Is It an Ember or Is It a Flame? The Natural History of Smoldering Multiple Myeloma

The Oxford Dictionary defines “smolder” as “to burn slowly with smoke and no flame.” This definition was clearly on their minds when Drs. Robert Kyle and Philip Greipp first coined the term “smoldering multiple myeloma” (SMM) based on a small cohort of patients who, based on their tumor burden, appeared to have myeloma but had a relatively indolent course with no evidence of end-organ damage that was evident for a considerable period.¹  With increasing understanding of the natural history of SMM and its underlying biology, it is now clear that the analogy of an ember with the potential to become a flame does not quite capture the essence of this condition.

SMM occupies an intermediate position in the spectrum of monoclonal gammopathies, ranging from monoclonal gammopathy of undetermined significance (MGUS) at one end to symptomatic or active myeloma (MM) at the other, with a very heterogenous clinical course from the time of diagnosis determined by a variety of factors, including those related to the clonal plasma cells and tumor microenvironmental factors. It is becoming increasingly clear that SMM is not a distinct biological entity, but rather a mix of individuals with MGUS or MM without obvious manifestation of the end-organ damage required for making the diagnosis (Figure 1). This notion is further supported by the natural history of SMM, where nearly two-thirds of patients will demonstrate end-organ damage within 10 years of diagnosis, after which the rate of development of active MM is approximately 1 percent per year, as one would expect with MGUS.^{2, 3}  In essence, there is no biological characteristic of the clonal plasma cells that distinguishes SMM from the rest, but it is more of a population-based categorization that identifies a group of individuals who need closer follow-up than those with MGUS. This, in turn, justifies the continued need to maintain this disease categorization at least until we develop tools that identify those destined to develop MM in the short term with a high degree of sensitivity and specificity.

We have made significant progress toward identification of patients with higher risk of progression, fully realizing that this is a continuum with more risk factors having a cumulative effect on the progression risk. The recently developed Mayo 20-2-20 system, subsequently validated and improved by the International Myeloma Working Group (Figure 2), provides a valuable prognostic scoring system.^{3, 4}  The ability to identify a cancer precursor stage is a double-edged sword, as it induces significant anxiety for the patient, especially when it is being observed. At the same time, it offers an opportunity to explore interventions that can potentially reduce the risk of developing active disease or, in a best-case scenario, eradicating (i.e., curing) the malignant clone. Both of these options are being explored. In fact, two randomized phase III trials have explored the impact of treatment with lenalidomide and dexamethasone (Quiridex trial)⁵  or lenalidomide (E3A06),⁶  with both showing an improved time to progression to MM; the former also showed improved overall survival. While there are some differences in the patient population and the sensitivity of the imaging employed between the two trials, the latter clearly showed benefit for patients with high-risk SMM, as defined by the 20-2-20 system. Attempts to eradicate the clone have taken the form of single-arm phase II trials (GEM-CESAR and ASCENT among others) using the most effective MM therapies given for a defined period.⁷  While the minimal residual negativity rates are high, it is unclear if we are truly curing anyone yet. For the patients with SMM in your clinic, it is recommended that those with high risk be encouraged to participate in a trial or go on treatment with lenalidomide; otherwise, a very close follow-up is mandatory.⁸ 

The next few years will likely be transformative for the field of myeloma precursor diseases, with a better understanding of not only the changes in the clonal plasma cell, but also the tumor microenvironment that determines the fate of the condition. The addition of genomic characteristics to the clinical features in use currently, especially at a single-cell level, along with the measures of the immune microenvironment, will allow us to accurately distinguish between individuals with true MGUS (the ember) and those who already have malignancy (the flame) without relying on presence or absence of end-organ damage.⁹  Once we get there, we may not need the term “smoldering myeloma,” but it will have served its purpose. Until then, smoldering myeloma is a clinically important entity that carries a higher risk of progression than MGUS and in which biomarkers can be used to identify patients who can benefit from early intervention.