Circulating Tumor Cells for the Staging of Patients With Newly Diagnosed Transplant-Eligible Multiple Myeloma

Abstract

PURPOSE Patients with multiple myeloma (MM) may show patchy bone marrow (BM) infiltration and extramedullary disease. Notwithstanding, quantification of plasma cells (PCs) continues to be performed in BM since the clinical translation of circulating tumor cells (CTCs) remains undefined.PATIENTS AND METHODS CTCs were measured in peripheral blood (PB) of 374 patients with newly diagnosed MM enrolled in the GEM2012MENOS65 and GEM2014MAIN trials. Treatment included bortezomib, lenalidomide, and dexamethasone induction followed by autologous transplant, consolidation, and maintenance. Next-generation flow cytometry was used to evaluate CTCs in PB at diagnosis and measurable residual disease (MRD) in BM throughout treatment.RESULTS CTCs were detected in 92% (344 of 374) of patients with newly diagnosed MM. The correlation between the percentages of CTCs and BM PCs was modest. Increasing logarithmic percentages of CTCs were associated with inferior progression-free survival (PFS). A cutoff of 0.01% CTCs showed an independent prognostic value (hazard ratio: 2.02; 95% CI, 1.3 to 3.1; P 5 .001) in multivariable PFS analysis including the International Staging System, lactate dehydrogenase levels, and cytogenetics. The combination of the four prognostic factors significantly improved risk stratification. Outcomes according to the percentage of CTCs and depth of response to treatment showed that patients with undetectable CTCs had exceptional PFS regardless of complete remission and MRD status. In all other cases with detectable CTCs, only achieving MRD negativity (and not complete remission) demonstrated a statistically significant increase in PFS.CONCLUSION Evaluation of CTCs in PB outperformed quantification of BM PCs. The detection of $ 0.01% CTCs could be a new risk factor in novel staging systems for patients with transplant-eligible MM.

High Levels of Circulating Tumor Plasma Cells as a Key Hallmark of Aggressive Disease in Transplant-Eligible Patients With Newly Diagnosed Multiple Myeloma

“…45 Recently, the International Myeloma Working Group updated and reduced from 20% to 5% the cutoff for the diagnosis of plasma cell leukemia. 46 Our study and its companion 26 showed that a lower threshold for the definition of high CTC levels by FC (0.01%-0.07%, ie, 100 times lower than 5%) was associated with a poor prognosis. Moreover, the two research groups reproduced each other's findings in the context of two important prospective trials including highly effective modern drug combinations (ie, proteasome inhibitors, immunomodulatory drugs, ASCT, and maintenance), and the slight difference between the two cutoffs was likely because of differences in patient treatment (carfilzomib-based v bortezomib-based), in the FC sensitivity, and, probably, in the number of patients with high CTC levels.…”

Circulating Tumour Cells, Cell Free DNA and Tumour-Educated Platelets as Reliable Prognostic and Management Biomarkers for the Liquid Biopsy in Multiple Myeloma

“…MM subjects with undetectable CTCs had extraordinary progression-free survival regardless of complete remission and MRD condition. In patients with detectable CTCs, only obtaining MRD negativity displayed a significant increase in progression-free survival [ 50 ].…”

Circulating Tumor Cell Burden as a Component of Staging in Multiple Myeloma: Ready for Prime Time?

“…12 Furthermore, the prognostic impact of CTCs was independent of fluorescent in situ hybridization cytogenetics, such that high-risk patients with low CTC burden had superior PFS compared with standard-risk patients with high CTC burden. 12,13…”

“…These findings also have important implications in the design of high-risk enrichment trials where a high CTC burden on NGF or PCL-like transcriptome can potentially be used as an inclusion criterion even in the absence of clinical PCL with > 5% CTCs on morphology. 22 However, before formal incorporation in staging and routine clinical practice, the ≥ 0.01% cutoff for CTC burden using NGF 12 needs to be validated in external data sets of transplant-eligible and transplant-ineligible patients receiving anti-CD38 monoclonal antibody–based frontline combination therapies.…”

“…11 Although these preliminary results were encouraging regarding the incorporation of CTC quantification as a prognostic marker and for minimally invasive tumor burden assessment, they were plagued with significant limitations such as heterogeneity in treatments, retrospective design, and low sensitivity of flow cytometry assays used to measure CTCs. There are three articles accompanying this editorial (Garc és et al, 12 Bertamini et al, 13 and Hofste op Bruinink et al 14 ) on the prognostic impact of CTC burden and transcriptomic profile in newly diagnosed myeloma in the context of several recent randomized controlled trials. The salient features of these three studies and CTC cutoffs are summarized in Table 1.…”