A Comparative Analysis of Infectious Complications in Patients with Multiple Myeloma Treated with BCMA-Targeted Bispecific Antibodies and CAR T-Cell Therapy
Authors: Nath Karthik , Shekarkhand Tala , Costa Bruno Almeida , Nemirovsky David , Derkach Andriy , Nishimura Noriko , Farzana Tasmin , Rueda Colin , Chung David , Landau Heather , Lahoud Oscar Boutros , Scordo Michael , Shah Gunjan L. , Hassoun Hani , Maclachlan Kylee H , Korde Neha , Shah Urvi A , Tan Carlyn Rose , Hultcrantz Malin , Giralt Sergio A. , Usmani Saad Z , Shahid Zainab , Mailankody Sham , Lesokhin Alexander 
Published: December 2023

Introduction: There is limited data comparing infectious toxicities in patients with relapsed/refractory multiple myeloma (RRMM) treated with T-cell engaging therapies, which include chimeric antigen receptor T-cell therapy (CAR-T) and bispecific antibodies (BsAb). There are now three US FDA approved B-cell maturation antigen (BCMA)-targeting T-cell engagers, and several more in ongoing clinical development. Awareness regarding their infectious toxicities may inform treatment selection and mitigation strategies.

Methods: We conducted a single-center, observational study in patients with RRMM comparing infectious complications in patients treated with a commercial or investigational autologous BCMA-targeting CAR-T versus patients treated with a commercial or investigational BCMA-targeting BsAb. The date of CAR infusion (day 0) was between 03/22/2017 - 02/27/2023 for the CAR-T patients. For the BsAb cohort, the date of treatment initiation (day 0) was between 01/21/2020 - 02/07/2023. All infection-specific variables were collected from day 0 until the date of next line of therapy or last follow-up, with a data cut-off of 06/01/23. Infectious events were graded according to CTCAE version 5.0. Prophylactic antimicrobials were administered according to institutional and protocol guidelines. The primary endpoint was the incidence of severe (grade ≥3) infections. Secondary objectives included the time to 1 st infection, infection rate over time, infectious organisms, the impact of prolonged cytopenias, and the utility of intravenous immunoglobulin (IVIg) administration in preventing infections.

Results: Of the total 147 patients, there were 92 CAR-T and 55 BsAb treated patients. The median age of the CAR-T and BsAb cohort was 62yrs vs 65yrs, respectively (P=0.043). CAR-T patients had a median of 6.5 prior lines of therapy (IQR 5-8) versus 6.0 (IQR 4-9) in the BsAb cohort (P = 0.7); 97% of CAR-T patients had a prior autologous transplant compared to 75% in the BsAb cohort (P &lt; 0.001). In keeping with current clinical practice, 18 patients (33%) in the BsAb cohort had prior exposure to CAR-T whilst no patients in the CAR-T cohort had prior BsAb exposure. The median follow-up duration for infectious events was similar in both groups at 5.8 months (IQR 3.8-9.2) for CAR-T and 4.3 months (IQR 3.2-9.8) for the BsAb cohort.

A total of 209 infections were reported: 115 with CAR-T and 94 with BsAb. In the CAR-T cohort 24/92 patients (26%) experienced ≥1 severe infection, all of which were grade 3 and there were no grade 4 or 5 events. A numerically higher incidence was seen in the BsAb cohort with 21/55 BsAb patients (38%) experiencing ≥1 severe infection (P = 0.14). Nineteen BsAb patients (35%) experienced grade 3 infections, 2 (3.6%) had grade 4 infections and 4 (7.3%) had grade 5 infections. Six CAR-T (6.5%) and 10 BsAb patients (18.2%) had &gt;1 grade 3 infection. The incidence of ≥1 severe infection remained high in the BsAb cohort at 16/37 (43%) even after excluding the 18 BsAb patients with prior CAR-T exposure.

The median time from treatment initiation to the first infection of any-grade was 2.5 months (95% CI 1.2 - NR) with CAR-T compared to 3.4 months (95% CI 1.6 - 6.8) with BsAb (P = 0.6). The rate of any-grade infections was similar between the two groups early post-therapy (before day 100). However, there was a significantly higher infection rate of any-grade after day 100 with BsAb compared to CAR-T with a median of 0.24 (IQR 0.18 -0 .34) vs 0.13 (IQR 0.08 - 0.17) infections per 30 days, respectively (P &lt; 0.001) (Figure 1A). Regarding the time to the first grade ≥3 infection, 79% occurred within day 100 for CAR-T patients compared to only 48% in the BsAb cohort (Figure 1B).

The proportion of bacterial, viral, fungal, and parasitic infections in the CAR-T group was 49% (n = 56), 48% (n = 55), 4.3% (n = 5) and 0.9% (n = 1) respectively, and in the BsAb group was 51% (n = 48), 44% (n = 41), 3.2% (n = 3), and 0 respectively.

Conclusion: Infectious complications were common early after BCMA-targeting BsAb and BCMA CAR-T and declined over time. In this real-world comparison, distinct from their CAR-T counterparts, BsAb recipients appeared to have a more persistent infection risk and higher incidence of severe infections, which included four patients having a grade 5 infection. Further analysis, including the impact of prolonged cytopenias and the utility of IVIg administration will be presented at the meeting.