 Multiple myeloma (also known as MM, myeloma, plasma cell myeloma, or as Kahler's disease after Otto Kahler) is a type of cancer of plasma cells which are immune system cells in bone marrow that produce antibodies. Its prognosis, despite therapy, is generally poor, and treatment may involve chemotherapy and stem cell transplant. It is part of the broad group of diseases called hematological malignancies.
Clinical Features
Because many organs can be affected by myeloma, the symptoms and signs vary greatly. A mnemonic sometimes used to remember the common tetrad of multiple myeloma is CRAB - C = Calcium (elevated), R =Renal failure, A = Anemia, B = Bone lesions. Myeloma has many possible symptoms, and all symptoms may be due to other causes. They are presented here in decreasing order of incidence.
Bone pain
Myeloma bone pain usually involves the spine and ribs, and worsens with activity. Persistent localized pain may indicate a pathological fracture. Involvement of the vertebrae may lead to spinal cord compression. Myeloma bone disease is due to proliferation of tumor cells and release of IL-6, also known as osteoclast activating factor (OAF), which stimulates osteoclasts to break down bone. These bone lesions are lytic in nature and are best seen in plain radiographs, which may show a "punched-out" resorptive lesions. The breakdown of bone also leads to release of calcium into the blood, leading to hypercalcemia and its associated symptoms.
Infection
The most common infections are pneumonias and pyelonephritis. Common pneumonia pathogens include S pneumoniae, S aureus, and K pneumoniae, while common pathogens causing pyelonephritis include E coli and other gram-negative organisms. The increased risk of infection is due to immune deficiency resulting from diffuse hypogammaglobulinemia, which is due to decreased production and increased destruction of normal antibodies.
Renal failure
Renal failure may develop both acutely and chronically. It is commonly due to hypercalcemia (see above). It may also be due to tubular damage from excretion of light chains, which can manifest as the Fanconi syndrome (type II renal tubular acidosis). Other causes include glomerular deposition of amyloid, hyperuricemia, recurrent infections (pyelonephritis), and local infiltration of tumor cells.
Anemia
The anemia found in myeloma is usually normocytic and normochromic. It results from the replacement of normal bone marrow by infiltrating tumor cells and inhibition of normal red blood cell production (hematopoiesis) by cytokines.
Neurological symptoms
Common problems are weakness, confusion and fatigue due to hypercalcemia. Headache, visual changes and retinopathy may be the result of hyperviscosity of the blood depending on the properties of the paraprotein. Finally, there may be radicular pain, loss of bowel or bladder control (due to involvement of spinal cord leading to cord compression) or carpal tunnel syndrome and other neuropathies (due to infiltration of peripheral nerves by amyloid). It may give rise to paraplegia in late presenting cases.
Diagnosis
Investigations
The presence of unexplained anemia, kidney dysfunction, a high erythrocyte sedimentation rate (ESR) and a high serum protein (especially raised immunoglobulin) may prompt further testing. A doctor will request protein electrophoresis of the blood and urine, which might show the presence of a paraprotein (monoclonal protein, or M protein) band, with or without reduction of the other (normal) immunoglobulins (known as immune paresis). One type of paraprotein is the Bence Jones protein which is a urinary paraprotein composed of free light chains (see below). Quantitative measurements of the paraprotein are necessary to establish a diagnosis and to monitor the disease. The paraprotein is an abnormal immunoglobulin produced by the tumor clone. Very rarely, the myeloma is nonsecretory (not producing immunoglobulins).
In theory, multiple myeloma can produce all classes of immunoglobulin, but IgG paraproteins are most common, followed by IgA and IgM. IgD and IgE myeloma are very rare. In addition, light and or 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.
Additional findings include: a raised calcium (when osteoclasts are breaking down bone, releasing calcium into the bloodstream), raised serum creatinine due to reduced renal function, which may be due to paraprotein deposition in the kidney.
Treatment
Treatment for multiple myeloma is focused on disease containment and suppression. If the disease is completely asymptomatic (i.e. there is a paraprotein and an abnormal bone marrow population but no end-organ damage), treatment may be deferred.
Although allogeneic stem cell transplant might cure the cancer, it is considered investigational given the high treatment-related mortality of 5-10% associated with the procedure. In addition to direct treatment of the plasma cell proliferation, bisphosphonates (e.g. pamidronate or zoledronic acid) are routinely administered to prevent fractures and erythropoietin to treat anemia.
Initial therapy
Initial treatment is aimed at treating symptoms and reducing disease burden. Commonly used induction regimens include dexamethasone with or without thalidomide and cyclophosphamide, and VAD (vincristine, adriamycin, and dexamethasone). Low-dose therapy with melphalan combined with prednisone can be used to palliate symptoms in patients who cannot tolerate aggressive therapy. Plasmapheresis can be used to treat symptomatic protein proliferation (hyperviscosity syndrome).
In younger patients, therapy may include high-dose chemotherapy, melphalan, and autologous stem cell transplantation. This can be given in tandem fashion, i.e. an autologous transplant followed by a second transplant. Nonmyeloablative (or "mini") allogeneic stem cell transplantation is being investigated as an alternative to autologous stem cell transplant, or as part of a tandem transplant following an autologous transplant (also known as an "auto-mini" tandem transplant).
Relapse
The natural history of myeloma is of relapse following treatment. Depending on the patient's condition, the prior treatment modalities used and the duration of remission, options for relapsed disease include re-treatment with the original agent, use of other agents (such as melphalan, cyclophosphamide, thalidomide or dexamethasone, alone or in combination), and a second autologous stem cell transplant.
Later in the course of the disease, "treatment resistance" occurs. This may be a reversible effect, and 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.
Renal failure in multiple myeloma can be acute (reversible) or chronic (irreversible). Acute renal failure typically resolves when the calcium and paraprotein levels are brought under control. Treatment of chronic renal failure is dependent on the type of renal failure and may involve dialysis.
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