CAR-BCMA T Cells Show Promising Activity in Relapsed/Refractory Multiple Myeloma

James N. Kochenderfer, MD

James N. Kochenderfer, MD

Treatment with chimeric antigen receptor B-cell maturation antigen (CAR-BCMA) T cells induced substantial antitumor activity in patients with heavily treated relapsed/refractory multiple myeloma, according to results from a first-in-human clinical trial.¹

A total of 24 patients were treated in the trial (NCT02215967). Investigators published data for the 16 who received infusions of 9 × 10⁶CAR⁺T cells/kg, the highest dose, in theJournal of Clinical Oncology. The overall response rate (ORR) was 81% and all but 1 patient experienced a substantial reduction in serum multiple myeloma marker.

Two patients had stringent complete response (CR) and 9 had very good partial response. Investigators found that responders had peak CAR T-cells levels higher than those of nonresponders.

The median event-free survival was 31 weeks. Responses are ongoing in 6 patients while 10 others experienced disease progression.

In findings published in 2016, only 2 of 10 patients who received a dose of 0.3 to 3 × 10⁶CAR⁺T cells/kg responded to treatment.²

“These results should encourage efforts to increase the efficacy of anti-BCMA CAR T-cell therapies by increasing blood CAR T-cell levels, increasing CAR T-cell survival in vivo, targeting antigens other than BCMA, combining CAR T cells with other anti-multiple myeloma therapies, and administering multiple doses of CAR T cells,” corresponding author James N. Kochenderfer, MD, of the Center for Cancer Research at the National Cancer Institute in Bethesda, and colleagues wrote.

In the current study, patients received 3 daily doses of 300 mg/m²of cyclophosphamide and 30 mg/m²of fludarabine prior to infusion to enhance T-cell activity. CAR-BCMA was expressed on a median of 40% of the infused T cells (range, 23.2-66.0).

The median number of prior lines of therapy was 9.5 (range, 3-19) and 63% of patients were refractory to their last treatment regimen. One-third of patients had 17p deletion and 40% had high-risk cytogenetics overall.

Nine patients underwent bone marrow biopsy and immunohistochemistry staining for CD138 at baseline and again 2 months after infusion. All 9 experienced a decrease in bone marrow plasma cells. Similarly, all 11 patients who underwent bone marrow flow cytometry were negative for minimal residual disease.

All patients who responded to treatment saw a decline in serum BCMA while nonresponders had only minimal changes in serum BCMA.

There was no incidence of grade 3/4 cytokine release syndrome (CRS) in the previous findings, but 6 (38%) patients treated at the 9 &times; 10⁶dose level experienced grade 3/4 CRS. The first 2 patients treated at the higher dose experienced severe CRS and had tumor burdens of 90% and 80%, so investigators required the other 14 patients to have <30% bone marrow plasma cells prior to infusion.

&ldquo;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 multiple myeloma burdens,&rdquo; investigators wrote.

Michael W. Becker, MD, associate professor and director of the blood and marrow transplant program at the University of Rochester Medical Center, said in an accompanying podcast that these results highlight issues in CAR T-cell therapy and offer future avenues of research to optimize response while limiting toxicity.

&ldquo;This is an exciting report on the application of CAR T-cell therapy for patients with multiple myeloma,&rdquo; he said. &ldquo;CAR-BCMA therapy was associated with deep and sustained responses in a subset of patients who were heavily pretreated.&rdquo;

References:

1. Brundno 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(22):2267-2280. doi: 10.1200/JCO.2018.77.8084.
2. Ali SA, Shi V, Maric I, et al. T cells expressing an anti-B-cell maturation antigen chimeric antigen receptor cause remissions of multiple myeloma.Blood.2016;128(13):1688-700. doi: 10.1182/blood-2016-04-711903.
3. Becker MW. Multiple myeloma joins the CAR T race [podcast].J Clin Oncol. doi: 10.1200/JCO.2018.77.8084.