Page 178 - Haematologica Vol. 110 - January 2025

ARTICLE - Multiple myeloma and the risk of infections
C.H. Blimark et al.
the first 6 months after MM diagnosis and the risk factors were high tumor burden and renal failure.27
Most significant infections seen in our study were bac- terial, but viral and fungal significant infections seem to gain importance. We see an even greater difference in the risk of viral infection such as RS virus infection compared to controls in the first year after diagnosis, and it seems to be confirmed by other studies. Lim et al. (2021) found in a recent chart review study of 345 infectious episodes in 148 patients that 50% were due to viruses, where bor- tezomib and many lines of treatment were risk factors.28 This study may have found less significant infections than in our study as they had several modes of detection, but points out that new infectious agents may play a more important role as the treatment panorama changes. In two comprehensive consensus recommendations on infection prophylaxis in MM from 2023 to 2024 the importance of anti-viral and anti-fungal prophylaxis is underscored, es- pecially in patients with neutropenia.3,29 We saw a 3-fold risk of SARS-Cov-2 infections compared to controls but believe that the number is underestimated due to lack of testing in the beginning of the pandemic, and the total number of registered infections (N=278) was too small to draw any strong conclusions.
In our study, MM patients had a slight decrease in the risk of all, bacterial, fungal and viral infections in the last cal- endar period. There may be a number of reasons for this, but it may have to do with better guidelines and preventive measures. More effective treatments will also decrease the disease-related immunosuppression and therein the risk of infections.
In Sweden, we have also adjusted our treatment accord- ing to the result of studies by Rajkumar et al.30 showing that low-dose dexamethasone added to lenalidomide was equally effective but with less infections than high-dose dexamethasone in the elderly population. This is reflected in the Swedish National Multiple Myeloma Guidelines31 which since 2016 have recommended lower doses of dexametha- sone than in many original studies and refrained from high- dose dexamethasone over the age 75. This may also have contributed to the relatively lower risk of viral and fungal infections in the elderly, as could the repeated and more intensive treatment more common in younger patients. We found an infection-related mortality of approximately 30% 3 months and 1 year after MM diagnosis. This was based on infections that were registered as a cause of death. In participants surviving only 90 days after diagnosis or in- clusion to the study, 49% of MM patients died within 30 days of infection compared to 37% of controls. This reflects the burden of infections in early mortality among MM pa- tients. Similarly, in two retrospective registry studies from Denmark in patients diagnosed 2005-2012 and 2005-2013, in non-ASCT-eligible patients, infections were a cause of death in 51% of the 22% patients dying during the first 3 months,32 and in patients eligible for ASCT 9.6% of patients
succumbed to an early death (<2 years). Causes of early death were progressive disease and infections, and infec- tions were seen in 44% of deceased patients.33 Caravita et al. reported on 127 patients treated with lenalidomide combinations and found that overall survival (OS) was sig- nificantly shorter in patients developing an infection than not (median OS 26 vs. 33 months; P=0.001).34 In a single center study by Hsu et al., a 60-day mortality was seen in 12.6% of patients diagnosed 2002-2015, and pneumonia and other infections were the largest contributors to early mortality (65%).35
This study has several strengths, a large sample size, the population-based nature of the Swedish registries, and a matched control population. The study included a stable population of symptomatic MM patients from the Swedish Myeloma Registry with characteristics at diagnosis available, including the first line of treatment. Moreover, the whole population had access to public and free health care, with equal availability to new MM drugs. Almost every patient (92%) had received at least one line of treatment and 26% ASCT. Through the nationwide register-based design and age-matched controls we could avoid recall bias and en- sure the generalization of our findings.
Our registry-based study has some limitations. In 4.9% of patients, we have no record on ASCT treatment. In patients diagnosed up to 2021 with follow-up through 2022, some may not yet have an annotation of first-line treatment in the Swedish Myeloma Registry at data cut-off, hence some transplanted patients would be part of the “ASCT Missing” cohort shown in Table 1. To support this statement, we have reported on a steady increase of ASCT patients >65 years, and in later years ASCT is performed in approximately 40% of patients 66-70 years at diagnosis in Nordic countries.36 Other patients younger than 70 years diagnosed 2020 and 2021 may however have received less intensive treatment due to COVID-19.
The discharge diagnosis in hospital registries as a single source of infection diagnosis may lead to underreporting of infections, as the hospital visit often is labelled only by the MM diagnosis. We therefore did a sensitivity analysis based on prescribed antibiotics, with each different prescription of antibiotics acting as a proxy for infection, excluding prophylactic antivirals and antibiotics commonly used. The results were the same, with a 5-fold increase in infections for MM patients compared to controls. On the other hand, the surveillance of infections in MM patients may be more vigilant than in the general population. Underreporting may happen even to a higher degree in the in the Cause of Death Register, where MM more often is annotated as the only cause of death. Another limitation is the lack of data on the severity of the infection. However, most infections that were shown to have increased risks in MM patients were severe, and would have been captured in the control group as they would need treatment in the hospital. In order to avoid the risk of overreporting infections, we only
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