Background: Patients with multiple myeloma (MM), an age-dependent neoplasm of antibody-producing plasma cells, have compromised immune systems due to multiple factors that may increase the risk of severe COVID-19. The NCATS’ National COVID Cohort Collaborative (N3C) is a centralized data resource representing the largest multi-center cohort of ̃12M COVID-19 cases and controls nationwide. In this study, we aim to analyze risk factors associated with COVID-19 severity and death in MM patients using the N3C database. Methods: Our cohort included MM patients within the N3C registry diagnosed with COVID-19 based on positive PCR or antigen tests or ICD-10–CM. The outcomes of interest include all-cause mortality (including discharge to hospice) during the index encounter, and clinical indicators of severity (hospitalization/ED visit, use of mechanical ventilation, or extracorporeal membrane oxygenation/ECMO). Results: As of 09/10/2021, the N3C registry included 690371 cancer patients, out of which 17791 were MM patients (4707 were COVID-19+). The mean age at diagnosis was 65.9yrs, 57.6% were >65yo, 46.4% were females, and 21.8% were Blacks. 25.6% had a Charlson Comorbidity Index (CCI) score of ≥2. 55.6% required an inpatient or ED visit, and 3.65% required invasive ventilation. 11.4% developed acute kidney injury during hospitalization. Multivariate logistic regression analysis showed histories of pulmonary disease (OR 2.2; 95%CI: 1.7-2.8), renal disease (OR 1.8; 95%CI: 1.4-2.4), and black race (p<0.001) were associated with higher risk of severity. Interestingly, smoking status was significantly associated with a lower risk of severity (OR 0.7; 95%CI: 0.5-0.9). Further, protective association was also observed between COVID-19 severity and blood or marrow transplant (BMT) (OR 0.52; 95%CI: 0.4-0.7), daratumumab therapy (OR 0.64; 95%CI: 0.42-0.99) and COVID-19 vaccination (OR 0.28; 95%CI: 0.18-0.44). IMiDs were associated increase in the risk of COVID-19 severity (OR 2.1; 95%CI: 1.6-2.7). 2.3% of N3C-myeloma COVID-19+ patients died within the first 10 days, while 4.95% died within 30 days of COVID-19 hospitalization. Overall, the survival probability was 90.5% across the course of the study. Multivariate cox proportional hazard model showed that CCI score ≥2 (HR 4.4; 95%CI: 2.2-8.8), hypertension (HR 1.6; 95%CI: 1.02-2.4), IMiD (HR 2.6; 95%CI: 1.8-3.8) and proteasome inhibitor (HR 1.6; 95%CI: 1.1-2.5) therapy were associated with worse survival. COVID-19 vaccination (HR 0.195; 95%CI: 0.09-0.45) and BMT (HR 0.65; 95%CI: 0.4-0.995) were associated with lower risk of death. Conclusions: We have identified previously unpublished potential risk factors for COVID-19 severity and death in MM as well as validated some published ones. To the best of our knowledge, this is the largest nationwide study on multiple myeloma patients with COVID-19.