Orthopaedic Surgery - Multiple Myeloma

Basics

Multiple myeloma is a malignant plasma-cell disorder characterized by clonal proliferation of abnormal plasma cells, usually within the bone marrow.

These malignant cells may produce large quantities of a monoclonal immunoglobulin or immunoglobulin fragment, leading to skeletal destruction and systemic complications.

Multiple myeloma is the most common and most severe form within a spectrum of plasma-cell dyscrasias.

Plasma-Cell Disorders

Several related conditions fall within the plasma-cell neoplasm spectrum.

Multiple Myeloma

Multiple myeloma is characterized by multifocal or systemic plasma-cell disease.

Patients may have:

Multiple bone lesions

Bone pain or pathologic fractures

Monoclonal protein production

Anemia or other cytopenias

Hypercalcemia

Renal dysfunction

Disease may involve multiple skeletal sites, bone marrow, and occasionally extramedullary tissues.

Solitary Plasmacytoma

A solitary plasmacytoma consists of a localized collection of malignant plasma cells involving only:

One bone site

or

A single extramedullary soft-tissue or organ site.

There is no widespread myeloma at presentation.

Some patients subsequently progress to multiple myeloma.

Monoclonal Gammopathy of Undetermined Significance

MGUS is characterized by production of a monoclonal immunoglobulin by an abnormal plasma-cell clone without the end-organ manifestations of multiple myeloma.

Patients generally have:

No destructive bone lesions

No significant hypercalcemia

No renal failure attributable to the plasma-cell disorder

No myeloma-related anemia

Bone marrow plasma cells are usually less than 10%.

Approximately 1% of patients per year progress to multiple myeloma or another related lymphoplasmacytic disorder.

POEMS Syndrome

POEMS syndrome is a rare plasma-cell dyscrasia characterized by:

Polyneuropathy

Organomegaly

Endocrinopathy

Monoclonal plasma-cell disorder

Skin changes

The multisystem manifestations are thought to be related partly to abnormal cytokine and growth-factor activity.

Unlike the predominantly lytic lesions of typical myeloma, POEMS syndrome may be associated with sclerotic bone lesions.

Epidemiology

Multiple myeloma is considerably more common than primary malignant bone sarcomas.

Older U.S. data described approximately 30,000 new cases annually, representing roughly 2% of newly diagnosed cancers.

It is much more common than all primary malignant bone tumors combined.

Risk Factors

Factors associated with an increased risk include:

Increasing age

Obesity

Family history of plasma-cell disorders

Prior radiation exposure

Certain occupational or chemical exposures

Some older reports also described associations with alcohol exposure, although this is not considered a major established causal factor.

Pathophysiology

Multiple myeloma develops from a genetically abnormal B-cell/plasma-cell clone.

A single clonal population expands and produces a monoclonal immunoglobulin or light chain.

Monoclonal Protein Production

The abnormal plasma cells may produce large quantities of:

Intact immunoglobulin

or

Free light chains.

These proteins can accumulate in the kidneys and contribute to renal injury.

Renal Injury

Renal dysfunction may result from several mechanisms, including:

Light-chain cast nephropathy

Hypercalcemia

Dehydration

Amyloid deposition

Medication-related nephrotoxicity

Abnormal light chains can obstruct and damage renal tubules.

Bone Destruction

Myeloma cells alter normal bone remodeling by stimulating osteoclast activity and suppressing osteoblast function.

They release or induce factors that increase:

Osteoclast differentiation and bone resorption.

This results in characteristic lytic bone lesions.

Osteoclast-Activating Factors

Myeloma cells and surrounding marrow cells produce signaling molecules that stimulate osteoclasts.

The resulting imbalance leads to:

Progressive bone loss, cortical weakening, pathologic fracture, and hypercalcemia.

Diagnosis

The diagnosis is based on evidence of a clonal plasma-cell disorder together with characteristic clinical, laboratory, marrow, or imaging findings.

Monoclonal Protein

Serum protein electrophoresis may demonstrate a characteristic:

Monoclonal or M-protein spike.

Additional testing may include:

Serum immunofixation

Urine protein electrophoresis

Serum free light-chain assay

Bone Marrow Examination

Bone marrow aspiration or biopsy commonly demonstrates:

At least 10% clonal plasma cells in established multiple myeloma.

The marrow may show diffuse or focal plasma-cell replacement.

End-Organ Damage

Classic myeloma-related organ injury is commonly summarized by the CRAB features:

C – Hypercalcemia

R – Renal insufficiency

A – Anemia

B – Bone lesions

These findings indicate clinically significant disease when attributable to the plasma-cell disorder.

Signs and Symptoms

Fatigue and Weakness

Fatigue is common and frequently results from:

Anemia caused by replacement of normal marrow and impaired red-cell production.

Bone Pain

Bone pain is one of the most common symptoms.

It may result from:

Lytic lesions

Microfractures

Vertebral compression fractures

Mechanical insufficiency

The spine, ribs, pelvis, and proximal long bones are frequently involved.

Pathologic Fracture

Patients may present with a fracture after:

Minimal trauma or ordinary activity.

Bleeding

Bleeding manifestations such as:

Epistaxis or easy bruising

may occur because of thrombocytopenia or abnormal protein effects.

Fever and Infection

Patients may develop recurrent or severe infections because normal antibody production and bone-marrow function are impaired.

Physical Examination

There are few findings that are specific for multiple myeloma.

Examination should focus on:

Areas of bone tenderness

Spinal deformity or compression fracture

Neurologic deficits

Pallor

Evidence of fracture

Signs of infection or bleeding

Neurologic Examination

Spinal lesions or vertebral collapse can lead to:

Nerve-root compression or spinal cord compromise.

Weakness, sensory change, bowel or bladder disturbance, or gait abnormality requires urgent evaluation.

Laboratory Tests

Typical investigations include:

CBC

Serum calcium

Creatinine and renal function

Serum protein electrophoresis

Serum immunofixation

Free light-chain assay

Urine protein studies

Beta-2 microglobulin

Albumin

Imaging

Plain Radiography

A skeletal survey has historically been used to detect myeloma-related osseous lesions.

Typical findings include:

Well-defined punched-out lytic lesions

Diffuse osteopenia

Ill-defined lytic destruction

Pathologic fractures

The skull is a classic site for punched-out lesions.

Bone Scintigraphy

Technetium bone scans may produce false-negative results because myeloma often causes little osteoblastic response.

Therefore, a normal bone scan does not exclude myeloma.

CT

CT is more sensitive than radiographs for detecting:

Cortical destruction

Small lytic lesions

Pathologic fracture

Spinal and pelvic involvement

Low-dose whole-body CT is commonly used for skeletal assessment.

MRI

MRI is highly sensitive for detecting bone-marrow replacement.

Typical lesions appear:

Low signal on T1-weighted imaging

and

High signal on fluid-sensitive or fat-suppressed T2-weighted imaging.

MRI is particularly useful for:

Spinal disease

Neurologic symptoms

Occult marrow lesions

Cord compression

Distinguishing benign from malignant vertebral compression fractures

Differential Diagnosis

When a destructive bone lesion is identified, important alternatives include:

Metastatic bone disease

Lymphoma

Chondrosarcoma

Undifferentiated primary bone sarcoma

Other hematologic malignancies

Metastatic Bone Disease

Metastatic carcinoma may closely resemble myeloma, particularly when multiple lytic skeletal lesions are present.

The distinction relies on:

Clinical history, laboratory evaluation, imaging, and biopsy.

Lymphoma

Lymphoma may replace marrow and produce destructive lesions that resemble plasma-cell disease.

Histologic examination is usually required when the diagnosis is uncertain.

Treatment

General Principles

Treatment is primarily systemic and is managed by hematology or oncology.

Modern therapy may include combinations of:

Proteasome inhibitors

Immunomodulatory drugs

Corticosteroids

Monoclonal antibodies

Traditional cytotoxic chemotherapy in selected settings

Cellular or targeted therapies

Autologous stem-cell transplantation

Treatment is individualized according to age, disease risk, organ function, cytogenetics, and transplant eligibility.

Stem-Cell Transplantation

Appropriate patients may undergo:

High-dose systemic therapy followed by autologous stem-cell transplantation.

This remains an important treatment strategy for eligible individuals.

Bone-Directed Therapy

Skeletal disease may also be treated with:

Bisphosphonates

or

RANKL inhibition such as denosumab.

These therapies reduce osteoclast-mediated bone destruction and skeletal complications.

Radiation Therapy

Local radiation can be used for:

Painful focal lesions

Plasmacytomas

Impending neurologic compromise

Lesions not adequately controlled by systemic treatment

Orthopaedic Management

Orthopaedic treatment is directed toward preserving structural integrity and mobility.

Impending Fracture

Prophylactic stabilization may be indicated when bone destruction creates a high risk of pathologic fracture.

Completed Fracture

Pathologic fractures may require operative stabilization to:

Control pain, restore function, and permit mobilization.

Nonoperative Healing

Some fractures or impending fractures may improve with:

Effective systemic treatment, radiation, activity protection, and bone-directed therapy

without surgery.

Treatment depends on location, mechanical stability, symptoms, and anticipated healing.

Surgery

Surgical indications may include:

Impending fracture of a weight-bearing bone

Completed pathologic fracture

Mechanical instability

Spinal instability

Neurologic compression

Failure of nonoperative treatment

Surgical Options

Depending on the site, options include:

Intramedullary fixation

Plate fixation

Cement augmentation

Prosthetic reconstruction

Spinal stabilization and decompression

Follow-Up

Patients require long-term hematologic and skeletal monitoring.

Those in remission should be evaluated for:

Disease recurrence or biochemical progression.

Patients with active disease should be monitored for:

Response to therapy and treatment toxicity.

Prognosis

Prognosis varies considerably according to:

Age

Stage

Cytogenetic risk

Renal function

Response to therapy

Overall fitness

Modern therapies have substantially improved survival compared with older historical estimates.

Some patients live many years following diagnosis.

Staging

The International Staging System uses:

Serum beta-2 microglobulin and albumin.

Modern risk assessment also incorporates:

Cytogenetic abnormalities and serum lactate dehydrogenase, as in the Revised International Staging System.

Stage I

Classic ISS Stage I includes:

Beta-2 microglobulin less than 3.5 mg/L

and

Albumin at least 3.5 g/dL.

This group historically has the most favorable prognosis.

Stage II

Stage II includes patients who meet neither Stage I nor Stage III criteria.

Stage III

Classic ISS Stage III is defined by:

Beta-2 microglobulin at least 5.5 mg/L.

High-risk cytogenetic abnormalities further worsen prognosis.

Complications

Multiple myeloma can produce numerous systemic and skeletal complications.

Renal Dysfunction

Abnormal immunoglobulin light chains can damage renal tubules.

Renal injury may also be worsened by:

Hypercalcemia, dehydration, infection, and nephrotoxic medications.

Hypercalcemia

Extensive bone resorption may produce severe hypercalcemia.

Potential manifestations include:

Weakness

Confusion

Constipation

Nausea

Dehydration

Cardiac rhythm disturbance

Severe hypercalcemia can be life-threatening.

Pathologic Fractures

Lytic bone destruction predisposes to:

Vertebral compression fractures and long-bone fractures.

Anemia

As malignant plasma cells replace normal marrow, red-cell production decreases.

This results in:

Fatigue, weakness, dyspnea, and reduced exercise tolerance.

Thrombocytopenia and Bleeding

Advanced marrow replacement may reduce platelet production and cause:

Easy bruising, mucosal bleeding, or epistaxis.

Leukopenia and Immunosuppression

Reduced normal leukocyte production and suppression of normal immunoglobulin function can markedly increase susceptibility to infection.

Spinal Cord Compression

Vertebral collapse, epidural tumor, or plasmacytoma may produce:

Spinal cord or cauda equina compression.

New weakness, sensory loss, or bowel/bladder dysfunction requires emergency evaluation.

Patient Monitoring

Patients with active disease require regular assessment of:

Monoclonal protein levels

Free light chains

CBC

Calcium

Renal function

Bone symptoms

Imaging findings when indicated

Monitoring in Remission

Patients in remission should continue surveillance for:

Biochemical relapse

New bone lesions

Renal deterioration

Cytopenias

Recurrent symptoms

Key Principle

Multiple myeloma is a systemic plasma-cell malignancy with major orthopaedic consequences because of osteoclast-driven bone destruction.

Management requires coordinated hematologic and orthopaedic care directed toward:

Controlling the plasma-cell disease, protecting bone strength, treating impending or completed fractures, preventing neurologic compromise, and monitoring for systemic complications.