P-427: REAL-WORLD PREVALENCE AND MULTI-OMIC ANALYSIS OF T(11;14)-POSITIVE MULTIPLE MYELOMA: FINAL ANALYSIS FROM THE MEDICI STUDY

Introduction: Multiple myeloma (MM) is characterized by complex cytogenetic abnormalities and diverse genomic subtypes that can determine disease course and treatment response. t(11;14)-positive MM is a distinct subset of MM with a unique biology that makes it highly susceptible to BCL-2 inhibition. The underlying biology and real-world (RW) prevalence of t(11;14)-positive MM remains to be fully investigated. Here, we present the final analysis (FA) from the global, noninterventional MEDICI study (NCT04721002), which evaluated RW t(11;14) status and associated disease and genomic characteristics in newly diagnosed MM (NDMM) and relapsed/refractory MM (RRMM).

Methods: Bone marrow (BM) aspirates of patients (pts) aged ≥18 y with MM who provided informed consent were collected at diagnosis and/or disease relapse and subjected to plasma cell enrichment (PCE) before fluorescence in situ hybridization (FISH), next-generation RNA sequencing before differential gene expression analysis (GEA), and whole-exome sequencing (WES). The primary objective was to evaluate t(11;14) prevalence in NDMM/RRMM using interphase FISH with PCE. The primary endpoint was t(11;14) status of the earliest BM sample collected.

Results: At the October 31, 2023 cutoff, 525 pts (306 NDMM; 219 RRMM) were enrolled. Median age was 66.0 y, and most pts were male (55.4%) and White (74.5%); 3.2% of pts were Black. ECOG PS was ≤2 in 83.2% of pts, and ≥3 in 2.9%. Disease was ISS stage I in 31.6% of pts, stage II in 23.8%, and stage III in 25.0%. FISH testing was evaluable in 498/525 pts (94.9%), of which only 12 (2.4%) samples had an indeterminate result. t(11;14) prevalence was 22.1% (95% CI: 18.5–26.0) in MM, 18.8% (14.5–23.7) in NDMM, and 27.0% (21.0–33.7) in RRMM. Distribution of t(11;14) across lines of therapy was 18.8% (14.5–23.7) in 1L, 27.4% (16.9–40.2) in 2L, and 28.7% (21.6–36.6) in 3L+. Distribution of t(11;14) across disease stage was 24.1% (17.6–31.5) in stage I, 20.0% (13.3–28.3) in stage II, and 21.3% (14.4–29.6) in stage III.

Whole transcriptome sequencing was evaluable in 487/525 (92.8%) pts. Differential GEA confirmed significant CCND1 (cyclin D1) overexpression in t(11;14)-positive vs -negative disease (NDMM, P=9.22e-18; RRMM, P=1.15e-22). The apoptotic sensitizer PMAIP1 (NOXA) was significantly overexpressed in t(11;14)-positive vs -negative disease (NDMM, P=1.02e-06; RRMM, P=1.18e-07). While BCL2 expression was similar between t(11;14)-positive vs -negative NDMM (P=.6313) and between t(11;14)-positive RRMM vs NDMM (P=.0632), BCL2 was significantly overexpressed in t(11;14)-positive vs -negative RRMM (P=4.78e-07). Increased levels of BCL-2 inhibitor resistance indicators were observed in t(11;14)-positive RRMM vs NDMM (BCL2A1, P=.0049; KRAS signaling pathway, P=.0039). WES will be presented.

Conclusions: MEDICI FA showed an overall RW t(11;14) prevalence of 22.1% in MM. Multi-omic analyses revealed increased genomic heterogeneity in t(11;14)-positive RRMM vs NDMM, which may harbor additional resistance mechanisms.