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Smoldering Multiple Myeloma and Monoclonal Gammopathies: Understanding Mechanisms of Progression and the Role of Early Therapeutic Intervention

  • Advances in Hematologic Malignancies
    Issue 15, Winter 2022

    Omar Nadeem, MD, Twitter: @OmarNadeemMD
    Catherine Marinac, PhD
    Irene Ghobrial, MD, Twitter: @IreneGhobrial


    Monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) are precursor plasma cell disorders that carry a variable risk of progression to symptomatic multiple myeloma (MM). There have been ongoing efforts to determine the optimal tools for risk stratification in SMM, including the Mayo 2018 "20-2-20" criteria, which uses the following independent risk factors for progression:

    • ≥ 20% plasmacytosis in the bone marrow,
    • ≥ 2 g/dl M protein concentration in the serum, or
    • a serum free light chain ratio ≥ 20.

    The presence of two of these variables predicts a roughly 50% chance of progression to overt MM in two years. Additional high-risk cytogenetic and molecular abnormalities are utilized to further enhance the prognostic capabilities of these available tools.

    Early intervention in high-risk SMM has shown promise based on two phase 3 studies of lenalidomide demonstrating an improvement in outcomes compared to observation. There are numerous ongoing efforts to further improve upon these results, particularly due to the effectiveness of combination therapies used in MM utilizing monoclonal antibodies, proteasome inhibitors, and immunomodulatory agents.

    The Center for Prevention of Progression (CPOP) at Dana-Farber Cancer Institute is a multidisciplinary clinic and research center dedicated to patients with precursor blood cancers. The Center's mission is to learn about mechanisms of progression, study various therapeutic interventions, identify the highest risk subgroups of patients, and enhance screening efforts for plasma cell disorders. This is achieved through collaboration with multiple specialists and a combination of screening, observational, and interventional studies, including our PROMISE and PCROWD studies, which are helping to define high-risk patient subsets and mechanisms of disease progression.

    Some examples of our intervention trials in high-risk SMM include a phase 2 study of daratumumab, bortezomib, lenalidomide, and dexamethasone (NCT04775550). This study utilizes this highly potent combination strategy and aims to achieve high rates of minimal residual disease (MRD) negativity in this population. Additional ongoing studies in this high-risk population include the combination of isatuximab, lenalidomide, and dexamethasone (NCT04270409) and other immunotherapy trials that are currently in progress.

    We are also increasing our efforts to examine whether milder therapeutic and possibly non-therapeutic interventions can benefit patients who have a lower risk of progression to MM. Accordingly, we recently launched a study examining whether metformin, a drug commonly used to treat type 2 diabetes but considered safe for non-diabetics, can help reduce or stabilize clinical signs of progression to MM. This is a phase 2 randomized controlled trial comparing metformin vs. placebo in patients with high-risk MGUS and low-risk SMM (REFORM, NCT 04850846). The metformin dose is 1500 milligrams/day, provided in 500 milligram pills. The primary objective of the study is to determine whether metformin can reduce or stabilize serum monoclonal (M) protein concentrations from baseline to 6 months; however, we will also examine the molecular evolution of tumor cells in response to metformin, as well as changes in other clinical laboratory parameters.

    In summary, the CPOP clinic at Dana-Farber is a one-of-a-kind, comprehensive, and multidisciplinary clinic solely dedicated to patients with precursor blood cancers — allowing us to offer patients a state-of-the-art risk assessment, along with any therapeutic interventions that may reduce their risk of progression to overt MM.

  • The CPOP Umbrella illustration


    The Center for Prevention of Progression utilizes screening, tissue banking, and interventional studies to understand the mechanisms of disease progression and prevent development of active disease.