Background. CTCs are independent prognostic biomarkers in NDMM patients (pts) stratified by International Staging System (ISS) and Revised ISS. However, the relevance of CTCs in the context of R2-ISS and the new IMS-IMWG definition of high-risk myeloma (Consensus Genomic Staging, CGS) has not been investigated. The aim of this analysis was to evaluate the clinical significance of CTCs in combination with R2-ISS and the IMS-IMWG CGS in a large cohort of NDMM pts.

Methods. The European CTC Consortium collected patient-level data of NDMM pts from 5 collaborative groups (Czech Republic, Greece, Italy, HOVON/Netherlands-Belgium, PETHEMA/Spain). All included pts had CTC enumeration by flow cytometry prior to treatment.

To investigate the role of CTCs in combination with R2-ISS we analyzed 1657 NDMM pts (R2-ISS cohort) with complete data on the R2-ISS defining variables [ISS, del(17p), t(4;14), LDH levels, 1q+]. A value was assigned to each risk feature and pts were stratified into 4 risk groups according to the total additive score (D'Agostino et al JCO 2022).

To investigate the role of CTCs in combination with IMS-IMWG CGS we analyzed 190 NDMM pts (CGS cohort) with molecular data available.

TP53 mutations, biallelic del(1p32) (CDKN2C log2 < -1.3219) and t(14;20) were analyzed by whole genome/exome sequencing of CD138+ tumor cells . CGS high risk was defined as per IMS/IMWG recommendations (Avet-Loiseau et al JCO 2025),

In both cohorts CTCs were analyzed as log10 increase (as a continuous variable and as discrete intervals from ≤0.001% to >1%) and using a binary cutoff (£ 0.02% vs >0.02%, Bertamini et al EHA 2025)

Results. In the R2-ISS cohort, 17% of pts were R2-ISS I, 29% R2-ISS II, 46% R2-ISS III and 9% R2-ISS IV. The distribution of pts with ≤0.001%, ≤0.01%, ≤0.1%, ≤1% and >1% CTCs was 20%, 20%, 31%, 18% and 10%.

After a median follow-up of 50 months, both CTCs log10 increments (HR 1.15 p<0.001 for PFS; HR 1.13 p<0.001 for OS) and R2-ISS (R2-ISS II vs I HR 1.20 for PFS 1.16 for OS; R2-ISS III vs I HR 1.67 for PFS 1.90 for OS; R2-ISS IV vs I HR 2.66 for PFS HR 3.77 for OS; p<0.001) were independent predictors of outcome in a multivariable model including site, transplant eligibility and age.

A prognostic model including CTCs as log10 intervals + R2-ISS (c-index 0.703 for PFS and 0.743 for OS) or CTCs with a binary cut-off + R2-ISS (c-index 0.698 for PFS and 0.736 for OS) performed better than R2-ISS alone (likelihood ratio test of both models vs R2-ISS p<0.001).

Using a 0.02% cut-off, in R2-ISS I 77% vs 33% of pts have low vs high CTCs (median PFS 99 vs 72 months); in R2-ISS II 60% vs 40% of pts have low vs high CTCs (median PFS 83 vs 48 months); in R2-ISS III 41% vs 59% of pts have low vs high CTCs (median PFS 40 vs 31 months); in R2-ISS IV 22% vs 78% have low vs high CTCs (median PFS 29 vs 15 months) (p<0.001).

In the IMS-IMWG CGS cohort, 45% of pts were high-risk possibly due to greater availability of molecular data in pts with high tumor burden. The distribution of pts with ≤0.001%, ≤0.01%, ≤0.1%, ≤1% and >1% CTCs was 17%, 9%, 31%, 29% and 13%. After a median follow-up of 91 months, both CTC log10 increments (HR 1.31 p<0.001 for PFS; HR 1.24 p=0.036 for OS) and IMS-IMWG CGS high risk (HR 1.55 p=0.047 for PFS; HR 2.51 p=0.003 for OS) were independent predictors of outcome in a multivariable model including site, transplant eligibility and age.

A prognostic model including CTCs as log10 intervals + CGS (c-index 0.669 for PFS and 0.730 for OS) or CTCs with a binary cut-off + CGS (c-index 0.650 for PFS and 0.719 for OS) performed better than CGS alone (likelihood ratio test of both models vs CGS p<0.05)

Using a 0.02% cut-off, 29% of pts were classified as CGS standard risk + low CTCs, 25% as CGS standard risk + high CTCs, 7% as CGS high risk + low CTCs and 38% as CGS high risk + high CTCs. Median PFS was not reached in CGS standard risk + low CTCs, 72 months in CGS standard risk + high CTCs, 64 months in CGS high risk + low CTCs and 33 months in CGS high risk + high CTCs (p<0.001). Overall CGS standard risk + low CTCs delineates a favorable prognosis group, CGS high risk + high CTCs delineates a poor prognosis group, while all other combinations identify pts with an intermediate prognosis.

Conclusions. CTC levels have independent prognostic value in NDMM pts stratified with R2-ISS and IMS-IMWG CGS. These data support the investigation of CTCs in combination with current prognostic models and high-risk definitions.

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2025
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