Smoldering Multiple Myeloma (SMM) is a pre-malignant plasma cell disorder that acts as an intermediate stage between Monoclonal Gammopathy of Undetermined Significance (MGUS) and active Multiple Myeloma (MM). SMM is characterized by abnormal plasma cells in the bone marrow and a monoclonal protein in the blood or urine, but it remains asymptomatic. The central challenge is determining the optimal time for intervention, as the progression risk is highly variable. The standard approach involves active surveillance, reserving immediate treatment for patients identified as having a high risk of imminent progression.
Defining Smoldering Myeloma
Smoldering Multiple Myeloma is defined by distinct thresholds of abnormal cell and protein levels while lacking the signs of organ damage seen in active MM. Diagnosis requires a bone marrow biopsy showing clonal plasma cells in the range of 10% to 60%. Additionally, patients must have a detectable monoclonal protein (M-protein) in the blood at a concentration of at least 3 grams per deciliter, or an equivalent amount in the urine. SMM carries a much higher risk of progression to active cancer than MGUS.
The absence of myeloma-defining events (MDEs), historically known as CRAB criteria, distinguishes SMM from active MM. These MDEs include high calcium levels, renal dysfunction, anemia, or bone lesions. If any of these end-organ damages are present, the diagnosis immediately shifts to active multiple myeloma, prompting the start of treatment.
The Rationale for Active Surveillance
For patients diagnosed with low- or intermediate-risk SMM, active surveillance, or “watchful waiting,” is the established standard of care. This approach is rooted in the understanding that SMM is a heterogeneous condition, and many patients will not progress to active MM for many years, if at all. Starting treatment too early exposes patients to the toxic side effects of therapy, such as neuropathy and fatigue, along with financial burdens, without a clear survival advantage. Therefore, for a significant number of patients, the harm of unnecessary treatment outweighs the benefit of early intervention.
The surveillance protocol involves frequent monitoring of key laboratory and imaging markers to detect the earliest signs of progression. In the first year after diagnosis, patients with low-to-intermediate risk are typically monitored every three to four months. Routine checkups include blood tests, such as serum protein electrophoresis to track the M-protein level, and a complete metabolic panel to monitor kidney function and calcium levels. Regular testing of serum free light chains (sFLC) is also performed to check for changes in the ratio of involved to uninvolved light chains, which is a sensitive indicator of plasma cell activity.
Beyond bloodwork, regular imaging is performed to look for skeletal damage that would indicate a progression to active MM. An annual whole-body CT or whole-body MRI is often recommended to identify any new bone lesions. If the disease remains stable after the first year, the frequency of laboratory monitoring may be extended to every six months.
Identifying High-Risk Progression
The decision to initiate therapy is determined by specific quantitative criteria defining a very high risk of progression. The International Myeloma Working Group (IMWG) established markers identifying patients with an approximately 80% chance of progressing to active MM within two years. When a patient meets any one of these ultra-high-risk criteria, the condition is reclassified as active multiple myeloma, and immediate treatment begins. These criteria include 60% or more clonal plasma cells in the bone marrow, an involved-to-uninvolved serum free light chain ratio of 100 or greater, or more than one focal lesion (at least 5 millimeters in size) on an MRI scan.
A separate group of patients is classified as “high-risk SMM” based on the “2/20/20” criteria, which is the population for whom early intervention is considered. This model identifies patients who possess two or three of the following risk factors: bone marrow plasma cells of 20% or more, an M-protein level of 2 grams per deciliter or more, or a serum free light chain ratio of 20 or more. Patients meeting these criteria have a significant risk of progression, often between 20% and 40% within two years, making them ideal candidates for clinical trials or early treatment.
Targeted Therapeutic Interventions
Therapeutic intervention for high-risk SMM (based on 2/20/20 criteria) aims to prevent or significantly delay the onset of active multiple myeloma. Early intervention strategies have centered on immunomodulatory drugs (IMiDs), which alter the immune system’s response to cancer cells. Lenalidomide, often combined with a low dose of the corticosteroid dexamethasone, has been a standard regimen tested in clinical trials for high-risk SMM, demonstrating the ability to delay progression compared to observation alone.
The landscape of early treatment has expanded to include monoclonal antibodies. The CD38-directed monoclonal antibody daratumumab, in combination with hyaluronidase, has been approved for adults with high-risk SMM. This agent works by binding to the CD38 protein on the surface of plasma cells, leading to their direct destruction and stimulating the immune response. Other drug classes, such as proteasome inhibitors, are also being studied in clinical trials to achieve deeper and more durable responses in this high-risk population.