Smoldering multiple myeloma (SMM) is an asymptomatic, precancerous condition characterized by abnormal plasma cells in the bone marrow and the presence of monoclonal protein in the blood or urine. It is considered an intermediate stage between a more benign condition called monoclonal gammopathy of undetermined significance (MGUS) and active multiple myeloma, a cancer of plasma cells. SMM itself is not a uniform diagnosis; it exists on a spectrum from low to high risk of progression.
Defining High Risk Smoldering Myeloma
The distinction between low- and high-risk smoldering myeloma is determined by specific clinical markers that predict the likelihood of progression to active disease. A widely used system for this is the “2/20/20” risk stratification model, which identifies patients with a higher chance of their condition worsening. Meeting at least two of the three criteria in this model classifies the SMM as high-risk.
One of the core components of this model is the percentage of plasma cells in the bone marrow. Plasma cells are a type of white blood cell that produces antibodies; in myeloma, these cells become abnormal and proliferate. A bone marrow plasma cell count greater than 20% is an indicator of risk.
Another element is the amount of monoclonal protein (M-protein) in the blood. The abnormal plasma cells produce a large quantity of a single, non-functional protein, which appears as a “spike” on a test called serum protein electrophoresis. An M-protein level greater than 2 grams per deciliter (g/dL) points to a substantial number of active myeloma cells.
The final criterion involves the serum free light chain (FLC) ratio. Plasma cells produce antibody proteins composed of heavy and light chains. In SMM, there is an overproduction of one type of light chain (kappa or lambda) compared to the other. A serum FLC ratio greater than 20 indicates an imbalance in this production and is strongly associated with the risk of the disease advancing.
Progression to Active Myeloma
A diagnosis of high-risk SMM carries a substantial probability of progressing to active multiple myeloma. Individuals in this category have approximately a 50% risk of their condition advancing to symptomatic cancer within two years of diagnosis. This elevated risk is what drives the need for closer surveillance and different management considerations.
Progression is defined as the point when the disease causes end-organ damage. The development of active multiple myeloma is identified by the CRAB criteria, which confirm the plasma cell disorder has become a symptomatic cancer requiring treatment. The appearance of one or more of these CRAB features marks the transition from asymptomatic SMM to active multiple myeloma.
The CRAB acronym represents the following indicators:
- High calcium levels (hypercalcemia), which occurs when advanced myeloma activity causes bone to break down, releasing calcium into the bloodstream.
- Renal or kidney impairment, which can happen when excess monoclonal proteins, particularly the light chains, damage the kidney’s filtering units.
- Anemia (a low red blood cell count), which develops as proliferating abnormal plasma cells crowd out healthy red blood cell-producing cells in the bone marrow.
- Bone lesions, where myeloma cells activate cells that dissolve bone, leading to weakened areas that can cause pain and increase fracture risk.
Monitoring and Diagnostic Procedures
A high-risk SMM diagnosis requires a structured monitoring schedule to detect signs of progression early. This surveillance involves regular tests that track the biological markers of the disease to identify the transition to active disease before significant organ damage occurs.
Patients undergo frequent blood tests to measure the M-protein spike and serum FLC ratio, as changes can signal increased disease activity. Blood counts are checked for anemia, and chemistry panels assess kidney function and calcium levels, which align with the CRAB criteria.
Urine tests are also part of monitoring to detect monoclonal proteins, specifically Bence-Jones protein (the urinary form of free light chains). Periodic 24-hour urine collections may be used to get a precise measurement of protein excretion.
Bone marrow biopsies and aspirates are performed periodically to re-evaluate the percentage of clonal plasma cells in the bone marrow. Advanced imaging techniques like whole-body MRI, PET-CT, or low-dose CT scans are also employed. These scans are sensitive for detecting bone lesions, which can identify progression to active myeloma before symptoms change.
Evolving Treatment Approaches
The management strategy for high-risk SMM is undergoing a transformation. Historically, the standard approach was “watch and wait,” where treatment was initiated only after the disease progressed to active myeloma. This approach was based on avoiding therapy side effects in asymptomatic patients.
This paradigm is shifting for the high-risk SMM population. Given the high probability of progression, there is a growing consensus that early intervention may be beneficial. Starting treatment before the onset of CRAB criteria could delay or prevent irreversible organ damage like kidney failure or bone fractures.
Clinical trials have shown that early treatment can delay the time to progression for patients with high-risk SMM. Therapies often involve immunomodulatory drugs, such as lenalidomide, sometimes used in combination with other agents to control the plasma cell disorder and reduce the production of harmful monoclonal proteins.
The field is advancing with ongoing research into novel therapies and combinations. For individuals with high-risk SMM, discussing early treatment or enrollment in a clinical trial with a hematologist is an important step in making an informed management decision.