Sequencing of Cell Therapies in Multiple Myeloma Continues Evolving

Tara K. Gregory, MD

Codirector, Plasma Cell Dyscrasia Program

Colorado Blood Cancer Institute

Denver, CO

KEY TAKEAWAYS FROM TARA K. GREGORY, MD

• Both BCMA- and GPRC5D-targeted cell therapies have shown responses in patients who had prior BCMA therapy.
• Prophylactic tocilizumab can reduce cytokine release syndrome caused by bispecifics.
• ICANS and other rare toxicities of cell therapies continue to be challenging, in Gregory’s experience.
• New cell therapies may support new approaches.

Targeted Oncology: When looking at bispecific T-cell engagers and chimeric antigen receptor (CAR) T-cell therapies for multiple myeloma, how did prior exposure to B-cell maturation antigen (BCMA) targeted therapies affect responses?

Tara K. Gregory, MD: These are the products, and this is where the patients had a previous BCMA therapy and response rates. Elranatamab [Elrexfio] had a [61%] overall response rate, generally speaking. Then there's the group who had previous BCMA, which still has a 54% response rate, so you can still [get responses with bispecifics, and the same is true] with CAR T cells; you're still able to [get responses].¹

How do you approach using talquetamab (Talvey) vs BCMA-targeted bispecifics?

I'm in a situation where teclistamab [Tecvayli] hit the market first, so everybody was on teclistamab, and then the GPRC5D [therapy] has become my salvage. But we don't have to think about it that way. You could definitely use the GPRC5D [therapy] first. I've done things where my patients are not on CAR T-cell therapy yet, but they don't want to lose the opportunity.

I have a couple of patients who have chosen to do talquetamab first, while they're thinking about [if] they want to get BCMA CAR T cells. Or they know that Arcellx’s [CART-ddBCMA] is coming, which has less CRS [cytokine release syndrome] and ICANS [immune effector cell–associated neurotoxicity syndrome]; we know that Gracell's [BBCMA/CD19 CAR-T GC012F] is coming, which is a bispecific that targets CD19 and BCMA and has an overall response rate [close to] 100% at top dose level right now, so that's [amazing].² So [patients] want to wait for those, and they want the GPRC5D [therapy] first. But I have patients who cannot afford to lose a single pound, and I know that [talquetamab] is not the drug for them. Or they know the adverse event profile and they don't want it. That’s what's happened to me in my practice. I feel like I have this super-educated group [of patients], and they dictate what they want.

How do you use the mSMART (Mayo Stratification for Myeloma and Risk-Adapted Therapy) algorithm for management of CRS and ICANS?

When you have CRS—in the beginning, we weren't sure what to do for these patients. Now, you [can be] aggressive and [follow] well-known algorithms about when to give tocilizumab [Actemra] and when you give steroids, and how long you keep the steroids going. The thing this doesn't touch on is that we are seeing HLH [hemophagocytic lymphohistiocytosis], so as soon as you see those liver [function tests go up], you have to be looking at their ferritin, their triglycerides and their soluble IL-6 and figure out what's going on there. We use anakinra [Kineret] pretty quickly for those. You can use ruxolitinib [Jakafi] for bad HLH, and you can use…ruxolitinib for bad CRS that won't end.

What I am having a lot of trouble with recently is ICANS. I'm seeing…pseudobulbar palsies, cranial nerve drops, and Parkinsonian-like syndromes, and when I'm checking their cerebrospinal fluid, there are T cells [in high numbers]. The anti-Parkinsonian drugs don't work, but there are no plaques on autopsy. It's just T cells infiltrating. We've started using a lot of intrathecal chemotherapy, but I don't have many [patients whom] I've salvaged without dying of some kind of brain infection… We’re still trying to figure that out in terms of the ICANS, but it's when it hits and it's bad, it's pretty awful. [The algorithm] talks about [management of] ICANS that's steroid based, and we're starting to think that maybe intrathecal chemotherapy is the way to go. That's something new that we've added; we use anakinra or siltuximab [Sylvant] quickly upfront, and so we make sure that we have those drugs in stock in our pharmacy and available to give.

What data support the use of outpatient step-up administration of bispecific T-cell engagers?

This is the OPTec trial that Robert Rifkin, MD, presented at the 2024 American Society of Clinical Oncology Annual Meeting. This was a teclistamab study. Patients received a single dose of tocilizumab and then they did their basic step-up, and investigators were looking at how often they had CRS after the first 2 cycles. This looks like you might be shutting down some of that early CRS, and you're making this an option for these patients to get treatment in the outpatient setting and make it easier without needing all the backups.³ So it’s definitely headed there.

In addition, we premedicate these patients. You do not want to keep the steroids going long term, so the one thing patients love about a bispecific is it is steroid sparing. The more dexamethasone you give, the more you're killing the T cells, and then you don't get a response. They only use the dexamethasone in the first cycle, and then it's done. They do get premedicated with diphenhydramine [Benadryl], [etc].

What data are there for patients receiving BCMA-directed therapy after GPRC5D-directed therapy?

There are some early [data] that were presented, and we saw that starting to [be presented at] the American Society for Transplantation and Cellular Therapy and American Society of Hematology meetings. We do see responses that look pretty good when you switch targets that stay on par. But I think that's a concern. I think they're [eventually] going to go up front, but if they go up front, what does that mean for CAR targets down the line, and how do you figure that out?

Is it appropriate to start a GPRC5D bispecific in patients intended to receive CAR T-cell therapy later?

There have been great reports about patients who are getting a GPRC5D while they're waiting for their CAR T-cell therapy. We’ve heard of those that are out there, because that's something that you can do quickly and get them under control. But I think the challenge a lot of people are coming up against is the T cell collection. How do you time the T cell collection with them? If you're able to get your cells collected and then get on the other bispecific to the other target, that’s doable.

Then the question is, do you use [another bispecific] afterwards? Do you throw in a different bispecific as a maintenance? We're seeing some maintenance [trials] out there. One of the clinical trials that we have open right now is called KarMMa-9 [NCT06045806] for patients who have an [autologous stem cell] transplant and…they don't hit a complete remission. They can be randomly assigned to lenalidomide [Revlimid] maintenance vs ide-cel [idecabtagene vicleucel; Abecma] with lenalidomide maintenance. Everybody does a month of maintenance while they're in their randomization and then we'll see what happens with those, with the ide-cel post-transplant trying to [improve maintenance].

REFERENCES:

1. Patel U, Oluwole OO, Kassim A, et al. Sequencing bispecific antibodies and CAR T cell therapy in multiple myeloma with prior exposure to BCMA-targeted therapies. J Clin Oncol. 2023;41(suppl_16):e20049. doi:10.1200/JCO.2023.41.16_suppl.e20049

2.Gracell Biotechnologies reports updated clinical data for FasTCAR-T GC012F for high-risk, newly diagnosed multiple myeloma, demonstrating 100% stringent complete response rate. News release. Gracell Biotechnologies Inc. September 27, 2023. Accessed October 2, 2023. https://tinyurl.com/2s628wrh

3. Rifkin RA, Schade HH, Simmons G, et al. OPTec: A phase 2 study to evaluate outpatient (OP) step-up administration of teclistamab (Tec), a BCMA-targeting bispecific antibody, in patients (pts) with relapsed/refractory multiple myeloma (RRMM). J Clin Oncol. 2024;42(suppl_16):7528. doi:10.1200/JCO.2024.42.16_suppl.7528