Despite high response rates to B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T-cell therapies, patients with multiple myeloma (MM) with central nervous system (CNS) involvement did not have durable remissions, according to a study published in Blood Advances. This analysis identified extensive extramedullary disease (EMD) as a risk factor for CNS involvement among patients with MM.
“Notably, we found that despite the very high systemic responses and CNS responses, the duration of response was relatively short. In our opinion, this may suggest that future studies may investigate the use of maintenance therapies post-CAR T-cell therapy in this patient population,” said study author Mahmoud R. Gaballa, MD, of the University of Texas MD Anderson Cancer Center in Houston.
“We tried to identify factors that pose a high risk for having CNS involvement and identified extensive EMD as a risk factor. Among patients for whom CAR T-cell therapy is an option, screening for CNS involvement prior to administration of CAR T cells may be warranted,” Dr. Gaballa added.
Dr. Gaballa and colleagues analyzed data from 10 patients with MM, six of whom received idecabtagene vicleucel (ide-cel) and four of whom received ciltacabtagene autoleucel (cilta-cel). All 10 patients had brain/cranial nerve or spinal cord involvement/leptomeningeal disease, or both, that was evident on MRI, and 40% had evidence of CNS involvement in the cerebrospinal fluid (CSF). The time between CNS diagnosis and CAR T-cell administration was 60 days or less in half of the patients and more than 300 days in three patients, and two patients were diagnosed within 14 days after CAR T-cell infusion. Seven patients received CNS-directed therapy during bridging in the form of different combinations of radiotherapy, intrathecal chemotherapy, and surgery.
Patients were a median age of 58 (range = 36-71), 70% were male, 20% were Black, and 40% had MM with high-risk cytogenetics. The patients had received a median of six (range = 4-10) prior lines of therapy — eight patients were triple-class refractory and seven were penta-class refractory. Three patients had been treated with prior BCMA-targeted therapy.
This study, a retrospective analysis from five academic cancer centers, according to Dr. Gaballa, is the first to systemically review and report on the use of BCMA CAR-T in patients with MM and CNS involvement, as such patients have previously been excluded from such trials.
The best overall response rate was 80%, and 70% of patients achieved a very good partial response or better, and a 100% CNS response. For those eight patients with CNS MM diagnosed prior to CAR T-cell therapy, after a median follow-up of 381 days, the median overall survival was 13.3 months, and the median progression-free survival was 6.3 months.
The best outcomes, the authors noted, were among four patients who had a response to bridging therapy, suggesting that optimizing pre-CAR T-cell therapy may be key for improved outcomes among patients with MM and CNS involvement.
There was no grade 3 or greater cytokine release syndrome (CRS), and one patient had grade 3 immune effector cell-associated neurotoxicity syndrome (ICANS). Two patients treated with ide-cel experienced delayed but treatable neurotoxicity with no reported Parkinsonian side effects. One patient had neurotoxicity with delayed lethargy that was treated with steroids, and the second had progressive multifocal leukoencephalopathy due to JC virus, which was treated with steroids plus pembrolizumab with an initial response followed by relapse.
“The levels of CRS and ICANS were similar to patients without CNS involvement,” Dr. Gaballa said. “The most important finding is that we showed there is no excess neurotoxicity with this BCMA CAR T-cell approach.”
Cytopenias were relatively common, with six patients experiencing this side effect at day 90 following CAR T-cell infusion, and no patient required a stem cell boost. Five patients developed infections, one requiring admission to the intensive care unit, but all cases were successfully managed.
“The systemic response rates we saw were close to those of patients with MM without CNS involvement,” Dr. Gaballa said. “However, the duration of response was relatively short. So, in our opinion, to mitigate this, future larger prospective trials may investigate adding post-CAR T-cell therapy maintenance therapies such as pomalidomide or sustained BCMA targeting using different approaches.”
He added, “Future studies can also conduct a CSF evaluation for the detection of BCMA CAR T cells as further evidence that they cross the blood-brain barrier.”
Any conflicts of interest declared by the authors can be found in the original article.
Reference
Gaballa MR, Puglianini OC, Cohen A, et al. BCMA directed CAR T-cell therapy in patients with multiple myeloma and CNS involvement [published online ahead of print, 2024 Dec. 27]. Blood Advances. doi: 10.1182/bloodadvances.2024014345.
