Multiple Myeloma

Slide 1 · Multiple Myeloma

Pathogenesis · Morphology · Clinical correlations · Diagnosis

A plasma cell neoplasm with skeletal and systemic consequences

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning objectives

Link clonal plasma cells to bone destruction and systemic injury.

Recognize marrow, bone, and peripheral blood morphology.

Interpret monoclonal immunoglobulin and free light-chain tests.

Apply CRAB findings and distinguish related plasma cell disorders.

Explain major prognostic markers and treatment mechanisms.

Slide 3 · The disease in one definition

Malignant proliferation of terminally differentiated B-lineage plasma cells.

Usually disseminated within bone marrow and associated with destructive skeletal lesions.

Frequently produces a monoclonal immunoglobulin or free light chain.

Organ injury arises from tumor infiltration, bone remodeling, and abnormal secreted proteins.

Three pathologic axes: Cell mass · bone injury · paraprotein

Slide 4 · Three mechanisms account for major manifestations

Marrow infiltration

Replacement of hematopoietic marrow

Anemia and skeletal tumor deposits

Paraprotein production

Monoclonal intact Ig and/or free light chains

Renal toxicity, hyperviscosity, amyloid

Immune dysregulation

Reduced normal immunoglobulins

Recurrent bacterial infection

Slide 5 · Plasma cell neoplasm: Biological context

Mature B cell

Terminal differentiation

Clonal plasma cell

Monotypic Ig production

Myeloma deposits

Marrow and axial skeleton

Systemic effects

Bone, kidney, blood, immunity

Myeloma retains the secretory phenotype of plasma cells.

Slide 6 · Intact immunoglobulin versus monoclonal M protein

Conceptual immunoglobulin (intact molecule)

An M component denotes a monoclonal immunoglobulin in blood.

The tumor population produces immunoglobulin with a shared molecular identity.

Its measurement can assist detection and longitudinal assessment.

Slide 7 · Free light chains and Bence Jones protein

κ

λ

κ

λ

κ

λ

Free light chains: Low-molecular-weight proteins

Plasma cells may secrete excess κ or λ light chain.

Small free light chains pass through the glomerular filter.

Urinary monoclonal light chains are termed Bence Jones proteins.

Slide 8 · One clone, several secretory phenotypes

Production pattern

Diagnostic implication

Intact monoclonal immunoglobulin

Detectable serum M component

Intact Ig plus free light chains

Serum M protein with urinary or serum FLC

Free light chain only

Routine serum electrophoresis can be less informative

Rare nonsecretory disease

No measurable monoclonal protein does not rule out myeloma

Slide 9 · Clinical epidemiology

Predominantly affects older adults; Peak age of incidence is 65–70 years.

Incidence is higher in males than in females.

Incidence is higher in people of African descent.

The clinical disease frequently presents through skeletal symptoms or organ dysfunction.

Slide 10 · From clonal expansion to clinical disease

Genetic lesions

Myeloma clone emerges

Marrow niche

IL-6 and stromal support

Skeletal remodeling

Osteoclast activity increases

End-organ injury

CRAB features appear

The genotype and microenvironment jointly shape the phenotype.

Slide 11 · Genetic heterogeneity is a defining feature

Frequent structural rearrangements involve IGH at chromosome 14q32.

Multiple different proto-oncogenes become dysregulated.

Myeloma is not defined by one universal fusion gene.

Additional genomic abnormalities are associated with aggressive disease.

Slide 12 · IGH rearrangements and cell-cycle dysregulation

IGH locus

Chromosome 14q32

Partner oncogene

Rearrangement / activation

Cyclin signaling

D1 or D3 dysregulation

Clonal advantage

Abnormal plasma-cell expansion

Illustrative pathway: Specific partners and consequences vary by tumor.

Slide 13 · Cyclin D1 and cyclin D3 in myeloma

CCND1 and CCND3 encode regulators of progression through G1.

Their deregulation can favor cell-cycle entry in clonal plasma cells.

Cyclin D1–associated rearrangements are described in a prognostically favorable subset.

Cyclin dysregulation is a recurrent molecular theme, not a unique diagnostic marker.

Slide 14 · Genetic abnormalities and biologic implications

IGH rearrangements

Dysregulate partner oncogenes

Heterogeneous initiating landscape

17p deletion / TP53

Loss involving a tumor suppressor locus

Poor-outcome association

MYC rearrangements

Noted in highly aggressive forms

Associated with plasma cell leukemia

Slide 15 · NF-κB signaling and myeloma survival

Acquired mutations

NF-κB pathway genes

Signaling effects

Pro-survival transcription

Plasma cell persistence

Enhanced tumor-cell survival

Recurrent lesions in this survival pathway.

Slide 16 · Interleukin-6 supports tumor growth

Stromal cells

Marrow-derived IL-6

Myeloma cells

Additional autocrine IL-6

Plasma cell growth

Proliferation / survival

Higher serum IL-6 in active disease is associated with adverse prognosis.

Slide 17 · The bone marrow microenvironment

Soluble signals

IL-6 is a major plasma-cell growth factor

Both stromal and tumor production

Cell contact

Direct interactions with marrow stromal cells

Additional survival advantage

Clinical result

Persistence within a supportive marrow niche

Potential therapeutic vulnerability

Slide 18 · Why do osteolytic lesions form?

Myeloma factors

MIP-1α / CCL3

Osteoclasts

Formation and activity rise

Osteoblasts

Wnt-modulating inhibitors suppress bone formation

Net effect

Bone resorption dominates

Bone destruction is not merely passive displacement by tumor.

Slide 19 · Coupled skeletal injury: Bone loss exceeds repair

Schematic: Cancellous bone and marrow

Focal loss of bone

Trabeculae

Osteoclast recruitment accelerates resorption.

Osteoblast suppression limits replacement of lost bone.

The imbalance produces lytic lesions and fragility.

Calcium released from bone contributes to hypercalcemia.

Slide 20 · Local signaling and the resulting skeletal phenotype

Tumor-associated signal

Pathologic consequence

MIP-1α (CCL3)

Facilitates osteoclast formation

Wnt-pathway modulators

Suppress osteoblast function

Increased resorption

Lytic defects and pathologic fracture

Excess skeletal calcium release

Hypercalcemia

Slide 21 · Integrated pathogenesis: Why multiple organs fail

Marrow plasmacytosis interferes with normal blood-cell production.

Osteoclast activation and osteoblast inhibition weaken bone.

Light chains injure renal tubules and sometimes form AL amyloid.

Suppression of polyclonal Ig compromises antibacterial defense.

Slide 22 · Skeletal distribution is typically axial

The vertebral column, ribs, skull, and pelvis are preferential sites.

Femur, clavicle, and scapula may also be involved.

Tumor deposits begin within medullary spaces.

Advanced lesions can erode cortex and produce fractures.

Slide 23 · Anatomy of a developing lytic lesion

Medullary deposit

Plasma cells accumulate

Cancellous erosion

Trabeculae are resorbed

Cortical destruction

Mechanical stability falls

Pathologic fracture

Often in vertebrae

Morphologic sequence of bone injury, not a measure of time.

Slide 24 · Punched-out skeletal defects

Schematic: Cancellous bone and marrow

Focal loss of bone

Trabeculae

Focal sharply circumscribed lytic lesions are characteristic.

Radiographic defects typically 1–4 cm.

Vertebrae and calvaria are common sites of involvement.

Diffuse osteopenia can replace discrete lesions in some patients.

Slide 25 · Two major patterns of myelomatous bone disease

Focal osteolysis

Diffuse skeletal loss

Discrete punched-out radiolucencies

Generalized demineralization / osteopenia

Local tumor deposits plus resorption

Widespread remodeling imbalance

May cause localized structural failure

Associated with generalized skeletal fragility

Slide 26 · Gross appearance of skeletal tumor deposits

Myeloma lesions are soft, red, and often gelatinous.

They occupy marrow cavities as expanding plasmacytomas.

Progressive bone erosion may penetrate the cortex.

Lesions at multiple sites support disseminated skeletal disease.

Slide 27 · Typical plasma cell: Morphologic landmarks

Stylized plasma cell morphology — schematic, not a micrograph

Eccentrically positioned nucleus.

Abundant basophilic cytoplasm.

Pale perinuclear Golgi zone (hof).

These features are preserved in many myeloma cells.

Slide 28 · Marrow myeloma: Cytologic variability

Stylized plasma cell morphology — schematic, not a micrograph

Relatively mature plasma cells may predominate.

Plasmablasts show vesicular chromatin and prominent nucleoli.

Bizarre or multinucleated cells also occur.

Morphology alone must be integrated with clonality and clinical findings.

Slide 29 · Mature-appearing versus plasmablastic cells

Relatively mature plasma cell

Plasmablastic morphology

Eccentric condensed nucleus

More open / vesicular nuclear chromatin

Perinuclear Golgi clearing

Conspicuous nucleolus

Usually recognizable plasma-cell outline

Greater cytologic atypia

Not benign merely because mature-looking

Requires full diagnostic correlation

Slide 30 · Mott cells and cytoplasmic immunoglobulin

Stylized plasma cell morphology — schematic, not a micrograph

Disordered secretory handling can accumulate Ig inside the cell.

Mott cells contain multiple droplet-like cytoplasmic inclusions.

Cytoplasmic Ig globules are called Russell bodies.

Recognize them as secretory abnormalities, not pathogen inclusions.

Slide 31 · Other plasma cell inclusion patterns

Flame cells show brightly eosinophilic, red-tinged cytoplasm.

Dutcher bodies appear as intranuclear immunoglobulin inclusions.

Crystal-like rods, fibrils, and globules may also be observed.

Such inclusions reflect dysregulated protein synthesis and handling.

Slide 32 · Marrow replacement produces cytopenia

Tumor expansion

Plasma cells occupy marrow

Hematopoietic suppression

Normal precursors displaced

Reduced red-cell output

Anemia develops

The marrow infiltration pattern may range from subtle to extensive.

Slide 33 · Marrow infiltration: Extent and pattern

Plasma cells often exceed 30% of marrow cellularity in overt myeloma.

Both interstitial infiltrates and near-complete replacement occur.

Sampling must be interpreted together with clinical and protein studies.

Slide 34 · Bone marrow versus extramedullary spread

Bone marrow disease

Advanced extramedullary involvement

Primary dominant compartment

Secondary dissemination late in course

Lytic skeletal lesions and cytopenias

Possible soft-tissue organ infiltrates

Axial skeleton commonly involved

Spleen, liver, kidney, lung and nodes can be affected

Slide 35 · Rouleaux: A peripheral blood clue

High concentrations of monoclonal protein promote linear red-cell stacking.

The appearance is called rouleaux formation.

It is supportive, not specific, for multiple myeloma.

Other high-protein states can produce the same smear pattern.

Slide 36 · Diagnostic morphology: What each specimen answers

Bone marrow aspirate

Plasma-cell cytology

Maturation, atypia, inclusions

Core biopsy

Infiltration architecture

Distribution and marrow replacement

Peripheral blood smear

Rouleaux / rare circulating plasma cells

Systemic hematologic effect

Slide 37 · Plasma cell immunophenotype

CD138

Syndecan-1: Supports plasma-cell identification

CD56

Frequently expressed in neoplastic plasma cells; Not universal

κ or λ

Cytoplasmic light-chain restriction supports clonality

No single immunostain independently establishes symptomatic myeloma.

Slide 38 · Clonality versus lineage: Distinguish the questions

Lineage evidence

Clonal evidence

CD138 establishes plasma-cell differentiation

κ or λ restriction supports a single clone

CD56 may aid tumor recognition

Correlate with marrow morphology and protein studies

Plasma-cell phenotype is not disease-stage proof

Myeloma requires clinical or biomarker-defining evidence

Slide 39 · CRAB: Four categories of myeloma injury

C

Hypercalcemia from bone resorption

R

Renal impairment; Often light-chain mediated

A

Anemia from marrow disease

B

Bone lesions: Osteolysis and fractures

CRAB injury must be attributable to the plasma-cell disorder.

Slide 40 · Why skeletal pain and fracture occur

Osteolysis weakens structural support of the bone.

Weight-bearing and vertebral lesions can become painful.

Compression fractures commonly involve the vertebral column.

Fractures are a major cause of disability and morbidity.

Slide 41 · Hypercalcemia: Biochemical injury from bone

Osteoclast-mediated resorption releases mineral into circulation.

Clinical effects can include constipation, polyuria, weakness, and lethargy.

More severe hypercalcemia may cause confusion.

Hypercalcemia also contributes to renal dysfunction.

Slide 42 · Light chains injure the renal tubule

Clonal secretion

Excess free light chains

Filtration

Light chains reach tubular lumen

Tubular toxicity

Epithelial damage and cast-associated injury

Renal dysfunction

Reduced kidney function

This is the major renal mechanism emphasized by Robbins.

Slide 43 · Renal impairment is multifactorial

Light-chain tubular toxicity is a major contributor.

Hypercalcemia can worsen kidney dysfunction.

Dehydration and other insults may compound damage.

AL amyloid deposition can contribute in affected patients.

Slide 44 · Monoclonal light chain can become AL amyloid

Light-chain production

Often amyloid-prone molecular forms

Protein misfolding

Amyloidogenic fibrils form

Tissue deposition

Kidney and other organs

Organ injury

Dysfunction beyond marrow infiltration

AL amyloidosis may occur with overt myeloma or smaller clones.

Slide 45 · Anemia in multiple myeloma

Marrow infiltration reduces effective erythropoiesis.

Renal dysfunction may also contribute to anemia.

The resulting fatigue can dominate early clinical presentation.

Anemia should be evaluated together with marrow and renal findings.

Slide 46 · Suppressed normal Ig drives recurrent infection

Clonal Ig production

One clone expands

Immunoparesis

Normal Ig production falls

Humoral defense

Antibacterial protection weakens

Clinical outcome

Recurrent bacterial infections

Cell-mediated immunity is described as relatively preserved.

Slide 47 · Serum protein electrophoresis: Pattern recognition

Normal polyclonal

Monoclonal

Band-width concept only; Not patient electrophoresis data

Normal polyclonal immunoglobulin gives a distributed pattern.

A narrow monoclonal band raises suspicion for an M component.

Immunofixation is needed to determine heavy- and light-chain identity.

Slide 48 · Immunofixation identifies the monoclonal protein

Type the immunoglobulin heavy chain, such as IgG or IgA.

Identify κ versus λ light chain pairing.

Confirm that the abnormal electrophoretic band is monoclonal.

Protein typing and disease activity are distinct diagnostic questions.

Slide 49 · Serum free light-chain evaluation

κ

λ

κ

λ

κ

λ

Free light chains: Low-molecular-weight proteins

Measure κ and λ free light chains in serum.

An imbalanced κ:λ relationship supports monoclonal secretion.

Interpret the ratio with involved-chain concentration and clinical context.

Free light-chain detection matters in light-chain-only myeloma.

Slide 50 · Urine testing adds complementary information

Urinary monoclonal free light chains are Bence Jones proteins.

Urine electrophoresis and immunofixation can characterize excreted proteins.

The renal effect of monoclonal light chains can be disproportionate to serum M-spike size.

Serum and urine testing should be integrated, not viewed in isolation.

Slide 51 · Major immunoglobulin classes in myeloma

IgG

Most frequent heavy-chain class

Approximately 55% of cases

IgA

Second most frequent class

Approximately 25%

Less frequent patterns

IgM, IgD, IgE rare

Light-chain-only and nonsecretory variants also occur

Percentages are textbook estimates, not current surveillance data.

Slide 52 · When an M spike is absent

Some tumors produce free light chains without intact immunoglobulin.

Rare tumors are nonsecretory.

A normal-looking serum electrophoretic trace therefore does not exclude myeloma.

Proceed with serum FLC, urine studies, marrow evaluation, and appropriate imaging when suspicion persists.

Slide 53 · Core diagnostic workup: Complementary domains

Marrow

Clonal plasma cells

Proteins

SPEP/IFE, serum FLC, urine

Organ injury

Calcium, renal tests, blood counts

Skeletal survey

CT / MRI as indicated

An integrated diagnosis cannot be made from a paraprotein alone.

Slide 54 · Bone marrow examination: Specific tasks

Quantify clonal plasma cells and examine infiltration architecture.

Document plasma-cell differentiation and light-chain restriction.

Assess morphology for plasmablastic or other atypical forms.

Obtain clinically indicated cytogenetic and molecular risk information.

Slide 55 · IMWG diagnostic framework: Two requirements

Clonal substrate

≥10% clonal marrow plasma cells, OR biopsy-proven plasmacytoma

Myeloma-defining event

At least one attributable CRAB feature OR validated SLiM biomarker

IMWG (2014; Clinical criteria), supplementary to the Robbins narrative.

Slide 56 · IMWG: Attributable CRAB thresholds

Calcium

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

Renal

Creatinine clearance <40 mL/min or serum creatinine >2 mg/dL

Anemia

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

Bone

≥1 osteolytic lesion on appropriate imaging*

*With <10% clonal marrow cells, >1 lesion is required to distinguish solitary plasmacytoma.

Slide 57 · IMWG: SLiM biomarkers of active myeloma

S

≥60% clonal plasma cells in bone marrow

Li

Involved:uninvolved serum FLC ratio ≥100 AND involved FLC ≥100 mg/L

M

More than one MRI focal lesion, each ≥5 mm

These biomarkers may define active disease without symptomatic CRAB injury.

Slide 58 · Myeloma-defining lesion versus incidental finding

Supported disease attribution

Potential diagnostic pitfall

Osteolysis attributable to the plasma-cell disorder

Other causes of lytic bone disease require assessment

Renal damage related to monoclonal protein

Coexisting kidney disease may have other etiologies

Anemia from marrow / systemic disease

Do not automatically attribute any anemia to myeloma

Clonal plasma cells plus defining event

M component alone does not prove active disease

The diagnostic criterion is disease-attributable end-organ damage.

Slide 59 · From precursor states to symptomatic myeloma

MGUS

Clonal protein without disease-defining injury

Smoldering disease

Higher burden, no defining event

Active myeloma

CRAB or SLiM myeloma-defining event

A biological continuum; Progression is not inevitable in an individual patient.

Slide 60 · MGUS, smoldering myeloma, and active myeloma

Disease state

Core discriminator

MGUS

Asymptomatic clone without defining events

Smoldering myeloma

Higher clonal burden without defining events

Active multiple myeloma

Clonal substrate plus attributable CRAB or SLiM finding

Formal clinical classification depends on contemporary diagnostic criteria, not M protein alone.

Slide 61 · Multiple myeloma versus solitary plasmacytoma

Systemic myeloma

Solitary plasmacytoma

Multiple marrow / skeletal sites

Single localized tumor mass

Myeloma-defining systemic pattern

No qualifying systemic myeloma-defining disease

May show multiple M-protein patterns

M protein may be absent or limited

Systemic treatment framework

Local management often central

Slide 62 · Multiple myeloma versus Waldenström syndrome

Multiple myeloma

Lymphoplasmacytic lymphoma

Plasma-cell neoplasm

B-cell neoplasm with plasmacytic differentiation

Commonly IgG or IgA

Usually monoclonal IgM

Lytic bone destruction prominent

Bone destruction is not characteristic

Light-chain kidney injury clinically important

Hyperviscosity from IgM dominates selected cases

Slide 63 · Multiple myeloma prognosis is heterogeneous

Disease burden and end-organ injury substantially influence outcome.

Genomic features contribute to risk stratification.

Approximately 60% 5-year survival as a historical summary.

Advances in therapy have steadily improved outcomes; Do not interpret older estimates as an individualized forecast.

Slide 64 · Selected prognostic genomic correlates

Favorable association

Cyclin D1 translocation

An association, not an absolute prediction

Adverse associations

Deletion of 17p / TP53

Deletion of 13q

Additional risk signal

T(4;14)

Aggressive biology in relevant contexts

Risk assignment requires an integrated, validated clinical framework.

Slide 65 · A biomarker may have different roles

Question

Example from myeloma

Diagnostic: Is the clone present?

Monotypic cytoplasmic κ or λ restriction

Prognostic: What is its likely course?

Del(17p), t(4;14), other risk markers

Predictive: Does a specific therapy work?

Treatment selection needs regimen-specific evidence; Do not infer prediction from prognosis

Slide 66 · Proteasome inhibition exploits protein stress

High Ig synthesis

Misfolded proteins accumulate

Proteasome block

Degradation is impaired

Proteotoxic stress

Misfolded load rises

Myeloma apoptosis

Tumor cell death

A mechanism-based therapeutic vulnerability highlighted by the textbook.

Slide 67 · Immunomodulatory drugs alter protein disposal

Lenalidomide

Redirects ubiquitin ligase activity

Critical substrates

Proteolysis of growth-supporting proteins

Myeloma growth

Cell survival is impaired

The mechanism differs from simple proteasome blockade.

Slide 68 · Treatment strategies: Pathology-based rationale

Skeletal support

Bisphosphonates inhibit bone resorption

Reduce fracture risk and hypercalcemia

Cellular therapy

Hematopoietic stem-cell transplantation

Extends survival; Not reliably curative

Antigen targeting

BCMA-directed CAR-T cells

Deep remissions with substantial toxicity risks

Slide 69 · Toxicity matters in BCMA-directed cell therapy

Cytokine-release syndrome as an important adverse effect.

Neurotoxicity may accompany immune-effector therapy.

Hypogammaglobulinemia can contribute to infection risk.

Treatment choices require specialized assessment beyond morphologic diagnosis.

Slide 70 · Clinical case: Evaluate the pattern

An older adult presents with persistent axial back pain, normocytic anemia, renal dysfunction and multiple punched-out calvarial lesions. Serum testing reveals a monoclonal immunoglobulin.

Which tissue lesion unifies bone pain and marrow-related anemia?

Which additional studies establish clonality and myeloma-defining injury?

Which component of the paraprotein may be directly nephrotoxic?

Slide 71 · Case resolution: Pathologic reasoning

The constellation raises strong suspicion for active plasma-cell myeloma; No single finding is sufficient on its own.

Confirm marrow plasma-cell clonality and burden.

Correlate imaging and CRAB results with the plasma-cell disorder.

Characterize serum and urinary immunoglobulins and free light chains.

Complete risk assessment and organ-function evaluation.

Slide 72 · Synthesis: One clone, three mechanisms of disease

Plasma-cell expansion

Marrow infiltration and cytopenia

Bone microenvironment

Resorption exceeds bone formation

Secreted proteins

Renal injury and suppressed normal immunity

Integrate molecular pathology, morphology, and clinical findings.

Slide 73 · References and scope

Robbins, Cotran & Kumar. Pathologic Basis of Disease, 11th ed. (2026), Chapter 13, pp. 552–555.

Rajkumar SV et al. International Myeloma Working Group updated diagnostic criteria. Lancet Oncol. 2014;15:e538–e548.

Current diagnostic biomarkers and thresholds are presented as an IMWG supplement; all other content derives principally from the supplied Robbins text.

Clinical diagnostic criteria and management are subject to subsequent guideline revisions.