Among the burgeoning options for treating multiple myeloma could be an approach that is proving to be exciting in leukemia: CAR-T (chimeric antigen receptor T cells) therapy. Preliminary results of the first-in-humans study in myeloma were presented as a late-breaking abstract at the 2015 ASH Annual Meeting and Exposition by James Kochenderfer, MD, of the Experimental Transplantation and Immunology branch of the National Cancer Institute’s Center for Cancer Research in Bethesda, Maryland.¹

“We have demonstrated for the first time that CAR-T cells can have powerful activity against measurable multiple myeloma,” Dr. Kochenderfer announced.

In this study, the B-cell maturation antigen was the target for CAR-T therapy. B-cell maturation antigen (CD269), which is a member of the tumor necrosis factor superfamily, is expressed in 60% to 70% of myeloma cases.

“Because B-cell maturation antigen is only expressed by plasma cells and a small fraction of B cells, it is a promising target for treating myeloma,” Dr. Kochenderfer explained. “T cells can be genetically engineered to express an anti–B-cell maturation antigen chimeric antigen receptor (CAR-BCMA).” 

Dr. Kochenderfer led a phase I study that examined the antimyeloma activity of CAR-BCMA T cells in 12 patients with advanced multiple myeloma, who received a median of seven prior lines of therapy. Patients were required to have at least three prior treatments as well as clear, uniform expression of B-cell maturation antigen on their myeloma cells by flow cytometry or immunohistochemistry. 

Prior to CAR-T cell infusion, study participants were treated with a chemotherapy regimen of cyclophosphamide (300 mg/m²) and fludarabine (30 mg/m²), with each agent given for 3 consecutive days. This particular regimen enhanced the activity of the CAR-T cells by depleting endogenous leukocytes. Four different dose levels of CAR-T cells were evaluated.

Activity of CAR-BCMA

“Anti–B-cell maturation antigen CAR-T cells eliminated plasma cells and, importantly, did not cause direct damage to essential organs,” Dr. Kochenderfer reported. “Responses included an ongoing stringent complete remission in a patient with a high burden of chemotherapy-resistant myeloma,” he added.

Among 12 treated patients, investigators observed a stringent complete response (n = 1) that was ongoing at more than 14 weeks, a very good partial response (n = 1), partial responses (n = 2), and stable disease (n = 8).

Balancing Efficacy and Toxicity

Patients with the best response to the CAR-B cell maturation antigen therapy also experienced the most toxicities; these patients were treated at the highest doses. Toxicity among the patients treated with the lowest three dose levels was mild and included cytopenias, fever, and signs of cytokine-release syndrome.

Dr. Kochenderfer described the course of two patients receiving the highest dose (9 ×10⁶ CAR-positive T cells/kg). Patient 10 had three prior lines of therapy. The chemotherapy resistance of his myeloma was demonstrated by relapse, with 90% of bone marrow plasma cells 3 months after autologous transplant. CAR-B cell maturation antigen treatment “rapidly eliminated” his myeloma.

“He obtained an ongoing stringent complete remission of chemotherapy-resistant IgA [immunoglobulin A] myeloma after CAR-B cell maturation antigen T-cell infusion,” he reported, noting that response continues at 14 weeks. “Multiple myeloma that made up more than 90% of Patient 10’s bone marrow cells was eliminated.”

“This is the first example of CAR-T cells completely eradicating or decreasing measurable multiple myeloma,” revealed Dr. Kochenderfer.

This success did not come easily, however. The patient experienced cytokine-release syndrome, starting 4 hours after infusion, including fever, tachycardia, hypotension, elevated liver enzymes, and elevated creatinine kinase, which all resolved in up to 2 weeks. His absolute neutrophil count was less than 500/µL at the time of infusion and remained this low for 40 days, and he was platelet transfusion–dependent for 9 weeks.

Patient 11, with 80% of his bone marrow composed of plasma cells, underwent treatment after five prior lines of therapy. He also experienced significant toxicity and had a dramatic reduction in myeloma. So far, he has had a partial response, but M protein is continuing to decrease.

Interestingly, patients 10 and 11, who had the most severe clinical signs of cytokine-release syndrome, had much higher serum levels of interleukin-6 than the other patients, he added.

Altogether, toxicity was “substantial but reversible” and similar to that seen on previous CAR-T cell trials. The highest dose level of anti–B-cell maturation antigen CAR-T cells will now be administered only to patients with < 50% bone marrow plasma cells, he indicated. ■

Disclosure: Dr. Kochenderfer reported research funding from Bluebird Bio.

Reference

1. Ali SA, Shi V, Wang M, et al: Remissions of multiple myeloma during a first-in-humans clinical trial of T cells expressing an anti-B-cell maturation antigen chimeric antigen receptor. 2015 ASH Annual Meeting. Abstract LBA-1. Presented December 8, 2015.