Incidence, outcomes and economic burden of cytokine release syndrome and immune effector cell associated neurotoxicity syndrome in patients undergoing CAR-T cell therapy for multiple myeloma

Abstract INTRODUCTION: Chimeric antigen receptor T-cell (CAR-T) therapy has revolutionised the landscape for patients with relapsed/refractory multiple myeloma (MM). However, like any other therapy, it carries the risk of immune mediated toxicities, particularly Cytokine release syndrome (CRS) and Immune effector cell associated neurotoxicity syndrome (ICANS). METHODOLOGY We queried the National Inpatient Sample database (2018-2022) for identifying patients with multiple myeloma who received CAR-T therapy using the International Classification of Diseases-10 diagnosis and procedure codes, C90.0x, XW033C3, and XW043G7. The primary outcome studied was in-hospital mortality, length of stay and total hospitalization cost. Descriptive statistics were used to summarise patient and hospital characteristics. Logistic regression was employed to evaluate the association between toxicities (CRS/ICANS) and primary outcomes. RESULTS A total of 1890 hospitalizations for multiple myeloma receiving CAR-T therapy were identified. Of this, 59.2% were males with a mean age of 61.3 years. Racial distribution showed 64.4% were white patients followed by black (16.7%) and Hispanic (11.8%). The Charlson Comorbidity Index indicated a high comorbidity burden (>3) in 61.8% patients. CRS and ICANS was seen in 21.6% and 9.3% patients respectively. Additional complications included sepsis in 13.5%, acute renal failure in 8.9% and acute respiratory failure in 5.7% of the patients. In hospital mortality was 2.1%. ICANS was significantly associated with increased mortality (aOR 2.26, 95% CI 1.10–4.64) while CRS showed no significant association. Mean length of stay (LOS) was 15 days (IQR: 11–22). Prolonged LOS was independently associated with CRS (aOR 1.78, 95% CI 1.42–2.24) and ICANS (aOR 1.91, 95% CI 1.42–2.58). Treatment in a teaching hospital (aOR 1.45, 95% CI 1.01–2.10) was also independently associated with prolonged stays. Mean hospitalization charges were $448,000 (IQR: $362,000–$612,000). Medicare was the most common insurance covering 62.8% of the patients, reflective of the age group. Complications such as ICANS and CRS were both independently associated with higher resource utilization costs, $645,000 (IQR: $522,000–$765,000) and $586,000 (IQR: $478,000–$710,000) respectively. DISCUSSION CRS has nearly double the incidence of ICANS in MM patients receiving CAR-T. CRS significantly prolongs the LOS and total hospitalization charges with no impact on mortality. Although less frequent, ICANS is associated with a twofold increase in the odds of mortality possibly suggestive of a potential for rapid deterioration and higher complexity in management . The high incidence and cost implications of these complications emphasize the need for early risk stratification, close monitoring, and standardized toxicity management protocols. Proactive mitigation strategies are essential to optimize outcomes and reduce healthcare expenditure in this growing patient population.