The Changing Landscape of Smoldering Multiple Myeloma: A European Perspective

Abstract

Smoldering multiple myeloma (SMM) is an asymptomatic clonal plasma cell disorder and bridges monoclonal gammopathy of undetermined significance to multiple myeloma (MM), based on higher levels of circulating monoclonal immunoglobulin and bone marrow plasmocytosis without end-organ damage. Until a Spanish study reported fewer MM-related events and better overall survival among patients with high-risk SMM treated with lenalidomide and dexamethasone, prior studies had failed to show improved survival with earlier intervention, although a reduction in skeletal-related events (without any impact on disease progression) has been described with bisphosphonate use. Risk factors have now been defined, and a subset of ultra-high-risk patients have been reclassified by the International Myeloma Working Group as MM, and thus will require optimal MM treatment, based on biomarkers that identify patients with a >80% risk of progression. The number of these redefined patients is small (∼10%), but important to unravel, because their risk of progression to overt MM is substantial (≥80% within 2 years). Patients with a high-risk cytogenetic profile are not yet considered for early treatment, because groups are heterogeneous and risk factors other than cytogenetics are deemed to weight higher. Because patients with ultra-high-risk SMM are now considered as MM and may be treated as such, concerns exist that earlier therapy may increase the risk of selecting resistant clones and induce side effects and costs. Therefore, an even more accurate identification of patients who would benefit from interventions needs to be performed, and clinical judgment and careful discussion of pros and cons of treatment initiation need to be undertaken. For the majority of SMM patients, the standard of care remains observation until development of symptomatic MM occurs, encouraging participation in ongoing and upcoming SMM/early MM clinical trials, as well as consideration of bisphosphonate use in patients with early bone loss.

Autotransplants in older multiple myeloma patients: hype or hope in the era of novel agents?

“…The most common indication for ASCT in Europe and the United States is MM, nevertheless elderly patients are often excluded from ASCTs, due to the patients' and/or physicians' choices, subjectivity towards its effectiveness in older cohorts, large prospective studies mostly lacking in elderly cohorts, the effectiveness and broad availability of novel agents and the fear of transplant-related toxicity. 1,2 The median age of MM patients at diagnosis is approximately 70 years, with 60% aged 65 or older and ~30% being older than 75 years. The transplant age cutoff has been proposed to be <70 years.…”

The serum heavy/light chain immunoassay: A valuable tool for sensitive paraprotein assessment, risk, and disease monitoring in monoclonal gammopathies

“…Therefore, the HLC assay may aid to identify high‐risk SMM patients, who should be considered for treatment initiation before CRAB criteria arise . Currently, a SFLC‐ratio >100 has been identified as a risk factor to define ultra‐high‐risk SMM or early MM, where active treatment initiation should be discussed . In analogy, our data suggest that a HLC κ/λ‐ratio of >100 or >200 may serve as a potential cut‐off, which—after future validation—may allow to identify SMM patients with earlier progression to symptomatic MM.…”

“…As depicted in Table , we also performed thorough follow‐up of the five SMM patients in order to evaluate, if HLCs could possibly serve as a risk factor for MM progression . In analogy to the SFLC‐ratio cut‐off level of >100, now defining ultra‐high‐risk SMM or active early MM, we assessed whether a defined HLC κ/λ‐ratio cutoff could help to identify SMM patients at risk to become symptomatic within ≤2 or ≤3 years: 2 of 5 of our SMM patients showed progression to symptomatic MM within 3.8 and 5.5 years, respectively. Of note, both had higher HLC IgGκ values and IgG κ/λ‐ratios compared with the remaining SMM patients (Table ).…”

Osteoprotective medication in the era of novel agents: a European perspective on values, risks and future solutions

“…[1][2][3] Regarding the definition of MM-defining events, there are important studies which suggest that asymptomatic patients with more than one focal lesion detectable by magnetic resonance imaging have a higher risk of progression to symptomatic MM (>70% within 2 years). 1,[4][5][6] These patients have been described by international myeloma experts as having symptomatic disease. 5,6 Based on phase 3 studies, the bisphosphonates, pamidronate and zoledronic acid, have been found to reduce skeletal-related events compared to placebo.…”

“…1,[4][5][6] These patients have been described by international myeloma experts as having symptomatic disease. 5,6 Based on phase 3 studies, the bisphosphonates, pamidronate and zoledronic acid, have been found to reduce skeletal-related events compared to placebo. [7][8][9] Three randomized studies have compared the effect of different bisphosphonates or different dosages of the same bisphosphonate.…”