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B-cell maturation antigen (BCMA)-directed CAR T-cell therapies are now established options for treating multiple myeloma after relapse, but efforts are underway to expand their use and to bring novel products to the clinic that target alternate antigens associated with the disease.

"CAR T-cell therapy began initial testing in hematologic cancers in about 2014. And even before randomized trials were done, this therapy had shown higher response rates and longer duration of control than standard treatments," said Sham Mailankody, MBBS, of Memorial Sloan Kettering Cancer Center in New York City. "This treatment is highly effective."

"Although it's not curative, this therapy has made a huge difference in controlling the disease," added Henry C.H. Fung, MD, of Fox Chase Cancer Center in Philadelphia. "Patients who used to live for 2 years after diagnosis are now living for 9 or 10 years or more."

In myeloma, the FDA has approved two anti-BCMA CAR-T products: idecabtagene vicleucel (ide-cel, Abecma) in 2021 and ciltacabtagene autoleucel (cilta-cel, Carvykti) in 2022. Under these initial approvals, eligible candidates had to have failed four previous regimens to qualify for use of CAR T cells.

Earlier Use of CAR-T Approved

This April, the FDA expanded the approvals of cilta-cel and ide-cel to include use as second- or third-line treatments for refractory myeloma in adults. It gave the nod to cilta-cel as treatment after one prior failure and ide-cel after two prior treatment failures. Common treatments for myeloma prior to CAR-T include a proteasome inhibitor like bortezomib (Velcade) and an immunomodulator drug such as lenalidomide (Revlimid).

The new CAR-T approvals came in the wake of positive trial results. Last year, the phase III CARTITUDE-4 study found a single cilta-cel infusion reduced the risk of disease progression or death by 74% compared with standard care in lenalidomide-refractory patients who had received one to three previous therapies. Progression-free survival at 12 months was 76% in the cilta-cel group compared with 49% with usual care.

In addition, more patients in the cilta-cel group than the usual-care group achieved an overall response (85% vs 67%), a complete response or better (73% vs 22%), and minimal residual disease-negativity (61% vs 16%).

Meanwhile, the phase III KarMMa-3 trial reported a 51% reduction in the risk of disease progression or death with ide-cel over standard care. Ide-cel tripled median progression-free survival time, from 4.4 months to 13.3 months, and 71% of those receiving this agent responded to treatment, with 39% having a complete response that lasted for a median of 20 months.

While the approvals for earlier use are welcome, "it will take years of well-conducted studies to show whether CAR T cells can be used as effective first-line therapy," said Fung, adding that ongoing trials are examining whether frontline use can deliver better results than standard induction regimens.

The bar will be high, added Mailankody. "We need to show that outcomes are actually better than with standard frontline therapies. Current survival is already measured in terms of up to 8 or 9 years, so CAR T-cell treatment would have to outperform that," he said, noting that the associated cell-manufacturing costs are high, at approximately $100,000.

Another significant concern is safety, Fung and Mailankody pointed out, with adverse side effects including cytokine release syndrome, central nervous system toxicity, and -- in a small number of patients -- Parkinson's-like movement symptoms and other cancers. "The dosing of CAR T cells is well-established, but we still need to minimize toxicity," Mailankody said.

Added Fung: "We also need to improve the assessment of patients after treatment and improve the specificity of agents for individuals. And we have to figure out how patients can be treated outside of major tertiary-care centers." Travel logistics are a major hurdle for both treatment and follow-up care, including out-of-town accommodation and time off work. "So some patients who could benefit decide not to do the treatment," he said.

And more accessible treatment is only one part of the equation, according to Fung. "These patients require an army of people for this complex chronic disease. They need supportive services in collaboration with surgical and palliative care and local medical centers."

Another issue is shortening the cell-manufacturing time (which currently takes as long as 6 weeks) and hopefully reducing the cost. "If we could switch from autologous to allogeneic T cells, we might be able to move to off-the-shelf agents," Fung said.

Going Forward

New immunotherapeutic targets are under investigation, including G protein-coupled receptor class C group 5 member D (GPRC5D). Preclinical studies have shown activity in a BCMA-antigen escape model. In 2022, a small phase I by Mailankody's group confirmed that GPRC5D-targeted CAR T-cell therapy (MCARH109) is clinically active in multiple myeloma.

This new target opens the door to homing in on alternate antigens, as opposed to using sequential BCMA-directed therapies in relapsed patients, and points to the potential role of combining BCMA- and GPRC5D-directed therapy to target low-antigen-density reservoirs of relapse, with the aim of inducing deeper and longer durations of response.

A of GPRC5D-targeted CAR T-cell therapy for relapsed or refractory multiple myeloma is currently enrolling patients. (FDA in 2023 approved talquetamab (Talvey), a bispecific T-cell-engaging antibody against CD3 and GPRC5D, for relapsed or refractory multiple myeloma.)

Another challenge, said Mailankody, "is to get allogeneic CAR T cells to be as effective as autologous." His group is exploring the potential of allogeneic cells, last year publishing early positive results for ALLO-715, a first-in-class, allogeneic, anti-BCMA CAR T-cell therapy designed to prevent graft-versus-host disease and minimize graft-cell rejection.

Another question to be investigated is whether CAR T-cell therapy could be used to replace grafting. "That might be an option for older or sicker patients who don't want to undergo stem-cell transplant," Mailankody said.

In the meantime, new data from dozens of clinical trials of CAR T-cell products are expected soon, as well as from studies of bispecific antibodies, novel drug combinations, and newer ways to target myeloma.

While the recent approvals of CAR T-cell therapies after first- or second-line treatments will have an immediate impact for myeloma patients, these and other immune therapies are expected to be used more widely in earlier multiple myeloma treatment. Promising preliminary data with allogeneic CAR T-cell therapy and the targeting of novel antigens may soon translate to new regimens. The abiding challenge will be ensuring timely and economical access to these new therapies.

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