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High-risk smoldering multiple myeloma

Overview

Plasma cell disorders constitute a spectrum ranging from premalignant conditions (monoclonal gammopathy of unknown significance [MGUS]) and smoldering multiple myeloma (SMM) to symptomatic malignancy (multiple myeloma [MM])1

diagnostic-criteria-icon

IMWG diagnostic criteria for plasma cell disorders

IMWG diagnostic criteria for plasma cell disorders are based on serum and/or urine M-protein, BMPC, and MM defining events1

m-protien-icon

M-protein1 serum urine

bmpc-Icon

BMPC1

mm-events-icon

MM defining
events1

MGUSa
Incidence2: 60–120
per 100,000

SMM
Incidence2: 0.4-0.9
per 100,000

MM
Incidence3: 7.2
per 100,000

<3 g/dL
<500 mg/24h

<3 g/dL
≥500 mg/24 h

N/A

<10%

10–60%

≥10% or biopsy-proven
plasmacytoma

None

CRAB symptoms or
SLiM biomarkers

  • CRAB criteria: hypercalcemia, renal insufficiency, anemia, bone lesions1

  • SLiM criteria: ≥60% BMPC, Serum FLCr ≥100, >1 focal lesion on MRI1

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MGUS and SMM risk of progression to MM

front-figure

Error bars denote 95% confidence intervals. Figure reproduced with permission

from: Kyle RA, et al. N Engl J Med. 2007;356(25):2582–90.4

Within 10 years of SMM diagnosis, about 70% of patients with SMM will progress to MM5

  • In the first 5 years, patients with SMM progress to MM at a rate of 10% per year5
  • Between 5 to 10 years, the progression rate drops to 3% per year5
  • After 10 years, the risk of progression is 1%, the same rate as patients with MGUS5
diagnostic-criteria-icon

Risk stratification of SMM

SMM is a heterogeneous disease, and consequently, time to progression to MM may vary significantly5

MAYO 2/20/20 (2018)6
Risk factors
  • BMPC >20%
  • M-protein >2 g/dL
  • FLC ratiob >20
Low-risk
  • No risk factors
  • Risk of progression at 2 years: 10%
Intermediate-risk
  • Any 1 risk factor
  • Risk of progression at 2 years: 26%
High-risk
  • ≥2 risk factors
  • Risk of progression at 2 years: 47%
hrsmm-figure
IMWG 20206
Risk assessment scoring toolc
BMPC Score FLC ratiob Score
0–15 0 0-10 0
>15–20 2 10-25 2
>20–30 3 25–40 3
>30–40 5 >40 5
>40 6 >40 5
M-protein Score
0–1.5 0
>1.5-3 3
>3 4
FISH Score
abnormalityd 2
Low-risk
  • Total points: 0–4
  • Risk of progression at 2 years: 4%
Low-intermediate risk
  • Total points: 5–8
  • Risk of progression at 2 years: 26%
Intermediate-risk
  • Total points: 9–12
  • Risk of progression at 2 years: 51%
High-risk
  • Total points: >12
  • Risk of progression at 2 years: 73%
bulb-icon

Risk stratification models continue to evolve as new technological capabilities and risk factors of progression are identified7

Considerations for management of SMM
  • Risk of progression from SMM to MM is variable; therefore, management strategies differ based on the risk of progression4
  • Patients with highest risk could be considered for treatment on clinical trials or per guidelines in addition to observation4
  • See the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for MM for more information8

aThis data refers to IgM MGUS, non-IgM MGUS and light chain MGUS. bInvolved to uninvolved serum-free light chain ratio.cScoring tool uses a logistic regression model that includes 3 risk factors (BMPC, M-protein, and FLC ratio) along with cytogenetic abnormalities to provide a more individualized risk assessment.dThe presence of high-risk features by FISH t(4;14), t(14;16), del(13q), or amp(1q).

BMPC, bone marrow plasma cell; CRAB, hyperCalcemia, Renal insufficiency, Anemia, Bone lesions; FISH, fluorescence in-situ hybridization; FLC, free light chain; FLCr, serum-free light chain ratio; HR, high-risk; IgA, immunoglobulin A; IMWG, International Myeloma Working Group; MGUS, monoclonal gammopathy of undetermined significance; MM, multiple myeloma; M-protein, monoclonal protein; MRI, magnetic resonance imaging; N/A, not applicable; NCCN, National Comprehensive Cancer Network; SLiM, ≥Sixty-percent (60%) clonal bone marrow plasma cells, Light chain ratio MRI; SMM, smoldering multiple myeloma.

1. Rajkumar SV, et al. Blood Cancer J. 2022;12(9):129. 2. Visram A, et al. Hematology Am Soc Hematol Educ Program. 2021;2021(1):673–681. 3. National Cancer Institute 2024, Cancer Stat Facts: Myeloma. Accessed January 2025. https://seer.cancer.gov/statfacts/html/mulmy.html. 4. Kyle RA, et al. N Engl J Med . 2007;356(25):2582–90. 5. Blum A, et al. Blood Lymphat Cancer. 2018;8:21–31. 6. Thorsteinsdottir S and Kristinsson SY. Hematology Am Soc Hematol Educ Program. 2022;2022(1):551–559. 7. Lussier T, et al. Cells. 2021;11(1):130. 8. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Multiple Myeloma V.1.2026. © National Comprehensive Cancer Network, Inc. 2025. All rights reserved. Accessed July 1, 2025. To view the most recent and complete version of the guideline, go online to NCCN.org. NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.

© Johnson & Johnson and its affiliates 2025 08/25 US-SFM–6750.

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