Each year before the American Society of Hematology (ASH) Conference, after the research abstracts that will be featured at ASH are released, myeloma specialists across the nation identify their top 10 Abstracts that they are excited to learn more about. 

After looking at the collective lists, I asked myself, “Why is data from a Phase I Study on a G protein-coupled receptor, class C, group 5, member D (GPRC5D) CAR-T cell therapy generating so much interest among doctors who shared their Top 10 ASH Abstract picks?” 

Today, I’ll share with you what I learned about this study’s importance and why this trial (and the upcoming Phase 2 trial and Phase 1 combination study) are worthy of your attention and perhaps even consideration for your future participation (or in other cutting-edge clinical trials). 

Watch the video and read the article below to learn more about this important topic.

Information About Immunotherapy Targets 

One of the first targets in immunotherapy treatment for multiple myeloma was B Cell Maturation Antigen (BCMA). Since 2021, four T-cell-directed therapies using this target have been approved by the FDA. 

Two of the BCMA-directed therapies are CAR-T cell treatments, ABECMA (Ide-Cel) and CARVYKTI (Cilta-Cel), and two of them are bispecific antibody therapies, TECVAYLI (Teclistimab) and ELREXFIO (Elranatamab). 

Currently, all of these BCMA-targeting therapies require four or more prior lines of therapy (LOT). 

Despite all four of the BCMA T-cell-directed therapies exhibiting previously unheard-of depth, duration, and rates of response, multiple myeloma patients continue to relapse. 

When BCMA was the only target for immunotherapies, myeloma specialists and researchers began studying how to optimize the sequencing of these treatments. Important considerations arose. 

For example, recent data has indicated that there is a decrease in the Overall Rate of Response (ORR) and progression-free survival (PFS) when treatment with BCMA-directed Bispecific Antibodies precedes BCMA-directed CAR-T cell therapy. 

Also, some patients have become refractory to two BCMA-directed therapies, and that number will only increase with the results of KARMMA-3 (3rd line) and CARTITUDE- 4 (2nd line) triggering FDA review for use in earlier lines of therapy, as they’ve showed improved progression-free survival (PFS) compared to the Standard of Care (SOC).

For all these reasons, other targets on myeloma cells are needed.

Information About GPRC5D

Thankfully, research in the myeloma field is providing more targets for immunotherapy, including the GPRC5D target we’re highlighting today. 

In August 2023, the first bispecific antibody that targets GPRC5D, known as TALVEY (Talquetamab), was FDA-approved.  

While the function of GPRC5D in humans is unclear, it is preferentially expressed on plasma cells in patients with multiple myeloma and has limited expression on normal human tissue, including skin (hair follicles and eccrine glands) and the testis (seminiferous tubules), making it a desirable target.

If you’d like to become familiar with the target known as GPRC5D before you read on, you can watch the following video by Dr. Benjamin Diamond: GPRC5D and FcRH5 Targeted Therapies in Myeloma (June 15, 2023)

Information on the GPRC5D CAR-T Study

At this year’s 2023 ASH conference, Dr. Susan Bal presented updated research from a Phase I study of BMS-986393 (CC-95266), a GPRC5D autologous CAR-T cell therapy in patients with Relapsed/Refractory Multiple Myeloma (RRMM).

The goal of a Phase I trial is to study safety and efficacy and attempt to find the Recommended Phase 2 Dose (RP2D). 

The RP2D (dosing) for this GPRC5D CAR therapy has been determined: 150x10⁶  (150 million cells per infusion).

A beautifully understandable Publication Plain Language Summary of this study was provided, with detailed data, graphics, study references, and a glossary. 

I will highlight some of the findings from the study below, but please open this link for a deeper dive into the data.

Clinical Trial Plain Language Report for GPRC5D Trial 

Key Eligibility Criteria for the Study 

Importantly, myeloma patients with prior BCMA and CAR-T-directed therapies were eligible to participate.

• ≥3 prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, anti-CD38 therapy and an autologous stem cell transplant (if eligible)
• Disease progression within 12 months of most recent treatment, unless treatment was with CAR T cells

Study Design 

After screening and leukapheresis (collection of T-cells), patients received bridging therapy if needed and underwent lymphodepletion followed by a single infusion of BMS-986393 (the GPRC5D-directed CAR-T cells that had been re-engineered.) 

Dose Escalation 

The dosing options ranged from 25 million to 450 million CAR-T cells per infusion.

Dose Expansion 

Within 48 observed patients, their T-cell counts ranged from 75 million to 450 million CAR-T cells per patient after the infusion. 

Who Participated in the Trial? 

The overall response rate (ORR) for those with no prior BCMA therapy was 87%, while those who had received any form of BCMA therapy actually had a 100% response rate, which is surprising but encouraging news. 

The complete response rate (CR) for those with no prior BCMA therapy was 40%, while those who had received any form of BCMA therapy had a CR of 63%. 

In both cases of response percentages, those patients who had received prior BCMA-directed immunotherapy performed better than those who were naive to it. 

These results include patients with extramedullary disease and high-risk cytogenetics, as seen in the table above. These are two cohorts of patients in need of promising treatment options. Their results from this trial were promising, although they can be improved. 

Median Duration of Follow-up 

The median duration of follow-up among this clinical trial patient subset was nine months. 

Median Duration of Response in Evaluable Responders 

43 out of the 64 patients could be evaluated at 13 months.

67% of the responses are ongoing.

84% of the MRD-evaluable patients with equal to or more than CR (complete response) achieved MRD negativity. 

Safety Profile of the Patients with Recommended Dose 

This was the safety profile for those in the trial who received the recommended dose of 150x10⁶.

Hematologic TEAEs (Treatment-Emergent Adverse Events) 

Non-Hematologic TEAEs

Comments on Side Effect Profile 

When looking at the side effect profile from this trial (among those at the 150x10⁶ dose), there are a couple of things that stand out to me: 

In regards to cytokine release syndrome (CRS), the reactions were dose-dependent, and thankfully, none of the reactions were more serious than Grade 2. The median onset of CRs was day three (ranging from day 1-16), and the median duration of symptoms was four days (ranging from 1-13 days). 

Outside of this subset, one patient had severe grade 5 CRS at the 450x10⁶ dosing schedule. 

Macrophage activation syndrome (MAS) and hemophagocytic lymphohistiocytosis (HLH) are two overlapping, potentially fatal syndromes classified by disorganization and malfunction of the immune system that result in widespread inflammation and end-organ damage.

Thankfully, neither MAS nor HLH was present in this trial. 

In terms of ICANS (Immune effector cell-associated neurotoxicity syndrome), there was one low-grade event at the 150x10⁶ dose. Non-ICANS-related neurotoxicity appeared to be dose-related. 4 patients had any grade (15.4%), with one incidence of grade 3 (3.8%). There appears to be some reversibility with these neurotoxicities. 

There were other side effects that presented themselves due to the GPRC5D-targeting medication (GPRC5D also exists in other cells within our body apart from myeloma cells). These included: 

• dysgeusia (loss or significant change in taste) 
• skin/nail issues 
• weight loss 

86% of said effects did not require treatment. These symptoms were generally transient (median 25 days), resolved by themselves, and occurred in a minority of patients, which is an initial indication that CAR-T with this target may be more tolerable than with bispecific antibodies with the same target (such as talquetamab).

GPRC5D-targeting therapies seem to spare B cells within the immune system. This particular phenomenon might be why there's a lower infection rate when compared to BCMA-targeting therapies, as in this trial, there was only an infection rate of 35%, and no opportunistic viruses were seen. Patients still get hypogammaglobulinemia within this GPRC5D-targeting product. 

Allo GPRC5D CAR-T

Though this highlighted GPRC5D-targeting therapy is an autologous CAR-T, meaning that a patient's own T-cells are re-engineered for this treatment, there are also GPRC5D allogeneic CAR-T treatments in the works, meaning that donor T-cells can be engineered and administrated into a patient's body. 

Dr. Jeremy Kinder, PhD, shared these initial findings at ASH through abstract 3290. He explained the complex process through which the T-cells are engineered to target GPRC5D. This technique allows rapid delivery of allogeneic GPRC5D CAR T cells from healthy donors with "non-self" recognition that can destroy myeloma cells. 

While further trials are being done to test the efficacy of these allo CAR-T cells, the research is promising. Having an off-the-shelf approach to CAR-T therapy, along with a separate target from the common BCMA protein, will allow this GPRC5D CAR-T to be more accessible and effective for many myeloma patients. 

Conclusion

In conclusion, it is important to remember that the GPRC5D autologous targeting CAR-T is being tested in a Phase 1 study with a small number of patients, but GPRC5D is proving to be a myeloma target worth further pursuit.

There are plans for two new trials for this CAR-T product around the corner. Consider talking to your doctor about these (or similar) trials to see if they are right for you. 

In myeloma-land, where we still live with relapse, the pursuit of new targets with promising efficacy and “manageable” toxicities is always welcome.

ASH 2023 Resources

Would you like to watch ASH 2023 myeloma research interviews from the investigators themselves? Click "ASH 2023" here: HealthTree University Conference Coverage

To read other ASH 2023 articles, click here: HealthTree 2023 ASH Articles