- Author: Dhaval Shah, MD; Chief Editor: Emmanuel C Besa, MD more...
Multiple myeloma (MM) is a debilitating malignancy that is part of a spectrum of diseases ranging from monoclonal gammopathy of unknown significance (MGUS) to plasma cell leukemia. First described in 1848, MM is characterized by a proliferation of malignant plasma cells and a subsequent overabundance of monoclonal paraprotein (M protein). See the image below.
Signs and symptoms
The presentation of MM can range from asymptomatic to severely symptomatic, with complications requiring emergent treatment. Systemic ailments include bleeding, infection, and renal failure; pathologic fractures and spinal cord compression may occur.
Presenting symptoms of MM include the following:
Infection (often pneumococcal)
Spinal cord compression
See Presentation for more detail.
MM is often discovered through routine blood screening when patients are being evaluated for unrelated problems. In one third of patients, the condition is diagnosed after a pathologic fracture occurs, usually involving the axial skeleton.
Examination for MM may reveal the following:
HEENT examination: Exudative macular detachment, retinal hemorrhage, or cotton-wool spots
Dermatologic evaluation: Pallor from anemia, ecchymoses or purpura from thrombocytopenia; extramedullary plasmacytomas (most commonly in aerodigestive tract but also orbital, ear canal, cutaneous, gastric, rectal, prostatic, retroperitoneal areas)
Musculoskeletal examination: Bony tenderness or pain without tenderness
Neurologic assessment: Sensory level change (ie, loss of sensation below a dermatome corresponding to a spinal cord compression), neuropathy, myopathy, positive Tinel sign, or positive Phalen sign
Abdominal examination: Hepatosplenomegaly
Cardiovascular evaluation: Cardiomegaly
In patients with MM and amyloidosis, the characteristic examination findings include the following:
Shoulder pad sign
Typical skin lesions
Postprotoscopic peripalpebral purpura
Carpal tunnel syndrome
The International Myeloma Workshop guidelines for standard investigative workup in patients with suspected MM include the following :
Serum and urine assessment for monoclonal protein (densitometer tracing and nephelometric quantitation; immunofixation for confirmation)
Serum free light chain assay (in all patients with newly diagnosed plasma cell dyscrasias)
Bone marrow aspiration and/or biopsy
Serum beta2-microglobulin, albumin, and lactate dehydrogenase measurement
Standard metaphase cytogenetics
Fluorescence in situ hybridization
Routine laboratory tests include the following:
Complete blood count and differential
Erythrocyte sedimentation rate
Comprehensive metabolic panel (eg, levels of total protein, albumin and globulin, BUN, creatinine, uric acid)
24-hour urine collection for quantification of the Bence Jones protein (ie, lambda light chains), protein, and creatinine clearance; proteinuria greater than 1 g of protein in 24 hours is a major criterion
Serum viscosity in patients with CNS symptoms, nosebleeds, or very high M protein levels
The 2016 National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines also recommend the use of serum free light chain assay and fluorescence in situ hybridization (FISH) for del 13, del 17p13, t(4;14), t(11;14), 1q21 amplification as part of the initial diagnostic workup.
Simple radiography for the evaluation of skeleton lesions; skeletal survey, including the skull, long bones, and spine
MRI for detecting thoracic and lumbar spine lesions, paraspinal involvement, and early cord compression
PET scanning in conjunction with MRI potentially useful
See Workup for more detail.
There is currently no cure for MM. However, advances in therapy, such as autologous stem cell transplantation, radiation, and surgical care in certain cases, have helped to lessen the occurrence and severity of adverse effects of this disease and to manage associated complications.[3, 4, 5]
Chemotherapy and immunosuppression
Several drug therapies are valuable in the treatment of symptomatic MM. Clinicians treat many patients with high-dose therapy and peripheral blood or bone marrow stem cell transplantation.
Chemotherapy regimens used in patients with MM include the following:
Thalidomide, either as a single agent or in combination with steroids or with melphalan
Lenalidomide plus dexamethasone
Bortezomib plus melphalan
VAD (vincristine, doxorubicin [Adriamycin], and dexamethasone)
Melphalan plus prednisone
The 2016 NCCN guidelines for MM list the following combinations as preferred regimens (category 1) for primary induction therapy in transplant candidates :
The 2016 National Comprehensive Cancer Network (NCCN) guidelines for MM list the following combinations as preferred regimens for primary induction therapy in patients who are not transplant candidates :
Bortezomib/lenalidomide/dexamethasone (category 1)
Lenalidomide/low-dose dexamethasone (category 1)
Melphalan/prednisone/bortezomib (MPB) (category 1)
Melphalan/prednisone/lenalidomide (MPL) (category 1)
Melphalan/prednisone/thalidomide (MPT) (category 1)
Patients with refractory disease or relapse may be treated with the following:
Any of the agents not previously used
Bortezomib plus cyclophosphamide and dexamethasone [2, 6]
Lenalidomide plus cyclophosphamide and dexamethasone 
Pomalidomide [7, 8]
Multiple myeloma (MM) is a debilitating malignancy that is part of a spectrum of diseases ranging from monoclonal gammopathy of unknown significance (MGUS) to plasma cell leukemia. First described in 1848, MM is characterized by a proliferation of malignant plasma cells and a subsequent overabundance of monoclonal paraprotein (M protein). An intriguing feature of MM is that the antibody-forming cells (ie, plasma cells) are malignant and, therefore, may cause unusual manifestations.
The proliferation of plasma cells in MM may interfere with the normal production of blood cells, resulting in leukopenia, anemia, and thrombocytopenia. The cells may cause soft-tissue masses (plasmacytomas) or lytic lesions in the skeleton. Feared complications of MM are bone pain, hypercalcemia, renal failure, and spinal cord compression.
The aberrant antibodies that are produced lead to impaired humoral immunity, and patients have a high prevalence of infection, especially with encapsulated organisms such as Pneumococcus. The overproduction of these antibodies may lead to hyperviscosity, amyloidosis, and renal failure. (See Pathophysiology.)
The American Cancer Society (ACS) estimates that about 30,330 new cases of MM (17,900 in men and 12,430 in women) will be diagnosed in 2016. In the United States, the lifetime risk of getting MM is one in 143 (0.7%). About 12,650 deaths from MM (6,430 in men and 6,220 in women) are expected to occur in 2016. (See Epidemiology.)
The presentation of MM can range from asymptomatic to severely symptomatic with complications requiring emergent treatment. Systemic ailments include bleeding, infection and renal failure; local catastrophes include pathologic fractures and spinal cord compression. (See Presentation.)
Although patients benefit from treatment (ie, longer life, less pain, fewer complications), currently no cure exists. Recent advances in therapy have helped to lessen the occurrence and severity of adverse effects of MM. (See Treatment.)
MM is characterized by neoplastic proliferation of plasma cells involving more than 10% of the bone marrow (see the images below). Increasing evidence suggests that the bone marrow microenvironment of tumor cells plays a pivotal role in the pathogenesis of myelomas. This information has resulted in the expansion of treatment options.
The malignant cells of MM, plasma cells, and plasmacytoid lymphocytes are the most mature cells of B-lymphocytes. B-cell maturation is associated with a programmed rearrangement of DNA sequences in the process of encoding the structure of mature immunoglobulins. It is characterized by overproduction of monoclonal immunoglobulin G (IgG), immunoglobulin A (IgA), and/or light chains, which may be identified with serum protein electrophoresis (SPEP) or urine protein electrophoresis (UPEP).
The role of cytokines in the pathogenesis of MM is an important area of research. Interleukin (IL)–6 is also an important factor promoting the in vitro growth of myeloma cells. Other cytokines are tumor necrosis factor and IL-1b.
The pathophysiologic basis for the clinical sequelae of MM involves the skeletal, hematologic, renal, and nervous systems, as well as general processes (see below).
Plasma-cell proliferation causes extensive skeletal destruction with osteolytic lesions, anemia, and hypercalcemia. Mechanisms for hypercalcemia include bony involvement and, possibly, humoral mechanisms. Isolated plasmacytomas (which affect 2-10% of patients) lead to hypercalcemia through production of the osteoclast-activating factor.
Destruction of bone and its replacement by tumor may lead to pain, spinal cord compression, and pathologic fracture. The mechanism of spinal cord compression symptoms may be the development of an epidural mass with compression, a compression fracture of a vertebral body destroyed by multiple myeloma, or, rarely, an extradural mass. With pathologic fracture, bony involvement is typically lytic in nature.
Bone marrow infiltration by plasma cells results in neutropenia, anemia, and thrombocytopenia. In terms of bleeding, M components may interact specifically with clotting factors, leading to defective aggregation.
The most common mechanisms of renal injury in MM are direct tubular injury, amyloidosis, or involvement by plasmacytoma.[14, 15] Renal conditions that may be observed include hypercalcemic nephropathy, hyperuricemia due to renal infiltration of plasma cells resulting in myeloma, light-chain nephropathy, amyloidosis, and glomerulosclerosis.
The nervous system may be involved as a result of radiculopathy and/or cord compression due to nerve compression and skeletal destruction (amyloid infiltration of nerves).
General pathophysiologic processes include hyperviscosity syndrome. This syndrome is infrequent in MM and occurs with IgG1, IgG3, or IgA. MM may involve sludging in the capillaries, which results in purpura, retinal hemorrhage, papilledema, coronary ischemia, or central nervous system (CNS) symptoms (eg, confusion, vertigo, seizure). Cryoglobulinemia causes Raynaud phenomenon, thrombosis, and gangrene in the extremities.
The precise etiology of MM has not yet been established. Roles have been suggested for a variety of factors, including genetic causes, environmental or occupational causes, MGUS, radiation, chronic inflammation, and infection.
MM has been reported in two or more first-degree relatives and in identical twins, although no evidence suggests a hereditary basis for the disease. A study by the Mayo clinic found MM in eight siblings from a group of 440 patients; these eight siblings had different heavy chains but the same light chains.
Some studies have shown that abnormalities of certain oncogenes, such as c-myc, are associated with development early in the course of plasma cell tumors and that abnormalities of oncogenes such as N-ras and K-ras are associated with development after bone marrow relapse. Abnormalities of tumor suppressor genes, such as TP53, have been shown to be associated with spread to other organs.
Ongoing research is investigating whether human leukocyte antigen (HLA)-Cw5 or HLA-Cw2 may play a role in the pathogenesis of multiple myeloma.
Environmental or occupational causes
Case-controlled studies have suggested a significant risk of developing MM in individuals with significant exposures in the agriculture, food, and petrochemical industries. An increased risk has been reported in farmers, especially in those who use herbicides and insecticides, and in people exposed to benzene and other organic solvents. Long-term (>20 y) exposure to hair dyes has been tied to an excessive risk of developing MM.
MGUS/Smoldering Multiple Myeloma (SMM)
Monoclonal gammopathy of undetermined significance (MGUS) is defined by the presence of three criteria:
Serum monoclonal M protein (M-protein) concentration < 3 g/dL
Bone marrow plasma cell concentration < 10%
No evidence of end organ damage
MGUS is seen in 2-3% of the elderly Caucasian population. It is divided into the following three subtypes:
Non IgM MGUS
Light chain MGUS
Patients with non-IgM MGUS have a risk of progression to MM at rate of 1% per year. For these patients, risk factors for progression to MM are as follows:
M protein concentration > 1.5 g/dL
An abnormal free light chain (FLC) ratio
Patients with IgM MGUS have a risk of progression to Waldenstrom macroglobulinemia and less frequently lymphoma or amyloid light chain (AL) amyloidosis. IgM MGUS rarely progresses into MM. Light chain MGUS has a tendency to progress to light chain MM, AL amyloidosis, or light chain deposition disease.
A study by Wadhera et al examined secondary MGUS that developed in patients with MM. Of 1942 patients with MM, 128 (6.6%) developed a secondary MGUS at a median of 12 months from the diagnosis of MM. Overall survival was superior in patients with MM who developed secondary MGUS compared with the rest of the cohort.
Smoldering MM is present when the serum M protein concentration is > 3 g/dL or the bone marrow plasma cell concentration is > 10% but there is no evidence of end-organ damage. Risk factors for progression of SMM to MM include any of the following:
M protein concentration > 3 g/dL
Abnormal FLC ratio
Bone marrow plasma cell concentration > 10%
The time to progression decreases with increasing numbers of risk factors, as follows:
One factor: 10 years
Two factors: 5.1 years
Three factors: 1.9 years
Radiation may play a role in some patients. An increased risk has been reported in atomic-bomb survivors exposed to more than 50 Gy: In 109,000 survivors of the atomic bombing of Nagasaki during World War II, 29 died from multiple myeloma between 1950 and 1976. Some more recent studies, however, do not confirm that these survivors have an increased risk of developing multiple myeloma.
A study of workers at the Oak Ridge Diffusion Plant in eastern Tennessee showed only a weak correlation of risk of multiple myeloma to uranium exposure.
A relationship between MM and preexisting chronic inflammatory diseases has been suggested. However, a case-control study provides no support for the role of chronic antigenic stimulation.
Human herpesvirus 8 (HH8) infection of bone marrow dendritic cells has been found in patients with MM and in some patients with MGUS.
MM accounts for 10% of all hematologic cancers.[18, 19] The age-adjusted annual incidence of MM is 4.3 cases per 100,000 white men, 3 cases per 100,000 white women, 9.6 cases per 100,000 black men, and 6.7 cases per 100,000 black women.
The American Cancer Society estimates that in the United States, approximately 30,330 new cases of MM (17,900 in men and 12,430 in women) will be diagnosed in 2016. The lifetime risk of getting MM is one in 143 (0.7%). Approximately 12,650 deaths from MM (6,430 in men and 6,220 in women) are expected to occur in 2016.
The median age of patients with MM is 68 years for men and 70 years for women. Only 18% of patients are younger than 50 years, and 3% of patients are younger than 40 years. The male-to-female ratio of MM is approximately 3:2.
In the United States, African Americans are twice as likely as whites to have myeloma, with a ratio of 2:1. Myeloma is rare among people of Asian descent, with an incidence of only 1-2 cases per 100,000 population. According to a study of the ethnic disparities among patients with MM, Hispanics had the youngest median age at diagnosis (65 years) and whites had the oldest (71 years). Asians had the best overall survival rates, while Hispanics had the worst.
MM is a heterogeneous disease, with survival ranging from 1 year to more than 10 years. Median survival in unselected patients with MM is 3 years. The 5-year relative survival rate is 46.6%. Survival is higher in younger people and lower in the elderly.
The tumor burden and the proliferation rate are the two key indicators for the prognosis in patients with MM. Many schemas have been published to aid in determining the prognosis. One schema uses C-reactive protein (CRP) and beta-2 microglobulin (which is an expression of tumor burden) to predict survival ,as follows :
If levels of both proteins are less than 6 mg/L, the median survival is 54 months.
If the level of only one component is less than 6 mg/L, the median survival is 27 months.
If levels of both protein values are greater than 6 mg/L, the median survival is 6 months.
Poor prognostic factors include the following:
Bence Jones proteinemia
Renal impairment (ie, stage B disease or creatinine level >2 mg/dL at diagnosis)
The prognosis by treatment is as follows:
Conventional therapy: Overall survival is approximately 3 years, and event-free survival is less than 2 years.
High-dose chemotherapy with stem-cell transplantation: The overall survival rate is greater than 50% at 5 years.
Infections are an important cause of early death in MM. In a United Kingdom study, 10% of patients died within 60 days after diagnosis of MM, and 45% of those deaths were due to infection. In a Swedish study, 22% of patients died of infection within the first year after diagnosis. The risk of both bacterial infections (eg, meningitis, septicemia, pneumonia) and viral infections (eg, herpes zoster, influenza) was seven times higher in patients with MM than in matched controls. The Swedish investigators also found that the risk of infections has increased in recent decades, and they argue that the use of more intensive treatment measures for MM (ie, newer drugs and high-dose chemotherapy with transplantation) has contributed to the increased risk.
Patient education is very important in the management of MM. The International Myeloma Foundation (IMF) offers educational resources, a quarterly newsletter, and conferences. Patients or physicians can contact the IMF by phone at (800) 452-CURE (800-452-2873) in the United States and Canada or on the Web at International Myeloma Foundation.
Patient education should address, at a minimum, the following questions:
What is MM, and how does it affect the body?
What are the causes of MM?
What is the treatment for MM?
What are the adverse effects of medicine? (As an example, patients should be informed of the risk of osteonecrosis of the jaw, which has been associated with bisphosphonate therapy in MM.)
What are some of the complications of MM?
Where can additional information be found?
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