CAR T-Cell Therapy Carves Out a Role in Multiple Myeloma

Yi Lin, MD, PhD

Autologous and allogeneic BCMA-directed CAR T-cell therapies are leading to deep and durable responses in patients with heavily pretreated multiple myeloma, with a low incidence of severe cytokine release syndrome (CRS) and neurotoxicity, explained Yi Lin, MD, PhD, who added that with a pending biologics license application (BLA), the field should start to consider which patients, who don’t fit the typical clinical trial eligibility criteria, might be a candidate for the treatment in real-world practice.

On September 22, 2020, the FDA granted a priority review designation to a BLA for idecabtagene vicleucel (ide-cel; bb2121) for the treatment of adult patients with multiple myeloma who have received at least 3 previous therapies, based on data from the pivotal phase 2 KarMMa trial (NCT03361748).

“When [these approaches are] available in practice, we’ll have to look at the FDA label,” said Lin. “Putting that in context with the trial experience and also with what we’re learning in standard-of-care practice in lymphoma and leukemia, what we will need to understand beyond the approved indication [in a certain] line of therapy is really patient characteristics, such as comorbidities and so on, because we would likely not be restricted by trial criteria anymore. Understanding what a safe condition to use CAR T-cell therapy in while still preserving the efficacy of the product [is something we’ll have to determine].”

In an interview with OncLive® during the 2020 Institutional Perspectives in Cancer webinar on multiple myeloma, Lin, consultant, Division of Hematology, Department of Internal Medicine, consultant, Division of Experimental Pathology and Laboratory Medicine, Department of Laboratory Medicine and Pathology, assistant professor of medicine and oncology, Mayo Clinic, discussed promising data with CAR T-cell therapy in multiple myeloma.

OncLive®: How do the CAR T-cell therapies under investigation compare? Are they all leading to deep and durable responses?

Lin: Cilta-cel [ciltacabtagene autoleucel; JNJ-68284528] and ide-cel are already in pivotal trials. With ide-cel, the BLA has been submitted to the FDA, so we’re anticipating review in early 2021. Cilta-cel is also getting ready for BLA submission to the FDA as well. Potentially in 2021, we may have these BCMA-targeted CAR T-cell therapies available in standard-of-care practice.

In these trials of heavily pretreated patients with poor-risk cytogenetics and penta-refractory disease, a single infusion of the CAR T [cells is leading to] very high overall response rates. A high percentage of these patients are having deep responses and reaching complete remission [CR] or stringent CR. A good proportion of those patients are also experiencing MRD [minimal residual disease]–negative disease. In myeloma, those are relevant metrics in terms of having more durable responses, and we’re seeing that [that’s true with] CAR T-cell therapy as well.

The median PFS [progression-free survival] is around 8.8 months for ide-cel, and the 12-month PFS rate for cilta-cel is close to 77%. That’s very exciting for a patient who has had continuous treatment. We have heard anecdotal reports from these patients on the CAR T-cell therapy trials that when they’re in remission, when they’re recovering post CAR T-cell therapy, it’s the “best they have felt.” It’s almost like before they had myeloma. Some of these metrics are being formally measured as quality-of-life outcomes in the pivotal trial. We’ve seen some of that reported as well in poster format at the 2020 ASH Annual Meeting and Exposition. Those data are very important to consider.

bb21217 is very interesting, because it’s one of these next-generation approaches we’re looking at to improve upon CAR T-cell therapy. There are a lot of emerging data regarding the phenotype of CAR T cells in myeloma, including other hematologic malignancies, [in that] the T cell that has more of a naïve with memory potential phenotype may contribute to better persistence and more active T cells. That’s one of the ways that bb21217 is trying to approach that.

During manufacturing, they’re exposing the T cells to a PI3K inhibitor to drive the phenotype functions of B cells. We’re seeing that with the CAR T cell that’s generated from patients on the study, the profiles of the CAR T-cell product do have more presence of these cells [compared with other products]. It’s still a little too early to say how the long-term clinical response will look, but initial results, in terms of response rates, are very encouraging.

Autologous products were the first to be developed, but now we’re starting to see allogeneic products as well. With longer follow-up, could they overtake autologous products?

That’s certainly a possibility. We’ve seen the data with ALLO-715; it’s very early yet. That study only has about 3 months of follow-up, but what we’ve seen has been very encouraging. The potential advantage of allogeneic CAR T-cell therapy [is that because] you’re generating [the allogeneic product] from a healthy donor, the T-cell function or the T-cell health or fitness might be better [than that of an autologous product from a patient with myeloma].

You can also make [the product] ahead of time, so it would be more ready off-the-shelf, but that comes with challenges. You are infusing T cells from somebody else, so there could be a risk for graft-versus-host-disease [GVHD], which we have seen with allogeneic stem cell transplant. This particular product comes with a lot of additional gene editing approaches to try to address that, and so far of about 31 patients who have been dosed, we haven’t seen any alarming signals for GVHD. These CAR T cells persist and are measurable in patients, which is also very encouraging, and we’re seeing early signals for response. We’re not seeing any concerns yet for the high incidence of more severe CRS, neurotoxicity, or infections.

The FDA recently approved selinexor [Xpovio] after 1 prior line of therapy. Given that we’re seeing a number of new novel agents being evaluated in earlier settings, are you concerned that when CAR T-cell therapy is approved, it’s not going to be used in the same population that it was studied in?

It will be interesting to see how it is adopted in the market. I’ve certainly heard concerns from others in the field that we’re not quite seeing a plateau in terms of PFS as we have seen in lymphoma. We have to keep in mind that these are very heavily pretreated patients that are studied on trials. I suspect, based on how the trials are designed, that the potential position of where it would be with the final FDA-approved indication would be after 3 lines of prior therapy and exposure to a proteasome inhibitor, IMiD [immunomodulatory drug], and a monoclonal antibody. If it is truly adopted for patients who would be eligible and have access to treatment centers, it could potentially buy them at least a period of time where they don’t need any therapies.

Though, we still have patients on these studies that are 2 years out or more in continued remission. I suspect because of how BCMA CAR T-cell therapy works––it’s really targeting a surface antigen, it’s not targeting particular cell signaling pathways, and we are seeing responses across other cytogenetic risks––that it wouldn’t necessarily impact how well it could function in real-world practice, but that’s something that we’ll need to learn as it becomes available.

What have we learned about managing CRS and neurotoxicity?

It’s certainly very encouraging to see that, across the CAR T-cell therapy studies, we have not generally seen a very high signal in terms of grade 3 or more severe CRS or neurotoxicity that would require ICU level monitoring. [Such scenarios have] generally [occurred] in single-digit percentages in less than 10% of cases.

There may be some component of how these CARs are designed. There may be some elements of the nature of the myeloma disease that contributes to this, but we’re also evolving in our understanding of when interventions like tocilizumab (Actemra) and steroids could be safely used to walk that balance between not losing response but preventing more severe toxicities. Within each protocol, the threshold for using tocilizumab and steroids do vary. Generally, there is a move towards using these drugs earlier in the onset of those symptoms, so patients don’t have to suffer through the more severe late effects. There’s a variable percentage of patients who get [these interventions], but it’s a higher percentage than in the earlier studies.

What novel agents caught your eye at the 2020 ASH Annual Meeting and Exposition?

I was most excited to see Allogene’s allogeneic product. What’s reassuring is that generally we are seeing response signals, but it’s a little too early to tell whether that will translate into an advantage in clinical response compared with the current generation CAR T cells. There are lots of products to keep an eye on, but it’s hard to pick a lead yet.

With the bispecific antibodies, we’re now seeing some reports from non-BCMA approaches. With a number of BCMA-targeted CAR T-cell therapies and bispecific antibody-drug conjugates, we do need to move into the non-BCMA space fairly quickly. It’s very exciting to see pretty high early response rate signals from those approaches as well. CAR T-cell therapies targeting those same antigens are also starting [to be developed], so probably by the 2021 ASH Annual Meeting and Exposition, we’ll hear some results from those studies as well. Immunotherapy approaches are moving very quickly in myeloma, and it’s always exciting to have those options for our patients.

Is it too early to start thinking about how you might approach patient selection once CAR T-cell therapies are approved?

It’s never too early to think about patient selection. It’s quite common that patients with myeloma need to get bridging therapy or continue some type of therapy while their autologous CAR T cells are being made. How that may impact or potentially be used to optimize the response of CAR T-cell therapy is not formally studied in a trial. We’ll learn from real-world practice. In terms of patient access to this product, is there a potentially broader range of conditions and comorbidities where CAR T-cell therapy can still be safely given with a reasonable expectation of response?

Are other targets emerging aside from BCMA?

GPRC5D and FcRH are the ones that are currently [being developed for] bispecific approaches. CAR T-cell therapy trials will be starting or have recently started [with those targets] as well. Thus far, based on the expression of these targets, they seem to have very limited off-target toxicities. Fingers crossed. We’ll continue to truly see that profile in the clinical trial settings. Those are the [targets] to really watch out for.

The very first report of CAR T activity in myeloma was with a CD19-directed approach. There’s still some continued effort to see if a combination of CD19 and BCMA have a role in myeloma. To that end, there are some combinations of BCMA-directed CAR T-cell therapy approaches with and CD38 or CS1. Ultimately, the novel targets are the ones to watch out for and likely will have a role, if we do see a desirable response, very quickly after BCMA-directed approaches.

Reference

US Food and Drug Administration (FDA) accepts for priority review Bristol Myers Squibb and bluebird bio application for anti-BCMA CAR T cell therapy idecabtagene vicleucel (ide-cel; bb2121). News release. Bristol Myers Squibb and bluebird bio, Inc. September 22, 2020. Accessed February 8, 2021. https://bit.ly/2G0K3Iq.