Immune Reconstitution and Infectious Complications Following BCMA-Targeted CAR-T Therapy in Relapsed/Refractory Multiple Myeloma (RRMM)

Background Although BCMA-targeted CAR-T therapy has demonstrated efficacy in RRMM, prolonged immunosuppression and infectious complications result in significant morbidity and mortality. Here, we characterize immune reconstitution and infectious complications after BCMA CAR-T therapy. Methods Patients with RRMM who received standard of care BCMA CAR-T therapy at our center between May 2021 and January 2023 were included. All patients received antimicrobial prophylaxis against herpes zoster (HZ) and Pneumocystis jirovecii pneumonia (PJP). Immunoglobulin replacement therapy (IRT) was recommended for patients with immunoglobulin G (IgG) levels < 400 mg/dL. Patients did not repeat routine childhood vaccines series. Outcomes involving benchmark timepoints included patients with data within a 15-day window. Results Of 38 patients, 10 received ciltacabtagene autoleucel (cilta-cel) and 28 received idecabtagene vicleucel (ide-cel). B cells ≥ 20/uL by 1, 3, and 6 months post-infusion were seen in 0 out of 9, 12 of 17 (71%), and 5 of 5 (100%) patients, respectively. CD4+ T cells≥ 200 cells/μL were seen in 5 of 18 (28%) patients by 3 months and 4 of 5 (80%) patients at 6 months. CD8+ T cells recovered more rapidly than CD4+ T cells with CD8+ T cells ≥ 200/μL in 10 of 18 patients (56%) by 3 months and 4 of 5 (80%) patients by 6 months (Fig. 1).IgG levels decreased after CAR-T with a nadir at 1 month. Twenty-seven (71%) patients received IRT during follow-up; 4 patients (14%) needed IRT at 12 months post-infusion. To interrogate protection against vaccine-preventable diseases, antigen-specific antibody titers were measured, which were available in 24 patients at 90 days post-infusion. Seroprotective titers were seen in 38% of patients for mumps, 70% for measles, 59% for rubella, 58% for hepatitis B, 76% for diphtheria and 66% for tetanus.Most infections were mild to moderate in severity, and one death was attributed to infection (Fig. 2). There were 24 bacterial infections in 14 patients: 6 bloodstream infections, 6 urinary tract infections, 3 episodes of Clostridioidesdifficile colitis, and 3 skin and soft tissue infections. There were 21 viral infections in 16 patients: 8 rhinovirus, 5 SARS-CoV-2, and 3 metapneumovirus. One fungal infection (Candida pyelonephritis) occurred. No cases of PJP or HZ were noted. Conclusions Immune reconstitution is delayed following CAR-T with persistent B-cell aplasia and low T-cell counts, especially CD4+ T cells. However, recovery seems to be quicker compared to CD19 CAR-T therapy. Many patients do not have serological evidence of immunity to vaccine-preventable diseases after CAR-T, suggesting that re-vaccination may be needed, but optimal timing is unclear given delayed B cell recovery. Data from additional cohorts to validate these findings are needed to formulate guidelines for infection prevention and vaccination in patients receiving BCMA CAR-T therapy.