Background: The combination of bortezomib (Bort) and alkylating agent (AA) is a frequently used first-line therapy for AL amyloidosis. Kastritis et al. compared melphalan and dexamethasone with or without bortezomib as primary therapy and demonstrated increased hematologic response rate with the bortezomib and melphalan combination. However, the role of AA is unclear. This study aimed to evaluate if adding AA to Bort improved patient outcomes in AL amyloidosis. Methods: We retrospectively reviewed clinical data on 209 patients with systemic AL Amyloidosis at Moffitt Cancer Center between 2008 and 2020. We excluded patients with localized amyloidosis or amyloid other than AL. Patients were divided into two groups based on upfront therapy: A) Bort and B) Bort + AA. All patients also received dexamethasone. The staging was per Mayo 2012. Organ involvement, response, and progression were defined based on the 2005 criteria. Overall survival (OS) was defined as the time from initial diagnosis until death or last contact. Time to next therapy (TTNT) was calculated in patients with the documented hematologic response from the time of initiation of therapy to time of the next therapy/last follow up/death. Results: Of 209 patients, 36% (n=76) received Bort+AA; 30% (n=62) received Bort. No significant difference in clinical characteristics was seen in both groups except for age (which was higher for arm A: median 65 and 62 years, respectively, p=0.043) (table). In addition, Bort+AA became more commonly used as a frontline therapy after 1/1/2014 (p=0.001). Group A and B had similar median OS (69.9 months [95% CI. 44.7-95.2] and 64.4 mo [95% CI 40.5-88.3] respectively, p=0.60). 86% of patients in group B achieved a hematologic response as compared to 74% of patients in group A (p=0.15). Similarly, 47% of patients in group B achieved an organ response as compared to 34% of patients in group A (p=0.22). TTNT was higher in group A than group B (16.9 mo [95% CI, 0-41.5] and 7.8 mo [95% CI, 3.5-12.0], respectively, p=0.08). Conclusions: While Bort+AA is a commonly used regimen for amyloidosis, the addition of AA to Bort did not result in superior OS, TTNT compared to Bort alone in this retrospective study. This finding should be confirmed in prospective studies. Baseline Characteristics.