Smoldering Myeloma

Slide 1 · Smoldering Myeloma

The asymptomatic clonal plasma cell state between MGUS and active myeloma

Classification • pathology • risk stratification • clinical decisions

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning objectives

Differentiate MGUS, smoldering myeloma, and active myeloma using modern IMWG criteria.

Interpret marrow clonality, monoclonal protein studies, and whole-body imaging.

Distinguish diagnostic myeloma-defining events from prognostic risk factors.

Apply risk stratification to monitoring and high-risk treatment decisions.

Slide 3 · A continuum of clonal plasma cell disorders

MGUS

Small clone

Smoldering myeloma

More burden, no defining event

Active multiple myeloma

Myeloma-defining event

These are clinical categories, not guaranteed sequential stages.

Slide 4 · The defining paradox of smoldering myeloma

Clonal plasma cells are already present and may be disseminated.

Disease burden exceeds the usual MGUS range.

Patients lack attributable myeloma-defining organ injury or defining biomarkers.

Risk of progression varies substantially across individuals.

Slide 5 · How a plasma cell clone becomes detectable

Clonal plasma cell expansion

Monoclonal immunoglobulin or free light chain secretion

Detectable serum or urine marker

Protein burden and marrow burden are related but not interchangeable measurements.

Slide 6 · M-protein is a measurable marker, not a diagnosis

An M component reflects monoclonal immunoglobulin synthesized by a clone.

Its concentration is quantified by serum protein electrophoresis when measurable.

A high M-protein level does not prove CRAB injury or active myeloma.

Interpret with marrow findings, free light chains and imaging.

Slide 7 · Electrophoresis versus immunofixation

Protein electrophoresis

Detects and quantifies a discrete M component.

Serial peak size tracks secretory tumor burden.

Very small components may be difficult to measure.

Immunofixation

Identifies immunoglobulin isotype and light chain.

Can detect a band not clearly quantified by electrophoresis.

Does not alone classify MGUS versus SMM.

Slide 8 · Serum free light chains add a second axis

Clonal plasma cells may produce excess κ or λ chains.

Involved/uninvolved FLC ratio estimates relative chain excess.

Involved FLC concentration is important for the ≥100 ratio myeloma-defining event.

Interpret assay values with renal function and laboratory context.

Slide 9 · Why urinary monoclonal light chains occur

Free light chains are small proteins

Glomerular filtration

Urinary light chain detection

Filtered monoclonal free light chains are traditionally called Bence Jones proteins.

Slide 10 · Marrow burden: Percentage of clonal plasma cells

Aspirate and trephine biopsy evaluate marrow infiltration.

The diagnostic percentage concerns clonal plasma cells, not all lymphoid cells.

Uneven distribution may create discordance between samples.

≥60% clonal plasma cells is itself an active-myeloma defining biomarker.

Slide 11 · Conceptual marrow infiltration in a plasma cell disorder

Clonal plasma cells: Eccentric nuclei and perinuclear pale zone

Morphology supports lineage; Clone proof requires light-chain restriction

Schematic illustration — not histology

Slide 12 · The original Robbins description

Smoldering myeloma occupies the middle ground between MGUS and active myeloma.

10%–30% plasma cells and serum M-protein >3 g/dL in asymptomatic patients.

The text estimates about 75% progress to myeloma over 15 years.

This textbook summary should not be substituted for current IMWG diagnostic rules.

Slide 13 · Modern IMWG definition: Two requirements

Disease-burden condition

Required absence

IgG/IgA serum M-protein ≥3 g/dL; And/or

No attributable myeloma-defining event

Urinary monoclonal protein ≥500 mg/24 h; And/or

No AL amyloidosis

Clonal marrow plasma cells 10% to <60%

Assess all CRAB and SLiM criteria

Slide 14 · The connective logic is OR, then AND

Burden criterion

Any qualifying serum, urine, or marrow threshold can establish the burden condition.

AND

All myeloma-defining events must be absent.

AND

AL amyloidosis must be absent.

A serum M-protein below 3 g/dL does not exclude SMM if marrow burden qualifies.

Slide 15 · Asymptomatic does not mean uninvestigated

SMM is clinically silent with respect to attributable myeloma-defining events.

A patient may feel well yet have an MRI or FLC biomarker defining active myeloma.

Assess anemia, kidney dysfunction, hypercalcemia, and bone lesions even without symptoms.

Evidence of concurrent illness must not automatically be attributed to the clone.

Slide 16 · Myeloma-defining events: CRAB and SLiM

CRAB

End-organ injury attributable to the plasma cell disorder.

SLiM

Three high-risk biomarkers that establish active myeloma.

Clinical decision

Any qualifying MDE shifts classification from SMM to active myeloma.

Slide 17 · CRAB: Attributable end-organ damage

Domain

IMWG threshold or finding

C — Hypercalcemia

Ca >11 mg/dL or >1 mg/dL above upper normal limit

R — Renal dysfunction

CrCl <40 mL/min or creatinine >2 mg/dL

A — Anemia

Hb <10 g/dL or >2 g/dL below lower normal limit

B — Bone lesions

≥1 osteolytic lesion on radiograph, CT or PET/CT

Slide 18 · Hypercalcemia requires attribution

Myeloma-associated osteolysis may elevate serum calcium.

IMWG defines the criterion using a measured calcium threshold.

Hyperparathyroidism, supplements, dehydration, and other cancers are alternatives.

A borderline elevation without attribution is not sufficient by itself.

Slide 19 · Renal impairment requires attribution

Filtered monoclonal light chains may injure renal tubules.

IMWG criterion: Creatinine >2 mg/dL or clearance <40 mL/min.

Diabetes, vascular disease, obstruction, and dehydration may coexist.

Avoid labeling unrelated chronic kidney disease as a myeloma-defining event.

Slide 20 · Anemia is a clinical feature, not merely a number

Marrow replacement and chronic inflammation can impair erythropoiesis.

IMWG criterion: Hb <10 g/dL or >2 g/dL below the lower normal limit.

Blood loss, nutritional deficiency, and renal disease require evaluation.

Only anemia attributable to the plasma cell disorder is a defining event.

Slide 21 · Osteolytic lesions change disease classification

Myeloma cells perturb bone-remodeling in favor of osteoclast activity.

A qualifying osteolytic lesion constitutes the “B” in CRAB.

CT evidence of osteolysis can meet criteria even if plain films are negative.

Generalized osteopenia alone is not a qualifying lytic lesion.

Slide 22 · The three SLiM biomarkers

S — Sixty

Clonal marrow plasma cells ≥60%.

Li — Light chains

Involved/uninvolved serum FLC ratio ≥100 plus involved FLC ≥100 mg/L.

M — MRI

More than one focal lesion, each ≥5 mm.

Each is a myeloma-defining event even in the absence of overt CRAB symptoms.

Slide 23 · Marrow plasma cells ≥60% is active myeloma

The percentage threshold is a diagnostic biomarker, not merely a risk score.

Even without symptoms, clonal plasma cells at ≥60% meet an MDE.

The modern SMM marrow range stops below 60%.

Check the percentage and clonality on adequate marrow material.

Slide 24 · The FLC biomarker has two simultaneous parts

Serum involved/uninvolved FLC ratio ≥100.

Absolute concentration of the involved serum free light chain ≥100 mg/L.

Both conditions are needed for this SLiM criterion.

An FLC ratio of 25 is a risk factor in the 20/2/20 model—not an MDE.

Slide 25 · MRI focal lesions require number and size

More than one focal marrow lesion is required for the SLiM MRI event.

Each counted lesion should be ≥5 mm.

A single focal lesion prompts clinical assessment but does not meet this MRI MDE.

MRI signal changes must be interpreted using radiologic expertise.

Slide 26 · Diagnostic comparison across the plasma cell spectrum

Feature

Non-IgM MGUS

SMM

Active myeloma

Serum M-protein

<3 g/dL

≥3 g/dL or other qualifying burden

Any level

Clonal marrow PCs

<10%

10%–<60% or qualifying protein

≥10% or plasmacytoma

Myeloma-defining event

Absent

Absent

Present

AL amyloidosis

Absent

Absent

Separate clinically important entity

Slide 27 · Localized plasmacytoma versus SMM

Solitary plasmacytoma

Biopsy-proven single bone/soft tissue lesion.

Requires focused systemic marrow and imaging evaluation.

A discrete mass is the organizing finding.

Smoldering myeloma

Systemic monoclonal disease burden without MDE.

No defining focal bone destruction or other end-organ injury.

Monoclonal protein alone cannot distinguish the two.

Slide 28 · AL amyloidosis cannot be ignored

Monoclonal light chains can form tissue-deposited amyloid.

The contemporary IMWG SMM definition requires absence of AL amyloidosis.

Proteinuria, cardiomyopathy, or neuropathy may prompt organ-focused investigation.

Low marrow tumor burden does not rule out clinically important AL amyloidosis.

Slide 29 · A practical diagnostic workflow

Confirm monoclonal protein

Quantify marrow clonality

Evaluate CRAB and SLiM

Classify and stratify risk

Do not assign SMM solely from an M-spike or a marrow percentage.

Slide 30 · History and examination: Seek organ injury

Document new bone pain, fractures, infections, fatigue, and neurologic symptoms.

Assess functional status and previous unexplained laboratory abnormalities.

Review comorbid causes of anemia, hypercalcemia and kidney impairment.

A lack of symptoms does not replace dedicated imaging.

Slide 31 · Initial routine laboratory panel

CBC with differential for anemia and other cytopenias.

Creatinine, eGFR/CrCl and metabolic panel for renal function and calcium.

Total protein, albumin and quantitative immunoglobulins provide context.

Repeat or corroborate an unexpected abnormality before attribution.

Slide 32 · Serum assays answer different questions

SPEP: How much monoclonal protein is measurable?

Immunofixation: Which heavy-chain/light-chain isotype?

Serum FLC: How asymmetric is κ versus λ production?

Quantitative immunoglobulins: Is there suppression of uninvolved isotypes?

Slide 33 · Urine studies remain clinically relevant

Urine electrophoresis and immunofixation detect monoclonal light chains.

A timed collection can quantify 24-hour monoclonal protein excretion.

≥500 mg per 24 h is one accepted SMM burden route in the IMWG criteria.

Distinguish albuminuria from light-chain predominant proteinuria.

Slide 34 · Bone marrow: Aspirate and core are complementary

Aspirate enables differential count and cellular studies.

Trephine biopsy evaluates spatial pattern and overall infiltration.

Discordant estimates require review of adequacy and focality.

Record the clonal plasma cell estimate and method, not “increased plasma cells” alone.

Slide 35 · Plasma cell morphology: What the schematic shows

Clonal plasma cells: Eccentric nuclei and perinuclear pale zone

Morphology supports lineage; Clone proof requires light-chain restriction

Schematic illustration — not histology

Slide 36 · Immunophenotyping establishes the clone

CD138 highlights plasma cells on marrow sections.

κ/λ restriction helps demonstrate clonality in the appropriate context.

Flow cytometry characterizes aberrant plasma cell populations.

No single stain is a substitute for clinical and biochemical integration.

Slide 37 · Cytogenetics and FISH are prognostic tools

FISH can identify adverse genomic features in a clonal plasma cell population.

The extended IMWG SMM model uses t(4;14), t(14;16), 1q gain and del(13q).

These findings refine progression risk rather than independently establish MDEs.

Risk marker and diagnostic marker are different concepts.

Slide 38 · Why sampling variation matters

Focal marrow infiltration

Aspirate and biopsy capture different locations

Different percentages may result

Interpret marrow results together with imaging and expert hematopathology review.

Slide 39 · Bone imaging in suspected SMM

Low-dose whole-body CT

Sensitive assessment for osteolytic destruction.

Whole-body/spine MRI

Detects marrow focal lesions before cortical destruction.

PET/CT

Combines metabolic activity with CT assessment of bone structure.

Appropriate modality depends on indication and local resources.

Slide 40 · CT: Identify structural osteolysis

Any qualifying osteolytic lesion may establish active myeloma.

Low-dose whole-body CT is superior to conventional plain films for subtle osteolysis.

An osteolytic focus on the CT component can matter even when plain films are normal.

PET avidity without accompanying lysis is not equivalent to a CRAB bone lesion.

Slide 41 · MRI detects marrow involvement before lysis

A focal MRI lesion can represent localized neoplastic marrow replacement.

More than one focal lesion ≥5 mm is an MDE.

Diffuse marrow signal changes alone require context and follow-up.

MRI and CT provide complementary biological and anatomical information.

Slide 42 · PET/CT: The distinction is metabolic versus structural

FDG uptake suggests metabolic activity but is not equivalent to osteolysis.

The CT portion must demonstrate corresponding destructive change for CRAB bone disease.

False-positive uptake can arise with infection or trauma.

Interpret focal PET findings with the complete clinical and imaging assessment.

Slide 43 · Osteopenia and fractures are not automatically CRAB

Generalized osteoporosis is common and may be unrelated to a plasma cell clone.

A vertebral compression fracture alone does not establish myeloma bone disease.

Seek imaging evidence of an osteolytic lesion and attribution to myeloma.

Misclassification may lead to unnecessary therapy.

Slide 44 · “Smoldering” encompasses widely different risks

Some patients remain stable for prolonged intervals.

Other patients progress rapidly despite initially lacking CRAB or SLiM events.

Single baseline measurements do not fully describe biological tempo.

Risk models aid surveillance and treatment decisions but do not guarantee outcomes.

Slide 45 · Natural history: Interpret estimates in context

Approximately 75% progression over a 15-year period.

A specific cohort estimate depends on diagnostic era and selection.

Modern criteria reclassify some formerly “high-risk SMM” patients as active myeloma.

Use contemporary risk models for current prognostic counseling.

Slide 46 · IMWG 20/2/20: Three measurable predictors

Marrow

Clonal plasma cells >20%

Monoclonal protein

Serum M-protein >2 g/dL

Light chains

Involved/uninvolved FLC ratio >20

These are prognostic risk-factor cutoffs, not diagnostic MDEs.

Slide 47 · IMWG 2020: Two-year progression risk

0 factors

6%

1 factor

18%

2–3 factors

44%

Observed cohort estimates; Not an individual patient probability.

Slide 48 · How to use the 20/2/20 score

Count one factor for each threshold strictly exceeded.

0 factors: Low-risk; 1: Intermediate-risk; 2–3: High-risk in the original model.

The estimated 2-year progression rates were 6%, 18%, and 44%, respectively.

Confirm SMM classification before assigning a risk tier.

Slide 49 · Extended IMWG model incorporates FISH

Additional cytogenetic factor

Clinical interpretation

T(4;14) or t(14;16)

Adverse disease biology in the IMWG model

1q gain

Adds progression-risk information

Deletion 13q

Adds progression-risk information

Combined factors

The extended model uses risk-group aggregation

Slide 50 · Risk models: Strengths and limitations

20/2/20 uses accessible baseline measurements.

Risk categories reflect population estimates, not deterministic trajectories.

Heterogeneous cohorts, evolving diagnostic criteria and evolving biomarkers affect calibration.

Serial trends and independent clinical events still matter.

Slide 51 · Surveillance: Reassess biology and organ health

Repeat monoclonal protein measures and serum FLC to detect dynamic change.

Recheck CBC, kidney function and calcium for new attributable injury.

Repeat imaging when clinically indicated or when a new lesion is suspected.

Individualize visit frequency by risk category and evolving findings.

Slide 52 · Monitoring frequency: Risk-sensitive approach

SMM group

2025 EHA–EMN guidance

Low-risk

Evaluate approximately every 6 months

Intermediate-risk

Evaluate every 3–6 months

Higher risk / evolution

More intensive specialist reassessment and management discussion

Slide 53 · Dynamic progression requires a fresh classification check

Increasing M-protein or FLC values may suggest clonal evolution.

New cytopenias, hypercalcemia or kidney abnormalities demand attribution.

New bone symptoms should trigger review of skeletal disease.

Re-evaluate CRAB and SLiM before labeling a patient “still smoldering.”

Slide 54 · Clinical decision: Surveillance or intervention?

Confirm absence of MDE

Risk stratify

Discuss surveillance versus high-risk therapy

Management decisions depend on current guidelines, indication and patient preferences.

Slide 55 · Why immediate treatment was historically deferred

Potential benefit

Prevents or delays end-organ injury.

Can lower risk of progression in selected high-risk SMM.

May reduce irreversible damage from active myeloma.

Potential cost

Adverse events in asymptomatic individuals.

Treatment burden and monitoring requirements.

Possible overtreatment of indolent disease.

Slide 56 · AQUILA: Randomized evidence for high-risk SMM

Open-label randomized trial compared subcutaneous daratumumab/hyaluronidase with active monitoring.

390 participants had high-risk smoldering myeloma.

Primary efficacy measure: Progression to active myeloma or death.

Trial eligibility/risk criteria should not be conflated with all SMM categories.

Slide 57 · AQUILA: Progression-free survival

Trial population

390 patients with high-risk SMM

Hazard ratio

0.49 (95% CI 0.36–0.67)

Active monitoring

Median PFS: 41.5 months

Median PFS was not reached in the daratumumab arm at the reported analysis.

Slide 58 · US regulatory update: November 2025

FDA approved subcutaneous daratumumab/hyaluronidase-fihj for adults with high-risk SMM.

It is not an indication for every patient with SMM.

Risks include infections, cytopenias and administration reactions.

Therapy should be considered with specialist assessment and shared decision-making.

Slide 59 · ASCO 2026: More than one defensible strategy

In high-risk SMM, ASCO permits active monitoring or daratumumab for up to 36 months.

Recommendation is conditional, with moderate-quality evidence.

Lenalidomide is not routinely recommended in the cited ASCO living guideline.

Patient values and toxicity tolerance inform choice.

Slide 60 · Treatment discussion: Benefits versus harms

Possible benefit

Reduce risk of progression to active disease.

Defer myeloma-related organ injury.

Offer an option to selected high-risk patients.

Potential harms

Infections and treatment-related cytopenias.

Hypersensitivity or administration reactions.

Burden of repeated therapy and monitoring.

Slide 61 · An individualized high-risk pathway

Reconfirm SMM and exclusion of MDEs

Check risk factors, comorbidities and preferences

Offer active monitoring or approved therapy

An FDA approval does not make treatment obligatory for every high-risk patient.

Slide 62 · Case A — incidental small IgG-κ component

Illustrative case: IgG-κ M-protein 1.5 g/dL.

Clonal marrow plasma cells 8%.

Normal hemoglobin, creatinine and calcium; No lytic lesions.

Question: Is this MGUS, SMM, or active myeloma?

Hypothetical diagnostic teaching vignette; Not patient data.

Slide 63 · Case A — classification

Burden

M-protein <3 g/dL and marrow <10%.

Defining event

No CRAB/SLiM or amyloidosis.

Answer

Non-IgM MGUS, not smoldering myeloma.

Neither qualifying SMM burden route is met.

Slide 64 · Case B — two positive 20/2/20 factors

Illustrative case: Serum M-protein 2.4 g/dL.

Clonal marrow plasma cells 22%.

FLC ratio 13; No CRAB/SLiM event or AL amyloidosis.

Question: Classification and number of risk factors?

Hypothetical diagnostic teaching vignette; Not patient data.

Slide 65 · Case B — classification and risk

Diagnosis

SMM: 22% clonal marrow PCs.

Risk factors

M-protein >2; Marrow >20; FLC ratio not >20.

Interpretation

2/20/20 high-risk SMM (2 factors).

A high prognostic score does not itself establish active myeloma.

Slide 66 · Case C — asymptomatic, but SLiM-positive

Illustrative case: Clonal marrow plasma cells 12%.

Involved/uninvolved FLC ratio 115.

Absolute involved serum FLC concentration 120 mg/L.

Normal CRAB labs and no reported symptoms.

Hypothetical diagnostic teaching vignette; Not patient data.

Slide 67 · Case C — a myeloma-defining biomarker

Marrow

≥10% clonal plasma cells.

FLC

Ratio ≥100 and involved FLC ≥100 mg/L.

Answer

Active myeloma by an IMWG SLiM event.

“Asymptomatic” alone does not justify an SMM label.

Slide 68 · Case D — high M-protein with marrow <10%

Illustrative case: IgG M-protein 3.2 g/dL.

Clonal marrow plasma cells 8%.

No CRAB, SLiM, AL amyloidosis, or plasmacytoma.

Question: Why can this still be SMM?

Hypothetical diagnostic teaching vignette; Not patient data.

Slide 69 · Case D — use the OR condition

Serum

IgG M-protein meets ≥3 g/dL threshold.

Marrow

8% does not meet the ≥10% route.

Answer

SMM because the serum route qualifies.

Modern SMM burden criteria are not a requirement that BOTH protein and marrow thresholds be high.

Slide 70 · Case E — MRI changes the diagnosis

Illustrative case: Marrow clonal plasma cells 18%.

Two discrete MRI focal lesions, each ≥5 mm.

No clinically evident CRAB abnormality.

Question: Remain SMM or reclassify?

Hypothetical diagnostic teaching vignette; Not patient data.

Slide 71 · Case E — MRI is a myeloma-defining event

MRI

>1 focal lesion of qualifying size.

Marrow

Clonal plasma cells exceed the 10% requirement.

Answer

Active myeloma by the SLiM MRI criterion.

Radiologic interpretation must establish that the lesions are compatible with myeloma.

Slide 72 · Final diagnostic checkpoint

Evidence of clone and sufficient burden

Any CRAB or SLiM event?

If no: SMM; Then stratify progression risk

Amyloidosis and alternate diagnoses must be considered separately.

Slide 73 · Core pathology distinctions to retain

Diagnostic category depends on clone burden AND the presence or absence of a defining event.

Risk factors >20%, >2 g/dL and >20 FLC ratio are not interchangeable with SLiM criteria.

Marrow morphology and monoclonal protein detection do not replace imaging and laboratory attribution.

High-risk management has changed; Confirm dated guidelines before counseling.

Slide 74 · Source readings for the lecture

Robbins, Cotran & Kumar. Pathologic Basis of Disease. 11th ed. Ch. 13, plasma cell neoplasms, pp. 552–555.

International Myeloma Working Group revised diagnostic criteria (2014); International Myeloma Foundation diagnostic resource.

Mateos et al. IMWG risk model for SMM. Blood Cancer J. 2020;10:102.

US FDA. High-risk SMM daratumumab approval, 6 November 2025.

ASCO. Treatment of Multiple Myeloma Living Guideline, Version 2026.1.1.