Circulating Multiple Myeloma Cells a Useful, Non-Invasive Prognostic Marker for Plasma Cell Disorders

In patients with plasma cell disorders, disease burden assessments and molecular subtyping are typically performed by invasive bone marrow sampling. According to a study presented at the AACR Annual Meeting, measuring levels of circulating multiple myeloma cells (CMMCs) can be a useful and non-invasive tool for monitoring and characterizing a range of plasma cell disorders.

“CMMCs have been detected in elevated numbers in the peripheral blood of patients with plasma cell disorders using flow cytometry or circulating cell enrichment platforms,” the authors, led by Brad Foulk, of Janssen Research & Development, wrote. To determine CMMCs’ ability to characterize disease, Mr. Foulk and colleagues developed “an automated [circulating tumor cell] assay to enrich, enumerate, and perform a triplex fluorescence in situ hybridization assay for t(4;14), t(14;16), and del17p on CMMC (CD138+, CD38+, CD45-CD19-) isolated from a 4 mL peripheral blood sample.”

The assay was tested in three patient cohorts:

  • Cohort 1: 698 patients with newly diagnosed multiple myeloma enrolled in the Multiple Myeloma Research Foundation’s CoMMpass study (a study that is mapping genomic profiles of patient tissue in an effort to understand response to MM treatments)
  • Cohort 2: 79 patients with intermediate/high-risk smoldering multiple myeloma (SMM) enrolled in a phase II study of siltuximab
  • Cohort 3: 35 patients across the plasma cell disease spectrum (with an emphasis on monoclonal gammopathy of undetermined significance [MGUS] and SMM)

In Cohort 1, one or more CMMC per 4 mL of blood were detected in 98 percent (n=684/698) of patients, with a median CMMC count of 413 per 4 mL of blood. When patients achieved remission, CMMC counts decreased significantly from baseline (p<0.001). Lower CMMC counts (<100/mL of blood) at remission were also associated with improved progression-free survival and overall survival, compared with patients who had CMMC counts >100/mL blood at remission.

CMMC FISH results, available in 57 patients, were highly correlated with bone marrow FISH results and bone marrow copy number variation/RNA sequencing for detecting t(4;14), t(14;16), and del17p: 85 percent, 91 percent, and 80 percent agreement for FISH, and 81 percent, 91 percent, and 95 percent agreement for CNV/RNA sequencing, respectively.

In Cohort 2, one or more CMMC per 4 mL of blood was detected at baseline in 94 percent of patients (n=74/49), with a median CMMC count of 100 per 4 mL of blood. Patients in the placebo arm of the study who had disease progression had significantly higher CMMC counts than those whose disease had not progressed (p=0.031). Results from the standard metrics of disease burden (bone marrow plasma cells and serum M protein levels), however, showed no statistically significant differences in CMMC counts between patients who progressed (p=0.068) and those who did not progress (p=0.070).

In Cohort 3, the researchers also found that CMMC counts were associated with the disease burden of patients (no additional data provided).

“In multiple myeloma, CMMC may be a useful prognostic marker at remission to delineate those patients whose disease is at risk for relapse,” the researchers concluded. “In SMM, CMMC may be useful for predicting patients at risk for progression to multiple myeloma.” Though potentially clinically significant, these findings need to be validated prospectively.


Foulk B, Schaffer M, Gross S, et al. Peripheral blood circulating multiple myeloma cells (CMMCs) correlate with disease burden and can be used to characterize high-risk cytogenetics in newly diagnosed and smoldering myeloma. Abstract 3163. Presented at the AACR Annual Meeting, April 19, 2016; New Orleans, LA.