Circulating Tumor Cells Predict Outcomes in Multiple Myeloma Treated With Daratumumab-Based Quadruplet Therapy

Advances in frontline therapy for multiple myeloma (MM) have significantly improved patient outcomes, particularly with the integration of daratumumab-based quadruplet regimens such as daratumumab (Darzalex; Janssen Biotech, Inc), bortezomib (Velcade; Takeda Pharmaceuticals America, Inc), lenalidomide (Revlimid; Bristol Myers Squibb), and dexamethasone (D-VRd; Decadron; Pragma). However, identifying biomarkers that can reliably predict prognosis and guide risk-adapted treatment remains a critical challenge. New findings published in Blood suggest that circulating tumor cells (CTCs) may serve as a powerful prognostic biomarker even in the era of modern quadruplet therapy.¹

The study evaluated the prognostic impact of CTCs in transplant-eligible patients with newly diagnosed MM treated in the phase 3 PERSEUS trial (NCT03710603). Investigators analyzed baseline blood samples from a subset of patients receiving either D-VRd followed by daratumumab-lenalidomide maintenance or the standard triplet regimen of VRd followed by lenalidomide maintenance.¹ Their findings demonstrate that the presence and quantity of CTCs at diagnosis are strongly associated with disease outcomes, highlighting the potential role of minimally invasive blood-based biomarkers in clinical risk assessment.

Understanding the Role of Circulating Tumor Cells

CTCs represent malignant plasma cells that have migrated from the bone marrow into the bloodstream. Although MM is traditionally considered a bone marrow–confined malignancy, the detection of CTCs reflects disease dissemination and may indicate more aggressive tumor biology.¹

Prior research data have demonstrated that elevated levels of circulating plasma cells are associated with poorer prognosis and may reflect disease characteristics similar to plasma cell leukemia when present at high levels.² In addition to representing tumor burden, CTCs may also reflect biologic features associated with increased proliferation and genomic instability.³ As a result, researchers have increasingly explored their potential as a minimally invasive biomarker for risk stratification and disease monitoring.

Findings From the PERSEUS Trial Analysis

In the PERSEUS analysis, investigators assessed CTC levels using highly sensitive flow cytometry in baseline blood samples from patients with newly diagnosed transplant-eligible MM. Among the analyzed cohort, CTCs were detected in the majority of patients, emphasizing their frequent presence even in early stages of treatment.¹

The results demonstrated that higher CTC levels at diagnosis were associated with inferior clinical outcomes, including shorter progression-free survival compared with patients who had lower or undetectable CTC levels.¹ These findings reinforce the concept that CTCs serve as an independent prognostic factor in MM.

Importantly, the study also evaluated outcomes among patients treated with the daratumumab-containing quadruplet regimen. Although D-VRd significantly improved overall outcomes, patients with elevated CTC levels still had poorer prognoses than those with lower levels, suggesting that the biomarker retains predictive value even with highly effective modern therapies.¹

Clinical Implications for Risk-Adapted Treatment

The integration of CTC analysis into clinical practice could provide several important advantages for clinicians managing MM. First, peripheral blood testing offers a minimally invasive alternative to repeated bone marrow biopsies for assessing disease biology. Because CTC detection relies on blood samples, it may enable more frequent monitoring of disease dynamics throughout treatment.³

CTC quantification may help identify patients with high-risk disease who could benefit from intensified therapy or closer monitoring. For example, patients with elevated CTC levels at diagnosis may require more aggressive treatment approaches or earlier consideration of novel therapeutic strategies.¹

Future Directions in Myeloma Biomarker Research

Although the findings from the PERSEUS trial analysis support the prognostic relevance of CTCs, further research is needed to standardize measurement techniques and establish clinically meaningful thresholds. Larger studies across diverse treatment settings will be essential to determine the optimal approach to incorporating CTC monitoring into routine practice.

The growing body of evidence underscores the potential of circulating tumor cells as a key biomarker in MM. As researchers continue to refine blood-based diagnostics, CTC analysis may become an important tool for improving prognostic assessment and guiding personalized treatment decisions for patients with this complex hematologic malignancy.

REFERENCES

1. Bertamini L, Fokkema C, Rodriguez-Otero P, et al. Circulating tumor cells predict myeloma outcomes in patients treated with daratumumab, bortezomib, lenalidomide, and dexamethasone. Blood. 2026;147(4):431-442. doi:10.1182/blood.2025030113

2. Liang D, Yan Y, Bai S, et al. Clinical outcome of ≥2% circulating tumor cells in newly diagnosed multiple myeloma: insights from a multicenter study. Ann Med. 2025;57(1):2496796. doi:10.1080/07853890.2025.2496796

3. Garces JJ, Diamond B, Sevcikova T, et al. Elevated circulating tumor cells reflect high proliferation and genomic complexity in multiple myeloma. Hemasphere. 2025;9(9):e70218. doi:10.1002/hem3.70218