# Clinical Cases: Plasma Cell Disorders

## Case 1: Multiple Myeloma with CRAB Features

### Patient Presentation
**Demographics:** 68-year-old male

**Chief Complaint:** Back pain and fatigue for 3 months

**History of Present Illness:**
The patient has had progressive lower back pain for 3 months that does not improve with rest. He also reports significant fatigue, decreased appetite, and constipation. He was recently found to have elevated creatinine on routine labs. He denies fever, weight loss, or night sweats.

**Past Medical History:**
- Hypertension
- Type 2 diabetes mellitus

**Physical Examination:**
- Blood pressure: 132/78 mmHg
- Heart rate: 84 bpm
- General: Pale, appears fatigued
- Spine: Tenderness to palpation at L2-L4
- No hepatosplenomegaly
- No lymphadenopathy
- No focal neurological deficits

### Workup and Results

**Laboratory Studies:**
- Hemoglobin: 9.2 g/dL
- Creatinine: 2.4 mg/dL (baseline 1.0)
- Calcium: 12.8 mg/dL (elevated)
- Albumin: 3.2 g/dL
- Total protein: 10.4 g/dL (elevated)
- Beta-2 microglobulin: 6.8 mg/L (elevated)
- LDH: 245 U/L (upper normal)

**Serum Protein Electrophoresis (SPEP):**
- M-spike: 4.2 g/dL (IgG kappa)

**Serum Free Light Chains:**
- Kappa: 285 mg/L (elevated)
- Lambda: 12 mg/L
- Ratio: 23.75 (abnormal)

**Skeletal Survey:**
- Multiple lytic "punched-out" lesions in skull, spine, and pelvis
- L3 compression fracture

**Bone Marrow Biopsy:**
- 65% clonal plasma cells
- CD138+, cytoplasmic kappa light chain restricted
- Cytogenetics: Standard risk

### Clinical Image

![Multiple Myeloma Skull](case_01_image.jpg)

*Skull X-ray demonstrating multiple "punched-out" lytic lesions characteristic of multiple myeloma. Bone scans are often negative because there is no osteoblastic activity.*

### Diagnosis
**Multiple Myeloma - IgG Kappa, ISS Stage III**

CRAB criteria present:
- **C**alcium elevation (12.8 mg/dL)
- **R**enal insufficiency (creatinine 2.4 mg/dL)
- **A**nemia (hemoglobin 9.2 g/dL)
- **B**one lesions (lytic lesions with compression fracture)

R-ISS Staging: Stage III (beta-2 microglobulin >5.5 mg/L)

### Discussion
This case illustrates classic multiple myeloma:

- **CRAB Criteria**: The lecture describes the CRAB criteria for myeloma-related organ damage: hypercalcemia, renal insufficiency, anemia, and bone lesions. Any of these in the presence of clonal plasma cells indicates symptomatic myeloma.

- **M-Protein Detection**: The lecture explains that SPEP is the primary screening test for M-protein. The tall, narrow spike in the gamma region indicates monoclonal protein production.

- **Lytic Bone Lesions**: The lecture notes that myeloma bone lesions are characteristically lytic "punched-out" lesions because plasma cells secrete factors that activate osteoclasts while suppressing osteoblasts. This is why bone scans are often negative.

- **Cast Nephropathy**: Renal failure in myeloma is often due to light chains binding to Tamm-Horsfall protein, forming obstructing tubular casts.

### Treatment Plan
1. **Pre-treatment Evaluation:**
   - Echocardiogram (baseline for cardiotoxic agents)
   - Consider fertility preservation discussion

2. **Induction Therapy:**
   - VRd regimen: Bortezomib (proteasome inhibitor) + Lenalidomide (IMiD) + Dexamethasone
   - Consider adding daratumumab (anti-CD38) in high-risk patients
   - 4-6 cycles

3. **Supportive Care:**
   - Bisphosphonates (zoledronic acid) for bone disease
   - IV fluids and bisphosphonates for hypercalcemia
   - VTE prophylaxis (IMiDs increase thrombosis risk)
   - Pain management

4. **Transplant Evaluation:**
   - Autologous stem cell transplant candidacy assessment
   - High-dose melphalan conditioning

5. **Maintenance:**
   - Lenalidomide maintenance post-transplant

### Teaching Points
1. CRAB criteria define symptomatic myeloma requiring treatment
2. M-protein detected on SPEP; immunofixation confirms type
3. Bone lesions are lytic (no osteoblastic activity) - bone scans are often negative
4. VRd (bortezomib-lenalidomide-dexamethasone) is standard induction
5. Autologous transplant improves survival in eligible patients

---

## Case 2: AL Amyloidosis with Cardiac Involvement

### Patient Presentation
**Demographics:** 62-year-old female

**Chief Complaint:** Progressive shortness of breath and leg swelling

**History of Present Illness:**
The patient has had progressive dyspnea on exertion over 6 months, now dyspneic at rest. She has developed bilateral leg swelling and reports feeling lightheaded when standing. She also notes easy bruising around her eyes and an enlarged tongue that makes eating difficult.

**Physical Examination:**
- Blood pressure: 95/65 mmHg (orthostatic hypotension present)
- Heart rate: 92 bpm
- JVP: Elevated to 14 cm
- Periorbital ecchymoses ("raccoon eyes")
- Macroglossia with lateral tongue scalloping
- Cardiac: Distant heart sounds, S4 gallop
- Lungs: Bibasilar crackles
- Abdomen: Hepatomegaly
- Extremities: 3+ pitting edema to thighs

### Workup and Results

**Laboratory Studies:**
- BNP: 2,450 pg/mL (markedly elevated)
- Troponin T: 0.08 ng/mL (elevated)
- Creatinine: 1.4 mg/dL
- Albumin: 2.8 g/dL
- 24-hour urine protein: 4.2 g

**Serum Studies:**
- SPEP: Small M-spike (0.4 g/dL, IgG lambda)
- Free light chains: Lambda 185 mg/L, Kappa 8 mg/L

**Echocardiogram:**
- Increased wall thickness (1.6 cm)
- "Sparkling" myocardium
- Diastolic dysfunction, restrictive filling
- EF 45%

**Cardiac MRI:**
- Diffuse late gadolinium enhancement
- Pattern consistent with cardiac amyloidosis

**Abdominal Fat Pad Biopsy:**
- Congo red positive with apple-green birefringence
- Mass spectrometry: AL (lambda) amyloid

**Bone Marrow Biopsy:**
- 12% clonal lambda-restricted plasma cells

### Clinical Image

![Cardiac Amyloidosis Echo](case_01_image.jpg)

*Echocardiogram demonstrating characteristic findings of cardiac amyloidosis: increased biventricular wall thickness with "sparkling" granular appearance of the myocardium and small pericardial effusion.*

### Diagnosis
**AL (Light Chain) Amyloidosis with Cardiac Involvement**

Features:
- Lambda light chain excess
- Congo red positive amyloid deposits
- Multi-organ involvement: heart, kidney (proteinuria), soft tissue (macroglossia, periorbital purpura)
- Advanced cardiac staging

### Discussion
This case illustrates AL amyloidosis:

- **Light Chain Deposition**: The lecture describes AL amyloidosis as deposition of misfolded immunoglobulin light chains in tissues. Unlike myeloma, the plasma cell burden is often small (<10%), but the secreted light chains cause organ damage.

- **Congo Red Staining**: The lecture identifies Congo red staining with apple-green birefringence under polarized light as the diagnostic test for amyloid.

- **Cardiac Involvement = Prognosis**: The lecture emphasizes that cardiac involvement is the most important prognostic factor in AL amyloidosis. Elevated cardiac biomarkers (troponin, BNP) indicate advanced cardiac staging.

- **Classic Clinical Features**: Macroglossia and periorbital purpura are classic but not universal findings. The purpura results from amyloid infiltration of blood vessel walls.

### Treatment Plan
1. **Staging and Risk Assessment:**
   - Mayo cardiac staging based on troponin and NT-proBNP
   - High-risk cardiac involvement present

2. **Treatment Options:**
   - Daratumumab-based regimen (Dara-VCd: daratumumab, bortezomib, cyclophosphamide, dexamethasone)
   - Autologous transplant if eligible (limited by cardiac involvement)

3. **Supportive Care:**
   - Diuretics for volume overload (careful - may worsen orthostatic hypotension)
   - Midodrine for orthostatic hypotension
   - Avoid digoxin (binds to amyloid fibrils)
   - Compression stockings

4. **Monitoring:**
   - Serial free light chains (goal: hematologic response)
   - Cardiac biomarkers
   - Organ response assessment

### Teaching Points
1. AL amyloidosis involves light chain deposition; plasma cell burden is often small
2. Congo red staining shows apple-green birefringence under polarized light
3. Cardiac involvement is the most important prognostic factor
4. Macroglossia and periorbital purpura are classic findings
5. Avoid digoxin (binds amyloid fibrils)

---

## Case 3: Waldenstrom Macroglobulinemia with Hyperviscosity

### Patient Presentation
**Demographics:** 72-year-old male

**Chief Complaint:** Blurred vision, headache, and nosebleeds

**History of Present Illness:**
The patient has had progressive fatigue for several months. Over the past 2 weeks, he developed blurred vision, headaches, and recurrent nosebleeds. He reports his gums bled significantly during a recent dental cleaning. He also notes numbness and tingling in his feet.

**Physical Examination:**
- Blood pressure: 148/92 mmHg
- General: Pale
- HEENT: Retinal exam shows dilated, tortuous veins ("sausage-link" appearance), flame hemorrhages, papilledema
- Lymph nodes: Cervical lymphadenopathy
- Abdomen: Splenomegaly (4 cm below costal margin)
- Neurologic: Decreased sensation in stocking distribution

### Workup and Results

**Laboratory Studies:**
- Hemoglobin: 8.8 g/dL
- WBC: 6,200/mcL
- Platelets: 125,000/mcL
- ESR: 125 mm/hr
- **Serum viscosity: 6.2 cP (normal <1.8)**

**Serum Studies:**
- SPEP: M-spike 4.8 g/dL
- Immunofixation: IgM kappa
- IgM level: 6,200 mg/dL (markedly elevated)

**Bone Marrow Biopsy:**
- Infiltration by lymphoplasmacytic cells (35%)
- CD20+, CD19+, CD138 partial+
- **MYD88 L265P mutation: Positive**

**CT Imaging:**
- Lymphadenopathy (cervical, axillary, retroperitoneal)
- Splenomegaly

### Clinical Image

![Hyperviscosity Fundoscopy](case_01_image.jpg)

*Fundoscopic examination demonstrating hyperviscosity syndrome findings: dilated, tortuous "sausage-link" retinal veins, flame hemorrhages, and papilledema.*

### Diagnosis
**Waldenstrom Macroglobulinemia with Hyperviscosity Syndrome**

Features:
- IgM monoclonal gammopathy
- Lymphoplasmacytic bone marrow infiltration
- MYD88 L265P mutation (present in >90%)
- Symptomatic hyperviscosity

### Discussion
This case demonstrates Waldenstrom macroglobulinemia:

- **IgM Paraprotein**: The lecture distinguishes WM from myeloma by the IgM isotype. IgM is a large pentameric molecule prone to causing hyperviscosity even at moderate concentrations.

- **MYD88 Mutation**: The lecture notes that the MYD88 L265P mutation is present in over 90% of WM cases, making it diagnostically useful.

- **Hyperviscosity Syndrome**: The lecture describes hyperviscosity as most commonly associated with WM due to the large IgM molecule. Symptoms include visual changes, bleeding, neurological symptoms, and cardiac failure.

- **Fundoscopic Findings**: "Sausage-link" veins (segmental dilation) are characteristic of hyperviscosity and visible on fundoscopic exam.

### Treatment Plan
1. **Emergency Treatment for Hyperviscosity:**
   - Plasmapheresis (immediate)
   - Typically 1-2 sessions achieve symptomatic relief
   - Avoid RBC transfusion before pheresis (worsens viscosity)

2. **Systemic Therapy:**
   - Rituximab-based regimen (avoid initial rituximab "flare")
   - Options: Bendamustine + rituximab, or BTK inhibitor (ibrutinib/zanubrutinib)
   - Avoid rituximab monotherapy initially if IgM very high (flare risk)

3. **Monitoring:**
   - Serial IgM levels
   - Serum viscosity
   - Peripheral neuropathy assessment

4. **Peripheral Neuropathy:**
   - May be due to anti-MAG antibodies or cryoglobulinemia
   - Gabapentin/pregabalin for symptom management

### Teaching Points
1. Waldenstrom macroglobulinemia is characterized by IgM M-protein
2. MYD88 L265P mutation present in >90% of cases
3. Hyperviscosity most common with IgM due to large pentameric structure
4. Plasmapheresis is emergency treatment for hyperviscosity
5. "Sausage-link" retinal veins are characteristic of hyperviscosity

---

## Image Reference

For visual reference of plasma cell disorder concepts, see:
- Radiopaedia: [Multiple myeloma](https://radiopaedia.org/articles/multiple-myeloma) - Skeletal findings
- Wikipedia: [Amyloidosis](https://en.wikipedia.org/wiki/Amyloidosis) - Congo red staining
- Radiopaedia: [Cardiac amyloidosis](https://radiopaedia.org/articles/cardiac-amyloidosis) - Echo findings

---

## Learning Points

1. **CRAB Criteria**: Calcium, Renal, Anemia, Bone - define symptomatic myeloma

2. **M-Protein Screening**: SPEP detects M-spike; immunofixation identifies type

3. **AL Amyloid Diagnosis**: Congo red stain with apple-green birefringence under polarized light

4. **Cardiac Amyloid Prognosis**: Most important factor; avoid digoxin

5. **WM and Hyperviscosity**: IgM (pentamer) causes viscosity; plasmapheresis is emergency treatment