Anti-BCMA CAR T-cell Therapy Reins in Myeloma

Autologous immune cells genetically engineered to target B-cell maturation antigen (BCMA) can help patients with relapsed or refractory multiple myeloma achieve deep molecular remissions, according to initial results of a phase I trial of the anti-BCMA chimeric antigen receptor (CAR) T-cell therapy idecabtagene vicleucel (ide-cel, formerly bb2121; Bluebird Bio and Celgene; N Engl J Med 2019;380:1726–37).

Of the first 33 patients to receive the therapy, 28 achieved an objective response, including 15 who had a complete response. Among 16 responders who could be evaluated for minimal residual disease (MRD), none had detectable disease in the bone marrow.

Notably, all but one of the nonresponders received a low dose of CAR T cells in the dose-escalation trial, researchers reported. However, “when we go up to the higher dose levels, we're getting responses from almost every patient,” says principal investigator James Kochenderfer, MD, of the NCI. Responses lasted a median of 10.9 months, with six patients experiencing ongoing remissions for at least a year. Median progression-free survival was 11.8 months.

“In a heavily pretreated patient population, the results are by far better than anything we could have expected from a more traditional therapy,” says Eric Smith, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York, NY, who was not involved in the trial. Still, he worries about how many patients will remain in remission long term, despite achieving MRD-negativity. “Where there seems to be room for improvement is durability.”

Ide-cel—which incorporates an anti-BCMA murine single-chain variable fragment, a 4-1BB costimulatory motif, and a CD3ζ signaling domain into a patient's own T cells via lentiviral transduction—triggered many of the same side effects as other CAR T-cell regimens, including blood-related toxicities and cytokine release syndrome. It did not, however, cause many severe neurologic problems, a side effect of other CAR T-cell products, including those targeting BCMA (Brain 2019;142:1334–48).

For example, three of 25 patients with myeloma who received CART-BCMA, which is structurally similar to ide-cel but with a humanized single-chain variable fragment, developed grade 3 or 4 encephalopathy, according to phase I trial data (J Clin Invest 2019;129:2210–21). (CART-BCMA is from Novartis and the University of Pennsylvania [Penn] in Philadelphia.) With ide-cel, only one of 33 patients experienced severe neurologic toxicity—cerebral edema treated with glucocorticoids that resolved within a month.

The response rate was also lower in the CART-BCMA trial—48%, compared with 85% in the ide-cel trial—“but as usual, with comparing trials, the devil is in the details,” says Penn's Adam Cohen, MD, and “whether these differences are due to a superior CAR product versus patient selection versus conditioning versus a combo of all three is difficult to determine in such small studies.”

According to Cohen, no further single-agent studies of CART-BCMA are planned, although it is being evaluated in a phase I combination trial with a CD19-targeted CAR T-cell product in patients with myeloma.

Compare that to ide-cel, which remains the focus of several monotherapy studies, including some that could soon usher in regulatory approval. In fact, among more than a half dozen BCMA-targeted CAR T-cell therapies in clinical development today—including candidates from Janssen, Autolus, Cartesian, and Poseida, as well as others from Celgene—ide-cel is the only one in phase III testing.

That pivotal trial, launched in October 2018, will evaluate ide-cel against standard triplet-drug regimens in 381 patients who did not respond to at least two prior therapies. A 181-person, phase II second-line treatment trial also began enrollment last year.

As R. Frank Cornell, MD, of Vanderbilt University Medical Center in Nashville, TN, who is not involved in any ongoing CAR T trials, points out, as less heavily pretreated patients receive the CAR T-cell product, “I think you're going to see more meaningful and durable responses to the treatment.” –Elie Dolgin

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