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Multiple Myeloma Diagnosis and Orthopaedic Implications
Multiple Myeloma Diagnosis and Orthopaedic Implications
Multiple Myeloma Diagnosis and Orthopaedic Implications
Abstract
Thomas J. Scharschmidt, MD Multiple myeloma is a hematologic malignancy that commonly
Joshua D. Lindsey, MD affects the skeletal system. The disease is primarily managed
medically with chemotherapeutic agents. Pathologic fractures are
Pamela S. Becker, MD, PhD
common in patients with diagnosed and undiagnosed disease. The
Ernest U. Conrad, MD number of patients diagnosed with multiple myeloma is increasing,
as is the incidence of associated pathologic fractures. Novel
chemotherapeutic agents and radiation therapy protocols have
been used to extend the average life span of patients with this
disease. Various methods that allow for restoration of function and
pain reduction can be used to stabilize and manage fractures
associated with multiple myeloma. The orthopaedic surgeon and
oncology team must work together to develop an individualized
treatment plan to improve patient quality of life and provide pain
relief.
Figure 1 detected on serum and/or urine elec- mediator of myeloma bone disease.
trophoresis, and evidence of end- Knowledge of this pathologic pro-
organ damage (eg, hypercalcemia, cess has led to increased use of
renal insufficiency, anemia, bone le- diphosphonates to treat patients
sions, more than two severe infec- with multiple myeloma.
tions per year, amyloidosis, hypervis-
cosity syndrome).2,3,7,8
Clinical Presentation
Dr. Becker or an immediate family member serves as a board member, owner, officer, or committee member of the National
Comprehensive Cancer Network; serves as a paid consultant to or is an employee of Alder Biopharmaceuticals; has received
research or institutional support from Amgen, Genzyme, Millenium: The Takeda Oncology Company, and Celgene; and has stock or
stock options held in Forest Laboratories. Dr. Conrad or an immediate family member serves as a paid consultant to or is an
employee of Zimmer; serves as an unpaid consultant to Stryker; has received research or institutional support from Zimmer; and has
received nonincome support (such as equipment or services), commercially derived honoraria, or other non-research–related funding
(such as paid travel) from Northwest Tissue Services/Puget Sound Blood Center. Neither of the following authors nor any immediate
family member has received anything of value from or owns stock in a commercial company or institution related directly or indirectly
to the subject of this article: Dr. Scharschmidt and Dr. Lindsey.
Table 1
Diagnosis and Management of Multiple Myeloma2,3,7,8
Diagnosis Diagnostic Criteria Management Prognosis
Symptomatic >10% clonal plasma cells present Transplant candidates: autologous ISS stage I, 62 mo; stage II, 44 mo;
myeloma on bone marrow biopsy stem cell transplantation with stage III, 29 mo
Monoclonal protein detected on induction chemotherapy
serum and/or urine Nontransplant candidates: chemo-
electrophoresis therapy
Evidence of end-organ damage
(eg, hypercalcemia, renal insuffi-
ciency, anemia, bone lesions,
>2 severe infections per year,
amyloidosis, hyperviscosity syn-
drome)
Asymptomatic (ie, Same as symptomatic myeloma, Routine surveillance (every 2-3 mo Once the patient progresses to
smoldering) but without evidence of end- by an oncologist) symptomatic myeloma, the prog-
myeloma organ involvement nosis is the same as that of
symptomatic myeloma
Monoclonal gammop- Asymptomatic, often discovered Annual electrophoresis for surveil- Prognosis is determined after pro-
athy of undeter- incidentally lance gression to symptomatic my-
mined significance Monoclonal band <30 g/L, plasma eloma. Approximately 10% pro-
cells <10% gress to symptomatic myeloma.
Nonsecretory Same as symptomatic myeloma, Transplant candidates: autologous ISS stage I, 62 mo; stage II, 44 mo;
myeloma except that plasma cells do not stem cell transplantation with in- stage III, 29 mo
produce protein, so electrophore- duction chemotherapy
sis is negative for protein Nontransplant candidates: chemo-
therapy
Plasmacytoma Solid tumor composed of plasma Radiation, surveillance Prognosis is determined after pro-
cells in bone or soft tissue gression to symptomatic my-
eloma. Approximately10%–15%
progress to symptomatic my-
eloma.
min levels. β2M is part of the major ease is characterized by the presence
histocompatibility complex protein Imaging of 5 to 20 focal bone lesions and/or
class that is present in all nucleated moderate diffuse spine disease visible
In the patient with suspected multi-
cells. β2M levels can be elevated in on MRI. In stage III disease, >20 fo-
ple myeloma, a radiographic skeletal
patients with renal disease, lym- cal bone lesions and/or severe diffuse
survey should be performed concur-
phoma, and other disease processes; spine disease is visible on MRI.
rently with bone marrow aspiration
therefore, the ISS should be applied
only to patients who match the crite- and either serum or urine electropho- Radiography
ria for the diagnosis of multiple my- resis. The survey should be scruti- Plain radiographs are the standard of
eloma. nized for multiple lytic lesions. The care for evaluation of persons with
ISS stage I disease is defined by a number of lytic bone lesions is one myeloma. A survey of the appendicu-
β2M level <3.5 mg/L and serum al- criterion in the Durie-Salmon staging lar skeleton, spine, pelvis, and skull
bumin level ≥3.5 g/dL. Patients with system. In 2003, the original system should be performed in persons with
stage II disease have β2M levels be- was updated to incorporate MRI suspected myeloma. However, le-
tween 3.5 and 5.4 mg/L. Stage III findings and was renamed Durie- sions are not evident on plain radio-
disease is characterized by β2M level Salmon PLUS.14 In the updated sys- graphs until approximately 50%
≥5.5 mg/L. The ISS correlates well tem, stage I disease is characterized bone destruction has occurred.2 Even
with average reported survival rates: by the presence of zero to four focal so, approximately 80% of patients
stage I, 62 months; stage II, 44 bone lesions and/or mild diffuse with multiple myeloma have positive
months; and stage III, 29 months.13 spine disease on MRI. Stage II dis- radiographic findings at presenta-
Figure 3 Figure 4
lidomide-dexamethasone); however, of autologous stem cells, followed by therapy, such as anemia and neurop-
no survival benefit has been shown.1 high-dose melphalan chemotherapy athy. Adjuvant agents and processes,
and infusion of stem cells.1 Tandem including diphosphonates, growth
Transplant Candidate sequential autologous (ie, double- factors, transfusion, and vitamin
Transplant candidates undergo in- auto) transplants have demonstrated supplements, can be used to manage
duction therapy consisting of dexa- an advantage in patients with resid- these complications (Table 2).
methasone combined with thalido- ual myeloma following the first
mide, lenalidomide, or bortezomib.1,3
transplant.3,27
Combinations include lenalidomide
Minimal myeloablative (ie, mini- Orthopaedic
and dexamethasone; bortezomib and Considerations
allo) regimens were developed in re-
dexamethasone; bortezomib, thalid-
sponse to substantial mortality fol- The orthopaedic surgeon may be
omide, and dexamethasone; and
lowing high-dose melphalan and consulted to perform a biopsy for
bortezomib, lenalidomide, and dex-
high-dose total body irradiation with
amethasone. Approximately 70% to initial diagnosis, provide recommen-
allogeneic stem cell transplantation.
90% of patients respond to initial dations for nonsurgical care, per-
A combination of autologous trans-
therapy.1 Side effects include myelo- form prophylactic fixation of im-
plant followed by mini-allo trans-
suppression, thrombosis, gastrointes- pending fractures, or stabilize
plant has been shown to be success-
tinal effects (eg, infection, diarrhea), pathologic fractures in the patient
ful.28 In one study, 6 of 13 patients
and neuropathy. Most of these side with myeloma bone disease. Typi-
who showed response to initial che-
effects are reversible. cally, a patient presents with an im-
motherapy and who achieved partial
pending or pathologic fracture with
or complete remission following the
Autologous and Allogeneic no prior diagnosis of myeloma. In
combined procedure were event-free
Stem Cell Transplantation the patient with a bone lesion and
at 2-year follow-up.29 Maintenance
Autologous stem cell transplantation unknown primary malignancy, the
therapy with interferon alpha or
involves transplantation of the pa- workup includes radiographs of the
prednisone can be considered after
tient’s own stem cells after chemo- entire bone; bone scan; MRI of the
autologous or allogeneic stem cell
therapy. This procedure is not cura- extremity; CT of the chest, abdomen,
transplant in an effort to prolong the
tive. However, it has been shown to and pelvis; complete blood count; se-
time to progression; however, con-
increase disease-free survival by 2 to rum and/or urine electrophoresis;
troversy persists regarding the bene-
3 years.3 Candidates are selected prostate-specific antigen in men; and,
fit of this therapy.1
based on age, performance status (ie, in women, a breast examination or
measure of disease burden on overall mammogram. In a prospective study
Salvage Therapy
patient activities), and evidence of of 40 patients with skeletal metasta-
preserved organ function. In younger Eventual relapse after treatment is ses of unknown origin who were
transplant candidates (ie, aged <65 the natural history of multiple my- evaluated using this strategy, the pri-
years), combinations of induction eloma. With relapse that occurs >6 mary site of the malignant tumor
chemotherapeutic drugs are recom- months after prior therapy, the was identified in 34 patients
mended. These drugs are not toxic to potential exists for a therapeutic re- (85%).31
the hematopoietic cells and do not sponse to the initial therapy regi- When the electrophoresis is posi-
impair the ability to collect adequate men.30 Regimens for relapsed my- tive, radiographic bone survey and
numbers of peripheral blood stem eloma that have been studied and bone marrow biopsy are performed
cells. Given the multiple treatments approved by the US FDA include for staging. However, no further bi-
available and the lack of consensus lenalidomide and dexamethasone, opsy of the lesion is required for di-
regarding which is most effective, pa- bortezomib and dexamethasone, and agnosis. Biopsy is required in some
tients are encouraged to enroll in bortezomib and liposomal doxoru- cases, such as in the patient with sus-
clinical trials in an effort to deter- bicin. pected plasmacytoma and when elec-
mine best practices. trophoresis is not obtained. Biopsy
In general, patients are treated Additional Adjuvant Agents must be done carefully because my-
with a chemotherapy regimen for Patients with multiple myeloma may eloma lesions can be very vascular,
several months until maximal re- suffer from conditions related to the and there is a risk of substantial
sponse is achieved, after which they complexity of the disease process blood loss. This should also be taken
undergo mobilization and collection and to complications associated with into account during preplanning for
Figure 5 Figure 6
AP radiograph demonstrating
humeral stabilization with an A, Preoperative AP radiograph of the hip demonstrating pathologic fracture
intramedullary implant in a patient through a myeloma lesion. B, Postoperative AP radiograph demonstrating a
with a myeloma lesion in the stable, durable construct achieved with a modular proximal femoral
humerus. prosthesis.
avoid creating new stress risers in intact, we prefer to perform curet- years after the procedure.39 MRI
pathologic bone (Figure 5). For a tage of the lesion and stabilize it with should be done preoperatively to as-
large defect, curettage can be per- polymethylmethacrylate cement and sess for extraosseous disease. In the
formed, and the bone can be stabi- modified Harrington pin fixation. If patient with considerable soft-tissue
lized with polymethylmethacrylate the subchondral plate is violated by involvement, radiation therapy to
cement around the intramedullary tumor extension, complex total hip the area before stabilization may be
device. reconstruction with an acetabular
helpful.
For a periarticular lesion, a custom cage is performed. Internal or exter-
Neural compression or more ex-
or megaprosthesis can be used, with nal hemipelvectomy can be consid-
tensive spinal bony involvement that
the goal of achieving an immediately ered in the patient with intractable
is not amenable to a percutaneous
durable construct that allows early pain.
procedure is relatively rare, given the
mobilization36 (Figure 6). Good func- Spinal compression fractures have
sensitivity of the disease to radiation
tional results and pain relief can be been identified in >40% of patients
therapy. In patients who present with
expected.36,37 The surgeon should with newly diagnosed myeloma.2 In
painful lesions, percutaneous verte- either neural compression or exten-
avoid using press-fit implants and
constructs that rely on bony in- broplasty has proved to be effective sive bony involvement, effective
growth. in alleviating pain.38 In that study, all management typically consists of spi-
The periacetabular region is a com- 10 patients with multiple myeloma nal cord decompression and stabili-
mon site of myeloma lesions. Periac- reported mild or moderate pain re- zation of the vertebral column
etabular lesions often present with lief. These interventions allow imme- through an anterior, a posterior, or a
large cavities and are painful as a re- diate improvement in quality of life combined approach. Although these
sult of their presence in a weight- following an outpatient procedure or procedures are extensive, they result
bearing area. Few appealing surgical a short hospital stay (80% reported in significant improvement in patient
interventions exist, given the com- pain relief within 7 days of the pro- quality of life and pain reduction,
plex anatomy of the bony pelvis. If cedure).38 In most patients, pain re- along with stabilization or improved
the acetabular subchondral plate is lief can be expected to last up to 2 neurologic function.39
lesions. Pain relief is typically ment of impending and pathologic 10. Vejlgaard T, Abildgaard N, Jans H,
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achieved with a dose of approxi-
bone turnover in monoclonal
mately 3,000 cGy administered in 10 gammopathy of undetermined
to 15 fractions.42 significance: Analyses of type I collagen
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