(PA-231) Elevated Levels of Circulating Tumor Cells (CTCs) in Newly-diagnosed Multiple Myeloma (NDMM) Patients Reflect a Highly Proliferative and Genomically Complex Profile

CTCs have emerged as a key prognostic factor in NDMM. However, it is unclear if high CTC counts only represent a surrogate of tumor burden or might also be driven by distinct genomic drivers. We aimed to define genomic and transcriptomic features associated with CTC burden.

Methods:

We interrogated 540 baseline patients from CoMMpass (IA22) with CTC information available, studied by the CellSearch System. Whole-exome/genome (WGS/WES) and RNA-seq data of bone marrow (BM) plasma cells (PC) were available for 85% and 51%. An external dataset (n=135) with CTCs assessed by next-generation flow was used for validation, with RNA-seq and WGS of BM PCs available for 52% and 9.6%.

Results:

Elevated CTCs at baseline showed shorter progression-free survival (PFS) in both datasets. Notably, patients with ≤10 CTCs or ≤0.001% exhibited outstanding overall survival (OS). High CTCs were significantly associated with ISS, R-ISS, R2-ISS, and IMS risk classifications (p≤.003). Moreover, gain/amp1q and del13q were enriched in high CTCs (p≤.005), as well as MAF and NSD2 translocations (p≤.03) in both datasets.

Considering the genomic classification in [Maura, JCO 2024], complex genomic subgroups (ie, NSD2_Gain/Amp1q_Del13q, CCND1_Complex, and MAF_HyperAPOBEC; p≤.02) were associated with high CTCs. Thus, we also observed a strong correlation between elevated CTCs and high-risk genomic features such as chromothripsis, gain/amp1q, APOBEC mutagenesis, MAF translocations, and RB1 (p≤.007). External validation also revealed an association between high CTC counts and complex genomics. As to clinical outcomes, a cutoff of 1000 CTCs showed an independent association with PFS when combined, for instance, with chromothripsis, APOBEC, gain/amp1q, or RB1 (p< .001). Only APOBEC plus CTCs retained prognostic value for OS (p=0.01).

We analyzed RNA-seq data using a linear model adjusted for BM infiltration, identifying 210 genes positively correlated with CTCs (eg, CENPF or TAGLN2) and enriched in proliferation and cell cycle functions. The validation set confirmed this enrichment. Other 452 genes negatively associated with CTCs (eg, CXCL12 or CCL25) were linked to immune activation and cell adhesion. Hence, CTCs correlated with published PR indexes (ie, Zhan, Blood 2006, or Skerget, Nat Gen 2024; p< .0001) or the PC leukemia-like signature (Bruinink, JCO 2022; p< .0001). Combining CTC levels with PR showed important prognostic value. Low or high values of both markers identified two groups with favorable and shorter outcomes, respectively (p< .0001), and, importantly, high CTCs and low PR also separated a third group of patients with poor PFS.

Conclusions:

Overall, the addition of CTC enumeration to genomic classification may further improve the risk stratification of MM patients. Moreover, they retain prognostic significance independently of the latest high‑risk genomic or stratifying systems and could serve as a surrogate for established markers of high‑risk disease and tumor proliferation.