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What is Smoldering Myeloma?
Dr. Ola Landgren
National Cancer Institute
Bethesda, Maryland

Smoldering multiple myeloma (SMM) is a diagnosis largely based on laboratory findings. Similar to multiple myeloma and monoclonal gammopathy of undetermined significance (MGUS), SMM is characterized by the presence of abnormal plasma cells in the bone marrow. Usually, these abnormal plasma cells secrete abnormal antibodies (monoclonal or M-proteins) and/or free light-chains (FLCs), which can be detected in blood and/or in urine.

All healthy humans have plasma cells in the bone marrow. These plasma cells are part of the immune system. One of the hallmarks of plasma cells is that they produce immunoglobulins, which help protect the body against infections. Normally, about 1-3% of all the cells in the bone marrow are plasma cells.

Occurrence of an M-protein and/or free light chains (FLCs) in the blood and/or in the urine will usually not produce any symptoms. As a general rule, detecting a lower concentration of M-protein and/or FLCs is typically not a concern and, per current clinical guidelines, extensive testing is generally not required unless there are symptoms that warrant a greater index of suspicion on the part of your physician. For individuals who have higher concentrations of M-protein and/or FLCs in the blood and/or the urine, a bone marrow biopsy and imaging of the skeleton is recommended based on current clinical guidelines.

In the absence of so called ‘end organ damage’ (one or more of these: hypercalcemia, renal failure, anemia, bone lesions), individuals who have M-protein concentrations of 3 g/dL or greater, 10% or more abnormal plasma cells in the bone marrow, or a combination of these, will be given the diagnosis SMM. In individuals who lack end organ damage, in whom the M-protein concentration is less than 3 g/dL, and in whom the percentage of abnormal plasma cells is less than 10, will be given the diagnosis MGUS. In contrast, multiple myeloma is characterized by more than 10% abnormal plasma cells in the bone marrow, detectable M-proteins and/or FLCs in the blood and/or urine, and the presence of end organ damage.

Follow-up is required for all SMM patients indefinitely. Your physician will monitor M-protein levels, blood counts, and a few other standard blood/urine tests regularly. Per current clinical guidelines, SMM patients are typically seen once every 3 months in the beginning. if stable, the follow-up can be less often (4-6 months), and if stable for more than 5 years, even less often (6-12 months).

The major reason for the close clinical follow-up is the increased risk of developing multiple myeloma. At this time, there is only limited information on this topic in the medical literature. Based on retrospective data from the Mayo Clinic, on average, the risk of progression from SMM to multiple myeloma is 10% per year for the first five years. Thereafter the risk goes down to around 5% per year for the subsequent five years. After 10 years of follow-up, the Mayo Clinic study showed very similar risk of progression from SMM to multiple myeloma as prior studies have found for MGUS (~1% risk per year on average). Based on crude clinical markers and a restricted number of patients, two risk-scores have been published in the literature, with the aim of defining risk groups for progression from SMM to multiple myeloma. Mayo Clinic has reported the size of the M-protein, the percentage of plasma cells in the bone marrow, and the occurrence of abnormal FLCs in the blood to be associated with a higher risk of progression. SMM patients with only one risk factor had a 25 percent risk of developing multiple myeloma at 5 years, and for SMM patients with three risk factors, the risk was over 75 percent at 5 years. The Spanish PETHEMA study group has done similar work and reported immunosuppression (decreased levels of normal immunoglobulins) and a high proportion of abnormal (vs. normal) plasma cells in the bone marrow (greater than 95%) to be associated with an increased risk of developing multiple myeloma. Patents with both these factors had over 75% risk of progression at 5 years of follow-up, while those with none of these factors had only a 5% risk at 5 years. These heterogeneous risk patterns suggest that SMM is not one biological entity, but rather a mix of subtypes with different biology and different risks. Clearly, more research is needed to better define risk on an individual level: who is at high risk of progression, and who is not? Such studies are under way.

Current clinical guidelines state that treatment for SMM is not required in the setting of standard clinical care, although research protocols are in existence for patients at centers that specialize in the treatment of SMM. At this time, there is no scientific data to support the initiation of therapy for SMM outside a clinical trial. It is important to assess effects and side effects from therapies given to patients diagnosed with SMM. Clinical studies are needed to determine if treatment of SMM translates into meaningful clinical outcomes. There are ongoing treatment studies for SMM patients in the U.S. and Europe.

As mentioned above, more research is needed to better define risk for individual patients. Prospective clinical studies focusing on molecular and imaging changes over time will likely be of major importance to better understand mechanisms of transformation. Ideally, such efforts could lead to the development of new treatment studies designed to delay and/or prevent multiple myeloma for high-risk patients. Given that a recent prospective study found that virtually all multiple myeloma patients run through a preceding precursor state (i.e. MGUS and/or SMM), future studies focusing on mechanisms that can be used to prevent and/or delay transformation have the potential to significantly change outcomes for myeloma patients.

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