Time to progression of disease (POD) after first line (1L) therapy is prognostic in mantle cell lymphoma (MCL), although studies have included a broad range of 1L, second (2L) and subsequent lines of therapy. The purpose of this study was to evaluate factors predicting outcomes in patients with relapsed/refractory (R/R) MCL exclusively initiating second line (2L) Bruton’s tyrosine kinase inhibitors (BTKi) after 1L rituximab-containing therapy. Patients were accrued from 8 international centers (7 main, 1 validation cohort). Multivariable models evaluating the association between time to POD and clinical/pathologic factors were constructed and converted into nomograms and prognostic indexes predicting outcomes in this population. A total of 360 patients were included: 160 in the main cohort and 200 in the validation cohort. Time to POD, Ki67 30%, and MIPI were associated with progression-free survival (PFS2) and overall survival (OS2) from the start of 2L BTKi. C-indexes were consistently 0.68 in both cohorts. Web/application-based calculators based on nomograms and prognostic indexes to estimate PFS2 and OS2 were constructed. The 2L BTKi MCL International Prognostic Index (MIPI) identifies 3 groups with distinct 2-year PFS2: high-risk (14%), intermediate-risk (50%), and low-risk (64%). Time to POD, Ki67, and MIPI are associated with survival outcomes in patients with R/R MCL receiving 2L BTKi. Simple clinical models incorporating these variables may assist in planning for alternative therapies such as chimeric antigen receptor T-cell therapy, allogeneic stem cell transplantation, or novel agents with alternative mechanisms of action.