Multiple Myeloma

Multiple Myeloma

First described in 1848, multiple myeloma (MM), also known as plasma cell myeloma, is characterized by a proliferation of malignant plasma cells and a subsequent overproduction of monoclonal paraprotein (M protein).

There are several types of plasma cell neoplasms. These diseases are all associated with a monoclonal (or myeloma) protein (M protein). They include monoclonal gammopathy of undetermined significance (MGUS), isolated plasmacytoma of the bone, extramedullary plasmacytoma, multiple myeloma, and plasma cell leukemia.

The incidence of multiple myeloma is 2 to 4/100,000. Male:female ratio is 1.6:1, and the median age is about 65 years. Prevalence in blacks is twice that in whites. Etiology is unknown, although chromosomal and genetic factors, radiation, and chemicals have been suggested.

Estimated new cases and deaths from multiple myeloma in the United States in 2016:

  • New cases: 30,330.
  • Deaths: 12,650.

Clinical features:

The presentation of multiple myeloma can range from asymptomatic to severely symptomatic, with complications requiring urgent treatment. Many patients are identified when routine laboratory tests show an elevated total protein level in the blood or anemia. Systemic complications include bleeding, infection, and renal failure; pathologic fractures and spinal cord compression may occur.

Presenting symptoms of MM include the following:

  • Bone pain: The most common symptom of myeloma is bone pain. About 7 in 10 people (70%) have lower back or rib pain. The lumbar spine is one of the most common sites of pain.
  • Pathologic fractures: Pathologic fractures are very common in Myeloma. MM causes both generalized bone loss throughout the body as well as areas of bone destruction “lytic lesions” on x-ray in specific areas. The bone loss and bony erosions can lead to osteoporosis and fractures. Many individuals with multiple myeloma experience fractures of the vertebrae, which can lead to a loss of height; about 30 percent of individuals experience fractures in other bones, often with little or no preceding trauma. For this reason they are called “pathologic fractures.”
  • Weakness and malaise: Anemia, which may be quite severe, is the most common cause of weakness in patients with MM.
  • Bleeding and anemia: Occasionally, a patient may come to medical attention for bleeding or anemia resulting from heavy bone marrow involvement by myeloma. Rarely, monoclonal protein may absorb clotting factors and lead to bleeding.
  • Infection (often pneumococcal): Abnormal humoral immunity and leucopenia may lead to infection. Pneumococcal organisms are commonly involved, but shingles (herpes zoster) and Haemophilus infections are also more common among patients with MM.
  • Hypercalcemia: Because bones contain large amounts of calcium, the breakdown of bone in MM can lead to hypercalcemia. High blood calcium levels occur in 10 to 15 percent of individuals, and the symptoms may include loss of appetite, nausea, vomiting, frequent urination, increased thirst, constipation, weakness, confusion, stupor, or coma. Symptoms are more common at high calcium blood values (12.0 mg/dL or 3 mmol/l). Severe hypercalcemia (above 15–16 mg/dL or 3.75–4 mmol/l) is considered a medical emergency: at these levels, coma and cardiac arrest can result.
  • Spinal cord compression: Myeloma can develop in the bones of the spine. Sometimes this can weaken the bone and put pressure on the spinal cord with spinal cord compression (SCC). SCC can cause pain, muscle weakness, and sometimes tingling and numbness of the limbs. If the lower spine is affected, it may also affect how the bowel and bladder work. The symptoms that should alert physicians to consider spinal cord compression are back pain, weakness, numbness, or dysesthesias in the extremities.  Multiple MyelomaBecause spinal cord compressions in MM occur at multiple levels, comprehensive evaluation of the spine is warranted including full spine MRI scan. Patients who are ambulatory at the start of therapy have the best likelihood of preserving function and avoiding paralysis. Spinal cord compression should be treated urgently with steroids and radiotherapy. Sometimes chemotherapy can be given to help reduce the pressure on the spinal cord. Or surgery may be needed to repair or remove the affected bone.
  • Renal failure: In many patients, renal failure (myeloma kidney) is present at diagnosis or develops during the course of the disorder. In the majority of cases, renal impairment is caused by the accumulation and precipitation of light chains, which form casts in the distal tubules, resulting in renal obstruction. Renal failure in myeloma has many other causes e.g. hypercalcemia, recurrent renal infections, analgesic-associated nephropathy (NSAIDs)hyperuricemia, and amyloidosis. Patients also often develop anemia usually due to kidney disease or suppression of erythropoiesis by cancer cells but sometimes also due to iron deficiency.
  • Hyperviscosity:  Rarely, myeloma causes a very high level of paraprotein in the blood. This means the blood can become thicker than normal. Normal plasma viscosity is between 1.4 and 1.8 centipoise while symptoms from hyperviscosity typically occur greater than 4 centipoise (about 4 times more viscous than water) and require emergency treatment. Hyperviscosity may be associated with a number of symptoms, including, generalized malaise, infection, fever, paresthesia, sluggish mentation, and sensory loss. Patients may report headaches and somnolence, and they may bruise easily and have hazy vision. Patients with MM typically experience these symptoms when their serum viscosity is greater than 4 times that of normal serum. Epistaxis may be a presenting symptom of MM with a high tumor volume. Occasionally, patients may have such a high volume of monoclonal protein that their blood viscosity increases, resulting in complications such as stroke, myocardial ischemia, or infarction. Plasmapheresis may be used to decrease viscosity.
  • Neurologic symptoms: Carpal tunnel syndrome is a common complication of myeloma. Meningitis (especially that resulting from pneumococcal or meningococcal infection) is more common in patients with MM. Some peripheral neuropathies have been attributed to MM. Long-term neurologic function is directly related to the rapidity of the diagnosis and the institution of appropriate therapy for multiple myeloma.


The M-protein produced by the malignant plasma cells is IgG in about 55% of myeloma patients and IgA in about 20%; of patients producing either IgG or IgA, 40% also have Bence Jones proteinuria, which is free monoclonal kappa (κ) or lambda (λ) light chains in the urine. In 15 to 20% of patients, plasma cells secrete only Bence Jones protein (light chain myeloma). IgD myeloma accounts for about 1% of cases. Rarely, patients have no M-protein in blood and urine, although a new serum free light chain assay now demonstrates monoclonal light chains in many of these patients.

Diffuse osteoporosis or discrete osteolytic lesions develop, usually in the pelvis, spine, ribs, and skull. Lesions are caused by bone replacement by expanding plasmacytomas or by cytokines that are secreted by malignant plasma cells that activate osteoclasts and suppress osteoblasts. The osteolytic lesions are usually multiple; occasionally, they are solitary intramedullary masses. Increased bone loss may also lead to hypercalcemia. Extramedullary solitary plasmacytomas are unusual but may occur in any tissue, especially in the upper respiratory tract.

Multiple Myeloma

In many patients, renal failure (myeloma kidney) is present at diagnosis or develops during the course of the disorder. Renal failure has many causes, most commonly, it results from deposition of light chains in the distal tubules or hypercalcemia. Patients also often develop anemia usually due to kidney disease or suppression of erythropoiesis by cancer cells but sometimes also due to iron deficiency.

Susceptibility to bacterial infection may occur in some patients. Viral infections, especially herpes zoster infections, are increasingly occurring as a result of newer treatment modalities, especially use of the proteasome inhibitors bortezomib (Velcade) and carfilzomib (Kyprolis).

It is estimated that 10 to 15 percent of multiple myeloma patients will experience symptoms from the development of amyloidosis during the course of their disease.  However, as many as 38 percent of myeloma patients may develop amyloidosis but experience none of its symptoms. Amyloidosis is a disease in which proteins accumulate in organs such as the heart, kidney, liver, nerves or intestines, leading to organ damage.


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Dhaval Shah, MD Multiple Myeloma: Practice Essentials, Background, Pathophysiology Last accessed December 8, 2016.

James R. Berenson, MD Multiple Myeloma – Hematology and Oncology – Merck Manuals Professional Edition Last accessed September, 2016.

Bekelman, J; Jackson, N; Donehower, R (2006). Oncologic emergencies (2nd ed.). Philadelphia: Saunders Elsevier.

Rajkumar SV, Kumar S. Multiple myeloma: diagnosis and treatment. Mayo Clinic Proc91(1):101-119, 2016.doi: 10.1016/j.mayocp.2015.11.007.

Melissa Cobleigh PhD (2010): Multiple Myeloma-Associated Amyloidosis – What Every Patient Should Know

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