(OA-45) Cell-Free BCL2 exRNA, but not MYC or MIZ1, Identifies Smouldering Myeloma with a High Risk of Progression among Patients in the Myeloma Related Disease Registry (MRDR)

Smouldering multiple myeloma (SMM) is a heterogeneous condition with various risk factors influencing disease progression. The widely used IMWG 2/20/20 risk score, although common in clinical practice, fails to accurately identify some patients who progress to active disease. This highlights the need for improved risk models that can more precisely identify high-risk patients for targeted intervention. While a perfect prognostic model may not be achievable, refining risk stratification strategies rooted in disease biology is crucial for identifying patients who need closer monitoring or early treatment. In this study, we developed a minimally invasive liquid biopsy approach to analyze the expression of MYC, MIZ1, and BCL2 in circulating extracellular RNA (exRNA). Peripheral blood samples were collected from the national M1000 liquid biopsy biobank, integrated with clinical data from the Myeloma and Related Diseases Registry (MRDR).

Methods:

We obtained plasma samples from 64 patients with smouldering multiple myeloma (SMM) enrolled in the M1000 project. Extracellular RNA (exRNA) was extracted from 3 mL of plasma, stored in Streck™ tubes, using the QIAamp Circulating Nucleic Acid Kit (QIAGEN) according to the manufacturer’s instructions. Genomic DNA contamination was removed using the TURBO DNA-free™ Kit. Quantification of exRNA targets was performed using the QIAcuity Digital PCR System. Two housekeeping genes, GAPDH and HPRT1, were included to ensure data robustness and normalization. Expression levels of MYC, MIZ1, and BCL2 exRNA were then correlated with clinical outcomes, including progression, using data from the Myeloma and Related Diseases Registry (MRDR). High and low expression groups were defined based on the top and bottom tertiles of expression levels, respectively.

Results:

The SMM cohort included 64 patients with samples collected between November 2014 and September 2021. To date, 21 out of the 64 patients have progressed to multiple myeloma (MM), with the median time to progression not reached (range: 2–48 months). Among patients with high BCL2 exRNA expression (top tertile), 12 out of 20 (60%) progressed, with a median time to progression of 41 months and a hazard ratio of 4.152 (p = 0.0064). In contrast, MYC and MIZ1 exRNA levels showed no statistically significant association with progression risk, suggesting that these markers may have limited prognostic value when assessed in peripheral blood.

Conclusions:

High BCL2 exRNA expression in peripheral blood appears to be a potential risk factor for progression from smouldering multiple myeloma to symptomatic disease. These findings warrant validation in larger, independent cohorts. If confirmed, BCL2 exRNA could serve as a valuable biomarker to identify high-risk patients who may benefit from early, targeted therapeutic intervention with BCL2 inhibitors, thereby potentially improving outcomes by reducing the risk of progression.