Practice Essential

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.

Bone marrow aspirate demonstrating plasma cells of multiple myeloma. Note the
blue cytoplasm, eccentric nucleus, and perinuclear pale zone (or halo). All images
and text are (c) 2002 by the American Society of Hematology. All rights reserved.
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:
Bone pain
Pathologic fractures
Weakness, malaise
Bleeding, anemia

Infection (often pneumococcal)

Hypercalcemia
Spinal cord compression
Renal failure
Neuropathies
See Presentation for more detail.
Diagnosis
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 cottonwool 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
Macroglossia
Typical skin lesions
Postprotoscopic peripalpebral purpura
Carpal tunnel syndrome

Subcutaneous nodules
Testing
The International Myeloma Workshop guidelines for standard investigative workup in
patients with suspected MM include the following [1] :
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
Skeletal survey
MRI
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
C-reactive protein
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. [2]
Imaging studies

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.
Management
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 [2] :
Bortezomib/dexamethasone
Bortezomib/doxorubicin/dexamethasone
Bortezomib/thalidomide/dexamethasone
Lenalidomide/dexamethasone
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 [2] :

Bortezomib/dexamethasone
Bortezomib/cyclophosphamide/dexamethasome
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]

Carfilzomib (Kyprolis)
Thalidomide
Lenalidomide plus cyclophosphamide and dexamethasone
Pomalidomide

[2]

[7, 8]

See Treatment and Medication for more detail.

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. Hyperviscosity syndrome (HVS) refers to the clinical sequelae of increased blood
viscosity. Increased serum viscosity usually results from increased circulating serum

immunoglobulins and can be seen in such diseases as Waldenstrm macroglobulinemia and

multiple myeloma. HVS can also result from increased cellular blood components (typically
white or red blood cells) in hyperproliferative states such as the leukemias, polycythemia, and
the myeloproliferative disorders.
The clinical presentation in HVS consists principally of the triad of mucosal bleeding, visual
changes, and neurologic symptoms.[1] Constitutional symptoms and cardiorespiratory symptoms
may also occur.
The diagnosis of HVS is confirmed by measurement of elevated serum viscosity in a patient with
characteristic clinical manifestations of HVS. No exact diagnostic cut-off exists for serum
viscosity, however, as different patients will have symptoms at different values.
Plasmapheresis is the treatment of choice for initial management and stabilization of HVS from
elevated immunoglobulin levels.[2] Leukapheresis, plateletpheresis, and phlebotomy are indicated
for HVS from leukostasis, thrombocytosis, and polycythemia, respectively.
Definitive treatment of HVS is treatment of the underlying disorder (eg, chemotherapy). If the
underlying disease process is left untreated, the hyperviscosity will recur.
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.[9] (See Epidemiology.)
The 5-year relative survival rate for MM is 46.6%.[10] Survival is higher in younger people and
lower in the elderly.[9, 11, 12] (See Prognosis.)
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.

Patofisiologi
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.[13] This information has resulted in the expansion of

treatment options.

Bone marrow aspirate

demonstrating plasma cells of multiple myeloma. Note the blue cytoplasm,
eccentric nucleus, and perinuclear pale zone (or halo). All images and text are (c)
2002 by the American Society of Hematology. All rights reserved.

Bone marrow biopsy

demonstrating sheets of malignant plasma cells in multiple myeloma. All images
and text are (c) 2002 by the American Society of Hematology. All rights reserved.
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).
Skeletal processes
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.
Hematologic processes
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.
Renal processes
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.
Neurologic processes
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 processes
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.

Etiologi
Genetic causes

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.[9]
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

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

Non-IgG isotype

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.[16]
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

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.[17]
Chronic inflammation

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.
Infection

Human herpesvirus 8 (HH8) infection of bone marrow dendritic cells has been found in patients
with MM and in some patients with MGUS.

Epidemiologi
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.[9]
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-tofemale 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.[20]

Prognosis
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%.[10]
Survival is higher in younger people and lower in the elderly.[9]
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[21] :

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:

Tumor mass

Hypercalcemia

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.[22] 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.[23

Patient Education
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?

For patient education information, see Blood and Lymphatic System Center, as well as Myeloma.

Presentation
History
Presenting symptoms of multiple myeloma (MM) include bone pain, pathologic fractures,
weakness, anemia, infection (often pneumococcal), hypercalcemia, spinal cord compression, or
renal failure. The diagnosis is incidental in 30% of cases. MM is often discovered through
routine blood screening when patients are being evaluated for unrelated problems. Typically, a
large gap between the total protein and the albumin levels observed on an automated chemistry
panel suggests a problem (ie, protein minus albumin equals globulin).
In one third of patients, MM is diagnosed after a pathologic fracture occurs; such fractures
commonly involve the axial skeleton. Two thirds of patients complain of bone pain, commonly
with lower back pain. This bone pain is frequently located in the back, long bones, skull, and/or
pelvis.
Patients may also complain of nonspecific constitutional symptoms related to hyperviscosity and
hypercalcemia.

Bone pain

Bone pain is the most common presenting symptom in MM. Most case series report that 70% of
patients have bone pain at presentation. The lumbar spine is one of the most common sites of
pain.
Pathologic fractures and bone lesions

Pathologic fractures are very common in MM; 93% of patients have more than one site of bony
involvement. A severe bony event is a common presenting issue.
Spinal cord compression

The symptoms that should alert physicians to consider spinal cord compression are back pain,
weakness, numbness, or dysesthesias in the extremities. Because spinal cord compressions in
MM occur at multiple levels, comprehensive evaluation of the spine is warranted. Patients who
are ambulatory at the start of therapy have the best likelihood of preserving function and
avoiding paralysis.
Bleeding

Occasionally, a patient may come to medical attention for bleeding resulting from
thrombocytopenia. Rarely, monoclonal protein may absorb clotting factors and lead to bleeding.
Hypercalcemia

Confusion, somnolence, bone pain, constipation, nausea, and thirst are the presenting symptoms
of hypercalcemia. This complication may be present in as many as 30% of patients with MM at
presentation. In most solid malignancies, hypercalcemia carries an ominous prognosis, but in
MM, its occurrence does not adversely affect survival.
Infection

Abnormal humoral immunity and leukopenia may lead to infection. Pneumococcal organisms are
commonly involved, but shingles (ie, herpes zoster) and Haemophilus infections are also more
common among patients with MM.
Hyperviscosity

Hyperviscosity may be associated with a number of symptoms, including, generalized malaise,

infection, fever, paresthesia, sluggish mentation, and sensory loss. Patients may report headaches
and somnolence, and they may bruise easily and have hazy vision. Patients with MM typically
experience these symptoms when their serum viscosity is greater than 4 times that of normal
serum.

Epistaxis may be a presenting symptom of MM with a high tumor volume. Occasionally, patients
may have such a high volume of monoclonal protein that their blood viscosity increases,
resulting in complications such as stroke, myocardial ischemia, or infarction.
Neurologic symptoms

Carpal tunnel syndrome is a common complication of myeloma. Meningitis (especially that

resulting from pneumococcal or meningococcal infection) is more common in patients with MM.
Some peripheral neuropathies have been attributed to MM. Long-term neurologic function is
directly related to the rapidity of the diagnosis and the institution of appropriate therapy for MM.
Anemia

Anemia, which may be quite severe, is the most common cause of weakness in patients with
MM.

Physical Examination
On head, ears, eyes, nose, and throat (HEENT) examination, the eyes may show exudative
macular detachment, retinal hemorrhage, or cotton-wool spots. Pallor from anemia may be
present. Ecchymoses or purpura from thrombocytopenia may be evident.
Bony tenderness is not uncommon in MM, resulting from focal lytic destructive bone lesions or
pathologic fracture. Pain without tenderness is typical. Pathologic fractures may be observed. In
general, painful lesions that involve at least 50% of the cortical diameter of a long bone or
lesions that involve the femoral neck or calcar femorale are at high (50%) risk for a pathologic
fracture. The risk of fracture is lower in upper-extremity lesions than in lower-extremity lesions.
Even a small cortical defect can decrease torsional strength by as much as 60% (stress riser
effect).
Neurologic findings may include a sensory level change (ie, loss of sensation below a
dermatome corresponding to a spinal cord compression), neuropathy, myopathy, a Tinel sign, or
a Phalen sign due to carpel tunnel compression secondary to amyloid deposition.
Extramedullary plasmacytomas, which consist of soft-tissue masses of plasma cells, are not
uncommon. Plasmacytomas have been described in almost every site in the body. Although the
aerodigestive tract is the most common location, reports also describe orbital, ear canal,
cutaneous, gastric, rectal, prostatic, and retroperitoneal lesions.
On evaluation of the abdomen, hepatosplenomegaly may be discovered. Cardiovascular system
examination may reveal cardiomegaly secondary to immunoglobulin deposition.
Amyloidosis may develop in some patients with MM. The characteristic physical examination
findings that suggest amyloidosis include the following:

Shoulder pad sign

Macroglossia

Typical skin lesions

Postprotoscopic peripalpebral purpura

The shoulder pad sign is defined by bilateral swelling of the shoulder joints secondary to
amyloid deposition. Physicians describe the swelling as hard and rubbery. Amyloidosis may also
be associated with carpal tunnel syndrome and subcutaneous nodules.
Macroglossia may occur secondary to amyloid deposition in the tongue and is a common finding
in patients with amyloidosis (see the image below).

Amyloidosis infiltrating the tongue in

multiple myeloma. All images and text are (c) 2002 by the American Society of Hematology. All
rights reserved.
Skin lesions that have been described as waxy papules or nodules may occur on the torso, ears,
or lips.
Postprotoscopic peripalpebral purpura strongly suggests amyloidosis. Patients may develop
raccoonlike dark circles around their eyes following any procedure that parallels a prolonged
Valsalva maneuver. The capillary fragility associated with amyloidosis may account for this
observation. In the past, this correlation was observed when patients underwent rectal biopsies to
make the diagnosis.

Renal failure and insufficiency are seen in 25% of patients with MM,[24] including the following
manifestations:

Myeloma kidney syndrome with multiple etiologies

Amyloidosis with light chains

Nephrocalcinosis due to hypercalcemia

Anemia, neutropenia, or thrombocytopenia is due to bone marrow infiltration of plasma cells.

Thrombosis and Raynaud phenomenon due to cryoglobulinemia may be present.
Bone disease may result in the following:

Severe bone pain, pathologic fracture due to lytic lesions: Lytic disease or fracture may
be observed on plain radiographs.

Increased bone resorption leading to hypercalcemia

Spinal cord compression: This is one of the most severe adverse effects of MM. Reports
indicate that as many as 20% of patients develop spinal cord compression at some point
during the course of their disease. Symptoms typically include back pain, weakness or
paralysis in the legs, numbness, or dysesthesias in the lower extremities. However,
depending on the level of involvement, patients may present with upper-extremity
symptoms.

Radiculopathy and/or cord compression may occur because of skeletal destruction and nerve
compression.
Bacterial infection may develop; it is the leading cause of death in patients with myeloma. The
highest risk is in the first 2-3 months of chemotherapy.
Purpura, retinal hemorrhage, papilledema, coronary ischemia, seizures, and confusion may occur
as a result of hyperviscosity syndrome.
Hypercalcemia may cause polyuria and polydipsia, muscle cramps, constipation, and a change in
the patients mental status.

Complication
Renal failure and insufficiency are seen in 25% of patients with MM,[24] including the following
manifestations:

Myeloma kidney syndrome with multiple etiologies

Amyloidosis with light chains

Nephrocalcinosis due to hypercalcemia

Anemia, neutropenia, or thrombocytopenia is due to bone marrow infiltration of plasma cells.

Thrombosis and Raynaud phenomenon due to cryoglobulinemia may be present.
Bone disease may result in the following:

Severe bone pain, pathologic fracture due to lytic lesions: Lytic disease or fracture may
be observed on plain radiographs.

Increased bone resorption leading to hypercalcemia

Spinal cord compression: This is one of the most severe adverse effects of MM. Reports
indicate that as many as 20% of patients develop spinal cord compression at some point
during the course of their disease. Symptoms typically include back pain, weakness or
paralysis in the legs, numbness, or dysesthesias in the lower extremities. However,
depending on the level of involvement, patients may present with upper-extremity
symptoms.

Radiculopathy and/or cord compression may occur because of skeletal destruction and nerve
compression.
Bacterial infection may develop; it is the leading cause of death in patients with myeloma. The
highest risk is in the first 2-3 months of chemotherapy.
Purpura, retinal hemorrhage, papilledema, coronary ischemia, seizures, and confusion may occur
as a result of hyperviscosity syndrome.
Hypercalcemia may cause polyuria and polydipsia, muscle cramps, constipation, and a change in
the patients mental status.

Differential Diagnosis
The most widely accepted schema for the diagnosis of multiple myeloma (MM) uses particular
combinations of laboratory, imaging, and procedure findings as diagnostic criteria. (See
Workup.) The findings are as follows:

I = Plasmacytoma on tissue biopsy

II = Bone marrow with greater than 30% plasma cells

III = Monoclonal globulin spike on serum protein electrophoresis, with an

immunoglobulin (Ig) G peak of greater than 3.5 g/dL or an IgA peak of greater

than 2 g/dL, or urine protein electrophoresis (in the presence of amyloidosis)

result of greater than 1 g/24 h

a = Bone marrow with 10-30% plasma cells

b = Monoclonal globulin spike present but less than category III

c = Lytic bone lesions

d = Residual IgM level less than 50 mg/dL, IgA level less than 100 mg/dL, or
IgG level less than 600 mg/dL

The following combinations of findings are used to make the diagnosis of MM:

I plus b, c, or d

II plus b, c, or d

III plus a, c, or d

a plus b plus c

a plus b plus d

Criteria for the diagnosis of active (symptomatic) MM are as follows[2] :

Clonal bone marrow plasma cells 10% or

Biopsy-proven bony or extramedullary plasmacytoma and

One or more myeloma-defining events

Myeloma-defining events include the following[2] :

Serum calcium level >0.25 mmol/L (>1 mg/dL) higher than the upper limit of
normal or >2.75 mmol/L (>11 mg/dL)

Renal insufficiency (creatinine >2 mg/dL [>177 mol/L] or creatinine

clearance <40 mL/min)

Anemia (hemoglobin <10 g/dL or hemoglobin >2 g/dL below the lower limit of
normal)

One or more osteolytic bone lesions on skeletal radiography, CT, or PET-CT

Clonal bone marrow plasma cells 60%

Abnormal serum free light chain (FLC) ratio 100 (involved kappa) or <0.01
(involved lambda)

One or more focal >5 mm lesions on MRI scans

Active disease may also be indicated by repeated infections, amyloidosis, or hyperviscosity.

Indolent MM is a subset of MM with the following features:

Bone disease absent (or very limited)

Performance status greater than 70%

Hemoglobin level greater than 10 g/dL

Serum calcium level within the reference range

Creatinine level <2 mg/dL

No infections

Low M protein levels (ie, <7 g/dL for IgG, <5 g/dL for IgA)

Smoldering (asymptomatic) MM is similar to indolent MM. Diagnostic criteria for smoldering

MM are as follows[2] :

Serum monoclonal protein: IgG or IgA 3 g/dL, or

Bence-Jones protein 500 mg/24 h and/or

Clonal bone marrow plasma cells 10%60% and

Absence of myeloma-defining events or amyloidosis

The NCCN recommends that a patient whose bone survey is negative should be assessed for
bone disease with whole-body MRI or PET/CT.[2]
Polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes
(POEMS) syndrome is a rare syndrome consisting of polyneuropathy, organomegaly,
endocrinopathy, M protein deviations, and skin changes.
Amyloidosis is often secondary to MM, but it may develop without MM. Patients with
amyloidosis typically lack sufficient numbers of plasma cells in the bone marrow or sufficiently
high levels of M protein to meet the diagnostic criteria for MM.

Differential Diagnoses

Malignant Lymphoma

Metastatic Bone Disease

Monoclonal Gammopathies of Undetermined Significance

Waldenstrom Macroglobulinemia

WORKUP
Approach Consideration
The International Myeloma Workshop developed guidelines for standard investigative workup in
patients suspected to have multiple myeloma. These guidelines include the following:[1]

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 beta-2 microglobulin, albumin, and lactate dehydrogenase measurement

Standard metaphase cytogenetics

Fluorescent in situ hybridization

Skeletal survey

Magnetic resonance imaging

Consider the risk of renal failure, especially in the setting of contrast medium injection for
imaging studies. Take care to limit patients exposure and maintain hydration.

Blood Studies
Perform a complete blood count (CBC) to determine if the patient has anemia,
thrombocytopenia, or leukopenia. The CBC and differential may show pancytopenia. The
reticulocyte count is typically low. Peripheral blood smears may show rouleau formation.

The erythrocyte sedimentation rate (ESR) is typically increased. Coagulation studies may yield
abnormal results.
Obtain a comprehensive metabolic panel to assess levels of the following:

Total protein, albumin, and globulin

Blood urea nitrogen (BUN) and creatinine

Uric acid (will be elevated if the patient has high cell turnover or is dehydrated

Urine Collection
Obtain a 24-hour urine collection for quantification of the Bence Jones protein (ie,
lambda light chains), protein, and creatinine clearance. Quantification of proteinuria
is useful for the diagnosis of MM (>1 g of protein in 24 h is a major criterion) and for
monitoring the response to therapy. Creatinine clearance can be useful for defining
the severity of the patients renal impairment.

Electrophoresis and Immunofixation

Serum protein electrophoresis (SPEP) is used to determine the type of each protein present and
may indicate a characteristic curve (ie, where the spike is observed). Urine protein
electrophoresis (UPEP) is used to identify the presence of the Bence Jones protein in urine.
Immunofixation is used to identify the subtype of protein (ie, IgA lambda).
The 2015 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.[2]
Chemical screening, including calcium and creatinine SPEP, immunofixation, and
immunoglobulin quantitation, may show azotemia, hypercalcemia, an elevated alkaline
phosphatase level, and hypoalbuminemia. A high lactate dehydrogenase (LDH) level is
predictive of an aggressive lymphomalike course.
SPEP is a useful screening test for detecting M proteins. An M component is usually detected by
means of high-resolution SPEP. The kappa-to-lambda ratio has been recommended as a
screening tool for detecting M-component abnormalities. An M-component serum concentration
of 30 g/L is a minimal diagnostic criterion for MM. In about 25% of patients, M protein cannot
be detected by using SPEP.
Routine urinalysis may not indicate the presence of Bence Jones proteinuria. Therefore, a 24hour urinalysis by means of UPEP or immunoelectrophoresis may be required. UPEP or
immunoelectrophoresis can also be used to detect an M component and kappa or lambda light

chains. The most important means of detecting MM is electrophoretic measurement of

immunoglobulins in both serum and urine.

Quantitative Immunoglobulin Levels (IgG, IgA, IgM)

Suppression of nonmyelomatous immunoglobulin is a minor diagnostic criterion for MM. The
level of MM protein (ie, M protein level), as documented by the immunoglobulin level, can be
useful as a marker to assess the response to therapy.

Beta-2 Microglobulin and C-Reactive Protein

Beta-2 microglobulin is a surrogate marker for the overall body tumor burden. The level of beta2 microglobulin is increased in patients with renal insufficiency without MM, which is one
reason that it is a useful prognosticator in MM.[21] (See Prognosis.) The prognosis of patients with
MM and impaired renal function is reduced.
C-reactive protein (CRP) is a surrogate marker of interleukin (IL)-6 activity. IL-6 is often
referred to as the plasma cell growth factor. Like beta-2 microglobulin, CRP is useful for
prognostication.[21] (See Prognosis.)

Serum Viscosity
Check the serum viscosity in patients with central nervous system (CNS) symptoms, nosebleeds,
or very high M protein levels. These findings may indicate hyperviscosity syndrome.

Radiography
Simple radiography is indicated for the evaluation of skeleton lesions, and a skeletal survey is
performed when myeloma is in the differential diagnosis. Plain radiography remains the gold
standard imaging procedure for staging newly diagnosed and relapsed myeloma patients,
according to an International Myeloma Working Group consensus statement.[25]
Perform a complete skeletal series at diagnosis of MM, including the skull (a very common site
of bone lesions in persons with MM; see the image below), the long bones (to look for
impending fractures), and the spine.

Radiograph of the skull

demonstrating a typical lytic lesion in multiple myeloma. All images and text are (c)
2002 by the American Society of Hematology. All rights reserved.

Conventional plain radiography can usually depict lytic lesions. Such lesions appear as multiple,
rounded, punched-out areas found in the skull, vertebral column, ribs, and/or pelvis. Less
common but not rare sites of involvement include the long bones. Plain radiographs can be
supplemented by computed tomography (CT) scanning to assess cortical involvement and risk of
fracture. Diffuse osteopenia may suggest myelomatous involvement before discrete lytic lesions
are apparent.
Findings from this evaluation may be used to identify impending pathologic fractures, allowing
physicians the opportunity to repair debilities and prevent further morbidity.

Magnetic Resonance Imaging

Magnetic resonance imaging (MRI) is useful in detecting thoracic and lumbar spine lesions,
paraspinal involvement, and early cord compression. Findings from MRI of the vertebrae are
often positive when plain radiographs are not. MRI can depict as many as 40% of spinal
abnormalities in patients with asymptomatic gammopathies in whom radiographic studies are
normal. For this reason, evaluate symptomatic patients with MRI to obtain a clear view of the
spinal column and to assess the integrity of the spinal cord.

Positron Emission Tomography

Comparative studies have suggested the possible utility of positron emission tomography (PET)
scanning in the evaluation of MM.[26, 27] For example, a comparison study of PET scanning and
whole-body MRI in patients with bone marrow biopsy-proven multiple myeloma found that
although MRI had higher sensitivity and specificity than PET in the assessment of disease

activity, when used in combination and with concordant findings, the 2 modalities had a
specificity and positive predictive value of 100%.
These researchers suggest that the combination of modalities may be valuable for assessing the
effectiveness of treatment, when aggressive and expensive regimens are used.[27] However, PET
scanning has not yet been integrated into standard practice. The International Myeloma Working
Group notes the potential usefulness of PET scanning in selected patients but suggests that such
studies ideally should be performed in the context of a clinical trial.[25]
A study by Zamagni et al found that 18-F fluorodeoxyglucose (FDG) PET/CT scan findings were
reliable predictors of prognosis among patients with multiple myeloma who had undergone
thalidomide-dexamethasone induction therapy and double autotransplantation.[28]

Bone Scan
Do not use bone scans to evaluate MM. Cytokines secreted by MM cells suppress osteoblast
activity; therefore, typically, no increased uptake is observed. On technetium bone scanning,
more than 50% of lesions can be missed.

Aspiration and Biopsy

MM is characterized by an increased number of bone marrow plasma cells. Plasma cells show
low proliferative activity, as measured by using the labeling index. This index is a reliable
parameter for the diagnosis of MM. High values are strongly correlated with progression of the
disease.
Obtain bone marrow aspirate and biopsy samples from patients with MM to calculate the
percentage of plasma cells in the aspirate (reference range, up to 3%) and to look for sheets or
clusters of plasma cells in the biopsy specimen. Bone marrow biopsy enables a more accurate
evaluation of malignancies than does bone marrow aspiration.

Histologic Findings
Plasma cells are 2-3 times larger than typical lymphocytes; they have eccentric nuclei that are
smooth (round or oval) in contour with clumped chromatin and have a perinuclear halo or pale
zone (see the image below). The cytoplasm is basophilic.

Bone marrow aspirate

demonstrating plasma cells of multiple myeloma. Note the blue cytoplasm,
eccentric nucleus, and perinuclear pale zone (or halo). All images and text are (c)
2002 by the American Society of Hematology. All rights reserved.

Many MM cells have characteristic, but not diagnostic, cytoplasmic inclusions, usually
containing immunoglobulin. The variants include Mott cells, Russell bodies, grape cells, and
morula cells. Bone marrow examination reveals plasma cell infiltration, often in sheets or clumps
(see the image below). This infiltration is different from the lymphoplasmacytic infiltration
observed in patients with Waldenstrom macroglobulinemia.

Bone marrow biopsy

demonstrating sheets of malignant plasma cells in multiple myeloma. All images
and text are (c) 2002 by the American Society of Hematology. All rights reserved.

Analysis of bone biopsy specimens may reveal plasmacytic, mixed cellular, or plasmablastic
histologic findings. Approximate median survival by histologic type is as follows:

Plasmacytic - 39.7 months

Mixed cellular - 16.1 months

Plasmablastic - 9.8 month

Cytogenetic Analysis
Cytogenetic analysis of the bone marrow may contribute significant prognostic information in
multiple myeloma. The most significant cytogenetic abnormality appears to be deletion of
17p13. This abnormality is associated with shorter survival, more extramedullary disease, and
hypercalcemia. This locus is the site of the TP53 tumor suppressor gene. Chromosome 1
abnormalities and c-myc defects are also significant prognostic factors in multiple myeloma.
Although not as well defined as in other hematologic malignancies, such as acute leukemia, riskadapted therapy based on cytogenetic abnormalities is at the forefront of myeloma research.

Staging
Staging is a cumulative evaluation of all of the diagnostic information garnered and is a useful
tool for stratifying the severity of patients disease. Currently, two staging systems for multiple
myeloma are in use: the Salmon-Durie system, which has been widely used since 1975; and the
International Staging System, developed by the International Myeloma Working Group and
introduced in 2005.[29, 30]
Salmon-Durie staging system

The Salmon-Durie classification of MM is based on three stages and additional

subclassifications.
In stage I, the MM cell mass is less than 0.6 1012 cells/m2, and all of the following are present:

Hemoglobin value greater than 10 g/dL

Serum calcium value less than 12 mg/dL (normal)

Normal bone structure (scale 0) or only a solitary bone plasmacytoma on

radiographs

Low M-component production rates (IgG value less than 5 g/dL, IgA value less
than 3 g/dL, urine light-chain M component on electrophoresis less than 4
g/24 h)

In stage II, the MM cell mass is 0.6-1.2 1012 cells/m2. The other values fit neither those of stage
I nor those of stage III.
In stage III, the MM cell mass is greater than 1.2 1012 cells/m2, and all of the following are
present:

Hemoglobin value equal to 8.5 g/dL

Serum calcium value greater than 12 mg/dL

Advanced lytic bone lesions (scale 3) on radiographs

High M-component production rates (IgG value greater than 7 g/dL, IgA value
greater than 5 g/dL, urine light-chain M component on electrophoresis greater
than 12 g/24 h)

Subclassification A includes relatively normal renal function (serum creatinine value < 2 mg/dL),
whereas subclassification B includes abnormal renal function (serum creatinine value > 2 mg/dL)
Median survival is as follows:

Stage I, >60 months

Stage II, 41 months

Stage III, 23 months

Disease in subclassification B has a significantly worse outcome (eg, 2-12 mo survival in 4

separate series).
International Staging System

The International Staging System of the International Myeloma Working Group is also based on
three stages.
Stage I consists of the following:

Beta-2 microglobulin less than or equal to 3.5 g/dL and albumin 3.5 g/dL

CRP 4.0 mg/dL

Plasma cell labeling index < 1%

Absence of chromosome 13 deletion

Low serum IL-6 receptor

Long duration of initial plateau phase

Stage II consists of the following:

Beta-2 microglobulin level 3.5 to < 5.5 g/dL, or

Beta-2 microglobulin < 3.5 g/dL and albumin < 3.5 g/dL

Stage III consists of the following:

Beta-2 microglobulin of 5.5 g/dL or more

Median survival is as follows:

Stage I, 62 months

Stage II, 44 months

Stage III, 29 months

Treatment
Approach Considerations
Physicians must understand both the natural history of multiple myeloma (MM) and the
limitations of current therapy in the treatment of the disease. The objective in therapy is to obtain
the deepest response in the first round by choosing the appropriate regimen; this should lead to
better overall survival in both transplant and non-transplant patients. In situations with no
definite data on therapeutic choices, participation in clinical trials should be encouraged. For a
summary of treatment approaches to MM, see Multiple Myeloma Treatment Protocols.
Progression of disease and timing of treatment

An important study by Dimopoulos and associates evaluated the risk of disease progression in
asymptomatic subjects with MM.[31] This study evaluated 638 consecutive untreated subjects with
MM. Of these subjects, 95 were asymptomatic and were not treated until their M protein value
rose to greater than 5 g/dL. These subjects developed increased bone disease or symptoms of
bone disease.
The individuals in this group were designated as either low risk (ie, no bone disease, M protein
level <3 g/dL, or Bence Jones protein level <5 g/24 h) or high risk (ie, lytic bone disease and
serum M protein level >3 g/dL or Bence Jones protein level >5 g/24 h). Intermediate-risk
subjects did not have bone disease or an M protein level greater than 3 g/dL or a Bence Jones
protein level greater than 5 g/24 h. The patients were evaluated every 2 months.
The median time for disease progression was 10 months in the high-risk group, 25 months in the
intermediate-risk group, and 61 months in the low-risk group.[31] At the time of progression,
subjects were treated with standard chemotherapy. Their response rates did not significantly
differ from those of unselected populations. Median survival time from the institution of

chemotherapy did not differ among the groups. Thus, asymptomatic subjects did not benefit from
early treatment, and delayed treatment did not affect treatment efficacy (ie, survival).
A systematic review by He et al demonstrated a reduction in vertebral compressions and time to
progression with early systemic treatment for asymptomatic patients, but this study also revealed
an increase in acute leukemia in the early treatment group.[32] The failure to demonstrate
improved survival may be due to the small number of patients studied.
The 2009 International Myeloma Workshop concluded that detection of any cytogenic
abnormality suggests higher-risk disease, including chromosomal 13 or 13q deletion, t(4;14), and
del17p and fluorescence in situ hybridization detection of t(4;14), t(14;16), and del17p.[33]
Fluorescence in situ hybridization detection of 13q deletion alone is not considered a high-risk
feature. International Staging System stages II and II and high serum beta(2)-microglobulin
levels are suggestive of higher risk disease.
A study by Klein et al determined that the prognostic significance of t(4;14) may be eliminated
or lessened among patients who receive lenalidomide and dexamethasone; however, del(17p13)
and +1q21 are still associated with a dismal overall survival.[34] A study by Neben et al concludes
that long-term administration of bortezomib in patients with del(17p13) may result in better
overall and progression-free survival.[35]
Current therapeutic approaches

Overall, the care of patients with MM is complex and should focus on treatment of the disease
process and any associated complications.[3, 4, 5] Although MM remains incurable, several drug
therapies are valuable in the treatment of patients with MM, as are autologous stem cell
transplantation, radiation, and surgical care in certain cases.
Several studies are evaluating the role of treatment in patients with high-risk smoldering multiple
myeloma (SMM). Previous smaller studies evaluating thalidomide did not show a clear evidence
of benefit with treatment in patients with SMM; however, these included patients with all risk
levels of SMM.
In a phase III trial that was restricted to patients with high-risk SMM, the PETHEMA group
found evidence of benefit from treatment with lenalidomide versus observation. After a median
follow-up of 40 months, study patients who were randomized to lenalidomide and
dexamethasone induction followed by lenalidomide maintenance demonstrated significantly
prolonged median time to progression (median not reached vs 21 months) and higher 3-year
survival rate (94% vs. 80%).[36] Larger trials are ongoing to validate this benefit. Concern for
second primary malignancies (SPMs) with the use of lenalidomide is also a significant issue.
Consequently, watchful observation and frequent monitoring remains the standard of care for
patients with SMM.

Patients with MM for whom therapy is indicated typically receive chemotherapy. Greater
understanding of the cell biology of MM and the ability to identify prognostic factors has led to
the increasing individualization of treatment for affected patients. Physicians treat many patients
with high-dose therapy and peripheral blood or bone marrow stem cell transplantation.
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[2] :

Bortezomib/dexamethasone

Bortezomib/cyclophosphamide/dexamethasome

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 should be assessed for response after two cycles of one of the above regimens.
Patients with MM who are treated with lenalidomide or thalidomide are at significantly increased
risk for thrombotic events, and many physicians incorporate anticoagulation strategies in their
management. A study by Palumbo et al determined that aspirin and low-dose warfarin had
similar efficacy in reducing serious thromboembolic events, acute cardiovascular events, and
sudden deaths in patients with myeloma receiving thalidomide-based regimens compared with
low-molecular weight heparin, except in elderly patients.[37]
As monotherapy or in combination, interferon alfa-2b and prednisone modestly prolong the
disease-free interval.
A study by the Southwest Oncology Group compared lenalidomide plus dexamethasone to
placebo plus dexamethasone in patients with newly diagnosed myeloma.[38] The study determined
that lenalidomide plus dexamethasone had superior 1-year progression-free survival, overall
response rate, and very good partial response rate, suggesting that it is safe and effective as initial
therapy for patients with newly diagnosed myeloma. In February 2015, the FDA approved an
expanded indication for MM to included newly diagnosed patients. The original indication was
for patients who had received at least 1 prior therapy.

A phase III randomized, open-label trial of 119 patients with high-risk smoldering MM found
that early treatment with lenalidomide plus dexamethasone, followed by maintenance therapy
with lenalidomide, delayed progression to symptomatic disease and increased overall survival.[39,
40]

Adjunctive therapy for MM includes radiation therapy to target areas of pain, impending
pathologic fracture, or existing pathologic fracture. Bisphosphonate therapy serves as
prophylaxis (ie, primary, secondary) against skeletal events (eg, hypercalcemia, spinal cord
compression, pathologic fracture, need for surgery, need for radiation). Evidence suggests that it
may be effective in treating bone pain and in decreasing the likelihood of lesion recurrence.[41, 42,
43]

Adjunctive therapy may also include any of the following, as appropriate:

Erythropoietin

Corticosteroids

Surgical intervention

Plasmapheresis

Bone disease guidelines

In May 2013, the International Myeloma Working Group released practice guidelines for the
management of MM-related bone disease.[44] The recommendations, which were based on a
review of the literature through August 2012 and a consensus of an interdisciplinary panel of
experts, include the following:

Consideration of bisphosphonates (BPs) in all patients with MM receiving firstline antimyeloma therapy, regardless of presence of osteolytic bone lesions
on conventional radiography

Intravenous (IV) zoledronic acid or pamidronate for preventing skeletalrelated events in patients with MM

Because of its potential antimyeloma effects and survival benefits, zoledronic

acid is preferred in newly diagnosed patients with MM

Bisphosphonates should be administered IV every 3 to 4 weeks during initial

therapy, but preventive strategies must be instituted to avoid renal toxicity or
osteonecrosis of the jaw

Zoledronic acid or pamidronate should be continued in patients with active

disease and should be resumed after disease relapse

Kyphoplasty should be considered for symptomatic vertebral compression

fractures

Orthopedic consultation should be sought for long-bone fractures, spinal cord

compression, and vertebral column instability

Low-dose radiation therapy can be used for palliation of uncontrolled pain,

impending pathologic fracture, or spinal cord compression

Chemotherapy and Immunosuppression

In patients with symptomatic MM, chemotherapy is required. In asymptomatic patients with
MM, treatment is delayed until disease clinically progresses or until serum or urine levels of M
protein substantially increase.
The M-component level in serum and/or urine is an indicator of the tumor burden; its reduction
after chemotherapy is used as a sign of response. A 50% reduction in M-component is considered
a good clinical response (according to the Chronic Leukemia-Myeloma Task Force). MP induces
a response in 50-60% of patients with MM. Disappearance of the M component on
electrophoresis occurs in only 3% of patients, and cure is extraordinarily rare.
The first step before starting therapy in MM is to determine whether a patient is a candidate for
an autologous stem cell transplant. Eligibility depends primarily on the patients age and
comorbidities. Typically an age of 65 years is used as a cut-off point for transplant eligibility.
Thus, treatment for MM is best looked at in terms of the following three categories of patients:

Young, newly diagnosed patients who are potential transplant candidates

High-risk patients who are potential transplant candidates

Newly diagnosed elderly patients who are not transplant candidates

Young, newly diagnosed patients who are potential transplant candidates

Conventionally, VAD (vincristine, doxorubicin [Adriamycin], and dexamethasone)

chemotherapy has been used to decrease the tumor burden in MM as preparation for
transplantation. VAD is administered as a 4-day continuous intravenous infusion of vincristine
and doxorubicin, with 4 daily oral doses of dexamethasone. Patients require a central venous
catheter for delivery of the infusion. In selected patients, this therapy can be performed in an
outpatient setting.
Many researchers feel that the high-dose steroid component of VAD accounts for much of its
efficacy. In some patients, high-dose dexamethasone alone may produce significant clinical
responses.

Significant concerns with the use of infusion therapy include the risk of soft-tissue injury if the
chemotherapy agent infiltrates, the risk of cardiac injury from the doxorubicin, and the risk of
infection or hyperglycemia from the high-dose steroids. Some patients also experience adverse
central nervous system (CNS) effects from the high-dose steroids. Given these risks, and the
higher response rates of new agents (thalidomide, lenalidomide, and bortezomib), VAD is now
considered suboptimal treatment.
Thalidomide has proved effective against MM. The superiority of induction regimens containing
thalidomide was demonstrated in randomized trials that compared VAD with thalidomide plus
dexamethasone[45] ; thalidomide and doxorubicin plus dexamethasone[46] ; and thalidomide plus
VAD.[47]
Thalidomide has a well-established role as first-line therapy, either as a single agent or in
combination with steroids in patients with MM. The toxicity of this drug is predominantly
sensory neuropathy, and because of the drugs teratogenicity, close monitoring is required to
avoid inadvertent administration during pregnancy.
An analogue of thalidomide, lenalidomide (Revlimid) is now a standard component of MM
therapy. In July 2013, Celgene Corp announced that a phase III trial of lenalidomide (Revlimid)
met the main goal of improving progression-free survival in patients with newly diagnosed MM.
[48]
The drug was already approved for use in previously treated MM, mantle cell lymphoma, and
transfusion-dependent anemia caused by myelodysplastic syndromes.
In the late-stage study, treatment with lenalidomide combined with dexamethasome in patients
with newly diagnosed MM resulted in a significant improvement in survival without the cancer
worsening, compared to treatment with a regimen consisting of melphalan, prednisone and
thalidomide (MPT).[48] Evaluation of safety and efficacy is ongoing.
In a randomized, double-blind, placebo-controlled trial, lenalidomide plus high-dose
dexamethasone proved superior to high-dose dexamethasone alone as treatment for newly
diagnosed MM.[45] The overall response rate was 84% in the lenalidomide plus high-dose
dexamethasone group versus 53% in the high-dose dexamethasone group, with 22% of patients
achieving complete remission in the lenalidomide plus high-dose dexamethasone arm.
Progression-free survival and overall survival favored lenalidomide plus high-dose
dexamethasone, but 12-month survival for both arms was >90%. A very important observation,
however, was the high incidence of deep venous thrombosis in the lenalidomide plus high-dose
dexamethasone arm.[45]
In another randomized trial of lenalidomide plus high-dose dexamethasone (LD) versus
lenalidomide plus low-dose dexamethasone (Ld) in newly diagnosed MM, Rajkumar found that

the overall response rate for LD was superior (82%) to that for Ld (70%), with an improvement
in the VGPR-or-better rate for LD (44% vs 26%) evaluated after 4 months.[49]
When best overall response was compared, LD again was superior, with an overall response rate
of 82% compared with 71% for Ld. However, there was no difference in progression-free
survival between the 2 arms. Overall survival continued to favor the Ld arm; however, for
patients younger than 65 years, there was no benefit in survival for Ld over LD.[49]
The second interim analysis from Rajkumar et al was completed after 1 year; the data
demonstrated that lenalidomide plus low-dose dexamethasone (Ld) was superior to lenalidomide
plus high-dose dexamethasone (LD).[50] Overall survival was 96% in the Ld group compared with
87% in the LD group. As a result, the trial was stopped, and patients on high-dose therapy were
crossed over to low-dose therapy.
Another trial assessed the safety and efficacy of the combination regimen clarithromycin
(Biaxin), lenalidomide (Revlimid), and dexamethasone (BiRD) as first-line therapy for MM.[51]
Of the 72 patients enrolled, 65 had an objective response (90.3%). A combined stringent and
conventional complete response rate of 38.9% was achieved, and 73.6% of the patients achieved
at least a 90% decrease in M-protein levels. BiRD was found to be an effective regimen with
manageable side effects in the treatment of symptomatic, newly diagnosed MM.
Patients tolerate lenalidomide therapy well, and nausea is usually minimal. Patients typically
experience total alopecia, but other adverse effects (eg, peripheral neurotoxicity, constipation)
are usually mild. Pancytopenia is expected, but is not severe enough to require hospitalization for
infection or transfusion unless the patient also has some other cause of bone marrow suppression.
Bortezomib, a proteosome inhibitor, has shown striking activity against MM. Objective
responses as high as 27.7% in patients with relapsed and heavily pretreated MM[52] led to its
approval by the US Food and Drug Administration (FDA) in 2003. Subsequent studies reported
response rates as high as 80% when bortezomib is combined with melphalan.
A randomized trial compared bortezomib plus dexamethasone with VAD for induction, showing
response rates of 80% for the bortezomib plus dexamethasone arm versus 62.8% for the VAD
arm.[53] This regimen has been shown to be active not only before but also after transplantation.
Following high-dose therapy and autologous transplantation, the rate of very good partial
response or better continued to favor bortezomib plus dexamethasone. This benefit was observed
independent of beta-2 microglobulin or adverse cytogenetic risk groups.
Similarly, a superior response rate was seen when the combination of bortezomib, thalidomide,
and dexamethasone was compared with thalidomide plus dexamethasone in a large phase III
study: 93% in the bortezomib-thalidomide-dexamethasone arm versus 80% in the thalidomide-

dexamethasone arm, in which patients went on to receive tandem autologous stem cell
transplantation.[54] As in other studies, response was independent of adverse prognostic risk
factors.
The phase III Velcade as initial standard therapy in MM (VISTA) trial found the combined
treatment of bortezomib, melphalan, and prednisone (VMP) significantly prolongs overall
survival compared with melphalan and prednisone (MP) after lengthy follow-up and extensive
subsequent antimyeloma therapy.[55]
A study by Harousseau et al confirms the role of bortezomib in the initial nonintensive
management of MM.[56]
A study by Sher et al found that a combination of bortezomib (V), pegylated liposomal
doxorubicin (D), and thalidomide (T), known as the VDT regimen, had overall response rate and
complete response plus near complete response rates of 78% and 35%, respectively.[57] The study
concluded VDT was a tolerable and effective regimen that may induce high response rates
among patients considered to be poor candidates for steroid-based treatments.
A notable outcome of this study showed that first-line bortezomib use does not induce more
resistant relapse. VMP used upfront appears more beneficial than first treating with conventional
agents and saving bortezomib-based and other novel agent-based treatment until relapse.[55]
Bortezomib appears to be of especial benefit in patients with plasma cell leukemia and renal
failure. The predominant adverse effects were neuropathy, hypotension, and thrombocytopenia.
Despite these results, the exact timing of bortezomib administration in the treatment plan of
patients with newly diagnosed multiple myeloma is still evolving through ongoing research.
Varicella-zoster virus reactivation occurs in 10%-60% of patients with MM treated with
bortezomib. Antiviral prophylaxis (eg, acyclovir, 400 mg daily) has been found effective for
preventing these reactivations.[58]
The FDA approved administration of bortezomib by the subcutaneous route in January 2012. A
study by Moreau et al found that the efficacy of subcutaneous bortezomib is not inferior to the
efficacy of standard intravenous administration and that the safety profile of the subcutaneous
administration is improved. Moreau also observed the incidence of grade 2 or greater peripheral
neuropathy was 24% for SC compared with 41% for IV; grade 3 or higher occurred in 6% when
administered SC vs 16% for IV administration.[59] Starting therapy with SC administration may
be considered for patients with pre-existing or at high risk of peripheral neuropathy.
A study by Mateos et al found that patients with cytogenetic abnormalities had similar response
to bortezomib therapy but shorter survival. The authors concluded that the present treatment

schema does not overcome the negative prognosis associated with high-risk cytogenetic
abnormalities.[60]
Overall, the data on these novel agents are very encouraging and promising. Nevertheless,
oncologists will need further studies to help define the exact timing and role of novel agents in
the treatment of MM.
High-risk patients who are potential transplant candidates

High-risk MM patients are those with advanced-stage disease (stage III according to the
International Staging System); those with poor cytogenetics, such as t (4:14), t (14:16), and t
(14:20), deletion of chromosome 13, inactivation of TP53; and those with a complex karyotype.
Patients with very high proliferative rates are also included in this classification.
This group represents about 25% of those with newly diagnosed MM, with an expected median
survival of 2 years or less. Although they respond to traditional therapies for induction, these
individuals tend to relapse rapidly. Therefore, novel agents should be considered up front for
these patients.
The advent of thalidomide, lenalidomide, and bortezomib has substantially improved outcomes
in these high-risk groups. In fact, these novel agents appear to overcome the influence
contributed by high-risk cytogenetics.[61, 62] Once a response has been achieved, then these
patients can be brought to autologous stem cell transplantation.
Newly diagnosed elderly patients who are not transplant candidates

All of the above regimens may be used in patients who are not being considered for autologous
stem cell transplantation. The following, however, can only be used in patients not going for
transplantation, as they impair stem cell reserve.
The gold standard has been the MP regimen as far back as the 1950s. This regimen typically
consists of melphalan 9 mg/m2 and prednisone 100 mg given on days 1-4, with courses repeated
at 4- to 6-week intervals for at least 1 year. A meta-analysis of 4930 patients from 20 randomized
trials compared MP to other drug combinations and showed a significantly higher response rate
(60%) with this combination, with a response duration of 18 months and overall survival of 24 to
36 months.[63]
A three-arm study looked at MP plus thalidomide versus MP versus VAD induction, followed by
high-dose melphalan and autologous stem cell transplantation in 447 patients between ages 65
and 75 years.[64] The patients were randomized, with overall survival as the primary endpoint.
The response rate in the MP plus thalidomide arm and transplantation arm was similar; the

complete response rate was significantly better in the MP plus thalidomide and the
transplantation arms than in the MP arm.[64]
MP plus thalidomide is now recommended as first-line treatment. MP plus lenalidomide has also
shown promise.[65]
Hulin et al conducted a randomized, placebo-controlled, phase III trial to investigate the efficacy
of adding thalidomide to MP in 229 elderly patients (> 75 y) newly diagnosed with MM.[66]
During each 6-week cycle, melphalan 0.2 mg/kg/d plus prednisone 2 mg/kg/d was given to all
patients on days 1-4 for 12 cycles. In addition, patients were randomly assigned to receive
thalidomide 100 mg/d PO (n = 113) or placebo (n = 116), continuously for 72 weeks.
Overall survival was significantly longer in the group that received thalidomide (median, 44 mo)
compared with placebo (median, 29.1 mo).[66] Progression-free survival was also significantly
prolonged in the thalidomide group (median, 24.1 mo) relative to the placebo group (median,
18.5 mo). However, the investigators noted peripheral neuropathy and neutropenia were
significantly increased in the thalidomide group.[66]
A randomized, controlled trial evaluated the addition of thalidomide to standard MP
chemotherapy in elderly patients with previously untreated MM. Although no impact on survival
was observed, more patients in the thalidomide group achieved an objective response. Of note,
thromboembolic events did not increase in the thalidomide group.[67]
A separate study by Fayers et al concluded that thalidomide added to MP therapy improved
overall survival and progression-free survival in previously untreated elderly patients with
multiple myeloma, extending the mean survival time by an average of 20%.[68]
A study by Gay et al assessed the addition of thalidomide and/or bortezomib to standard oral
melphalan-prednisone treatment in 1175 elderly patients with newly diagnosed myeloma.[69] The
study found that these novel agents helped achieve maximal response in these patients.
A study by Morgan et al found that cyclophosphamide, thalidomide, and dexamethasone (CTD)
produced higher response rates than melphalan and prednisolone among newly diagnosed elderly
patients with multiple myeloma; however, CTD was not associated with improved survival
outcomes.[70]
Maintenance therapy

In spite of advances in treatment, multiple myeloma remains an incurable disease. To improve

overall survival (OS) in these patients, a number of trials have evaluated the role of maintenance
therapy in both transplant-eligible and transplant- ineligible patients.

Five large phase III studies have looked at role of thalidomide maintenance after autologous stem
cell transplant (ASCT). Three initial studies showed an improvement in both progression-free
survival (PFS) and OS.[71, 72, 73] However, two subsequent studiesincluding one large study with
1970 patientsdid not show an improvement in OS with thalidomide maintenance.[74, 75] Longterm use of thalidomide is also associated with significant neuropathy, thus limiting its use in
maintenance therapy.
Given its favorable toxicity profile and efficacy at low doses, lenalidomide has also been studied
for maintenance therapy. Two large trials, CALGB 100104 and IFM 05-02, have evaluated the
role of lenalidomide in maintenance therapy, using slightly different protocols and having
somewhat different outcomes.[76, 77] Patients in both studies received induction treatment followed
by ASCT. In the IFM 05-02 study, however, all patients received 2 months of consolidation
treatment with lenalidomide before being randomized to lenalidomide or placebo.
Both studies showed a significant improvement in time to progression (46 vs 27 months in
CALGB study and 41 vs 23 months in IFM study). However, CALGB 100104 study showed
significant improvement in OS (85 % vs 77 %), whereas IFM 05-02 did not show an
improvement in OS. Both studies showed an increased incidence of hematologic toxicity and
second primary malignancies (SPMs), particularly acute myelogenous leukemia/myelodysplastic
syndrome in the lenalidomide arm.
The reason for the difference in the two studies in terms of OS benefit is not very clear. Since all
the patients in the IFM trial received 2 months of consolidation treatment with lenalidomide
following ASCT, it is possible that only short period of maintenance therapy, rather than
continuous maintenance therapy, is required to achieve all the OS benefit seen in the CALGB
trial.
A meta-analysis shows the benefit of maintenance lenalidomide, with a 51% reduction in the risk
of recurrence.[78] This benefit outweighs the risk of SPM seen in the trials of lenalidomide
maintenance.
Bortezomib has also been shown to be effective for maintenance therapy in the HOVON65/GMMG-HD4 trial.[79] In this trial, patients were randomized to either PAD (bortezomib,
doxorubicin [Adriamycin], and dexamethasone) induction followed by bortezomib maintenance
or to VAD induction followed by thalidomide maintenance. PFS in the PAD arm was
significantly better than in the VAD arm (35 vs 28 months). Patients with high-risk cytogenetics,
especially del(17p13) and t(4;14) abnormalities, seemed to benefit more with bortezomib
maintenance.

Although several trials have shown the benefit of maintenance therapy after ASCT, the risk of
SPM and the need for continuous treatment should be kept in mind. Individual patient
characteristics should be taken in consideration before recommending maintenance therapy.
Maintenance therapy has also been evaluated in nontransplant eligible patients. Thalidomide
has been studied as maintenance in a number of trials; most of the trials have shown only
advantage in PFS, with no advantage in OS. The main problem with thalidomide has been the
high incidence of neuropathy in these patients.
A trial of lenalidomide as maintenance therapy after induction with melphalan, prednisone, and
lenalidomide showed a significant improvement in PFS (26 vs 7 months) but similar 4-year OS.
Patients in the lenalidomide arm had more hematologic toxicity, including neutropenia,
thrombocytopenia, and higher risk of second primary malignancy. However, given its overall
tolerability, lenalidomide is a good option for induction and maintenance therapy in transplantineligible patients.[80]
A number of trials have also evaluated bortezomib in maintenance therapy. All of them have
showed benefit in PFS but no clear OS benefit. Bortezomib given once a week in maintenance
seems to be better tolerated and associated with lesser neuropathy.[81]
Patients with refractory disease or relapse

Patients who have a relapse after initial disease control may be treated with any of the agents not
already utilized. If the relapse occurs longer than 6 months after the initial therapy, then the
initial regimen can be used again.
Among the other choices for salvage therapy are the following preferred regimens[2] :

Bortezomib

Bortezomib/liposomal doxorubicin

Carfilzomib

Carfilzomib/dexamethasone

Carfilzomib/lenalidomide/dexamethasone

Lenalidomide/dexamethasone

Panobinostat/bortezomib/dexamethasone

Daratumumab

Ixazomib/lenalidomide/dexamethasone

Elotuzumab/lenalidomide/dexamethasone

Bortezomib has a well-established role as salvage therapy, based on a phase III randomized trial
showing a response rate of 38% versus 18% in patients receiving dexamethasone only.[52] Median
progression-free survival was 6.22 months in the bortezomib arm versus 3.49 months in the
dexamethasone-only group.
Panobinostat (Farydak) is a histone deacetylase (HDAc) inhibitor approved in February 2015. It
is indicated in combination with bortezomib and dexamethasone for treatment of MM in patients
who have received at least two prior regimens, including bortezomib and an immunomodulatory
agent. The FDA approval was based on efficacy and safety data in a prespecified subgroup
analysis of the phase III PANORAMA-1 (PANobinostat ORAl in Multiple MyelomA) trial, in
which patients treated with panobinostat (n = 94) had a median progression-free survival of 10.6
months, compared with 5.8 months for patients in the placebo arm (n= 99) (hazard ratio= 0.52
[95% confidence interval: 0.36, 0.76]).[82]
In 2012, the FDA approved carfilzomib (Kyprolis) for the treatment of patients with MM who
have received at least two prior therapies including bortezomib and an immunomodulatory agent,
and have demonstrated disease progression on or within 60 days of therapy completion. The
approval was based on a phase 2b, single-arm, multicenter clinical study of 266 patients with
relapsed multiple myeloma with other therapies. The study assessed for overall response rate
(ORR), which was 22.9% over a median duration of 7.8 months.[83]
In 2015, the FDA expanded carfilzomibs indication for multiple myeloma based on data from
the ASPIRE study. In this study, carfilzomib was combined with lenalidomide and
dexamethasone (KRd) for patients with relapsed multiple myeloma who had received 1-3 prior
lines of therapy. The study showed a significant improvement in progression-free survival (PFS)
for patients treated in the KRd arm compared with those treated with lenalidomide and low-dose
dexamethasone (Rd) alone. The median PFS was 26.3 months in the KRd arm compared to 17.6
months in the Rd arm.[84]
In January 2016, the FDA approved carfilzomib in combination with dexamethasone for relapsed
or refractory multiple myeloma in patients who have received 1-3 prior lines of therapy.
Approval was based on the ENDEAVOR study (n=929) where a statistically significant
improvement in median progression-free survival was observed with carfilzomib plus
dexamethasone compared with bortezomib plus dexamethasone in patients with relapsed
multiple myeloma (26.3 mo vs 17.6 mo; p=0.0001). Overall survival data are not yet available.[85]
The following three new drugs were approved in November 2015:

Daratumumab (Darzalex)

Ixazomib (Ninlaro)

Elotuzumab (Empliciti)

Daratumumab gained accelerated approval from the FDA for patients with MM who had
received at least three prior treatments, including a proteasome inhibitor (PI) and an
immunomodulatory agent (IMiD), or whose disease is refractory to both a PI and an IMiD. The
approval was based on the phase II MMY2002 (SIRIUS) study that showed treatment with
single-agent daratumumab resulted in an ORR of 29.2% in patients who received a median of
five prior lines of therapy, including a PI and an IMiD.[86]
Stringent complete response (sCR) was reported in 2.8%, very good partial response (VGPR)
was reported in 9.4%, and partial response (PR) was reported in 17% of patients. For responders,
the median duration of response was 7.4 months. At baseline, 97% of patients were refractory to
their last line of therapy, 95% were refractory to both a PI and an IMiD, and 77% were refractory
to alkylating agents.[86] These data are supported by similar results from a phase I/II trial.[87]
Ixazomib is a reversible proteasome inhibitor. It preferentially binds and inhibits the
chymotrypsinlike activity of the beta 5 subunit of the 20S proteasome. Ixazomib is indicated in
combination with lenalidomide and dexamethasone for patients with multiple myeloma who
have received at least 1 prior therapy. Approval was based on data from the phase 3
TOURMALINE-MM1 trial, an international, randomized, double-blind clinical trial of 722
patients with treatment-refractory or recurrent multiple myeloma. It compared ixazomib with
placebo the patients who also received lenalidomide and dexamethasone. Median progressionfree survival was improved by 35% with ixazomib compared with placebo (20.6 vs 14.7 months;
P = 0.012).[88]
Elotuzumab is a humanized IgG1 monoclonal antibody that specifically targets the SLAMF7
(signaling lymphocytic activation molecule family member 7) protein. SLAMF7 is expressed on
myeloma cells and natural killer cells and plasma cells. Elotuzmab facilitates the interaction with
natural killer cells to mediate the killing of myeloma cells through antibody-dependent cellular
cytotoxicity. It is indicated for use in combination with lenalidomide and dexamethasone for MM
in patients who have received 1-3 prior therapies.
Approval was based on the ELOQUENT-2 trial, a randomized, open-label clinical study that
included 646 participants with multiple myeloma who had experienced relapse or who had not
responded to previous treatment. The addition of elotuzumab to the combination of lenalidomide
and dexamethasone extended progression- free survival to 19.4 months, as compared with 14.9
months seen in patients treated with lenalidomide and dexamethasone (P<0.001). Additionally,

the overall response rate (including complete and partial responses) was 78.5%, compared with
60.1% in patients receiving lenalidomide and dexamethasone (P<0.001).[89]
Thalidomide is useful in the treatment of patients with relapsing and refractory MM. Its
antiangiogenic properties have become increasingly apparent as a critical step in the proliferation
and spread of malignant neoplasm.[90, 91] In a Mayo Clinic study, nearly one third of patients with
advanced MM in whom current standard chemotherapy or stem cell transplantation failed were
shown to respond to thalidomide for a median duration of nearly 1 year.[92]
An important prospective placebo-controlled trial of the addition of lenalidomide to
dexamethasone in relapsed cases of MM demonstrated spectacular results.[93] The major response
rate with lenalidomide was 61% compared with 19.9% in the placebo arm. There was a
significant improvement in time to progression (11.1 in the lenalidomide plus dexamethasone
group vs 4.7% in the placebo group). Overall survival was significantly improved.[93]
A study by Lacy et al found that pomalidomide overcame resistance in MM that was refractory
to both lenalidomide and bortezomib.[94] In February 2013, pomalidomide was approved by the
FDA for use in patients with MM who have received at least two previous therapies (including
lenalidomide and bortezomib) and have disease progression on or within 60 days of completion
of the last therapy.[7, 8]
This approval was supported by a phase II study comparing pomalidomide plus low-dose
dexamethasone with pomalidomide alone in patients with relapsed MM refractory to their last
therapy who had received lenalidomide and bortezomib. Of the 221 patients who were evaluable
for response, 29.2% in the pomalidomide plus low-dose dexamethasone arm achieved a partial
response or better, compared with 7.4% in the pomalidomide-alone arm.[7] The median duration
of response for the former was 7.4 months; the median had not been reached for the latter.
In a more recent study, Miguel et al found that the combination of pomalidomide with low-dose
dexamethasone yielded a longer median progression-free survival (PFS) in 455 patients with
refractory or relapsed and refractory MM than high-dose dexamethasone alone.[95] In the openlabel, randomized study patients received 28-day cycles of either pomalidomide (4 mg/day on
days 1-21) plus low-dose dexamethasone (40 mg/day on days 1, 8, 15, and 22) or only high-dose
dexamethasone (40 mg/day on days 1-4, 9-12, and 17-20). At follow-up (median, 10 months),
median PFS was 4.0 months for the combination therapy group, compared with 1.9 months for
the monotherapy group, for a hazard ratio of 0.48. Rates of most adverse events were similar in
the two groups.[95]

Transplantation
Using the patients own (ie, autologous) bone marrow or peripheral blood stem cells facilitates
more intense therapy for MM. After harvesting the stem cells from the patient, physicians can

use otherwise lethal doses of total body irradiation and chemotherapy and then rescue the
patient by reinfusing the harvested cells. This process of myeloablative therapy, followed by the
reinfusion of stem cells, is termed autologous stem cell transplantation.
This sequence of therapy allows physicians to use melphalan at an approximately 10-20 times
higher dose than is used in standard therapy.[46] In autologous transplantation, the reinfused stem
cells or bone marrow act as a support to the patient but do not offer additional anticancer effects.
Tandem autologous transplantation has been proposed as a way of overcoming the incomplete
response to a single transplant. A 2-arm trial of single versus tandem transplantation revealed no
difference in overall survival at 54 months.[96]
Another two-arm study that compared single versus tandem transplants for newly diagnosed MM
showed that whereas double autologous stem cell transplantation effected superior complete or
near-complete response rates, relapse-free survival, and event-free survival (EFS), it failed to
significantly prolong overall survival.[97] Benefits offered by double autologous stem cell
transplantation were particularly evident among patients who failed to achieve at least a nearcomplete response after one autotransplantation.
A review of long-term outcomes of several autotransplantation trials for MM found that tandem
transplantations were superior to both single transplantations and standard therapies and that
tandem transplantations with thalidomide were superior to trials without thalidomide.[98]
However, postrelapse survival (PRS) was superior when initial EFS exceeded 1280 days and
when tandem transplantations had been administered, whereas PRS was shorter when EFS lasted
803 days or less and when trials had included thalidomide and bortezomib.[98]
Two randomized prospective studies compared standard chemotherapy with high-dose
autologous transplantation. In the first study of 200 subjects, researchers observed better
response rates (ie, 81% for the transplantation group vs 57% for the conventionally treated
group) and better 5-year event-free survival rates (ie, 28% vs 10%).[99] The second study also
showed a significant improvement in event-free survival rates and superior quality of life for
subjects treated with the high-dose approach.
In highly selected patients with MM, physicians may use allogeneic (ie, from someone else)
transplantation. In this approach, physicians administer myeloablative therapy and infuse stem
cells (ie, peripheral blood or bone marrow) obtained from a donor, preferably a human leukocyte
antigen (HLA)-identical sibling.
The advantage of this approach over autologous transplantation is that the patient is not at risk of
being reinfused with MM cells. In addition, the donors immune system may fight the recipients

cancer (ie, graft vs myeloma effect). Unfortunately, the donors immune system may also attack
the recipients body (ie, graft vs host effect).
Physicians use allogeneic transplantation less often than autologous transplantation in MM
patients, for several reasons. First, the risks of complications and death from allogeneic
transplantation increase with age, and most patients with multiple myeloma are older than the
ideal age for allogeneic transplantation.
Second, the transplantation-related mortality rate is quite high in patients with MM who undergo
allogeneic transplantation. The death rate within 100 days of transplantation ranges from 10% to
56% in different case series.
Third, although some survivors experience long-term disease-free results after allogeneic
transplantation, a retrospective case-matched analysis of allogeneic versus autologous
transplantation showed a median survival of 34 months for the autologous transplantation group
and 18 months for the allogeneic group.
The exception to this rule is the rare patient with a twin donor. In a limited study of 25
transplantations involving twins, outcomes with syngeneic transplantations were superior, with
reduced transplantation-related mortality.
The development of a nonmyeloablative preparative regimen for MM allogeneic transplantation
is changing the equation. A republished report of 52 high-risk patients who underwent
nonmyeloablative transplants described a 17% mortality rate.[100] Progression-free survival at 18
months was roughly 30%.
A phase II trial of autologous stem cell transplantation followed by a nonmyeloablative matched
sibling related donor transplant demonstrated this approach to be feasible, with low treatmentrelated mortality.[101] Further studies are needed to evaluate relative efficacy.
Allotransplants have markedly reduced activity; therefore, the use of nonmyeloablative regimens
(mini-allotransplantation) may hold promise for more widely exploiting this feature.[102, 103]
A study by Moreau et al determined that achievement of very good partial response (VGPR)
after induction therapy is an important prognostic factor in patients undergoing autologous stem
cell transplantation.[104] VGPR was significantly improved with bortezomib-dexamethasone
induction therapy.
A study by Harousseau et al also concluded that this combination significantly improved
postinduction and posttransplantation complete response/near response rate at at least VGPR
rates compared with VAD.[105] Cavo et al also concluded that this combination represents a new
standard of care for patients with multiple myeloma who are eligible for transplant.[106]

In MM patients with progressive or relapsing disease following autologous stem-cell

transplantation, treatment with the combination of bortezomib, thalidomide and dexamethasone
is more effective than treatment with thalidomide and dexamethasone alone, although triple
therapy is associated with a greater risk of grade 3 neurotoxicity.[107]

Prophylactic Platelet Transfusion

The results of the Trial of Prophylactic Platelets (TOPPS) showed the benefit of prophylactic
platelet transfusions for reducing rates of clinically significant bleeding events in patients with
hematologic cancers.[108, 109] In this study of 600 blood cancer patients, 301 were randomly
assigned to the no-prophylaxis group and 299 to the group that received prophylactic platelet
transfusions.
The proportion of patients who had bleeding events of World Health Organization (WHO) grade
2, 3, or 4 was reduced by 7% in the group that received prophylactic platelet transfusions, as
compared with the group that did not.[109] Bleeding of WHO grade 2, 3, or 4 occurred in 151 of
300 patients in the no-prophylaxis group and in 128 of 299 in the prophylaxis group (50% vs
43%; adjusted difference in proportions, 8.4 percentage points; 90% confidence interval [CI],
1.7-15.2; P = .06 for noninferiority).

Interferon Alfa Therapy

Intense research has focused on the use of interferon alfa to treat MM. This drug does not appear
to be effective for inducing remission, and a randomized controlled trial showed that patients do
not benefit from the addition of interferon to melphalan and prednisone.[110] Interferon alfa does
appear to prolong remission in selected patients with MM. For this use, it may be administered
after conventional chemotherapy or bone marrow (ie, stem cell) transplantation has been
completed.
The toxicity of interferon and the availability of alternate interventions have significantly limited
the role of interferon alfa.

Radiation Therapy
MM is extremely sensitive to radiation. Physicians use radiation to treat symptomatic lesions and
to stabilize bones at risk for fracture. Physicians also use radiation to treat spinal cord
compression. Low-dose, double-hemibody irradiation has been studied as systemic therapy for
refractory or relapsed MM, but without dramatic success.
If the pain is mild and if less than 50% of the bone is involved, a course of irradiation can be
initiated. Radiation treatment can result in additional early bone loss due to inflammation, and
weight bearing should be limited for the first 4-6 weeks.

Bisphosphonate Therapy
Bisphosphonates are specific inhibitors of osteoclastic activity and are used to treat bone
resorption. They also have a role in the secondary prevention of bony complications in MM,
including hypercalcemia, pathologic fracture, and spinal cord compression. Intravenous (IV)
pamidronate (Aredia) has been shown to be effective in preventing skeletal complications;
zoledronic acid (Zometa) may be significantly more potent than pamidronate. A study by Morgan
et al found that the early use of zoledronic acid was superior to clodronic acid in preventing
skeletal-related events among patients with newly diagnosed MM, irrespective of bone disease
status at baseline.[41]
A randomized placebo-controlled trial of pamidronate in subjects with MM who had experienced
one skeletal event demonstrated that the medication reduced the likelihood of a second skeletal
event from 41% to 24% after 9 months of therapy.[42] The investigators also noted improvements
in pain, narcotic usage, and quality of life scores.
A 2007 systematic review of the use of bisphosphonates in MM confirmed a number-needed-totreat (NNT) of 10 for the prevention of vertebral fractures, although no impact on mortality was
seen.[43]
The American Society of Clinical Oncology (ASCO) issued a clinical practice guideline
governing bisphosphonate therapy for MM patients who have lytic destruction of bone or
compression fracture of the spine from osteopenia.[43] ASCO recommends IV pamidronate, 90
mg delivered over at least 2 hours, or zoledronic acid, 4 mg delivered over at least 15 minutes
every 3-4 weeks. Because the risk for osteonecrosis of the jaw is 9.5-fold greater with zoledronic
acid than with pamidronate, patients may prefer pamidronate.[43]
Zoledronic acid doses should be reduced in patients with preexisting mild to moderate renal
impairment (estimated creatinine clearance, 30-60 mL/min); the drug is not recommended for
use in patients with severe renal impairment.[43] All patients receiving pamidronate or zoledronic
acid therapy should be screened every 3-6 months for albuminuria. If unexplained albuminuria
(>500 mg/24 hours) is found, ASCO recommends discontinuation of the drug until the renal
problems resolve.[43]
A study by Morgan et al revealed the anticancer properties of zoledronic acid in addition to its
ability to reduce skeletal-related events in MM.[111]
Osteonecrosis of the jaw

Osteonecrosis of the jaw is a rare but severe adverse effect of bisphosphonate therapy. Level 1
evidence (ie, systematic reviews or randomized controlled trials) indicate that approximately 1%
of cancer patients exposed to zolendronic acid develop osteonecrosis of the jaw.[112] Dental
extractions appear to be a risk factor, and guidelines recommend avoiding this where possible.

A position paper by the American Association of Oral and Maxillofacial Surgeons describes the
differential diagnosis, prevention, and treatment of medication-related osteonecrosis of the jaw.
Consultation with an appropriate dental professional is advised before prescribing a
bisphosphonate.[112]

Adjunctive Therapy for Complications

Potential complications of MM include the following:

Skeletal complications (eg, pain, hypercalcemia, pathologic fracture, spinal

cord compression)

Infection

Anemia

Renal failure

Amyloidosis

Treatment for myeloma-induced hypercalcemia is the same as that for other malignancyassociated hypercalcemia; however, the dismal outcome observed with hypercalcemia in solid
tumors is not observed in MM.
To treat pathologic fractures, physicians should orthopedically stabilize (ie, typically pin) and
irradiate these lesions. Careful attention to a patients bony symptoms, intermittent radiographic
surveys, and the use of bisphosphonates may be useful to prevent fractures.[113, 114, 115] (See
Surgical Care and Bisphosphonate Therapy.)
Spinal cord compression is one of the most severe adverse effects of MM. The dysfunction may
be reversible, depending on the duration of the cord compression; however, once established, the
dysfunction is only rarely fully reversed. Patients who may have spinal cord compression need a
rapid evaluation, which may necessitate urgent transfer to a center equipped with MRI for
diagnosis or a center with a radiation oncologist for urgent therapy.
Patients with spinal cord compression due to MM should begin corticosteroid therapy
immediately to reduce swelling. Urgent arrangements must be made for radiation therapy in
order to restore or stabilize neurologic function. Surgery may be indicated. (See Surgical Care.)
Erythropoietin may ameliorate anemia resulting from either MM alone or from chemotherapy
and has been shown to improve quality of life.[116] A systematic review failed to demonstrate a
survival advantage for the use of erythropoietin agents in the treatment of patients with cancerrelated anemia.[117]

Acute renal impairment related to MM is typically managed with plasmapheresis to rapidly

lower circulating abnormal proteins. Data about this approach are limited, but a small
randomized study showed a survival advantage with the use of apheresis.[15] Hydration (to
maintain a urine output of >3 L/d), management of hypercalcemia, and avoidance of
nephrotoxins (eg, intravenous contrast media, antibiotics) are also key factors. Conventional
therapy may take weeks to months to show a benefit.
Renal impairment resulting from MM is associated with a very poor prognosis. A case series
demonstrated that patients with renal failure from myeloma may benefit from autologous stem
cell transplants, and as many as one third may demonstrate improvement in their renal function
with this approach.[118] A report by Ludwig et suggests that bortezomib-based therapy may restore
renal function in MM patients with renal failure.[14]
Guidelines on the management of multiple myeloma complications by the European Myeloma
Network include the following recommendations[119] :

Whole body low-dose computed tomography is more sensitive than

conventional radiography in depicting osteolytic disease and thus is
recommended as the novel standard for the detection of lytic lesions in
myeloma.

Myeloma patients with adequate renal function and bone disease at diagnosis
should be treated with zoledronic acid or pamidronate.

Symptomatic patients without lytic lesions on conventional radiography can

be treated with zoledronic acid, but its advantage is not clear for patien ts
with no bone involvement on computed tomography or magnetic resonance
imaging.

In asymptomatic myeloma, bisphosphonates are not recommended.

Zoledronic acid should be given continuously, but it is not clear if patients

who achieve at least a very good partial response benefit from its continuous
use.

Treatment with erythropoietic-stimulating agents may be initiated in patients

with persistent symptomatic anemia (hemoglobin <10g/dL) in whom other
causes of anemia have been excluded.

Erythropoietic agents should be stopped after 6-8 wk if no adequate

hemoglobin response is achieved.

For renal impairment, bortezomib-based regimens are the current standard of

care.

For the management of treatment-induced peripheral neuropathy, drug

modification is needed.

Vaccination against influenza is recommended; vaccination against

Streptococcus pneumoniae and Haemophilus influenzae is appropriate, but
efficacy is not guaranteed due to suboptimal immune response.

Prophylactic acyclovir (or valacyclovir) is recommended for patients receiving

proteasome inhibitors, or autologous or allogeneic transplantation

Surgical Care
Surgical therapy for MM is limited to adjunctive therapy. It consists of prophylactic fixation of
pending fractures, decompression of the spinal cord when indicated, and treatment of pathologic
fractures.
Prophylactic treatment of impending fractures and the treatment of pathologic fractures may
involve bracing. In general, bracing is not effective for the long bones, though it may be effective
for treating spinal involvement without neurologic compromise.
Intramedullary fixation is the procedure of choice when surgery is necessary. If the metaphysis or
joint surface is involved, resection of the diseased bone and reconstruction with a total joint or,
more typically, a hemiarthroplasty is indicated. Modular implants may be required. Severe
destruction of the diaphysis may require reconstruction with combinations of
methylmethacrylate, intramedullary nails, or resection and prosthetic replacement.
Although surgical decompression of the spinal cord is sometimes appropriate, posterior
laminectomy in this population has been reported to have a mortality rate of 6-10% and to not be
superior to radiation. This surgical approach is probably best reserved for cases of MM in which
radiation fails. Newer surgical interventions, such as kyphoplasty, in which cement is injected
into compressed vertebrae, have been shown to improve function with few complications,
although the studies reported have been small.

Dietary Measures
Patients with MM who are receiving bisphosphonate therapy should include adequate calcium in
their diet.
The dietary supplement curcumin may slow the progression of smoldering multiple myeloma.[120]

Physical Activity
Patients with MM should be encouraged to be physically active to the extent appropriate for their
individual bone status. Physical activity may help maintain bone strength.

In general, patients with activity-related pain in either the femur or the tibia should be given a
walker or crutches until a radiographic workup has been completed. Radiation therapy elicits an
inflammatory response, and for the first 6 weeks or so, bony resorption may actually weaken the
target bone. Given that prophylactic treatment of an impending fracture is usually easier than
reconstruction of a pathologic fracture, one should have a low threshold for initiating protected
weight bearing.

Prevention of Multiple Myeloma

No preventive measures for MM are known. A study by Chang et al found that routine residential
ultraviolet radiation exposure may have a protective effect against lymphomagenesis through
mechanisms that may be independent of vitamin D.[121]

Consultations
Patients with MM often benefit from the expertise of an orthopedic surgeon who is versed in
oncologic management because prophylactic fixation of impending pathologic fractures is
occasionally warranted.
From the orthopedic perspective, because patients with MM have significant systemic
comorbiditiesincluding potentially severe hematologic, infectious, and metabolic diseases
the orthopedic surgeon treating the skeletal disease in a patient with myeloma should work in
conjunction with the radiation oncologists and the medical oncologists.

Long-Term Monitoring
Patients with MM may require hospitalization for the treatment of pain or bony pathology.
Patients with MM are at high risk of infection, especially from encapsulated organisms.
Vaccinations against pneumococcal organisms and influenza are recommended. Consider
vaccinating patients against Haemophilus influenzae type b. Use of the herpes zoster vaccine
should be considered.
The following laboratory results are helpful in the follow-up care of patients with MM:

Complete blood count (CBC), chemical profile 7 (especially blood urea

nitrogen [BUN] and serum creatinine), serum calcium, and serum uric acid,
and serum protein electrophoresis (SPEP) findings.

M-component level in the serum and/or urine. (This is an indicator of tumor

burden; a reduction with chemotherapy is used as a sign of a treatment
response.)

Serum beta-2 microglobin. (An elevated level indicates a large malignant cell
mass, renal impairment, or both.)

Serum lactate dehydrogenase (LDH) level. (A high level is predictive of an

aggressive lymphomalike course.)