Years Before Myeloma, Blood Shows Changes
The vast majority of patients with multiple myeloma develop signature changes in their blood that can be identified years before the cancer is diagnosed, according to a new study. The changes associated with this precursor stage, called monoclonal gammopathy of undetermined significance (MGUS), are detectable up to a decade before symptoms of the cancer appear.
The study, reported online January 29 in Blood, is not likely to affect patients immediately, because only a tiny fraction of people with MGUS develop multiple myeloma. But the findings could help researchers understand the natural history of the disease and eventually discover markers for predicting which people with MGUS will progress to cancer.
“We now have a window of time for studying how multiple myeloma begins and progresses,” said lead investigator Dr. Ola Landgren of NCI. “From a research perspective, that’s a big step forward.”
Multiple myeloma is a cancer that affects plasma cells, which are a type of white blood cell. It has been known for decades that some individuals diagnosed with MGUS go on to develop multiple myeloma.
The field has been divided, however, about whether multiple myeloma is always preceded by MGUS. Until now, there has been no good way to explore the question. After all, most myeloma patients do not have prediagnostic blood samples available for analysis, as there would have been no reason to collect them.
Dr. Landgren and his colleagues in NCI’s Division of Cancer Epidemiology and Genetics (DCEG) found such samples in the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. Since 1992, this NCI-sponsored study has collected serial blood samples from more than 77,000 people, making it an invaluable resource for investigating early markers of cancer.
Among this group, the researchers identified 71 people who developed multiple myeloma during the trial. When the team examined prediagnostic blood samples—in essence, looking back in time—almost every patient showed evidence of MGUS, in some cases as early as 10 years before the diagnosis of multiple myeloma.
“This shows once and for all that there is a premalignant stage that preceded virtually every multiple myeloma,” said senior author Dr. S. Vincent Rajkumar of the Mayo Clinic in Rochester, MN. Comparing MGUS to polyps that may precede colon cancer, he said the “study gives us the impetus to find ways to identify the precursor stage and use the information eventually to help patients.”
Dr. John Shaughnessy, who studies multiple myeloma at the University of Arkansas for Medical Sciences and was not involved in the research, called the findings “very provocative.” He praised the study for its scope and size and said that it may encourage the medical community to further scrutinize these precursor states.
“The ultimate question is whether the findings will eventually lead to more preemptive types of therapies,” Dr. Shaughnessy added.
Tracking an Entity
In theory, one could essentially wipe out multiple myeloma by “treating” MGUS, but no one has figured out how to do this, said study coauthor Dr. Robert A. Kyle of the Mayo Clinic. There currently are no drugs available, and considering how few people with MGUS progress to multiple myeloma, screening for the condition would lead to unnecessary costs and anxiety for many people who would never develop the disease.
Dr. Kyle first described “an entity” called MGUS about 30 years ago. The condition, which is usually discovered incidentally, affects 3 percent of Americans over age 50. About 1 percent of these individuals progress to multiple myeloma each year. Several reports, including a DCEG study in Ghana, show that people of African descent have higher rates of MGUS than Caucasians.
“I’ve felt that MGUS is a precursor lesion of multiple myeloma, and that all patients with the disease have a preceding MGUS or smoldering myeloma,” said Dr. Kyle, referring to another precursor condition that typically involves no symptoms. “The new findings confirm our suspicions.”
He added: “There has been a remarkable increase in knowledge in a relatively short period of time.”
Another new study, published online last week in Blood, confirms the findings. The retrospective analysis of prediagnostic blood samples from a military population found that at least 27 of 30 multiple myeloma cases identified were preceded by MGUS. As in the PLCO Cancer Screening Trial, the researchers tested stored prediagnostic blood samples that, in this case, had been collected about every 2 years.
“We came up with a very similar answer [as the PLCO study], which gives us reassurance that the findings are valid,” said Dr. Michael Kuehl of NCI’s Center for Cancer Research (CCR), who co-led the study with Dr. Brendan Weiss of the Walter Reed Army Medical Center.
These rare prediagnostic samples, such as those from the military or PLCO study, are the only way to study the frequency of MGUS in multiple myeloma, Dr. Kuehl stressed. “You can take patients who have MGUS and follow them prospectively, but you can’t identify the patients who have ‘de novo’ multiple myeloma, if these people exist,” he said.
The samples at hand will be used to look for markers to predict who will progress to cancer. In addition, Dr. Landgren, who recently joined CCR, Dr. Kuehl, and others are developing a longitudinal study for people with MGUS and smoldering myeloma. The goal is to discover markers of progression and, ultimately, strategies for early intervention.
Similar Story in Leukemia
In the February 12 New England Journal of Medicine, Dr. Landgren and his colleagues describe using PLCO samples to explore a precursor state associated with chronic lymphocytic leukemia (CLL). Although this is the most common leukemia among adults in Western countries, the causes and natural history of the disease are largely a mystery.
The researchers identified 45 patients with CLL in the PLCO trial, and all but one had a preexisting condition called monoclonal B-cell lymphocytosis (MBL). Evidence of MBL, which has been reported in family members of CLL patients and others, was present up to 6.4 years prior to a diagnosis of CLL.
“The startling result was that the changes were present in virtually all the CLL cases in the study with prediagnostic blood samples,” said senior author Dr. Neil Caporaso of DCEG. “In a disease with so many unknowns, our findings will have a dramatic effect on the research agenda by giving investigators new leads,” he predicted.
MBL may be present in about 5 percent of Caucasians over age 50. Of this group, 1 percent will progress to CLL that requires therapy. Many researchers have wanted to assess the frequency of MBL prior to a diagnosis of CLL, and a recent technical advance, along with the PLCO samples, finally made the study feasible.
“The PLCO study is an incredible resource,” said Dr. Caporaso. “This blood is a window on the past.”
—Edward R. Winstead