Clinical Features of Multiple Myeloma

Myeloma causes symptoms by infiltration, production of paraproteins and production of cytokines. The common manifestations include  anemia, bone pain, renal impairment, fatigue and weight loss, hypercalcaemia, and neurological manifestations.

Anaemia

Anaemia is the commonest manifestation of multiple myeloma. It has been reported in 73% of the patients at diagnosis 93% sometime in the course of the illness (Mayo Clin Proc. 2003;78(1):21.)

Anaemia is normocytic normochromic without reticulocytosis. It is caused by 

1. Cytokines secreted by myeloma cells and 
2. infiltration of the bone marrow
3. Renal insufficiency contributes when present. 

Bone Pain

Bone pain is the second most common symptom of myeloma. It is seen in 60% of the patients (Mayo Clin Proc. 2003;78(1):21.). Patients most often present with backache or pain of the ribs. Extremities are involved less often. Pain is induced by movement. Back pain is often present in recumbent position and may be associated with neurological symptoms. Rib pain may be associated with local swelling due to an underlying plasmacytoma. Pathological fractures occur.

Hypercalcaemia 

Hypercalcaemia is seen in about 15% of the patients with multiple myeloma (Mayo Clin Proc. 2003;78(1):21.). Patients with mild hypercalcaemia are usually asymptomatic. Moderate or severe hypercalcaemia results in confusion, stupor, coma, anorexia, nausea and constipation. It is more common in patients with high tumour load. The mechanisms underlying hypercalcaemia include

1. Widespread osteoclast activation because bone resorbing cytokines that often act through RANK/RANKL. 
2. Renal impairment hampering calcium clearance 

Renal Insufficiency

About a fourth of patients with multiple myeloma have renal insufficiency (serum creatinine greater than 2mg/dL). The prevalence is higher in patients with Bence-Jones proteins and in patients with IgD myeloma. Renal failure is associated with a worse outcome. The renal failure is reversible in about half the patients. Patients whose renal failure reverses have a substantially better outcome than those whose renal failure does not. The cause of renal failure includes

1. Toxic effects of monoclonal light chains
2. Hypercalcaemia
3. Dehydration
4. Use of nephrotoxic drugs: Non-steroidal anti-inflammatory agents used for relief of back pain are often implicated.

Neurological Disease

Neurological dysfunction manifests as cord compression, peripheral neuropathy, symptoms due to central nervous system dysfunction.

1. Cord compression: Cord compression is seen in about 5% of myeloma patients. Thoracic spine is more commonly involved than other part of spine. It manifests as back pain, radicular pain, numbness of lower extremity, weakness of lower extremity. The cause of compression is a plasmacytoma of the vertebra of a retro-pulsed vertebral bone fragment. Acute cord compression is a medical emergency.
2. Peripheral Neuropathy: Neuropathy is seen in less than 10% of patients with myeloma. Neuropathy may be caused by paraprotein, amyloid or treatment. 
   1. Neuropathy Associated with Paraprotein: Myeloma causes axonal length dependent neuropathy that is mainly sensory. Motor symptoms are late and may be unevenly distributed. The neuropathy usually predates the diagnosis of myeloma.
   2. Amyloid Neuropathy: Amyloid neuropathy is a painful sensory neuropathy. Patients may complain of burning. Autonomic neuropathy resulting in orthostatic hypotension, importance and gastric motility disorders may be seen.
   3. Treatment related neuropathy is seen with the use of bortezomib, thalidomide and vincristine, All drugs cause a length dependent axonal sensory neuropathy with pain that is dose dependent. Bortezomib neuropathy presents early and is partially reversible. The symptoms of thalidomide and vincristine neuropathy can worsen even after discontinuation of the drugs.
3. Central Nervous System Dysfunction: Central nervous system dysfunction may be seen due to pressure from a plasmacytoma of the skull base, encephalopathy because of hyperviscosity or hyperammonaemia or rarely due to leptomengeal involvement. Lesions exerting external compression on the brain most often arise in the bones of the skull. Isolated dural plasmacytomas are exceedingly rare. Hyperviscosity presents with visual disturbances, headache, encephalopathy and bleeding (see later). Leptomengeal involvement presents with radiculopathy, corda-equina syndrome, encephalopathy and cranial nerve palsies. 

Infections

Patients with multiple myeloma are at increased risk of infection by encapsulated organisms, gram negative bacteria and staphylococcus. Decrease levels of normal immunoglobulin contributes to immune dysfunction.  The risk of highest at diagnose and in the first two months after therapy.

Bleeding 

Bleeding in myeloma patients is related to thrombocytopenia, uraemia or hyperviscosity. Rarely it may be due acquired coagulation factor deficiency due to M component directed against a coagulation factor.

Thrombosis

Patients with myeloma may be at risk of thrombosis. Thrombosis is a significant risk patients being treated with a combination of thalidomide and dexamethasone.

Hyperviscosity

Hypereviscosity is most commonly seen with IgM monoclonal proteins. IgM monoclonal paraprotein is uncommon in myeloma.  The risk of hyperviscosity is greater with IgA than IgG. Hyperviscosity manifests as bleeding especially nasopharyngeal,  puyrpura, decreased visual acute, retinopathy, neurological symptoms, dyspnoea and congestive heart failure. Symptoms are usually seen at viscosity greater than 6-7 cP.