TO THE EDITOR:
Chimeric antigen receptor (CAR) T-cell therapy and bispecific antibodies (BsAbs) targeting B-cell maturation antigen (BCMA) and G protein-coupled receptor class C group 5 member D (GPRC5D) have introduced highly effective treatment options for multiple myeloma (MM). However, infections remain a significant concern, with high rates of serious and sometimes fatal complications. 1 , 2 , 3 Polyvalent immunoglobulin G (IgG) replacement appears to reduce the risk of severe infections in retrospective studies. 4 , 5 , 6 Nevertheless, low-grade, long-lasting infections, often underreported in clinical trials due to current adverse event reporting practices, can substantially impair quality of life. 7
Therefore, it is essential to not only report severe infections but also to systematically capture the frequency and duration of low-grade infections, particularly in patients on continuous therapy. To address this gap in knowledge, we conducted a single-center retrospective study evaluating the spectrum and duration of infectious complications in patients treated with BCMA-directed CAR T cells or BsAbs-targeting BCMA or GPRC5D.
We retrospectively analyzed infectious complications in 137 patients with MM treated with BCMA-directed CAR T cells (n = 58), BCMA-BsAbs (n = 47), or GPRC5D-BsAbs (n = 32) between October 2016 and December 2023 at a single academic center in Germany. Infections were graded per Common Terminology Criteria for Adverse Events (CTCAE 5.0) and recorded from therapy initiation until the start of the next treatment line. Extensive infectious workup was routinely performed, particularly during the SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) pandemic. The duration of infections was determined clinically, based on the number of days during which symptoms were present. Clinical data were extracted from electronic medical records. Statistical analyses included χ 2 , Fisher exact test, analysis of variance, Kruskal-Wallis, and multivariate logistic regression.
Most patients experienced infections: 76% in the CAR T-cell group, 85% with BCMA-BsAbs, and 81% with GPRC5D-BsAbs, without significant differences between groups. Most patients were heavily pretreated. Triple-refractory disease was present in 91%, 83%, and 100%, and pentarefractory disease in 71%, 55%, and 81% of the CAR T-cell, BCMA-BsAb, and GPRC5D-BsAb cohorts, respectively. The GPRC5D group also had a higher median number of prior therapies (6 vs 4) ( supplemental Table 1 ).
The most common infection sites were the upper and lower respiratory tracts (31%, 39%, and 29%, respectively). SARS-CoV-2 was the leading viral pathogen (19%), followed by rhinovirus ( Figure 1 A; supplemental Tables 2 and 3 ). Severe (grade 3-5) infections were less frequent than reported in clinical trials: 19% (CAR T cell), 19% (BCMA-BsAb), and 8% (GPRC5D-BsAb), possibly due to our center’s consistent use of immunoglobulin prophylaxis for immunoglobulin G (IgG) <400 mg/dL. However, not all patients received IV immunoglobulin because their treatment time was either very short or their IgG level did not fall below the threshold of 400 mg/dL. Prophylaxis for varicella-zoster virus and Pneumocystis jirovecii pneumonia was routinely administered. Nine patients developed rare or opportunistic infections, including cytomegalovirus pneumonia and endophthalmitis; Corynebacterium striatum septic arthritis; bloodstream infection with Candida krusei ; and P jirovecii pneumonia and pulmonary aspergillosis. Notably, 1 patient developed spondylodiscitis and endophthalmitis, resulting in permanent vision loss, caused by Spiroplasma eriocheiris , a bacterium typically considered nonpathogenic in humans and previously associated primarily with crustacean infections. Detection was only possible via eubacterial polymerase chain reaction.
Hospitalization due to infection occurred in 21% (CAR T-cell), 20% (BCMA-BsAb), and 8% (GPRC5D-BsAb) of the patients, whereas intensive care unit admissions were rare (5%, 3%, and 0%, respectively). Median hospitalization duration was similar across groups (13, 11, and 12 days), as was infection duration (2, 3, and 3 weeks). Consistent with clinical trial findings and real-world data, severe infections were more prevalent in the CAR T-cell group and in patients receiving BsAb combination therapy (affecting 36% of BCMA-BsAb recipients and <1% of GPRC5D-BsAb recipients, primarily with anti-CD38 antibodies and immunomodulatory drugs). 8 Prior CAR T-cell therapy within 1 year also trended toward higher infection rates in subsequent BsAb recipients, although not statistically significant. GPRC5D-BsAb therapy was associated with a significantly lower incidence of severe infections as was the administration of IV immunoglobulin substitution. In the CAR T-cell group, 5 fatal infections occurred within 3 months after infusion, all associated with high-grade neutropenia. Overall, combining BsAbs with other agents and CAR T-cell therapy posed the greatest risk of severe infection followed by BCMA-BsAb monotherapy. GPRC5D-BsAb therapy appeared to have a more favorable infection profile ( Figure 1 B).
Remarkably, over 80% of all infections were low-grade (grades 1-2), likely due to heightened patient awareness and routine testing during the pandemic. Low-grade infections, although less severe, were often prolonged and recurrent, significantly impacting patients’ quality of life. Here, a swimmer plot analysis highlighted striking differences in infection profiles: BCMA-BsAb therapy was associated with a higher infection frequency and prolonged recovery, whereas GPRC5D-BsAb therapy showed faster resolution and fewer events. Patients on BCMA-BsAb treatment experienced infectious symptoms during 20% of their treatment time, compared to 9% among those receiving GPRC5D-BsAb. This equates to about 6 vs 2.7 days per month affected by infections, respectively ( Figure 2 ).
Infections remain a leading cause of nonrelapse mortality in MM, particularly in the era of immunotherapy. 9 , 10 Understanding differences across treatment modalities and targets is essential to mitigate this risk. 11 In our study, all fatal infections occurred within 3 months after CAR T-cell infusion and were associated with high-grade neutropenia, emphasizing the importance of close monitoring, G-CSF support, IV immunoglobulin supplementation, and possibly antibacterial and antifungal prophylaxis during this critical period. 12 These findings align with a multicenter German study reporting a comparable post-CAR T-cell therapy fatal infection rate of 5.4%. 13
For BsAbs, clinical trials have consistently shown higher severe infection rates with BCMA-directed therapies compared to GPRC5D-directed agents. 14 , 15 , 16 , 17 Our results support this observation, with fewer high-grade infections seen in patients treated with GPRC5D-BsAbs. Additionally, recent real-world data suggest that BsAb recipients, particularly those with severe hypogammaglobulinemia, may be at higher infection risk than CAR T-cell therapy patients. 18 , 19 Notably, in our cohort, the rate of severe infections with BCMA-BsAbs was lower than reported in clinical trials, which may reflect the protective effect of our routine prophylactic IV immunoglobulin use. 20 , 21 , 22 Nevertheless, the retrospective nature of the study, the heterogeneity of the subgroups (mono-, combination, and sequential therapies), and the small sample size require careful interpretation of these findings.
A key novel finding of our study is the high burden of prolonged, low-grade infectious complications during BsAb therapy, particularly after BCMA-directed treatment—an aspect that remains underreported in clinical trials. Although most reports focus on severe infections, our data reveal that persistent, low-grade infections substantially impact patients’ quality of life. We agree with Ludwig et al that measuring the number of infection events per patient per month offers a more comprehensive understanding of infectious morbidity. 7 GPRC5D BsAb therapy appeared to have a more favorable infection profile, with fewer high-grade infections, hospitalizations, and reduced overall health care resource use.
In our BCMA-BsAb cohort, the striking frequency of an infection occurring during 20% of treatment time underscores a sustained immune dysfunction and symptom burden that is often overlooked. In this context, it is worth noting that the resolution of respiratory infections, for example, depends not only on IgG but also on CD4 + T cells, immunoglobulin class switching to IgA, the presence of B lymphocytes, and the formation of transient lymphoid structures such as inducible bronchus-associated lymphoid tissue. 23 Our understanding of how BCMA-directed therapies affect these immunological components remains limited. Our findings highlight an urgent need to investigate treatment strategies such as fixed-duration regimens or reduced maintenance dosing after deep responses, to facilitate immune system recovery and improve patient outcomes. 24 , 25
This study was approved by the internal review board of the University of Würzburg (Germany, reference no. 8/21) and adhered to the tenets of the Declaration of Helsinki of 2008.
Conflict-of-interest disclosure: J.M. reports an advisory role for Johnson & Johnson and Pfizer; and honoraria from Johnson & Johnson, Sanofi, Pfizer, and Skyline Dx. J.W. reports personal fees from Johnson & Johnson, Sanofi, Takeda, Pfizer, Oncopeptides, Menarini-Stemline, Skyline Dx, and GSK; and research support from Bristol Myers Squibb (BMS). K.M.K. reports personal fees from Celgene, BMS, AbbVie, GSK, and Takeda; and grants and personal fees from Johnson & Johnson. H.E. reports grants and other support from Johnson & Johnson, BMS, Amgen, GSK, and Sanofi; and further support from Takeda and Novartis. L.R. reports honoraria from Amgen, BMS, GSK, Johnson & Johnson, Pfizer, and Sanofi; research support from BMS; and serving on advisory boards for Amgen, BMS, Sanofi, Johnson & Johnson and Pfizer. The remaining authors declare no competing financial interests.
Acknowledgments
Contribution: J.M., L.B., and L.R. conceptualized and designed the study, performed data analysis and interpretation, and wrote the manuscript; and all authors collected and assembled data and gave final approval of the manuscript.
Footnotes
The data sets generated in this study are available from the corresponding author, Julia Mersi ( mersi_j@ukw.de ) on reasonable request.
The full-text version of this article contains a data supplement.
Supplementary Material
Supplemental Tables
References
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