Beyond BCMA-Directed CAR T-Cell Therapy

Although survival rates for patients with multiple myeloma are improving, with a 5-year rate of about 60%, many patients relapse after treatment.

“Patients have seen impressive advances in survival because of the widespread use of proteasome inhibitors, immunomodulatory drugs, monoclonal antibodies, and autologous stem cell transplantation — all developed in the past 30 years,” said Andrew Cowan, MD, of Fred Hutch Cancer Center in Seattle. “However, with each successive line of therapy, we see attrition due to disease progression and other causes, so it is critical to use our best therapies early on to achieve optimal long-term outcomes.”

Already proving effective are B-cell maturation antigen (BCMA)-directed CAR T-cell therapies, including idecabtagene vicleucel (Abecma) and ciltacabtagene autoleucel (Carvykti). As earlier novel therapies have increased multi-refractoriness in heavily treated patients, researchers have identified new targets and innovative pathways for relapsed/refractory multiple myeloma, as well as for newly diagnosed disease.

“The progress in immunotherapeutic approaches has been tremendous, with the regulatory approvals of CAR-T therapies targeting BCMA, as well as bispecific T-cell antibodies targeting BCMA and GPRC5D [G protein-coupled receptor 5D],” said Hans Lee, MD, of the University of Texas MD Anderson Cancer Center in Houston. “We’re seeing unprecedented responses in patients who have been on many previous treatments.”

Lee also pointed to a new class of oral drugs called cereblon E3 ligase modulators (CELMoDs). “Some of these drugs show promise both as single agents and in combination with other myeloma drugs and are being evaluated in several clinical trials,” he noted.

Such developments are reshaping the prognostic outlook for relapsed/refractory multiple myeloma. Newer agents may especially benefit older or frailer patients who are not good candidates for stem cell transplantation and have an unmet need for well-tolerated therapies, Lee said.

“Having different approaches for different patients is essential,” he added. “Many patients, even though they’re older and have comorbidities, can still get CAR-T and bispecific antibodies, but these may not be the best options for certain patients. Therefore, oral therapies such as CELMoDs or belantamab mafodotin [Blenrep], which have shown promising results in clinical trials, may be options for such patients in the future.”

Bispecific Antibodies

Bispecific T-cell engagers are double-binding agents that attach to both plasma cells expressing BCMA and myeloma cells, allowing them to cross-link, thereby activating the T cells to produce cytotoxic cytokines. Some also target emerging multiple myeloma markers such as FcRH5 and GPRC5D.

The approval of teclistamab (Tecvayli), the first approved off-the-shelf BCMA-directed bispecific for refractory multiple myeloma, was based on findings from the MajesTEC-1 study, which included patients with a median of five prior treatments, showing that 43% of patients achieved a complete response with a median duration of response of 24 months. Median progression-free survival was 12.5 months, and median overall survival was 21.9 months.

GPRC5D is a receptor highly expressed on malignant plasma cells and is associated with poor outcomes. This target may offer an alternative treatable pathway to BCMA-targeted CAR T-cells.

Another therapy in this class for myeloma is talquetamab (Talvey), a bispecific targeting GPRC5D and CD3. Talquetamab’s efficacy was demonstrated in the MonumenTAL-1 study, which showed a more than 70% response rate in patients with heavily pretreated relapsed or refractory multiple myeloma. High response rates were also seen in those with prior T-cell redirection therapy.

Antibody-Drug Conjugates

While the anti-BCMA monoclonal antibody belantamab mafodotin was withdrawn from the market for patients with relapsed/refractory multiple myeloma in late 2022, the drug appears to be making a comeback, with two recent positive phase III trials recently reported — DREAMM-7 and DREAMM-8 trial — in myeloma.

CELMoDs

The ubiquitin ligase substrate receptor protein cereblon (CRBN) degrades the proteins Ikaros and Aiolos, which are highly expressed in B-cell malignancies, and lead to downstream antiproliferative and immune-stimulating activity.

While the immune modulators lenalidomide (Revlimid) and pomalidomide (Pomalyst) activate CRBN, CELMoDs are showing greater potency and greater immunomodulatory and antiproliferative activity. These agents bind CRBN with higher affinity, even in lenalidomide-resistant cells, and thereby induce faster degradation of Ikaros or Aiolos.

This class includes the small-molecule oral agent mezigdomide, which in combination with dexamethasone, led to an objective response rate of 41% in patients with triple class-refractory multiple myeloma.

Several Issues Remain

Despite positive findings with novel agents, several issues remain unresolved, including how to select patients for each strategy or how to sequence these therapies. As data mature from studies in relapsed/refractory multiple myeloma, these therapies will likely be advanced to earlier lines of therapy.

High-dose chemotherapy and autologous stem cell transplantation are still considered the standard of care for newly diagnosed multiple myeloma in eligible patients, Lee said. “However, because regimens for newly diagnosed multiple myeloma are becoming much more effective in patients, including the fraction who attain measurable residual disease negativity, there has been a trend toward deferring upfront high-dose chemotherapy with autologous stem cell rescue in some patients with standard-risk disease.”

He pointed to the head-to-head CARTITUDE-6 study comparing the BCMA CAR T-cell agent ciltacabtagene autoleucel with autologous stem cell transplant as consolidation for newly diagnosed multiple myeloma.

“It’s a very exciting time in myeloma research, with a number of new promising therapies on the horizon,” Lee said.

Looking to the future, he foresees an increasing use of immunotherapies. “Hopefully these approaches will increase the depth and durability of responses in newly diagnosed patients, as well as the tolerability and quality of life during longer treatment,” he said. “Ultimately, these novel treatments may even lead to a cure in some patients or a very deep and durable remission so they can be treated for fixed durations of therapy without the need for continuous therapies.”

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