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

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%).

Reference

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