Increased risk of infection reporting with <scp>anti‐BCMA</scp> bispecific monoclonal antibodies in multiple myeloma: A worldwide pharmacovigilance study

Abstract

Patients with multiple myeloma (MM) are at high risk of infections, with a sevenfold increased risk as compared with healthy controls.1 Infectious complications are the leading cause of death in these patients despite significant efforts focused on prevention.2 MM treatment strategy has dramatically evolved recently, notably with the development of new targeted therapies, including chimeric antigen receptor-T (CAR-T) cells3 and bispecific monoclonal antibodies (BsMAbs).4 These therapies can both target the B-cell maturation antigen (BCMA)5; others have been developed to target the G-protein coupled receptor family C group 5 member D (GPRC5D) or Fc Receptor-Like 5 (FcRH5). Anti-BCMA BsMAbs have proven efficacy in relapsed and refractory MM after triple-class exposure (exposure to an immunomodulatory drug, a proteasome inhibitor, and an anti-CD38 antibody).6, 7 Safety analyzes of clinical trials evaluating BsMAbs in MM have suggested an association with a marked increased risk of infectious complications, which might have been underestimated or not accurately reported in published trials.8 Notably, severe infections appeared to be more important with anti-BCMA antibodies than with BsMAbs directed to different targets.9 Here, we analyzed the worldwide WHO pharmacovigilance database VigiBase to better evaluate the risk of infections with anti-BCMA BsMAbs, as compared with other MM treatments and especially non-anti-BCMA BsMAbs and anti-BCMA CAR-T cells. Methods are detailed in the Appendix S1. Our cohort included 273 491 safety reports concerning patients with MM between 01/01/2018 and 05/23/2023, among which 44 994 were related to an infectious adverse reaction. Anti-BCMA BsMAbs accounted for 692 safety reports, of which we identified, after case-by-case review, 188 (27.4%) infection cases (168 with teclistamab, 20 with elranatamab). Study flowchart is provided in Figure S1. Reported cases originated mostly from Europe (128, 68%) and North America (44, 23%) and were reported most of the time by a healthcare professional. Overall, median time to infection onset after starting anti-BCMA BsMAbs was 44 days [IQR 13–107]. Most of the cases were considered as serious (166, 88%), including 106 (56%) with hospitalization or prolonged hospitalization and 43 (23%) with fatal outcome because of the infectious event. Most frequent reported infections were respiratory tract infections (including COVID-19 [34, 18%], pneumonia [32, 17%]), bacterial sepsis (23, 12%), and sepsis/septic shock not otherwise specified (NOS, 22, 12%). No temporal or geographical clusters of COVID-19 could be identified. Other reported infections consisted in Cytomegalovirus (CMV) reactivation (16, 9%), Pneumocystis jiroveci-related pneumonia (PJP, 7, 4%), and other opportunistic infections (three, 2%). Non-COVID-19 and non-CMV viral infections involved 16 (9%) of reported cases. Two patients (1%) presented with invasive fungal infections. Reported infections with fatal outcome consisted mostly in septic shock NOS (14, 33%), COVID-19 (8, 19%), and bacterial sepsis (6, 14%). The study population details are provided in Table 1. No safety report has been identified with forimtamig, while the non-anti-BCMA BsMAbs group contained 56 safety reports with cevostamab (including seven [12.5%] infection cases) and 17 safety reports with talquetamab (including four [23.5%] infection cases). The CAR-T cells group included 241 safety reports with cilta-cel (involving 36 [15%] infection cases) and 404 safety reports with ide-cel (involving 41 [10%] infection cases). Other MM treatments group comprised 272 081 safety reports including 44 713 (16.4%) infection cases. The disproportionality analyses are presented in the Table 2. Every comparison evidenced a significantly increased ROR of infection with anti-BCMA BsMAbs, as compared with all other myeloma treatments (ROR 1.9 [1.6–2.3]), non-anti-BCMA BsMAbs (ROR 2.1 [1.1–4.1]), and anti-BCMA CAR-T cells (ROR 2.8 [2.1–3.7]). Conversely, the ROR of infection was not statistically disproportionate with teclistamab as compared with elranatamab (ROR 1.1 [0.6–1.8]). In this study, based on the WHO global pharmacovigilance database, we found that anti-BCMA BsMAbs were associated with a doubled risk of reporting infectious complications as compared with other MM treatments, including non-anti-BCMA BsMAbs and anti-BCMA CAR-T cells. The reported infections were early, mainly within 2 months after starting therapy. They comprised a substantial amount of COVID-19 and bacterial sepsis, but also infections usually associated with significant levels of immunosuppression, such as CMV reactivations, PJP, and other opportunistic infections, including invasive fungal diseases. No disproportionality of reporting infection was found with teclistamab versus elranatamab (both anti-BCMA BsMAbs). Our results are in line with previously published clinical studies. Infectious complications of BsMAbs in MM are very common since 20%–45% of grade 3–4 infections have been identified in elranatamab and teclistamab clinical trials. However, there were likely underestimation and flaws in attributing the infectious complication to the treatment under study, especially for fatal infections that may affect 11% of treated patients.8 Among our cohort, mortality was mainly reported with a sepsis or sepsis shock. A monocentric clinical study suggested as early as 2021 that BsMAbs for MM were associated with a significant risk of infection, and perhaps even higher than CAR-T cells.10 Another retrospective monocentric study reported a severe infection rate of 41% under BsMAbs for MM, including mostly viral infections, with 57% of patients requiring hospital admission.11 The largest study to date pooled 1185 patients with MM from 11 clinical trials.9 The authors reported a grade 3–4 infection rate of 24.5%, which was higher in patients receiving anti-BCMA BsMAbs than non-anti-BCMA-BsMAbs (30% versus 11.9%, respectively). Hypogammaglobulinemia was very common (75.3%) and 25.5% of deaths were attributed to infection. Another recent study on 37 patients found a severe hypogammaglobulinemia (IgG < 200 mg/dL) in all patients.12 Time to infection onset was shorter in our study (median of 44 days) than previously reported with anti-BCMA BsMAbs (3.8 months).12 Several pathophysiological hypotheses may be raised. Patients with MM receiving BsMAbs have been heavily treated before to receive such targeted therapy. B-cell lymphodepletion is often profound and associated with a high frequency of hypogammaglobulinemia, which might be even more pronounced in patients receiving anti-BCMA BsMAbs, as indicated by the increased reporting risk of infection as compared with patients treated with non-anti-BCMA BsMAbs. The duration of treatment may also play a role given the prolonged toxicity of a continuous treatment with BsMAbs versus “one-shot” treatment with CAR-T cells, in accordance with the result that anti-BCMA BsMAbs were associated with an increased risk of reporting infection as compared with anti-BCMA CAR-T cells. Moreover, this suggests that infectious complications with anti-BCMA immunotherapies are not solely a consequence of targeting BCMA. Finally, T-cell exhaustion may be critical in patients receiving BsMAbs, increasing the risk of treatment resistance and relapse, but also the risk of emergence or lack of control of infection.4, 13, 14 Our data involved infections associated mainly with B-cell dysfunction and hypogammaglobulinemia such as pneumonia, as well as infections secondary to T-cell defect such as PJP. It is well known that MM leads to B-cell as well as T-cell, dendritic cell, and NK-cell immunity impairment, especially when the disease is not controlled.15 Anti-BCMA BsMAbs could then exacerbate this immune deficiency of relapsing MM, through the mechanisms mentioned above, such as B-cell depletion, hypogammaglobulinemia, and T-cell exhaustion. Prevention of infections in patients receiving BsMAbs in MM is thus a cornerstone of management. Several measures should be proposed to patients, including vaccination, drug prophylaxis, immunoglobulins, and monthly screening for several viral infections (such as CMV).4 Recent consensus guidelines from the European Myeloma Network have been published and detailed applicable prevention interventions.16 Furthermore, treatment-free intervals might improve T-cell exhaustion, but such strategy remains to be evaluated with regard to its benefit–risk balance. Several limitations of our study must be acknowledged. First, the exposed group to BsMAbs and the number of analyzed infectious cases were limited. This reflects the novelty of these treatments as well as the timeliness of this issue. Second, our study based on spontaneous reporting may be enriched of serious safety reports and did not allow to assess the real incidence of infectious adverse reactions. Third, our cohort did not allow us to investigate on details regarding patients' history such as previous MM treatments (notably some patients might have been exposed to CAR-T cells before BsMAbs or conversely), medical history, or other confounding conditions such as the concomitant use of immunoglobulins. Nonetheless, disproportionality analyses have proven their interest in comparing the risk of several treatments in real-world setting.17 Here, given the similar indications of BsMAbs and CAR-T cells in MM, we hypothesized that treated patients would be comparable, thus minimizing potential indication bias. Last, drug causality is not the same in all cases. Disproportionality studies do not allow for drawing definite conclusions, yet laying the foundation for a larger scale prospective clinical study. In conclusion, we found a disproportionate reporting of infections with anti-BCMA BsMAbs in patients with MM, as compared with other MM treatments including non-anti-BCMA BsMAbs and anti-BCMA CAR-T cells. This finding, in line with previous literature, suggests an increased risk of infection with anti-BCMA BsMAbs. The reported infections were early in treatment course and included notably opportunistic, fungal, or viral infections as well as bacterial pneumonia and sepsis with severe outcome. These pharmacovigilance data should be confirmed with large multicentric study to better assess this risk. Meanwhile, the use of BsMAbs is an important and powerful treatment in triple refractory MM and should be accompanied by a robust and systematic strategy for infection prevention. AC and LC designed the study. LC extracted data from VigiBase. AC and LC analyzed the data. AC drafted the manuscript. All authors critically revised the manuscript for important intellectual content and gave final approval for the version to be published. All authors had full access to all the data in the study. AC, CC, and LC had final responsibility for the decision to submit for publication. AC: MSD (grants), Pfizer (Support for attending meeting), Sandoz (Support for attending meeting); CZ: Sandoz (Support for attending meeting). All other authors declare no conflict of interest in relation with this manuscript. Information from VigiBase comes from a variety of sources and the probability that the suspected adverse effect is drug-related is not the same in all cases. The information does not represent the opinion of the Uppsala Monitoring Center (UMC) or the World Health Organization and only reflects the authors' opinion. The original data of VigiBase are available through http://www.vigiaccess.org/ or upon reasonable requests. Appendix S1. Supporting Information. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

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