Opportunistic Infections in Patients Receiving Daratumumab Regimens for Multiple Myeloma (MM)
Authors: Burns Ethan A. , Ensor Joe E. , Anand Kartik , Gentille Cesar , Guerrero Carlo , Kieser Ryan B. , Umoru Godsfavor , Shah Shilpan S. , Petkova Jenny H. , Ganguly Siddhartha , Rice Lawrence , Pingali Sai Ravi Kiran 
Published: November 2021

Abstract
Background
Daratumumab-based treatment regimens for MM have improved outcomes for both transplant-eligible and ineligible patients. As a result, patients are receiving longer exposure to this CD38 targeting monoclonal antibody. Adverse events (AE) including hypogammaglobulinemia, neutropenia, and lymphopenia have been reported in both clinical trials and retrospective studies, but with limited and contrasting data on the associated risk of developing infections. Furthermore, there remains a paucity of data on the risk of developing opportunistic infections in this growing patient population. The aim of this study is to assess the association between daratumumab-containing regimens and the development of opportunistic infections as reported to the Food and Drug Administration's Adverse Events Reporting System (FAERS), a pharmacovigilance monitoring database.
Methods/Materials
FAERS was queried for AE reports to evaluate the association of Cytomegalovirus reactivation (CMVr), Hepatitis B reactivation (HBVr), progressive multifocal leukoencephalopathy (PML), Herpes Zoster (HZ), Tuberculosis (TB), Pneumocystis Jirovecii (PJP), and Bronchopulmonary Aspergillosis (BA) with daratumumab-containing regimens from 2015-2021. The strength of an association between an infection reported with daratumumab in MM was compared with all events reported in MM treated patients, and the composite of all reported AE cases in FAERS. Signal disproportionality was calculated by using the reporting odds ratio (ROR), with the precision of the ROR determined by 95% confidence intervals (95% CI). Associated p-values were calculated by using chi-squared or Fisher's Exact test, with a p-value &lt;0.05 considered statistically significant. Other reported variables concomitantly reported with daratumumab-treated patients were collected, including reported chemotherapy, &gt;1 MM regimen, proteasome inhibitor (PI) use, or lenalidomide use.
Results
Out of the 12,393,747 AE cases reported to FAERS, there were 288,294 (2.3%) AE reported with MM patients, of which 7,152 (2.5%) were reported with daratumumab. There were 195 (2.7%) opportunistic infections reported with daratumumab, with a median age of 64 (42-89) years, and 64 (32.8%) were females. HZ (N=49, 25.1%) was the most common, followed by CMVr (N=43, 22.0%), PML (N=35, 17.9%), PJP (N=34, 17.4%), BA (N=16, 8.2%), HBVr (N=13, 6.7%), and TB (N=5, 2.5%). Neutropenia was reported in 29 (14.9%) of these patients, lymphopenia in 6 (3.1%), and hypogammaglobulinemia in 1 (0.51%) case. With comparison to all reported events in the FAERS database, a significant signal disproportionality was found with HZ (ROR 3.48 [95% CI 2.63, 4.61], p&lt;0.0001), CMVr (ROR 33.31 [95% CI 24.61, 45.08], p&lt;0.0001), PML (ROR 16.69 [95% CI 11.96, 23.31], p&lt;0.0001), PJP (ROR 12.87 [95% CI 9.18, 18.05], p&lt;0.0001), BA (ROR 9.82 [95% CI 6.01, 16.06], p&lt;0.0001), and HBVr (ROR 9.35 [95% CI 5.42, 16.14], p&lt;0.0001). When comparing reported infections with AE associated with MM patients in FAERS, HZ (ROR 1.59 [95% CI 1.19, 2.11], p=0.0015), CMVr (ROR 28.82 [95% CI 19.44, 42.72], p&lt;0.0001), PML (ROR 13.04 [95% CI 8.89, 19.12], p=&lt;0.0001), PJP (ROR 9.58 [95% CI 6.59, 13.96],p&lt;0.0001), BA (ROR 11.46 [95% CI 6.56, 20.01], p&lt;0.0001), HBVr (ROR 4.41 [95% CI 2.49, 7.83],p&lt;0.0001), and TB (ROR 6.15 [95% CI 2.39, 15.78], p&lt;0.0001) met statistical significance (Table 1). The proportion of concomitant medications reported with daratumumab is reported in Figure 1.
Conclusion
This study suggests a significant association between daratumumab-based regimens and multiple opportunistic infections. Patients with known chronic viral infections or who are heavily pretreated should be monitored for these potential complications. FAERS data is beneficial in reporting associations between medications and AE but does not necessarily indicate causality. Further studies are needed to corroborate these findings.
Figure 1 Figure 1.

Disclosures
Ganguly: Kadmon: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Bristol Myer Squibb: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees.