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Abstract Introduction: The chromosomal translocation t(11;14)(q13;q32) is found in nearly 20% of multiple myeloma (MM) patients. MIDAS trial (NCT04934475) reported only 24% MRD-negativity rates in t(11;14) MM compared to 59% in non-t(11;14) MM patients treated with a novel four-drug regimen, which suggests further evaluation of treatment options for this genetic subtype. Recent phase 3 clinical trials BELLINI (NCT02755597) and CANOVA (NCT03539744) have reported varied response to venetoclax, VEN - a novel BCL2 inhibitor, in patients with t(11;14) and high-BCL2 expressing tumors, which emphasizes the need to understand t(11;14) biology better. We present a retrospective study on the largest cohort of t(11;14) MM patients spanning pre-malignant (monoclonal gammopathy of undetermined significance - MGUS and smoldering MM – SMM), NDMM, ERMM, and late relapsed refractory MM (LRMM) offering unique insights into the evolution of t(11;14) biology and it's impact on response to VEN. Evolution of t(11;14) Biology by FISH: Fluorescence in situ hybridization (FISH) analyses of tumor samples from 381 MM patients revealed that 100% of MGUS samples have t(11;14) only (simple biology – no amp/gain1q21, del1p, del13q, or del17p), which reduces to 43.8%, 41.8%, and 36.4% in SMM, NDMM, and ERMM respectively, to 10.3% in LRMM samples, where the remaining samples have complex t(11;14) biology characterized by t(11;14) and one or more of other cytogenetic abnormalities. A Kaplan-Meier comparison of time since MM diagnosis for simple (median probability at 1.48 years) and complex (median probability at 3.13 years) events shows a statistically significant difference (log-rank test, p=0.002). In 70 t(11;14) MM patients with sequential FISH biopsies, a Kaplan-Meier comparison of time to loss of complexity (median probability at 1.65 years) and gain of complexity (median probability at 2.79 years) events revealed a statistically significant difference (Wilcoxon test, p=0.029). Evolution of t(11;14) Biology by RNAseq: RNAseq of CD138-enriched cells followed by estimation of single-sample gene set enrichment analysis (ssGSEA) scores of UAMS subgroups (Zhan et. al., Blood, 2006; CD1/CD2 – CCND1/CCND3, MF – MAF, PR – proliferation, LB – low bone disease), which showed that all t(11;14) MM patients had statistically significant, positive ssGSEA scores for CD1 and CD2. However, a subgroup of patients was also enriched for MF, PR, or LB leading to CD1/CD2 exclusive (simple) and CD1/CD2+MF/PR/LB (complex) groups. The CD1/CD2 simple biology was found in 75% SMM, 63.6% NDMM, 51.5% ERMM, and 37.9% LRMM t(11;14) patients. A statistically significant (paired t-test, p=0.0257) lowering of CD1 and CD2 ssGSEA enrichment scores were observed over time in 43 t(11;14) MM patients with sequential RNAseq biopsies. VEN Treatment in t(11;14) MM: Overall survival (OS) comparison of t(11;14) MM patients who received VEN (n=97, 11.9 years OS at median probability) at any point in time versus those who didn't (n=284, 8 years OS at median probability) shows a statistically significant difference (log-rank test, p=0.0003). In 97 (out of 381) t(11;14) MM patients who received VEN-based therapy, a Kaplan-Meier comparison of PFS revealed an improvement by nearly one year at median probability for the simple t(11;14) group (by FISH), albeit non-significantly (log-rank test, p = 0.1). Furthermore, a non-significant difference (unpaired t-test, p=0.74) in BCL2 expression between t(11;14) simple and complex tumors using 200 samples with paired RNAseq and FISH was noted, which suggests that a genetic simplicity of t(11;14) biology may confer limited benefit with VEN treatment. However, in 25 t(11;14) MM patients (out of 97 treated with VEN), who had RNAseq data available shortly before treatment; we note a statistically significant (log-rank test, p=0.02) difference in PFS between CD1/CD2 simple (PFS 2.69 years at median probability) and complex (PFS 0.69 years at median probability) groups, which suggests that functional simplicity in t(11;14) biology captured via RNAseq is a robust biomarker for sensitivity to VEN. Conclusions: Evolution of t(11;14) biology in MM is characterized by an early, genetically and functionally simple state, which acquires complexity with time. Treatment with VEN for t(11;14) MM patients confers a significant benefit in OS, where treating patients early on, prior to the onset of CD1/CD2 functional complexity confers a significant benefit in PFS as well.