A rapid, low-cost assay measuring DNA and immunoglobulin in multiple myeloma cells is both a powerful predictor of prognosis and a tool for identifying new, previously unidentified therapeutic targets, its developers say.
The test, labeled DNA/CIG, uses two-color flow cytometry to evaluate DNA in the nucleus and immunoglobulin in the cytoplasm of bone marrow taken from patients with multiple myeloma (MM) at baseline, before the start of the aggressive “Total Therapy 3b” (TT3b) protocol developed at the Myeloma Institute for Research and Therapy at the University of Arkansas for Medical Sciences in Little Rock.
The light chain cytoplasmic immunoglobulin (CIg) index generated by the test, combined with an associated 12-gene panel, serves as an independent prognostic factor in patients with myeloma. The CIg index is a marker for immunoglobulin production in myeloma cells, with lower index scores suggesting ineffective immunologic responses.
“We show that the presence of low CIg as detected by DNA/CIG is a major adverse prognostic factor in TT3b, even when other GEP [gene expression profiling]–derived prognostic factors were accounted for,” Dr. Xenon Papanikolaou of the University of Arkansas and colleagues wrote in the journal Leukemia (2015;29:1713-20).
The investigators performed DNA/CIG as part of the routine work-up of patients with newly diagnosed MM who were scheduled to undergo the current iteration of the Total Therapy protocol, consisting of two induction chemotherapy cycles of VTD-PACE (bortezomib, thalidomide, dexamethasone and 4-day continuous infusions of cisplatin, doxorubicin, cyclophosphamide and etoposide), two planned hematopoietic stem cell transplants, and 3 years of planned maintenance with bortezomib, lenalidomide and dexamethasone.
The authors looked at the association of the CIg index, gene-expression profiling, and standard prognostic measures with both overall and progression-free survival (OS and PFS).
They found that both the percentage of light chain–restricted cells and the CIg as determined by DNA/CIG were associated with poor clinical outcomes. Additionally, a CIg lower than 2.8, albumin lower than 3.5 g/dL, and age 65 and older were significantly associated with worse PFS and OS, independent of gene-expression profiling data.
Any CIg lower than 2.8 was associated with a twofold risk for worse OS (hazard ratio, 2.08; P = .012) and a nearly doubling of risk for worse PFS (HR, 1.84; P = .001).
In multivariate models, CIg remained an independent predictor for prognosis when GEP-defined high-risk and low albumin were added in. CIg was also linked to other prognostic factors, including beta2-microglobulin greater than 5.5 mg/L, percentage of LCR cells exceeding 50%, C-reactive protein equal to or greater than 8 mg/L, and GEP-derived high centrosome index.
Low CIg was also associated with an experimental group of 12 gene probes believed to be involved in cell cycle regulation, cell differentiation, and cellular drug transport. The investigators used the gene signatures to develop a risk score, called GEP12, that offered important prognostic information for patients in TT3b and in earlier clinical studies.
The finding that a low CIg index was linked to a high centrosome index as defined by GEP points to a possible role for CIg index as a treatment selection tool.
“Interestingly, a centrosome inhibitor has shown promising activity in preclinical models of MM, thus potentially providing a selective drug for patients with low CIg myeloma,” the authors write.
The study was supported in part by a grant from the National Cancer Institute. Senior author Dr. Bart Barlogies reports research funding from Celgene Corp and Millennium Pharmaceuticals, and consulting with those companies as well as Onyx Pharmaceuticals and Amgen. He is a coinventor on patents and patent applications related to use of gene expression profiling in cancer medicine that have been licensed to Myeloma Health, but has no financial interests in this company. The remaining authors reported having no conflicts of interest.