Risk of Infections in Multiple Myeloma in the Era of Novel Agents, a Population-Based Study Based on 8672 Multiple Myeloma Patients Diagnosed 2008-2021 from the Swedish Myeloma Registry
Authors: Blimark Cecilie Hveding , Carlson Kristina , Day Christopher , Einarsdottir Sigrun , Juliusson Gunnar , Karma Moshtak , Knut-Bojanowska Dorota , Larfors Gunnar , Turesson Ingemar , Villegas Scivetti Mariana , Sverrisdottir Ingigerdur 
Published: December 2023

Introduction
Despite modern therapies, infections are still a major cause of morbidity and mortality in patients with myeloma (MM). We therefore performed a large population-based study to evaluate the risk of bacterial, viral and fungal infections among 8672 Swedish symptomatic MM patients diagnosed 2008-2021 compared to 34,567 matched controls.
Materials and methods
Symptomatic patients reported to the Swedish Myeloma Registry and four matched controls per patient were analysed with occurrence and date of all infections in the centralized Swedish Patient registry that captures information on individual patient-based discharge diagnosis from inpatient and outpatient care. The Swedish MM patients were followed until death or until 31 st December 2022.
Statistical analysis
Cox proportional hazard models, with the occurrence of infection as a time dependant co-variate and cumulative incidence with competing risk models were used to estimate the risk of infections in MM compared to controls. All models were adjusted for sex, age and year of diagnosis. The effect of gender, age and calendar period of were evaluated separately. Hazard ratio (HR) and confidence intervals (95% CI) were calculated for the risk of different infections. All p-values were two-sided and a value below 0.05 was considered statistically significant. All analyses were performed with R version 4.3.1 and ethics approved.
Results
In this population-based study, 8672 Swedish symptomatic MM patients diagnosed 2008-2021 and 34,567 matched controls were included. The majority of patients (73 %) were 65 years or older at diagnosis, 57% were male, and 30 % treated with up-front autologous stem cell transplantation (auto-SCT). The median time of follow-up was 5 years. Overall, MM patients had a 5-fold (HR=4.73; [95% CI=4.59-4.89]) risk of developing any infection compared to matched controls. Bacterial infection had a 4-fold increased risk (HR=4.40; [4.24-4.57]), viral infection 6-fold (HR=6.11; [5.76-6.49]), and fungal infection 6-fold (HR=6.14; [5.56-6.79]) compared to controls.
More specifically, MM patients had an increased risk (p&lt;0.05) of the following bacterial infections compared to controls: meningitis (HR=19.6; [ 10.0-38.1]), septicaemia (HR=8.05; [7.52-8.62]), pneumonia (HR=7.72; [7.21-8.27]), endocarditis (HR=4.9; [3.70-6.48]), cellulitis (HR=3.13;[2.57-3.80]), osteomyelitis (HR=2.89; [1.95-2.92]), pyelonephritis (HR=2.3; [2.03-2.59]), and for the viral infections influenza (HR=9.40; [8.19-10.8]) and herpes zoster (HR=9.33; [8.19-10.6]) (Table 1). The risk of infections compared to controls was 4 to 5-fold the first year after diagnosis and remained elevated up to 5 years after the myeloma diagnosis. Figure 1 illustrates the cumulative incidence of infections compared to controls over time.
MM patients diagnosed 2018 to 2021 had a slightly lower risk of infection, (HR=0.87 ([0.82-0.93] p&lt; 0.05) compared to patients diagnosed 2008-2012, whilst the risk of infections was slightly higher 2013-2017 compared to the first time period (HR=1.06 ([1.00-1.11], p&lt; 0.05).
The cumulative risk of infection compared to controls remained 5-fold in patients diagnosed 2008-2012 (HR=5.03; [4.78-5.29], p&lt;0.05) and 2013-2017 (HR=4.82; [4.59-5.06], p&lt;0.05), and 4-fold (HR=3.93, [3.66-4.21], p&lt;0.05) in patients diagnosed 2018-2021. Females had a significantly lower risk of infections compared to males (p&lt;0.001). Older age at diagnosis increased the risk of a first infection (p&lt;0.001).
Discussion
This study constitutes the largest population-based study to date on the risk of infections compared to the normal population in the era of modern MM therapies. Infections still represent a major threat to myeloma patients, with an equally about five-fold increased risk for bacterial, viral and fungal infections during the first year and up to 5 years after the myeloma diagnosis, even in more recent years.