Early Detection of Precursor Diseases of Multiple Myeloma.

Precursor diseases of multiple myeloma (MM) are monoclonal gammopathy of uncertain significance and smoldering MM. While it is well known that a percentage of those affected by these conditions will progress to MM, it is difficult to predict who will progress and when, and guidelines for screening for these conditions are lacking. Moreover, there are various models for risk stratification, though there are ongoing efforts to improve these models in order to predict who may benefit from treatment. Finally, there are various clinical trials, both past and ongoing, expanding the scope of possible treatment options for precursor diseases.

Smouldering multiple myeloma: To seek or not to seek? To treat or not to treat. That is the question.

In this issue, the British Society for Haematology presents guidelines for the diagnosis and management of patients with smouldering multiple myeloma (SMM). The authors provide a practical, evidence-based approach to managing these patients. Key questions remain yet unsolved. Commentary on: Hughes et al. Diagnosis and management of smouldering myeloma: A British Society for Haematology Good Practice Paper. Br J Haematol 2024;204:1193-1206.

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.

Mode of progression in smoldering multiple myeloma: a study of 406 patients.

The approach to patients with high-risk smoldering multiple myeloma (SMM) varies among clinicians; while some advocate early intervention, others reserve treatment at progression to multiple myeloma (MM). We aimed to describe the myeloma-defining events (MDEs) and clinical presentations leading to MM diagnosis among SMM patients seen at our institution. We included 406 patients diagnosed with SMM between 2013-2022, seen at Mayo Clinic, Rochester, MN. The 2018 Mayo 20/2/20 criteria were used for risk stratification. Median follow-up was 3.9 years. Among high-risk patients who did not receive treatment in the SMM phase (n = 71), 51 progressed by last follow-up; the MDEs included: bone lesions (37%), anemia (35%), hypercalcemia (8%), and renal failure (6%); 24% met MM criteria based on marrow plasmacytosis (≥60%) and/or free light chain ratio (>100); 45% had clinically significant MDEs (hypercalcemia, renal insufficiency, and/or bone lesions). MM diagnosis was made based on surveillance labs/imaging(45%), testing obtained due to provider suspicion for progression (14%), bone pain (20%), and hospitalization/ED presentations due to MM complications/symptoms (4%). The presentation was undocumented in 14%. A high proportion (45%) of patients with high-risk SMM on active surveillance develop end-organ damage at progression. About a quarter of patients who progress to MM are not diagnosed based on routine interval surveillance testing.

Smoldering Multiple Myeloma: Observation Versus Control Versus Cure.

Smoldering multiple myeloma (SMM) is an intermediate clinical stage in the spectrum of monoclonal plasma cell disorders. It represents a heterogeneous clinically defined condition in which some patients (approximately 50%) have monoclonal gammopathy of undetermined significance (premalignancy), and some (approximately 50%) have multiple myeloma (biologic malignancy). Using specific prognostic factors, patients with SMM, in whom malignant transformation has already likely occurred, can be identified. These patients are considered to have high-risk SMM. Patients with newly diagnosed high-risk SMM are candidates for early intervention with lenalidomide or lenalidomide plus dexamethasone for 2 years, or enrollment in clinical trials.

Clinical characteristics and outcomes in risk-stratified patients with smoldering multiple myeloma: data from the Czech Republic Registry of Monoclonal Gammopathies.

Smoldering multiple myeloma (SMM) is an asymptomatic precursor to active multiple myeloma (MM). The aim of this study was to report clinical characteristics and outcomes of patients with SMM stratified based on their risk of progression to MM using the Mayo 20/2/20 criteria. Data were leveraged from the Czech Myeloma Group Registry of Monoclonal Gammopathies (RMG). Key outcomes included progression-free survival from SMM diagnosis to active MM diagnosis or death (PFS), progression-free survival from SMM diagnosis to progression on first line (1 L) MM treatment or death (PFS2), and overall survival (OS). Of 498 patients, 174 (34.9%) were classified as high risk and 324 (65.1%) as non-high risk. Median follow-up was approximately 65 months. During follow-up, more patients in the high-risk vs non-high-risk group received 1 L MM treatment (76.4% vs 46.6%, p < 0.001). PFS, PFS2, and OS were significantly shorter in high-risk vs non-high-risk patients (13.2 vs 56.6 months, p < 0.001; 49.9 vs 84.9 months, p < 0.001; 93.2 vs 131.1 months, p = 0.012, respectively). The results of this study add to the growing body of evidence that patients with high-risk vs non-high-risk SMM have significantly worse outcomes, including OS.

Understanding high-risk smoldering multiple myeloma.

Smoldering multiple myeloma (SMM) is an asymptomatic condition with heterogeneous biology and various risks of progression to symptomatic disease. The best-known risk stratification models are Mayo-2018, and IWWG based on tumor burden. Recently, the personalized risk assessment tool PANGEA was introduced. New markers of SMM progression, including genomic and immune characteristics of plasma cells (PCs) and tumor microenvironment, are under investigation, and some have been incorporated into traditional scoring systems. Only one phase 3 clinical trial demonstrated an overall survival benefit of lenalidomide for high-risk SMM patients. The study has limitations, and most guidelines recommend observation or participation in clinical trials for high-risk SMM. High-intensity time-limited treatment strategies for high-risk SMM demonstrated deep responses in single-arm studies. But these treatments can cause adverse effects in asymptomatic patients.This review aims to understand better the risk of SMM progression from a clinical and biological point of view.

Early Intervention With a Curative Intent Through an Intensive Therapy Versus Immunologic Disease Control Using a Minimal Intensity Approach in the Management of High-risk Smoldering Multiple Myeloma: A Systematic Review of Evidence From Clinical Trials.

A subset of individuals with smoldering myeloma (SMM) are at a high risk of progression to symptomatic myeloma. Current efforts are focused on identifying this high-risk group and intercepting the disease process before its progression. There is no consensus on what the goal of an intervention should be, whether to aim for a cure through a high-intensity intervention or pursue immunologic disease control using the least intense approach. This systematic review summarized current evidence in support of the optimum approach. A database search of Medline/PubMed, Scopus, EMBASE, Web of Science, CINAHL, Wiley Cochrane Library, clinicaltrials.gov, and conference proceedings of ASH, EHA, ASCO, ESMO was performed. Results were presented using narrative synthesis of quantitative data. Of the 2088 identified records, a total of 10 eligible studies made up of 6 minimal-intensity clinical trials, 3 moderate-intensity trials, and 1 high-intensity trial were included in this review with a total demographic population of 588 high-risk SMM patients. Minimal intensity lenalidomide-based regimen demonstrated clinical effectiveness in delaying disease progression and improving overall survival in high-risk SMM. The single-agent monoclonal antibodies did not have any major impact on improving overall survival, although the studies were not powered to do so. There is a marked increase in the depth of response as the intensity of treatment increases without a proportional improvement in overall survival. Moderate- and high-intensity interventions yielded similar minimal residual disease negativity rates and overall survival. The minimal, moderate, and high-intensity approaches all demonstrated clinical benefits in delaying disease progression and improving overall survival in patients with high-risk SMM and increasing intensity of intervention does not necessarily translate to improved overall survival.

The consultant's guide to smoldering multiple myeloma.

Smoldering multiple myeloma (SMM) is an asymptomatic precursor condition to multiple myeloma (MM). The prevalence of SMM is 0.5% in persons over 40 years old; it is higher in men than women and increases with age. When SMM is diagnosed, a thorough diagnostic workup is necessary to exclude myeloma-defining events and stratify patients according to risk of progression to MM. While close monitoring for progression remains the best management for most patients with SMM, in this article, we discuss if treatment initiation before myeloma-defining events occur might be relevant in selected high-risk cases. Two randomized clinical trials have shown a clinical benefit of initiating treatment at the SMM stage, whereof 1 showed an overall survival benefit for those receiving treatment. We discuss various risk stratification models in SMM, important treatment trials, and ongoing trials. Finally, we present how to approach the clinical management of patients with SMM.

Immune biomarkers of response to immunotherapy in patients with high-risk smoldering myeloma.

Patients with smoldering multiple myeloma (SMM) are observed until progression, but early treatment may improve outcomes. We conducted a phase II trial of elotuzumab, lenalidomide, and dexamethasone (EloLenDex) in patients with high-risk SMM and performed single-cell RNA and T cell receptor (TCR) sequencing on 149 bone marrow (BM) and peripheral blood (PB) samples from patients and healthy donors (HDs). We find that early treatment with EloLenDex is safe and effective and provide a comprehensive characterization of alterations in immune cell composition and TCR repertoire diversity in patients. We show that the similarity of a patient's immune cell composition to that of HDs may have prognostic relevance at diagnosis and after treatment and that the abundance of granzyme K (GZMK)+ CD8+ effector memory T (TEM) cells may be associated with treatment response. Last, we uncover similarities between immune alterations observed in the BM and PB, suggesting that PB-based immune profiling may have diagnostic and prognostic utility.

Smoldering multiple myeloma current treatment algorithms.

Smoldering multiple myeloma (SMM) is an asymptomatic condition that occupies a space between monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma (MM) along the spectrum of clonal plasma cell proliferative disorders. It is not a biologic intermediate stage between MGUS and MM, but rather represents a heterogeneous clinically defined condition in which some patients (approximately two-thirds) have MGUS (pre-malignancy), and some (approximately one-third) have MM (biologic malignancy). Unfortunately, no single pathologic or molecular feature can reliably distinguish these two groups of patients. For purposes of practice and clinical trials, specific risk factors are used to identify patients with SMM in whom malignant transformation has already likely occurred (high risk SMM). Patients with newly diagnosed high risk SMM should be offered therapy with lenalidomide or lenalidomide plus dexamethasone (Rd) for 2 years, or enrollment in clinical trials. Patients with low risk SMM should be observed without therapy every 3-4 months.

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.

Smoldering multiple myeloma: Reviewing the rationale for intervention.

Smoldering multiple myeloma has been recognized for over 40 years and represents a pre-symptomatic phase of the 2nd most common hematologic malignancy. 1/3 of patients will remain asymptomatic at 10 years. There is an identifiable subset of patients that will develop CRAB within 2 years of recognition and these patients are considered for therapeutic intervention before the development of potentially irreversible complications. Obstacles to widespread implementation of therapeutic guidelines are limited by the variable definitions associated with this high-risk group as well as the poor concordance between classification schemes. Analysis of clinical trial outcomes as well as uniform eligibility helps determine whether a given patient should be considered for therapeutic intervention outside of a clinical trial.

Smoldering multiple myeloma: biology, clinical manifestations and management.

Smoldering multiple myeloma (SMM) is a heterogeneous group of asymptomatic plasma cell disorder characterized by the presence of monoclonal protein ≥ 30 g/L and/or 10-60% of bone marrow plasma cells and no evidence of SLiM-CRAB criteria according to the 2014 International Myeloma Working Group (IMWG) recommendations. Once the effort to reclassify SMM with active disease as MM requiring treatment was completed, the need to redefine new high-risk SMM arose. The 20/2/20 and the IMWG risk model with the add-on high-risk cytogenetic abnormalities allow to identify high-risk SMM with 50% risk of progression to MM within 2 years, and therefore might help to propose a better therapeutic approach, either with the goal to « cure ¼ by profoundly debulk the MM with aggressive therapies, or alternatively to restore the immune surveillance like a « delay ¼ strategy with immune-based therapies. The debate is still ongoing but clearly challenges the watch-and-wait standard of care.

Smoldering multiple myeloma: evolving diagnostic criteria and treatment strategies.

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.

Assessing the prognostic utility of smoldering multiple myeloma risk stratification scores applied serially post diagnosis.

The Mayo-2018 smoldering multiple myeloma (SMM) risk score is used routinely in the clinical setting but has only been validated at diagnosis. In SMM patients, the progression risk decreases over time. However, the utility of applying risk stratification models after diagnosis is unknown. We retrospectively studied 704 SMM patients and applied the Mayo 2018 and IMWG-2020 risk stratification models at annual landmark timepoints up to 5 years post diagnosis. The Mayo-2018 and IMWG-2020 models reliably stratified patients based on progression risk when applied post diagnosis. The respective 2-year progression risk in Mayo-2018 high risk patients versus IMWG-2020 intermediate-high risk patients was 51% versus 62% at the 1-year landmark and 47% versus 45% at the 4-year landmark. We showed that patients categorized at Mayo-2018 high-risk at follow-up had a similar risk of progression if the baseline risk assessment was low-intermediate versus high-risk (HR 1.04, 95% CI 0.46-2.36, p = 0.931 at 5-year landmark). Patients migrating to a higher risk category during follow up had a higher progression risk compared to patients with stable/decreased risk categorization. Our findings support the use of these risk scores post-diagnosis and suggest that patients evolving to a high-risk category may benefit from early intervention therapeutic approaches.

Smoldering Myeloma Treatment: Who, What, and When.

ABSTRACT: Smoldering multiple myeloma (MM) is a clonal plasma cell disorder characterized by excess marrow involvement and immunoglobulin production. It is the precursor of MM, differing by the lack of end-organ damage. Smoldering MM encompasses a heterogeneous group of patients, with a median risk of progression to active disease of 50% in the first 5 years. Until recently, the standard of care would dictate observation off therapy until the development of end-organ damage. The recognition of high-risk and ultrahigh-risk subgroups of smoldering MM, with more likely evolution to MM, has led to earlier initiation of therapy in the disease course. Ongoing studies to define the ideal timing and patient population are underway, as well as identification of which agents would be of greatest benefit, as the armamentarium for MM continues to grow.

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.