P-255: The Specific Transcriptional Profile and Clonal Selection of MGUS-like Behavior Predict an Exceptionally Favorable Prognosis in Multiple Myeloma

Introduction: Achieving persistent undetectable minimal residual disease (MRD) status is considered the cornerstone of functional cure in myeloma. It is interesting to note that some myeloma patients do not achieve complete response or undetectable MRD after systematic treatment, but can achieve a plateau in their survival curve, which has been hypothesized as monoclonal gammopathy of undetermined significance-like (MGUS-like) behavior. However, this unusual MGUS-like behavior is not well-known and is poorly understood.

Methods: To address this issue, we retrospectively identified 35 (6.4%) MGUS-like patients from the National Longitudinal Cohort of Hematological Diseases in China (NICHE, NCT04645199) who have a progression-free period of ≥5 years but persistent detectable MRD or M-protein. We used a multi-omics approach including DNA and RNA sequencing to investigate the distinct clinical features, transcriptional profile, genomic landscape, and clonal evolution patterns that contribute to MGUS-like behavior.

Results: These patients exhibiting MGUS-like behavior demonstrated infrequent anemia and bone lesions, achieving a significantly good prognosis even with suboptimal remission. Transcriptional analysis unveiled a distinct transcriptome resembling the earliest precursor condition (MGUS), enriched in immune response and low proliferation pathways, and showed a tendency towards CD-2 classification and dormant state, indicating an indolent clinical course. Based on differentially expressed genes, we constructed a specific gene signature predicting MGUS-like status and validated its excellent performance in the MMRF cohort. Whole-exome sequencing of paired diagnostic and MRD/first relapse tumor samples revealed two distinct clonal evolution patterns: the majority exhibited stable evolution, while a few patients experienced differential clonal response evolution, both leading to MGUS-like behavior. These findings suggest that MGUS-like behavior not only arises from the unique transcriptional profile of tumor cells but also results from clonal evolution under treatment pressure.

Conclusions: In summary, we identified a distinct myeloma subgroup that shows unexpectedly long progression-free period but with persistent residual tumor, exhibiting MGUS-like status. This distinctive MGUS-like behavior seems to not only arise from the specific transcriptional profile of tumor cells at diagnosis but also be attributed by the tumor clonal selection under treatment pressure. Furthermore, we have developed and validated a 44-gene signature which can predict potential MGUS-like status characterizing by a favorable prognosis irrespective of response depth.