What Are Precursor Blood Conditions and How Are They Treated?

Precursor conditions are early phases of diseases that may develop into cancers such as lymphoma, leukemia, Waldenström’s macroglobulinemia, and multiple myeloma. Most people with precursor conditions do not experience symptoms, and since doctors rarely screen for these conditions, they are sometimes found through routine blood tests but often remain undiagnosed. 

“Many diagnoses are purely incidental,” says Irene Ghobrial, MD, director of the Center for Early Detection and Interception of Blood Cancers and senior vice president of experimental therapeutics at Dana-Farber and a medical oncologist in the Jerome Lipper Multiple Myeloma Center at Dana-Farber Brigham 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) is 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) is 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% 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. 
• Immunoglobulin M Monoclonal Gammopathy of Undetermined Significance (IgM MGUS) is a sub-type of MGUS that can develop into Waldenström macroglobulinemia or other slow-growing B-cell cancers. Most people with IgM MGUS do not experience symptoms, but the IgM protein itself may cause other health problems. 
• Smoldering multiple myeloma (SMM), 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. 
• Clonal hematopoiesis of indeterminate potential (CHIP) is an age-related condition in which a subpopulation of blood cells harbor a distinct genetic mutation. Like other precursor syndromes, CHIP doesn’t produce any symptoms, but people with the condition have increased risk for leukemia and heart disease. 
• Clonal cytopenia of undetermined significance, (CCUS) is marked by a low blood count and a set of blood cells carrying a genetic mutation. It can place individuals at risk for myelodysplastic syndrome or acute myeloid leukemia. 
• Smoldering Waldenström macroglobulinemia (SWM) is a condition in which there are abnormal lymphocytes and plasma cells in the bone marrow that secrete monoclonal proteins of IgM type. This condition may progress to Waldenström macroglobulinemia. 
• Monoclonal B cell lymphocytosis (MBL) is a condition marked by small populations of B cells in the blood sharing genetic abnormalities. It is linked to the development of chronic lymphocytic leukemia (CLL). 
• Lymphoid clonal hematopoiesis (Lymphoid-CH) is an age-related condition marked by the emergence of a set of blood-forming stem cells carrying specific genetic mutations.  It’s associated with an increased risk of myeloid malignancies such as MDS and AML. 
• Low-grade lymphomas, including marginal zone lymphoma (MZL) and follicular lymphoma, can progress into faster growing lymphomas. Marginal zone lymphoma is a group of slow-growing B-cell non-Hodgkin lymphomas. All types of MZL start in lymphoid tissues, including the skin, lymph nodes, or spleen. Follicular lymphoma is the most common type of slow-growing B-cell non-Hodgkin lymphoma. In some cases, follicular lymphoma can transform into a fast-growing lymphoma, usually one called diffuse large B-cell lymphoma (DLBCL). 

Research update 

Researchers at Dana-Farber’s Center for Early Detection and Interception of Blood Cancers are working to understand why some patients with precursor conditions develop cancer and others do not. The goal is to develop treatments that can delay or prevent the progression of precursor conditions, and ultimately eradicate them.  

Clinical trials currently underway at the Center include:  

• PROMISE, which is working to identify new ways to prevent multiple myeloma in people with precursor conditions such as MGUS and SMM. Open to people age 30 and over who are African American or have a close family member with blood cancer, it seeks to establish a screening method for high-risk individuals and is gathering data to help understand why some patients progress to myeloma and others do not. The Reform trial, for patients with high-risk MGUS or low-risk SMM, is evaluating the whether the drug metformin can stabilize markers of disease and help reduce risk of progression to multiple myeloma. 
• PCROWD is an ongoing research study that collects tissue samples from patients with precursor hematologic conditions. The goal is to understand the cellular changes that occur as the disease advances in order to develop targeted therapies to prevent progression to cancer. 
• Immuno-PRISM is evaluating the effectiveness of various immunotherapies in preventing high-risk SMM from advancing to multiple myeloma. Currently, the drug teclistamab, a bispecific antibody targeting the protein BCMA is being compared to the standard therapy of lenalidomide and dexamethasone. 
• The B-PRISM study is assessing the effectiveness of a combination of the drugs daratumumab, bortezomib, lenalidomide, and dexamethasone in patients with high-risk SMM. 
• CAR-PRISM is the first study of the CAR T-cell therapy ciltacabtagene autoleucel (cilta-cel) in patients with high-risk SMM. It focuses on the benefit and safety of administering CAR T-cell therapy at an early stage of the disease to prevent development of multiple myeloma. 
• PROFAST is a four-month randomized trial of prolonged nightly fasting in 40 overweight and obese individuals with MGUS, SMM, or SWM. The aim is to understand if fasting for a prolonged period during the nighttime hours can improve metabolic health and prevent overweight and obese individuals from developing blood cancer.