Smoldering multiple myeloma requiring treatment: time for a new definition?

Abstract

Smoldering multiple myeloma (SMM) bridges the gap between monoclonal gammopathy of undetermined significance (a mostly premalignant disorder) and active multiple myeloma (MM). Until recently, no interventional study in patients with SMM showed improved overall survival (OS) with therapy as compared with observation. A report from the PETHEMA-GEM (Programa Español de Tratamientos en Hematologica) group described both fewer myeloma-related events and better OS among patients with high-risk SMM who were treated with lenalidomide and dexamethasone. This unique study prompted us to review current knowledge about SMM and address the following questions: (1) Are there patients currently defined as SMM who should be treated routinely? (2) Should the definitions of SMM and MM be reconsidered? (3) Has the time come when not treating is more dangerous than treating? (4) Could unintended medical harm result from overzealous intervention? Our conclusion is that those patients with the highest-risk SMM (extreme bone marrow plasmacytosis, extremely abnormal serum immunoglobulin free light chain ratio, and multiple bone lesions detected only by modern imaging) should be reclassified as active MM so that they can receive MM-appropriate therapy and the paradigm of careful observation for patients with SMM can be preserved.

Figure 1

Risk of SMM progression to active MM according to different prognostic systems as compared with risk of progression of MGUS to active MM. Gray shading includes 2-year time point. (A) SMM risk based on BMPCs ≥ 10%, M protein ≥ 30 g/L. Bold solid line, both above threshold; solid line, BMPCs ≥ 10% but M-protein < 30 g/L; dashed line, BMPC < 10% but M-protein ≥ 30 g/L. (B) SMM risk based on BMPC ≥ 10, M protein ≥ 30 g/L, and involved FLC/uninvolved FLC ≥ 8. Bold solid line, all 3 factors above threshold; solid line, any 2 factors above threshold; dashed line, any 1 factor above threshold. (C) SMM risk based on involved FLC/uninvolved FLC ≥ 100. Bold solid line, above threshold; solid line, below threshold. (D) SMM risk based on absence of CD19 and/or CD45 expression, overexpression of CD56, or weak expression of CD38 and immunoparesis of either of the uninvolved immunoglobulins. Bold solid line, both risk factors present; solid line, either risk factor present; dashed line, neither risk factor present. (E) SMM risk based on presence (bold solid) or absence (solid) of more than 1 focal lesion on whole-body MRI. (F) SMM risk based on FISH. Bold solid line, del17p,or t(4;14); solid line, trisomies alone; dashed line, any other interphase FISH abnormality; dotted line, normal or insufficient interphase FISH. (G) SMM risk based on high-risk interphase FISH [del17p, t(4;14), +1q21, or hyperdiploidy] and high tumor burden (M-protein ≥ 20 g/L). Bold solid line, both high-risk factors present; solid line, interphase FISH low risk and tumor high risk; dashed line, FISH high risk and tumor low risk; dotted line, both low risk. (H) MGUS risk of progression to MM based on M protein ≥ 30 g/L, abnormal rFLC, and heavy chain IgA or IgM. Bold solid line, all risk factors present; solid line, 2 risk factors present; dashed line, 1 risk factor present; dotted line, no risk factor present.

Figure 2

Distribution and outcomes based on FISH abnormalities among patients with SMM. (A) No interphase FISH abnormalities, white; standard risk: t(11;14), t(14;16), or t(14;20) or other/unknown IgH or del 13/13q, light gray; intermediate risk: trisomy without IgH translocation, dark gray; high risk: t(4;14)or del (17p), black. Solid bars, progression from SMM to MM; stippled bars, OS from SMM diagnosis. (B) Duration of time a patient lives with labels ranging from MGUS to SMM to active MM is in part related to interphase FISH. Although individuals harboring trisomies (ii) appear to progress more rapidly through their diagnosis of SMM than patients with normal FISH or non-t(4;14) translocations (i), they survive much longer than those with deletion 17p (iii) and about as long as patients with normal or non-t(4;14) translocations (i). Mo, months.

Figure 3

Present, future, and ideal state for distribution of patients with MGUS, SMM, and MM.

Figure 4

Algorithm for reclassifying SMM and active MM. *Consider including patients with the following FISH: deletion 17p, t(4;14), and 1q21 gains as active MM; this population could account for as many as 30% of SMM patients. ^§Consider using more than 1 fluorodeoxyglucose-avid lesion on PET/CT in lieu of MRI. iFLC, involved FLC; uFLC, uninvolved FLC; WbMRI, whole-body MRI.