A new technique developed by researchers at Dana-Farber Cancer Institute makes it possible to detect tumor cells in people at heightened risk for multiple myeloma, assess risk of progression in patients with myeloma, and track genetic changes in tumor cells over time – all from a small blood sample.
The approach, known as MinimuMM-seq, has the potential to replace a bone marrow biopsy as the standard method of screening people for conditions that often precede myeloma and of determining the extent of the disease, the researchers report in a study posted online today by the journal Cancer Discovery. Because it requires only a blood draw, MinimuMM-seq is less intrusive and painful for patients than a bone marrow biopsy, which involves inserting a needle into bone, withdrawing a small amount of marrow, and examining it for signs of cancer.
Multiple myeloma is a cancer that occurs when abnormal plasma cells – antibody-producing cells in the bone marrow – proliferate uncontrollably and cause organ damage. It's often preceded by conditions that have no symptoms but are marked by an abnormal protein in the blood known as an M protein. These conditions – monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) – are usually detected as a result of a routine blood test, but a formal diagnosis usually entails a bone marrow biopsy.
"Bone marrow biopsy is used to fully characterize myeloma precursor conditions and, for patients with overt myeloma, to measure tumor burden and genetics – how advanced the disease is," says the study's co-first author, Ankit Dutta, PhD, of Dana-Farber and the Broad Institute of MIT and Harvard. "Tumor cells from the marrow are analyzed by fluorescence in situ hybridization [or FISH, a technique for probing DNA] for the presence of certain genetic abnormalities.
"In this study, we asked whether MinimuMM-seq, which takes advantage of a variety of recent advances in cellular analysis, could be used to detect and genomically profile myeloma cells circulating in the blood for the same information."
In contrast to FISH, which looks for a pre-determined set of genetic abnormalities, MinimuMM-seq uses whole-genome sequencing to probe the entirety of myeloma cells' DNA and can therefore pick up abnormalities invisible to FISH.
To determine if MinimuMM-seq can accomplish in circulating tumor cells what FISH does in tumor cells from the bone marrow, investigators used it to analyze circulating myeloma cells from 51 patients, some of whom had myeloma and some of whom had a precursor condition. In 24 of the patients, investigators also extracted bone marrow samples and biopsied them.
"We found that MinimuMM-seq was able to detect the same genetic abnormalities in circulating tumor cells that existed in bone marrow biopsy samples, including hallmark features of myeloma," says co-first author Jean-Baptiste Alberge, PhD, of Dana-Farber and the Broad Institute.
In eight patients, the investigators took blood samples on two separate occasions and tested the circulating tumor cells using MinimuMM-seq. "The genetic changes that occurred from the first set of samples to the second enabled us to track the shifting dynamics of the disease – how some genetic subtypes of tumor cells become more prevalent while others become less over time. We could also track the emergence of subtypes associated with more high-risk forms of myeloma," Alberge says.
The findings suggest that MinimuMM-seq could be used to monitor the genetic course of the disease in patients and determine when changes in treatment are called for. "It can help us stratify patients by the risk level of their disease and get an early indication when the disease is taking a turn for the worse," Dutta says. "And because MinimuMM-seq requires only a simple blood draw, it can be done regularly in a more patient-friendly manner for close monitoring compared to a bone marrow biopsy."
"The study offers a proof of concept of the utility of MinimuMM-seq for screening, early diagnosis, monitoring, and managing multiple myeloma in patients," says the study's senior author, Irene Ghobrial, MD, of Dana-Farber.
The co-authors of the study are Annie N. Cowan, Erica M. Horowitz, Hadley Barr, Laura Hevenor, Jenna B. Beckwith, MPH, Jacqueline Perry, MPH, Amanda Cao, and Omar Nadeem, MD, of Dana-Farber; Elizabeth D. Lightbody, PhD, Cody J. Boehner, Romanos Sklavenitis-Pistofidis, MD, Tarek H. Mouhieddine, MD, and Nang Kham Su, MS, of Dana-Farber and the Broad Institute; Andrew Dunford, Ziao Lin, PhD, Chip Stewart, PhD, and Gad Getz, PhD, of the Broad Institute; Frank K. Kuhr, PhD, and Richard G. Del Mastro, PhD, of Menarini Silicon Biosystems, Huntingdon Valley, Penn.; Patricia T. Greipp, DO, of the Mayo Clinic Comprehensive Cancer Center; and Daniel Auclair, PhD, of the Multiple Myeloma Research Foundation.
Funding for the research was provided by: the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation; the National Institutes of Health (grants R01CA205954 and R35CA263817-01A1); the International Myeloma Society; a Dana-Farber Cancer Institute Medical Oncology Grant Award; and Stand Up To Cancer.