San Diego, California—The novel chimeric antigen receptor (CAR) T-cell therapy, P-BCMA-101, demonstrated significant efficacy with no neurotoxicity in patients with relapsed or refractory multiple myeloma, according to ongoing clinical trial data presented by Tara Gregory, MD, Colorado Blood Cancer Institute, Denver, at the 2018 ASH Annual Meeting.

BCMA, a protein highly expressed in multiple myeloma cells, is targeted by P-BCMA-101, which was designed to increase efficacy while minimizing toxicity. Previous data from mice studies have demonstrated the efficacy of P-BCMA-101 in reducing tumor burden and controlling disease recurrence.

To further assess the safety and efficacy of P-BCMA-101, Dr Gregory and colleagues began a phase 1 3+3 dose escalation trial in human patients with relapsed or refractory multiple myeloma.

“Rather than using a traditional antibody-based binder, P-BCMA-101 utilizes an anti-BCMA Centyrin fused to a CD3ζ/4-1BB signaling domain. Centyrins are fully human and have high binding affinities, but are smaller, more stable and potentially less immunogenic,” explained Dr Gregory and colleagues.

“P-BCMA-101 is produced using the piggyBac DNA Modification System instead of a viral vector, and requires only plasmid DNA and mRNA,” they said, adding that this is less costly, removes the need for virus, and produces purified CAR T-cells.

Patients in the study by Dr Gregory and colleagues were not required to have a pre-specified level of BCMA expression. Through apheresis, T-cells were harvested from the patients. P-BCMA-101 was then manufactured and administered to patients as a single intravenous dose, following a standard 3-day cyclophosphamide plus fludarabine conditioning regimen.

The patients in the study were heavily pre-treated, all had taken but not responded to immunomodulatory imide drugs, proteasome inhibitors, and daratumumab; 64% had high-risk cytogenetics.

As of July 31, 2018, 12 patients spread out across 3 weight-based cohorts have received P-BCMA-101 CAR T-cells. Improvements have been seen in all patients via myeloma assessments, but only 1 (8%) patient developed cytokine release syndrome (CRS).

In cohort 1, 3 patients attained a partial response, and 1 with nonsecretory disease near complete response of her plasmacytomas. Of the subsequent 6 patients, 3 have achieved a partial response, 1 a very good partial response, and 1 a stringent complete response.

According to Dr Gregory and colleagues, of the yet evaluable patients treated above cohort 1, the overall response rate (ORR) is 83%, despite the fact that only 1 patient had CRS. This grade 2 CRS was short-lived and managed with intravenous fluids and antibiotics, with minimal CRS marker elevations.

Similarly, CRS markers were minimally elevated in other patients. The highest interleukin-6 level in any patient (86 pg/mL) is lower than that generally reported in patients with meaningful CRS after CAR-T therapy.

Dr Gregory and colleagues detected circulating P-BCMA-101 cells in the blood using flow and polymerase chain reaction, which was consistent with the hypothesis of the early memory phenotype conveying durability. The cells peaked at 2 to 3 weeks, and remained detectable at the last time-point tested in all patients.

Infusions were generally well-tolerated; cytopenias, including transfusion-requiring cytopenias and febrile neutropenia, were the most common adverse events of grade 3 or higher.

None of the patients in the study required treatment with tocilizumab or safety switch activation. Similarly, there have been no patient deaths, and no neurotoxicities, dose-limiting toxicities, or unexpected/off-target toxicities related to therapy.

“[C]urrent clinical trial data in patients with r/r MM [relapsed or refractory multiple myeloma] support preclinical findings that the novel design of P-BCMA-101 can produce significant efficacy, comparing favorably with other anti-BCMA CAR-T products at similar doses, with notably less CRS and no neurotoxicity, consistent with the hypothesis of an improved therapeutic index,” Dr Gregory and colleagues concluded.—Hina Khaliq

Gregory T, Cohen AD, Costello CL, et al. Efficacy and safety of P-BCMA-101 CAR-T cells in patients with relapsed/refractory (r/r) multiple myeloma (MM). Presented at: the 60th ASH Annual Meeting and Exposition; December 1-4, 2018; San Diego, CA. Abstract 1012.