IN AN UPDATE of a phase I trial, a heavily pretreated population of patients with multiple myeloma continued to respond to the chimeric antigen receptor (CAR) T-cell therapy bb2121.1 The results presented at the 2018 ASCO Annual Meeting confirmed previous findings for bb2121 in the dose-escalation cohort of the CRB-401 study. The U.S. Food and Drug Administration granted bb2121 Breakthrough Therapy designation in November 2017.
The bb2121 construct is the most mature CAR T-cell approach in development for myeloma. Its target is a common myeloma cell-surface protein known as B-cell maturation antigen (BCMA), which is associated with myeloma cell growth, survival, and proliferation.
Noopur Raje, MD
“We found that bb2121 at active doses induces deep and durable responses in a heavily pretreated population with relapsed or refractory multiple myeloma,” said Noopur Raje, MD, of Massachusetts General Hospital in Boston, in an update of CRB-401.
The CRB-401 trial included 43 patients in dose-escalation (n = 21) and dose-expansion (n = 22) cohorts, the latter being the focus of the update. Patients had received a median of 8 prior regimens (range, 3–23). One-third were penta-refractory, having progressed on lenalidomide (Revlimid), bortezomib, pomalidomide (Pomalyst), daratumumab (Darzalex), and carfilzomib (Kyprolis), and almost all had received a stem cell transplant. Patients received various doses of CAR T cells (50, 150, 450, or 800 million cells) after undergoing lymphodepletion with fludarabine and cyclophosphamide. The dose-escalation analysis showed that at least 150 × 106 (150 million) CAR T cells would be needed to achieve optimal outcomes.
Deep Response, Prolonged Progression-Free Survival
DESPITE THE disease refractoriness of the population, the overall response rate to CAR T-cell therapy was 95.5% among patients treated with > 150 million cells, 57.1% among patients receiving 150 million cells, and 33.3% among those treated with the lowest dose, 50 million cells. For the highest-dose cohort, the median duration of response was 10.8 months, compared to 1.9 months for the lowest-dose cohort, Dr. Raje reported.
The investigators also analyzed outcomes for patients receiving the “active dose” of at least 150 million cells. In this group, median progression-free survival was 11.8 months, compared to 2.7 months for those treated with the “inactive dose” of 50 million cells. Among the 16 dose-expansion patients who responded and who also achieved minimal residual disease (MRD) negativity, median progression-free survival was 17.7 months, she said.
A median progression-free survival of a year and a half in respondents was encouraging in such a refractory population. Still, some CAR T-cell “watchers” were disappointed, hoping that this apparently potent therapy might have presumably cured these patients.
The treatment was considered safe, but 63% of patients did experience cytokine-release syndrome. The majority of cases were mild to moderate; 5% were grade ≥ 3, which resolved within 24 hours, and the 1 grade ≥ 4 event was reversible. Most patients developing cytokine-release syndrome (81%) had received > 150 million cells.
“Cytokine-release syndrome was mostly low-grade and manageable in this study, and we used tocilizumab [Actemra] and corticosteroids infrequently,” Dr. Raje said. In addition, 33% of patients experienced neurotoxicity, 81% developed neutropenia, 61% had thrombocytopenia, and 56% had anemia. “To date, the safety profile of bb2121 has been manageable at doses as high as 800 million CAR T cells,” she said.
A phase II international clinical trial of bb2121 known as KarMMa is currently underway, with a planned enrollment of approximately 100 patients. Additional trials in earlier lines of treatment are also planned. Another CAR T-cell therapy being developed in myeloma, JNJ-68284528, also targets BCMA. In a study presented at the 2017 ASCO Annual Meeting, the response rate to this product was 100%.2 A phase I/IIb clinical trial of JNJ- 68284528 is slated to start later this year. ■
DISCLOSURE: Dr. Raje has been a consultant and/or advisor for Amgen, Bristol-Myers Squibb, Celgene, Merck, Novartis, and Takeda.
1. Raje NS, et al: bb2121 anti-BCMA CAR T-cell therapy in patients with relapsed/refractory multiple myeloma: Updated results from a multicenter phase I study. 2018 ASCO Annual Meeting. Abstract 8007. Presented June 1, 2018.
2. Fan F, et al: Durable remissions with BCMA specific chimeric antigen receptor-modified T cells in patients with refractory/relapsed multiple myeloma. 2017 ASCO Annual Meeting. Abstract LBA3001. Presented June 5, 2017.
Parameswaran Hari, MD
FORMAL DISCUSSANT Parameswaran Hari, MD, of the Medical College of Wisconsin, Milwaukee, was impressed by many aspects of the bb2121 study, which represents the “largest and most mature” data set for the chimeric antigen receptor (CAR) T-cell approach in myeloma, he...!-->!-->