Reference: Update February 2026 | Issue 2 | Vol 12 | Page 34
The absence of circulating tumour cells (CTCs) defines a subtype of multiple myeloma (MM) with unique clinical and biological features, according to research presented at (ASH) Annual Meeting and Exposition the 67th American Society of Hematology.
The study investigated disease characteristics and clinical outcomes associated with undetectable CTCs in 1,093 transplant-eligible and ineligible newly diagnosed MM (NDMM) patients enrolled in the GEM2012MENOS65, GEM-Claridex, and GEM2017FIT clinical trials. Validation was performed in a European pooled analysis of 1,601 NDMM patients.
The research team also investigated the prognostic value of undetectable CTCs after two cycles of induction in 251 participants of the GEM2017FIT trial, and after prior salvage therapy in 242 relapsed MM (RRMM) patients enrolled in the GEM KyCyDex and SeliBorDara trials.
Risk of transformation in the absence of CTCs was investigated in 1,487 monoclonal gammopathy of undetermined significance (MGUS) and 324 smouldering MM (SMM) patients. Molecular alterations associated with CTC egress were evaluated by exome and RNA sequencing.
Among NDMM patients, 10 per cent showed undetectable CTCs before treatment. Compared to those with detectable CTCs, these patients had significantly less anaemia and tumour burden.
Only one had R-ISS 3. MGUS-like profiles were more frequent. In contrast, the incidence of plasmacytomas was higher (33% vs 15%; p<.001). Altogether, patients with undetectable CTCs showed clinical features linked to macrofocal disease.
When compared to NDMM patients with detectable CTCs, those with undetectable CTCs showed significantly higher five-year progression-free survival (PFS; 80% vs 50%) and overall survival (OS; 92% vs 72%).
Patients with undetectable CTCs achieving minimal residual disease (MRD)-negative complete response (CR) displayed exceptional five-year PFS (92%) and OS (98%).
In the European pooled analysis, undetectable CTC status was confirmed as an independent prognostic factor for PFS (HR 0.5; p<.001) and OS (HR 0.4; p<.001).
Absence of CTCs was also associated with longer PFS after two cycles of induction in transplant-ineligible NDMM (HR 0.47; p=.003) and before a new line of therapy in RRMM (HR 0.5; p=.01).
Although the absence of CTCs was associated with lower risk of progression in MGUS (HR 0.1; p<.001) and SMM (HR 0.4; p<.001), just 1 per cent of MGUS and 10 per cent of SMM patients with sustained undetectable CTCs progressed to active MM.
The study also investigated the biology of bone marrow tumour cells in this subgroup and found that, while the median number of coding mutations was similar, copy number alterations were less frequent in patients with undetectable compared to patients with detectable CTCs. The former displayed a lower frequency of del(17p) and 1q21 gain.
The results suggest there is a subgroup of NDMM patients who have undetectable CTCs throughout the disease course. This group of patients tends to have less aggressive tumours, macrofocal disease, and favourable clinical outcomes by the time they progress to active MM.
These patients display less genetic alterations and lower expression of genes linked to CTC egress. which results in less aggressive and macrofocal disease. This new myeloma subtype accounts for 10 per cent of NDMM patients, and is associated with unprecedented survival.
