Smoldering Multiple Myeloma: A New Story to Tell

Mini Review

Ann Hematol Oncol. 2015;2(6): 1043.

Smoldering Multiple Myeloma: A New Story to Tell

Silvia Gentili*

Italian Multiple Myeloma Network, GIMEMA, Italy

*Corresponding author: Silvia Gentili, Italian Multiple Myeloma Network, GIMEMA, Italy

Received: May 02, 2015; Accepted: May 20, 2015; Published: June 02, 2015


Smoldering Multiple Myeloma (SMM) is characterized by an M spike of 3 g/dL or more and/or a bone marrow containing at least 10% plasma cells with no evidence of end organ damage. Historically management of SMM patients has been based on a “watch and wait” strategy, but after understanding the heterogeneity of the behavior of this disease, several objections have been raised regarding need to start a therapy in some patients.

The identification of several risk factors associated with a risk of progression of approximately 80% within 2 years of diagnosis, has allowed the identification of a small sub-category of SMM patients who gain benefit from early treatment. However, for all other patients, to date, a no-intervention approach is still recommended outside clinical trials. In this review, we provide an overview of SMM including definitions, current diagnostic work-up, risk factors associated with progression, and data from clinical trials performed with the objective of providing early treatment to SMM patients.

Keywords: Smoldering multiple myeloma; Prognosis; Risk-stratification; Treatment of high-risk smoldering myeloma


Smoldering Multiple Myeloma (SMM) is a clinical entity initially recognized by Kyle and Greipp in 1980. The authors described six patients presenting Multiple Myeloma (MM) criteria, but who did not show an aggressive disease course [1]. Subsequently, the International Myeloma Working Group (IMWG) defined SMM as a plasma cell disorder characterized by the presence of =3 g/dL serum M-protein and/or =10% Bone Marrow Plasma Cells (BMPC), and the absence of end-organ damage such as hypocalcaemia (serum calcium =11.5 mg/dL), renal insufficiency (serum creatinine =2 mg/ dL), anemia (hemoglobin value below the lower limit of normal by >2 g/dL or hemoglobin value <10 g/dL), and lytic bone lesions (CRAB features) [2]. Finally, Kyle and Rajkumar clarified that the M-protein needed to be of the IgG or IgA subtype and that the BMPCs must be clonal [3]. SMM differs from indolent MM, an asymptomatic disease but with evidence of minimal end-organ damage [3]. Kristinsson et al., evaluating the Swedish Myeloma registry, showed that 14% of newly diagnosed MM patients had SMM [4]. The Mayo Clinic group, analyzing data of 276 SMM patients, showed the annual risk of progression to symptomatic MM was 10% per year for the first 5 years, 5% per year during the subsequent 5 years, and 1% per year after the 10th year [5]. Thus, SMM represents an intermediate clinical stage between Monoclonal Gammopathy of Undetermined Significance (MGUS) and MM. This observation was confirmed by genetic studies, in which it has been demonstrated that most genetic lesions typical of MM are already present in both MGUS and SMM patients. Accordingly, a multistep model of progression, starting with MGUS and transformation to MM, has been proposed. The most important difference between these three clinical entities is the number of clonal PCs with genetic abnormalities, which increases from MGUS to MM, suggesting a clonal expansion [6].

Diagnostic Work-Up

The diagnostic work-up of patients with suspected SMM is the same used to diagnose symptomatic MM (Table 1) [7]. The gold standard for the evaluation of bone disease remains the skeletal survey; however the IMWG consensus highly recommends that spine and pelvis Magnetic Resonance Imaging (MRI) studies be performed for this category of patients, with the aim of detecting occult lesions not visible with the more conventional skeletal survey [7]. In the setting of SMM patients the role of 18F-fluorodeoxyglucosePET/ CT is currently under investigation. Evaluation of PC infiltration is mandatory in the case of bone marrow aspirate/biopsy. Flow cytometry or FISH analysis are not mandatory, but can help to estimate the risk of progression towards active MM. The followup includes the evaluation of the monoclonal component, as well as hemoglobin, calcium, and creatinine levels every 3-4 months; however the frequency of follow-up should be adapted according to the patient’s risk of progression to symptomatic MM.