CAR Ts and BiTEs Shine in Multiple Myeloma

Median overall survival (OS) in relapsed or refractory (r/r) multiple myeloma is poor: Patients whose disease resists three classes of drugs have a median OS of 1 year, and the median OS for patients for whom five prior therapies have failed is less than 6 months. Soon, chimeric antigen receptor (CAR) T cell–based treatments and bispecific T-cell engager (BiTE) therapies may improve the prognosis for some patients, but whether one approach will best the other is unclear.

Several recent trials of CAR T cells and BiTEs offer encouraging results. In the phase Ib/II CARTITUDE-1 trial, an infusion of ciltacabtagene autoleucel—a CAR T-cell product with dual targeting of BCMA, an almost ubiquitously expressed antigen on myeloma cells—yielded an overall response rate of 94.8% among 97 patients with r/r multiple myeloma (clinicaltrials.gov/ct2/show/NCT03548207). The stringent complete response rate was 55.7%, and responses appeared durable: The OS rate at 6 months was 93.8%. The data were presented at the 2020 American Society of Hematology Annual Meeting, held virtually in December.

“It's quite exceptional to see these kinds of response rates with a one-time treatment,” says Deepu Madduri, MD, of the Icahn School of Medicine at Mount Sinai in New York, NY, the trial's lead investigator.

Additionally, a first-in-human, phase I trial of AMG 701, a BiTE targeting myeloma-cell BCMA and T-cell CD3, was presented (clinicaltrials.gov/ct2/show/NCT03287908). A BiTE is an engineered protein in which parts of two antibodies are fused: One binds a T-cell surface protein, such as CD3, while the other binds a tumor cell surface protein, such as BCMA, tethering T cells to tumor cells. The trial included a patient population similar to that of CARTITUDE-1, with the 75 enrolled patients having had a median of six prior therapies. Although efficacy was not the primary endpoint, an early potential signal was observed: The response rate was 36% across all doses and 83% among those given what was determined to be the optimal dose.

“It's producing quite nice response rates at the most recently explored dose cohorts, and we're now going into the expansion phase,” says Simon Harrison, PhD, of the Peter MacCallum Cancer Centre and Royal Melbourne Hospital in Melbourne, Australia, the study's lead investigator.

The high response rates seen in these and other recent CAR T-cell and BiTE trials for historically recalcitrant r/r multiple myeloma are difficult to overlook. However, these treatments are new, and researchers will undoubtedly explore alternate dosing regimens and different target antigens. Further development of CAR T cell–based therapies and BiTEs remains, and the two treatments work via disparate mechanisms, making cross-trial comparisons even more fraught with pitfalls than usual.

In addition, researchers need greater understanding of the basic biology of multiple myeloma and how it affects treatment efficacy. For instance, immunosuppression is a hallmark of multiple myeloma that may arise even at precursor stages, raising the question of how BiTEs, which rely on functional T cells, can exhibit high efficacy.

If these therapies are approved for multiple myeloma, one might not be superior to the other; rather, CAR T cells may be more suitable for some patients than BiTEs or vice versa, or perhaps the treatments could be used sequentially following relapse.

Multiple myeloma experts aren't ready to place bets on whether one strategy will be more successful. “At this point, there's not a clear winner,” says Lawrence Boise, PhD, of Emory University in Atlanta, GA. “Hopefully, the winners are the patients.” –Nicole Haloupek