Precursor conditions are early phases of blood diseases that may develop into cancers such as lymphoma, leukemia, Waldenström’s macroglobulinemia, and multiple myeloma. Most people do not experience symptoms, and since doctors rarely screen for precursor conditions, they are often diagnosed after routine blood tests.
“Many diagnoses are purely incidental,” says Irene Ghobrial, MD, co-principal investigator at the Center for Prevention of Progression of Blood Cancers (CPOP) at Dana-Farber Cancer Institute and medical oncologist in the Jerome Lipper Multiple Myeloma Center at Dana-Farber/Brigham and Women’s Cancer Center. Patients with a precursor condition are often told to “watch and wait.” In other words, the condition is monitored and treatment only begins if it develops into cancer. Not every person diagnosed with a precursor condition will be diagnosed with a blood cancer, but many cases of blood cancer do develop from precursor conditions.
Precursor blood conditions include:
- Early myelodysplastic syndrome (MDS), a condition in which the bone marrow does not produce enough healthy blood cells. In advanced stages, MDS may progress to acute myeloid leukemia (AML).
- Monoclonal gammopathy of undetermined significance (MGUS), a condition in which there are abnormal plasma cells in the bone marrow. These cells produce monoclonal proteins, which routine blood and urine tests sometimes detect. In some cases, MGUS progresses into multiple myeloma. About 3 percent of adults over age 50 have MGUS, according to Ghobrial. Multiple myeloma is almost always preceded by MGUS, although not every case of MGUS will evolve into multiple myeloma, she explains.
- Smoldering multiple myeloma, a condition in which there are abnormal plasma cells in the bone marrow that produce monoclonal proteins or free light-chains, smaller units of the immunoglobulin produced by plasma cells.
- Smoldering Waldenström’s macroglobulinemia, a condition in which there are abnormal lymphocytes and plasma cells in the bone marrow that secrete monocolonal proteins of IgM type. This condition may progress to Waldenström’s macroglobulinemia.
Researchers at the CPOP seek to understand why some patients with precursor conditions develop cancer and others do not, with the goal of some day developing treatments that can delay or stop the progression of precursor conditions, and eventually eradicate them. The research is driven by the center’s PCROWD study, which collects, processes, and stores tissue samples from people with precursor conditions from across the United States.
2019 research update
The first clinical trials of treatments to prevent multiple myeloma from developing in people with a precursor condition of this malignancy are beginning to generate results — and optimism.
The first trial, led by Spanish researchers, examined whether a two-drug combination could delay or prevent the onset of myeloma in individuals with high-risk smoldering multiple myeloma (SMM), a precursor condition that has no symptoms but often progresses to myeloma. The investigators found that participants treated with lenalidomide and dexamethasone lived longer, on average — and had a longer time without their condition worsening — than those who were untreated. Over 75 months, 86% of the untreated participants developed multiple myeloma, compared to only 39% of those who were treated.
Although myeloma experts in the U.S. haven’t endorsed the results of the Spanish trial (mainly because the Spanish investigators used old imaging technology for tracking the development of myeloma within the bones), data from American trials — including two led by researchers in CPOP — are also raising hopes that myeloma can be intercepted and prevented.
In a phase II study, for example, Dana-Farber investigators found that after a median follow-up of three years of treatment with the drugs elotuzumab, lenalidomide, and dexamethasone, 95% of participants were alive with no advance of their high-risk SMM. Only three participants had developed symptomatic multiple myeloma later on.
Another phase III study led by the Eastern Cooperative Oncology Group (ECOG) treated SMM patients regardless of their risk stage with lenalidomide until progression to multiple myeloma vs. observation. The results were presented this year at the annual meeting of the American Society of Clinical Oncology (ASCO). The investigators reported that after a median follow-up of three years, patients in the treatment arm had a longer time to progression compared to the observation arm.
Interim results from another Dana-Farber-led phase II trial, in which 29 patients were treated with the drug ixazomib, lenalidomide, and dexamethasone, show that all participants who completed four cycles of therapy had a deep response based on their disease biomarkers. More than half had a complete or very good partial response to the treatment, meaning that a telltale sign of myeloma, known as M protein, was not detected in their blood or urine by a sensitive test known as serum protein electrophoresis.
“The field of precursor conditions of multiple myeloma and other blood cancers is evolving rapidly, and our goal is to prevent progression and end-organ damage from happening with the best and safest drug combinations,” Ghobrial says.
“A variety of studies are underway to find better methods and biomarkers to address the unmet need of identifying patients who are at a high risk of disease progression,” says Mark Bustoros, MD, of the CPOP and Ghobrial lab. “We are studying the molecular differences within the tumor cells of those patients to better tailor management and therapy for them.”