Insights from Experts at Mayo Clinic on Translating Evidence to Clinical Practice - Episode 10

Bispecifics and CAR-T Therapies in the Management of Multiple Myeloma

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Broad discussion on novel therapies, including bispecifics and CAR-T therapies, that are evolving the treatment landscape of multiple myeloma.

Transcript:

Shaji Kumar, MD: In the bispecifics, we saw a lot of data from ASH [American Society of Hematology Annual Meeting]. Do you want to briefly touch upon the data with the teclistamab and talquetamab?

Morie Gertz, MD: The 2 I have are teclistamab with VGPR [very good partial response] 57% over a response rate of 70%. That was a dose-escalation trial, phase 1/2, so you know that when you get to the MTD [maximum tolerated dose], that result is going to be better. With talquetamab subcutaneously, they had 85% continuing on therapy. That’s early, so we don’t have the big numbers, but the fact that patients were staying on therapy implies that they weren’t progressive.

Shaji Kumar, MD: David, Morie started talking about that comparison between CAR T and bispecifics. We have 2 different CAR [chimeric antigen receptor] T cell therapies approved. How are you making that choice? If you had both drugs in hand, how would you make the choice of the bispecific vs a CAR T?

David Dingli, MD: Bispecifics and CAR Ts are complementary in that there are patients with myeloma who are not candidates for CAR T because of their functional status or their comorbidities, just as we have patients who will never be able to go to transplant. I want to point out that whereas we can take patients who have renal failure to transplant, that becomes somewhat more problematic if you want to use fludarabine for depletion in a patient with impaired renal function.

Not all patients are able to go to CAR T because of their functional state or their physiology, but there are patients who can’t wait for the cells to be manufactured. When bispecifics become available, they’ll be a great boost for patients who need therapy immediately or who can’t consider CAR T for a number of reasons, which we’ve discussed. There’s going to be room for both. In my mind, the advantage of the CAR T is if the patient is fit and has a good performance status. We still have a lot of patients with relapsed/refractory disease who meet those 2 criteria. They cherish the idea of having a treatment-free period that perhaps can be a year or 2. Then the prospect of a CAR-T therapy, especially if we’re using a cilta-cel [ciltacabtagene autoleucel], when that prospect is quite reasonable, is a very attractive option.

Shaji Kumar, MD: Prashant, given the results, maybe you can talk about the CARTITUDE-1 and KarMMa studies in terms of efficacy with the CAR T. Given those results and what we’ve seen so far with the bispecifics, what do you anticipate the future would look like in terms of how we could sequence these modalities?

Prashant Kapoor, MD: We would need head-to-head comparison. In the absence of that, the bispecifics would be somewhat more practical to use by community oncologists for the exact reasons that Morie alluded to. They’re easier to use, with less grade 3 CRS [cytokine release syndrome]. Also, they’re off the shelf, so no bridging is required. We now have bispecifics against different targets, so if a patient has progressed on anti-BCMA bispecifics, one can go to GPRC5 antibodies such as talquetamab or another antibody such as cevostamab. These are all being evaluated in clinical trial settings, but because of such good overall response rates in a heavily pretreated population, hopefully they’ll be approved in the coming years.

Shaji Kumar, MD: An interesting aspect with the bispecifics would be the ability to combine them with other drugs. We already saw some data with the daratumumab combination presented at ASH, and the efficacy looked significant in that relapsed/refractory patient population. It’s quite conceivable that you’re going to start seeing these bispecifics combined with some of the triplet regimens we talked about in the newly diagnosed setting. That might also influence how and where we use the CAR T therapies. We also heard at ASH about a variety of other therapies outside immunological therapies, particularly newer cell modes and other targeted therapies. Do you want to speak on that?

Prashant Kapoor, MD: There was 1 interesting abstract presented by Dr Sagar Lonial on iberdomide. He specifically talked about cohort D of the CC-220-MM-001 trial and cohort I. The difference between these 2 cohorts was that cohort D had enrolled patients who had received at least 3 prior lines of therapy, but cohort I had patients who had previously seen anti-BCMA therapy. Iberdomide is a next-generation immunomodulatory drug that binds to cereblon and is much more potent than its predecessors, lenalidomide and pomalidomide. It attaches to cereblon and leads to degradation of certain transcription factors, aiolos and ikaros. Dr Lonial’s study showed that the overall response rate was about 25%, 26% in both cohorts. The clinical benefit rate was upward of 75%.

The good thing about this compound is that there aren’t necessarily any new adverse effects that are not seen in other IMiDs [immunomodulatory imide drugs]. Patients can get fatigued or experience diarrhea. They can have constipation. These are some of the major adverse effects. The follow-up is short, so we don’t know the long-term adverse effects of iberdomide, but overall it’s a well-tolerated drug.

There were some data, particularly regarding a specific type of CAR-T product, that Dr Noopur Raje talked about in her study. These CAR Ts bb21217 were specifically prepared to ensure that the PI kinase inhibitor that’s used—bb007, externally—could specifically allow CAR T cells with memory phenotype to be administered to the patient. It was selected specifically for the memory T phenotype CAR T cells. That led to somewhat good results. There isn’t a head-to-head comparison with the parent compound, which is ide-cel [idecabtagene vicleucel], but these CAR-T cells persisted for over 2 years. Patients who had achieved stringent complete remission—for about 40% of the patient population that was studied—had a duration of remission of approximately 3 years. These were very good results. There were some other CAR T cells studied against other targets, including this GPRC5 compound target. That showed good response rates—upward of 65%—grade 3 CRS rates, and no neurotoxicity. It was a small study, but it’s definitely worth looking at for future meetings.

Shaji Kumar, MD: Definitely. It’s a fast-evolving field, especially with CAR T cells, with so many modifications happening, in terms of manufacturing, the targets being looked at, and trying to make them more efficient and persistent. There are a lot of advances. I’m sure the treatment of myeloma 5 years from now will look a lot different from what we talked about today, especially with all these drugs coming online.

I’d like to thank you all for joining us in this lively discussion on the treatment of patients with multiple myeloma, brought to you by CancerNetwork®. Thank you to our viewing audience. We hope you found this interactive discussion to be informative and beneficial to your clinical practice.

Transcript edited for clarity.