Multiple myeloma 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, multiple
myeloma is a disease characterized by a proliferation of malignant plasma cells and
a subsequent overabundance of monoclonal paraprotein. An intriguing feature of
multiple myeloma is that the antibody-forming cells (ie, plasma cells) are malignant
and, therefore, may cause unusual manifestations.
The presentation of multiple myeloma 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. 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
multiple
myeloma.
For excellent patient education resources, visit eMedicine's Blood and Lymphatic
System Center. Also, see eMedicine's patient education article Myeloma.

I.

Pathophysiology

Multiple myeloma can cause a wide variety of problems. The proliferation of

plasma cells 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
multiple myeloma 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.
Increasing evidence suggests that the bone marrow microenvironment of tumor
cells plays a pivotal role in the pathogenesis of myelomas. This information has
resulted in the expansion of treatment options.

a) Frequency
United States
The age-adjusted annual incidence of multiple myeloma 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.

Mortality/Morbidity

Multiple myeloma affects the kidneys in several ways. The most

common mechanisms of renal injury are direct tubular injury, amyloidosis, or
involvement by plasmacytoma. Physicians manage the acute clinical
condition 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. Conventional therapy may take
weeks to months to show a benefit. Renal impairment resulting from multiple
myeloma is associated with a very poor prognosis. A recent 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.
Spinal cord compression is one of the most severe adverse effects of multiple
myeloma. 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.
The mechanism of these 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. The dysfunction may be
reversible, depending on the duration of the cord compression; however,
once established, the dysfunction is only rarely fully reversed.
A frequent complication of multiple myeloma is pathologic fractures. Bony
involvement is typically lytic in nature. Physicians should orthopedically
stabilize (ie, typically pin) and irradiate these lesions. Careful attention to a
patient's bony symptoms, intermittent radiographic surveys, and the use of
bisphosphonates may be useful to prevent fractures.
Patients with multiple myeloma commonly develop hypercalcemia. The
mechanisms include bony involvement and, possibly, humoral mechanisms.
Treatment for myeloma-induced hypercalcemia is the same as that for other
malignancy-associated hypercalcemia; however, the dismal outcome
observed with hypercalcemia in solid tumors is not observed in multiple
myeloma.

Race
Multiple myeloma accounts for 1.1% of the malignancies in white US
residents and 2.1% of the malignancies in black residents.

Sex
The male-to-female ratio of multiple myeloma is 3:2.

Age

The median age of patients with multiple myeloma is 68 years for men and
70 years for women.

II. Clinical
History
Presenting symptoms of multiple myeloma include bone pain, pathologic
fractures, weakness, anemia, infection (often pneumococcal), hypercalcemia, spinal
cord compression, or renal failure. Increasingly, physicians are identifying
asymptomatic patients through routine blood screening. 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).

Bone pain
This is the most common presenting symptom in multiple myeloma. 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 multiple myeloma; 93% of patients
have more than one site of bony involvement. A severe bony event is a
common presenting issue.

Spinal cord compression

This complication occurs in approximately 10-20% of patients with multiple
myeloma at some time during the course of disease.
The symptoms that should alert physicians to consider spinal cord
compression are back pain, weakness, numbness, or dysesthesias in the
extremities. It is common for spinal cord compressions in multiple myeloma
to occur at multiple levels, so 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
multiple myeloma at presentation. In most solid malignancies, hypercalcemia
carries an ominous prognosis, but in multiple myeloma, 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 multiple myeloma.

Hyperviscosity
Epistaxis may be a presenting symptom of multiple myeloma 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.
Patients may report headaches and somnolence, and they may bruise easily
and have hazy vision. Patients with multiple myeloma typically experience
these symptoms when their serum viscosity is greater than 4 times that of
normal serum.

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 multiple myeloma. Some peripheral
neuropathies have been attributed to multiple myeloma.

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

III.

Physical

Pallor from anemia may be present. Ecchymoses or purpura from

thrombocytopenia may be evident. Bony tenderness is not uncommon in multiple
myeloma, resulting from focal lytic destructive bone lesions or pathologic fracture.
Pain without tenderness is typical. Neurologic findings may include a sensory level
change (ie, loss of sensation below a dermatome corresponding to a spinal cord
compression),
weakness,
or
carpal
tunnel
syndrome.
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.
Amyloidosis may develop in some patients with multiple myeloma. The
characteristic physical examination findings that suggest amyloidosis include the
following:
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.
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. The most
widely accepted schema for the diagnosis of multiple myeloma uses particular
combinations of laboratory, imaging, and procedure findings as diagnostic criteria.
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 multiple
myeloma:

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

IV.

Causes
Genetic causes
A study by the Mayo clinic found multiple myeloma in 8 siblings from a group
of 440 patients; these 8 siblings had different heavy chains but the same light
chains. 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
multiple myeloma in individuals with significant exposures in the agriculture,
food, and petrochemical industries. Long-term (>20 y) exposure to hair dyes
has been tied to an excessive risk of developing multiple myeloma.

MGUS
Approximately 19% of patients with MGUS develop multiple myeloma within
2-19 years.

Radiation
Radiation has been linked to the development of multiple myeloma. In
109,000 survivors of the atomic bombing of Nagasaki during World War II, 29
died from multiple myeloma between 1950 and 1976; however, some more
recent studies do not confirm that these survivors have an increased risk of
developing multiple myeloma.
A recent 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.

V.

Laboratory Studies
CBC count
Perform a complete blood cell (CBC) count to determine if the patient has
anemia, thrombocytopenia, or leukopenia.

Metabolic panel

Obtain a comprehensive metabolic panel to assess levels of total protein,

albumin and globulin, blood urea nitrogen (BUN), creatinine, and uric acid
(uric acid will be high if the patient has high cell turnover or is dehydrated).

Obtain serum protein electrophoresis, urine protein electrophoresis,

and
immunofixation
Serum protein electrophoresis 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 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).

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 multiple myeloma
(>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
patient's renal impairment.

Quantitative immunoglobulin levels (ie, IgG, IgA, IgM)

Suppression of nonmyelomatous immunoglobulin is a minor diagnostic
criterion for multiple myeloma. The level of multiple myeloma 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
Beta-2 microglobulin is a very strong predictor of multiple myeloma outcome;
some studies suggest it is more powerful than the disease stage. Beta-2
microglobulin is a surrogate marker for the overall body tumor burden. The
level of beta-2 microglobulin is increased in patients with renal insufficiency
without multiple myeloma, which is one reason that it is a useful
prognosticator in multiple myeloma. The prognosis of patients with multiple
myeloma and impaired renal function is reduced.

C-reactive protein (CRP)

CRP is useful for prognostication. CRP is a surrogate marker of interleukin
(IL)-6 activity. IL-6 is often referred to as the plasma cell growth factor.

Serum viscosity

Check the serum viscosity in patients with central nervous system (CNS)
symptoms, nosebleeds, or very high M protein levels.

VI.

Imaging Studies

Skeletal series
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.
Perform a complete skeletal series at multiple myeloma diagnosis, including
the skull (a very common site of bone lesions in persons with multiple
myeloma; see image below), the long bones (to look for impending fractures),
and the spine. 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. Do not use
bone scans to evaluate multiple myeloma. Cytokines secreted by multiple
myeloma cells suppress osteoblast activity; therefore, typically, no increased
uptake is observed.

Magnetic resonance imaging (MRI)

Findings from MRIs of the vertebrae are often positive when plain radiographs
are not. 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 (PET) scanning

Comparative studies have suggested the possible utility of PET scanning in
the evaluation of multiple myeloma. 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.
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.

VII.

Procedures

Obtain bone marrow aspirate and biopsy samples from patients with
multiple myeloma 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. 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 p53 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, risk-adapted therapy based on cytogenetic abnormalities is at
the forefront of myeloma research.

VIII.

Histologic Findings

In patients with multiple myeloma, plasma cells proliferate within the bone
marrow, typically in sheets. 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. The cytoplasm is
basophilic. Many multiple myeloma 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. This infiltration is different
from the lymphoplasmacytic infiltration observed in patients with Waldenstrom
macroglobulinemia.

IX.

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, 2 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.

Salmon-Durie Staging System for Multiple Myeloma

Stage I

Hemoglobin level greater than 10 g/dL

Calcium level less than 12 mg/dL

Radiograph showing normal bones or solitary plasmacytoma

Low M protein values (ie, IgG <5 g/dL, IgA <3 g/dL, urine <4 g/24 h)

Stage II

Findings that fit neither stage I nor stage III criteria

Stage III

Hemoglobin level less than 8.5 g/dL

Calcium level greater than 12 mg/dL

Radiograph showing advanced lytic bone disease

High M protein value (ie, IgG >7 g/dL, IgA >5 g/dL, urine >12 g/24 h)

Subclassification A involves a creatinine level less than 2 g/dL.

Subclassification B involves a creatinine level greater than 2 g/dL.

Median survival is as follows:

Stage I, >60 months

Stage II, 41 months

Stage III, 23 months

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

separate series).

International Staging System for Multiple Myeloma

Stage I

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

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

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

Stage III

Beta-2 microglobulin of 5.5 g/dL or more

Median survival is as follows:

X.

I.

Stage I, 62 months

II.

Stage II, 44 months

III.

Stage III, 29 months

Medical Care

Physicians must understand both the natural history of multiple myeloma and
the limitations of current therapy in the treatment of the disease. An important
study by Dimopoulos and associates evaluated the risk of disease progression in
asymptomatic subjects with multiple myeloma. This study evaluated 638
consecutive untreated subjects with multiple myeloma. 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. At the
time of progression, subjects were treated with standard chemotherapy. The
subjects' response rates did not significantly differ from those of unselected
populations. The median survival time from the institution of chemotherapy did not
differ among the groups. To summarize, asymptomatic subjects did not benefit from
early treatment, and delayed treatment did not affect the efficacy of the treatment
(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. The failure to demonstrate improved survival may be due to the small
number of patients studied.
Patients with multiple myeloma for whom therapy is indicated typically receive
chemotherapy. Our understanding of the cell biology of multiple myeloma 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. A
randomized prospective study showed that this approach results in higher response
rates and better disease-free survival rates. Recent advances in treatment include
establishment of thalidomide, lenalidomide, and bortezomib as active agents in
multiple myeloma. Patients with myeloma who are treated with lenalidomide or
thalidomide are at significantly increased risk of thrombotic events, and many
physicians incorporate anticoagulation strategies in their management.
A randomized, controlled trial evaluated the edition of thalidomide to standard
melphalan and prednisone chemotherapy in elderly patients with previously
untreated multiple myeloma. 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.
Adjunctive therapy for multiple myeloma 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). Erythropoietin may ameliorate anemia
resulting from either multiple myeloma alone or from chemotherapy and has been
shown to improve quality of life. A systematic review failed to demonstrate a
survival advantage for the use of erythropoietin agents in the treatment of patients
with cancer-related anemia.
Patients with spinal cord compression due to multiple myeloma should begin
corticoteroid therapy immediately to reduce swelling. Urgent arrangements must be
made for radiation therapy in order to restore or stabilize neurologic function.
Although surgical decompression 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
multiple myeloma 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.
Patients with multiple myeloma who present with acute renal failure may benefit
from plasmapheresis. 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. A report by Ludwig et suggests that
bortezomib-based therapy may restore renal function in multiple myeloma patients
with renal failure.

Transplantation

Using the patient's own (ie, autologous) bone marrow or peripheral blood
stem cells facilitates more intense therapy for multiple myeloma. 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 an 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. 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.
In another 2-arm study that compared single versus tandem transplants for
newly diagnosed multiple myeloma, Cavo et al showed that double autologous stem
cell transplantation effected superior complete response or near complete response
rates, relapse-free survival, and event-free survival (EFS), but it failed to
significantly prolong overall survival. Benefits offered by double autologous stem
cell transplantation were particularly evident among patients who failed to achieve
at least a near-complete response after one autotransplantation.
Similarly, a review of long-term outcomes of several trials of autologous
transplantation in myeloma by Barlogie et al found that tandem transplantations
were superior to both single transplantations and standard therapies (P <0.001), as
were tandem transplantations with added thalidomide versus trials without
thalidomide (P <0.001). 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.

In highly selected patients with multiple myeloma, 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 an HLA-identical sibling. The advantage
of this approach over autologous transplantation is that the patient is not at risk of
being reinfused with multiple myeloma cells. Also, the donor's immune system may
fight the recipient's cancer (ie, graft vs myeloma effect). Unfortunately, the donor's
immune system may also attack the recipient's body (ie, graft vs host effect).
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%). The second study also showed a significant improvement in eventfree survival rates and superior quality of life for subjects treated with the high-dose
approach.
Physicians use allogeneic transplantation less often than autologous
transplantation in multiple myeloma 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 multiple myeloma 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 multiple
myeloma allogeneic transplantation is changing the equation. A republished report
of 52 high-risk patients who underwent nonmyeloablative transplants described a
17% mortality rate. Progression-free survival at 18 months was roughly 30%. A
recently reported 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 treatment-related mortality. Further studies are
needed to evaluate relative efficacy.

Radiation

Multiple myeloma 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 multiple
myeloma, but without dramatic success.

Surgical Care
Surgical therapy for multiple myeloma is limited to adjunctive therapy.

Consultations

Patients with multiple myeloma 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.

Diet

Patients with multiple myeloma who are receiving bisphosphonate therapy

should include adequate calcium in their diet.

Activity

Encourage patients with multiple myeloma to be physically active, as

appropriate to their individual bone status. Physical activity may help maintain bone
strength.

Medication

Multiple myeloma is treated with several categories of medications.

Chemotherapeutic agents are used to reduce the disease burden, and
bisphosphonates are used to promote bone healing and to provide secondary
prophylaxis against skeletal-related events (eg, hypercalcemia, bone fracture, spinal
cord compression, need for radiation, and need for surgery). In addition,
erythropoietin is used to treat anemia, either alone or in conjunction with
chemotherapy.
Treatment for multiple myeloma is best categorized on the basis of the
patient's age and prognostic factors. We will look at 3 separate categories: (1) the
young, newly diagnosed patient, who is potentially a transplant candidate; (2) highrisk patients who are potentially transplant candidates; and (3) newly diagnosed
elderly patients who are not transplant candidates.

1. The young, newly diagnosed patient, who is potentially a transplant

candidate
Conventionally, VAD (vincristine, doxorubicin [Adriamycin], and
dexamethasone) chemotherapy has been used to decrease the tumor burden in

multiple myeloma as preparation for transplantation. VAD is administered as a 4day 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 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 multiple myeloma. The superiority of
induction regimens containing thalidomide was demonstrated in randomized
trials that compared VAD with thalidomide plus dexamethasone ; thalidomide
and doxorubicin plus dexamethasone ; and thalidomide plus VAD.
Thalidomide has a well-established role as first-line therapy, either as a single
agent or in combination with steroids in patients with multiple myeloma. 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.
Bortezomib, a proteosome inhibitor, has shown striking activity against multiple
myeloma. Objective responses as high as 27.7% in patients with relapsed and
heavily pretreated multiple myeloma led to its approval by the 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 (P < .001). This regimen has
been shown to be active not only in the pretransplantation setting but also
posttransplantation.
Following
high-dose
therapy
and
autologous
transplantation, the rate of very good partial response or better continued to
favor bortezomib plus dexamethasone (61.7% vs. 41.7%, P < .001). 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 3 study: 93% in the bortezomibthalidomide-dexamethasone arm versus 80% in the thalidomide-dexamethasone

arm, in which patients went on to receive tandem autologous stem cell

transplantation. As in other studies, response was independent of adverse
prognostic risk factors.
The phase III Velcade as initial standard therapy in multiple myeloma (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. 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 bortezomibbased and other novel agent-based treatment until relapse.
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. Varicellazoster virus reactivation occurs in 10%-60% of patients with multiple myeloma
treated with bortezomib. Antiviral prophylaxis (eg, acyclovir, 400 mg daily) has
been found effective for preventing these reactivations.
An analogue of thalidomide, lenalidomide (Revlimid) is now a standard
component of multiple myeloma therapy. 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
multiple myeloma. 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.
In another randomized trial of lenalidomide plus high-dose dexamethasone
(LD) versus lenalidomide plus low-dose dexamethasone (Ld) in newly diagnosed
multiple myeloma, 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. 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.
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). 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 lowdose therapy.
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.
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 multiple myeloma.

2. High-risk patients who are potentially transplant candidates

High-risk multiple myeloma patients are those with advanced-stage

disease, according to the International Staging System stage III; those with poor
cytogenetics, such as t (4:14), t (14:16), and t (14:20), deletion of chromosome
13, inactivation of P53; 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 multiple myeloma, 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. Once a
response has been achieved, then these patients can be brought to autologous
stem cell transplantation.

3. 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 melphalan and prednisone (M and P) as far
back as the 1950s. A meta-analysis of 4930 patients from 20 randomized trials
compared melphalan and prednisone 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.
A 3-arm study looked at melphalan and prednisone plus thalidomide versus
melphalan and prednisone versus VAD induction, followed by high-dose
melphalan and autologous stem cell transplantation in 447 patients between
ages 65 and 75 years. The patients were randomized, with overall survival as the
primary endpoint. The response rate in the melphalan and prednisone plus
thalidomide arm and transplantation arm was similar; the complete response
rate was significantly better in the melphalan and prednisone plus thalidomide
and the transplantation arms than in the melphalan and prednisone arm.
Melphalan and prednisone plus thalidomide is now recommended as first-line
treatment. Melphalan and prednisone plus lenalidomide has also shown promise.
Hulin et al conducted a randomized, placebo-controlled, phase III trial to
investigate the efficacy of adding thalidomide to a regimen of melphalan and
prednisone in 229 elderly patients (> 75 y) newly diagnosed with multiple
myeloma. 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; P =
0.028). Progression-free survival was also significantly prolonged in the
thalidomide group (median, 24.1 mo) relative to the placebo group (median,
18.5 mo; P = 0.001). However, the investigators noted peripheral neuropathy
and neutropenia were significantly increased in the thalidomide group.

Interferon alfa

Intense research has focused on the use of interferon alfa to treat multiple
myeloma. 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. Interferon alfa appears to prolong
remission in selected patients with multiple myeloma. For this use, interferon
alfa 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 has significantly limited the role of
interferon alfa.

Bisphosphonates

Bisphosphonates have a role in the secondary prevention of bony

complications in multiple myeloma, including hypercalcemia, pathologic fracture,
and spinal cord compression. A randomized placebo-controlled trial of
pamidronate (eg, Aredia) in subjects with multiple myeloma 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.
The investigators also noted improvements in pain, narcotic usage, and quality

of life scores. A 2007 systematic review of the use of bisphosphonates in

multiple myeloma confirmed a number-needed-to-treat (NNT) of 10 for the
prevention of vertebral fractures, although no impact on mortality was seen.
Zoledronic acid (Zometa) may be significantly more potent than pamidronate.
Recent evidence suggests that osteonecrosis of the jaw may occur in some
patients receiving bisphosphonate therapy. The management of osteonecrosis of
the jaw is evolving, and no definitive data have yet been published.
Collaboration with knowledgeable dentists and oral surgeons is essential. Dental
extractions appear to be a risk factor, and guidelines recommend avoiding this
where possible.
The American Society of Clinical Oncology (ASCO) issued a clinical
practice guideline governing bisphosphonate therapy for multiple myeloma
patients who have lytic destruction of bone or compression fracture of the spine
from osteopenia. ASCO recommends intravenous 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.
Zolendronic 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.
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.
Refractory or relapsed multiple myeloma

XI.

Patients who have a relapse after initial disease control may be treated
with any of the agents not already utilized. If the multiple myeloma
relapse occurs longer than 6 months after the initial therapy, then the
initial regimen can be used again. Bortezomib has a well-established
role as salvage therapy based on a phase III randomized trial showing
a response rate of 38% relative to 18% in patients receiving
dexamethasone only. Median progression-free survival was 6.22
months in the bortezomib arm versus 3.49 months in the
dexamethasone-only group.
An important prospective placebo controlled trial of the addition of
lenalidomide to dexamethasone in relapsed cases of multiple myeloma
demonstrated spectacular results. 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.

Chemotherapeutic Agents

The choice of chemotherapy depends on several factors, including the

patient's performance status, age, renal function, desire for inpatient or outpatient

therapy, and likelihood of receiving future autologous stem cell transplantation. In

patients with renal failure or highly aggressive disease, VAD may be preferred. In
elderly patients or patients in whom autologous transplantation is not possible in
the future, M and P is preferred because of its ease of administration and low
toxicity.