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.

From MGUS to multiple myeloma: Unraveling the unknown of precursor states.

In the 1960s, through laboratory-based investigations of peripheral blood partnered with detailed clinical annotations, Dr. Waldenström described a condition he called "benign monoclonal gammopathy". These patients were asymptomatic with a detectable monoclonal protein, and did not meet imaging and laboratory criteria for multiple myeloma. In 1978, through observational retrospective review of medical records, Dr. Kyle observed that not all cases of monoclonal gammopathy were benign. He introduced the term monoclonal gammopathy of undetermined significance (MGUS) to describe a condition that may potentially progress to multiple myeloma (MM), highlighting clinical inability in predicting which patients might progress. In 1980, Drs. Kyle and Greipp described 6 cases which did not fit the definitions of MGUS or MM, and they remained asymptomatic after at least 5 years of follow-up; they were proposed to have smoldering multiple myeloma (SMM). Over time, SMM was defined by arbitrary numerical values (≥10 % plasma cells in the bone marrow and serum M-protein concentration ≥ 3 g/dL). Numerous clinical scores have been developed to define high-risk groups for progression to MM. Current statistical models for progression provide only average risk scores, offering limited clinical utility since the risk of progression at an individual level remains unknown. Physician-scientists are focusing on emerging technologies, such as whole genome sequencing, tumor microenvironment analysis, and single-cell RNA sequencing, to understand precursor states at a molecular level. The overarching goal of these technologies is to better characterize monoclonal gammopathy and other myeloma precursor states. This will enable clinicians to provide more precise, individualized risk assessments and ultimately improve patient outcomes. This review outlines the history of MM precursor states, current definitions, challenges in risk stratification models, and the role of emerging technologies in enhancing predictions and outcomes.

Regression of Intermediate-High Risk Monoclonal Gammopathy of Undetermined Significance (MGUS) With Long-term Use of Curcumin: A Case Report.

Patients with intermediate-high risk MGUS are not offered therapeutic options to date and standard of care remains observation with re-evaluations of the patient every 3 to 6 months. Given the persistent risk of progression as well as potential complications experienced by some, and anxiety experienced by most patients, early intervention with non-toxic curcumin, aimed at potentially slowing down or stopping disease progression might be therapeutic. We present here an intermediate-high risk MGUS patient who has been taking curcumin for 16 years and has shown a decrease in disease markers and an increase in uninvolved immunoglobulins, adding to the body of evidence of benefit of curcumin to MGUS patients.

Single-cell characterization of tumor evolution from precursor diseases.

Elucidating the characteristics of precursor diseases is important to the understanding of malignant transformation during tumor progression. In a recent study, Dang et al. characterized the cellular and molecular evolution from precursor conditions to multiple myeloma (MM) by integrating single-cell RNA sequencing (scRNA-seq) and B cell-receptor sequencing (scBCR-seq).

The road to cure in multiple myeloma starts with smoldering disease.

INTRODUCTION: Smoldering multiple myeloma (SMM) is a heterogeneous clinical entity that defines patients in the spectrum of disease progression from monoclonal gammopathy of undetermined significance to multiple myeloma (MM). Current standard of care is observation until end organ damage occurs. In spite of this, the scientific community has begun to question whether the strategy of watchful waiting should be replaced with earlier therapeutic intervention with the ultimate goal of preventing clonal heterogeneity and end organ damage. AREAS COVERED: In this review, we challenge the concept of observation as the best option of therapy in SMM. We present current data on diagnosis, prognostic factors of disease progression and studies that have been conducted to date to determine whether earlier therapeutic interventions will lead to an improvement in overall survival of patients with MM. EXPERT OPINION: If the recommendations of treatment of SMM were to change, the scientific body of evidence would have to overcome four major hurdles: to demonstrate that early intervention leads to prolonged survival and delay in development of end organ damage, that it does not have long-term toxicities, that it is implemented in patients with a high-likelihood of developing myeloma and that it does not lead to the outgrowth of more resistant clones. Only well-designed clinical trials will determine whether cure can be achieved with earlier interventions.