Multiple Myeloma

Multiple myeloma (also known as MM, myeloma, plasma cell myeloma, or as Kahler's disease after Otto Kahler) is a presently incurable hematological malignancy of plasma cells, the cells of the immune system that produce antibodies. Its prognosis despite therapy is generally poor, and treatment may involve chemotherapy and stem cell transplant.

Signs and symptoms

Symptoms can include: malaise, bone pain, anemia, infections (due to decreased immunity) and fractures (due to breakdown of bone by malignant cells, as well as a tendency to brittle bones)^[1]. Often, the diagnosis of multiple myeloma is made incidentally during routine blood tests for other conditions. The antibody that is produced in excess may cause specific medical problems, such as amyloid, acute renal failure and chronic renal failure, polyneuropathy and other disorders.

A mnemonic doctors use to remember the common tetrad of multiple myeloma is CRAB - C = Calcium (elevated), R =Renal failure, A = Anemia, B = Bone lesions^[2].

Diagnosis

Investigations

The existence of unexplained anemia, kidney dysfunction, a high erythrocyte sedimentation rate (ESR) and a high serum protein (especially raised globulin) may suggest further testing. A doctor will then order protein electrophoresis of the blood and urine, on which a paraprotein (monoclonal protein, or M protein) band can be noticed. A type of paraprotein is the Bence Jones protein which is paraprotein composed of free light chains (see below). Quantitative measurements of the paraprotein are necessary to determine the severity of the disease. The paraprotein is a deviant immunoglobulin produced by the tumor clone. Very rarely, the myeloma is nonsecretory (not producing immunoglobulins).

In theory, myeloma can produce all classes of immunoglobulin, but IgD, IgM and IgE myeloma are very rare compared to IgG and IgA. In addition, light and heavy chains (the building blocks of antibodies) may be secreted in isolation: κ- or λ-light chains or any of the five types of heavy chains (α-, γ-, δ-, ε- or μ-heavy chains).

Additional findings are: a raised calcium (when myeloma cells are breaking down bone, releasing calcium into the bloodstream) and decreased renal function, which may be due to paraprotein deposition in the kidney).

Workup

The workup of suspected multiple myeloma includes a skeletal survey. This is a series of X-rays of the skull, axial skeleton and proximal long bones. Myeloma deposits appear as "lytic lesions" (with local disappearance of normal bone due to resorption), and on the skull X-ray as "punched-out lesions". A CT scan may be performed to measure the size of soft tissue plasmacytomas.

A bone marrow biopsy is usually performed to estimate the percentage of bone marrow occupied by plasma cells. This percentage is used in the diagnostic criteria for myeloma. Immunohistochemistry (staining particular cell types using antibodies against surface proteins) can detect plasma cells which express immunoglobulin in the cytoplasm but usually not on the surface; myeloma cells are typically CD56, CD138 positive and CD19 negative^[2]. Cytogenetics may also performed in myeloma for prognostic purposes.

Other useful laboratory tests include quantitative measurement of IgA, IgG, IgM and β2-microglobulin.

Criteria

New international critera^[2], agreed in 2003, require the following:

• Plasma cells >10% on bone marrow biopsy or (in any quantity) in a biopsy from other tissues (plasmacytoma)
• A monoclonal protein in either serum (of >30 g/L) or urine
• Evidence of end-organ damage (related organ or tissue impairment, ROTI):
  • Hypercalcemia
  • Renal insufficiency
  • Anemia
  • Bone lesions
  • Frequent severe infections (>2 a year)
  • Amyloidosis of other organs
  • Hyperviscosity syndrome

Some myelomas do not secrete any paraprotein. These are termed "non-secretory myeloma" with low or undetectable paraproteins on routine serum or urine protein electrophoresis. Measurement of serum free light chains may often be helpful to follow the disease burden in nonsecretory myeloma. It is rare compared to the secretory forms.

Related conditions are solitary plasmacytoma (a single tumor of plasma cells, typically treated with irradiation), plasma cell dyscrasia (where only the antibodies produce symptoms, e.g. amyloidosis) and monoclonal gammopathy of undetermined significance (MGUS). Most cases of myeloma probably start as MGUS.

Staging

International Staging System (ISS):

• Stage I: β₂-microglobulin (β2M) < 3.5 mg/L, albumin >= 3.5 g/dL
• Stage II: β2M < 3.5 and albumin < 3.5; or β2M between 3.5 and 5.5
• Stage III: β2M > 5.5

Pathophysiology

Multiple myeloma develops in post-germinal center B lymphocytes.

A chromosomal translocation between the immunoglobulin heavy chain gene (on the fourteenth chromosome, locus 14q32) and a oncogene (often 11q13, 4p16.3, 6p21, 16q23 and 20q11^[1]) is frequently observed in patients with multiple myeloma. This mutation results in dysregulation of the oncogene which is thought to be important initiating event in the pathogenesis of myeloma. The result is proliferation of a plasma cell clone and genomic instability that leads to further mutations and translocations. The chromosome 14 abnormality is observed in about 50% of all cases of myeloma. Deletion of (parts of) the thirteenth chromosome is also observed in about 50% of cases.

Production of cytokines (especially IL-6) by the plasma cells causes much of their localised damage, such as osteoporosis, and creates a microenvironment in which the malignant cells thrive. Angiogenesis (the attraction of new blood vessels) is increased.

The produced antibodies are deposited in various organs, leading to renal failure, polyneuropathy and various other myeloma-associated symptoms.

Epidemiology

There are approximately 45,000 people in the United States living with multiple myeloma, and the American Cancer Society estimates that approximately 14,600 new cases of myeloma are diagnosed each year in the United States. It follows from here that the median prognosis is about three years^[1].

Multiple myeloma is the second most prevalent blood cancer (10%) after non-Hodgkin's lymphoma. It represents approximately 1% of all cancers and 2% of all cancer deaths. Although the peak age of onset of multiple myeloma is 65 to 70 years of age, recent statistics indicate both increasing incidence and earlier age of onset.

Multiple myeloma affects slightly more men than women. African Americans and Native Pacific Islanders have the highest reported incidence of this disease and Asians the lowest. Results of a recent study found the incidence of myeloma to be 9.5 cases per 100,000 African Americans and 4.1 cases per 100,000 Caucasian Americans. Among African Americans, myeloma is one of the top 10 leading causes of cancer death.

Treatment

Treatment for multiple myeloma is focused on disease containment and suppression. Although allogeneic stem cell tranplant might cure the cancer, it is considered investigational given the high treatment related mortality of the procedure. In addition to direct treatment of the plasma cell proliferation, bisphosphonates (e.g. pamidronate) are routinely administered to prevent fractures and erythropoietin to treat anemia.

Initial therapy

Initial therapy is aimed at treating symptoms and reducing the burden of disease. A commonly used induction regimens include thalidomide with or without dexamethasone, and VAD (vincristine, doxorubicin (Adriamycin), and dexamethasone). Low-dose therapy with melphalan combined with prednisone can be used to palliate symptoms in patients who cannot tolerate aggressive therapy.

In patients who have good performance status, the next step in therapy is high-dose chemotherapy with melphalan with autologous stem cell transplantation. This can be given in tandem fashion, i.e. an autologous transplant followed by a second transplant. Nonmyeloablative allogeneic stem cell transplant is being investigated as an alternative to autologous stem cell transplant.

Relapse

Frequently, myeloma progresses despite treatment. It has been observed^[1] that "treatment resistance" is a reversible effect, and that some new treatment modalities may re-sensitize the tumor to standard therapy. For patients with relapsed disease, bortezomib (or Velcade) is a recent addition to the therapeutic arsenal, especially as second line therapy. Bortezomib is a proteasome inhibitor. Finally, lenalidomide (or Revlimid), a less toxic thalidomide analog, is showing promise for treating myeloma. It awaits FDA approval.

Renal failure in multiple myeloma can be acute (reversible) or chronic (irreversible). Acute renal failure typically resolves when the calcium levels are brought under control. Treatment of chronic renal failure is dependent on the type of renal failure and may involve dialysis. Which type of renal failure a given patient has is difficult to determine at presentation.

Prognosis

Advanced age (age greater than 60), elevated lactate dehydrogenase, and decreased platelets are associated with a poorer prognosis. Cytogenetics may also be important for determining prognosis.

Patients

Some well-known patients include:

• Geraldine Ferraro
• Mel Stottlemyre
• Don Baylor
• Mel Goldstein
• Roy Scheider

Deceased:

• Ann Landers
• Mark Lenard

See also

• Waldenström macroglobulinemia
• Multiple Myeloma Research Foundation

References

• 1. ^  Kyle RA, Rajkumar SV. Multiple myeloma. N Engl J Med 2004;351:1860-73. PMID 15509819.
• 2. ^  International Myeloma Working Group. Criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders: a report of the International Myeloma Working Group. Br J Haematol 2003;121:749-57. PMID 12780789.

External links

• International Myeloma Foundation
• Multiple Myeloma Research Foundation