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The effect of intervention versus watchful waiting on disease progression and overall survival in smoldering multiple myeloma: a systematic review of randomized controlled trials



Smoldering multiple myeloma (SMM) is an intermediate pre-malignant condition with individuals having a distinct risk of progression to overt myeloma. The optimal management option has remained controversial due to the heterogeneous nature of the condition in which progression to overt diseases is variable. The question of who, when, and what to use for the treatment of SMM remains equivocal. We performed a systematic review of randomized controlled trials and summarized the current evidence supporting the best approach to the management of SMM.


A comprehensive literature search of Medline/PubMed, PubMed Central, Embase, Scopus, Web of Science, Wiley Cochrane Library, CINAHL,, and conference proceedings of ASCO, ASH, EHA, and ESMO was performed on October 25, 2020. Synthesis of the result was done using narrative analysis.


Of the total 1560 identified records, 10 eligible studies involving 1157 patients made up of 580 in the intervention group and 577 in the control group were included in this review. Three early trials of melphalan and prednisone fail to demonstrate any significant impact on disease progression with major toxicities reported. Three trials on bisphosphonate monotherapy show reduced skeletal-related events without any clinical effect on disease progression. Lenalidomide monotherapy or as part of a combination therapy demonstrates superiority in delaying disease progression over observation. Only Lenalidomide and dexamethasone combination demonstrated superior overall survival over observation across the trials.


Trials of lenalidomide in a less intensive approach has shown promise in delaying disease progression and should be investigated further in clinical trials.

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This research did not receive any grant from funding agencies in the public, not-for-profit or commercial sectors.

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Correspondence to Ademola S. Ojo.

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Appendix I

Search Strategy.

Asymptomatic multiple myeloma or smoldering myeloma or smoldering multiple myeloma.


Clinical trial or randomized controlled trial or intervention or therapy or drug treatment or Lenalidomide or Dexamethasone or Daratumumab or Thalidomide or Zoledronic acid or Carfilzomib or Siltuximab.


Controlled or observation or no treatment or no intervention or Placebo.


Disease progression or active multiple myeloma.

Search example:

"smoldering multiple myeloma"[MeSH Terms] OR ("smoldering"[All Fields] AND "multiple"[All Fields] AND "myeloma"[All Fields]) OR "smoldering multiple myeloma"[All Fields] OR ("smoldering"[All Fields] AND "myeloma"[All Fields]) OR "smoldering myeloma"[All Fields].

Appendix II

figure a

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Ojo, A.S., Ojukwu, S.G., Asemota, J. et al. The effect of intervention versus watchful waiting on disease progression and overall survival in smoldering multiple myeloma: a systematic review of randomized controlled trials. J Cancer Res Clin Oncol 148, 897–911 (2022).

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  • Smoldering multiple myeloma
  • Multiple myeloma
  • Randomized controlled trial
  • Clinical trial
  • Early intervention