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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.

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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.

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Introduction: Smoldering multiple myeloma (SMM) is a clonal plasma cell (PC) disorder considered a prelude to MM due to its greater malignant potential compared to monoclonal gammopathy of undetermined significance (MGUS). Despite tectonic changes in the SMM landscape that occurred since it was first distinguished four decades ago, SMM continues to represent a complex and controversial entity causing a great deal of diagnostic and management turmoil.Areas covered: Author addresses increasingly complicated, ambiguous, as well as some overlooked and misjudged aspects of SMM such as the disease identity, relationship to its counterparts, MGUS and overt MM, its niche in the modern classification of monoclonal gammopathies and management. The PubMed search (1980-2020) was conducted and the current NCCN guidelines reviewed in reference to the diagnosis and treatment of smoldering multiple myeloma.Expert opinion: A plethora of clinical and biological evidence points to SMM as a source of the ongoing and expanding uncertainty of this condition and calls into question its authenticity as a discrete entity. Until comprehensive testing can predict the progression of pre-myeloma conditions with the utmost precision, attempts at preemptive treatments will fail to answer the basic question of who will benefit from the early treatment and who will not.

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Minimal residual disease (MRD) assessment is incorporated in an increasing number of multiple myeloma (MM) clinical trials as a correlative analysis, an endpoint or even as a determinant of subsequent therapy. There is substantial heterogeneity across clinical trials in how MRD is assessed and reported, creating challenges for data interpretation and for the design of subsequent studies. We convened an international panel of MM investigators to harmonize how MRD should be assessed and reported in MM clinical trials. The panel provides consensus on which MM trials should include MRD, the recommended time points for MRD assessment, and expected analytical validation for MRD assays. We subsequently outlined parameters for reporting MRD results implementing the intention-to-treat principle. The panel provides guidance regarding the incorporation of newer peripheral blood-based and imaging-based approaches to detection of residual disease. Recommendations are summarized in 13 consensus statements that should be followed by sponsors, investigators, editors, and reviewers engaged in designing, performing, and interpreting MM trials.

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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.

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INTRODUCTION: In 2014, the International Myeloma Working Group determined that patients with ultra-high-risk smoldering multiple myeloma (SMM) should be considered for treatment as per patients with symptomatic multiple myeloma (MM), despite not having CRAB (hyperCalcemia, Renal insufficiency, Anemia, Bone disease) symptoms. Current research is elucidating whether patients with high-risk, and even intermediate-risk, SMM could benefit from early therapeutic strategies aimed at delaying progression to active MM and prolonging survival. Areas covered: The authors conducted a systematic literature search using PubMed to identify a series of patients with SMM in which prognostic and predictive factors for progression were investigated, plus the main clinical trials in SMM. Additionally, a search of active clinical trials in SMM was conducted at ClinicalTrials.gov. Expert opinion: Patients with high-risk SMM can benefit from active treatment strategies, which may prolong survival and, perhaps, provide a possible path to cure. Enabled by the limited toxicity of new drugs investigated in MM, this approach, together with consolidation with autologous transplantation, is under investigation by American and European groups. In patients with high-risk SMM who are not candidates for transplantation, combinations of oral drugs may prolong time to progression. In the near future, these approaches may be endorsed by results of ongoing clinical trials.

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