BCMA-Directed CAR T-Cell Therapy Makes Strong Entrance in Myeloma

Noopur Raje, MD

B-cell maturation antigen (BCMA)-specific chimeric antigen receptor (CAR) T-cell therapy is delivering impressive results in multiple myeloma, demonstrating durable responses and acceptable toxicities, according to Noopur Raje, MD, a professor of medicine at Harvard Medical School and director of the Multiple Myeloma Center at Massachusetts General Hospital.

Raje spoke at the 23rd Annual International Congress on Hematologic Malignancies^® presented by Physicians Education Resource^®, LLC, in Miami. Survival in relapsed/refractory (R/R) disease has improved significantly over the past 5 years owing to new agents in multiple myeloma. However, CAR-T cells directed to BCMA and variations of this approach are demonstrating strong gains in R/R populations, given the expression of BCMA, found on nearly all myeloma cells but limited in normal tissue largely to plasma and mature B cells, Raje explained.

Raje limited her overview mostly to BCMA CAR T cells, although she noted added potential in BCMA antibodies and BCMA bispecific T-cell engagers or BiTES, which link myeloma cells to T cells for close combat.

Raje discussed results from the phase I CRB-401 trial, which was presented at the 2018 American Society of Clinical Oncology Annual Meeting.¹ The trial employed bb2121, a CAR T-cell design incorporating the 4-1BB costimulatory signaling domain, which is considered to imbue T cells with greater persistence compared with CD28 CAR T cells. Less acute toxicity results, as well.

Patients in the escalation and expansion cohorts (n = 43) were heavily pretreated (medians of 7 and 8 lines of treatment, respectively), variably exposed or refractory to bortezomib (Velcade), carfilzomib (Kyprolis), lenalidomide (Revlimid), pomalidomide (Pomalyst), and daratumumab (Darzalex). Although the trial population was very refractory, “we were able to manufacture in 100% of patients the CAR T-cell product,” Raje said, noting also that this was possible without consideration of absolute lymphocyte count ratios. Many patients were penta-refractory.

Investigators reported that the toxicity profile was acceptable. Cytokine release syndrome occurred in 63% (n = 27) of the overall infused population, neurotoxicity in 33% (n = 14), neutropenia in 81% (n = 35), and thrombocytopenia in 61% (n = 26). Rates of grade ≥3 events were 5%, 2%, 79%, and 51%, respectively. “There is a subset of patients we saw with a delayed recovery of counts—platelets as well as neutrophil counts,” she said.

Tumor response was strong whether patients were low or high for BCMA expression, with high defined as >50% of plasma cells expressing BCMA. As long as the CAR T-cell infusion measured 150 million cells or more, “we saw that patients actually responded,” Raje said. The objective response rate (ORR) for patients with low-BCMA expression was 100% versus 91% for the high-expression cohort. Of those responses, 37.5% in the low-BCMA group and 54.5% in the high BCMA group were stringent complete responses (CRs) or CRs.

Bb2121 was associated with a median progression-free survival (PFS) of 11.8 months at active doses (≥150 x 10⁶ CAR T cells) in 18 patients in the dose-escalation phase. Median PFS was 17.7 months in 16 patients who were minimal residual disease (MRD) negative.

Results also were promising for patients with R/R myeloma in a trial of bb21217, a next-generation CAR T product based on bb2121 combining the 4-1BB costimulatory domain and PI3K inhibitor bb007 to enrich for T cells demonstrating a memory-like phenotype, Raje noted.² Patients had ≥3 prior regimens including immunomodulatory agents and proteasome inhibitors. Patients were selected for ≥50% BCMA expression.”

This trial roughly mirrored CRB-401 in terms of patient characteristics and the toxicity profiles, Raje said. ORR was seen in 10 (83.3%) of 12 treated patients and responses deepened over time, with a CR achieved as late as month 10. Responses are ongoing in all but 1 responder, and the first patient dosed has a continuing response >1 year after treatment. MRD negativity was 100% in evaluable responders.

A key question going forward is whether the bb007 construct is delivering an improvement in this memory phenotype and translating into greater persistence of these CAR T cells, Raje said. “I think we just have to wait a little bit longer. We do see a robust expansion of the infused CAR T cells and we do see an enrichment of these central memory like T cells. The question is, ‘Is this going to translate into a better PFS, compared to what we see with bb2121?’”

Raje also discussed JNJ-68284528, a bispecific CAR that binds with high affinity to 2 different epitopes on BCMA, enabling stronger binding of the CAR T cells to BCMA-expressing tumor cells. “The thought is that the binding to the BCMA antigen is going to be better, and we’ll see whether that pans out in terms of response,” she said. The product was developed in a China-based investigation and is now being codeveloped by Janssen in a phase Ib/II study.

In discussion of early results for JNJ-68284528, Raje noted an ORR of 88% (50 of 57 patients), a median duration of response (mDOR) of 16 months (95% CI, 12-NR), and mDOR for MRD-negativity CR of 22 months (95% CI, 14-NR). Median time to initial response was 1 month.

Although responses were strong, an important difference between this trial and the previous 2 trials was that the patients were less-heavily pretreated, given that the variety of treatment options was not as robust in China. “PFS was better in those who achieved MRD negativity, and the median OS of this patient population was about 12 months,” Raje said.

Ultimately, she concluded, BCMA makes for a good target in myeloma, and cellular therapy provides durable disease control. She said high-risk disease can be identified and should be specifically targeted with these approaches and expressed optimism that BiTEs and CAR T cells with other therapies “will lead to a curative platform.”

References

1. Raje NS, Berdeja JG, Lin Y, et al. bb2121 anti-BCMA CAR T-cell therapy in patients with relapsed/refractory multiple myeloma: updated results from a multicenter phase I study. J Clin Oncol. 2018;36(suppl 15; abstr 8007). doi: 10.1200/JCO.2018.36.15_suppl.8007.
2. Shah N, Alsina M, Siegel DS, et al. Initial results from a phase 1 clinical study of bb21217, a next-generation anti Bcma CAR T therapy. Blood. 2018;132(488). doi: 10.1182/blood-2018-99-116953.

<<< 2019 International Congress on Hematologic Malignancies