From the Journals

CAR T-cell therapy bb2121 performs well in phase 1 trial of refractory multiple myeloma



Chimeric antigen receptor (CAR) T-cell therapy bb2121, which targets B-cell maturation agent (BCMA), appears safe and effective for treating patients with refractory multiple myeloma, according to results of a phase 1 trial.

The objective response rate of 85% among 33 heavily pretreated patients suggests “promising efficacy,” reported lead author Noopur Raje, MD, of Massachusetts General Hospital Cancer Center in Boston and colleagues.

“Although comparisons among studies are complicated by differences in patient populations, CAR constructs, administered doses, and grading scales of toxic effects, the results observed with bb2121 indicate a favorable safety profile,” the investigators wrote in a study published in the New England Journal of Medicine.

The study initially involved 36 patients with refractory multiple myeloma who had received at least three lines of prior therapy, including an immunomodulatory agent and a proteasome inhibitor. Although leukapheresis and therapy manufacturing were successful in all patients, three patients were excluded from receiving the infusion because of disease progression.

The 33 remaining patients were lymphodepleted with fludarabine and cyclophosphamide. Bridging therapy was allowed during the manufacturing process but was stopped at least 2 weeks prior to infusion. In the dose-escalation phase of the study, b2121 was delivered as a single infusion at one of four dose levels: 50 × 106, 150 × 106, 450 × 106, or 800 × 106 CAR T cells. In the expansion phase, the treatment was given at either 150 x 106 or 450 x 106 CAR T cells. The primary endpoint was safety; the secondary endpoints were response rate and duration of response.

After a median follow-up of 11.3 months, most patients (85%) had responded to therapy, and almost half (45%) had achieved a complete response. Of the 15 complete responders, 6 relapsed. The median progression-free survival was 11.8 months; stated differently, two out of five patients (40%) had not experienced disease progression after 1 year. CAR T cells were detectable 1 month after infusion in 96% of patients; however, this value dropped to 86% at 3 months, 57% at 6 months, and 20% at 12 months. The investigators noted that CAR T-cell persistence was associated with treatment response.

All patients had adverse events. Most (85%) had grade 3 or higher hematologic toxicity, which the investigators considered to be the “expected toxic effects of lymphodepleting chemotherapy.” Although other adverse events occurred in the majority of patients, these were generally mild to moderate. Cytokine release syndrome occurred in 25 patients (76%), including two instances of grade 3 toxicity but none of grade 4 or higher. Fourteen patients (42%) developed neurologic toxicities: Most were grade 1 or 2, but one patient had a grade 4 toxicity that resolved after a month. Infections occurred at the same rate (42%), although, again, most were grade 1 or 2.

The study was funded by Bluebird Bio and Celgene. The investigators disclosed financial relationships with Bluebird and other drug companies.

SOURCE: Raje N et al. NEJM. 1 May 2019. doi: 10.1056/NEJMoa1817226.

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