The FDA has approved ciltacabtagene autoleucel (cilta-cel), a chimeric antigen receptor T-cell therapy targeting BCMA, as a fifth-line option for patients with relapsed/refractory multiple myeloma. Cilta-cel is the second agent in its class to get a regulatory thumbs-up in less than a year.

A second chimeric antigen receptor (CAR) T-cell therapy has been added to multiple myeloma's treatment arsenal, with ciltacabtagene autoleucel, or cilta-cel (Carvykti; Janssen/Legend Biotech), receiving the FDA's nod on February 28. Like idecabtagene vicleucel, or ide-cel (Abecma; Bristol Myers Squibb)—which was greenlighted less than a year ago—cilta-cel targets BCMA and is a fifth-line option for this disease.

Having two CAR T-cell therapies available “will be great,” says Adam Cohen, MD, of the University of Pennsylvania in Philadelphia, given that “bottlenecks in manufacturing ide-cel have led to long waitlists at many centers.”

Cilta-cel's launch “will take a few months—just because it's approved doesn't mean we can offer it to patients immediately,” adds Eric Smith, MD, PhD, of Dana-Farber Cancer Institute in Boston, MA. “Even when it gets going, I don't know that both CAR-Ts will be able to fulfill the demand out there right away.”

Updated, longer-term results from the pivotal CARTITUDE-1 trial, presented during the American Society of Hematology's annual meeting in December 2021, secured cilta-cel's approval. Among 97 patients who had received multiple prior treatments—including all three mainstays, proteasome inhibitors, anti-CD38 drugs, and immunomodulatory agents—the objective response rate to cilta-cel was 98%. After 22 months, the stringent complete response rate was 83%, and median progression-free and overall survival were not reached.

“These are really exciting, encouraging data,” Smith says. Before CAR T-cell therapy, one of the most recent approvals for relapsed/refractory multiple myeloma was selinexor (Xpovio; Karyopharm), a selective inhibitor of nuclear export, “which benefited a minority of these difficult-to-treat patients, and on average, only for a few months,” he points out. “By contrast, cilta-cel and ide-cel are dramatic advances.”

With all caveats of cross-trial comparisons duly noted, “the depth and duration of responses do seem better with cilta-cel” than ide-cel, Cohen says. However, “there could be an increased risk of late-developing neurotoxicity involving parkinsonian symptoms that we'd want to discuss with patients.” One way to reduce this risk, clinicians have learned, “is to control the disease burden as much as possible—through aggressive bridging therapy, if necessary—before starting cilta-cel.”

Both Cohen and Smith observed that cilta-cel doesn't stick around long—unlike ide-cel, where CAR-bearing T cells are detectable in many patients after 12 months. Interestingly, this lack of persistence doesn't appear to influence response durability, at least based on preliminary data. More analyses are underway to suss out whether persistence matters, and whether enriching for particular T-cell subsets—perhaps those with central memory or stem-like phenotypes—is important.

As well, trials of both immunotherapies are ongoing “in earlier disease settings,” Cohen says, “and the hope is, ultimately, first-line CAR-T, which could benefit a subset of high-risk patients whose outcomes are consistently poor despite all the treatments we have.”

Additional multiple myeloma targets, such as FcRH5 and GPRC5D, have recently emerged, Smith notes. He is interested in sending CAR T cells after the latter protein, with CC-95266 (Bristol Myers Squibb) among several products now in phase I trials stemming from his lab research. Others are pursuing T-cell–engaging bispecifics, including talquetamab (Janssen) for GPRC5D and cevostamab (Genentech) for FcRH5.

“My sense is these therapies will first be used for patients who have relapsed following BCMA CAR-T,” Cohen remarks. “However, once they're all on the market, we can begin testing the best sequences or, possibly, combinations. It could take years, but it's a good problem to have.”

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Multiple myeloma.

“A cure remains elusive,” Smith adds, “but it's great to get patients into durable remissions and, meanwhile, find options for their next relapse. We can keep kicking the can down the road, so to speak, with new therapies becoming available each year.” –Alissa Poh

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