What is the rationale for early intervention in high-risk smoldering MM?

The Multiple Myeloma Hub spoke with Shaji Kumar, Mayo Clinic, Rochester, US. We asked, What is the rationale for early intervention in high-risk smoldering multiple myeloma (MM)?

In this interview, Dr Kumar explored the evolving paradigm of early intervention in multiple myeloma, with a focus on smoldering MM. Kumar discussed the risk of progression to active disease, the development of risk stratification tools, and the growing body of clinical trial evidence supporting early treatment in patients with high-risk smoldering MM. Kumar also emphasized the increasing importance of delaying disease onset and the potential to achieve a cure in some patients.

Key learnings

• The risk of progression from monoclonal gammopathy of undetermined significance (MGUS) to active MM is approximately 1% per year.^1,2

• Approximately 40% of patients with smoldering MM will progress to active myeloma within the first 5 years of diagnosis, with an additional 12–15% of patients progressing in the subsequent 5 years.^1,2

• Historically, early intervention was avoided due to limited understanding of disease progression, as well as a lack of safe treatments or evidence of benefit from prospective studies.

• Improved risk stratification tools, such as the International Myeloma Working Group 2/20/20 criteria and Mayo 20/20/20 risk stratification system, enable better identification of patients with smoldering MM at the highest risk of progression to active MM.^3,4

• Therapeutics used to treat active myeloma, such as lenalidomide and daratumumab, are well-tolerated and are increasingly being explored for early use in high-risk smoldering MM.

• There are three trials which support early intervention:

  • QuiRedex (NCT00480363): A phase III study of lenalidomide plus dexamethasone vs observation for the treatment of patients with high-risk smoldering MM. Data demonstrated improvement in progression-free survival (PFS) and overall survival; however, the study was limited due to a lack of advanced imaging and, therefore, the potential enrolment of patients with active myeloma.⁵

  • ECOG-E3A06 (NCT01169337): A phase III study of lenalidomide as a sole agent vs observation in high-risk smoldering MM, which showed improved PFS with lenalidomide.⁶

  • AQUILA (NCT03301220): A phase III study of subcutaneous daratumumab as a sole agent vs observation for high-risk smoldering MM, demonstrating a reduced risk of progression to active MM or death, with higher OS rates, vs active monitoring.⁷

• These data suggest a shift toward early intervention being beneficial in selected patients with high-risk smoldering MM.

• Future directions include evaluation of multi-drug regimens, and the use of novel immunotherapies, with the aim to completely eradicate the clone in early disease stages, leading to potential cure. 

• Recent advances have enabled identification of patients with high-risk smoldering MM. This permits application of early treatment strategies, with safe and effective drugs that can delay disease progression and, potentially, eradicate the disease in some cases.