Multiple Myeloma

A 68 year old male presents with progressive lower back pain, fatigue, and unintentional weight loss for several months. He reports recurrent respiratory infections. Physical examination reveals pallor and vertebral tenderness. Laboratory investigations show normocytic normochromic anemia, elevated creatinine, elevated calcium, and markedly elevated ESR. Serum protein electrophoresis demonstrates an M spike. Bone marrow biopsy reveals clonal plasma cells. Diagnosis?

Diagnosis is multiple myeloma.

1. Definition

Multiple myeloma is a plasma cell malignancy characterized by clonal proliferation of plasma cells within the bone marrow producing monoclonal immunoglobulin (M protein), resulting in end-organ damage.

It classically presents with SLiM-CRAB criteria:

SLiM biomarkers

• S: ≥60% clonal plasma cells in bone marrow
• Li: Involved/uninvolved serum free light chain ratio ≥100 and involved free light chain concentration ≥100 mg/L
• M: >1 focal lesion on MRI measuring at least 5 mm

CRAB features

• C: Hypercalcemia (serum calcium >11 mg/dL or >1 mg/dL above upper limit of normal)
• R: Renal impairment
• A: Anemia
• B: Bone lesions

2. Pathophysiology

1. Neoplastic proliferation of plasma cells in bone marrow
2. Production of monoclonal immunoglobulin (M protein)
3. Excess free light chains may deposit in kidneys
4. Increased osteoclast activity and suppressed osteoblast activity cause bone destruction
5. Suppression of normal hematopoiesis leads to anemia and infection susceptibility

3. Clinical Features

3.1 CRAB Features

Hypercalcemia

1. Polyuria
2. Constipation
3. Confusion
4. Dehydration

Renal Impairment

1. Elevated creatinine
2. Cast nephropathy
3. Light chain mediated kidney injury

Anemia

1. Fatigue
2. Pallor
3. Weakness

Bone Disease

1. Bone pain
2. Osteolytic lesions
3. Pathologic fractures
4. Vertebral compression fractures

3.2 Other Clinical Features

1. Recurrent infections
2. Weight loss
3. Amyloidosis
4. Hyperviscosity syndrome may occur, particularly in IgA myeloma
5. Peripheral neuropathy

Hyperviscosity is classically associated with Waldenström macroglobulinemia

4. Diagnosis

Diagnosis requires:

1. Clonal bone marrow plasma cells ≥10% or biopsy-proven plasmacytoma

AND

2. One or more myeloma-defining events:

SLiM Criteria

1. ≥60% clonal plasma cells in bone marrow
2. Involved/uninvolved serum free light chain ratio ≥100 and involved free light chain ≥100 mg/L
3. More than one focal lesion on MRI measuring at least 5 mm

OR

CRAB Features attributable to plasma cell disorder

1. Hypercalcemia
2. Renal impairment
3. Anemia
4. Bone lesions

4.1 Laboratory Findings

1. Normocytic normochromic anemia
2. Elevated BUN and creatinine
3. Hypercalcemia
4. Elevated LDH
5. Elevated uric acid
6. Elevated ESR causing rouleaux formation

4.2 Serum Studies

Serum Protein Electrophoresis (SPEP)

1. Monoclonal M spike

Serum Immunofixation

1. Identifies monoclonal protein subtype

Serum Free Light Chain Assay

1. Detects excess free light chains
2. Free light chain ratio ≥100 with involved chain ≥100 mg/L is a myeloma-defining biomarker

4.3 Urine Studies

Urine Protein Electrophoresis (UPEP)

1. Detects monoclonal free light chains (historically called Bence Jones proteins)

Clinical pearl:

• Urine dipstick may be negative because it primarily detects albumin and may miss light chains

4.4 Bone Marrow

1. Bone marrow biopsy shows ≥10% clonal plasma cells

4.5 Imaging

Preferred Imaging

1. Whole-body low-dose CT is preferred for skeletal evaluation
2. MRI is most sensitive for marrow infiltration and spinal disease
3. PET-CT evaluates active disease burden

Classical Findings

1. Osteolytic lesions
2. Punched-out lesions
3. Diffuse marrow infiltration

Plain skeletal survey is less sensitive and no longer preferred when advanced imaging is available

5. Staging and Prognosis

International Staging System (ISS)

Uses:

1. Serum beta-2 microglobulin
2. Serum albumin

Poor prognostic factors:

1. Elevated beta-2 microglobulin
2. Elevated LDH
3. High-risk cytogenetics:
• del(17p)
• t(4;14)
• t(14;16)

6. Differential Diagnosis

1. MGUS (monoclonal gammopathy of undetermined significance)
2. Smoldering multiple myeloma
3. Waldenström macroglobulinemia
4. Metastatic bone disease
5. Amyloidosis

7. Management

7.1 Initial Therapy

Common induction regimens:

1. Bortezomib + lenalidomide + dexamethasone (VRd)
2. Daratumumab + VRd in selected patients
3. Cyclophosphamide-containing regimens when indicated

7.2 Transplant

1. Autologous hematopoietic stem cell transplantation is preferred in eligible patients
2. Allogeneic transplantation is rarely performed due to higher toxicity

7.3 Supportive Care

1. Bisphosphonates for bone disease
2. Hydration for hypercalcemia
3. Infection prevention and vaccination
4. Pain control
5. Radiation therapy for focal painful lesions

8. Complications

1. Renal failure
2. Pathologic fractures
3. Hypercalcemia
4. Spinal cord compression
5. Amyloidosis
6. Recurrent infections

9. Key Clinical Insight

Older patient with persistent bone pain, anemia, renal dysfunction, hypercalcemia, elevated ESR, and M spike strongly suggests multiple myeloma

10. Key Exam Points

1. Plasma cell malignancy with monoclonal immunoglobulin production
2. SLiM-CRAB criteria define active multiple myeloma
3. SPEP shows M spike
4. Bence Jones proteins are monoclonal free light chains
5. Bone marrow plasma cells ≥10% support diagnosis
6. Whole-body CT and MRI are more sensitive than plain X-ray
7. Beta-2 microglobulin predicts prognosis
8. Autologous stem cell transplantation is preferred in eligible patients
9. Bisphosphonates reduce skeletal complications
10. Infection remains a major cause of morbidity and mortality