Increasing Circulating Tumor Cell Levels May be an Independent High-Risk Factor in Newly Diagnosed Multiple Myeloma


Minimal residual disease negativity might be an important prognostic indicator in patients with newly diagnosed multiple myeloma, investigators say.

Increasing circulating tumor cells (CTC) above the optimal cutoff proved to be a high-risk factor for patients with newly diagnosed multiple myeloma, according to results from a CTC analysis from the phase 2 FORTE trial (NCT02203643) published in the Journal of Clinical Oncology.

The optimal CTC cutoff was 0.07% (5 cells/µL; 95% CI, 0.02%-0.33%). The multivariate analysis assessed CTC-high and -low patients. Investigators found those who were CTC-high had shorter 4-year progression-free survival rate of (PFS) 38% (95% CI, 31%-48%) vs the CTC-low patients at 69% (95% CI, 64%-75%; hazard ratio [HR], 2.66; 95% CI, 1.95-3.61; P <.001). The 4-year overall survival (OS) rates between those in the CTC-high and CTC-low groups were 68% (95% CI, 60%-77%) vs 92%, respectively, (95% CI, 88%-95%; HR, 4.43; 95% CI, 2.67-7.35; P <.001).

A total of 401 patients were included in the analysis with a median follow-up of 50 months. Second generation multiparameter flow cytometry was used to assess minimal residual disease in the population; CTCs were identified in 67% of patients at diagnosis. The median CTC percentage was 0.02% with a median absolute number of 1.24 cells/µL.

A total of 130 patients were classified as CRC high and 271 were CTC low. About half of the patients in the CTC-low population had undetectable CTC with a sensitivity of 4 x 10-5. Although more adverse prognostic factors were identified in the CTC-high population, 27% of patients were considered to be standard risk

Lower rates of minimal residual disease (MRD) negativity were observed in the CTC-high population during premaintenance (42%) compared with the CTC-low group (59%; P = .001), as well as lower rates of a complete response in (43% vs 54%; P = .55).

The cutoff value’s performance selected for a companion study of FORTE was confirmed in the dataset, with an HR of 1.76 for PFS (95% CI, 1.26-2.47; P <.001) and 2.3 for OS (95% CI, 1.29-4.09; P <.005).

The multivariate analysis demonstrated that high CTC was significantly associated with shorter PFS (HR; 2.11; 95% CI, 1.49-2.97; P <.001) along with high lactate dehydrogenase (LDH; HR; 2.22, 95% CI, 1.48-3.33; P <.001) and amp(1q; HR, 2.03, 95% CI, 1.42-2.91; P <.001). Lower OS was associated with high CTC status (HR, 2.61, 95% CI, 1.49-4.56; P <.001), high LDH (HR, 4.77, 95% CI, 2.77-8.19; P <.001), amp(1q; HR, 1.94; 95% CI, 1.06-3.54, P = .030), and high-risk CA (HR, 2.53, 95% CI, 1.43-4.48; P = .001). Achieving MRD negativity prior to maintenance resulted in a reduction in risk of disease progression and death.

Investigators determined the only prognostic factor that affected CTC level was MRD negativity (PFS; interaction P = .039). A better HR for OS in patients with MRD negativity (HR, 1.63; 95% CI, 0.63-4.19) vs positivity (HR, 2.89; 95% CI, 1.50-5.57); the difference, however, was not significant (P = .311).

At 12 months, the evaluation of baseline CTC and premaintenance MRD status showed patients who were CTC-low and MRD negative had the best prognosis, with a 4-year PFS rate of 78% (95% CI, 71%-85%) and a 4-year OS rate of 96% (95% CI, 93%-99%). Those who were CTC-high with MRD positive disease had a 4-year PFS rate of 37% (95% CI, 25%-54%) and a 4-year OS rate of 66% (95% CI, 55%-79%). Those with CTC-high, MRD negative disease had a 4-year PFS rate of 62% (95% CI, 50%-77%) and a 4-year OS rate of 88% (95% CI, 79%-98%). Those with CTC-low, MRD positive disease had a 4-year PFS rate of 67% (95% CI, 58%-79%) and a 4-year OS rate of 89% (95% CI, 83%-96%).


Bertamini L, Oliva S, Rota-Scalabrini D, et al. High levels of circulating tumor plasma cells as a key hallmark of aggressive disease in transplant-eligible patients with newly diagnosed multiple myeloma. J Clin Oncol. 2022;40(27):3120-3131. doi:10.1200/JCO.21.01393

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