Background: Patients hospitalized with hematologic malignancy are particularly vulnerable to infection. We sought to determine the risk of Clostridium difficile infection (CDI) in hospitalization with multiple myeloma (MM), as well as its outcomes and trends, using a nationally representative database. Methods: The Nationwide Inpatient Sample (NIS) from January 2010 to September 2015 was used for this study. We identified all patients aged 18 years or older with a diagnosis of MM using the International Classification of Disease, Ninth Revision, Clinical Modification (ICD-9-CM) codes. We identified trends in the annual rates of CDI in MM using negative binomial regressions with robust error variance. We conducted multivariate logistic regression to determine the incidence and the associated risk factors of CDI in MM and compared the outcomes between those with and without CDI using the propensity score method inverse probability weighting to adjust for baseline covariates. Results: In our cohort study of 114,249 MM patients, 45.96% were females and 54.04% were males. CDI was present in 3.1% of the MM patients. The number of CDI cases increased over the study period with an average rate of 3.27% per year. The mortality rate decreased over the same period with an average rate of 10% decrease per year. Hematopoietic stem cell transplantation (HSCT), neutropenia, inflammatory disease, atrial fibrillation (AF), and chronic kidney disease (CKD) were significant associated risk factors of CDI in MM patients. After adjusting for covariates, patients with CDI had a prolonged hospital stay, inpatient mortality, and significantly increased odds of acute kidney injury (AKI) and AKI requiring hemodialysis, along with higher healthcare resources utilization with significantly higher hospital costs. Conclusion: MM patients with CDI have significantly increased odds of inpatient mortality, AKI, and AKI requiring hemodialysis. They also have increased healthcare resource utilization compared with those without CDI. Despite the increased rate of the CDI over the years, the mortality rate is going down.

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