Prophylactic Dexamethasone Fails to Reduce Delayed Neurotoxicity Risk After CAR T-Cell Therapy in Myeloma

The prophylactic use of dexamethasone did not reduce peak absolute lymphocyte counts (ALC) or reduce the risk of delayed neurotoxicity (DNT) in patients with multiple myeloma who had high ALC following treatment with ciltacabtagene autoleucel (cilta-cel; Carvykti), according to findings from a retrospective analysis presented at the 2026 Transplantation & Cellular Therapy Meetings.¹

Findings showed the 120-day immune effector cell–associated Parkinsonism (IEC-PKS) event-free survival (EFS) rate was 96% with prophylactic dexamethasone (n = 56) vs 90% with no prophylactic dexamethasone (n = 97; HR, 0.34; 95% CI, 0.07-1.55; P = .16). The 120-day IEC cranial nerve palsies (IEC-NP) EFS rates were 83% vs 86%, respectively (HR, 1.04; 95% CI, 0.45-2.38; P = .93). Overall, the 120-day EFS rate for any DNT was 82% with prophylactic dexamethasone vs 76% without prophylactic dexamethasone (HR, 0.77; 95% CI, 0.37-1.58; P = .47).

Furthermore, the investigators saw no noticeable differences in the severity or duration of presentation of DNT, the laterality of cranial nerve involvement, or the rates of multiple cranial nerve involvement among patients with IEC-NP who received prophylactic dexamethasone (n = 9) compared with those in a historical cohort of patients who did not receive prophylactic dexamethasone (n = 15). Additionally, no notable differences were reported in the severity of IEC-PKS presentation among patients who received prophylaxis (n = 2) vs those in the historical cohort who did not (n = 11).

However, ALC peaks below 3 x 10⁹/L were shown to have a high negative predictive value for any DNT. In the overall study cohort (n = 121; new cohort), among 61 patients with ALC peaks of at least 3 x 10⁹/L, 14 experienced delayed toxicities; 2 patients among 60 with ALC peaks lower than 3 x 10⁹/L experienced DNTs. This translated to a negative predictive value (NPV) of 97% and a positive predictive value (PPV) of 23% for the development of any DNT (OR, 8.63; 95% CI, 1.87-39.9; P = .0022). In comparison, among the total historical cohort population (n = 230), 97 patients had high ALC peaks of at least 3 x 10⁹/L, and 24 experienced delayed toxicities; 2 of 132 patients with lower peak ALC had any DNT. The NPV and PPV rates were 99% and 25%, respectively (OR, 21.5; 95% CI, 4.9-93.7; P < .0001).

“[Although] we’ve demonstrated that an ALC peak of greater than 3 [x 10⁹/L] predicts a risk for DNT…the use of [prophylactic] dexamethasone unfortunately does not appear to reduce ALC peaks, nor reduce the risk of DNT, Parkinsonism, or nerve palsies,” lead study author Kenneth Jin Chang Lim, MBBS, said in a presentation of the data.

Lim is a hematology fellow at St Vincent’s Hospital Melbourne in Australia.

What was the rationale for investigating prophylactic measures for DNT reduction in patients with CAR T-cell therapy–treated myeloma?

Previously, Lim and colleagues reported that among a retrospective cohort of 235 patients with relapsed/refractory multiple myeloma who had received cilta-cel in standard-of-care practice, 6.4% developed IEC-NP, and 3.8% developed IEC-PKS.² Additionally, 1 patient developed both neurotoxicities. High peak ALC was shown to be a statistically significant predictor for both IEC-NP and IEC-PKS development, and investigators identified a peak ALC of at least 3 x 10⁹/L as a meaningful predictive threshold for late-onset neurotoxicity.

Based on these findings, Lim and colleagues aimed to determine the role of prophylactic dexamethasone on DNT risk reduction and lymphocyte expansion kinetics among cilta-cel–treated patients with multiple myeloma and high ALC.¹

What was the design of the retrospective analysis of dexamethasone prophylaxis in cilta-cel–treated myeloma?

The new cohort of this retrospective analysis included patients who had received post-prophylactic dexamethasone prior to receiving cilta-cel between December 1, 2024, and August 31, 2025. Prophylactic dexamethasone was administered orally at 10 mg twice a day for a minimum of 3 days in patients whose ALC exceeded or were rapidly approaching 3 x 10⁹/L on serial ALC testing within the first 3 weeks following CAR T-cell therapy infusion, which the investigators defined as high ALC for the purposes of the study.

The new cohort was compared with a historical cohort of patients who had received cilta-cel between February 1, 2022, and November 30, 2024, but had not routinely received prophylactic dexamethasone for high ALC.

DNT EFS served as the primary outcome.

What baseline characteristics are important to note from the analysis of prophylactic dexamethasone in cilta-cel–treated myeloma?

“Based on the historical cohort and the new cohort, we noted that the new cohort was slightly older,” Lim explained. “However, there were no differences between pre-lymphodepletion disease burden; high-risk cytogenetics; [or] the rates of cytokine release syndrome, IEC-associated neurotoxicity syndrome, IEC hemophagocytic lymphohistiocytosis–like syndrome, or their relevant interventions.”

Notably, high baseline ALC peaks were seen in 50% of patients in the new cohort vs 42% of those in the historical cohort (P = .14) At baseline in the new cohort, DNT cases comprised 11.6% of the population, including 2.5% of patients who IEC-PKS and 9.9% of patients who had IEC-NP. In the historical cohort, these respective baseline rates were 11.3%, 4.8%, and 7.0%.

What additional findings were seen in the analysis of dexamethasone prophylaxis in cilta-cel–treated myeloma?

The investigators also stratified patients into 2 cohorts: those with high ALC peaks in the historical cohort who did not receive dexamethasone (n = 97), and patients in the new cohort who received dexamethasone during peak ALC expansion (n = 56). Among patients in the non-dexamethasone group, the rates of DNT, IEC-PKS, and IEC-NP were 25%, 10%, and 15%, respectively. These respective rates in the dexamethasone group were 19%, 4%, and 16%.

Prophylactic dexamethasone use was shown to induce a slight decrease in the ALC area under the curve from 0 to 28 days (P = .037) but did not result in a change in peak ALC compared with no prophylactic dexamethasone use (P = .196). Additionally, among patients in the new cohort, the investigators observed no difference in ALC kinetics between the patients who experienced a DNT vs those who did not. Although a trend toward higher peak ALC expansion was noted in patients who developed DNT, this difference was not statistically significant (P = .143).

“Other strategies to reduce ALC peaks or modulate T-cell function may need to be studied,” Lim concluded.

Disclosures: Lim reported no financial conflicts of interest.

References

1. Lim KJC, Parrondo R, Chhabra S, et al. Investigating the role of dexamethasone prophylaxis for the risk reduction of immune effector cell delayed neurotoxicity in cilta-cel treated patients. Presented at: 2026 Transplantation & Cellular Therapy Meetings. February 4-7, 2026. Salt Lake City, Utah. Abstract 14.
2. Lim KJC, Tan M, Parrondo R, et al. Clinical course, risk factors and mitigating strategies for Immune effector cell-associated late onset neurotoxicities after ciltacabtagene autoleucel CAR-T in multiple myeloma. Blood Cancer J. 2025;16(1):18. doi:10.1038/s41408-025-01441-3