Overview
Multiple Myeloma
1. Clinical Overview
Summary
Multiple Myeloma is a malignant neoplasm of Plasma Cells (Terminally differentiated B lymphocytes that produce antibodies/Immunoglobulins). Clonal plasma cells proliferate in the bone marrow and produce a Monoclonal Immunoglobulin (M-protein/Paraprotein) that can be detected in serum and/or urine. Myeloma is the second most common haematological malignancy after Non-Hodgkin Lymphoma, primarily affecting older adults (Median age ~70). The classic clinical features are remembered by the mnemonic "CRAB": Calcium elevation (Hypercalcaemia), Renal insufficiency, Anaemia, and Bone disease (Lytic lesions, Pathological fractures). Diagnosis requires ≥10% clonal plasma cells on bone marrow biopsy (Or a plasmacytoma) plus evidence of end-organ damage (CRAB) or specific biomarkers. Treatment has improved dramatically with novel agents (Proteasome inhibitors – Bortezomib, IMiDs – Lenalidomide, Thalidomide, Monoclonal antibodies – Daratumumab) and Autologous Stem Cell Transplant (ASCT) in eligible patients. Myeloma remains incurable but is now a chronic manageable disease with median survival of 5-7+ years. [1,2,3]
Clinical Pearls
"Old Man + Back Pain + Anaemia = Think Myeloma": Classic presentation. Don't miss it. Check FBC, U&Es, Calcium, Serum Protein Electrophoresis.
"Rain Drop Skull": Classic X-ray appearance of multiple lytic lesions in the skull. Myeloma causes LYTIC (Not sclerotic) lesions.
"Normal Immunoglobulins Reduced (Immunoparesis)": The clonal M-protein dominates. Normal (Polyclonal) IgG, IgA, IgM levels are suppressed → Infection risk.
"Rouleaux Formation": On blood film – Stacked red cells due to high protein (Paraprotein). Non-specific but suggestive.
2. Epidemiology
Demographics
| Factor | Notes |
|---|---|
| Age | Median age at diagnosis: ~70 years. Rare less than 40 years. |
| Sex | Male > Female (Slightly). |
| Race | Black populations have ~2x higher incidence than White. |
| Incidence | ~6-7 per 100,000 per year (UK). |
Precursor Conditions
| Condition | Notes |
|---|---|
| MGUS (Monoclonal Gammopathy of Undetermined Significance) | Precursor state. ~1% per year progress to myeloma. |
| Smouldering Myeloma (Asymptomatic) | Higher risk than MGUS. ~10% per year progress to active myeloma (High-risk) or ~2-3% (Standard-risk). |
3. Pathophysiology
Plasma Cell Biology
- Plasma cells are terminally differentiated B cells.
- Normally produce polyclonal immunoglobulins (Antibodies – IgG, IgA, IgM, IgD, IgE).
- In myeloma, a single clone proliferates and produces a Monoclonal Immunoglobulin (Paraprotein or M-protein).
Paraprotein
| Type | Frequency |
|---|---|
| IgG Myeloma | ~55% |
| IgA Myeloma | ~25% |
| Light Chain Only (Bence Jones) | ~15-20% |
| IgD, IgE, IgM, Non-Secretory | Rare |
Mechanisms of End-Organ Damage (CRAB)
| Manifestation | Mechanism |
|---|---|
| Calcium (Hypercalcaemia) | Osteoclast activation by myeloma cells → Bone resorption → Calcium release. |
| Renal Insufficiency | Light chain cast nephropathy ("Myeloma Kidney"), Hypercalcaemia, Dehydration, NSAIDs, Contrast. |
| Anaemia | Bone marrow infiltration. Cytokine suppression of erythropoiesis. Renal failure. |
| Bone Disease | Osteoclast activation + Osteoblast inhibition → Lytic lesions (Not blastic). Pathological fractures. |
Additional Pathology
| Manifestation | Mechanism |
|---|---|
| Immunoparesis | Suppression of normal polyclonal immunoglobulin production → Infection susceptibility. |
| Hyperviscosity | High paraprotein levels (Especially IgA, IgM) → Blood viscosity increases → Visual changes, Confusion, Bleeding. (More common in Waldenström's than Myeloma). |
| Amyloidosis (AL) | Light chains deposit as amyloid in tissues (Heart, Kidneys, Nerves). |
4. Clinical Presentation
CRAB Criteria
| Feature | Presentation |
|---|---|
| C – Calcium Elevated | Thirst, Polyuria, Constipation, Confusion, Nausea. |
| R – Renal Insufficiency | Fatigue, Oedema. May be asymptomatic. Raised Creatinine. |
| A – Anaemia | Fatigue, Dyspnoea, Pallor. |
| B – Bone Disease | Back pain (Most common presenting symptom), Pathological fractures, Bone pain. |
Other Presentations
| Feature | Notes |
|---|---|
| Infections | Recurrent bacterial infections (Pneumonia, UTI). Immunoparesis. |
| Spinal Cord Compression | Emergency! Back pain + Leg weakness + Bladder/Bowel dysfunction. From vertebral collapse or plasmacytoma. |
| Hyperviscosity | Visual disturbance (Blurred vision), Mucosal bleeding, Confusion, Headache. |
| Neuropathy | Peripheral neuropathy. Can be from amyloid or treatment-related. |
| Incidental Finding | Raised ESR, Raised total protein, Abnormal protein on electrophoresis. |
Red Flags / Emergencies
| Emergency | Action |
|---|---|
| Spinal Cord Compression | Urgent MRI whole spine. Dexamethasone. Radiotherapy/Surgery. |
| Hypercalcaemia (Severe) | IV Fluids (~3-4L/24h), IV Bisphosphonate (Zoledronic Acid), Consider Calcitonin. |
| Hyperviscosity | Plasmapheresis. |
| Renal Failure | Hydration. Avoid nephrotoxins. May need dialysis. |
5. Investigations
First-Line Investigations (Myeloma Screen)
| Test | Notes |
|---|---|
| FBC | Anaemia (Normocytic, Normochromic). May see rouleaux formation on film. |
| U&Es, Creatinine | Renal impairment. |
| Calcium | Hypercalcaemia. |
| LDH, Albumin | Prognostic (ISS staging). |
| Serum Protein Electrophoresis (SPEP) | Detects M-protein (Paraprotein band). |
| Serum Free Light Chains (SFLC) | Elevated Kappa or Lambda. Abnormal ratio. Essential for light chain myeloma. |
| Urine Protein Electrophoresis (UPEP) / 24h Urine | Detects Bence Jones Protein (Light chains in urine). |
| Immunofixation | Identifies type of M-protein (IgG Kappa, IgA Lambda, etc.). |
Bone Marrow Biopsy
| Finding | Notes |
|---|---|
| Clonal Plasma Cells ≥10% | Diagnostic criterion. |
| Morphology | Abnormal plasma cells. |
| Cytogenetics / FISH | Prognostic. High-risk: t(4;14), t(14;16), t(14;20), del(17p), 1q gain. |
| MRD (Minimal Residual Disease) | Used to assess depth of response post-treatment. |
Imaging
| Modality | Notes |
|---|---|
| Whole Body Low-Dose CT (WBLDCT) | First-line. Detects lytic lesions better than X-ray. |
| Skeletal Survey (X-Ray) | Older method. Misses early lesions. Shows "punched out" lytic lesions, Osteopenia, Pathological fractures. |
| MRI Spine | For spinal cord compression or to assess bone marrow involvement. |
| PET-CT | Increasingly used. Shows active disease. Used in staging and response assessment. |
Diagnostic Criteria (IMWG 2014)
Requires:
- Clonal Plasma Cells ≥10% in Bone Marrow (Or biopsy-proven plasmacytoma).
- PLUS at least ONE of:
- CRAB criteria: Hypercalcaemia, Renal insufficiency (Cr >177 µmol/L), Anaemia (Hb less than 100 g/L), Bone lesions (≥1 lytic lesion).
- OR Myeloma Defining Events (SLiM): Plasma cells ≥60%, SFLC ratio ≥100, >1 focal lesion on MRI.
6. Staging
Revised International Staging System (R-ISS)
| Stage | Criteria | Median Survival |
|---|---|---|
| I | Albumin ≥35 g/L AND β2-microglobulin less than 3.5 mg/L AND Standard-risk cytogenetics AND Normal LDH | ~80 months |
| II | Not Stage I or III | ~60 months |
| III | β2-microglobulin ≥5.5 mg/L AND (High-risk cytogenetics OR Elevated LDH) | ~40 months |
7. Management
Management Algorithm
MULTIPLE MYELOMA DIAGNOSED
(≥10% Clonal Plasma Cells + CRAB/SLiM)
↓
MANAGE EMERGENCIES FIRST
- Spinal Cord Compression → MRI, Dexa, RT/Surgery
- Hypercalcaemia → Fluids, Bisphosphonates
- Renal Failure → Hydration, Avoid nephrotoxins
- Infection → Antibiotics
↓
ASSESS TRANSPLANT ELIGIBILITY
- Age (Usually less than 70, Sometimes less than 75)
- Performance status
- Comorbidities (Cardiac, Renal, Lung)
┌────────────────┴────────────────┐
TRANSPLANT ELIGIBLE TRANSPLANT INELIGIBLE
↓ ↓
INDUCTION THERAPY INDUCTION THERAPY
(VRd, VTd, VCd) (VRd, Rd, VMP)
↓ ↓
STEM CELL COLLECTION CONTINUE UNTIL PROGRESSION
↓ OR MAINTENANCE
HIGH-DOSE MELPHALAN +
AUTOLOGOUS SCT (ASCT)
↓
MAINTENANCE THERAPY
(Lenalidomide)
Treatment Regimens
| Regimen | Components | Use |
|---|---|---|
| VRd | Bortezomib, Lenalidomide, Dexamethasone | Standard induction (Transplant eligible & Ineligible). |
| VTd | Bortezomib, Thalidomide, Dexamethasone | Induction. |
| VCd | Bortezomib, Cyclophosphamide, Dexamethasone | Alternative. |
| Rd | Lenalidomide, Dexamethasone | Transplant-ineligible. Continuous. |
| DaraVRd | Daratumumab + VRd | Newer regimen. Improved outcomes. |
Key Drug Classes
| Class | Examples | Mechanism |
|---|---|---|
| Proteasome Inhibitors (PIs) | Bortezomib, Carfilzomib, Ixazomib | Inhibit proteasome → Protein accumulation → Apoptosis. |
| IMiDs (Immunomodulatory Drugs) | Thalidomide, Lenalidomide, Pomalidomide | Multiple mechanisms: Anti-angiogenic, Immune modulation, Direct cytotoxicity. |
| Monoclonal Antibodies | Daratumumab (Anti-CD38), Elotuzumab (Anti-SLAMF7) | Target myeloma cell surface proteins. |
| Alkylating Agents | Melphalan, Cyclophosphamide | DNA crosslinking. |
| Corticosteroids | Dexamethasone, Prednisolone | Direct anti-myeloma effect. Anti-inflammatory. |
Supportive Care
| Intervention | Notes |
|---|---|
| Bisphosphonates | Zoledronic Acid monthly (Or Denosumab). Prevents skeletal events. |
| Radiotherapy | For painful bone lesions, Cord compression. |
| Erythropoiesis-Stimulating Agents | For anaemia (If renal impairment). |
| Thromboprophylaxis | VTE risk with IMiDs. Aspirin or LMWH. |
| Infection Prophylaxis | Aciclovir (Herpes reactivation with PIs). May give IVIg for recurrent infections. Pneumocystis prophylaxis if on steroids. Vaccinations. |
8. Complications
| Complication | Notes |
|---|---|
| Spinal Cord Compression | Emergency. Vertebral collapse/Plasmacytoma. |
| Pathological Fractures | Vertebral, Femoral, Humeral. |
| Renal Failure | Common. May need dialysis. |
| Infections | Leading cause of death. Immunoparesis. |
| Hyperviscosity | Rare. More common in Waldenström's. |
| Amyloidosis | AL type. Cardiac, Renal, Neuropathy. |
| Treatment-Related | Neuropathy (Bortezomib, Thalidomide). VTE (Lenalidomide). Secondary malignancies (Lenalidomide). |
9. Prognosis and Outcomes
| Factor | Notes |
|---|---|
| Median Survival | ~5-7 years overall. Varies widely by stage and risk. |
| High-Risk Cytogenetics | del(17p), t(4;14), t(14;16) – Worse prognosis. |
| R-ISS Stage III | Median ~40 months. |
| Response to Treatment | Depth of response (VGPR, CR, MRD-negative) correlates with survival. |
| Age / Comorbidities | Influence treatment tolerance and outcomes. |
| Incurable | Myeloma remains incurable. Relapse is expected. Multiple lines of therapy often needed. |
10. Evidence and Guidelines
Key Guidelines
| Guideline | Organisation | Key Recommendations |
|---|---|---|
| Myeloma Diagnosis and Management | NICE NG35 (2016, Updated) | VRd/VTd induction. ASCT in eligible. Bisphosphonates. |
| IMWG Criteria | International Myeloma Working Group | Diagnostic criteria (CRAB + SLiM). Staging. Response criteria. |
| BSH Guidelines | British Society for Haematology | Management pathways. Supportive care. |
Landmark Trials
| Trial | Findings |
|---|---|
| SWOG S0777 | VRd superior to Rd for newly diagnosed myeloma. |
| CASSIOPEIA | DaraVTd superior to VTd induction for transplant-eligible. |
| MAIA | DaraRd superior to Rd for transplant-ineligible. |
11. Patient and Layperson Explanation
What is Multiple Myeloma?
Multiple Myeloma is a type of blood cancer. It affects cells called plasma cells, which are found in your bone marrow (The soft tissue inside your bones). Plasma cells normally make antibodies to fight infection. In myeloma, one plasma cell becomes abnormal and multiplies out of control, producing an abnormal protein.
What problems does it cause?
- Bone damage: Causes weak, painful bones that can break easily (Especially in the back).
- Anaemia: Low red blood cells → Tiredness.
- Kidney problems: The abnormal protein can damage kidneys.
- High calcium: From bone breakdown → Confusion, Thirst, Constipation.
- Infections: Because normal antibodies are reduced.
Can it be cured?
Currently, myeloma cannot be cured. However, treatments are very effective and have improved dramatically. Many people live for many years with good quality of life. It is considered a "chronic" cancer that can be controlled.
What is the treatment?
- Chemotherapy drugs (Combination treatments like VRd).
- Stem cell transplant (In younger, fitter patients – Uses your own stem cells).
- Maintenance therapy (Long-term tablets to keep myeloma controlled).
- Bone-strengthening drugs (Bisphosphonates).
12. References
Primary Sources
- Rajkumar SV, et al. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol. 2014;15(12):e538-548. PMID: 25439696.
- National Institute for Health and Care Excellence. Myeloma: diagnosis and management (NG35). 2016. nice.org.uk/guidance/ng35
- Palumbo A, et al. Revised International Staging System for Multiple Myeloma. J Clin Oncol. 2015;33(26):2863-2869. PMID: 26240224.
13. Examination Focus
Common Exam Questions
- CRAB Mnemonic: "What does CRAB stand for in Myeloma?"
- Answer: Calcium (Elevated), Renal Insufficiency, Anaemia, Bone Disease.
- Type of Bone Lesions: "Are myeloma bone lesions lytic or sclerotic?"
- Answer: LYTIC (Punched-out lesions). (Sclerotic lesions are seen in prostate metastases).
- Most Common Presenting Symptom: "What is the most common presenting symptom?"
- Answer: Bone Pain (Especially lower back pain).
- Investigation for Monoclonal Protein: "What investigation detects the Paraprotein?"
- Answer: Serum Protein Electrophoresis (SPEP) + Serum Free Light Chains.
Viva Points
- MGUS vs Myeloma: MGUS = less than 10% plasma cells, No CRAB, Low M-protein. Watch and wait.
- Light Chain Myeloma: SPEP may be negative. Need SFLC and UPEP.
- Rouleaux Formation: Red cells stack on blood film – Due to high protein. Non-specific.
- Bence Jones Protein: Light chains in urine. Detectable by UPEP (Not standard urine dipstick).
Medical Disclaimer: MedVellum content is for educational purposes and clinical reference. Clinical decisions should account for individual patient circumstances. Always consult appropriate specialists.