# Smouldering multiple myeloma

Source: https://onco.cc/cancers/smouldering-myeloma/  
OnCo record `smouldering-myeloma` (Cancer). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

Smouldering myeloma is myeloma that has not yet damaged bones, kidneys or blood counts. Most people are watched, but those at high risk of progressing can now be treated: the AQUILA trial showed daratumumab alone delays active myeloma, and it was approved for this use in 2025.

## Summary

Smouldering myeloma is defined by a serum M-protein of 30 g/L or more, or urinary M-protein of 500 mg a day or more, or clonal marrow plasma cells of 10 to 60 percent, with none of the myeloma-defining events (the CRAB features of hypercalcaemia, renal failure, anaemia and bone lesions, or the SLiM markers of 60 percent plasma cells, a light chain ratio of 100 or more, or more than one focal lesion on MRI). The Mayo 20/2/20 model, with M-protein above 20 g/L, a free light chain ratio above 20 and marrow plasma cells above 20 percent, separates a high-risk group in which about half progress within two years from a low-risk group that may never need treatment. Whole-body MRI or PET-CT to exclude occult bone disease is part of the work-up.

Active monitoring every three to six months was the only standard until lenalidomide was tested: the ECOG E3A06 trial (2020) showed lenalidomide alone delayed progression in intermediate- and high-risk disease, with three-year progression-free survival of 91 percent against 66 percent under observation, at the price of side effects that most patients on a watch-and-wait footing found hard to accept. AQUILA, reported in 2024, randomised 390 patients with high-risk smouldering myeloma to subcutaneous daratumumab monotherapy for up to three years or active monitoring: five-year progression-free survival 63.1 percent versus 40.8 percent (hazard ratio 0.49), with a survival signal, and daratumumab was approved for high-risk smouldering myeloma in the United States in late 2025, the first drug licensed before myeloma becomes active.

Whether to treat at all remains argued: many high-risk patients would have lived years without symptoms, no trial has yet shown that early treatment lengthens life, and intensive curative-intent regimens (carfilzomib-lenalidomide-dexamethasone and transplant in the Spanish GEM-CESAR and US ASCENT studies) trade heavy therapy for deep remissions of uncertain meaning. Bispecific antibodies such as linvoseltamab and quadruplets are being tested in the same population, and population screening for M-protein (iStopMM in Iceland) is asking whether finding the disease earlier helps anyone.

## Fields

- Kind: Cancer
- Last checked: 2026-09-17
- Also known as: Smoldering multiple myeloma; SMM; High-risk smouldering myeloma; Asymptomatic myeloma
- Tags: subtype-page
- Group: haematologic
- Burden: Found in about one in seven people diagnosed with a plasma cell cancer, usually by chance on a blood test; about one in ten progress to active myeloma each year for the first five years, and the high-risk half progress much faster.
- Subtypes: Low-risk smouldering myeloma (Mayo 20/2/20 score 0); Intermediate-risk smouldering myeloma; High-risk smouldering myeloma (20/2/20 score 2 or more; about half progress within two years); Monoclonal gammopathy of undetermined significance (MGUS, precursor with under 10 percent plasma cells)
- Biomarkers: Serum M-protein and immunofixation; Free light chain ratio; Marrow plasma cell percentage; Mayo 20/2/20 and IMWG risk scores; High-risk cytogenetics: t(4;14), del(17p), gain 1q; Whole-body MRI or PET-CT for focal lesions; Evolving M-protein over time

## Standard of care

- Low- and intermediate-risk: Active monitoring with blood tests every three to six months and imaging when the M-protein or light chains rise; no treatment. ([Smouldering myeloma / MGUS](https://onco.cc/terms/smoldering-myeloma/), [Whole-body MRI](https://onco.cc/technologies/whole-body-mri/))
- High-risk (Mayo 20/2/20 or IMWG high risk): Daratumumab monotherapy for up to three years (AQUILA), or lenalidomide with or without dexamethasone (E3A06), or a clinical trial; monitoring remains acceptable after shared decision-making. ([Daratumumab](https://onco.cc/drugs/daratumumab/), [Lenalidomide](https://onco.cc/drugs/lenalidomide/), [Dexamethasone](https://onco.cc/drugs/dexamethasone/), [Smouldering myeloma / MGUS](https://onco.cc/terms/smoldering-myeloma/))
- Trials of interception: Bispecific antibodies (linvoseltamab), isatuximab-lenalidomide-dexamethasone and curative-intent quadruplets in high-risk disease; population screening studies. ([Linvoseltamab](https://onco.cc/drugs/linvoseltamab/), [Isatuximab](https://onco.cc/drugs/isatuximab/), [A Study to Compare Linvoseltamab and Daratumumab Treatment in High-Risk Smoldering Multiple Myeloma (HR-SMM)](https://onco.cc/trials/nct07393282/), [A Proof-of-Concept Trial to Study the Safety and Activity of Linvoseltamab in Adult Participants With Smoldering Multiple Myeloma at High Risk of Deve](https://onco.cc/trials/nct05955508/), [Isatuximab in Combination With Lenalidomide and Dexamethasone in High-risk Smoldering Multiple Myeloma](https://onco.cc/trials/nct04270409/), [iStopMM](https://onco.cc/trials/istopmm/))

## State of the art

- AQUILA made daratumumab the first drug approved for high-risk smouldering myeloma, delaying progression to active disease.
- Risk models based on M-protein, light chains and marrow burden separate patients who need close watching from those who may never need treatment.
- Whether early treatment lengthens life, rather than only delaying the diagnosis of active myeloma, is still unproven.

## Open problems

- No trial has shown that treating smouldering myeloma lengthens life rather than delaying the label of active disease.
- Risk models still misclassify many patients in both directions.
- Whether curative-intent treatment of a precursor is justified, and for whom.

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/Smouldering_myeloma
- Wikipedia: https://en.wikipedia.org/wiki/Smouldering_myeloma
- NCCN Guidelines: Multiple Myeloma: https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1445

## Connected records

- technologies: [PET/CT](https://onco.cc/technologies/pet-ct/), [Whole-body MRI](https://onco.cc/technologies/whole-body-mri/)
- targets: [CD38](https://onco.cc/targets/cd38/)
- terms: [High-risk cytogenetics (myeloma)](https://onco.cc/terms/high-risk-myeloma/), [R-ISS / R2-ISS staging](https://onco.cc/terms/r-iss/), [Smouldering myeloma / MGUS](https://onco.cc/terms/smoldering-myeloma/)
- drugs: [Daratumumab](https://onco.cc/drugs/daratumumab/), [Dexamethasone](https://onco.cc/drugs/dexamethasone/), [Isatuximab](https://onco.cc/drugs/isatuximab/), [Lenalidomide](https://onco.cc/drugs/lenalidomide/), [Linvoseltamab](https://onco.cc/drugs/linvoseltamab/)
- trials: [A Proof-of-Concept Trial to Study the Safety and Activity of Linvoseltamab in Adult Participants With Smoldering Multiple Myeloma at High Risk of Deve](https://onco.cc/trials/nct05955508/), [A Study to Compare Linvoseltamab and Daratumumab Treatment in High-Risk Smoldering Multiple Myeloma (HR-SMM)](https://onco.cc/trials/nct07393282/), [Isatuximab in Combination With Lenalidomide and Dexamethasone in High-risk Smoldering Multiple Myeloma](https://onco.cc/trials/nct04270409/), [iStopMM](https://onco.cc/trials/istopmm/)
- cancers: [Multiple myeloma](https://onco.cc/cancers/multiple-myeloma/)

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