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Mutations in Target Proteins Provide Fresh View of Multiple Myeloma Resistance to T-Cell Therapies

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NEW YORK – Newly identified genomic alterations associated with relapse and resistance to targeted T-cell therapies in multiple myeloma patients may offer opportunities for tailoring treatment, according to a study published Thursday in Nature Medicine

A group of researchers from City of Hope, the University of Miami, the University of Calgary in Canada, and the University Hospital of Würzburg in Germany found that certain mutations in the B-cell maturation antigen (BCMA) and G-protein coupled receptor family C group 5 member D (GPRC5D) differentially disrupt targeted CAR T-cell and bispecific T-cell engager therapies from binding their respective epitopes on the tumor cell surface, leading to disease relapse. They speculated in the Nature Medicine paper that screening for these mutations in multiple myeloma patients could enable personalized treatment with the current generation of T-cell therapies and inform the development of next-generation agents.

Study author Francesco Maura, an assistant professor at the University of Miami Miller School of Medicine, said the goal of the study was to identify mechanisms of resistance in multiple myeloma and ultimately to extend the benefits of T-cell therapies by finding ways to overcome it.

Maura's team looked for evidence of antigen escape in bone marrow plasma cells collected from 33 multiple myeloma patients who had been treated with anti-BCMA or anti-GPRC5D CAR T-cell therapies, bispecific T-cell engagers, or other agents. Patients had received a median of five previous lines of therapy, and two had received both anti-BCMA and anti-GPRC5D therapies. The researchers searched for genomic alterations associated with disease relapse using bulk whole-genome sequencing and single-cell copy number variant analysis of bone marrow aspirates collected before patients started therapy and once their disease progressed.

BCMA and GPRC5D have become significant immunotherapeutic targets in multiple myeloma. BCMA is a transmembrane protein encoded by the TNFRSF17 gene on chromosome 16p, which regulates B-cell proliferation and survival. BCMA is overexpressed on the surface of multiple myeloma cells, which shed a soluble form of the protein that is detectable in the bloodstream and is commonly used as a biomarker for diagnosis, disease progression, and treatment response.

The US Food and Drug Administration has approved several anti-BCMA therapies. Bristol Myers Squibb and 2seventybio's Abecma (idecabtagene vicleucel) in 2021 became the first FDA-approved, BCMA-directed autologous CAR T-cell therapy for multiple myeloma. FDA approval for Legend Biotech and Janssen's BCMA-directed CAR T-cell therapy Carvykti (ciltacabtagene autoleucel) followed in 2022. The FDA also approved Pfizer's bispecific BCMA-directed CD3 T-cell engager Elrexfio (elranatamab) this month. Outside of the US and Europe, regulators in China in July approved the autologous anti-BCMA CAR T-cell therapy Fucaso (equecabtagene autoleucel) developed by Innovent Biologics and IASO Bio.

GPRC5D, meanwhile, is a transmembrane protein encoded by the eponymous gene on chromosome 12p. Currently, the only marketed GPRC5D-directed therapy in the US is Janssen's bispecific antibody Talvey (talquetamab), approved earlier this month as a treatment for patients with relapsed or refractory multiple myeloma who have undergone at least four previous lines of therapy. Numerous other investigational T-cell therapies targeting BCMA and GPRC5D are in clinical development.

Despite the availability of treatments targeting these proteins, it is not always clear which treatment or combination of treatments would be most effective for a given multiple myeloma patient. And although CAR T-cell and T-cell engager therapies have demonstrated strong efficacy in clinical trials, patients' responses are typically not long-lasting.

For example, in the Phase II KarMMA trial of Abecma as a fourth or later-line multiple myeloma treatment, 94 out of 128 patients, or 73 percent, responded to the therapy. This was very encouraging efficacy considering the heavily pretreated population, and although the high response rate convinced the FDA to approve the drug, median progression-free survival was 8.8 months. Among those patients who had a complete response, the duration of response was 19 months, and the median progression-free survival was 20.2 months. Extending multiple myeloma patients' durability of response has been an important goal for drugmakers and researchers advancing the next-generation of CAR T-cell and bispecific antibody therapies.

While it's well known that immune escape to T-cell-based therapies develops within a year or two in multiple myeloma patients, antigenic drift has not previously been considered a significant driver of that process. Few studies have focused on the mechanisms of resistance in patients who have been treated with these therapies.

In the KarMMA study, loss of BCMA expression in myeloma cells upon progression after treatment with Abecma occurred in only three of 71 patients, or just 4 percent. That led some to believe that antigenic escape is not common with BCMA-directed therapies. The evidence has been a bit stronger for loss of GPRC5D, which was observed in all six multiple myeloma patients who progressed after receiving an anti-GPRC5D CAR T-cell therapy in a Phase I clinical trial sponsored by Memorial Sloan Kettering Cancer Center.

Maura's group found that BCMA mutations were indeed an important mechanism in the development of resistance to BCMA-targeted therapies in multiple myeloma patients. They discovered that these mutations in the extracellular TNFRSF17 domain could disrupt binding of targeted therapies without resulting in loss or reduced expression of BCMA overall.

"[BCMA] provides an essential function for the cell. That's why it's so hard to lose," explained Maura. "But then what these mutations do is they block the [CAR T-cell therapies] and [bispecific T-cell engagers] from binding the receptor," which he said is basically equivalent to an antigenic escape but without complete loss of the protein.

While the latest research by Maura's group isn't based on a large dataset, he pointed out that "almost half of the patients that progressed experienced antigen escape, so it's more prevalent than what we believed."

For example, the researchers observed a substitution of arginine for proline at position 27 (Arg27Pro) in the protein chain for BCMA in a patient who had relapsed following treatment with a BCMA-directed T-cell engager therapy. Subsequent in vitro studies evaluating the binding efficacies and cytotoxic effects of several anti-BCMA bispecific antibodies showed that cells with the Arg27Pro mutation were resistant to Janssen's Tecvayli (teclistamab-cqyv) and Elrexfio but retained sensitivity to an in-house version of Abecma and two T-cell BCMA/CD3 bispecific antibodies, Bristol Myers Squibb's investigational bispecific antibody alnuctamab and another produced for research use by BPS Bioscience.

In another patient who relapsed after receiving an anti-BCMA bispecific antibody, researchers identified a deletion of proline at position 34 that disrupted binding of Elrexfio to tumor cells in vitro. Those same cells, however, remained sensitive to alnuctamab.

Looking at GPRC5D, Maura and colleagues found multiple mutations that led to loss of GPRC5D expression in patients who relapsed after treatment. One patient, after receiving the BCMA -binding Tecvayli, was treated with GPRCD5D-binding Talvey, Janssen's CD38 monoclonal antibody Darzalex (daratumumab), Bristol Myers Squibb's anti-angiogenic drug Pomalyst (pomalidomide), and dexamethasone.

Upon relapse, the patient had significant loss of GPRC5D but detectable BCMA protein expression with no mutations detected in the TNFRSF17 gene. Maura's team reported several similar cases in which patients had loss of GPRC5D after anti-GPRC5D bispecific T-cell engager therapy.

Based on these findings, the researchers concluded that loss of BCMA as detected by common immunohistochemistry testing methods fails to account for relevant mutations that can cause resistance to anti-BCMA therapy. They further concluded that GPRC5D is lost more readily than BCMA during treatment with targeted immunotherapies.

Maura said his team will continue work with collaborators at the University of Calgary to investigate what other mechanisms might be contributing to resistance in the other half of patients that don't show antigenic drift in response to targeted T-cell therapies and dig into why patients developed certain patterns of resistance.

Ultimately, Maura hopes that these studies will be translated into the clinic and help doctors identify the immunotherapy among the myriad options that a multiple myeloma patient is likely to respond best to. "One possibility is that the use of comprehensive genomic analysis will allow us to better stratify patients for the different products," Maura said. "To use the most effective first or organize the right sequence of drugs."

While it might be possible to perform single-gene tests for the specific alterations identified in this study, Maura expects that next-generation sequencing-based comprehensive genomic profiling will likely provide a better picture of patients' tumors' vulnerabilities to therapy. While Maura's group is not yet at the stage of developing a test based on their research, he noted that "synergy between academia and pharma is essential to accelerate the development and clinical applicability of these discoveries."