In a study reported in the Journal of Clinical Oncology, Bertamini et al found that higher levels of circulating tumor cells (CTCs) at diagnosis were associated with poorer progression-free and overall survival in transplant-eligible patients with newly diagnosed multiple myeloma. The prognostic association was attenuated by the achievement of measurable residual disease (MRD)-negative status.
Study Details
The study involved CTC analysis by flow cytometry with sensitivity of 4 × 10–5 in 401 patients in the randomized FORTE trial. MRD was assessed by flow cytometry with a sensitivity of 10–5. Potential cutoff values for CTCs were evaluated in a series of multivariate analyses of progression-free survival to identify a value with the best C-statistic.
In multiple myeloma, increasing levels of CTCs above an optimal cutoff represent an easy-to-assess, robust, and independent high-risk factor. The achievement of MRD negativity is the most important factor that modulates their negative prognostic impact.— Bertamini et al
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Key Findings
Median follow-up was 50 months (interquartile range = 45–54 months). The optimal CTC cutoff was identified as 0.07% (approximately 5 cells/mL, C-index = 0.64). Patients with levels > 0.07% constituted the CTC-high group (n = 130), and those with levels ≤ 0.07%, the CTC-low group (n = 271; 132 with undetectable CTCs).
In multivariate analysis including baseline features and treatment, CTC-high patients had significantly poorer progression-free survival (hazard ratio [HR] = 2.61, 95% confidence interval [CI] = 1.49–2.97, P < .001; 4-year rates of 38% vs 69%) and overall survival (HR = 2.61, 95% CI = 1.49–4.56, P < .001; 4-year rates of 68% vs 92%) vs CTC-low patients.
A modest correlation was found between percentages of CTCs and bone marrow plasma cells (ρ = 0.38). In multivariate analysis including CTCs and bone marrow plasma cells as continuous variables, only CTCs were predictive of progression-free survival and overall survival.
Achievement of MRD-negative status (59% of CTC-low and 42% of CTC-high patients) attenuated the effect of high CTCs. For progression-free survival, hazard ratios for CTC-high vs CTC-low were 2.54 (95% CI = 1.69–3.83) among MRD-positive patients and 1.26 (95% CI = 0.72–2.22) among MRD-negative patients (P = .039 for interaction). For overall survival, hazard ratios were 2.89 (95% CI = 1.50–5.57) among MRD-positive patients and 1.63 (95% CI = 0.63–4.19) among MRD-negative patients, although the interaction was not significant (P = .3112).
The investigators concluded, “In multiple myeloma, increasing levels of CTCs above an optimal cutoff represent an easy-to-assess, robust, and independent high-risk factor. The achievement of MRD negativity is the most important factor that modulates their negative prognostic impact.”
Francesca Gay, MD, PhD, of SSD Clinical Trial in Oncoematologia e Mieloma Multiplo, Division of Hematology, University of Torino, is the corresponding author for the Journal of Clinical Oncology article.
Disclosure: The FORTE trial was funded by an unrestricted grant from Amgen and Celgene/Bristol Myers Squibb. For full disclosures of the study authors, visit ascopubs.org.
