UNASSIGNED: Monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) are asymptomatic precursor conditions to multiple myeloma and related disorders. Smoldering multiple myeloma is distinguished from MGUS by 10% or greater bone marrow plasma cells (BMPC) on sampling, has a higher risk for progression, and requires specialist management.
UNASSIGNED: To develop a multivariable prediction model that predicts the probability that a person with presumed MGUS has 10% or greater BMPC (SMM or worse by bone marrow criteria) to inform the decision to obtain a bone marrow sample and compare its performance to the Mayo Clinic risk stratification model.
UNASSIGNED: iStopMM (Iceland Screens, Treats or Prevents Multiple Myeloma), a prospective population-based screening study of MGUS. (ClinicalTrials.gov: NCT03327597).
UNASSIGNED: Icelandic population of adults aged 40 years or older.
UNASSIGNED: 1043 persons with IgG, IgA, light-chain, and biclonal MGUS detected by screening and an interpretable bone marrow sample.
UNASSIGNED: Monoclonal gammopathy of undetermined significance isotype; monoclonal protein concentration; free light-chain ratio; and total IgG, IgM, and IgA concentrations were used as predictors. Bone marrow plasma cells were categorized as 0% to 4%, 5% to 9%, 10% to 14%, or 15% or greater.
UNASSIGNED: The c-statistic for SMM or worse was 0.85 (95% CI, 0.82 to 0.88), and calibration was excellent (intercept, -0.07; slope, 0.95). At a threshold of 10% predicted risk for SMM or worse, sensitivity was 86%, specificity was 67%, positive predictive value was 32%, and negative predictive value was 96%. Compared with the Mayo Clinic model, the net benefit for the decision to refer for sampling was between 0.13 and 0.30 higher over a range of plausible low-risk thresholds.
UNASSIGNED: The prediction model will require external validation.
UNASSIGNED: This accurate prediction model for SMM or worse was developed in a population-based cohort of persons with presumed MGUS and may be used to defer bone marrow sampling and referral to hematology.
UNASSIGNED: International Myeloma Foundation and the European Research Council.

BACKGROUND: High levels of physical activity are associated with reduced risk of the blood cancer multiple myeloma (MM). MM is preceded by the asymptomatic stages of monoclonal gammopathy of undetermined significance (MGUS) and smouldering multiple myeloma (SMM) which are clinically managed by watchful waiting. A case study (N = 1) of a former elite athlete aged 44 years previously indicated that a multi-modal exercise programme reversed SMM disease activity. To build from this prior case study, the present pilot study firstly examined if short-term exercise training was feasible and safe for a group of MGUS and SMM patients, and secondly investigated the effects on MGUS/SMM disease activity.
METHODS: In this single-arm pilot study, N = 20 participants diagnosed with MGUS or SMM were allocated to receive a 16-week progressive exercise programme. Primary outcome measures were feasibility and safety. Secondary outcomes were pre- to post-exercise training changes to blood biomarkers of MGUS and SMM disease activity- monoclonal (M)-protein and free light chains (FLC)- plus cardiorespiratory and functional fitness, body composition, quality of life, blood immunophenotype, and blood biomarkers of inflammation.
RESULTS: Fifteen (3 MGUS and 12 SMM) participants completed the exercise programme. Adherence was 91 ± 11%. Compliance was 75 ± 25% overall, with a notable decline in compliance at intensities > 70% V̇O2PEAK. There were no serious adverse events. There were no changes to M-protein (0.0 ± 1.0 g/L, P =.903), involved FLC (+ 1.8 ± 16.8 mg/L, P =.839), or FLC difference (+ 0.2 ± 15.6 mg/L, P =.946) from pre- to post-exercise training. There were pre- to post-exercise training improvements to diastolic blood pressure (- 3 ± 5 mmHg, P =.033), sit-to-stand test performance (+ 5 ± 5 repetitions, P =.002), and energy/fatigue scores (+ 10 ± 15%, P =.026). Other secondary outcomes were unchanged.
CONCLUSIONS: A 16-week progressive exercise programme was feasible and safe, but did not reverse MGUS/SMM disease activity, contrasting a prior case study showing that five years of exercise training reversed SMM in a 44-year-old former athlete. Longer exercise interventions should be explored in a group of MGUS/SMM patients, with measurements of disease biomarkers, along with rates of disease progression (i.e., MGUS/SMM to MM).
BACKGROUND: https://www.isrctn.com/ISRCTN65527208 (14/05/2018).

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.

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Monoclonal gammopathy of undetermined significance (MGUS) is the earliest discernible stage of multiple myeloma (MM) and Waldenström\'s macroglobulinemia (WM). Early diagnosis of MG may be compromised by the low-level infiltration, undetectable to low-sensitive methodologies. Here, we investigated the prevalence and immunophenotypic profile of clonal (c) plasma cells (PC) and/or cB-lymphocytes in bone marrow (BM) and blood of subjects with a serum M-component from the iSTOPMM program, using high-sensitive next-generation flow cytometry (NGF), and its utility in the diagnostic classification of early-stage MG. We studied 164 paired BM and blood samples from 82 subjects, focusing the analysis on: 55 MGUS, 12 smoldering MM (SMM) and 8 smoldering WM (SWM). cPC were detected in 84% of the BM samples and cB-lymphocytes in 45%, coexisting in 39% of cases. In 29% of patients, the phenotypic features of cPC and/or cB-lymphocytes allowed a more accurate disease classification, including: 19/55 (35%) MGUS, 1/12 (8%) SMM and 2/8 (25%) SWM. Blood samples were informative in 49% of the BM-positive cases. We demonstrated the utility of NGF for a more accurate diagnostic classification of early-stage MG.

BACKGROUND: Smoldering multiple myeloma (SMM) is a heterogeneous asymptomatic precursor to multiple myeloma (MM). It is the intermediate stage between monoclonal gammopathy of undetermined significance (MGUS) and MM, where there is a subset of patients with an indolent disease and a subset with progressive disease. The Mayo Clinic published a risk stratification model to help to differentiate these patients into 3 groups.
OBJECTIVE: To describe the demographic features of patients with SMM treated at the Italian Hospital of Buenos Aires.
METHODS: Retrospective cohort study, between 01/2005 and 05/2022. Consecutive patients with a confirmed diagnosis of SMM were included. Patients were followed from diagnosis until death, progression or loss to follow-up.
RESULTS: Thirty-nine patients with SMM were included, of whom 16 (41%) were men. The median age at diagnosis was 69 years (95% CI: 55-77). 25 (64%) had a previous MGUS; the median time to progression (TTP) from MGUS to SMM was 6.4 months. 19 (49%) of patients had progression to MM. Eight (20%) of patients died, 3 (37%) secondary to myeloma. The most common type of band was IgG kappa with 55%. The median of monoclonal band was 1.5 (CI: 1.2-2), the median of plasma cells in bone marrow biopsy was 15% (CI: 12-20), 29 patients (74.36%) presented evaluation of lytic lesions, 6 patients (15%) presented risk assessment by FISH, of which 2 were positive for del(17p). The median follow-up of the cohort was 92 months (95% CI: 72.4-127.2). The estimated median TTP for the entire cohort was 71 months (95% CI, 55-94). Eight (21%) patients presented a high risk of progression according to the Mayo clinic score. The median TTP according to the Mayo Clinic score was 44 months (CI: 27-62) for high-risk patients, 86.5 months (CI: 69-94) for intermediate-risk patients, and 75 months for low risk. Of the patients who presented del(17p) all progressed to myeloma during follow-up with a median TTP of 49 months (CI: 35-64). 1 patient entered the research protocol.
CONCLUSIONS: Our cohort demonstrated characteristics similar to those published. Patients with high-risk Mayo score and del(17p) by FISH showed faster progression, which emphasizes the need to include them in research protocols.

Smoldering multiple myeloma (SMM) is a heterogeneous disease in terms of progression to myeloma (MM), but its standard of care continues to be observation.
The QuiRedex phase 3 trial initiated in 2007 included 119 high-risk patients with SMM randomized to treatment or observation. Treatment consisted of nine 4-week induction cycles (lenalidomide [Rd], 25 mg on days 1-21 plus dexamethasone, 20 mg on days 1-4 and 12-15), followed by maintenance (R, 10 mg on days 1-21) for up to 2 years. The primary end-point was time to progression (TTP) to myeloma based on per protocol population. Secondary end-points were overall survival (OS), response rate, and safety. An update of the trial after a long-term follow-up is presented here. This trial was registered with ClinicalTrials.gov (NCT00480363).
After a median follow-up time of 12.5 years (range: 10.4-13.6), the median TTP to MM was 2.1 years in the observation arm and 9.5 years in the Rd arm (HR: 0.28, 95% CI: 0.18-0.44, p < 0.0001). The median OS was 8.5 years in the abstention arm and not reached in the Rd group (HR: 0.57, 95% CI: 0.34-0.95, p = 0.032). Patients who progressed received optimized treatments according to the standards of care, and the OS from progression was comparable in both arms (p = 0.96).
This analysis confirms that early treatment with Rd for high-risk SMM translates into a sustained benefit in both TTP and OS.
Pethema (Spanish Program for the Treatment of Hematologic Diseases), Spain.

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