Smoldering multiple myeloma: taking the narrow over the wide path?

ABSTRACT: Smoldering multiple myeloma (MM) is an asymptomatic clonal plasma cell condition considered as a premalignant entity that may evolve over time to symptomatic MM. Based on a "poorly defined" risk of progression, some well-intended investigators proposed prospective interventional trials for these individuals. We believe this may be a harmful intervention and favor a close "wait and watch" approach and rather enroll these patients in dedicated observational biological studies aiming to better identify patients who will evolve to MM, based on their plasma cells' biology, including genomics, epigenetics, and the immune microenvironment.

Diagnosis and management of smouldering myeloma: A British Society for Haematology Good Practice Paper.

Multiple myeloma is a bone marrow-based plasma cell tumour that develops from asymptomatic pre-cursor conditions smouldering myeloma and monoclonal gammopathy of uncertain significance and all are characterised by the presence of a monoclonal protein in the blood. Diagnosis and distinction between these conditions is based on blood tests, the bone marrow biopsy and cross sectional imaging. There are various risk stratification models that group patients with smouldering myeloma into risk groups based on risk of progression to symptomatic disease. Management is mainly observational for patients with smouldering myeloma although clinical trials for high-risk disease may be available. Restaging is required if evidence for progression.

How I approach smoldering multiple myeloma.

The current standard of care in smoldering multiple myeloma (SMM) is close surveillance, outside of clinical trials. Efforts are being made to understand the pathobiologic process that leads to the progression of SMM to active MM. This review provides a critical description of available data, including risk factors and risk models of progression, as well as clinical trials investigating interventions for this patient population. We describe 2 cases in which patients were seen before the concept of a myeloma-defining event was established. Today, based on the International Myeloma Working Group criteria, both patients would have been identified as experiencing myeloma-defining events, and therapy would have been initiated. These cases show that occasionally, patients can undergo observation only, even when they exceed criteria for high-risk SMM.

Three-dimensional telomere profiling predicts risk of progression in smoldering multiple myeloma.

Smoldering multiple myeloma (SMM) is a precursor stage that precedes multiple myeloma (MM). SMM is heterogenous with nearly 40% of patients progressing to MM in the first 5 years. The high rate of progression of SMM patients highlights the need for early intervention, which underscores the importance of identifying SMM patients with the highest risk of progression. Several risk stratification models showed utility in identifying high-risk SMM patients; however, these systems showed limited sensitivity. To date, identifying high-risk SMM patients remains an important clinical need. In this study, we present the 3-dimensional telomere profiling as a structural biomarker capable of stratifying SMM patients as a function of genomic instability. Quantifying telomere dysfunction using the TeloView technology showed utility in risk stratification of cancer patients, particularly hematological malignancies. In this study, we analyzed 168 SMM patients. We report an AUC in ROC analysis of 0.8 using a subset of the patients as a training dataset. We then conducted a blind validation on a different cohort and demonstrated a positive predictive value of 85% and negative predictive value of 73%, with sensitivity and specificity of 83% and 76%, respectively. We examined the correlation between the TeloView prediction and the 20-2-20 scoring system, and cytogenetic abnormalities. We report a correlation of 53% with the 20-2-20 scores and over 60% correlation with cytogenetic abnormalities. The result of this study presents the telomere profiling as an effective biomarker able to stratify SMM patients to their respective risk groups with high sensitivity and specificity.

Autoimmune retinopathy in a patient with smoldering multiple myeloma: a case report.

PURPOSE: Multiple myeloma (MM) is a plasma cell dyscrasia leading to proliferation of monoclonal plasma cells. Ocular involvement in multiple myeloma is uncommon but can occur. The ocular manifestations of MM may include the cornea, uvea, and retinal vasculature. We present a rare case of autoimmune retinopathy associated with smoldering MM. CASE: A 76-year-old female with no significant past medical or ocular history presented with four months of worsening vision, difficulty with night driving, and loss of peripheral vision. Examination was notable for pallor of the optic nerves and vascular attenuation. Visual field testing demonstrated significant and progressive field loss in both eyes. An electroretinogram was extinguished under all conditions. Serum protein electrophoresis showed a significant elevation of IgG with an M-spike, and a subsequent bone marrow biopsy was performed showing 12.5% plasma cells, consistent with the diagnosis of MM. CAR antibody testing was positive for anti-enolase, anti-GAPDH, and anti-Rab6 antibodies, consistent with autoimmune retinopathy. DISCUSSION: Autoimmune retinopathy associated with MM is exceedingly rare. Management of this condition is challenging, as treatment of the underlying disease does not often lead to improvement in visual symptoms. Ultimately, visual prognosis is very poor, and both patients and clinicians should be aware of the guarded visual potential. CONCLUSION: The association of autoimmune retinopathy with multiple myeloma is rare. It is crucial for physicians to be aware of such manifestations to ensure timely and appropriate diagnosis and management for patients.

Persistent challenges with treating multiple myeloma early.

Over the past decade, 2 strategies have advanced the treatment of patients with multiple myeloma and its precursor diseases. First, the definition has changed to include patients without end organ damage, who previously would not have been treated. Second, there is widespread enthusiasm for treating high-risk, smoldering multiple myeloma. In this commentary, we explore the evidence supporting these therapeutic expansions. Although early treatment adds cost and therapeutic burden, it remains unknown whether survival and health-related quality of life are improved by early treatment. Herein, we consider the implications of diagnostic expansion in multiple myeloma.

Diagnostic performance of 18 F-FDG-PET/CT compared to standard skeletal survey for detecting bone destruction in smouldering multiple myeloma: time to move forward.

Skeletal survey (SS) continues to be used in the community to detect bone disease in patients with multiple myeloma (MM). While the false-negative rate is high, the specificity of SS is less well characterised. Here, we compare the diagnostic accuracy of SS compared to 18 F-FDG-PET/CT (positron emission tomography/computed tomography) in 79 patients referred to our tertiary centre with a diagnosis of smouldering MM. SS had a specificity of 83·1% (95% confidence interval: 72·0-90·5%). This study reinforces the importance of using more specific imaging techniques to avoid inaccurate diagnosis that could lead to the risks associated with unnecessary therapy in patients with smouldering MM.

Rare Association between Sarcoidosis and Smoldering Multiple Myeloma: A Case Report.

While several case reports suggest an association between sarcoidosis and multiple myeloma (MM), few cases involve smoldering MM. We report a case of sarcoidosis and smoldering MM discovered simultaneously in a patient admitted for hypercalcemia. Initial tests raised suspicion for sarcoidosis and MM, prompting invasive testing. Surgical lung biopsy revealed necrotizing granulomas, which could represent sarcoidosis in the appropriate setting. Thus, sarcoidosis was diagnosed following a negative infectious workup. Bone marrow biopsy revealed 13% plasma cells leading to subsequent diagnosis of smoldering MM. This case demonstrates the challenge of determining disease activity when other causes of CRAB symptoms are present.

2021 European Myeloma Network review and consensus statement on smoldering multiple myeloma: how to distinguish (and manage) Dr. Jekyll and Mr. Hyde.

According to the updated International Myeloma Working Group criteria, smoldering multiple myeloma (SMM) is an asymptomatic plasma cell disorder characterized by an M-component >3 g/dL, bone marrow plasma cell infiltration >10% and <60%, and absence of any myeloma-defining event. Active multiple myeloma is preceded by SMM, with a median time to progression of approximately 5 years. Cases of SMM range from the extremes of "monoclonal gammopathy of undetermined significance-like", in which patients never progress during their lifetimes, to "early multiple myeloma", in which transformation into symptomatic disease, based on genomic evolution, may be rapid and devastating. Such a "split personality" makes the prognosis and management of individual patients challenging, particularly with regard to the identification and possible early treatment of high-risk SMM. Outside of clinical trials, the conventional approach to SMM generally remains close observation until progression to active multiple myeloma. However, two prospective, randomized trials have recently demonstrated a significant clinical benefit in terms of time to progression, and of overall survival in one of the two studies, for some patients with higher-risk SMM treated with lenalidomide ± dexamethasone, raising the question of whether such an approach should be considered a new standard of care. In this paper, experts from the European Myeloma Network describe current biological and clinical knowledge on SMM, focusing on novel insights into its molecular pathogenesis, new prognostic scoring systems proposed to identify SMM patients at higher risk of early transformation, and updated results of completed or ongoing clinical trials. Finally, some practical recommendations for the real-life management of these patients, based on Delphi consensus methodology, are provided.

Baseline serum B-cell maturation antigen levels predict time to disease progression for patients with smoldering multiple myeloma.

Multiple myeloma (MM) patients with smoldering (S) disease are defined by a lack of CRAB/SLiM criteria but may transform into disease requiring treatment. The International Myeloma Working Group risk stratification model for SMM uses serum M-protein, serum-free light chain ratio, and bone marrow plasma cell percentage. We investigated whether baseline serum B-cell maturation antigen (sBCMA) levels are predictive of disease progression among 65 patients with SMM. A receiver operating characteristic curve was used to establish a definition for high-risk baseline sBCMA. Mantel Byar analysis was used to examine whether high-risk sBCMA was correlated with shorter time to transformation, and a time-dependent cox proportional hazard was used to determine whether it is independent of other risk factors. A z test for proportions was used to compare the percentage of patients that progressed among high-risk versus low-risk sBCMA patients. A baseline sBCMA level ≥137.5 mg/ml was found to be the optimal cutoff between high- and low-risk SMM patients. Patients with high-risk sBCMA levels had a shorter time to transformation (P = .000332). sBCMA was also higher at the time of transformation than baseline levels (P = .0116). sBCMA was the only variable found to be significantly predictive of time to transformation and additionally was found to be independent of other risk factors. In this study, we have shown for the first time that sBCMA levels predict transformation of SMM to active disease and that these levels increase at the time of transformation. These results are consistent with other studies showing that active MM patients undergoing therapy with higher baseline sBCMA levels are more likely to progress early and its levels increase at the time of disease progression.

Monitoring treatment response and disease progression in myeloma with circulating cell-free DNA.

Circulating cell-free DNA (cfDNA) has the potential to capture spatial genetic heterogeneity in myeloma (MM) patients. We assessed whether cfDNA levels vary according to risk status defined by the 70 gene expression profile (GEP70). cfDNA levels in 77 patients were significantly higher in the GEP70 high-risk (HR) group compared to the low-risk (LR) group and correlated weakly with clinical markers including lactate dehydrogenase, ß2 -microglobulin, and ISS. Patients with high cfDNA levels were associated with a worse PFS (hazard ratio 6.4; 95% CI of ratio 1.9-22) and OS (hazard ratio 4.4; 95% CI of ratio 1.2-15.7). Circulating tumor DNA (ctDNA) was elevated in the HR group and ctDNA correlated strongly with GEP70 risk score (Spearman r = .69, P = .0027). cfDNA concentrations were significantly elevated between days 3-5 after chemotherapy before falling back to baseline levels. ctDNA in two patients showed a similar spike in levels between days 3 and 5 after chemotherapy with a concomitant increase in allele fraction of KRAS mutations. We assessed cfDNA levels in 25 patients with smoldering myeloma with serial samples and showed increased allele fraction of mutated KRAS at progression in cfDNA. Our study shows that cfDNA is a dynamic tool to capture genetic events in myeloma.

Identification of patients with smouldering multiple myeloma at ultra-high risk of progression using serum parameters: the Czech Myeloma Group model.

Smouldering multiple myeloma (SMM) presents without MM defining symptoms. We aimed to identify patients with SMM with an 80% risk of progression within 2 years using only serum parameters. In total, 527 patients with SMM were included and divided into a training group (287 patients from the Czech Myeloma Group [CMG]) and an independent validation group (240 patients from Heidelberg). The median follow-up was 2·4 and 2·5 years, respectively. Progression to MM occurred in 51·9% of the CMG and 38·8% of the Heidelberg patients, respectively. The median risk of progression was 11·0% (CMG) and 9·7% (Heidelberg) per year, during the 5 years after diagnosis. A serum involved/uninvolved free light-chain ratio of >30, immunoparesis, and serum monoclonal (M) protein of ≥2·3 g/dl emerged as powerful predictors of 2-year progression rate with a hazard ratio (HR) of 2·49 (95% confidence interval [CI] 1·49-4·17), HR of 2·01 (95% CI 1·36-2·96) and HR of 2·00 (95% CI 1·44-2·79) (P < 0·001) in univariate Cox regression analysis, respectively. Based on this, the CMG model identified patients with SMM with a 2-year risk of progression of 78·7% (95% CI 53·1-95·7; HR 6·8; P < 0·001, CMG) and 81·3% (95% CI 47·1-98·8; HR 38·63; P < 0·001, Heidelberg). Serum parameters in the CMG model allow identification of patients with SMM with an 80% risk of progression to symptomatic MM within 2 years.

Practical approach to the management of smoldering myeloma.

PURPOSE OF REVIEW: The aim of this article is to review the diagnosis and risk stratification of smoldering myeloma (SMM), describe recently published data regarding the early treatment of SMM, and to provide practical strategies on how to manage patients with SMM in the clinic. RECENT FINDINGS: Recently published data from the ECOG E3A06 and GEM-CESAR studies supporting early intervention for certain subsets of high-risk SMM patients will be presented, and the relevance of these findings in relation to real-life application will be explored. SUMMARY: Accurate risk-stratification and standard of care for SMM is evolving, and here we summarize the pertinent clinical data and provide recommendations for clinical management of SMM patients.

Diagnosis and Management of Monoclonal Gammopathy and Smoldering Multiple Myeloma.

The presence of monoclonal proteins is common, with a prevalence in the United States around 5% that increases with age. Although most patients are asymptomatic, most cases are caused by a clonal plasma cell disorder. Monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) are asymptomatic precursor conditions with variable risk of progression to multiple myeloma. In recent years, significant progress has been made to better understand the factors that lead to the development of symptoms and progression to myeloma. This review summarizes the current diagnosis treatment guidelines for MGUS and SMM and highlights recent advances that underscore a shifting paradigm in the evaluation and management of plasma cell precursor conditions.

Prognostic value of involved/uninvolved free light chain ratio determined by Freelite and N Latex FLC assays for identification of high-risk smoldering myeloma patients.

Background Smoldering multiple myeloma (SMM) is an asymptomatic plasma cell disorder with a high risk of progression to symptomatic multiple myeloma (MM). The serum free light chain (sFLC) ratio is a powerful prognostic factor for SMM: an sFLC ratio ≥8 has been reported to be associated with a high risk of progression to MM, and an sFLC ratio ≥100 has been described as a criterion for ultra-high-risk SMM, and has been integrated into the definition criteria for MM since 2014. However, all recommendations were based on sFLC measured using the first commercialized assay, Freelite™, while other assays are now available. We aimed to evaluate the safety and accuracy of N-Latex sFLC to identify high-risk and ultra-high-risk SMM. Methods The sFLC ratio was measured at diagnosis with both Freelite and N-Latex assays in a cohort of 176 SMM patients on a BN Prospec nephelometer. Demographic, clinical, therapeutic and laboratory data were collected at the time of diagnosis and at follow-up. Results Sixty-two patients (35.2%) progressed to MM within 2 years. Compared to Freelite™ sFLC, N Latex sFLC ratios ≥8 and ≥100 provided similar performances for the identification of high-risk and ultra-high risk SMM patients. Conclusions Our results evidenced that the N-Latex assay could be used for SMM monitoring, like Freelite. However, an N-Latex sFLC ratio ≥70 appears to provide similar performances to a Freelite sFLC ratio ≥100, with a slightly better positive predictive value. Both assays provided accurate identification of high-risk and ultra-high risk SMM patients. These results should be confirmed in an independent study.

[Correlation between Morphological Typing and Monoclonality of Bone Marrow Plasma Cells and Its Diagnostic Value for High-Risk Smoldering Multiple Myeloma].

OBJECTIVE: To investigate the correlation between morphological typing and monoclonality of bone marrow plasma cells, and explore the diagnostic value of plasma cell morphological typing for high-risk smoldering multiple myeloma(HR-SMM). METHODS: The correlation between the morphological characteristics and the monoclonality of bone marrow plasma cells was analyzed in 84 patients with HR-SMM who treated in our hospital. The consistency of morphologically abnormal bone marrow plasma cells with serum free light chain (sFLC) ratio, next-generation sequencing (NGS) detection results, and its correlation with monoclonal plasma cells detected by flow cytometry (FCM) were further verified. The immunoglobulin types and levels of non-involved immunoglobulins in serum of the patients were detected, and the distribution of plasma cell clusters in patients with different disease was observed. RESULTS: The mean percentage of mature plasma cells were decreased successively in the order of reactive plasmacytosis (RP) group, monoclonal gammopathy of undetermined significance (MGUS) group, smoldering multiple myeloma (SMM) group, HR-SMM group and multiple myeloma (MM) group; while the mean percentage of immature, primitive, reticular and flaming plasma cells were increased successively in the order of RP group, MGUS group, SMM group, and HR-SMM group, and the difference between any two groups was statistically significant (P < 0.05).The average proportion of abnormal plasma cells in the bone marrow of HR-SMM patients was 96.2% of the total plasma cells. The proportion of abnormal plasma cells were in good agreement with the sFLC ratio and the results of NGS detection in HR-SMM patients (kappa=0.879 and kappa=0.891, both >0.75)，and showed good correlation with the monoclonal plasma cells with immunophenotype of CD45-/CD38+/CD138+/CD56+/CD19-( γ=0.825). The levels of non-involved immunoglobulin in IgG, IgA and IgM type HR-SMM patients were all decreased by more than 25% compared with the normal reference range, and the differences were statistically significant (P < 0.05). There was no significant difference in the distribution ratio of plasma cell clusters among different disease groups (P >0.05). CONCLUSION: In HR-SMM patients, the immature, primitive, reticular and flaming plasma cells in bone marrow are considered as abnormal plasma cells, and they are correlated with monoclonal plasma cells. The proportion of abnormal plasma cells in total plasma cells of bone marrow and the reduction extent of non-involved immunoglobulin level in patients have certain reference value for the diagnosis of HR-SMM.