Background: PC proliferation correlates with outcomes in MM. Increased proliferation identifies asymptomatic patients with an 80% probability of progression to symptomatic disease within 2 years, fulfilling International Myeloma Working Group (IMWG) criteria for a myeloma defining biomarker. However, the IMWG does not include proliferation in its criteria because it is rarely offered in the clinical setting due to lack of feasible methods. We devised and validated an mIHC method to determine PC proliferation, feasible in any diagnostic lab, using standard equipment and reagents. Methods: On a single trephine biopsy or clot section slide, Syndecan 1 (CD138) IHC with a red chromogen is performed in multiplex with Ki67 and a brown chromogen. 200 CD138+ PCs are counted as either proliferating (coexpressing Ki67) or not, and reported as a percent index, "SynKii" (Syn + Ki + Index). For clinical validation, we performed 3 retrospective cohort studies. Results: In the 1st study, 26 relapsed patients treated with bone marrow transplant (BMT), SynKii > 5% correlated with overall survival (OS) [P = 0.006]. In the 2^nd study, 151 newly diagnosed, treatment nave patients, divided into SynKii low (² 5%, n = 87) and high ( > 5%, n = 64), median OS was not reached vs. 78.9 months (P = 0.043); using a cutpoint of 10%, median progression free survival (PFS) was 232 weeks vs 110 weeks (P = 0.03); each 1% increase in SynKii was associated with a 3% increased risk of progression (HR 1.03, 95% CI 1.01,1.05, P = 0.02). In the 3^rd study, 37 treated symptomatic patients evaluated by SynKii at diagnosis and at relapse, patients whose SynKii increased by ³5% had shorter OS with a median of 72 months vs not reached (p = 0.0069) and shorter PFS with a median of 25 vs 47 months (p = 0.036). Conclusions: SynKii is a clinically validated mIHC method for plasma cell proliferation using standard IHC equipment and reagents. SynKii predicts shorter OS in newly diagnosed/treatment nave patients and in relapsed patients after BMT. Increase in SynKii at relapse is associated with shorter OS and PFS in patients treated with a current standard regimen. SynKii can be used for clinical risk stratification and may eventually be included as an MM defining biomarker.