(also known as '''MM''', '''myeloma''', '''plasma cell myeloma''', or as '''Kahler's disease''' after
Otto Kahler ) is a type of
Cancer of
Plasma Cell s,
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 .
Because many organs can be affected by myeloma, the symptoms and signs are very variable. A
Mnemonic sometimes used to remember the common tetrad of multiple myeloma is ''CRAB'' - C = Calcium (elevated), R =Renal failure, A = Anemia, B = Bone lesionsInternational 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.. 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
Osteoclast Activating Factor s (OAF) which stimulate
Osteoclast s 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 ).
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 (α-, γ-, δ-, ε- or μ-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 .
The workup of suspected multiple myeloma includes a
Skeletal Survey . This is a series of
X-ray s of the skull, axial skeleton and proximal long bones. Myeloma activity sometimes appear as "lytic lesions" (with local disappearance of normal bone due to resorption), and on the skull X-ray as "punched-out lesions" (pepper pot skull).
Magnetic Resonance Imaging (MRI) is more sensitive then simple X-ray in the detection of lytic lesions, and may supercede skeletal survey, especially when vertebral disease is suspected. Occasionally a
CT Scan is 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.
Cytogenetics may also performed in myeloma for prognostic purposes.
Other useful laboratory tests include quantitative measurement of IgA, IgG, IgM (
Immunoglobulin s) to look for immune paresis, and β2-microglobulin which provides prognostic information.
The recent introduction of a commercial immunoassay for measurement of free light chains potentially offers an improvement in monitoring disease progression and response to treatment, particularly where the paraprotein is difficult to measure accurately by electrophoresis (for example in light chain myeloma, or where the paraprotein level is very low). Initial research also suggests that measurement of free light chains may also be used, in conjunction with other markers, for assessment of the risk of progression from
Monoclonal Gammopathy Of Undetermined Significance (MGUS) to multiple myeloma.
In
2003 , the International Myeloma Working Group agreed on diagnostic criteria for symptomatic myeloma, asymptomatic myeloma and
MGUS (monoclonal gammopathy of uncertain significance):
Related conditions include ''solitary
Plasmacytoma '' (a single tumor of plasma cells, typically treated with irradiation), ''plasma cell
Dyscrasia '' (where only the antibodies produce symptoms, e.g. AL
Amyloidosis ) and
POEMS Syndrome (peripheral neuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder, skin changes).
;International Staging System
The International Staging System (ISS) for myeloma was published by the International Myeloma Working Group in 2003 Greipp PR, San Miguel J, Fonseca R, Avet-Loiseau H, Jacobson JL, Rasmussen E, Crowley J, Durie BMG. Development of an international prognostic index (IPI) for myeloma: report of the international myeloma working group. ''Hematology Journal'' 2003;4:S42. NLM ID 100965523.:
- 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
;Durie-Salmon staging system
First published in 1975, the Durie-Salmon staging system Durie BG, Salmon SE. A clinical staging system for multiple myeloma. Correlation of measured myeloma cell mass with presenting clinical features, response to treatment and survival. ''Cancer'' 1975;36:842–854. PMID 1182674. is still in use, but has largely been superceded by the simpler ISS:
- stage 1: all of
- --- Hb > 10g/dL
- --- normal calcium
- --- Skeletal survey: normal or single plasmacytoma or osteoporosis
- --- Serum paraprotein level < 5 g/dL if IgG, < 3 g/dL if IgA
- --- Urinary light chain excretion < 4 g/24h
- stage 2: fulfilling the criteria of neither 1 nor 3
- stage 3: one or more of
- --- Hb < 8.5g/dL
- --- high calcium > 12mg/dL
- --- Skeletal survey: 3 or more lytic bone lesions
- --- Serum paraprotein >7g/dL if IgG, > 5 g/dL if IgA
- --- Urinary light chain excretion > 12g/24h
Stages 1, 2 and 3 of the Durie-Salmon staging system can be divided into A or B depending on serum creatinine:
- A: serum creatinine < 2mg/dL (< 177 umol/L)
- B: serum creatinine > 2mg/dL (> 177 umol/L)
Multiple myeloma develops in post-germinal center
B Lymphocytes .
A 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
Cytokine s (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.
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 average prognosis is about three years.
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 for multiple myeloma is focused on disease containment and suppression. Although
Allogeneic Stem Cell Transplant 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,
Bisphosphonate s (e.g.
Pamidronate ) are routinely administered to prevent fractures and
Erythropoietin to treat anemia.
''Initial therapy'' is aimed at treating symptoms and reducing the burden of disease. Commonly used
Induction Regimens include
Dexamethasone with or without
Thalidomide , 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 Transplantation is being investigated as an alternative to autologous stem cell transplant.
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 .
The
International Staging System can help to predict survival, with a median survival of 62 months for stage 1 disease, 45 months for stage 2 disease, and 29 months for stage 3 disease .
Cytogenetic analysis of myeloma cells may be of prognostic value, with deletion of chromosome 13, non-hyperdiploidy and the balanced translocations t(4;14) and t(14;16) conferring a poorer prognosis. The 11q13 and 6p21 cytogenetic abnormalities are associated with a better prognosis.
Prognostic markers such as these are always generated by retrospective analyses, and it is likely that new treatment developments will improve the outlook for those with traditionally 'poor-risk' disease.
