Multiple myeloma (MM) is a potential target for chimeric antigen receptor (CAR) T-cell therapies, according to final results from a first-in-human trial of B-cell maturation antigen (BCMA)-targeting CAR (CAR-BCMA) T cells published in the Journal of Clinical Oncology. Eighty-one percent of patients with heavily pretreated MM enrolled in this small trial responded to treatment with CAR-BCMA T cells; however, “toxicity was substantial,” noted the authors, led by Jennifer Brudno, MD, from the National Cancer Institute. BCMA, a member of the tumor necrosis factor receptor superfamily, is expressed on malignant plasma cells in most patients with MM.
“The infrequent [administration schedule] nature of CAR T-cell therapy allows some patients treatment-free intervals when they often enjoy a high quality of life without therapy-related toxicities,” the investigators wrote. “However, the short-term [cytokine release syndrome (CRS)] toxicities after CAR T-cell infusions are a disadvantage of [this modality].”
The trial included 24 patients with relapsed/refractory MM who received CAR-BCMA T cells at doses ranging from 0.3×106 cells/kg to 9×106 cells/kg. The article reports results from the 16 patients who were treated at the highest dose (9×106 cells/kg).
The participants had received a median of 9.5 therapies (range = 3-19) prior to enrollment, and most (63%) were refractory to their last treatment regimen. Six patients had high-risk cytogenetics, including del(17p) or t(4;14).
From 5 to 3 days prior to CAR-BCMA T-cell infusion, patients underwent conditioning with cyclophosphamide 300 mg/m2 and fludarabine 30 mg/m2 daily; antimyeloma chemotherapy also was administered to enhance the activity of adoptively transferred T cells. Patients were monitored monthly until 6 months after infusion, then every 6 months afterward.
Thirteen of the 16 patients responded to treatment, including:
- partial response (PR): 3 patients (duration of anti-MM response range = 2-24+ weeks)
- very good PR: 8 patients (range = 11-66 weeks)
- stringent complete response: 2 patients (range = 17-37+ weeks)
The median event-free survival (EFS) was 31 weeks (range not reported), and six patients had ongoing responses at the time of publication. The remaining 10 patients experienced MM progression.
Nine patients had evaluable bone marrow biopsies and immunohistochemistry staining for CD138 before and after CAR-BCMA infusion. By 2 months after infusion, all patients had a decrease in bone marrow plasma cells. Among the 11 patients who were evaluated for minimal residual disease (MRD) by flow cytometry, all 11 were determined to be MRD-negative.
“All but [one patient] had a substantial decrease in their serum MM marker,” the authors added. They also noted several factors that appeared to be associated with response to CAR-BCMA T-cell therapy: Serum BCMA declined in responders, while nonresponders experienced only minor changes in their serum BCMA levels (p<0.001), and peak levels of CAR-positive cells were higher in responders than nonresponders (p=0.013).
All but one patient experienced CRS, including six with grade 3/4 CRS, which led to “substantial CRS-related toxicities,” the researchers noted.
The first two patients who were treated with CAR-BCMA T-cells at the 9×106 cells/kg dose developed CRS and experienced severe CRS toxicities, and each had high MM burdens (90% and 80%, respectively, of bone marrow cells were MM plasma cells). Based on this observation, the subsequent patients treated at this dose were required to have lower MM burdens (<30% MM plasma cells). “Patients with CRS of grade 3 or 4 had higher levels of bone marrow plasma cells compared with patients who had less than grade 3 CRS, which indicates an increased chance of severe CRS in patients with high MM burdens,” the authors added.
Five patients received tocilizumab and four received corticosteroids to manage adrenal insufficiency or CRS-related toxicities.
Six patients (38%) required vasopressors for hypotension, and one patient required mechanical ventilation. The other most common grade 3/4 toxicities included leukopenia (n=15), neutropenia (n=14), and thrombocytopenia (n=10).
“CAR T cells have the advantage of being mechanistically different from all other MM modalities, and this trial has demonstrated anti-MM activity by CAR-BCMA T cells against MM resistant to other therapies,” the authors concluded. They added, though, that this early-phase study was limited by lack of a comparator arm and the small number of enrolled patients.
The researchers also noted several areas for improving the use of CAR-BCMA T-cell therapies in patients with MM. These include enhancing in vivo CAR T-cell proliferation and survival, combining CAR T cells with other anti-MM therapies, and the prevention and management of toxicities.
The authors report no relevant conflicts of interest.
Brudno JN, Maric I, Hartman SD, et al. T Cells genetically modified to express an anti–B-cell maturation antigen chimeric antigen receptor cause remissions of poor-prognosis relapsed multiple myeloma. J Clin Oncol. 2018;36:2267-80.