Smoldering multiple myeloma: evolving diagnostic criteria and treatment strategies

Abstract

The adage for smoldering myeloma (SMM) has been to observe without treatment, until criteria for active multiple myeloma were satisfied. Definitions and risk stratification models have become more sophisticated, with prognostication tailored to include high-risk cytogenetics as per the most recent International Myeloma Working Group 2020 risk model. Moreover, progress in defining genomic evolution and changes in the bone marrow microenvironment through the monoclonal continuum have given insight into the complexities underlying the different patterns of progression observed in SMM. Given recent data showing improved progression-free survival with early intervention in high-risk SMM, the current dilemma is focused on how these patients should be treated. This case-based article maps the significant advancements made in the diagnosis and risk stratification of SMM. Data from landmark clinical trials will also be discussed, and ongoing trials are summarized. Ultimately, we outline our approach to SMM and hope to impart to the reader a sound concept of the current clinical management of SMM.

Graphical abstract

Figure 1.

Timeline leading to the current diagnosis and management of SMM. CRAB, C-hyperCalcemia, R-Renal impairment, A-Anemia, B-Bone lesions related to Multiple Myeloma.

Figure 2.

Diagnostic workup, risk stratification, and management of SMM. BUN, blood urea nitrogen; CBC, complete blood count; CrCl, creatinine clearance; IFE, immunofixation; LLN, lower limit of normal; SPEP, serum protein electrophoresis; ULN, upper limit of normal; WBLDCT, whole-body low-dose CT.

Figure 3.

The evolutionary biology leading to SMM. The post–germinal B cell acquires a primary genetic defect at the MGUS stage, which triggers a dominant clone. The secondary genetic events that incite the transition to SMM include the development of chromosomal copy number alterations, translocations and single-nucleotide variants, and epigenetic changes. Some of the key high-risk secondary genomic events triggering the transition to SMM are RAS oncogene activation, MYC overexpression and dysregulation, and APOBEC-mediated mutations. Several theories are proposed for the clonal evolution from MGUS to MM. The dominant theory is the branching pattern of evolution, where generations of subclones develop from the parent clone. With stable clonal evolution, there is no major change in the clonal architecture throughout the monoclonal continuum to MM. Progressive changes in the stromal and cellular compartments of the bone marrow microenvironment facilitate expansion of the plasma cell clone and loss of immune surveillance.

Figure 4.

Commonly used risk stratification models in clinical practice. The risk factors and scoring PETHEMA, Mayo Clinic 2018, and IMWG 2020 scores are summarized, and the risk of progression based on scoring is outlined. FISH, fluorescence in situ hybridization; NR, not reached; PC, plasma cell; qIg, quantitative immunoglobulin. *The 5-year progression risk of the IMWG 2020 model is extrapolated from the Kaplan-Meier curve (figure 4 of the original publication).

Figure 5.

Hypothetical changes in the monoclonal protein markers of patients with SMM over time. While there are multiple possible trajectories that a patient's biomarkers may take, this figure is meant to illustrate that patients may have steady increases in the tumor burden, whereas other patients have a rapidly “evolving” presentation. Patients in “trajectory B,” with rapidly increasing biomarkers, should be considered for early therapeutic intervention.