Multiple Myeloma: Plasma Cell Dyscrasias

• Multiple myeloma is one of the plasma cell dyscrasias
• It is characterized by an increase in a single immunoglobulin (IgG, IgA) with its corresponding light chain (kappa or lambda), known as an M spike
• The condition involves a problem with plasma cells, which originate from B-lymphocytes
• Multiple myeloma is a B-cell neoplasm (monoclonal), resulting in the monoclonal expansion of plasma cells
• One immunoglobulin becomes excessively abundant
• There is an increased risk of infection by S. aureus and E. coli, but not by viruses, due to crowding out of other antibodies, causing immunodeficiency

M Component Production

• An M component can be produced by an intact immunoglobulin (any subclass IgG, IgA, IgE) or fragments of heavy and light chains
• These proteins are called paraproteins, found in cancer or other diseases
• Monoclonal gammopathies are known as paraproteinemias

Epidemiology

• Multiple myeloma accounts for 10% of hematological malignancies
• It is more common in African Americans
• It is rare under 40 years, with a median onset age of 70, and is more prevalent in males
• Largely unknown etiology but there is an increased risk with exposure to benzene (petroleum products) and pesticides
• Light chains end up in the urine as Bence Jones proteins
• Serum M protein is ≥ 3 g/dL

Pathogenesis

• Involves dysregulation of cyclin D, chromosomal abnormalities, and bone marrow fibroblasts and macrophages leading to IL-6 production by myeloma cells
• Osteoprotegerin normally inhibits osteoclasts, but in multiple myeloma, osteoprotegerin is inhibited
• IL-1, also known as osteoclast-activating factor, and RANK-ligand stimulates osteoclasts, leading to bone lesions

Clinical Picture

• Skeletal system: disseminated bone disease
• Bone pain the most common symptom; ribs, skull and vertebrae most common locations
• May present "punched-out" lytic bone lesions and pathological fractures
• Hypercalcemia is also common
• Hematology: normocytic normochromic anemia (MCV 80-100)
• Rouleaux formation occurs when RBCs clump together, increasing ESR
• Bleeding time is increased due to crazy immunoglobulins covering platelets, preventing aggregation, and M protein interacts with coagulation factors
• Amyloidosis damages the endothelium
• Neurology: radiculopathy from vertebral fractures compressing nerve roots
• May have oncological emergencies, like loss of bowel and bladder control
• Neuropathy: carpal tunnel syndrome from amyloid deposition around the median nerve at the flexor retinaculum
• Lethargy, confusion, and weakness due to elevated calcium
• Shortness of breath, headache, and fatigue due to hyperviscosity syndrome; M protein present "everywhere"

Kidney involvement

• Can lead to renal failure
• Light chain cast nephropathy, tubular obstruction by Bence Jones protein
• Immunoglobulins, albumin, and Tamm-Horsfall protein cause proteinaceous tubular casts
• Nephrocalcinosis due to elevated calcium leads to metastatic calcification of tubular basement membranes
• Amyloidosis: AL fibrillar protein derived from immunoglobulin light chains deposits in glomeruli or interstitium
• Pyelonephritis: B-lymphocytes go crazy
• Proteinuria :Bence-Jones protein is so abundant it exceeds the ability of the tubule to reabsorb

Further Complications

• Recurrent infections occur due to impaired humoral immunity from crazy B-lymphocytes due to decreased antibodies
• Infections include S. aureus, Streptococcus pneumoniae, Klebsiella, E. coli, and Haemophilus influenzae due to decrease in opsonization
• Hyperviscosity syndrome manifested as shortness of breath, headache, fatigue, and visual disturbances, due to M protein buildup

Local tumors (plasmacytomas)

• Produce local symptoms depending on their location

End-Organ Damage (CRAB)

• Calcium elevation: > 10.5 mg/dl
• Renal insufficiency
• Anemia: normocytic and normochromic
• Bone lesions

Diagnostic Tests

• Serum protein electrophoresis (SPEP) quantifies the M component (M spike), is quantitative but not qualitative
• Urine protein electrophoresis (UPEP) quantifies light chains in the urine (Bence-Jones), is quantitative but not qualitative

Summary

• Median age is 70; more common in males; more common in blacks than whites; suspect MM with CRAB symptoms
• Renal failure can be caused by, amyloidosis, nephrotic syndrome, brown line pigment, easy bruising, neuropathy and metabolic acidosis etc.
• Bacterial infection may manifest in the eye and through retinal bleeding etc.
• CNS-related manifestations; headache, blurry vision, lethargy, confusion etc.

Diagnostics

• Blood tests include- ESR, CBC, BMP, SPEP, serum viscosity, serum ALP, B2 microglobulin level, and plasma immunoglobulin level etc.
• Urine tests include- Urinalysis, UPEP, kidney function tests etc.
• Radiology includes- plain X-ray and MRI
• Histopathology includes- Bone marrow biopsy and immunostains.
• UPEP is used to quantify Bence-Jones proteins in urine, while urine immunoelectrophoresis with immunofixation characterizes the type of Bence-Jones protein
• Plain X-ray: multiple punched out lytic lesions; Radiculopathy occurs when doing MRI because bone compresses the spinal cord

Histopathology of Multiple Myleoma

• Monoclonal plasma cells make up ≥10% of bone marrow Examine:
• Clock-face chromatin
• Abundant RER
• Prominent Golgi
• Dark blue cytoplasm
• Peripheral nucleus
• Perinuclear halo
• Bone marrow plasma cells may be identified with CD138+

Criteria for Diagnosis

• Plasma cells > 10% of Bone marrow
• Evidence of end organ damage "CRAB"- serum Calcium > 11 mg/dL,Renal: Serum Cr > 2 mg/dl and Anemia: Hgb<10 g/dl etc.
• One of these biomarkers for cancer- plasma cells > 60%; serum light chains > 100 mg/dl

Treatment

• Involves managing end-organ damage (CRAB)
• High-dose chemotherapy includes immunomodulators, proteasome inhibitors, steroids; and
• younger patients undergo autologous stem cell transplant and elderly patients receive palliative care (alkylating agents and prednisone) and plasmacytoma gets radiation.