Plasma cell dyscrasias (PCDs) includes a heterogenous group of disorders characterized by clonal proliferation of aberrant plasma cells within the bone marrow (BM). It is a continuous spectrum that ranges from the precursor conditions monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) to overt multiple myeloma (MM) and plasma cell leukemia (PCL). PCDs are generally considered incurable and their prevalence varies by disease stage. As of 2024, MM is diagnosed in over 35,000 individuals per year in the US alone accounting for 10 % of all hematologic malignancies [1]. Notably, the prevalence of MM is gradually increasing over time as survival rates continues to improve with the current 5-year survival estimated to be at 61 % [1]. In contrast, MGUS can be detected in up to 5 % of individuals ≥50 years of age [2,3], while SMM is found in around 0.5 % of individuals who are ≥40 years [4].

Although MGUS and SMM represent a continuum of precursor conditions, clinical thresholds have been established over the years to facilitate their differentiation and guide patient management. MGUS is defined as having clonal plasma cells involving <10 % of the BM, a serum monoclonal (M)-protein level <3 g/dL and/or presence of <500 mg of Bence Jones Proteins (BJPs) per 24 h of urine, without the end-organ damage that characterizes MM5. On the other hand, individuals with SMM can exhibit aberrant plasma cell involvement in 10–60 % of the BM along with a serum M-protein of ≥3 g/dL and/or presence of ≥500 mg of BJPs per 24 h of urine, without end-organ damage [5].

MGUS is classified based on the immunoglobulin isotype of the involved plasma cell clone into non-IgM, IgM, and light-chain subtypes. Non-IgM and light chain MGUS exhibit an annual progression rate of around 1 % to MM, a lymphoproliferative disorder, amyloidosis or light-chain deposition disease [6,7]. Notably, IgM MGUS confers a heightened annual progression risk of 1.5 % to hematologic malignancies including non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia (CLL), light-chain amyloidosis, and Waldenström's Macroglobulinemia (WM) [8].

In contrast to MGUS, individuals with SMM exhibit a markedly higher risk of progression to MM. Historically, the annual rate of progression to MM has been estimated at around 10 % per year for the first five years following diagnosis, before decreasing to around 3 % per year during the subsequent 5 years, and further declining to roughly 1.5 % per year thereafter [7,9,10]. Furthermore, numerous studies have addressed the inherent heterogeneity of SMM, enabling risk stratification of individuals into low, intermediate, high and ultra-high-risk categories. These stratifications delineate a broad spectrum of progression probabilities to MM, ranging from nearly 5 % to as high as 80 % within a two-year period.

Given the substantially greater risk of progression to MM associated with SMM relative to MGUS, it is imperative from a clinical standpoint to distinguish between these two entities. It is equally critical that high-risk SMM is accurately differentiated from lower risk categories, as this differentiation is essential for tailoring monitoring protocols and optimizing therapeutic strategies.

This review delves into the clinical implications of the broad spectrum of the precursor conditions MGUS and SMM. We describe their distinctive characteristics, evaluate current management protocols, examine the evolving research landscape, and emphasize on prospective advancements in both diagnostic and therapeutic strategies.