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  • Review Article
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Diagnosis, risk stratification and management of smouldering multiple myeloma

Nature Reviews Clinical Oncology (2026)Cite this article

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Abstract

New therapies have markedly improved survival outcomes for patients with multiple myeloma (MM). However, the onset of active disease, as defined by the 2014 International Myeloma Working Group SLiM–CRAB criteria, is often linked to substantial and irreversible morbidity. MM always develops from an asymptomatic precursor state called smouldering multiple myeloma (SMM). The clinical trajectory of SMM varies considerably; low-risk SMM often has an indolent course, similar to monoclonal gammopathy of undetermined significance, whereas nearly half of the subset of patients with high-risk SMM have progression to symptomatic MM within 2 years. Highly active treatments for MM, which remains an incurable disease, are being investigated for the management of SMM, with the aim of delaying or even preventing such progression. Both early therapeutic intervention and active surveillance are reasonable management options for patients with high-risk SMM, with decisions individualized through a detailed risk–benefit discussion with the patient. In this Review, we discuss current approaches for diagnostic evaluation, risk stratification and management of SMM, as well as future challenges and emerging opportunities in the field.

Key points

  • Within the first 5 years following diagnosis, smouldering multiple myeloma (SMM) has a tenfold higher risk of progression to MM compared with monoclonal gammopathy of undetermined significance.

  • The clinical course of SMM is heterogeneous; high-risk SMM is associated with a 40–50% risk of progression to MM within the first 2 years of diagnosis.

  • Advanced imaging, especially PET–CT and MRI, is crucial in the diagnosis of SMM, to rule out overt MM and enhance prognostication.

  • Current risk-stratification tools for SMM, although validated and reproducible, are suboptimal; new approaches based on the disease biology are needed to enhance prognostication.

  • For patients with high-risk SMM, both early therapeutic intervention and active surveillance are reasonable management options, with decisions individualized through a detailed risk–benefit discussion with the patient.

  • Rational end point selection, focused on improving long-term patient outcomes, is key for future clinical trial strategies.

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Fig. 1: Disease spectrum of clonal plasma cell disorders.
Fig. 2: Algorithm for the management for smouldering multiple myeloma.

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Acknowledgements

The work of S.V.R. is supported by the NIH (R01 and SPORE).

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Authors and Affiliations

  1. Division of Hematology, Mayo Clinic, Rochester, MN, USA

    Saurabh Zanwar, Shaji Kumar & S. Vincent Rajkumar

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  1. Saurabh Zanwar
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  2. Shaji Kumar
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The authors contributed equally to all aspects of the article.

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Correspondence to S. Vincent Rajkumar.

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Competing interests

S.K. has acted as a consultant or adviser (with all payments made to his institution) for AbbVie, Bristol Myers Squibb/Celgene, Genentech/Roche, Janssen Oncology/Johnson & Johnson, K36, Pfizer, Regeneron, Sanofi and Takeda; declares research funding (to his institution) from AbbVie, Allogene Therapeutics, Bristol Myers Squibb/Celgene, CARsgen Therapeutics, GlaxoSmithKline, Janssen Oncology/Johnson & Johnson, MedImmune, Novartis, Regeneron, Roche/Genentech, Sanofi and Takeda; and has received reimbursement for travel, accommodation and expenses from AbbVie, Beigene, Janssen/Johnson & Johnson and Pfizer. S.V.R. is Chair of the International Myeloma Foundation Board of Directors; has received honoraria for CME Lectures for Medscape; declares intellectual property and royalties as an author and section editor for UpToDate (covering topics on plasma cell disorders); and served as principal investigator of the AQUILA trial, and in that capacity has also presented on behalf of Johnson & Johnson to the FDA ODAC in support of the approval of daratumumab for high-risk smouldering multiple myeloma. S.Z. declares no competing interests.

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Zanwar, S., Kumar, S. & Rajkumar, S.V. Diagnosis, risk stratification and management of smouldering multiple myeloma. Nat Rev Clin Oncol (2026). https://doi.org/10.1038/s41571-026-01119-0

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