Studies Reinforce Prognostic Role for Circulating Tumor Cells in Myeloma

Levels of circulating tumor cells (CTCs) in newly diagnosed multiple myeloma identified high-risk disease associated with shorter progression-free and overall survival (OS), prospective data involving 400 patients showed.

A CTC level exceeding 5 cells/µL (CTC-high) more than doubled the hazard for disease progression or death and the survival hazard. Patients with CTCs above the cutoff at diagnosis had a 4-year OS of 68% versus 92% for patients with lower CTC levels. Bone marrow plasma cells (BMPCs) did not have a significant association with outcome.

Treatment that achieved minimal residual disease (MRD)-negative status was the only factor that offset the negative impact of CTC-high, reported Francesca Gay, MD, PhD, of the University of Torino in Italy, and coauthors, in the Journal of Clinical Oncology (JCO).

A companion study, published simultaneously in JCO, confirmed that CTCs outperformed BMPCs for identifying high-risk myeloma but yielded a different CTC cutoff level for high risk.

"We believe that these data can open the way to the incorporation of CTC into a wider clinical use for the routine diagnosis of patients with MM [multiple myeloma]," the authors concluded. "Future analyses of larger cohorts (including transplant-ineligible patients, patients treated with anti-CD38 monoclonal antibodies, and real-life patients) will help overcome the differences between our study and its companion study, to identify a definitive cutoff. This will be the next step for the implementation of CTC in comprehensive staging systems and risk-adapted therapeutic approaches."

BMPCs are a marker of disease burden in monoclonal gammopathies and help discriminate among monoclonal gammopathy of undetermined significance, smoldering multiple myeloma, and symptomatic myeloma. The International Myeloma Working Group included BMPC ≥60% in criteria for starting myeloma treatment. However, BMPC has only a modest role in myeloma prognosis, probably because of patchy bone disease, Gay and coauthors noted.

CTCs detected in peripheral blood are a distinctive diagnostic feature of plasma cell leukemia (an aggressive plasma cell dyscrasia), defined by the proportion of plasma cells in white blood cells. Newer methods of detection and quantification have lowered potential cutoffs associated with progression-free survival (PFS) and OS, the authors continued.

Prior published data for the prognostic role of CTCs in myeloma are retrospective or observational, and no cutoff for use in clinical practice has been adopted. Gay and coauthors sought to identify an optimal CTC cutoff by means of multiparametric flow cytometry within the context of concomitant prognostic factors. They also wanted to apply the cutoff to patients to predict PFS in patients with newly diagnosed myeloma treated with novel agents.

Randomized Trial Data

Investigators prospectively assessed CTC at diagnosis of myeloma in the phase II multicenter, randomized FORTE trial, which included transplant-eligible patients younger than 65. Data on CTC analysis included 401 patients, 269 of whom had detectable levels. The median CTC percentage was 0.02%, which corresponded to a median absolute number of 1.24 cells/µL. Median follow-up for the study population was 50 months.

Increasing levels of CTCs as a continuous variable were associated with worse PFS, and including CTCs in different statistical models with traditional risk factors increased CTCs' prognostic impact on PFS, the authors stated. Investigators performed a proportional hazards analysis of PFS adjusted for established risk factors and identified a CTC cutoff of 0.07% (95% CI 0.02-0.33), corresponding to about 5 cells/µL.

Using the 0.07% cutoff, investigators identified 130 patients as CTC-high and 271 as CTC-low. About half of the CTC-low group had undetectable CTCs. Patients in the CTC-high group had lower rates of MRD negativity (42% vs 59%, P=0.001) and lower rates of complete response to induction therapy (43% vs 54%, P=0.055).

By multivariable analysis, the CTC-high group had significantly worse PFS (HR 2.61, 95% CI 1.49-2.97, P<0.001) and OS (HR 2.61, 95% CI 1.49-4.56, P<0.001). The CTC-high group had inferior 4-year PFS (38% vs 69%) and 4-year OS (68% vs 92%).

Only achievement of MRD status prior to maintenance therapy altered the negative impact of CTC-high status on PFS (P=0.039 for interaction). In the OS analysis, MRD-negative status lowered the adverse hazard ratio but the test for interaction did not achieve statistical significance.

"The incorporation of CTC detected at diagnosis by flow cytometry into the standard risk assessment improves the identification of high-risk patients to better define treatment intensity," the authors said of the findings.

Complementary Findings

The companion study included 374 patients from the GEM2012MENOS65 and GEM2014MAIN trials that evaluated different treatment strategies for transplant-eligible patients younger than 65 with newly diagnosed myeloma. CTCs were measured by flow cytometry at baseline and MRD assessment, reported Bruno Paiva, PhD, of the University Clinic of Navarra in Pamplona, Spain, and coauthors.

Consistent with the analysis of the FORTE study, increasing percentages of CTCs in peripheral blood correlated with poorer PFS. By multivariable analysis, Paiva and colleagues found that a lower cutoff value for CTCs (0.01%) was associated with a doubling of the hazard for disease progression or death (HR 2.02, 95% CI 1.3-3.1, P=0.001). Combining CTCs with the International Staging System, lactate dehydrogenase levels, and cytogenetics 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," Paiva and coauthors stated. "In all other cases with detectable CTCs, only achieving MRD negativity (and not complete remission) demonstrated a statistically significant increase in PFS."

"Our data support the inclusion of CTCs into the list of laboratory examinations in peripheral blood at diagnosis and urge considering its utility to enhance the current stratifying systems for patients with newly diagnosed transplant-eligible MM," they added.

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