Multiple myeloma

Multiple myeloma (from Greek myelo-, bone marrow), also known as plasma cell myeloma or Kahler's disease (after Otto Kahler), is a cancer of plasma cells, a type of white blood cell normally responsible for the production of antibodies. Collections of abnormal cells accumulate in bones, where they cause bone lesions (abnormal areas of tissue), and in the bone marrow where they interfere with the production of normal blood cells. Most cases of myeloma also feature the production of a paraprotein, an abnormal antibody that can cause kidney problems and interferes with the production of normal antibodies leading to immunodeficiency. Hypercalcemia (high calcium levels) is often encountered.

Myeloma is diagnosed with blood tests (protein electrophoresis, peripheral blood smear), microscopic examination of the bone marrow (bone marrow biopsy), and radiographs of commonly involved bones. Myeloma is generally thought to be incurable, but remissions may be induced with steroids, chemotherapy, thalidomide and stem cell transplants. Newer drugs, such as lenalidomide and bortezomib, are often used in more advanced disease. Radiation therapy is sometimes used to treat bone lesions that are causing symptoms.

The disease develops in 1–4 per 100,000 people per year. It is more common in men, and is twice as common in blacks as it is in whites. With conventional treatment, the prognosis is 3–4 years, which may be extended to 5–7 years or longer with advanced treatments. Multiple myeloma is the second most common hematological malignancy (13%) and constitutes 1% of all cancers.

Signs and symptoms
Because many organs can be affected by myeloma, the symptoms and signs vary greatly. A mnemonic sometimes used to remember the common tetrad (four parts) 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 bone fracture. Involvement of the vertebrae may lead to spinal cord compression. Myeloma bone disease is due to the overexpression of Receptor Activator for Nuclear Factor κ B Ligand (RANKL) by bone marrow stroma. RANKL activates osteoclasts, which resorb bone. The resultant bone lesions are lytic (cause breakdown) in nature and are best seen in plain radiographs, which may show "punched-out" resorptive lesions (including the "pepper pot" appearance of the skull on radiography). 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 greatest risk period for the occurrence of infection is in the initial few months after the start of chemotherapy. 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. A selected group of patients may benefit from replacement immunoglobulin therapy to reduce the risk of infection.

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, also called Bence Jones proteins, 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.

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 (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 is mainly due to casts of paraprotein deposition in the kidney, although the cast may also contain complete immunoglobulins, Tamm-Horsfall protein and albumin.

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 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 than simple X-ray in the detection of lytic lesions, and may supersede skeletal survey, especially when vertebral disease is suspected. Occasionally a CT scan is performed to measure the size of soft tissue plasmacytomas. Bone scans are typically not of any additional value in the workup of myeloma patients (no new bone formation, lytic lesions not well visualized on bone scan).

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 and occasionally on the cell surface; myeloma cells are typically CD56, CD38, CD138 positive and CD19 and CD45 negative. Cytogenetics may also be performed in myeloma for prognostic purposes, including a myeloma-specific FISH and Virtual Karyotype.

Other useful laboratory tests include quantitative measurement of IgA, IgG, IgM (immunoglobulins) to look for immune paresis, and Beta 2-microglobulin which provides prognostic information. On peripheral blood smear the rouleaux formation of red blood cells is commonly seen.

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.

This assay, the serum free light chain assay, has recently been recommended by the International Myeloma Working Group for the screening, diagnosis, prognosis, and monitoring of plasma cell dyscrasias.

The prognosis of myeloma varies widely depending upon various risk factors. The Mayo Clinic has developed a risk-stratification model termed Mayo Stratification for Myeloma and Risk-adapted Therapy (mSMART) which divides patients into high-risk and standard-risk categories. Patients with deletion of chromosome 13 or hypodiploidy by conventional cytogenetics, t(4;14), t(14;16) or 17p- by molecular genetic studies, or with a high plasma cell labeling index (3% or more) are considered to have high-risk myeloma.

Diagnostic criteria
In 2003, the International Myeloma Working Group agreed on diagnostic criteria for symptomatic myeloma, asymptomatic myeloma and MGUS (monoclonal gammopathy of undetermined significance), which was subsequently updated in 2009:

Note: Recurrent infections alone in a patient who has none of the CRAB features is not sufficient to make the diagnosis of myeloma. Patients who lack CRAB features but have evidence of amyloidosis should be considered as amyloidosis and not myeloma. CRAB like abnormalities are common with numerous diseases, and it is imperative that these abnormalities are felt to be directly attributable to the related plasma cell disorder and every attempt made to rule out other underlying causes of anemia, renal failure etc.
 * Symptomatic myeloma:
 * Clonal plasma cells >10% on bone marrow biopsy or (in any quantity) in a biopsy from other tissues (plasmacytoma)
 * A monoclonal protein (paraprotein) in either serum or urine(except in cases of true non-secretory myeloma)
 * Evidence of end-organ damage felt related to the plasma cell disorder (related organ or tissue impairment, ROTI, commonly referred to by the acronym "CRAB"):
 * HyperCalcemia (corrected calcium >2.75 mmol/L)
 * Renal insufficiency attributable to myeloma
 * Anemia (hemoglobin <10 g/dL)
 * Bone lesions (lytic lesions or osteoporosis with compression fractures)
 * Asymptomatic myeloma:
 * Serum paraprotein >30 g/L AND/OR
 * Clonal plasma cells >10% on bone marrow biopsy AND
 * NO myeloma-related organ or tissue impairment
 * Monoclonal gammopathy of undetermined significance (MGUS):
 * Serum paraprotein <30 g/L AND
 * Clonal plasma cells <10% on bone marrow biopsy AND
 * NO myeloma-related organ or tissue impairment

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).

Staging
The International Staging System (ISS) for myeloma was published by the International Myeloma Working Group in 2005:
 * International Staging System
 * Stage I: β2-microglobulin (β2M) < 3.5 mg/L, albumin >= 3.5 g/dL
 * Stage II: β2M < 3.5 mg/L and albumin < 3.5 g/dL; or β2M 3.5 mg/L - 5.5 mg/L irrespective of the serum albumin
 * Stage III: β2M >= 5.5 mg/L

Note that the ISS should be used only in patients who meet diagnostic criteria for myeloma. Patients with MGUS and asymptomatic myeloma who have renal dysfunction from unrelated causes such as diabetes or hypertension may have elevated β2M levels just from the renal dysfunction and cannot be considered as stage III myeloma. This is one of the main drawbacks of the ISS. It does not really quantify tumor burden or extent unlike staging systems used in other cancers. It is more of a prognostic index rather than a true staging system. For this reason, it is recommended that the ISS be used along with the Durie Salmon Staging System (see below)

First published in 1975, the Durie-Salmon staging system is still in use:
 * Durie-Salmon staging system
 * stage I: 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 II: fulfilling the criteria of neither I nor III
 * stage III: one or more of
 * Hb < 8.5g/dL
 * high calcium > 12 mg/dL
 * Skeletal survey: Three or more lytic bone lesions
 * Serum paraprotein > 7g/dL if IgG, > 5 g/dL if IgA
 * Urinary light chain excretion > 12g/24h

Stages I, II, and III of the Durie-Salmon staging system can be divided into A or B depending on serum creatinine:
 * A: serum creatinine < 2 mg/dL (< 177 umol/L)
 * B: serum creatinine > 2 mg/dL (> 177 umol/L)

Pathophysiology
B lymphocytes start in the bone marrow and move to the lymph nodes. As they progress, they mature and display different proteins on their cell surface. When they are activated to secrete antibodies, they are known as plasma cells.

Multiple myeloma develops in B lymphocytes after they have left the part of the lymph node known as the germinal center. The normal cell line most closely associated with MM cells is generally taken to be either an activated memory B cell or the precursor to plasma cells, the plasmablast.

The immune system keeps the proliferation of B cells and the secretion of antibodies under tight control. When chromosomes and genes are damaged, often through rearrangement, this control is lost. Often, a promoter gene moves (or translocates) to a chromosome where it stimulates an antibody gene to overproduction.

A chromosomal translocation between the immunoglobulin heavy chain gene (on chromosome 14, locus q32) and an oncogene (often 11q13, 4p16.3, 6p21, 16q23 and 20q11 ) is frequently observed in patients with multiple myeloma. This mutation results in dysregulation of the oncogene which is thought to be an 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) chromosome 13 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.

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.

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 of multiple myeloma depends on the patient’s age and comorbidities. In recent years, high-dose chemotherapy with hematopoietic stem-cell transplantation has become the preferred treatment for patients under the age of 65. Prior to stem-cell transplantation, these patients receive an initial course of induction chemotherapy. The most common induction regimens used today are thalidomide–dexamethasone, bortezomib based regimens, and lenalidomide–dexamethasone. Autologous stem cell transplantation (ASCT), the transplantation of a patient’s own stem cells after chemotherapy, is the most common type of stem cell transplantation for multiple myeloma. It is not curative, but does prolong overall survival. Allogeneic stem cell transplantation, the transplantation of a healthy person’s stem cells into the affected patient, has the potential for a cure, but is only available to a small percentage of patients. Furthermore, there is a 5-10% treatment-associated mortality rate.

Patients over age 65 and patients with significant concurrent illness often cannot tolerate stem cell transplantation. For these patients, the standard of care has been chemotherapy with melphalan and prednisone. Recent studies among this population suggest improved outcomes with new chemotherapy regimens. Treatment with bortezomib, melphalan and prednisone had an estimated overall survival of 83% at 30 months, lenalidomide plus low-dose dexamethasone an 82% survival at 2 years and melphalan, prednisone and lenalidomide had a 90% survival at 2 years. Head-to-head studies comparing these regimens have not been performed.

A 2009 review noted "Deep venous thrombosis and pulmonary embolism are the major side effects of thalidomide and lenalidomide. Lenalidomide causes more myelosuppression, and thalidomide causes more sedation. Peripheral neuropathy and thrombocytopenia are major side effects of bortezomib."

Treatment of related hyperviscosity syndrome may be required to prevent renal failure

Maintenance therapy
Sometimes after the initial treatment an ongoing maintenance therapy is offered. A 2009 review of maintenance therapy concluded "In younger patients, post-ASCT maintenance therapy with thalidomide appears to increase tumor burden reduction further, which translates in[to] prolonged PFS (progression free survival)."

Another 2009 review stated "the role of maintenance therapy with thalidomide, lenalidomide, or bortezomib for patients with multiple myeloma is not definitively established; such therapy should be performed only in the context of a clinical trial."

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, since 2005. Bortezomib is a proteasome inhibitor. Finally, lenalidomide (or Revlimid), a less toxic thalidomide analog, is showing promise for treating myeloma. More and more patients survive longer and longer, thanks to stem cell transplant (with their own or a donor's) and treatments combining Bortezomib (Velcade), Dexamethasone (corticoid) and melphalan or cyclophosphamide (Endoxan).This seems to maintain the monoclonal peak at a reasonable level.Survival expectancy is then rising, and new treatments are being developed.

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.

Prognosis
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.

SNP array karyotyping can detect copy number alterations of prognostic significance that may be missed by a targeted FISH panel. In MM, lack of a proliferative clone makes conventional cytogenetics informative in only ~30% of cases.
 * 1) Virtual karyotyping identified chromosomal abnormalities in 98% of MM cases
 * 2) del(12p13.31)is an independent adverse marker
 * 3) amp(5q31.1) is a favorable marker
 * 4) The prognostic impact of amp(5q31.1) over-rides that of hyperdiploidy and also identifies patients who greatly benefit from high-dose therapy.

Array-based karyotyping cannot detect balanced translocations, such as t(4;14) seen in ~15% of MM. Therefore, FISH for this translocation should also be performed if using SNP arrays to detect genome-wide copy number alterations of prognostic significance in MM.

The prognoses for patients with multiple myeloma, as those with other diseases, are not the same for everyone. The average age of onset is 70 years. Older patients often are experiencing other serious diseases, which affect survival. Younger patients might have much longer survival rates.

Some myeloma centers now employ genetic testing, which they call a “gene array.” By examining DNA oncologists can determine if patients are high risk or low risk. Myeloma patients identified as high risk are at high risk of having the cancer return more quickly following treatment. Low risk patients are at low risk of having the cancer return quickly following treatment.

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.

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 in the United States 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.

In other species
Multiple myeloma affects many other species. The disease has been diagnosed in dogs, cats, and horses.

In dogs, multiple myeloma accounts for around 8% of all haemopoietic tumours. Multiple myeloma occurs in older dogs, and is not particularly associated with either males or females. No species appear over represented in case reviews that have been conducted. Diagnosis in dogs is usually delayed due to the initial non specificity and range of clinical signs possible. Diagnosis usually involves bone marrow studies, X-rays, and plasma protein studies. In dogs, protein studies usually reveal the monoclonal gammaglobulin elevation to be IgA or IgG in equal incidence. In rare cases where IgM represents the globulin elevation, the disease is referred to as Waldenstrom's macroglobulinaemia. The prognosis for initial control and return to good quality of life in dogs is good. 43% of dogs started on a combination chemotheraputic protocol achieved complete remission. Long term survival is normal with a median of 540 days reported. Recurrence is expected eventually with a tumour that is resistant to available chemotheraputics, rescue protocols can be attempted, however death eventually follows from complications, usually renal failure, sepsis or pain related owner initiated euthanasia.