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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_2915_Библиотеки_им_академика_М_И_Перельмана.pdf
Chapter 15
Multiple Myeloma
Introduction
Multiple myeloma (MM) is recognized since 1845, when the first case was noted with
bone pain. The term MM was coined in 1873, reflecting distinct sites of bone involvement.
Currently MM is considered part of a spectrum of diseases ranging from monoclonal
gammopathy of unknown significance (MGUS) to plasma cell leukemia.
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.
Complications typically seen with MM are bone pain, hypercalcemia, renal failure, and spinal
cord compression.
Although patients benefit from treatment in terms of quality of life, currently there is no
cure. In this chapter we will discuss the role of radiotherapy in the management of this
disease.
1. Epidemiology
• About 20000 cases of myeloma are diagnosed each year, and approximately 10,000
people died from the disease in the United States.
• Myeloma increases in incidence with age. The median age at diagnosis is 68 years; it
is uncommon in people younger than age 40.
• Males are more commonly affected than females, and blacks have nearly twice the
incidence of whites.
• Myeloma accounts for ∼1% of all malignancies in whites and 2% in blacks; 13% of
all hematologic cancers in whites and 33% in blacks.
• The higher incidence in more developed countries may be a result from the
combination of a longer life expectancy and more frequent medical surveillance.
Gustavo Arruda Viani
232
Chronic inflamation
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.
Associated conditions
Obesity, RA, MGUS
Family History
4 fold increased risk (autosomal dominant)
Occupational
Exposures
Case-controlled studies have suggested a significant risk of developing MM in
individuals with significant exposures in the agriculture, food, and
petrochemical industries.
Infection
Human herpesvirus 8 (HPV8) infection of bone marrow dendritic cells was
found in patients with MM and in some patients with MGUS.
Radiation exposure
Radiation may play a role in some patients. An increased risk has been reported
in atomic-bomb survivors exposed to more than 50 Gy.
Reference
Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin. 2012;62(1):10.
2. Risk Factors
The cause of myeloma remains unknown. But, several factors Roles have been suggested,
including genetic causes, environmental or occupational causes, MGUS, radiation, chronic
inflammation, and infection.
Table 1. Risk factors for developing multiple myeloma
References
Waxman AJ, Mink PJ, Devesa SS, Anderson WF, Weiss BM, Kristinsson SY, McGlynn KA,
Blood. 2010;116(25):5501.
Lynch HT, Sanger WG, Pirruccello S, Quinn-Laquer B, Weisenburger DD. Familial multiple
myeloma: a family study and review of the literature. J Natl Cancer Inst. 2001;93
(19):1479.
3. Clinical Features
Presenting symptoms of multiple myeloma (MM) include:
• Bone disease. The most common symptom in patients with myeloma is bone pain.
Bone pain affects nearly 70% of patients. Persistent localized pain in a patient with
myeloma usually signifies a pathologic fracture. The bone lesions of myeloma are
caused by the proliferation of tumor cells, activation of osteoclasts that destroy bone,
and suppression of osteoblasts that form new bone.
• Anaemia. Anaemia, which may be quite severe, is the most common cause of
weakness in patients with MM.
Multiple Myeloma
233
Description
Monoclonal gammopathy of undetermined significance (MGUS)
M protein in serum <30 g/L
Bone marrow clonal plasma cells <10%
No evidence of other B cell proliferative disorders
No myeloma-related organ or tissue impairment
(no end organ damage, including bone lesions)a
Asymptomatic myeloma (smouldering myeloma)
M protein in serum ≥30 g/L and/or
Bone marrow clonal plasma cells ≥10%
No myeloma-related organ or tissue impairment (no end
organ damage, including bone lesions) or symptoms
Symptomatic multiple myeloma
M protein in serum and/or urine
Bone marrow (clonal) plasma cells ≥10% or plasmacytoma
Myeloma-related organ or tissue impairment
(end organ damage, including bone lesions)
• Hypercalcaemia. 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.
• 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.
Reference
Kyle RA, Gertz MA, Witzig TE et al. Review of 1027 patients with newly diagnosed multiple
myeloma. Mayo Clin Proc. 2003;78(1):21.
4. Diagnostic and Evaluation
• The clinical evaluation of patients with myeloma includes a careful physical
examination searching for tender bones and masses.
• The classic triad of myeloma is marrow plasmacytosis (>10%), lytic bone lesions,
and a serum and/or urine M component.
• The most important differential diagnosis in patients with myeloma involves their
separation from individuals with monoclonal gammopathies of uncertain significance
(MGUS), asymptomatic myeloma, nonsecretory myeloma nad plasmocytoma of
bone. MGUS are vastly more common than myeloma, occurring in 1% of the
population >50 years of age and in up to 10% individuals >75 years. The diagnostic
criteria for MM and other conditions, are described in Table- 2.
Table 2. Criteria of diagnostic for MM and other conditions
Gustavo Arruda Viani
234
Description
Nonsecretory myeloma
No M protein in serum and/or urine with immunofixation
Bone marrow clonal plasmacytosis ≥10% or
plasmacytoma
Myeloma-related organ or tissue impairment
(end organ damage, including bone lesions)a
Solitary plasmacytoma of bone
No M protein in serum and/or urinec
Single area of bone destruction due to clonal plasma cells
Bone marrow not consistent with multiple myeloma
Normal skeletal survey (and MRI of spine and pelvis if done)
No related organ or tissue impairment
Test
Description
Laboratory
tests
A complete blood count and differential with examination of the peripheral blood
smear.
A chemistry screen that includes measurements of serum calcium, creatinine,
albumin, lactate dehydrogenase, beta-2 microglobulin, and C-reactive protein.
Serum free monoclonal light chain (FLC) analysis.
A serum protein electrophoresis (SPEP) with immunofixation and quantitation of
immunoglobulins.
A routine urinalysis and a 24-hour urine collection for electrophoresis (UPEP) and
immunofixation. Serum free FLC analysis may be used in place of a 24-hour urine
collection in conjunction with SPEP and immunofixation for screening purposes
only.
Bone marrow
aspiration
Bone marrow aspiration and biopsy with immunophenotyping, conventional
cytogenetics, and fluorescence in situ hybridization (FISH)
Radiographs
Radiographs of humeri and femoral bones should be performed in all patients
(figure-1). If patients have a normal bone survey in the setting of bone pain, or
have neurological deficits that may be due to spinal cord compression, additional
imaging such as MRI, CT, or PET/CT should be performed.
Table 2. (Continued)
• The evaluation of patients suspected of having MM should include a complete
history and physical examination. The history should pay specific attention to
complaints such as; bone pain, constitutional symptoms, neurological symptoms, and
infections. Laboratory studies are also requerid as an initial evaluation for MM.
Table-3 sumarizes the tests requerid for evaluation of patients suspeted of MM.
Table 3. Tests for evaluation and diagnosis of MM
Figure 1. X-ray showing osteolitic bone lesions.
Multiple Myeloma
235
Stage
Criteria
I
II
III
All of the following:
1. Hemoglobin >100 g/L (>10 g/dL)
2. Serum calcium <3 mmol/L (<12 mg/dL)
3. Normal bone x-ray or solitary lesion
4. Low M-component production
a. IgG level <50 g/L (<5 g/dL)
b. IgA level <30 g/L (<3 g/dL)
c. Urine light chain <4 g/24 h
Fitting neither I nor III
One or more of the following:
1. Hemoglobin <85 g/L (<8.5 g/dL)
2. Serum calcium >3 mmol/L (>12 mg/dL)
3. Advanced lytic bone lesions
4. High M-component production
a. IgG level >70 g/L (>7 g/dL)
b. IgA level >50 g/L (>5 g/dL)
c. Urine light chains >12 g/24 h
Stage
I
II
II
New international staging system
Criteria MS (months)
Serum b2-microglobulin <3.5 mg/L
Serum albumin >3.5 g/dL 62
Neither stage I nor stage III 44
Serum b2-microglobulin >5.5 mg/L 29
Reference
Smith A, Wisloff F, Samson D, UK Myeloma Forum, Nordic Myeloma Study Group, British
Committee for Standards in Haematology. Guidelines on the diagnosis and management
of multiple myeloma 2005. Br J Haematol. 2006;132(4):410.
5. Staging
The Durie-Salmon staging system is based on the hemoglobin, calcium, M component,
and degree of skeletal involvement; the total body tumor burden is estimated to be low (stage
I), intermediate (stage II), or high (stage III), and the stages are further subdivided on the
basis of renal function [A if serum creatinine < 2 mg/dL), B if > 2]. Patients in stage IA have
a median survival of >5 years and those in stage IIIB about15 months.
Table 4. Durie-salmon staging system
Reference
Greipp P, San Miquel J, Durie B et al. International staging system for multiple myeloma. J
Clin Oncol. 2005; 23:3412–3420
Gustavo Arruda Viani
236
High risk markers
Conventional cytogenetics
Deletion of chromosome 13 (monosomy)
Hypodiploidy
Either hypodiploidy or deletion 13
Fluorescent in-situ hybridization
t(4;14)
t(14;16)
17p-
Plasma cell labeling index (PCLI) studies: PCLI ≥3 percent
Any one of the above high-risk abnormalities
6. Prognostic Factors
• Staging at diagnosis is the most important prognostic factor for multiple myeloma.
• Hypodiploidy and chromosome 13 deletion are prognostic factors associated with
poor survival.
• t(4;14) and 17p13 deletions are associated with poor survival independent of the ISS
staging.
• Patients with t(4;14) and 17p13 deletion have a median disease free progression less
than 1 year after stem cell transplantation. (Gertz et al. 2005).
Reference
Gertz MA, Lacy M. Dispenzieri A, et al (2005) Clinical implications of t(11;14)(q13;q32),
t(4;14)(p16.3;q32), and -17p13 in myeloma patients treated with high-dose therapy.
Blood 106:2837–2840
7. Treatment
To guide treatment of patients with MM, they are stratified at the time of diagnosis into
two main risk categories (standard risk and high risk). This system has a prognostic value, as
described in table-5.
Table 5. Risk group defition for MM
• On the other hand, patients without any high risk markers are classified as standard
risk myeloma. For these patients chemotherapy alone or chemotherapy plus
hematopoietic cell transplantation (HCT) are reasonable options.
• For patients who will be undergone to HCT, induction therapy followed by
autologous HCT should be recommended. Another option is chemotherapy alone
with HCT delayed at the time of first relapse. The chemotherapy regimens suggested
for standard risk are melphalan, prednisone, and thalidomide (MPT) or bortezomib,
melphalan, and prednisone (VMP) rather than melphalan plus prednisone (MP).
Multiple Myeloma
237
• Patients at high risk for MM who are candidates for HCT, bortezomib-based regimen
as initial treatment, delaying HCT until first relapse is a reasonable option. On the
other hand, patients at high risk who are not candidates for HCT should be treated by
bortezomib-based regimens.
8. Radiotherapy Techniques
Computed tomography (CT) simulation can be used to design the treatment fields.
Particularly for treatment to the long bones, the choice of immobilization device and
position must be made individually, considering field arrangement, as well as the
reproducibility and comfort of the patient. The gross tumor is usually best visualized on
imaging studies and should be encompassed with a field margin of at least 2 cm for long
bones.
This involved-field design is preferred to minimize bone marrow toxicity, especially in
patients planned for stem cell transplant (figure-2).
For disease in long bones, at least 2-cm margins to radiographic lesion is sufficient and
not shown to be inferior to whole bone irradiation (figure-xx). For diseases of vertebral
bodies the treatment fields including 1 or 2 vertebral bodies above and below should be used.
Dose of radiation depends on disease factors (e.g., indication for treatment), patient factors
(e.g., performance status), and treatment factors (surgical or systemic options).
Typical schedules for MM radiation therapy include 8 Gy in 1 fraction, 20 Gy in 5
fractions, 30 Gy in 10 fractions, and 37.5 Gy in 15 fractions.
Figure 2. Involved field design for multiple myeloma.
Gustavo Arruda Viani
238
Conclusion
• The treatment for multiple myeloma remains based on high-dose therapy with stem
cell transplantation.
• Recently, three novel agents, thalidomide, lenalidomide, and bortezomib have been
approved for treatment of multiple myeloma.
• The use of these novel agents prior to transplantation and as maintenance therapy has
greatly improved outcomes.
• On the other hand, for non–transplant- eligible patients, the incorporation of novel
agents into their treatments has greatly improved survival.
• Radiation therapy has an important role in treating symptomatic bone disease.
Section - V. Palliative Radiotherapy
