Exosomal Vesicles: A Therapeutic Strategy Against Severe Sars-Cov-2 in Multiple Myeloma Patients
Authors: Leyfman Yan , Joshi Muskan , Menon Gayathri P. , Van de Kieft Alexandra , Park Chandler Howard 
Published: December 2023

During the early phase of the pandemic, studies revealed that COVID-19 patients with multiple myeloma (MM) had significantly higher hospitalization rates (56%), with 20% requiring critical care and 18% facing an increased risk of mortality. MM patients undergoing anticancer therapy showed a 55% higher risk of mortality when infected with COVID-19. Even in the post-pandemic world, MM patients remain at heightened risk for breakthrough infections and severe SARS-CoV-2 due to their immunocompromised status, necessitating hospitalization. While both active and remission MM patients exhibited worse outcomes than COVID-19 patients without cancer, limited research exists to elucidate the underlying causes. In this study, we aimed to (1) develop a model elucidating the pathogenesis and interplay between MM and severe SARS-CoV-2, and (2) explain the efficacy and therapeutic potential of Exosomal Vesicles (EVs) as an intervention against severe SARS-CoV-2, supported by clinical evidence.

Severe SARS-CoV-2 infection triggers multi-organ dysfunction through IL-6 mediated inflammation. Concurrently, malignancies like multiple myeloma cause apoptosis via hypoxia-induced metabolic changes, also involving IL-6. Within the tumor microenvironment, IL-6 propagates inflammation, tumorigenesis, angiogenesis, invasion, and metastasis, while inhibiting apoptosis. In MM, IL-6 serves as a survival factor, impeding apoptosis in myeloma cells and reshaping the bone marrow's tumor microenvironment, resulting in disease progression. In this model, infection with severe SARS-CoV-2 exacerbates the pro-inflammatory state in MM patients due to increased IL-6 production, stimulating increased complement and acute phase reactant production, ultimately resulting in severe systemic injury ( Figure 1).

Given the virus's complexity, therapeutic options against severe SARS-CoV-2 remain limited, especially in the immunocompromised. However, EVs have shown promising therapeutic efficacy in severe SARS-CoV-2 cases, acting as both SARS-CoV-2 entry neutralizers and immunomodulators. Their capacity to deliver therapeutic cargo enhances the immune response and associated therapeutic interventions in immunocompromised individuals, while promoting angiogenesis and tissue repair. This multi-faceted therapeutic approach enables EVs to target various points in the severe SARS-CoV-2 pathway, neutralizing viral replication and mitigating systemic injury ( Figure 1). Clinically, EVs have demonstrated an impressive overall survival rate of over 90% in severe SARS-CoV-2 patients aged 18 or older, persisting for at least six months after treatment.

In conclusion, EVs have proven to be safe and well-tolerated in severe COVID-19 patients, leading to improved survival rates. The unique biology of EVs allows them to effectively target disease pathogenesis at multiple steps, mitigating direct injury, suppressing IL-6, and reducing systemic inflammation, while promoting tissue repair. Moreover, their potential to work individually or synergistically with other therapeutic interventions makes them valuable in countering the virus's heterogeneity and mutational adaptations. Notably, EVs exhibit limited drug interactions and side-effects, making them a viable approach to combat SARS-CoV-2 without disrupting the treatment regimens of MM patients.