Myeloma: The Next Frontier for CAR T-Cell Therapy

Chimeric antigen receptor (CAR) T-cell therapies have shown great success in acute lymphocytic leukemia and non-Hodgkin lymphoma, and the results of a study presented at the 2017 ASH Annual Meeting suggest that myeloma is the next frontier for these revolutionary therapies.

“[CAR T-cell therapy] is an approach that has been exploding over the last 10 years, and in myeloma in particular, we have seen exciting results with this anti–B-cell maturation antigen CAR,” James N. Kochenderfer, MD, from the National Cancer Institute at the National Institutes of Health Clinical Center in Bethesda, Maryland, told ASH Clinical News.

He presented updated results from a multicenter, phase I study of the anti-BCMA CAR T-cell therapy bb2121 in patients with relapsed and/or refractory multiple myeloma (MM). The trial enrolled patients who had received three or more prior regimens, including a proteasome inhibitor and an immunomodulatory agent, or whose disease was refractory to bortezomib and thalidomide and/or lenalidomide. Participants also were required to have at least 50 percent BCMA expression on malignant cells. “[bb2121] is a second-generation CAR construct targeting BCMA to redirect T cells to myeloma cells,” Dr. Kochenderfer explained. “BCMA is a member of the tumor necrosis factor superfamily that is expressed primarily by malignant myeloma cells, plasma cells, and some mature B cells.”

The study followed a standard 3+3 design with planned dose levels ranging from 50×106 to 1,200×106 cells/kg. Prior to CAR T-cell infusion, patients underwent lymphodepletion with fludarabine 30 mg/m2 and cyclophosphamide 300 mg/m2 daily for three days.

As of October 2, 2017 (data cutoff), 21 patients were enrolled (median age = 58 years; range = 37-74 years) at a median of four years (range = 1-16 years) since MM diagnosis. This was a heavily pretreated group, Dr. Kochenderfer noted. Patients had a median of seven prior lines of therapy (range = 3-14 therapies), and all had prior autologous hematopoietic cell transplantation. Fifteen of 21 patients (71%) had exposure to five prior therapies (bortezomib, lenalidomide, carfilzomib, pomalidomide, daratumumab) and six of 21 (29%) were refractory to them. Two-thirds had high-risk cytogenetics.

Eighteen patients were evaluable for initial clinical response at one month, all of whom had been treated with doses ranging from 150×106 to 800×106 cells/kg. (Lower doses were found to be clinically inactive, Dr. Kochenderfer noted.)

After a median follow-up of 35 weeks (range = 6.6-69 weeks) after bb2121 infusion, 17 patients (94%) had responded, including 10 complete responses (CRs), six very good partial responses, and one partial response.

Among the people who responded, after a median follow-up of 40 weeks (range = 6.6-69.1 weeks), the median time to first response was 1.02 months (range = 0.5-3.0 months), the authors reported. The median duration of response and median progression-free survival (PFS) had not been reached. Rates of PFS at six months and nine months were 81 percent and 71 percent, respectively.

Safety analyses of all infused patients showed that no dose-limiting toxicities (DLTs) and no treatment-emergent grade ≥1 neurotoxicities occurred, comparable to findings from other CAR T-cell clinical trials.

“In my experience, this protocol seems to be trending toward having less severe toxicity [than other regimens and other CAR T-cell therapies]. We have to wait for the final analysis, but so far, it’s clearly a favorable toxicity profile,” Dr. Kochenderfer said. Any-grade cytokine release syndrome (CRS) was reported in 15 of 21 patients (71%); two patients had grade 3 CRS that resolved within 24 hours, and four patients received tocilizumab (one with steroids) to manage CRS. Five deaths occurred, including three patients whose disease progressed at the clinically inactive dose of 50×106 cells/kg. The other two patients were treated at active doses and were in CR at the time of death (from cardiac arrest or development of myelodysplastic syndrome following bb2121 discontinuation).

The findings of this study initially support the potential of CAR T therapy with bb2121 as a new treatment paradigm in relapsed/refractory MM, Dr. Kochenderfer added.

Though the results are limited by the small number of patients enrolled and the lack of a comparator arm, he was optimistic about the role of CAR T-cell therapy in this patient population. “CAR T-cell therapy is completely different from other available treatments for MM,” he said. “We have patients who have a sustained response and have been able to go for [more than] a year with no additional myeloma therapy and tolerable adverse effects.”

The authors report financial relationships with Bluebird Bio and Celgene, both of which provided funding for the study.


Reference

Kochenderfer JN, Berdeja JG, Lin Y, et al. Durable clinical responses in heavily pretreated patients with relapsed/refractory multiple myeloma: Updated results from a multicenter study of bb2121 anti-bcma CAR T cell therapy. Abstract #740. Presented at the 2017 American Society of Hematology Annual Meeting, December 11, 2017; Atlanta, GA.

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