Background: The recognition of prognostically distinct subtypes of DLBCL by gene expression profiling has, until now, not led to improved outcomes. Conducting targeted studies in prospectively identified, molecularly distinct entities is challenging. PYRAMID and LYM2034 are prospectively identifying and enrolling non-GCB patients (pts). This subtype has inferior outcomes vs GCB following (R-)CHOP alone (Lenz, NEJM 2008; Fu, JCO 2008). The rationale for these studies is provided by data suggesting bortezomib shows benefit specifically in non-GCB DLBCL resulting from inhibition of the critical NF-κB survival pathway, which is activated in the non-GCB subtype. Bortezomib + dose-adjusted EPOCH showed superior response rates and survival in non-GCB vs GCB relapsed DLBCL (Dunleavy, Blood 2009), and in newly diagnosed DLBCL, bortezomib + R-CHOP showed similar outcomes in GCB and non-GCB pts (Ruan, JCO 2010). Methods: PYRAMID is enrolling pts at 55 centers in the US; LYM2034 is enrolling pts at 86 sites in Canada, Australia, and countries in Central and South America, Europe, and Asia. Pts aged ≥18 yrs with previously untreated non-GCB DLBCL (PYRAMID: all stages; LYM2034: stages II–IV), ECOG PS 0–2, and ≥1 measurable tumor mass are eligible. Non-GCB tumor subtyping for both studies is done at a single central laboratory via the Hans immunohistochemical assay (Hans, Blood 2004). Non-GCB pts are then randomized to receive six 3-week cycles of R-CHOP alone (rituximab 375 mg/m², cyclophosphamide 750 mg/m², doxorubicin 50 mg/m², vincristine 1.4 mg/m², all on day 1, plus prednisone 100 mg, days 1–5), or bortezomib 1.3 mg/m² on days 1 and 4 plus R-CHOP (PYRAMID) or bortezomib 1.3 mg/m² on days 1, 4, 8, and 11 plus R-CAP (R-CHOP minus vincristine; LYM2034). The primary endpoint is PFS at 2 yrs in PYRAMID and CR rate in LYM2034. To date in PYRAMID and LYM2034, respectively, 100 and 167 DLBCL pts have been screened, and 34 of the planned 190 and 62 of the planned 164 non-GCB pts have been randomized. PYRAMID (NCT00931918) and LYM2034 (NCT01040871) are registered with ClinicalTrials.gov.