Proteasome Inhibitor Restores BCMA Expression After CAR T-Cell Therapy Failure in Myeloma

The proteasome inhibitor carfilzomib (Kyprolis) prevented rapid degradation of B-cell maturation antigen (BCMA) from the plasma cell surface in preclinical models and was associated with re-expression of BCMA and renewed antitumor activity in a small cohort of patients whose BCMA-directed chimeric antigen receptor (CAR) T-cell therapy had previously failed, according to a study published in Blood.

Loss of BCMA expression has emerged as a clinically relevant mechanism of resistance to BCMA-directed CAR T-cell therapy in relapsed or refractory multiple myeloma (R/R MM). New translational and early clinical data suggest that pharmacologic inhibition of the ubiquitin-proteasome system may reverse this process and in select patients restore responsiveness to prior CAR T-cell therapy.

Researchers from the Technical University of Munich (TUM) in Germany investigated the molecular basis of BCMA surface loss. Using in vitro and in vivo models, they identified the ubiquitin-proteasome system as a regulator of BCMA degradation and demonstrated that BCMA can be rapidly ubiquitinated and targeted for proteasomal degradation, resulting in reduced cell-surface expression. Importantly, this process appeared to affect membrane proteins, extending the functional scope of the ubiquitin-proteasome system beyond intracellular protein turnover.

BCMA is a validated therapeutic target in multiple myeloma and the target of the approved CAR T-cell products idecabtagene vicleucel (Abecma) and ciltacabtagene autoleucel (Carvykti). Despite high initial response rates even in heavily pretreated populations, most patients eventually experience disease progression. Mechanisms of resistance include antigen escape through BCMA downregulation or loss.

Pharmacologic inhibition with carfilzomib, an irreversible proteasome inhibitor approved for R/R MM, prevented BCMA degradation in laboratory models and restored surface expression. When used on in vitro cocultures, carfilzomib elevated BCMA levels which increased susceptibility to CAR T cells by 28% and 26% in 2 different myeloma cell lines. In mouse xenograft models, proteasome inhibition enhanced the activity of BCMA-targeted CAR T cells but did not appear to affect viability, activity, or exhaustion of T cells.

Notably, the expression of GPRC5D and SLAMF7 proteins, which are also considered targets of CAR T cells in R/R MM, did not increase after use of carfilzomib in laboratory models.

The investigators then evaluated this strategy in 10 patients with R/R MM who had previously received BCMA-directed CAR T-cell therapy and experienced disease progression. Two were primary refractory to CAR T and 8 had relapsed later. All were triple-class refractory and had prior exposure to the PI bortezomib (Velcade) as well as carfilzomib.

The 10 patients received on-label carfilzomib-based therapy starting with 20 mg/m2 on days 1 and 2 and escalating to 56 mg/m2 on days 8 and 9 and 15 and 16 if tolerated. According to the authors, BCMA surface expression increased in malignant plasma cells in all 10 patients following treatment.

Clinical responses were observed in 6 of the 10 patients—specifically those with detectable persistence of functional CAR T cells at the time of carfilzomib administration. In these individuals, the re-emergence of BCMA expression appeared to re-enable CAR T-cell–mediated cytotoxicity. One patient who was primary refractory to CAR T-cell therapy had had rapidly progressive disease through bridging therapy achieved a rapid very good partial response. Patients without sufficient residual CAR T cells did not experience renewed clinical benefit, underscoring the dependence of this strategy on CAR T-cell persistence.