First-in-Human CAR T-Cell Therapy in Multiple Myeloma

CHICAGO-Chimeric antigen receptor (CAR) T-cell therapy may have a role in combating relapsed/refractory multiple myeloma (MM), according to new data from a phase I study presented (abstract 3010) at the 2017 American Society of Clinical Oncology (ASCO) Annual Meeting, held June 2–6 in Chicago.

Researchers have developed a product called bb2121, which shows promising efficacy at dose levels above 5 x 10⁷ CAR-positive T cells. An initial study with 21 patients is suggesting good clinical responses in a significant number of patients with mild and manageable cytokine release syndrome (CRS). Most of the cases involved grade 1 and 2. However, two patients suffered with grade 3 CRS that resolved in 24 hours. One unrelated death occurred in this trial due to cardiopulmonary arrest in a patient who had an extensive cardiac history. This death occurred more than 4 months after bb2121 infusion.

“We found that in a very heavily pretreated relapsed/refractory MM patient population there was an overall response rate of 100% beyond the first dose level tested,” study investigator Jesús Berdeja, MD, who is the Director of Myeloma Research at the Sarah Cannon Research Institute in Nashville, Tennessee, told OncoTherapy Network.

The goal of the current study was to test the safety and effectiveness of a CAR T-cell modality in patients with relapsed/refractory MM. Researchers developed a second-generation CAR construct targeting B-cell maturation antigen (BCMA) to redirect T cells to MM.   

This product contains autologous T cells transduced with a lentiviral vector encoding a novel CAR. The CAR contains an anti-BCMA scFv, a 4-1BB costimulatory motif and a CD3-zeta T-cell activation domain.

In this multicenter phase I dose escalation trial, all the patients had received ≥ 3 prior regimens, including a proteasome inhibitor and an immunomodulatory agent, or the patients were double-refractory and had ≥ 50% BCMA expression on plasma cells. The patients received lymphodepletion with Flu (30 mg/m²)/Cy (300 mg/m²) daily for 3 days. Next, they receive one infusion of bb2121. The study utilized a standard 3+3 design with planned dose levels of 5, 15, 45, 80, and 120 x 10⁷ CAR-positive T cells.

The median age of the patients was 58 years (range: 37–74 years) and the median time since diagnoses was 5 years (range: 1–16 years). In this cohort, the median number of prior lines of therapy was 7 (range: 3–14) and 100% had prior autologous stem cell transplant. Prior therapies included bortezomib, carfilzomib, lenalidomide, pomalidomide, and daratumumab.

“The high overall response rates and in particular the depth of responses (>/= VGPR 73%) achieved with CAR T therapy in such a refractory patient population is beyond what has ever been seen in multiple myeloma,” Berdeja told the OncoTherapy Network. “In this study, cytokine release syndrome was common, but the vast majority was grade 1/2 and required no intervention. Only four patients overall required tocilizumab and one patient required steroids. No grade 3/4 neurotoxicity was seen. The degree of toxicity is less than that described in other CAR T trials in myeloma and other diseases.”