Clinical Perspectives on GPRC5D-Targeted CAR T-Cell Therapy for Multiple Myeloma

In an interview with Pharmacy Times, Omar Nadeem, MD, clinical director of the Myeloma Immune Effector Cell Therapy Program at the Dana Farber Cancer Institute, and assistant professor of medicine at Harvard Medical School, shared compelling data and positive outcomes linked to GPRC5D-targeted CAR T-cell therapy. He presented the findings from the CC-95266-MM-001 (NCT04674813) study at the European Hematology Association (EHA) 2024 Hybrid Congress.

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Pharmacy Times: Can you elaborate on the specific mechanisms through which CAR (chimeric antigen receptor) T-cell therapy targets GPRC5D and its potential implications for the treatment of relapsed/refractory multiple myeloma (MM)?

Omar Nadeem, MD: GPRC5D is a new target that's been discovered on the [MM] cells. We now have several agents that are either in development or already approved for targeting GPRC5D that have led to pretty impressive results. We have a bispecific antibody called talquetamab [Talvey; Janssen Biotech, Inc] that is currently approved for prior lines of therapy in relapsed/refractory [R/R] [MM] that uses a T-cell mechanism to redirect the T-cells towards [MM] cells using this antigen. Then CAR T-cell therapy—which we also have 2 approved products that currently target BCMA [B-cell maturation antigen]—we now have CAR T-cell products that are also targeting GPRC5D using the mechanism of CAR T-cell directed killing in patients with [R/R MM].

Pharmacy Times: Given the high response rates observed in patients with 1 to 3 prior regimens, how do you envision GPRC5D CAR T-cell therapy fitting into the current treatment landscape for [MM], particularly in comparison to existing therapies?

Nadeem: In our trial that we presented at EHA, this was the cohort C update of the phase 1 study looking at the GPRC5D CAR T-cell product in [R/R MM]. In that particular study, we looked at a cohort of 1 to 3 prior lines of therapy. As you mentioned, the median prior lines of therapy in that cohort were 2 and the majority of patients had triple class exposure and all of them were at least refractory to immunomodulatory agents and a proteasome inhibitor. In that early line population, the overall response rate was 96%, with a complete response rate that was 42%. These numbers look in line with what we had seen in the heavily pretreated cohort. In this phase one study where patients had 3 or more lines of therapy. So, responses do seem to be quite high in both early and late line therapy in this phase 3 trial. What we also know is that we have now several approvals of combination therapies for patients with 1 or more prior lines of therapy. We recently had an approval of CAR T-cell therapy, cilta-cel [ciltacabtagene autoleucel (Carvykti; Janssen Biotech, Inc)] in 1 prior line of therapy for patients that are lenalidomide (Revlimid; Celgene Corporation) refractory. So, putting this into context, these numbers do match up pretty well against what we've seen with the earlier line cohorts for cilta-cel, which is a BCMA-targeted CAR T-cell product. And having this option available in the future will allow patients to have the choice of choosing between either a traditional combination regimen or choosing between one of several CAR T-cell therapy options that have different targets and mechanisms. Each of these CAR T-cell products have unique toxicities and considerations in terms of safety. So, I do think that's going to be nice to have an option for patients that are choosing between CAR T-cell therapies and earlier lines.

Pharmacy Times:How do you plan to incorporate patient-reported outcomes and quality of life assessments to evaluate the holistic impact of GPRC5D CAR T-cell therapy on patients with relapsed/refractory (MM)?

Nadeem: GPRC5D has very unique toxicities associated with it. We see very high rates of dysgeusia, in particular, and weight loss in patients that are receiving talquetamab, which is the bispecific antibody that targets GPRC5D. That has been quite a limiting factor in terms of its widespread use in the clinic and has significant quality-of-life implications when patients do have these tastes changes that then leads to weight loss, and, frequently in the clinic, we have to either dose reduce these patients, hold therapy, or modify their schedule over time. The good thing about this CAR T-cell product is that it is a 1-time therapy and perhaps because of that, we're seeing more transient on-target off-tumor effects with this particular product. We will be looking at patient reported outcomes and looking to see what impact these toxicities have on patients; but had an early look of the data, we do see lower incidence of this. So, what we're hoping for over time is that, when you compare it to the already approved product, we're going to see better quality-of-life reports from patients, particularly as they get further and further out from their CAR T-cell therapy.

Pharmacy Times: How does GPRC5D CAR T-cell therapy address the challenges posed by high-risk disease features, and what strategies are in place to optimize outcomes for these patients specifically?

Nadeem: So, high-risk [MM], both in the newly diagnosed and the relapse setting, does remain an unmet need. We have had tremendous progress with [MM] therapies, over the past 10 plus years or so. But unfortunately, patients with high risk [MM] still have, significantly inferior outcomes compared to those without high-risk disease. So, this particular product does have activity against high-risk patients. These include patients, about 1/3 of patients in cohort C had extramedullary disease [when (MM) cells form tumors outside of the bone marrow (EMD)]. So, despite this being an earlier line cohort about 1/3 of patients had EMD, and about 1/4 of patients had high risk cytogenetics, highlighting the high-risk nature of this particular population in this cohort. Along with that, despite that the use of CD38 monoclonal antibodies was not mandated for enrollment into this cohort, 3/4 of patients had prior CD38 directed therapy, and a little over 1/2 of the patients were triple-class refractory. Again, highlighting the refractory nature of this patient population. And despite that, we saw high response rate and see a pretty high complete response rate that we'll see hopefully deepened over time. So, the activity of this particular product seems to be in patients both with standard and high-risk disease, whether that's measured by high-risk cytogenetics, prior lines of therapy, refractoriness, or presence of any of the [EMD] components.

Pharmacy Times: The abstract highlights the rapid cellular expansion and deep tumor clearance post-infusion with GPRC5D CAR T-cell therapy. How do these findings influence your understanding of the treatment's mechanism of action and long-term effectiveness?

Nadeem: We know the effectiveness of CAR T-cell therapies highly dependent on the expansion of the CAR T-cell product in vivo. What we see with this particular CAR product is very similar to what we've seen with other CAR products, is that you have this sort of rapid expansion and then it's clearance over time. And that is very much seen with this product. We had studied in the phase 1 component of this several different dose levels and the 150 million dose, which is what's been studied in this cohort, has been selected as the phase 2 dose. And with that, we do see very, very good levels of robust cellular expansion. And then we typically see peak expansion levels about 2 weeks out, and that is exactly where we see the expansion in many other CAR products that are known to be quite effective. And so far, that seems to be playing out very nicely in this particular CAR T-cell product as well. So what that tells me is that this is a very active CAR product that seems to be leading to high response rates, and then it does have the kinetics that mirror some of the other approved products that have already shown pretty tremendous efficacy and good safety in the [R/R] [MM] population.

Pharmacy Times: As the trial continues, what additional data or endpoints are you particularly interested in exploring to further elucidate the potential of this CAR T-cell therapy in the management of (MM)?

Nadeem: So far, we've enrolled 31 patients into cohort C of this trial in 1 to 3 prior lines of therapy. With that, the median follow-up duration is only about 5 months, so far. With that being said, what we're hoping for is that these complete response rates will deepen or improve further over time, as many of the patients at the time of this data cut off had just received therapy. So, some of the responses hopefully will deepen. The other thing we would like to see, with more time, is what the actual progression free survival is by using CAR T-cell therapy in this earlier line cohort. And hopefully we’ll yield good results there along with higher rates of [minimal residual disease] negativity, which we're hoping to capture at several time points as patients go beyond receiving their cell infusion. Of course, you want to look at both early and late toxicities. So far, the data seems quite promising, where we are seeing expected toxicities with this CAR T-cell product. We see [cytokine release syndrome (CRS) ] rates of about 80%, and no high-grade CRS events have been reported. And so far, we've seen a lower incidence of some of the on-target off-tumor effects that we see with GPRC5D-targeted therapy such as dysgeusia [a condition that alters taste perception], nail and skin changes. We saw pretty low rates of that, where about 30 patients or less had dysgeusia and it was all low grade and mostly self-limiting. So, we're hoping to see that we don't have any recurrence of that with longer follow up or any other toxicities that have not yet been identified with this particular product.