Opportunistic Infections in Patients Receiving Daratumumab Regimens for Multiple Myeloma (MM)

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 <0.05 considered statistically significant. Other reported variables concomitantly reported with daratumumab-treated patients were collected, including reported chemotherapy, >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<0.0001), CMVr (ROR 33.31 [95% CI 24.61, 45.08], p<0.0001), PML (ROR 16.69 [95% CI 11.96, 23.31], p<0.0001), PJP (ROR 12.87 [95% CI 9.18, 18.05], p<0.0001), BA (ROR 9.82 [95% CI 6.01, 16.06], p<0.0001), and HBVr (ROR 9.35 [95% CI 5.42, 16.14], p<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<0.0001), PML (ROR 13.04 [95% CI 8.89, 19.12], p=<0.0001), PJP (ROR 9.58 [95% CI 6.59, 13.96],p<0.0001), BA (ROR 11.46 [95% CI 6.56, 20.01], p<0.0001), HBVr (ROR 4.41 [95% CI 2.49, 7.83],p<0.0001), and TB (ROR 6.15 [95% CI 2.39, 15.78], p<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.

Toxicity management strategies for next-generation novel therapeutics in multiple myeloma

“…42 disseminated cryptococcosis are reported. [43][44][45][46][47][48][49][50] As expected, infections occur at a higher rate in those patients with higher grade neutropenia and lymphopenia, notably heavily pretreated patients treated with combination regimens within the initial 6 months of treatment. In this population treated with daratumumab, the median time to severe infection was ~50 days in patients with severe lymphopenia versus ~90 days in those without severe lymphopenia.…”

“… 42 Atypical infections are uncommon, however, reactivation of herpes zoster and Epstein–Barr virus/cytomegalovirus, pneumocystis jirovecii pneumonia (PJP), progressive multifocal leukoencephalopathy, bronchopulmonary aspergillosis, fungal meningitis, listeriosis, and disseminated cryptococcosis are reported. 43 – 50 As expected, infections occur at a higher rate in those patients with higher grade neutropenia and lymphopenia, notably heavily pretreated patients treated with combination regimens within the initial 6 months of treatment. In this population treated with daratumumab, the median time to severe infection was ~50 days in patients with severe lymphopenia versus ~90 days in those without severe lymphopenia.…”

Risk of Infections Associated with the Use of Monoclonal Antibodies in Multiple Myeloma (MM)

“…Unfortunately, from an extended clinical review of the pivotal randomized phase 3 clinical trials examining the current use of anti-CD38 mAbs in MM, the addition of anti-CD38 mAbs resulted in a higher rate of AEs in the overall population, particularly in terms of infections (including pneumonia) and neutropenia plus lymphocytopenia. In fact, as regards infectious diseases, the FAERS suggests a significant association between daratumumab-based regimens and multiple opportunistic infections [4] and pivotal randomized phase 3 clinical trials documented that the rates of infectious complications, in particular respiratory tract infections including viral complications, are higher in the anti-CD38 mAbs combination with IMiDs or PIs plus dexamethasone group than IMiDs or PIs and dexamethasone alone. In the same line, a recent metanalysis of clinical trials [39], pooling five randomized phase 3 studies (ALCYONE, MAIA, CASSIOPEIA, CASTOR and POLLUX), confirmed that the incidence of TD due to infection/pneumonia was slightly higher with daratumumab than in the control group (0.95% vs 0.73%); conversely, the rates of TD due to treatment-emergent adverse events (TEAEs) (6.77% vs 10.08%) and treatment-related deaths (3.61% vs 4.34%) were significantly lower in the daratumumab group than in the control arm.…”

“…The anti-CD38 monoclonal antibodies (mAbs)-based therapies are approved for NDMM and RRMM and their use has changed the frequency and epidemiology of infections. The Food and Drug Administration's Adverse Events Reporting System (FAERS), a pharmacovigilance monitoring database, recently reported the characteristics and incidence of infections in patients with MM treated by daratumumab [4]. The FAERS showed that 2.7% of 7152 adverse events (AEs), in the period 2015-2021, were opportunistic infections from Herpes Zoster (25.1%), CMV (22.0%) and Hepatitis B Virus reactivation (6.7%), Pneumocystis Jirovecii Pneumonia (17.4%), bronchopulmonary Aspergillosis (8.2%) and tuberculosis (2.5%) [4,5].…”