Can baseline cytomegalovirus IgG titers predict cytomegalovirus reactivation after ide-cel therapy? Open Access

TO THE EDITOR:

Chimeric antigen receptor T-cell (CAR-T) therapy is an effective treatment modality for patients with relapsed or refractory multiple myeloma following triple-class exposure.^1-4 

Idecabtagene vicleucel (ide-cel), which is a CAR-T therapy targeting B-cell maturation antigen,¹ demonstrates superior outcomes compared to that of conventional treatment options.⁵ However, CAR-T therapy is associated with complications, including cytokine release syndrome (CRS), immune effector cell–associated neurotoxicity syndrome, prolonged cytopenia, and hypogammaglobulinemia,⁶ which significantly affect treatment outcomes. Beyond CRS and immune effector cell–associated neurotoxicity syndrome, infectious complications, particularly cytomegalovirus (CMV) reactivation, remain a major concern influencing CAR-T therapy outcomes.^7-9 Our institution previously reported a 6-month cumulative incidence of 9.2% for CMV retinitis following ide-cel infusion¹⁰ with CMV reactivation exclusively observed in CMV-seropositive patients.

This study aimed to stratify the risk of CMV reactivation in CMV-seropositive individuals by examining the predictive value of baseline CMV immunoglobulin G (IgG) titers before CAR-T therapy. In this retrospective, noninterventional cohort study, electronic medical records from patients with multiple myeloma treated with ide-cel for relapsed or refractory multiple myeloma at the Japanese Red Cross Medical Center (JRCMC; Tokyo, Japan) were analyzed. The institutional review board of JRCMC approved this study (approval number: 1738). Informed consent was obtained from all participants under the opt-out consent principle. No participants were excluded, and the study was conducted in accordance with the Declaration of Helsinki.

CMV seropositivity was defined as a CMV IgG level of ≥6.0 AU/mL, as measured via chemiluminescent immunoassay before ide-cel administration. CMV reactivation was defined as the presence of CMV antigenemia or CMV DNA in peripheral blood, with CMV DNA detected in plasma using a commercial real-time polymerase chain reaction (PCR) assay (detection limit: 35 IU/mL). Although weekly CMV PCR testing was preferred following ide-cel administration, the testing frequency was at the discretion of the attending physician. Fisher exact test was utilized for intergroup comparisons of categorical variables, whereas Student t test or the Mann–Whitney U test was employed for continuous variables. The probability of CMV reactivation was estimated utilizing cumulative incidence curves to account for relapses or deaths without CMV reactivation as competing events. Statistical significance was set at P < .05. All statistical analyses were performed utilizing EZR software (https://www.jichi.ac.jp/saitama-sct/SaitamaHP.files/statmedEN.html).¹¹ 

Between October 2022 and April 2025, a total of 67 patients received ide-cel therapy. Among them, 44 were seropositive and 8 were seronegative for CMV, whereas CMV serostatus was unknown in 15 patients. No cases of CMV reactivation were observed among the CMV-seronegative patients. Therefore, the present analysis was conducted in the 44 patients who were CMV-seropositive. Table 1 summarizes the patient characteristics. The median age was 64 years (range, 36-76), with 15 patients (34.1%) being female. The median CMV IgG titer was 187.15 AU/mL (range, 20.6-250). No patients received CMV prophylaxis or bispecific antibodies as bridging therapy. The cumulative incidence of CMV reactivation was 49.5% at 3 months (95% CI, 34.7-66.6) and 57.2% at 6 months (95% CI, 41.2-74.2) (supplemental Figure 1). Receiver operating characteristic curve analysis showed 115.6 AU/mL as the optimal CMV IgG cutoff for predicting CMV reactivation. Patients were subsequently categorized into high (≥115.6 AU/mL) and low (<115.6 AU/mL) CMV IgG groups. No differences were observed between the 2 groups in the frequency or duration of CMV monitoring or in baseline characteristics, including the use of tocilizumab and corticosteroids for CRS (Table 1). Consequently, the cumulative incidence of CMV reactivation in the high CMV IgG group was 61.3% at 3 months (95% CI, 43.2-79.7) and 71.8% at 6 months (95% CI, 52.8-88.2) (Figure 1). In contrast, the incidence in the low CMV IgG group remained at 20% at both 3 and 6 months (95% CI, 5.4-59.1) (Figure 1), with a statistically significant difference observed between the groups (Gray test, P = .011). In the overall cohort, neither prophylactic immunoglobulin administration nor the use of high-dose cyclophosphamide as bridging therapy significantly affected the cumulative incidence of CMV reactivation (P = .34 and .62, respectively). However, in the high CMV IgG group, prophylactic immunoglobulin significantly reduced the cumulative incidence of CMV reactivation at 3 months following ide-cel therapy (54.7% vs 75.0%, P = .026; supplemental Figure 2). Clinically significant CMV reactivation, which was defined as a CMV PCR value ≥500 IU/mL or CMV antigenemia ≥10 positive cells per 2 slides, was observed in 30.8% of patients in the high CMV IgG group at 6 months (95% CI, 15.6-55.1), compared to 0% in the low CMV IgG group. Although this difference did not reach statistical significance, a trend toward a higher incidence was observed in the high CMV IgG group (P = .058; supplemental Figure 3). Antiviral therapy was given to 10 patients, mostly in the high CMV IgG group (9/10), with a nonsignificant trend toward higher incidence (P = .23). Antiviral therapy consisted of valganciclovir in 8 patients, foscarnet in 1, and both agents in 1. CMV disease was observed in 3 patients, all of whom had CMV retinitis (2 in the high CMV IgG group and 1 in the low CMV IgG group).

Prior studies indicate elevated CMV IgG titers as a risk factor for CMV reactivation following allogeneic hematopoietic stem cell transplantation.^12,13 Kawamura et al^12,13 used a different assay to measure CMV IgG titers, whereas Arcuri et al,^12,13 who employed the same method as in our study, reported a cutoff value of 109 AU/mL—nearly identical to our finding, even when accounting for potential interinstitutional variation. Consistent with these reports, our findings suggest that CMV IgG titers may serve as a predictive marker for CMV reactivation following ide-cel therapy. Preinfusion measurement of baseline CMV IgG titers may help identify patients at higher-risk of CMV reactivation, guiding strategies such as more frequent and extended CMV PCR monitoring, prophylactic immunoglobulin administration, and potentially in the future, antiviral prophylaxis using agents such as letermovir for high-risk individuals. Although this study focused on CMV reactivation rather than overt CMV disease, a nonsignificant trend toward higher rates of clinically significant CMV reactivation in the high CMV IgG group. This lack of statistical significance may reflect the limited sample size. Nonetheless, our findings suggest that baseline CMV IgG titers might also help predict overt CMV disease, warranting further validation in large-scale studies. The limitations of this single-center, retrospective design and the limited sample size highlight the need for further large-scale studies. Additionally, variability in CMV IgG assay methods across institutions may limit the generalizability of our findings, underscoring the importance of external validation. Despite these limitations, the potential utility of baseline CMV IgG titers as a surrogate marker for reactivation risk is encouraging and warrants further investigation.

These findings may contribute to improved CMV infection management, optimization of monitoring strategies, and the development of practical approaches for managing high-risk patients.

The institutional review board of JRCMC approved this study (approval number: 1738).

Acknowledgments: The authors express their deep gratitude to Koji Kawamura from the Department of Hematology, Tottori University Hospital, for providing valuable advice that served as a catalyst for the initiation of this study. The authors thank Editage for the English language editing.

Contribution: T.K. treated the patients and wrote the manuscript; N.T. treated the patients and provided important opinions regarding the study; U.K., S.S., M.W., K.K., M.N.Y., H.S., K. Sato, T.T., M.O., Y.A., and K. Suzuki treated the patients; C.M. and O.H. were responsible for data collection; T.I. provided important opinions regarding this study; and all authors critically reviewed and approved the final version of the manuscript.

Conflict-of-interest disclosure: T.K. reports personal fees from Janssen Pharmaceuticals, Takeda, Bristol Myers Squibb (BMS), Pfizer, and Sanofi. N.T. reports personal fees from Janssen and Sanofi. T.I. reports honoraria from Ono Pharmaceutical Co, Ltd, Takeda, Celgene/BMS, and Janssen. K.S. reports honoraria from Takeda, Celgene, Ono, Amgen, Novartis, Sanofi, BMS, AbbVie, and Janssen; consultancy fees from Takeda, Amgen, Janssen, and Celgene; and research funding from BMS, Celgene, and Amgen. The remaining authors declare no competing financial interests.

Correspondence: Taku Kikuchi, Department of Hematology, Japanese Red Cross Medical Center, 4-Chōme-1-22 Hiroo, Shibuya-ku, Tokyo 150-8935, Japan; email: taku_k_1123@mac.com.