickly, so what are the kinetics of the patient’s relapse, and how sick are they? Are they fit enough? CAR T cells must be manufactured. Everyone knows all about this, especially Dr Khouri. They need to be manufactured. You need someone who has a good bridging therapy available, who’s fit enough to go on to CAR T. And that’s in the early days of CAR T; it’s challenging. With teclistamab, the response rates are a little lower, but it’s off the shelf. In general, if you’re comparing teclistamab with cell to cell, there’s less CRS [cytokine release syndrome]. It’s a cross-trial comparison, but it’s something that has to be given continually. With younger, fitter patients, I try to get to CAR T cell and give them that time off treatment. Patients are relapsing quickly, so we don’t think we can do teclistamab. Maybe I’m oversimplifying.

Beth Faiman, PhD, MSN, APN-BC: No, it’s specific. Dr Khouri, you lead apheresis at Cleveland Clinic. What are your thoughts on the manufacturing process of CAR T cells? Is that a barrier to recommending somebody who’s progressing on fourth-line therapy?

Jack Khouri, MD: Slot allocation has been an issue. It’s getting a little better, but it’s been an issue since the inception of the whole concept and the FDA approval. Initially, the way we think about it is if somebody’s disease kinetics are very fast and the tempo is very rapid, we tend not to get them to CAR T-cell therapy because it can’t wait. We’ve had cases where we collected cells, and then patients unfortunately passed away before getting their cells infused. Slot allocation has been an issue, and I tend to favor teclistamab for patients if I can’t wait to control their disease.

Beth Faiman, PhD, MSN, APN-BC: Absolutely.

Jack Khouri, MD: We have many patients with plasma cell leukemia who have a very fast disease tempo. From an apheresis perspective, collecting T cells is similar to stem cells. The main issue has been slot allocation.

Beth Faiman, PhD, MSN, APN-BC: Dr Mazzoni, we heard about the mechanism of action of teclistamab. What are some of the things you share with your patients? Let’s say you have a patient with 4 prior lines of therapy and rapid progression. You’re like, “I want to give them teclistamab.” Our standard of care is admitting to the hospital for 9 days and stepping up dosing according to the prescribing information. [The physician] has to be a REMS [Risk Evaluation and Mitigation Strategy]–certified prescriber, and we talk to them about CRS because of the 48-hour monitoring. What are some of the discussions you have with your patients if you want them to consider that drug?

Sandra Mazzoni, MD: I have very honest conversations with them about this. The risk of infection is the biggest problem, not the CRS. We have all the tocilizumab in the world to fix this. We can use dexamethasone. We’re not worried about destroying a CAR T product. It’s the infection risk. It was underreported in the clinical studies. There’s a lot of worry with COVID-19 going around; that’s where many of the deaths were associated. The biggest thing to discuss with my patients is infectious risk.

Beth Faiman, PhD, MSN, APN-BC: And infection prophylaxis. We use a lot of Bactrim [sulfamethoxazole and trimethoprim], acyclovir, and CD4 counts. Many of these folks have been heavily pretreated with IVIg [intravenous immunoglobulin] therapy. Getting these drugs approved is an issue, though. We were fortunate to get our program up and running not long after the drug was approved. [We have to get] insurance approval for tocilizumab, because it’s not in the prescribing information, and hypogammaglobulinemia with the IVIg. It takes a village to monitor that. Who wants to talk about talquetamab, the MonumenTAL study? Anybody want to discuss that clinical trial?

Louis Williams, MD: I’ll chime in. Talquetamab is an anti-GPRC5D bispecific antibody; it works in a similar fashion. The antigen on the T cell is the same. We’re running into cross-trial comparisons, but the response rates, the CRS rates, were in the neighborhood of what we see with teclistamab. The adverse effect profiles were a bit different—you get some skin and nail toxicity.

Beth Faiman, PhD, MSN, APN-BC: It’s expressed on them.

Louis Williams, MD: Yes, there’s a problem with infections. They’re a promising thing, and we’re going to have bispecifics available. The promising thing is that we may have something that works.

Sandra Mazzoni, MD: That’s a novel target.

Jack Khouri, MD: Another option.

Louis Williams, MD: Yes, right.

Beth Faiman, PhD, MSN, APN-BC: What about sequencing? Let’s say this patient has an opportunity to have belantamab-mafodotin in the context of the clinical trial. At the time of relapse, would you go from BCMA to BCMA? If you had the option of CAR T and they were younger, would you do CAR T and then still give teclistamab at relapse? We had patients who had short remissions with CAR T.

Jack Khouri, MD: Yes.

Sandra Mazzoni, MD: Nobody really knows.

Jack Khouri, MD: The elranatamab data that were presented at ASH [American Society of Hematology Annual Meeting] included patients with prior BCMA. They saw a 53% response rate, which I thought was impressive. The other thing is the large cohort study that came out of the consortium that was just published in the Journal of Clinical Oncology. We had a subset of patients in that study, which was about 200 patients who had received prior BCMA therapy. The response rates were still pretty good. They were less than patients who were not exposed to prior BCMA therapy. The progression-free survival was shorter for those patients. What seemed to matter was the duration of time between prior BCMA therapy and CAR T, where people who had a longer period of time between therapies were the people who fared better. That’s a subset analysis. It’s a retrospective study but I would consider sequencing BCMA treatment.

Beth Faiman, PhD, MSN, APN-BC: One thing we didn’t talk about when we mentioned cytokine release syndrome and neurotoxicity is that our standard of care is to admit to the hospital for 9 days, and patients are monitored closely for CRS. We talked about tocilizumab and dexamethasone, but sometimes, unfortunately, patients aren’t prepared for this until they’re in the event. They can get into the intensive care unit, but we’re at grade 1: CRS, tocilizumab, page the physician attending, and then dexamethasone as well. Prolonged cytopenia can be also an issue. Our standard of care is to have them see the advanced practitioner or physician weekly as an outpatient and regular get labs, especially for that first cycle. Once they get through that and the disease responds, then we all breathe a sigh relief and worry about the next therapy.

Transcript edited for clarity.

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