Smoldering multiple myeloma (SMM) is a condition representing an intermediate stage in the development of a blood cancer called multiple myeloma. It is considered an asymptomatic, precancerous state where abnormal changes in the bone marrow are present, but the body has not yet developed the severe symptoms associated with active cancer. A diagnosis of SMM requires specific laboratory findings, including a high burden of abnormal plasma cells and monoclonal protein, without any evidence of organ damage. The distinction between SMM and active multiple myeloma is paramount because it dictates the management strategy, which typically involves close monitoring rather than immediate treatment.
Understanding the Precursor State
Smoldering multiple myeloma is a disorder of plasma cells, which are a type of white blood cell responsible for producing antibodies. In SMM, a clone of abnormal plasma cells begins to proliferate excessively within the bone marrow. This uncontrolled growth leads to a higher concentration of these abnormal cells. The abnormal plasma cells produce a single, non-functional antibody, known as a monoclonal protein (M-protein), which is detectable in the blood or urine. Since SMM is asymptomatic, it is often discovered incidentally through routine blood work. This precursor state falls between Monoclonal Gammopathy of Undetermined Significance (MGUS) and active multiple myeloma.
Defining the Diagnostic Markers
The diagnosis of smoldering multiple myeloma relies on meeting specific quantitative thresholds. One of the primary markers is the concentration of monoclonal protein (M-protein) in the blood serum. For an SMM diagnosis, the serum M-protein level must be 3 grams per deciliter (g/dL) or greater, or the monoclonal protein in a 24-hour urine collection must be 500 milligrams or more. A bone marrow biopsy is also performed to assess the percentage of clonal plasma cells within the marrow. A diagnosis of SMM requires that these clonal plasma cells make up 10% or more of the cells in the bone marrow. This percentage must not exceed 60%, because a bone marrow plasma cell percentage of 60% or greater is considered a Myeloma-Defining Event (MDE), classifying the condition as active multiple myeloma. A patient must meet one or both criteria without any symptoms or signs of organ damage.
The Critical Difference from Active Multiple Myeloma
The fundamental distinction between smoldering multiple myeloma and active multiple myeloma is the presence or absence of end-organ damage or Myeloma-Defining Events (MDEs). Active multiple myeloma is defined by the presence of both clonal plasma cells and at least one MDE. These MDEs were historically summarized by the “CRAB” criteria: Calcium elevation, Renal impairment, Anemia, and Bone lesions. A person with SMM has high levels of M-protein and clonal plasma cells but lacks any of these clinical complications. Current diagnostic guidelines have expanded MDEs beyond the traditional CRAB criteria, incorporating certain biomarkers of malignancy. These newer criteria, sometimes known as SLiM features, include having a clonal plasma cell percentage of 60% or more, a specific ratio of involved to uninvolved serum free light chains that is 100 or greater, or more than one focal bone lesion detected by magnetic resonance imaging (MRI). If a patient meets the laboratory criteria for SMM but also presents with any of these MDEs, the diagnosis immediately changes to active multiple myeloma, requiring treatment.
Risk Stratification and Monitoring Protocols
The management approach for smoldering multiple myeloma is primarily one of “watchful waiting,” meaning patients are closely monitored without immediate treatment. This strategy is based on the fact that SMM is a highly heterogeneous condition, and the overall risk of progression to active multiple myeloma varies significantly among patients. The progression risk is highest in the first few years after diagnosis, averaging about 10% per year for the first five years, before dropping to a much lower rate. To guide the intensity of monitoring, doctors stratify SMM patients into low, intermediate, or high-risk categories based on the likelihood of progression. Risk models often use a combination of factors, such as the percentage of bone marrow plasma cells, the serum M-protein concentration, and the ratio of free light chains in the blood. Patients in the low-risk group may be monitored every six to twelve months, while those in the high-risk group require more frequent testing, often every three to four months. Monitoring typically involves regular blood tests and imaging studies, such as skeletal surveys or whole-body low-dose computed tomography (CT) scans, to check for the development of bone lesions. Treatment with anti-myeloma drugs is generally reserved for patients who progress to active multiple myeloma. However, some high-risk SMM patients may be offered treatment through clinical trials aimed at delaying or preventing progression.