clinical topic updates

Updates on Smoldering Multiple Myeloma

by S. Vincent Rajkumar, MD


High-risk smoldering multiple myeloma represents a subset of disease that is more likely to progress to active multiple myeloma. Efforts to refine risk stratification and to intervene effectively in patients with high-risk smoldering multiple myeloma have been gaining momentum.

Expert Commentary

S. Vincent Rajkumar, MD

Edward W. and Betty Knight Scripps Professor of Medicine
Mayo Clinic
Rochester, MN

“Now, if you believe that patients with high-risk smoldering multiple myeloma should be treated, the questions that follow are: What is your rationale, and how should they be treated?” 

S. Vincent Rajkumar, MD

There is a lot of heterogeneity in smoldering multiple myeloma, an asymptomatic condition, and not every patient is at the same risk of progression to malignancy. Thus, to avoid toxicity and other harms, the emphasis has been on selecting only a subset of patients for possible intervention (ie, those patients with smoldering multiple myeloma who are at high risk of progression).

Many different risk factors have been described and utilized in the risk stratification of smoldering multiple myeloma. Before the International Myeloma Working Group (IMWG) revised the multiple myeloma diagnostic criteria in 2014, smoldering multiple myeloma had traditionally been defined by the presence of a serum monoclonal (M) protein of 3 g/dL or higher and greater than or equal to 10% bone marrow plasma cells without evidence of any CRAB symptoms (ie, hypercalcemia, renal failure, anemia, or lytic bone lesions) or other multiple myeloma–defining events. Overall, the risk of progression to malignancy in the first 5 years was 10% per year in patients with smoldering multiple myeloma. 

Subsequently, we risk stratified individuals with smoldering multiple myeloma using the Mayo Clinic 2018 risk stratification system (also called the 20/2/20 criteria), which takes into consideration the following 3 risk factors for progression: bone marrow plasma cells greater than 20%, M protein greater than 2 g/dL, and a ratio of involved to uninvolved free light chains greater than 20. We can identify a subset of patients who have the highest risk of progression by the presence of 2 or 3 of these risk factors, and that is the group that we target for therapy. The same IMWG paper included a scoring system that allows for an even more accurate prediction of who is likely to progress. 

Outside of clinical trials, the conventional approach to smoldering multiple myeloma used to be close observation until progression to active multiple myeloma. This is now changing for the subset of patients with high-risk smoldering multiple myeloma for whom we are recommending consideration for early therapy. Now, if you believe that patients with high-risk smoldering multiple myeloma should be treated, the questions that follow are: What is your rationale, and how should they be treated? Two randomized trials have compared lenalidomide-based therapy with observation in high-risk smoldering multiple myeloma. These trials differed in the definitions used for high-risk smoldering multiple myeloma and in the lenalidomide-based treatment regimens; however, both studies demonstrated an 80% to 90% risk reduction in end-organ damage, and one demonstrated an improvement in overall survival. 

Regarding the question of the type of treatment that might be the most appropriate for patients with high-risk smoldering multiple myeloma, we have data on lenalidomide and dexamethasone from the randomized trials, but additional work is being done. These patients might benefit from a multiple myeloma–like regimen such as daratumumab-lenalidomide-dexamethasone. Therefore, the National Cancer Institute and the ECOG-ACRIN Cancer Research Group are investigating lenalidomide plus dexamethasone with or without daratumumab in the treatment of patients with high-risk smoldering multiple myeloma (NCT03937635). We also want to continue to gain insights on the molecular pathogenesis of smoldering multiple myeloma that leads to early transformation.


Bolli N, Sgherza N, Curci P, et al. What is new in the treatment of smoldering multiple myeloma? J Clin Med. 2021;10(3):421. doi:10.3390/jcm10030421

Bustoros M, Sklavenitis-Pistofidis R, Park J, et al. Genomic profiling of smoldering multiple myeloma identifies patients at a high risk of disease progression. J Clin Oncol. 2020;38(21):2380-2389. doi:10.1200/JCO.20.00437 Lenalidomide, and dexamethasone with or without daratumumab in treating patients with high-risk smoldering myeloma. Accessed July 29, 2021.

Joseph NS, Dhodapkar MV, Lonial S. The role of early intervention in high-risk smoldering myeloma. Am Soc Clin Oncol Educ Book. 2020;40:1-9. doi:10.1200/EDBK_278915.

Lakshman A, Rajkumar SV, Buadi FK, et al. Risk stratification of smoldering multiple myeloma incorporating revised IMWG diagnostic criteria. Blood Cancer J. 2018;8(6):59. doi:10.1038/s41408-018-0077-4

Mateos M-V, Hernández M-T, Giraldo P, et al. Lenalidomide plus dexamethasone for high-risk smoldering multiple myeloma. N Engl J Med. 2013;369(5):438-447. doi:10.1056/NEJMoa1300439

Mateos M-V, Hernández M-T, Giraldo P, et al. Lenalidomide plus dexamethasone versus observation in patients with high-risk smouldering multiple myeloma (QuiRedex): long-term follow-up of a randomised, controlled, phase 3 trial. Lancet Oncol. 2016;17(8):1127-1136. doi:10.1016/S1470-2045(16)30124-3

Mateos M-V, Kumar S, Dimopoulos MA, et al. International Myeloma Working Group risk stratification model for smoldering multiple myeloma (SMM). Blood Cancer J. 2020;10(10):102. doi:10.1038/s41408-020-00366-3

Rajkumar SV, Landgren O, and Mateos M-V. Smoldering multiple myeloma. Blood. 2015;125(20):3069-3075. doi:10.1182/blood-2014-09-568899

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