Plasma Cell Neoplasm | Lytic Bone Disease | CRAB Criteria
CRAB Criteria for End-Organ Damage
Critical Must-Knows
- CRAB criteria define symptomatic myeloma requiring treatment - must have end-organ damage
- Lytic lesions show NO blastic response - purely osteolytic, unlike metastases which may show healing
- Bisphosphonates are mandatory for all patients with bone disease to prevent skeletal events
- Pathological fractures common in vertebrae, ribs, and long bones - prophylactic fixation for impending fractures
- Diagnosis requires serum protein electrophoresis (SPEP), urine protein, and bone marrow biopsy showing over 10% plasma cells
Clinical Pearls
- "Purely lytic lesions with NO sclerotic response differentiates myeloma from metastatic disease
- "Whole-body MRI or PET-CT more sensitive than skeletal survey for detecting bone involvement
- "Impending pathological fracture needs prophylactic fixation - use intramedullary nails for long bones
- "Spinal cord compression is an emergency - dexamethasone, radiotherapy, and consider surgery
Clinical Imaging
Imaging Gallery
Critical Multiple Myeloma Exam Points
CRAB Criteria Essential
Must know CRAB backwards and forwards. This defines symptomatic myeloma requiring treatment. Without CRAB features, patient has smoldering myeloma and only needs observation.
No Blastic Response
Purely osteolytic lesions with NO sclerosis. This is pathognomonic - osteoblasts are inhibited by DKK1 and sclerostin from myeloma cells. Healing or sclerotic lesions suggest metastases instead.
Surgical Indications
Fix impending and actual pathological fractures. Use intramedullary devices for long bones. Mirels score over 8 indicates prophylactic fixation. Vertebroplasty for painful compression fractures.
Bisphosphonates Mandatory
All patients with bone disease need bisphosphonates. Reduces skeletal events by 40%. Beware osteonecrosis of jaw - dental clearance before starting. Hold before surgery.
At a Glance
Multiple myeloma is a plasma cell malignancy causing purely lytic skeletal lesions (no blastic component). It presents with the "CRAB" criteria: Calcium elevation, Renal insufficiency, Anemia, Bone lesions. The spine and pelvis are most commonly affected. Unlike metastatic disease, bone scans are cold (no bone formation). Pathological fractures are common and require internal fixation (avoid arthroplasty at spine). All patients need bisphosphonates to reduce skeletal events. Key orthopaedic decision: stabilize prophylactically using Mirels' criteria, and cementation is preferred for rapid stability.
Multiple Myeloma vs Common Differentials
| Feature | Multiple Myeloma | Metastatic Disease | Osteoporosis |
|---|---|---|---|
| Lesion appearance | Purely lytic, punched-out, NO sclerosis | Mixed lytic-blastic or purely blastic | Diffuse osteopenia, no focal lesions |
| Serum protein | M-protein spike on SPEP | Normal protein electrophoresis | Normal protein electrophoresis |
| Bone marrow | Over 10% clonal plasma cells | Metastatic carcinoma cells | Normal marrow |
| Common fracture sites | Vertebrae, ribs, proximal femur/humerus | Vertebrae, femur, pelvis | Vertebrae, distal radius, hip |
| Treatment approach | Chemotherapy plus bisphosphonates | Treat primary cancer plus targeted therapy | Bisphosphonates, calcium, vitamin D |
CRABCRAB Criteria for Myeloma End-Organ Damage
| C | Calcium elevated Serum calcium over 2.75 mmol/L (or 11 mg/dL) |
| R | Renal insufficiency Creatinine over 173 micromol/L (or 2 mg/dL) |
| A | Anemia Hemoglobin under 100 g/L (or 10 g/dL) |
| B | Bone lesions One or more lytic lesions on imaging |
| C | Calcium elevated Serum calcium over 2.75 mmol/L (or 11 mg/dL) | A | Anemia Hemoglobin under 100 g/L (or 10 g/dL) |
| R | Renal insufficiency Creatinine over 173 micromol/L (or 2 mg/dL) | B | Bone lesions One or more lytic lesions on imaging |
Hook:When myeloma gets CRABBY, it needs treatment! Any one CRAB feature = symptomatic myeloma requiring chemotherapy.
BUMPSDiagnostic Workup for Suspected Myeloma
| B | Bone marrow biopsy Over 10% clonal plasma cells required for diagnosis |
| U | Urine protein electrophoresis Bence Jones protein (light chains) |
| M | M-protein (SPEP) Serum protein electrophoresis shows monoclonal spike |
| P | PET-CT or whole-body MRI Most sensitive for detecting bone lesions |
| S | Skeletal survey Traditional imaging - shows punched-out lesions |
| B | Bone marrow biopsy Over 10% clonal plasma cells required for diagnosis | P | PET-CT or whole-body MRI Most sensitive for detecting bone lesions |
| U | Urine protein electrophoresis Bence Jones protein (light chains) | S | Skeletal survey Traditional imaging - shows punched-out lesions |
| M | M-protein (SPEP) Serum protein electrophoresis shows monoclonal spike |
Hook:When you suspect myeloma, look for BUMPS - the diagnostic workup essentials!
SPINAL FRACTURESOrthopaedic Complications of Myeloma
| S | Spinal cord compression Emergency - dexamethasone and radiotherapy |
| P | Pathological fractures Vertebrae, ribs, long bones |
| I | Impending fractures Mirels score over 8 needs prophylactic fixation |
| N | Nerve root compression Radiculopathy from vertebral collapse |
| A | Avascular necrosis From steroid therapy |
| L | Lytic lesions diffuse Multiple sites of skeletal involvement |
| S | Spinal cord compression Emergency - dexamethasone and radiotherapy | I | Impending fractures Mirels score over 8 needs prophylactic fixation | A | Avascular necrosis From steroid therapy |
| P | Pathological fractures Vertebrae, ribs, long bones | N | Nerve root compression Radiculopathy from vertebral collapse | L | Lytic lesions diffuse Multiple sites of skeletal involvement |
Hook:Myeloma causes SPINAL FRACTURES - remember the skeletal complications requiring orthopaedic intervention!
Overview and Epidemiology
Multiple myeloma is a malignant neoplasm of plasma cells characterized by clonal proliferation in the bone marrow, production of monoclonal immunoglobulin (M-protein), and end-organ damage. It accounts for approximately 1-2% of all cancers and represents the most common primary malignancy of bone in adults over 40 years of age.
Why Multiple Myeloma Matters to Orthopaedic Surgeons
Skeletal involvement occurs in 90% of patients and is often the presenting feature. Patients present with pathological fractures, severe bone pain, or spinal cord compression. Orthopaedic surgeons must recognize the characteristic punched-out lytic lesions without sclerotic response and understand when surgical intervention is indicated. Bisphosphonate therapy is critical to prevent skeletal complications.
Demographics
- Median age: 65 years at diagnosis
- Rare under 40: Only 2% of cases
- Gender: Slight male predominance (1.4:1)
- Ethnicity: 2-fold higher in African populations
- Incidence: 4-6 per 100,000 per year
Skeletal Distribution
- Vertebral column: 70% (most common site)
- Ribs: 50%
- Skull: 40% (classic "punched-out" lesions)
- Pelvis: 30%
- Proximal long bones: Femur and humerus 25%
- Distal skeleton: Rarely involved
Risk Factors and Precursor Conditions
- M-protein under 30 g/L
- Bone marrow plasma cells under 10%
- No CRAB features
- Progresses to myeloma at 1% per year
- Requires annual monitoring
- M-protein 30 g/L or higher OR bone marrow plasma cells 10-60%
- No CRAB features (key distinction)
- Progresses to symptomatic myeloma at 10% per year in first 5 years
- Observation only - do not treat
- One or more CRAB criteria present
- OR malignant biomarkers: Bone marrow plasma cells over 60%, serum free light chain ratio over 100, or over 1 focal lesion on MRI
- Requires chemotherapy and supportive care
Pathophysiology and Skeletal Mechanisms
Plasma Cell Biology and Bone Destruction
Multiple myeloma represents a clonal proliferation of malignant plasma cells in the bone marrow. These cells produce excessive amounts of monoclonal immunoglobulin (M-protein), which can be detected in serum and urine. The characteristic skeletal manifestations result from profound disruption of normal bone remodeling.
Osteoclast Activation
Myeloma cells secrete RANKL (receptor activator of nuclear factor kappa-B ligand) which dramatically increases osteoclast activity. This drives bone resorption and creates lytic lesions. Additionally, decreased OPG (osteoprotegerin) removes the natural brake on osteoclast function.
Osteoblast Inhibition
Myeloma cells produce DKK1 and sclerostin which inhibit the Wnt signaling pathway essential for osteoblast function. This explains why myeloma lesions show NO sclerotic or healing response - osteoblasts cannot form new bone.
Cytokine Dysregulation
IL-6, IL-1, and TNF-alpha are overproduced, promoting myeloma cell growth and survival while further stimulating bone resorption. These cytokines also contribute to systemic symptoms like fatigue and weight loss.
Angiogenesis
VEGF production by myeloma cells promotes new blood vessel formation in the bone marrow microenvironment, supporting tumor growth and creating the vascular network seen on MRI.
Why Lesions Are Purely Lytic
Pathognomonic Finding
The absence of any sclerotic or blastic response in myeloma bone lesions is pathognomonic and distinguishes myeloma from metastatic carcinoma. This occurs because:
- DKK1 and sclerostin from myeloma cells completely suppress osteoblast differentiation and function
- Even with successful chemotherapy, lesions rarely show healing or sclerosis
- Any sclerotic change in a presumed myeloma lesion should prompt reconsideration of the diagnosis
Classification
Multiple myeloma is classified based on:
By Clinical Stage:
- Smoldering (asymptomatic) myeloma: M-protein or clonal plasma cells present without CRAB features
- Symptomatic myeloma: Presence of CRAB features or myeloma-defining biomarkers
By Immunoglobulin Type:
- IgG myeloma (most common, 50-55%)
- IgA myeloma (20-25%)
- Light chain only (Bence Jones, 15-20%)
- IgD, IgE, or non-secretory (rare)
By Prognostic Risk:
- Standard risk cytogenetics
- High-risk cytogenetics: del(17p), t(4;14), t(14;16), gain 1q
See "Classification and Staging" section below for detailed ISS and R-ISS staging systems.
Clinical Presentation and CRAB Criteria
Presenting Symptoms
Most patients present with one or more symptoms related to skeletal involvement or systemic effects of plasma cell proliferation.
Skeletal Symptoms
- Bone pain: Persistent, often in back or chest
- Pathological fractures: Minimal trauma fractures
- Height loss: From vertebral compression fractures
- Spinal cord compression: Emergency presentation
Systemic Symptoms
- Fatigue and weakness: From anemia
- Recurrent infections: Hypogammaglobulinemia
- Weight loss: Cachexia from tumor burden
- Bleeding tendency: Hyperviscosity syndrome (rare)
Renal Symptoms
- Renal insufficiency: Light chain cast nephropathy
- Dehydration: Hypercalcemia-induced
- Amyloidosis: AL amyloid deposition (10-15%)
- Tubular dysfunction: Fanconi syndrome
CRAB Criteria in Detail
CRAB criteria define symptomatic myeloma requiring treatment. The presence of ANY ONE CRAB feature (or myeloma-defining biomarker) mandates initiation of chemotherapy. Without CRAB features, patients have smoldering myeloma and should NOT be treated.
CRAB Criteria Detailed
| CRAB Feature | Definition | Pathophysiology | Management |
|---|---|---|---|
| C - Calcium elevated | Serum calcium over 2.75 mmol/L (or corrected calcium over 2.75 mmol/L or ionized calcium over 1.30 mmol/L) | Osteoclast-mediated bone resorption releases calcium; renal insufficiency impairs calcium excretion | Aggressive IV hydration (3-4L per day), bisphosphonates (zoledronic acid), calcitonin if severe, treat underlying myeloma |
| R - Renal insufficiency | Creatinine clearance under 40 mL/min or creatinine over 173 micromol/L (over 2 mg/dL) | Light chain cast nephropathy (myeloma kidney), hypercalcemia, dehydration, nephrotoxic drugs | Hydration, treat hypercalcemia, avoid NSAIDs and contrast, dialysis if needed, chemotherapy to reduce light chains |
| A - Anemia | Hemoglobin under 100 g/L (under 10 g/dL) or over 20 g/L below normal | Bone marrow infiltration by plasma cells suppresses normal hematopoiesis; renal insufficiency decreases EPO | Transfusion if symptomatic, erythropoietin, treat underlying myeloma to restore marrow function |
| B - Bone lesions | One or more osteolytic lesions on skeletal survey, CT, or PET-CT | RANKL-mediated osteoclast activation plus DKK1/sclerostin-mediated osteoblast suppression creates purely lytic lesions | Bisphosphonates (zoledronic acid or pamidronate monthly), fixation for fractures/impending fractures, vertebroplasty for painful VCFs |
Myeloma-Defining Biomarkers (SLiM Criteria)
In addition to CRAB, the following biomarkers define symptomatic myeloma even in the absence of CRAB features:
- 60 or more percent clonal plasma cells on bone marrow biopsy
- Light chain ratio 100 or higher (involved/uninvolved free light chain ratio)
- MRI with more than 1 focal lesion at least 5mm in size
These "SLiM" criteria allow earlier treatment initiation in high-risk patients before end-organ damage occurs.
Investigations
Laboratory Investigations
Essential Laboratory Tests
| Test | Purpose | Typical Finding in Myeloma | Clinical Significance |
|---|---|---|---|
| SPEP (Serum Protein Electrophoresis) | Detect and quantify M-protein | Monoclonal spike in gamma region (70% IgG, 20% IgA) | Diagnostic - quantifies disease burden; M-protein level correlates with tumor mass |
| UPEP (Urine Protein Electrophoresis) | Detect Bence Jones protein | Monoclonal light chains (kappa or lambda) | Present in 75% - indicates light chain production; nephrotoxic |
| Free Light Chain Assay (Serum FLC) | Quantify free light chains | Elevated involved FLC; abnormal kappa/lambda ratio | More sensitive than UPEP; useful for monitoring non-secretory myeloma |
| Bone Marrow Biopsy | Confirm clonal plasma cells | Over 10% clonal plasma cells; often 30-90% | Diagnostic gold standard - required for diagnosis |
| Complete Blood Count | Assess cytopenias | Anemia common (Hb under 100 g/L); leukopenia and thrombocytopenia in advanced disease | Monitors CRAB criteria (anemia); assesses bone marrow reserve |
| Renal Function (Creatinine, eGFR) | Assess renal impairment | Elevated creatinine over 173 micromol/L in 25% | Monitors CRAB criteria (renal); impacts chemotherapy dosing |
| Calcium (Serum corrected) | Detect hypercalcemia | Elevated over 2.75 mmol/L in 20-30% | Monitors CRAB criteria (calcium); emergency if severe |
| Beta-2 Microglobulin | Prognostic marker | Elevated in advanced disease | Part of ISS staging - higher levels = worse prognosis |
| Albumin | Prognostic marker | Low in advanced disease | Part of ISS staging - lower levels = worse prognosis |
| LDH | Tumor burden marker | Elevated in high tumor burden | Part of revised ISS (R-ISS); indicates aggressive disease |
Imaging Investigations
Imaging Modalities Compared
| Modality | Sensitivity | Advantages | Disadvantages | Clinical Use |
|---|---|---|---|---|
| Skeletal Survey (Plain X-rays) | 40-50% (low) | Widely available; low cost; traditional standard | Misses early lesions; requires 30-50% bone loss to visualize; radiation exposure | Initial screening; shows classic punched-out lesions; useful for fracture assessment |
| Whole-Body MRI | 90% (very high) | Most sensitive for bone marrow involvement; no radiation; detects early focal lesions | Expensive; time-consuming; not widely available; claustrophobia | Preferred first-line imaging; detects disease before skeletal survey positive |
| PET-CT | 85-90% (high) | Detects metabolically active disease; whole-body assessment; useful for monitoring response | Radiation exposure; expensive; false negatives in low-grade disease | Alternative to MRI; excellent for assessing treatment response and detecting extramedullary disease |
| CT (Low-dose whole-body) | 70-80% (moderate-high) | Better than X-ray; detects smaller lesions; fast acquisition | Radiation exposure; less sensitive than MRI/PET-CT for marrow disease | Alternative when MRI unavailable; good for cortical bone assessment and surgical planning |
Why NOT Bone Scan?
Technetium-99m bone scans are NOT useful in myeloma because they rely on osteoblastic activity to show uptake. Since myeloma lesions are purely osteolytic with suppressed osteoblast function, bone scans are typically negative or show decreased uptake ("cold spots"). This is the opposite of metastatic disease, which usually shows "hot spots" of increased uptake.
Radiographic Features
Skull
"Punched-out" lesions: Multiple well-defined, round lytic lesions with sharp margins and no sclerotic rim. Classic "moth-eaten" or "Swiss cheese" appearance. Most visible in lateral skull X-ray.
Spine
Vertebral compression fractures: Often multiple levels. Diffuse osteopenia. Vertebral body collapse creating "coin-on-edge" appearance. Posterior elements usually spared (unlike metastases).
Pelvis
Multiple lytic lesions: Involvement of ilium, pubis, and ischium. May cause pathological fractures. Pelvic insufficiency fractures in osteopenic bone.
Long Bones
Proximal involvement: Preferentially affects proximal femur and humerus (red marrow sites). Endosteal scalloping. Risk of pathological fracture with cortical destruction over 50%.
Diagnostic Criteria (IMWG 2014)
Multiple myeloma diagnosis requires:
-
Clonal bone marrow plasma cells ≥10% OR biopsy-proven plasmacytoma
PLUS
-
One or more of the following:
- CRAB features (any one of: Calcium elevated, Renal insufficiency, Anemia, Bone lesions)
- OR Myeloma-defining biomarkers (any one of: 60% or more clonal plasma cells, serum FLC ratio 100 or higher, over 1 focal MRI lesion)
Classification and Staging
International Staging System (ISS)
ISS Staging System
| Stage | Criteria | Median Survival | Frequency |
|---|---|---|---|
| Stage I | Beta-2 microglobulin under 3.5 mg/L AND albumin 35 g/L or higher | 62 months | 30% of patients |
| Stage II | Neither Stage I nor Stage III | 44 months | 40% of patients |
| Stage III | Beta-2 microglobulin 5.5 mg/L or higher | 29 months | 30% of patients |
Revised International Staging System (R-ISS)
The R-ISS incorporates ISS stage plus LDH and high-risk cytogenetics for improved prognostication.
R-ISS Staging (Preferred Current System)
| R-ISS Stage | Criteria | 5-Year Survival | Clinical Implication |
|---|---|---|---|
| R-ISS I | ISS Stage I AND standard-risk cytogenetics AND normal LDH | 82% | Excellent prognosis - may defer treatment in smoldering myeloma |
| R-ISS II | Not R-ISS I or III | 62% | Intermediate prognosis - standard treatment approach |
| R-ISS III | ISS Stage III AND (high-risk cytogenetics OR elevated LDH) | 40% | Poor prognosis - consider novel agents and early transplant |
High-Risk Cytogenetics
Detected by FISH on bone marrow plasma cells:
- del(17p) - TP53 deletion - worst prognosis
- t(4;14) - FGFR3/MMSET translocation - high risk
- t(14;16) - MAF translocation - high risk
- Gain 1q - chromosome 1q gain/amplification - adverse
- del(13) - Chromosome 13 deletion - adverse when detected by conventional cytogenetics
Cytogenetics in Myeloma
Unlike other hematological malignancies, myeloma plasma cells often have low mitotic index, making conventional karyotyping difficult. FISH (fluorescence in situ hybridization) is essential to detect high-risk translocations and deletions. Presence of del(17p) or t(4;14) indicates aggressive disease requiring intensive treatment.
Management Algorithm
Treatment Approach by Disease Status
- No CRAB criteria and no myeloma-defining biomarkers
- Close monitoring every 3-6 months
- Repeat SPEP, free light chains, imaging
- Do NOT treat - observation superior to early treatment in trials
- Treat only when progression to symptomatic myeloma
- Induction chemotherapy: Bortezomib + lenalidomide + dexamethasone (VRd) for 4-6 cycles
- Autologous stem cell transplant: High-dose melphalan followed by stem cell rescue
- Maintenance therapy: Lenalidomide continued until progression
- Bisphosphonates: Zoledronic acid or pamidronate monthly
- Median progression-free survival: 50+ months
- Induction chemotherapy: VRd or daratumumab + lenalidomide + dexamethasone (DRd)
- Continue until disease progression or intolerance
- Bisphosphonates: Zoledronic acid or pamidronate monthly
- Median overall survival: 4-5 years
- Second-line agents: Carfilzomib, ixazomib, daratumumab, elotuzumab, pomalidomide
- CAR T-cell therapy (ide-cel, cilta-cel) for heavily pretreated patients
- Clinical trials
- Palliation and supportive care
Key Drug Classes
Proteasome Inhibitors
Bortezomib, carfilzomib, ixazomib
- Inhibit protein degradation causing myeloma cell apoptosis
- Backbone of most regimens
- Side effects: Peripheral neuropathy, thrombocytopenia
Immunomodulatory Drugs (IMiDs)
Lenalidomide, pomalidomide, thalidomide
- Immune modulation and anti-angiogenic effects
- Highly effective in combination regimens
- Side effects: Thrombosis (require anticoagulation), neuropathy, teratogenicity
Monoclonal Antibodies
Daratumumab, isatuximab, elotuzumab
- Target CD38 or SLAMF7 on myeloma cells
- Dramatic responses in combination therapy
- Side effects: Infusion reactions, infections, cytopenias
Corticosteroids
Dexamethasone, prednisone
- Direct anti-myeloma effect and anti-inflammatory
- Used in all regimens
- Side effects: Hyperglycemia, insomnia, AVN, infections
Bisphosphonate Therapy - Essential for Skeletal Protection
ALL patients with myeloma bone disease should receive bisphosphonates. This is a class I recommendation based on randomized trials showing 40% reduction in skeletal-related events (pathological fractures, spinal cord compression, need for radiotherapy or surgery).
Bisphosphonate Options
| Agent | Dosing | Advantages | Precautions |
|---|---|---|---|
| Zoledronic acid (IV) | 4mg IV over 15 minutes every 4 weeks | Most potent bisphosphonate; convenient monthly dosing | Requires renal dose adjustment if CrCl under 60; risk of ONJ; hold before dental procedures |
| Pamidronate (IV) | 90mg IV over 2-4 hours every 4 weeks | Alternative if renal impairment | Longer infusion time; less potent than zoledronic acid; risk of ONJ |
| Denosumab (SubQ) | 120mg SubQ every 4 weeks | Can use in renal failure; no dose adjustment needed | Higher risk of hypocalcemia; ensure calcium/vitamin D supplementation; risk of ONJ |
Duration: Continue monthly for first 2 years, then consider reducing to every 3 months if complete response achieved.
Osteonecrosis of Jaw (ONJ) Prevention:
- Dental examination and clearance before starting bisphosphonates
- Maintain excellent oral hygiene
- Avoid invasive dental procedures while on therapy
- If dental surgery required, hold bisphosphonates for 2-3 months before and after
- Risk increases with duration of therapy (cumulative effect)
Orthopaedic Management and Surgical Indications
Principles of Orthopaedic Management
Surgical Philosophy in Myeloma
Myeloma is a systemic disease requiring systemic treatment. Surgery is palliative and aims to:
- Stabilize actual or impending pathological fractures to restore function
- Decompress neural structures in spinal cord compression
- Provide pain relief through stabilization or vertebroplasty/kyphoplasty
- Improve quality of life by restoring mobility and independence
Surgery alone NEVER cures myeloma - chemotherapy is essential for disease control.
Impending Pathological Fracture Assessment
Mirels Scoring System for Impending Fracture Risk
| Variable | 1 Point | 2 Points | 3 Points |
|---|---|---|---|
| Location | Upper limb | Lower limb | Peritrochanteric |
| Pain | Mild | Moderate | Functional (severe) |
| Lesion type | Blastic | Mixed | Lytic |
| Size | Less than 1/3 diameter | 1/3 to 2/3 diameter | Over 2/3 diameter |
Interpretation:
- Score ≤7: Low fracture risk - observation, bisphosphonates, radiotherapy if painful
- Score 8: Intermediate risk - consider prophylactic fixation
- Score ≥9: High fracture risk - prophylactic fixation indicated
Mirels scoring was developed for metastatic disease, but myeloma lesions have NO sclerotic response and may be at higher fracture risk than the score suggests. Cortical destruction over 50% or lesion over 3cm in long bone should prompt strong consideration of prophylactic fixation regardless of score.
Long Bone Pathological Fractures
Surgical Technique for Long Bone Fractures
Surgical Principles
Device Selection
Intramedullary nailing preferred over plate fixation for:
- Load sharing vs load bearing
- Protection of entire bone including skip lesions
- Lower reoperation rate with progression
- Allows early weight-bearing
Fixation Strategy
Long segment fixation:
- Protect entire bone at risk
- Assume disease may progress
- Bridge all lytic lesions
- Use locked interlocking screws
Cement Augmentation
PMMA cement indicated for:
- Large segmental defects
- Periarticular fractures
- Adjunct to intramedullary nails
- Immediate pain relief and stability
Adjuvant Radiotherapy
Consider postoperative RT:
- Local disease control
- Pain management
- Timing: 2-3 weeks post-op (allow wound healing)
- Typical dose: 20-30 Gy in 5-10 fractions
Femur Fractures - Specific Considerations
Proximal femur (intertrochanteric/subtrochanteric):
- Long cephalomedullary nail (e.g., long Gamma nail, trochanteric femoral nail)
- Protect entire femur down to supracondylar region
- Consider cemented hip arthroplasty if extensive femoral head/neck involvement
Femoral shaft:
- Long antegrade intramedullary nail
- Protect from subtrochanteric to supracondylar region
- Ream if cortical destruction significant
- Static locking proximally and distally
Distal femur:
- Retrograde intramedullary nail OR lateral locked plate
- Cement augmentation of screw holes
- Consider distal femoral replacement if extensive metaphyseal involvement
Humerus Fractures
Proximal humerus:
- Antegrade humeral nail OR shoulder hemiarthroplasty/reverse shoulder arthroplasty
- Arthroplasty preferred if extensive humoral head destruction or elderly patient
Humeral shaft:
- Antegrade humeral nail preferred
- Alternative: Plate fixation if radial nerve concern or very distal lesion
- Protect full length of diaphysis
This completes the long bone surgical principles section.
Spinal Involvement and Cord Compression
Spinal cord compression is an orthopaedic and oncological EMERGENCY. Prognosis depends on neurological status at treatment initiation - patients who lose ambulation rarely regain it. Immediate dexamethasone 10mg IV, MRI whole spine, and urgent oncology consultation are mandatory.
Presentation
- Back pain (95%) - often first symptom
- Motor weakness (75%) - lower extremity weakness
- Sensory changes (50%) - numbness, paresthesias
- Bladder/bowel dysfunction (40%) - late finding, poor prognosis
- Cauda equina syndrome - saddle anesthesia, urinary retention
Imaging
- MRI whole spine - gold standard
- Identifies level(s) of compression
- Assesses spinal stability
- Detects multiple levels (30% have multiple sites)
- STIR sequence best for edema/disease
Treatment Algorithm for Spinal Cord Compression
| Neurological Status | Spinal Stability | Treatment | Prognosis for Ambulation |
|---|---|---|---|
| Intact neurology, pain only | Stable spine | Dexamethasone + radiotherapy + bisphosphonates + chemotherapy | Over 90% maintain ambulation |
| Intact neurology, pain only | Unstable spine | Posterior stabilization + decompression, then radiotherapy | Over 90% maintain ambulation |
| Ambulatory with weakness | Stable or unstable | Dexamethasone + URGENT radiotherapy OR surgery if unstable + chemotherapy | 60-80% maintain/regain ambulation |
| Non-ambulatory under 48 hours | Any stability | Dexamethasone + EMERGENCY surgery (decompression + stabilization) + radiotherapy | 40-60% regain ambulation |
| Non-ambulatory over 48 hours | Any stability | Dexamethasone + radiotherapy (surgery unlikely to help) + chemotherapy | Under 20% regain ambulation |
Vertebroplasty and Kyphoplasty
Indications
- Painful vertebral compression fractures
- Failed conservative management (analgesia, bracing)
- No spinal cord compression
- Fracture under 3 months old (better outcomes)
- Vertebral body height over 33% preserved
Contraindications
- Spinal cord compression
- Posterior vertebral wall disruption
- Infection (osteomyelitis, discitis)
- Uncorrectable coagulopathy
- Extensive vertebral collapse (under 33% height)
Vertebroplasty vs Kyphoplasty
| Feature | Vertebroplasty | Kyphoplasty |
|---|---|---|
| Technique | Direct PMMA injection into vertebral body | Balloon inflation to create cavity, then PMMA injection |
| Height restoration | Minimal (10-20%) | Moderate (30-40%) |
| Cement extravasation risk | 10-15% (higher) | 5-7% (lower) |
| Pain relief | 75-85% achieve significant relief | 80-90% achieve significant relief |
| Cost | Lower | Higher (balloon equipment) |
| Procedure time | 30-45 minutes | 60-90 minutes |
Outcomes:
- Pain relief: 75-90% of patients achieve significant improvement within 24-48 hours
- Functional improvement: Reduced analgesic requirements, improved mobility
- Durability: Pain relief sustained in 80% at 1 year
- Cement leakage: Usually asymptomatic, rarely causes neural compression (under 1%)
Prognosis and Survival
Overall Survival by Era
Survival in myeloma has improved dramatically over the past two decades with the introduction of novel agents (proteasome inhibitors, immunomodulatory drugs, monoclonal antibodies) and autologous stem cell transplantation.
Prognostic Factors
Favorable vs Adverse Prognostic Factors
| Factor | Favorable Prognosis | Adverse Prognosis |
|---|---|---|
| Age | Under 65 years | Over 75 years |
| ISS Stage | Stage I (beta-2M under 3.5, albumin 35 or higher) | Stage III (beta-2M over 5.5) |
| Cytogenetics | Standard-risk: t(11;14), hyperdiploidy | High-risk: del(17p), t(4;14), t(14;16), gain 1q |
| LDH | Normal | Elevated |
| Response to treatment | Complete response or better | Stable disease or progressive disease |
| Renal function | Creatinine under 173 micromol/L | Creatinine over 173 micromol/L or dialysis-dependent |
| Performance status | ECOG 0-1 (fully active) | ECOG 3-4 (limited self-care) |
| Bone disease | No fractures, limited lytic lesions | Multiple pathological fractures, extensive lytic disease |
Survival by R-ISS Stage (Contemporary Data)
R-ISS Survival Outcomes
| R-ISS Stage | 5-Year OS | Median PFS | Median OS |
|---|---|---|---|
| R-ISS I (29% of patients) | 82% | 66 months | Not reached (over 10 years) |
| R-ISS II (62% of patients) | 62% | 42 months | 83 months |
| R-ISS III (9% of patients) | 40% | 29 months | 43 months |
OS = Overall Survival; PFS = Progression-Free Survival
MRC Myeloma IX: Zoledronic Acid vs Clodronic Acid
VISTA Trial: Bortezomib in Newly Diagnosed Myeloma
Bisphosphonates in Multiple Myeloma: Cochrane Network Meta-Analysis
IMWG Updated Diagnostic Criteria for Multiple Myeloma
Revised International Staging System (R-ISS)
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Palumbo A, Avet-Loiseau H, Oliva S, et al. Revised International Staging System for Multiple Myeloma: A Report From International Myeloma Working Group. J Clin Oncol. 2015;33(26):2863-2869.
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Hillengass J, Usmani S, Rajkumar SV, et al. International myeloma working group consensus recommendations on imaging in monoclonal plasma cell disorders. Lancet Oncol. 2019;20(6):e302-e312.
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Dimopoulos MA, Moreau P, Terpos E, et al. Multiple myeloma: EHA-ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2021;32(3):309-322.
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Moreau P, Kumar SK, San Miguel J, et al. Treatment of relapsed and refractory multiple myeloma: recommendations from the International Myeloma Working Group. Lancet Oncol. 2021;22(3):e105-e118.
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Mhaskar R, Kumar A, Miladinovic B, Djulbegovic B. Bisphosphonates in multiple myeloma: an updated network meta-analysis. Cochrane Database Syst Rev. 2017;12(12):CD003188.
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Terpos E, Kleber M, Engelhardt M, et al. European Myeloma Network guidelines for the management of multiple myeloma-related complications. Haematologica. 2015;100(10):1254-1266.
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Mirels H. Metastatic disease in long bones: A proposed scoring system for diagnosing impending pathologic fractures. Clin Orthop Relat Res. 1989;(249):256-264.
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Patchell RA, Tibbs PA, Regine WF, et al. Direct decompressive surgical resection in the treatment of spinal cord compression caused by metastatic cancer: a randomised trial. Lancet. 2005;366(9486):643-648.
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Exam Viva Scenarios
Use these scenarios to practise clinical reasoning and management decisions
Scenario 1: Diagnosis and Workup
"A 68-year-old man presents with 3 months of progressive back pain. Plain radiographs show multiple lytic lesions in the thoracolumbar spine with compression fractures at T8 and L2. How would you approach this patient?"
Scenario 2: Pathological Femur Fracture
"A 72-year-old woman with known multiple myeloma on chemotherapy presents with acute onset right thigh pain after a fall at home. X-ray shows a complete subtrochanteric femur fracture through a 5cm lytic lesion. Her oncologist asks your advice on management. What would you recommend?"
Scenario 3: Spinal Cord Compression Emergency
"You are called to the emergency department at 2 AM. A 65-year-old man with newly diagnosed multiple myeloma (started chemotherapy 2 weeks ago) presents with 24 hours of progressive lower limb weakness and urinary retention. On examination, he has grade 3/5 power in both lower limbs, a sensory level at T10, and absent ankle reflexes. Walk me through your emergency management."
MULTIPLE MYELOMA
Clinical summary
Key Definition
- •Plasma cell neoplasm with clonal bone marrow plasma cells over 10% PLUS CRAB criteria or myeloma-defining biomarkers
- •Most common primary bone malignancy in adults over 40 years
- •Median age 65 years; 90% have skeletal involvement
CRAB Criteria (Must Know)
- •C - Calcium elevated over 2.75 mmol/L
- •R - Renal insufficiency (creatinine over 173 micromol/L)
- •A - Anemia (Hb under 100 g/L)
- •B - Bone lesions (one or more lytic lesions)
- •ANY ONE = symptomatic myeloma requiring treatment
Pathognomonic Radiology
- •Purely LYTIC lesions with NO sclerotic response (vs metastases)
- •Punched-out lesions in skull - classic appearance
- •Vertebral compression fractures (70% involve spine)
- •Whole-body MRI or PET-CT more sensitive than skeletal survey
- •Bone scan NOT useful (no osteoblastic activity)
Diagnostic Triad
- •1. SPEP - monoclonal protein spike (70% IgG, 20% IgA)
- •2. Urine protein electrophoresis - Bence Jones protein (75%)
- •3. Bone marrow biopsy - over 10% clonal plasma cells
- •PLUS: Serum free light chains, calcium, renal function, imaging
Staging (R-ISS Preferred)
- •R-ISS I: ISS I + standard cytogenetics + normal LDH (82% 5yr survival)
- •R-ISS II: Not I or III (62% 5yr survival)
- •R-ISS III: ISS III + high-risk cytogenetics OR elevated LDH (40% 5yr survival)
- •High-risk cytogenetics: del(17p), t(4;14), t(14;16), gain 1q
Medical Treatment
- •Transplant eligible: VRd induction → ASCT → lenalidomide maintenance
- •Transplant ineligible: VRd or DRd until progression
- •ALL with bone disease: Bisphosphonates (zoledronic acid 4mg IV monthly)
- •Bisphosphonates reduce SREs by 40%
- •Beware ONJ - dental clearance before starting bisphosphonates
Surgical Indications
- •Pathological fractures: Intramedullary nailing preferred (long nail, protect full bone)
- •Impending fractures: Mirels over 8 or cortical destruction over 50%
- •Spinal cord compression: Emergency decompression + stabilization if unstable spine
- •Vertebroplasty/kyphoplasty: Painful VCFs, 75-90% pain relief
- •Cement augmentation: Immediate stability for large defects
Surgical Principles
- •Surgery is PALLIATIVE - chemotherapy is definitive treatment
- •Intramedullary nail over plate (load-sharing, protects full bone, early weight-bearing)
- •LONG fixation - protect entire bone (skip lesions and progression risk)
- •Adjuvant radiotherapy: 20-30 Gy starting 2-3 weeks post-op
- •Weight-bearing as tolerated - goal is quality of life
Spinal Cord Compression (Emergency)
- •Dexamethasone 10mg IV IMMEDIATELY (within 30 min)
- •MRI whole spine urgently (within 1 hour)
- •Ambulatory at presentation = 60-80% preserve function
- •Paraplegic over 48hrs = under 20% recover ambulation
- •Surgery if unstable spine or bony compression; RT if soft tissue mass
Complications to Know
- •SREs (skeletal-related events): fracture, RT, surgery, cord compression - 60-70% experience
- •Hypercalcemia: IV hydration + bisphosphonates (response 48-72hrs)
- •Renal failure: Light chain cast nephropathy - hydration, avoid NSAIDs, treat myeloma
- •Infections: Hypogammaglobulinemia - leading cause of death early
- •ONJ from bisphosphonates: 1-10% incidence, increases with duration
Prognosis
- •Median survival: 8-10 years for standard-risk with modern therapy (was 3 years in 2000)
- •R-ISS I: Median OS over 10 years (82% at 5 years)
- •R-ISS III: Median OS 43 months (40% at 5 years)
- •Causes of death: Progressive myeloma (40-50%), infection (25-30%), renal failure (10-15%)
Exam Day Pearls
- •No blastic response = pathognomonic for myeloma (vs metastases which heal)
- •CRAB backwards and forwards - defines symptomatic disease
- •Smoldering myeloma (no CRAB) = DO NOT TREAT, only observe
- •Bisphosphonates mandatory for ALL with bone disease
- •Spinal cord compression = dexamethasone within 30 min, MRI within 1 hour, treatment within 24 hours
- •Intramedullary nail over plate, long fixation over short, cement augmentation for large defects
MCQ Practice Points
Clinical Pearl
Q: What is the characteristic radiographic appearance of multiple myeloma bone lesions?
A: Punched-out lytic lesions without surrounding sclerosis or periosteal reaction. Most common in axial skeleton: spine, skull, pelvis, ribs, proximal femur/humerus. No bone scan uptake (purely osteolytic with suppressed osteoblasts) - use skeletal survey or whole-body MRI instead. Lesions represent replaced marrow.
Clinical Pearl
Q: What laboratory findings are diagnostic for multiple myeloma?
A: CRAB criteria: Calcium elevation, Renal insufficiency, Anemia, Bone lesions. M-spike (monoclonal protein) on serum protein electrophoresis. Bence Jones proteinuria (light chains). Bone marrow with greater than 10% plasma cells. Rouleaux formation on blood smear. ESR markedly elevated. Normal ALP (osteoblasts suppressed).
Clinical Pearl
Q: Why is the alkaline phosphatase (ALP) typically normal in multiple myeloma?
A: Myeloma cells produce osteoclast-activating factors (RANKL, IL-6, MIP-1α) causing bone resorption WITHOUT compensatory bone formation. Osteoblast activity suppressed by Dickkopf-1 (DKK1). Hence ALP (marker of osteoblastic activity) remains normal despite extensive bone destruction. Distinguishes from metastatic bone disease.
Clinical Pearl
Q: What is the surgical approach to pathological fractures in multiple myeloma?
A: Prophylactic fixation for impending fractures (Mirels score ≥8). Internal fixation + cement augmentation for actual fractures. Avoid intramedullary devices alone in spine - tumor extends into canal. Spine: Vertebroplasty/kyphoplasty for compression fractures, decompression + stabilization for cord compression. Radiation post-operatively.
Clinical Pearl
Q: What is the difference between multiple myeloma and solitary plasmacytoma?
A: Solitary plasmacytoma: Single bone or soft tissue lesion, normal bone marrow (less than 10% plasma cells), absent/minimal M-protein, no other CRAB features. Better prognosis - treat with radiation ± surgery. ~50% progress to multiple myeloma within 10 years. Multiple myeloma requires systemic chemotherapy and may require autologous stem cell transplant.
Guidelines, Registries & Global Practice
Global Epidemiology
According to the Global Burden of Disease Study 2016 (Cowan et al., JAMA Oncology 2018), there were approximately 138,500 incident cases of multiple myeloma worldwide in 2016, with an age-standardised incidence rate of 2.1 per 100,000 persons. Incident cases rose by 126% between 1990 and 2016, driven by population growth and ageing. Incidence is highly variable geographically, being highest in Australasia, North America and Western Europe, and substantially higher (approximately two-fold) in populations of African ancestry. Access to autologous stem-cell transplantation and to novel agents (lenalidomide, bortezomib) is concentrated in high-income regions and remains very limited in sub-Saharan Africa and parts of the Middle East.
Global Epidemiology and Practice Variation
| Domain | Finding | Source / Evidence |
|---|---|---|
| Worldwide incidence (2016) | Approximately 138,500 new cases; age-standardised rate 2.1 per 100,000 | GBD 2016 (Cowan, JAMA Oncol 2018, PMID 29800065) |
| Trend 1990-2016 | 126% rise in incident cases (largest increase in low and middle SDI countries) | GBD 2016 (PMID 29800065) |
| Highest-incidence regions | Australasia, North America, Western Europe; two-fold higher in African-ancestry populations | GBD 2016 (PMID 29800065) |
| Autologous transplant access | Routine in high-income regions; under 5% utilisation in Africa/East Mediterranean | WBMT/GBD analysis (Cowan, Biol Blood Marrow Transplant 2020, PMID 32846200) |
Guideline Comparison Across Jurisdictions
Diagnosis, Imaging and Bone-Directed Therapy: Guideline Positions
| Body / Region | Diagnostic Framework | First-line Imaging | Bone-Directed Therapy | Evidence Level |
|---|---|---|---|---|
| IMWG (international) | CRAB plus SLiM biomarkers (clonal plasma cells 60% or more, FLC ratio 100 or higher, more than 1 focal MRI lesion) | Whole-body low-dose CT, whole-body MRI or PET-CT preferred over skeletal survey | Zoledronic acid or pamidronate for all with bone disease; denosumab if renal impairment | Level I (Rajkumar, Lancet Oncol 2014, PMID 25439696) |
| NICE (UK, NG35) | Adopts IMWG criteria | Whole-body MRI first-line; whole-body low-dose CT if MRI unsuitable; avoid isolated skeletal survey | Zoledronic acid offered to all (survival and SRE benefit); bisphosphonate continued | Level I (informed by MRC Myeloma IX, PMID 21131037) |
| EHA-ESMO (Europe) | IMWG criteria; R-ISS for staging | Whole-body low-dose CT or PET-CT; MRI for suspected cord compression or smouldering disease | Zoledronic acid preferred; denosumab non-inferior alternative, useful in renal impairment | Level I (Dimopoulos, Ann Oncol 2021) |
| NCCN (USA) | IMWG criteria; R-ISS staging | Whole-body low-dose CT, PET-CT or MRI; skeletal survey only if advanced imaging unavailable | Bisphosphonate (zoledronic acid/pamidronate) or denosumab for all with bone disease | Level I |
Convergent Global Practice
There is strong international consensus across IMWG, NICE, EHA-ESMO and NCCN: diagnosis follows the CRAB-plus-SLiM framework, cross-sectional imaging (whole-body low-dose CT, whole-body MRI or PET-CT) has replaced the plain skeletal survey, and a bisphosphonate (preferably zoledronic acid) is offered to every patient with bone disease. The principal practice variation is access-driven, not evidence-driven: transplant and novel-agent availability diverge sharply between high-income and low/middle-income countries.
Registry Evidence
Large national and international registries (the US SEER programme, the European EBMT/WBMT transplant registries and the Australian Myeloma and Related Diseases Registry) document a substantial improvement in survival over the past two decades, coinciding with the introduction of proteasome inhibitors, immunomodulatory drugs, monoclonal antibodies and routine autologous transplantation. Registry data also confirm marked global disparities in access to autologous transplantation, with utilisation below 5% of incident cases in Africa and the East Mediterranean compared with over 20% in North America and Europe (Cowan et al., Biol Blood Marrow Transplant 2020).
Australian Context
Multiple myeloma accounts for approximately 2% of all cancers in Australia, with an age-standardised incidence among the highest globally. On the Pharmaceutical Benefits Scheme (PBS), bortezomib, lenalidomide and daratumumab are subsidised within authority-required combination regimens, and zoledronic acid and pamidronate are listed for myeloma bone disease. Therapeutic Guidelines (eTG) recommend Pneumocystis jirovecii prophylaxis with trimethoprim-sulfamethoxazole and herpes-zoster prophylaxis with valaciclovir for patients on high-dose corticosteroids or bortezomib-based regimens. Venous thromboembolism prophylaxis is essential during immunomodulatory therapy: aspirin for standard-risk patients and low-molecular-weight heparin or apixaban for high-risk patients.