The International Myeloma Foundation and Black Swan Research Initiative® announced the recently published cohort study by the iStopMM team on the “Development of a Multivariable Model to Predict the Need for Bone Marrow Sampling in Persons with Monoclonal Gammopathy of Undetermined Significance : A Cohort Study Nested in a Clinical Trial.” The study was published in the Annals of Internal Medicine on April 2.
STUDIO CITY, Calif., April 11, 2024 (GLOBE NEWSWIRE) -- The International Myeloma Foundation (IMF) and Black Swan Research Initiative® (BSRI) announced the recently published cohort study by the iStopMM (Iceland Screens, Treats, or Prevents Multiple Myeloma) team on the “Development of a Multivariable Model to Predict the Need for Bone Marrow Sampling in Persons with Monoclonal Gammopathy of Undetermined Significance (MGUS): A Cohort Study Nested in a Clinical Trial.” The study was published in the Annals of Internal Medicine on April 2.
“This paper provides an evidence-based approach to selecting persons with MGUS in whom bone marrow sampling may be deferred and has the potential to decrease the number of people unnecessarily exposed to bone marrow sampling and to improve the efficiency and cost-effectiveness of the diagnostic evaluation of MGUS,” said iStopMM Principal Investigator Dr. Sigurður Y. Kristinsson (University of Iceland—Reykjavik, Iceland).
As stated in the study, the objective of the original research is “to develop a multivariable prediction model that predicts the probability that a person with presumed MGUS has 10 percent or greater bone marrow plasma cells or BMPC (smoldering multiple myeloma 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.”
The research aims to create a predictive model “using commonly available laboratory parameters” to predict whether someone with presumed MGUS has smoldering multiple myeloma (SMM) or a more severe condition, based on bone marrow tests. This can help decide whether obtaining a bone marrow sample is necessary.
IMF Chief Scientific Officer and co-author of the iStopMM cohort study Dr. Brian G.M. Durie said that “this study is a major step forward in efforts to make screening a practical approach to achieving early diagnosis by significantly reducing the need for automatic bone marrow sampling.”
Data Sources and Study Population
Using data from the population-based screening study for MGUS conducted by iStopMM beginning 2016 (with 75,422 Icelanders aged 40 and above providing blood samples), 1,043 individuals “with IgG, IgA, light-chain, and biclonal MGUS detected by screening and an interpretable bone marrow sample” were identified and included in the current cohort study. Median age was 68 years (IQR, 60 to 75 years); 55.4 percent of participants were males.
Participants who showed MGUS in their screening test results were enrolled in a randomized controlled trial, which was divided into three groups: “Group 1 continued to receive care from the Icelandic Health Service as though they had never been screened. Groups 2 and 3 were evaluated at the study clinic for initial assessment and follow-up, including bone marrow sampling,” according to the study.
Participants with presumed MGUS who were randomly assigned to groups 2 and 3 were included in this current cohort study, with some exclusions: “those with IgM MGUS (does not progress to MM); those who were randomly assigned to group 2 but were categorized as low-risk MGUS based on the Mayo Clinic risk stratification model (protocol did not include bone marrow sampling); those who never presented to the study clinic after randomization; those who never had bone marrow sampling; those who had bone marrow sampling more than 365 days from the screening blood sample; and those whose trephine biopsy and bone marrow aspirate results were both uninterpretable with regards to the percentage of BMPC.”
Measurements used for the study include: MGUS isotype; monoclonal protein concentration; free light-chain ratio; and total IgG, IgM, and IgA concentrations as predictors. Bone marrow plasma cells were categorized as: 0-4 percent; 5-9 percent, 10-14 percent, or 15 percent or greater.
Results and Conclusion
According to the results: “The c-statistic for SMM or worse was 0.85 (95 percent CI, 0.82 to 0.88), and calibration was excellent (intercept, —0.07; slope, 0.95). At a threshold of 10 percent predicted risk for SMM or worse, sensitivity was 86 percent, specificity was 67 percent, positive predictive value was 32 percent, and negative predictive value was 96 percent. 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.”
One of the authors of the study, Elías S. Eyþórsson, MD, Ph.D. (University of Iceland—Reykjavik, Iceland) said: “Clinicians who use our model to help with the decision to obtain a bone marrow sample in persons with MGUS could defer the sometimes-painful procedure in a larger proportion of persons with MGUS while missing fewer cases of smoldering multiple myeloma than they could using previous decision aids.”
The study concludes that “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.”
The prediction model “leverages laboratory parameters commonly available at the time of diagnosis of presumed MGUS and could therefore be used in the clinic to facilitate shared decision-making regarding referral for bone marrow sampling.”
Limitations
In terms of limitations, the study notes that “the prediction model will require external validation before clinical use. The model does not supersede clinical judgment and should only be used if there is no clinical suspicion of MM or related lymphoproliferative disorders, including light-chain amyloidosis.”
The study’s model “has possible weaknesses that must be addressed.”
“Although sample size was adequate and bootstrap resampling with optimism correction was used to combat overfitting, [the] model will need to be externally validated in other screened and clinical cohorts to ensure generalizability. This is especially important as [this] model was developed in the predominantly White and genetically homogeneous population of Iceland. Furthermore, many clinicians and persons with MGUS may want to base their decision on whether to obtain bone marrow sample on the probability of 20 percent or greater BMPC, as this is a component of the International Myeloma Working Group (IMWG) 2/20/20 risk stratification model for SMM.”
Moreover, “the study does not provide evidence that identifying persons with SMM and monitoring them more intensely would result in superior outcomes. In fact, no prospective study has shown that monitoring of MGUS or SMM improves outcomes of MM after progression. This is a critical research question in the field of monoclonal gammopathies and is the main subject of the iStopMM trial.”
Finally, the iStopMM research team stated that the study “provides an evidence-based approach to selecting persons with presumed MGUS in whom bone marrow sampling may be deferred and has the potential to both decrease the number of persons unnecessarily exposed to this safe but invasive procedure by facilitating shared decision-making, allowing for personalized care of MGUS by applying different risk thresholds depending on each unique case. However, [this] model requires validation in other populations.”
To know the full details of the iStopMM cohort study, view it online. This research was funded by the International Myeloma Foundation and the European Research Council.
ABOUT THE ISTOPMM PROJECT
Launched in 2016, the iStopMM (Iceland Screens, Treats, or Prevents Multiple Myeloma) Project is the first population-based screening study for monoclonal gammopathy of undetermined significance (MGUS), with Dr. Sigurdur Y. Kristinsson of the University of Iceland as principal investigator. The study also includes a randomized trial of follow-up strategies. The iStopMM Project is one of several global research projects supported by the IMF Black Swan Research Initiative® (BSRI) which is committed to finding a cure for myeloma.
ABOUT THE BLACK SWAN RESEARCH INITIATIVE®
The International Myeloma Foundation (IMF) has banded together the world’s brightest minds in research, oncology, and health studies to form the IMF’s Black Swan Research Initiative® (BSRI) – a leading-edge project that pits our scientists and leaders on the frontlines against myeloma. The IMF’s BSRI was established in 2012, following a scientific brainstorming meeting linked to the International Myeloma Working Group (IMWG) Summit in Amsterdam. Together, the IMF and BSRI’s mission is to find the first definitive cure for myeloma and to help bridge the gap from long-term remission to cure. Led by an international consortium of myeloma experts, BSRI is bridging the gap from long-term remission to cure by sharing collective data and tracking myeloma through multiple, simultaneous drug trials and therapies to determine which work best.
ABOUT THE INTERNATIONAL MYELOMA FOUNDATION
Founded in 1990, the International Myeloma Foundation (IMF) is the first and largest global foundation focusing specifically on multiple myeloma. The Foundation’s reach extends to more than 525,000 members in 140 countries worldwide. The IMF is dedicated to improving the quality of life of myeloma patients while working toward prevention and a cure by focusing on four key areas: research, education, support, and advocacy. The IMF has conducted more than 250 educational seminars worldwide, maintains a world-renowned InfoLine, and in 2001, established the International Myeloma Working Group (IMWG), a collaborative research initiative focused on improving myeloma treatment options for patients. In 2012, the IMF launched the Black Swan Research Initiative®, a groundbreaking research project aimed at curing myeloma. The IMF can be reached at (800) 452-CURE (2873). The global website is www.myeloma.org.
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