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I.
Pathophysiology
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
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.
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
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:
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.
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
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.
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.
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.
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
Stage I
Low M protein values (ie, IgG <5 g/dL, IgA <3 g/dL, urine <4 g/24 h)
Stage II
Stage III
High M protein value (ie, IgG >7 g/dL, IgA >5 g/dL, urine >12 g/24 h)
Stage I
Stage II
Stage III
X.
I.
Stage I, 62 months
II.
III.
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.
Radiation
Surgical Care
Surgical therapy for multiple myeloma is limited to adjunctive therapy.
Consultations
Diet
Activity
Medication
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
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.
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
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