Expression profile of CASSIOPEIA patients refines prognostic value of MRD negativity in multiple myeloma.

Long-term follow-up of the CASSIOPEIA trial (NCT02541383) demonstrated superior progression-free survival (PFS) with daratumumab, both in combination with bortezomib, thalidomide, and dexamethasone during induction and consolidation, and during maintenance therapy, in transplant-eligible patients newly diagnosed with multiple myeloma (MM). However, outcomes among CASSIOPEIA patients remain heterogeneous across treatment groups. Measurable residual disease (MRD) is a strong indicator of the depth and duration of therapeutic response and is independently associated with both PFS and overall survival (OS), but it does not fully capture the biological diversity of MM. We performed a risk prediction analysis based on transcriptomic subgroups in CASSIOPEIA patients. A subset of 628 patients was characterized using RNA sequencing and consensus clustering identified five subtypes of MM grouped into three transcriptomic risk categories, with estimated 72-month PFS rates of 70%, 51%, and 27% for low, intermediate, and high-risk groups, respectively, among patients who received daratumumab in at least one treatment phase. We showed that post-consolidation MRD negativity was higher in low- and high-risk groups compared to intermediate, and that its prognostic impact was distinct and reduced in high-risk patients. These findings indicate that transcriptomic profiling refines the prognostic value of MRD by identifying high-risk patients in whom MRD alone is insufficient to predict clinical outcome. This suggests that MRD negativity may not capture clinically relevant residual disease in this subgroup, potentially reflecting aggressive disease dynamics. Overall, these results support integrating baseline molecular features with MRD assessment and highlight the need for novel therapeutic strategies in high-risk MM.