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Unique CAR T-Cell Construct Studied in Multiple Myeloma


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James N. Kochenderfer, MD

James N. Kochenderfer, MD

CD19-DIRECTED chimeric antigen receptor (CAR) T-cell therapy has been approved by the U.S. Food and Drug Administration for the treatment of leukemia (tisagenlecleucel [Kymriah]) and lymphoma (axicabtagene ciloleucel [Yescarta]), but another type of CAR T-cell therapy is generating interest as a treatment for multiple myeloma. A CAR T-cell product designed specifically for multiple myeloma—bb2121—produced responses in an early proof-of-principle, dose-escalation study in patients with multiple myeloma for whom a median of seven prior therapies had failed. 

A second-generation construct targeting B-cell maturation antigen with a 4-1BB costimulatory domain, bb2121 induced complete remission in 56% of patients with relapsed multiple myeloma, according to updated findings of an early study presented at the 2017 American Society of Hematology (ASH) Annual Meeting & Exposition.1

“Durable ongoing responses are seen over 1 year, and responses continue to improve as late as month 15,” said senior author James N. Kochenderfer, MD, of the Center for Cancer Research at the National Cancer Institute, Bethesda, Maryland. “These are impressive responses compared with my previous experience in treating multiple myeloma. Some data show a deepening of response over time,” he said. 

“Durable ongoing responses are seen over 1 year, and responses continue to improve as late as month 15.”
— James N. Kochenderfer, MD

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“We are excited about the early results in a patient population with advanced myeloma for whom previous therapies have failed. We have patients who have a sustained response and have been able to go for over a year with no additional myeloma therapy and tolerable adverse effects,” Dr. Kochenderfer said in a statement. 

Study Findings 

THE OBJECTIVE response rate with bb2121 infusion was 94%, with 89% of patients having a very good partial response or better and 56%, a complete response or better. The median time to first response was 1.02 months; the median time to best response was 3.74 months. 

Median progression-free survival was not yet reached at a follow-up of 40 weeks. At 6 months, the progression-free survival rate was 81%; at 9 months, progression-free survival was 71%. 

Minimal residual disease was eradicated in 90% of patients evaluable for this measurement. Four patients had disease progression after one bb2121 CAR T-cell infusion, and three of three evaluable patients remain B-cell maturation antigen–positive at disease progression. 

“The [bb2121 CAR T-cell] manufacturing success rate was 100%,” he commented. 

Safety Data 

THE SAFETY of bb2121 CAR T has been manageable at doses up to 800 × 106 CAR T cells. Two reported cases of grade 3 cytokine-release syndrome resolved within 24 hours. One case of delayed-onset, reversible grade 4 neurotoxicity occurred in association with tumor-lysis syndrome and cytokine-release syndrome. This patient had the highest tumor burden in the trial. 

“The bb2121 CAR T-cell product is well tolerated, compared with other trials of CAR T cells,” Dr. Kochenderfer noted. Five deaths were reported, with three due to progressive disease. Fourteen patients experienced one or more serious adverse events. 

“We are excited about early results in a patient population with advanced myeloma...”
— James N. Kochenderfer, MD

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Based on these preliminary findings, a global pivotal trial called KarMMa is now open for enrollment. Patients with relapsed or refractory multiple myeloma will receive bb2121 CAR T cells in a dose range of 150 to 300 × 106 cells. 

Background on bb2121 

B-CELL MATURATION antigen is expressed nearly universally on multiple myeloma cells, making it an attractive target, Dr. Kochenderfer explained. Targeting that antigen, bb2121 consists of autologous T cells transduced with a lentiviral vector encoding a novel CAR incorporating an antigen-recognition moiety (scFv), a 4-1BB costimulatory motif, and a CD3 zeta T-cell activation domain. 

The CRB-401 study was a 3 + 3 dose-escalation trial of bb2121 CAR T cells. The T cells were collected from 24 patients, and 21 received 1 dose of the experimental treatment. All 21 patients were evaluable for response. 

Median age was 58 years, and 62% were male. Median time from diagnosis was 4 years. Six patients (29%) had International Staging System (ISS) stage I disease; 11 (52%) had ISS stage II; and 4 (19%) had ISS stage III. All patients had an Eastern Cooperative Oncology Group performance status of 0 to 1. Nine (43%) had high-risk cytogenetics. 

CAR T-CELL THERAPY IN MULTIPLE MYELOMA

  • B-cell maturation antigen–directed therapy with bb2121 CAR T cells has achieved positive results in an early trial of heavily pretreated patients with multiple myeloma for whom other therapies have failed.
  • This is a small trial of 21 patients, but results are favorable, and this CAR T-cell product will continue to be developed.

The median number of prior lines of therapy was seven. Treatment with a prior autologous stem cell transplant, as well as prior bortezomib (Velcade) and lenalidomide (Revlimid), had failed in all 21 patients; 19 patients also had experienced treatment failure on pomalidomide (Pomalyst) and carfilzomib (Kyprolis); and 15 patients had treatment failure on prior daratumumab (Darzalex). 

“Multiple myeloma is essentially incurable. New treatments are needed for this disease,” Dr. Kochenderfer commented. 

At a press conference held during the ASH meeting, Dr. Kochenderfer noted that 12 more patients have been treated on an expansion cohort, but the data had not yet been fully analyzed. 

DISCLOSURE: The study was sponsored by Bluebird Bio and Celgene. Dr. Kochenderfer has received research funding from Bluebird Bio and Kite Pharma, and he has multiple patents in the CAR T-cell field. 

REFERENCE 

1. Berdeja J, Lin Y, Raje N, et al: Durable clinical responses to heavily pretreated patients with relapsed/refractory multiple myeloma: Updated results from a multicenter study of bb2121 anti-BCMA CAR T-cell therapy. 2017 ASH Annual Meeting. Abstract 740. Presented December 11, 2017.


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