Therapeutic options for patients with multiple myeloma (MM) have undergone a rapid expansion recently, with three new drug approvals by the U.S. FDA in November 2015 alone. The results of a late-breaking abstract presented at the 2015 ASH Annual Meeting suggest that patients may soon have another option to consider: T cells modified by an anti-B-cell maturation agent (BCMA) chimeric antigen receptor (CAR).
This phase I study examined the anti-myeloma activity of CAR-BCMA T cells in 12 patients with MM; autologous T cells are genetically modified to express the CAR with a gamma-retroviral vector. “BCMA is uniformly expressed on 60 to 70 percent of cases of multiple myeloma,” investigator James Kochenderfer, MD, from the Experimental Transplantation and Immunology branch of the National Cancer Institute’s (NCI’S) Center for Cancer Research in Bethesda, Maryland, explained in his discussion of the results. “Because BCMA is only expressed by plasma cells and a small fraction of B cells, it is a promising target for treating multiple myeloma.”
Prior to CAR T-cell infusion, study participants received a chemotherapy regimen of cyclophosphamide (300 mg/m2) and fludarabine (30 mg/m2), with each agent given for three consecutive days. The researchers noted that the chemotherapy regimen was specifically chosen to enhance activity of the CAR T cells by depleting endogenous leukocytes.
At the time of data presentation, 12 patients had been enrolled in the study, and 11 had been treated on one of the four following dose levels:
- 0.3×106 CAR + T cells/kg (n=3)
- 1×106 CAR + T cells/kg (n=3)
- 3×106 CAR + T cells/kg (n=3)
- 9×106 CAR + T cells/kg (n=2)
Patients included in the study have advanced MM and had received a median of seven prior therapies.
Among the six patients treated on the lowest two dose levels, one patient had a transient partial remission (PR) that lasted for two weeks, while the other five patients had responses of stable disease (SD).
At the third level of dosing, two patients reached SD, and one patient achieved a very good PR (VGPR), with complete eradication of MM cells (according to positron emission tomography [PET] scan, normalization of serum free light chains, and clearance of bone marrow plasma cells).
Toxicity among the nine patients treated with the lowest three dose levels was mild and included cytopenias (attributable to chemotherapy), fever, and signs of cytokine release syndrome (including tachycardia and hypotension).
Two patients have been treated at the highest dose level (9×106 CAR + T cells/kg). Notably, while the first patient on this dose level had MM involving 90 percent of total bone marrow cells prior to treatment, his MM was “rapidly eliminated” following CAR BCMA T-cell infusions, the authors noted, with bone marrow plasma cells decreasing 0 percent one month after infusion. The serum M-protein levels also decreased to undetectable levels two months after treatment. Fourteen weeks after treatment, the patient remains in stringent CR, according to Dr. Kochenderfer. “This is the first example of CAR T cells, or any kind of T-cell therapy, completely eradicating or decreasing measurable multiple myeloma,” he said. “For the first time, we have demonstrated that CAR T cells can eradicate large burdens of multiple myeloma.”
However, four hours after infusion, the patient showed signs of cytokine release syndrome, including fever, tachycardia, dyspnea, acute kidney injury, coagulopathy, hypotension requiring vasopressor support, and muscle damage.
The second patient in the highest dose level had 80 percent of his bone marrow composed of plasma cells prior to treatment; again, this patient experienced toxicities, including signs of cytokine release syndrome, fever, tachycardia, hypotension, delirium, hypoxia, and coagulopathy. This patient also experienced a drop in M-protein after treatment, from 3.6 g/dL to 0.8 g/dL four weeks after infusion, and bone marrow plasma cells were undetectable.
“The findings [of the current study] suggest that CAR-BCMA is a promising option for advanced multiple myeloma patients who have failed several previous therapies,” Dr. Kochenderfer said. Since the patient who had the best response to the CAR-BCMA therapy also experienced the most toxicities, further investigation into how to predict and avoid these toxicities is needed. However, he added, “toxicity was substantial, but reversible, and similar to that seen in previous CAR T-cell trials.”
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. Abstract #LBA-1. Presented at the 2015 ASH Annual Meeting, December 8, 2015; Orlando, Florida.