Background: Maintenance therapy in multiple myeloma (MM) after first autologous hematopoietic cell transplantation (AHCT1) is considered standard of care. Data regarding maintenance therapy after a salvage AHCT (AHCT2) in the setting of relapsed MM are scarce. Therefore, we used data from the Center for International Blood and Marrow Transplant Research (CIBMTR) registry to examine the use of maintenance therapy after AHCT2 in MM patients and its effect on post-transplant patient outcomes. Methods: We included US adult MM patients who underwent AHCT2 after melphalan conditioning regimen from 2010-2018, and excluded patients who underwent tandem transplants. Outcomes of interest included non-relapse mortality (NRM), relapse/progression (REL), progression-free and overall survival (PFS, OS). Cox proportional hazards models were developed to study the main effect (maintenance use) with other covariates of interest including age, sex, race, performance status, HCT-comorbidity index, MM subtype, stage, creatinine, cytogenetic, conditioning melphalan dose, disease status at transplant, and time from AHCT1 to AHCT2. Results: Of 522 patients, 342 received maintenance therapy and 180 did not after AHCT2. Baseline characteristics were similar between the two groups. Median follow up was 58 months in the maintenance group and 61.5 months in the no-maintenance group. Common maintenance regimens included immunomodulatory drugs (IMID)-lenalidomide (N = 145, 42%) or pomalidomide (N = 46, 13%) and proteasome inhibitor, bortezomib (N = 45, 13%). Univariate analysis showed superior outcomes at 5 years in maintenance compared to the no-maintenance group: NRM 2 (0.7-3.9)% vs 9.9 (5.9-14.9)%, p < 0.001, REL 70.2 (64.4-75.8)% vs 80.3 (73.6-86.3)%, p 0.003, PFS 27.8% (22.4-33.5) vs. 9.8% (5.5-15.2), p < 0.001, and OS 54% (47.5-60.5) vs 30.9% (23.2-39.2) p < 0.001, respectively. IMID-containing maintenance regimens were associated with an improved 5-year PFS and OS compared to other maintenance regimens. Use of maintenance therapy retained its association with improved outcomes in multivariate analysis, including NRM: hazard ratio (HR) 0.19 (0.08-0.44), p 0.0001, REL: HR 0.58 (0.47-0.72), p < 0.0001, PFS HR 0.52 (0.43-0.64), p < 0.0001, and OS HR 0.46 (0.36-0.60), p < 0.0001. We conducted additional analyses to investigate a possible selection bias in the maintenance group including landmark analysis at 100-days and 6-months post-AHCT2 as well as a subgroup analysis of patients who received melphalan 200mg/m² as conditioning for AHCT2 (as a surrogate for fitness)- all these analyses also showed improved outcomes in the maintenance group. Second cancers were reported in 17 (5%) patients in the maintenance group and 6 (3%) patients and no-maintenance group (p 0.39). Conclusions: Maintenance therapy after AHCT2 is associated with superior outcomes in MM patients.