Chapter 79
Plasma Cell Myeloma and Plasmacytoma
David C. Hodgson
Joseph Mikhael
Richard W. Tsang
Epidemiology and Etiology
Plasma cell neoplasms account for 22% of all mature B-cell
neoplasms in the Surveillance, Epidemiology, and End Results (SEER) program in
the United States (85). The majority of plasma cell neoplasms are multiple
myeloma, with solitary plasmacytoma accounting for ≤6% of cases and rarely
plasma cell leukemia. Although the incidence of multiple myeloma has gradually
increased in the 1970s through the 1990s (100), recently there has been a
downward trend, with an annual decrease of 0.3% from 1992 to 2002 (101). Data
from SEER indicate an incidence rate of 5.5/100,000 per year and mortality rate
of 3.8/100,000 per year during the period 1998 to 2002 (101). For 2007, it is
estimated that there will be 19,900 new cases and 10,790 deaths due to multiple
myeloma in the United States (5). The incidence rate exceeds that of Hodgkin's
lymphoma and is about one-quarter that of non-Hodgkin's lymphoma. The incidence
rate rises with advancing age, with a median age at diagnosis of 70 years
(101), and <1% of cases are diagnosed in persons <35. Nonregistry studies
usually report a lower median age ranging from 60 to 66 years (50,68). There is
a slight male predominance, and for black Americans, the incidence and
mortality rates are approximately double that of whites. The 5-year relative
survival rates have increased, from 26% in 1975 to 1977, to 33% in 1996 to 2002
(p <.05) (5). The etiology of multiple myeloma is not known, but there are
studies reporting association with prior exposure to radiation (e.g., atomic
bomb survivors in Hiroshima) (88), certain chemicals such as petroleum products
(18,29), and monoclonal gammopathy of unknown significance (MGUS) (69). The
previously reported association with herpes simplex virus type 8 does not
appear to be causally related (113).
Natural History, Genetic Mechanisms
Multiple myeloma is a disease with a wide clinical spectrum,
ranging from the condition known as MGUS to the most aggressive form, plasma
cell leukemia (Table 79.1). In all cases, a plasma cell clone exists but to
varying degrees. The secretion of a monoclonal protein by these plasma cells,
along with their interaction with the bone marrow environment, is the source of
organ damage in patients with this illness (54). These concepts have become
particularly important as the molecular mechanisms by which the disease
progresses through these “stages” provide essential information that may help
to better understand the disease and its potential therapies.
Monoclonal Gammopathy of Unknown Significance
MGUS has traditionally been considered a benign or a
premalignant condition in which only a small proportion of patients will
progress to multiple myeloma or related diseases (see Table 79.1). In MGUS, the
monoclonal protein is ≤3 g/dL and the bone marrow clonal plasma cells are <10%
with no related organ damage. This condition is likely much more common than
initially thought, as it has been documented in 3% of the overall population
and 5% in those over the age of 70 (70). The risk of transformation to myeloma
and related diseases (such as amyloidosis or Waldenstrom's macroglobulinemia)
has been estimated at 1% per year, based on a 30-year follow-up of 1,384
patients at the Mayo Clinic (69).
Asymptomatic Multiple Myeloma (Smoldering Myeloma)
Asymptomatic multiple myeloma represents an intermediate
form of myeloma whereby patients meet serological monoclonal protein and bone
marrow criteria for the diagnosis of myeloma (in excess of 10% clonal
plasmacytosis) but have yet to develop evidence of end organ damage (see Table
79.1). These patients are not significantly anemic, do not have renal
insufficiency, and do not have bony disease. Although the risk of
transformation to multiple myeloma is much higher than in MGUS (5–10% per
year), some patients may “smolder” for many years. These patients generally do
not require therapy but should be followed closely to monitor for progression.
Pathophysiology
Multiple myeloma arises from malignant transformation of a
late-state B cell. Although the seminal event has yet to be defined, one of the
earliest genetic events is the illegitimate switch recombination of partner
oncogenes into the immunoglobulin heavy (IgH) chain (65). Other events may
occur such as cytogenetic hyperploidy and upregulation of cell cycle control
genes. The result of these genetic abnormalities is the development and
propagation of a clonal population of B cells within the bone marrow; this,
however, is common and can be seen in up to 5% of the general population over
the age of 70 (70). Most of these will not go on to develop myeloma, so there
must be additional events to create the malignant phenotype of multiple
myeloma. These secondary events may include mutations of kinases, deletions of
chromosomes, and up-regulation of enzymes such as c-myc (43). Having sustained
a secondary event, the malignant plasma cells begin to proliferate in the bone
marrow microenvironment, producing monoclonal proteins and causing osteolytic
bone disease. The slow accumulation of these malignant cells gradually results
in the characteristic clinical features of myeloma of anemia, bone resorption,
hypercalcemia, renal failure, and immunodeficiency. Established myeloma is
dependent and sustained on a number of microenvironment features, including the
bone marrow stroma itself and the cytokines interleukin-6 and insulinlike
growth factor-1 (54). The bone disease that arises in myeloma appears to be
mediated in part by RANK ligand/osteoprotegerin and the Wnt-signaling
antagonist dickkopf 1 (DKK1) (114).
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Clinical Presentation
Solitary Plasmacytomas
The median age at diagnosis of solitary plasmacytoma (SP) is
55 to 65 years, on average about 10 years younger than patients with multiple
myeloma (90,110,117). Males are affected predominately (male:female ratio 2:1)
(90). A diagnosis of SP is made if all the following criteria are satisfied at
presentation: a histologically confirmed single lesion with negative skeletal
imaging outside the primary site, normal bone marrow biopsy (<10% monoclonal
plasma cells), and no myeloma-related organ dysfunction (37). A monoclonal
protein is present in 30% to 75% of cases (particularly for an osseous
presentation), the level is usually minimally elevated (IgG <3.5 g/dL, IgA
<2.0 g/dL, and urine monoclonal kappa or lambda <1.0 g per 24 hours)
(37,121).
The disease more commonly presents in bone (80%). Such cases
are considered stage I multiple myeloma according to the Durie and Salmon (38)
staging system. The most common location is the vertebra (90). Patients with
bone involvement often present with pain, neurologic compromise, and
occasionally pathologic fracture. A lytic lesion is typical, with or without
adjacent soft tissue mass. Less commonly SP presents in an extramedullary site
(20%), usually as a mass in the upper aerorespiratory passages that produces local
compressive symptoms (4,90,110,116). The histologic diagnosis of extramedullary
plasmacytoma (EMP) can be difficult, with the main differential diagnosis being
extranodal marginal zone lymphoma (MALT type), where there can be extensive
infiltration by plasmacytoid cells (4,58).
Multiple Myeloma
Bone pain and symptoms due to anemia, such as easy
fatigability, are the most common (68). Because of the myriad effects of the
disease, other insidious symptoms can result from a combination of
hypercalcemia, renal impairment, infection, neurologic compression, and
occasionally, hyperviscosity. Bone disease manifesting as generalized
osteopenia and multiple lytic bone lesions can frequently lead to pathologic
fractures. In the vertebral column, this often results in a diminished height.
Sclerotic lesions at presentation are rare.
Laboratory evaluation generally confirms anemia, high
erythrocyte sedimentation rate, and a variable degree of granulocytopenia and
thrombocytopenia. An abnormal monoclonal immunoglobulin (M-protein) in the
blood and/or urine is characteristic (68), most commonly immunoglobulin G (IgG)
or immunoglobulin A (IgA). Biclonal disease is also recognized, and, rarely,
nonsecretary disease. Occasionally only monoclonal light chains are detected. It
is important to assess for hypercalcemia, renal dysfunction, and integrity of
the skeleton because these complications require appropriate management. A
constellation of polyneuropathy, organomegaly, endocrinopathy, M-protein, and
skin changes characterize a rare plasma cell dyscrasia known as polyneuropathy,
organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS)
syndrome (33,89).
Plasma Cell Leukemia
Plasma cell leukemia is a very rare variant of multiple
myeloma, where the proliferation of plasma cells is not confined to the bone
marrow but may be detected in the peripheral blood. It carries a very poor
prognosis with median survival of only 3 to 6 months (123). There is currently
no standard therapy for this condition, but patients are usually treated with
high-dose, multiagent chemotherapeutic regimens or with experimental therapies.
Diagnostic Work-Up and Staging
The recommended tests for the diagnosis of plasma cell
neoplasms are outlined in Table 79.2. The most important components relate to
the measurement and quantification of the M-protein, bone marrow examination
with ancillary
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studies, serum β2 microglobulin and albumin, and diagnostic
imaging of involved bony sites. The M-protein should be measured with serum
protein electrophoresis (SPEP). Quantification of the monoclonal immunoglobin
with immunofixation techniques is also acceptable and especially useful if the
M component is at a low level. If no M-protein is detectable, assays for free
light chains should be performed in the serum and in the urine (Bence-Jones
proteinuria). The standard imaging is the skeletal survey, as radionuclide bone
scan usually does not detect lytic disease and has limited value (37). For
localized areas of concern, both computed tomography (CT) or magnetic resonance
imaging (MRI) should be liberally utilized. MRI is preferred to assess the
extent of vertebral disease and the presence of spinal cord or nerve root
compression. With advances in diagnostic imaging, it is likely that “stage
migration” has occurred (41). It has been documented that some patients with
presumed solitary plasmacytoma of bone will be upstaged following the detection
of multiple vertebral lesions or bone marrow disease by MRI (74,76,118) or by
18F-fluorodeoxyglucose positron emission tomography (FDG-PET) (105). The
staging criteria for the widely used Durie and Salmon staging system are
detailed in Table 79.3 (38). The newer International Myeloma staging system is
simple, validated, and of importance particularly for present and future
clinical trials (see Table 79.3) (50). Criteria for the diagnosis of MGUS and
asymptomatic (smoldering) myeloma are also well established (37,51).
Prognostic Factors
Solitary Plasmacytoma
Age is a factor affecting the risk of progression to myeloma
in some series (14,24,117) but not in others (20,56,77,90,106). A bony
presentation has been consistently demonstrated to have a significantly higher
risk of subsequent development of myeloma with a 10-year rate of 76%, compared
with an extramedullary presentation where the 10-year rate was 36% (Fig. 79.1)
(90). Subclinical bone disease, either detected as generalized osteopenia (45)
or through abnormal MRI scan of the spine (76,86,118), predicts for rapid
progression to symptomatic multiple myeloma. A suppression of the normal
immunoglobulin classes, also known as immunoparesis, has been shown to
correlate with a higher risk of progressing to myeloma (45,59). Where there was
an elevation of M-protein pretreatment, the persistent of the M-protein
following radiation therapy (RT) predicts for progression to myeloma (74,121).
Many of these factors reflect the presence of occult myeloma. Therefore, it is
not surprising that generalized disease becomes manifest once the local disease
is controlled. Pathologic factors have been examined in some studies, with the
finding that anaplastic plasmacytomas (those with a higher histologic grade)
(112), and those tumors expressing a high level of angiogenesis (67) are
associated with a poor outcome. Anaplastic plasmacytomas share some common
pathologic and clinical features with aggressive B-cell lymphomas
(plasmablastic type) and can arise in the context of immunosuppression and Epstein-Barr
virus infection (28,42).
With respect to local control, tumor bulk appears to be an
important unfavorable factor. Tumors <5 cm achieved a high level of local
control with 35 Gy, whereas those >5 cm had a local failure rate of 58%
(7/12 patients, total dose range 25 to 50 Gy) (117). The importance of tumor
bulk is also supported by other studies (56,77,90).
Multiple Myeloma
Univariate analysis of over 1,000 patients evaluated at the
Mayo Clinic revealed the following adverse prognostic risk factors: Eastern
Cooperative Oncology Group performance status 3 or 4, serum albumin <3 g/dL,
serum creatinine ≥2 mg/dL, platelet count <150,000/µL, age ≥70 years, β2
microglobulin >4 mg/L,
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plasma cell labeling index ≥1%, serum calcium ≥11 mg/dL,
hemoglobin <10 g/dL, and bone marrow plasma cell ≥50% (68).
A new International Staging System has been validated to
assist in prognostication (50). Over 10,000 patients were evaluated, and the
three-stage system was developed based on two variables: serum albumin and β2
microglobulin (see Table 79.3). In addition to stage, the other area emerging
as important to prognosis is cytogenetics. Much like acute leukemia,
cytogenetic and molecular features are influencing treatment options. Some
abnormalities demonstrated to carry a poorer prognosis include: deletion of
chromosome 13 (39), presence of the t(4;14) translocation (25), and p53
deletion (92). It is expected that additional cytogenetic and molecular
features of prognostic significance will be identified, especially with
enhanced techniques such as fluorescence in situ hybridization and gene
microarray analysis.
Management of Solitary Plasmacytoma
RT is the standard treatment for solitary plasmacytoma.
Surgery should be considered for structural instability of bone or rapidly
progressive neurologic compromise such as spinal cord compression (37,109,111).
For patients treated with gross tumor excision, RT is still indicated due to a
high likelihood of microscopic residual disease. Surgery alone without RT leads
to an unacceptably high local recurrence rate (90). A review of the literature
for solitary bone plasmacytoma in Table 79.4 indicates a high local control
rate with RT (79% to 95%), yet a modest overall survival of approximately 50%
at 10 years. This is due to a high rate of progression to multiple myeloma in
the bone plasmacytomas, a finding consistently reported from all series (see
Fig. 79.1) (14,24,44,45,56,59,63,90,117,121). As shown in Table 79.4, over 60%
of patients with solitary bone tumor progressed to myeloma, at a median of 2 to
3 years after treatment. When actuarial methods were not used, the progression
rate is slightly lower (crude rates ranges 53% to 54%) (44,56). Therefore,
solitary plasmacytoma of the bone appears to be an early form of multiple
myeloma. Studies have documented about 29% to 50% of patients with apparent
solitary plasmacytoma will have multiple asymptomatic lesions detected in the
spine on MRI (76,87,118). Provided that all the other diagnostic criteria for
solitary plasmacytoma are satisfied, it is still appropriate to treat with
local RT to the presenting site (109). For these patients the risk of
developing symptomatic myeloma in a short time is high (76,86,118).
Chemotherapy can be started at the time of symptomatic progression. The
presence of low level M-protein preradiation is extremely common and is not
associated with a higher risk of progression to multiple myeloma. However, its
persistence following radiation is highly predictive of subsequent systemic
failure (31,45,74,121), attesting to the importance of monitoring this as part
of posttreatment follow-up.
The addition of adjuvant chemotherapy is theoretically
attractive, both in enhancing local control and eradicating subclinical disease
to prevent the development of myeloma. One randomized trial suggested a benefit
with adjuvant melphalan and prednisone given for 3 years after RT (10). With a
median follow up of 8.9 years, those treated with chemotherapy had a myeloma
progression rate of 12%, whereas with RT alone it was 54% (10). However, this
was a small study and the concerns regarding prolonged use of alkylating agents
on the bone marrow (negative effect on stem cell reserve and risk of leukemia)
do not justify its routine use.
It has been observed that some patients recur with
plasmacytoma(s) of bone or soft tissues, without bone marrow involvement
(14,56,64). This is infrequent and the subsequent development of multiple
myeloma is high, 75% in one series (14).
In the management of EMP, while complete surgical excision
may be curative for small lesions, most patients with larger lesions or those
with tumor location not amenable to complete excision should receive local RT.
Postoperative RT is indicated for incompletely excised lesions. In contrast to
bone plasmacytoma, EMPs are frequently controlled with local radiation (Table
79.5), with a lower rate of progression to myeloma, ranging from 8% to 44%
(22,27,46,61,64,75,90,108,110,112,116,122), indicating a significant proportion
of patients are cured of their disease. Although the 10-year survival varies
widely in the reported literature (range 31% to 90%), the two largest series
report 10-year survival rates of 72% (90) and 78% (46). The issue of dose will
be discussed later.
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Management of Multiple Myeloma
A description of therapy of myeloma would not be complete
without addressing the need to treat not only the disease itself, but the
complications of this disease. Patients often present with both bony disease
and anemia—both of these complications are treatable, allowing an improved
quality of life. Erythropoietic agents have become the mainstay of anemia
management, as have bisphosphonates (15,16,17,35) and local RT for bony
disease. Newer surgical techniques such as vertebroplasty and kyphoplasty are also
being used to improve back pain and spinal symptoms. Other supportive care
interventions being addressed include diet, exercise, and patient support
groups.
Initial Treatment of Symptomatic Multiple Myeloma
Patients who have symptomatic multiple myeloma require
treatment of the malignant plasma cell clone. Once the decision is made to
treat, however, the first step is to determine candidacy for autologous stem
cell transplantation (ASCT) (Fig. 79.2). As this modality has become the
standard of care for eligible patients, it is necessary to stratify patients
initially so that the ability to collect stem cells is not compromised by
induction therapy (49).
Patients Eligible for Autologous Stem Cell Transplantation
In patients who are candidates for ASCT, various regimens
can be used to induce response prior to stem cell collection. Historically most
regimens are high dose and steroid based, either with high-dose dexamethasone
alone (3) or with vincristine, adriamycin, and dexamethasone (VAD) (104). An
alternative induction is the combination of thalidomide and dexamethasone.
Rajkumar et al. (95) demonstrated in 50 patients that this combination yields a
response rate of 64% (similar to VAD), without compromising the ability to
collect stem cells, but with a rate of deep vein thrombosis of 12% (95). Newer
agents that have been validated in the relapse setting, such as bortezomib and
lenalidomide, are now being tested as initial therapy with impressive results.
Early studies with bortezomib, a first-in-class proteosome inhibitor, have
produced response rates of 75% to 100%, with complete remission rates of 20% to
30% (97). Lenalidomide, a derivative of thalidomide, has also been tested in
newly diagnosed patients. Rajkumar et al. (96) evaluated the combination of
lenalidomide with dexamethasone in 34 patients, with a response rate of 91%.
Patients Not Eligible for Autologous Stem Cell
Transplantation
In patients who will not be undergoing a transplant, there
are various options available for initial therapy. Most will receive
alkylator-based therapy, commonly melphalan and prednisone (MP) (94). This
regimen yields partial remissions in approximately 55% of patients, with the
occasional complete response. Recent trials have evaluated the addition of
thalidomide to melphalan and prednisone (MPT). For patients aged 60 to 85,
Palumbo et al. (91) demonstrated a 76% response rate with MPT, superior to the
48% in the MP arm; however, thromboses were more common with thalidomide with
an incidence of 12% (vs. 2% in the MP group). Newer agents are now being
incorporated into trials in this population as well, including bortezomib and
lenalidomide. The precise role of these agents in older patients has yet to be
determined.
Autologous Stem Cell Transplantation
ASCT has become the standard of care for eligible patients,
as it has been demonstrated in multiple trials to improve the likelihood of
complete response, prolong disease-free survival, and
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extend overall survival (9,19,66). Treatment-related
mortality rates are now <2%, and often the transplant can be performed
entirely as an outpatient. Melphalan 200 mg/m2 is the most commonly used
conditioning regimen, although it may be reduced in elderly patients or
patients with renal insufficiency.
Tandem Transplantation
Tandem or double transplantation refers to a planned second
ASCT after the patient has recovered from the first. A phase III trial in
France evaluated tandem transplant versus single ASCT and demonstrated superior
overall survival in the tandem group (8); however, when further analyzed, the
patients who benefited most from the second transplant were those who did not
achieve a 90% reduction in their disease after the first ASCT. Therefore, it
may be more prudent to consider tandem transplantation only in patients whose
response to the first ASCT is suboptimal.
Allogeneic Stem Cell Transplantation
Myeloablative stem cell transplant is perhaps the only
current potential cure for patients with myeloma, as the graft is not
contaminated with tumor cells and may produce a profound graft versus myeloma
effect (79). However, its use is very limited due to the lack of donors, age
restriction, high treatment-related mortality, and graft versus host disease.
The general approach to myeloma is to provide sequential
therapies to patients, knowing each will not be curative but will prolong the
period of disease control. The goal is to convert the disease into a chronic
illness. Whereas there used to be very limited treatment options, the
armamentarium available has grown considerably over the past few years. This
has contributed to a prolongation of the median survival of patients with
myeloma. Patients will relapse after a median of 2 years after first ASCT (81),
and several options may be pursued for treatment (Table 79.6). The most
exciting is the development and availability of novel, biological agents.
Bortezomib is the first proteosome inhibitor to be used in clinical trials.
Various phase I and II studies have been completed, and a large multicenter
phase III trial compared bortezomib to high-dose dexamethasone (99). The
updated results of 669 patients revealed time to progression of 6.2 months in
the bortezomib arm and 3.5 months in the dexamethasone arm, along with a
superior 1-year overall survival (80% vs. 67%) favoring bortezomib (98). Side
effects included peripheral neuropathy, cyclical thrombocytopenia, and
diarrhea.
Lenalidomide is an immunomodulatory drug derived from
thalidomide and is currently undergoing extensive clinical investigation
worldwide. Its role has been established for relapsed disease based on a large
phase III trial comparing the combination of lenalidomide and dexamethasone
with dexamethasone alone (32). The trial was stopped prematurely due to a large
difference between the treatment groups favoring the lenalidomide combination
arm. Time to progression was 4.7 months with dexamethasone alone and 11.3
months in the combination arm. Overall response rates were 24% (4% complete
response [CR] and 20% partial response [PR]) with dexamethasone alone and 59%
(17% CR and 42% PR) in the combination group. There was also an overall
survival advantage, with median overall survival of 104 weeks in the
dexamethasone alone arm, but this end point had not been reached yet in the
lenalidomide arm (32). Side effects included neutropenia, thrombocytopenia, and
constipation.
Radiation Therapy of Multiple Myeloma
Total Body Irradiation
Some high dose chemotherapy protocols for multiple myeloma
incorporate total body irradiation (TBI) into the conditioning regimen. Because
of toxicity concerns (mucosal and
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hematologic) with TBI, many programs use chemotherapy alone,
most commonly melphalan. A phase III French study (Intergroupe Francophone du
Myelome [IFM] trial 9502) examined melphalan, 200 mg/m2 alone (M200) versus
melphalan 140 mg/m2 with TBI, 8 Gy in four fractions (M140/TBI) (84) and found
that patients in the TBI-containing arm suffered more grade 3 or 4 mucosal
toxicity, heavier transfusion requirement, and longer hospitalization stay.
There was a higher toxic death rate in the M140/TBI arm (3.6% vs. 0% for the
M200 arm). The event-free survival was no different between the two treatments,
but the 45-month overall survival favored the M200 arm (M200: 65.8%, M140/TBI:
45.5%; p = .05) (84).
Similarly, another IFM protocol tested TBI in the tandem
transplant setting by intensifying the conditioning regimen for the second
transplant to melphalan 200 mg/m2 without TBI and comparing with the standard tandem
regimen (M140 for the first, M140/TBI for the second). There was no benefit
with TBI, and increased toxicity was again observed. Therefore, all subsequent
IFM trials abandoned the use of TBI (52). Another study from the Spanish bone
marrow transplant registry compared M140/TBI with three other chemotherapy
conditioning regimens (71). There were no significant differences in the
hospitalization duration, hematologic recovery, event-free survival, and
overall survival among the four regimens. The authors concluded that no one
regimen was clearly superior to another.
The Toronto protocol with intensification of the
conditioning regimen to melphalan 140 mg/m2, etoposide 60 mg/kg, and
fractionated TBI (12 Gy in six fractions over 3 days, with a high dose rate)
was used in 100 patients. The main toxicity was interstitial pneumonitis (28%
of patients) of whom seven died (1), leading to discontinuation of the TBI in
the subsequent protocol. Presently, the use of TBI is based on institutional
experience and the specific drug regimen used for conditioning. The tandem
transplant program at the University of Arkansas (11,12,30) and the Memorial
Sloan-Kettering Cancer Center (57) continue to use TBI in their ASCT programs
for specific indica-tions.
Hemibody Radiation
Diffuse bone pain involving wide areas of the skeleton can
be effectively palliated by half body radiation with single doses of 5 to 8 Gy
(21,78,115), although this is rarely used now. The bone marrow in the
unirradiated half body serves as a stem cell reserve and will slowly repopulate
the irradiated marrow after treatment. The dose for upper half body should not
exceed 8 Gy due to lung tolerance (119). The main toxicity is myelosuppression.
The use of hemibody radiation must be carefully considered in patients heavily
pretreated with chemotherapy. Growth factor support may be helpful, while
transfusions of blood products should be given as needed. The sequential
hemibody radiation technique has been used in phase II (102,107) and phase III
trials as “systemic” treatment to control myeloma, in patients with or without
skeletal pain. A phase III trial by the Southwest Oncology Group (SWOG)
included newly diagnosed patients treated initially with chemotherapy, with
complete responders randomized to sequential hemibody radiation (7.5 Gy in five
fractions, upper hemibody, followed 6 weeks later by lower hemibody) or further
chemotherapy. Survival was significantly poorer with radiation compared with
chemotherapy (103). At present, there is no standard role for sequential
hemibody radiation as systemic treatment for myeloma outside of a clinical
trial, although it may remain useful for palliation of advanced disease in
chemotherapy-refractory patients.
Local External Beam for Palliation
The most common use of RT in the management of plasma cell
tumors is for palliative treatment of bony disease (2,21,73), relief of
compression of spinal cord (6,93,120), cranial nerves, or peripheral nerves. It
has been estimated that approximately 40% of patients with multiple myeloma
will require palliative RT for bone pain at some time during the course of
their disease (40). In practice the actual proportion is lower than estimated
varying from 24% to 34%, leading investigators in Australia to suggest that
this potentially useful modality of treatment has been underutilized, even
taking into account the beneficial effect of bisphosphonates, particularly for
the elderly (40). Palliative RT to the spine reduces the incidence of future
vertebral fractures or appearance of new lesions (72). However, the role of RT
in preventing impending pathologic fracture is unclear. In general, lesions at
high risk for pathologic fracture should be referred for surgical
stabilization, and RT can be administered after surgery for control of residual
disease at the local site.
When RT is given for pain due to disease involving a long
bone, a local field suffices. It is unnecessary to treat the entire bone (23).
Doses of 10 to 20 Gy (in five to 10 fractions) are effective, although the pain
relief is often partial (82). With an average dose of 25 Gy given to 306 sites
in 101 patients, Leigh et al. (73) found a symptomatic response rate of 97%
(complete pain relief in 26%, and partial relief in 71%). There was no
dose-response relationship above 10 Gy. Recurrence of symptoms requiring
further treatment was seen in 6% of sites after a median of 16 months.
It is not clear if pain relief is better if RT is given
concurrently with chemotherapy. A study by Adamietz et al. (2) reported
complete pain relief in 80% of patients receiving RT with chemotherapy,
compared with 40% among those receiving RT alone. In contrast, Leigh et al.
(73) found no significant difference in pain relief when RT was given with or
without concurrent chemotherapy. For spinal cord compression, motor improvement
is expected in approximately 50% of irradiated patients. A multicenter study
suggested that a longer fractionated regimen (30 Gy in 10 fractions or higher)
was associated with better neurologic recovery than 20 Gy in five fractions or
a single 8 Gy fraction (93). With the availability of newer drugs, the
advantage of radiation sensitizing efforts with drug-radiation combinations
requires continued investigation, both in terms of enhancing local control (48)
and possible toxicity. Bortezomib and spinal radiation given concurrently was
reported to result in severe enteritis (83). The use of bisphosphonates (e.g.,
pamidronate) has been shown to reduce skeletal complications and pain
(15,16,17,35) with a reduction of the use of RT from 50% to 34% in one study
(16).
Radioimmunotherapy Approaches
Bone seeking radiopharmaceuticals targeting the bone marrow
have been studied as an alternative to TBI. Typically a β-emitting isotope is
conjugated to a phosphonate complex, such as 153Samarium-ethylene diamine
tetramethylene phosphonate (153Sm-EDTMP). The isotope also emits a γ-ray
permitting scanning to locate areas of uptake. This agent has been used for
palliation of bone metastasis (7,13). The feasibility of this approach in a
small number of myeloma patients has been reported for stem cell
transplantation both in the autologous (34,55) and allogeneic settings (62).
Another bone-seeking pharmaceutical is 166Holmium-DOTMP
(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetramethylene-phosphonic acid), with
a higher energy β-emission (maximum energy 1.85 MeV) than 153Sm, and a shorter
T1/2 of 26.8 hours. It also has a γ-emission (81 KeV) suitable for imaging. A
phase I/II study incorporating 166Holmium-DOTMP into a transplant regimen has
been performed at the M.D. Anderson Cancer Center with encouraging results
(47). With the ability to deliver much higher doses to the bone marrow than
TBI, in the range of 30 to 60 Gy, yet sparing the dose-limiting normal tissues
such as lung, mucosa, and kidneys, the concept of targeted radiation therapy is
tantalizing.
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However, there remains a problem of heterogeneity of uptake
in the skeleton, and the dosimetric variation may be even larger at a
microscopic level due to the limited range of the β particle. Whether this
approach will have a more favorable therapeutic ratio than standard
conditioning regimens in the transplant setting awaits larger scale phase II
and phase III trials.
Radiation Therapy Techniques
Radical Radiation Therapy for Local Control of Solitary
Plasmacytoma
Accurate evaluation of tumor extent is an important feature
of radical RT for solitary plasmacytoma. MRI is useful to evaluate the extent
of disease both within and beyond bone. This is particularly true for the
paranasal sinuses, where inflammatory changes may be difficult to distinguish
from tumor on CT imaging. Currently, the accuracy of FDG-PET in the evaluation
of tumor extent is uncertain.
There are few data to support specific guidelines regarding
RT treatment volumes. CT and MRI imaging should be used to determine gross
tumor volumes (GTV). Clinical target volumes (CTV) should encompass probable
routes of microscopic spread, recognizing that barriers to the extension of
local disease will vary according to anatomic location, as will the morbidity
of treating adjacent normal tissues (Fig. 79.3). For the spine, inclusion of
two vertebral bodies above and below the grossly involved vertebra(e) is a
common practice. As this is based on relapse patterns seen following RT for
spinal metastases for solid tumors rather than plasmacytomas, it may not be
directly applicable to solitary plasmacytoma.
For RT of long bone lesions, while coverage of the entire
involved bone has been recommended by some authors, a study of palliative RT to
only the symptomatic area for multiple myeloma found that recurrence in the
untreated portion of the involved bone was rare (23), and similarly, no
marginal recurrences were seen among 30 patients with solitary plasmacytoma
treated with RT that encompassed only the tumor with a margin (60).
Prophylactic regional nodal coverage is not necessary in solitary plasmacytoma
of bone as multiple studies have found a very low risk of regional nodal
failure after involved-field radiation without intentional coverage of adjacent
nodes (i.e., 0% to 4%) (60,75,112,117). For extramedullary plasmacytoma, nodal
involvement at presentation is observed in 10% to 20%, and occasional nodal
failure in the literature led to a common practice of extending the RT coverage
to the draining lymph node region (20,57,110). Some authors specifically
recommend this practice if the primary disease involves a lymphatic structure
(e.g., lymph nodes, or Waldeyer's ring) (53,64,117). However, this is
controversial as some series reported a low incidence of regional nodal failure
without routine prophylactic nodal irradiation (53,64,77), leading to variation
in practice between centers (110). After reviewing their own series of 26
patients with EMP and contrasting the results with the literature, Strojan et
al. (110) concluded that prophylactic nodal radiation is probably unnecessary.
Planning target volumes (PTV) should account for day-to-day
setup variation and will typically add 5 to 10 mm around CTV volumes depending
on the immobilization technique employed (see Fig. 79.3). Overall, RT field
edges are typically 2 to 3 cm from gross tumor seen on imaging. Although
parallel-opposed fields are commonly adequate to encompass disease without
significant irradiation of normal tissues, CT-based planning, and the use of
conformal techniques, including intensity modulated radiation therapy, should
be employed when needed to treat the PTV adjacent to critical structures. This
can be particularly important in extramedullary disease involving the paranasal
sinuses, where avoidance of the optic structures and salivary glands is
desirable.
Radiation Therapy Dose
Studies evaluating RT dose response in plasmacytoma have
produced differing results. Most studies have found response rates >85%
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among patients treated with ≥35 Gy; some investigators have
found better local control following doses ≥45 Gy (44,116), while others have
found no indication of improved outcome with higher doses (60,90). Based on a
dose–response analysis of 81 patients by Mendenhall et al. (80) reported in
1980, a minimum dose of 40 Gy was recommended, including osseous and
extramedullary lesions. A total dose of 40 Gy and above resulted in a local
failure rate of 6% versus 31% for lower doses. Therefore, the usual practice is
to administer a dose of 40 to 45 Gy or even higher for bulky tumors. However,
in the largest of these studies (n = 258), there was no evidence of improved
local control with RT doses ranging from 30 to 50 Gy, including a subset of
patients with tumors >4 cm (90). In fact there was a worse local control
rate for the group receiving total dose ≥50 Gy, although not statistically
significant (90). It should be noted, however, that retrospective studies of
dose response are typically confounded by selection bias, as higher doses are
prescribed to larger tumors with worse prognosis. Several studies have
demonstrated durable local control in >85% of tumors <5 cm with 35 to 40
Gy, and there is little evidence that higher doses are necessary for small
tumors, regardless of bone or EMP locations. In contrast, plasmacytomas >5
cm have worse local control (90,117), and doses of 45 to 50 Gy are recommended
in these bulkier tumors, which also tend to be EMPs. However, one should be
aware that the quality of evidence supporting the use of higher RT doses is
limited, and local failures are occasionally observed even after doses
exceeding 50 Gy (80,90,117).
Assessment of Response and Follow-Up
Reimaging is of greatest value in the response assessment of
extramedullary plasmacytoma. Repeat imaging, preferably MRI, should be done
approximately 6 to 8 weeks following completion of treatment. It is rare to
have symptoms suggestive of local progression that necessitate reimaging prior
to this. It is common for a residual soft-tissue abnormality to persist on
follow-up imaging, and periodic reimaging may be required every 4 to 6 months
until any residual mass disappears or remains stable on consecutive scans. It
is generally not beneficial to continue to reimage a stable abnormality.
Bone destruction caused by tumor can produce persistent
abnormalities on imaging following RT for painful bone metastases or isolated
plasmacytoma of bone. Consequently, repeat imaging is of less value in
establishing response in such cases.
With a high risk of recurrence of disease as multiple
myel-oma, the occurrence of new bone pain requires further investigations,
including imaging as appropriate. Repeat measurement of the M-protein often
detects the onset of systemic disease prior to the development of symptoms and
can be used as an indicator of disease burden (26,121). Complete blood counts
should be taken periodically to evaluate bone marrow function. A team of
international investigators have recently developed recommendations for uniform
response criteria for assessing the treatment of multiple myeloma (36).
RT doses used for myeloma are rarely associated with
significant delayed side effects. Treatment of significant volumes of the
parotid or submandibular glands may result in prolonged xerostomia and should
be avoided. As noted previously, TBI has been associated with significant
toxicity and is not widely used. Evaluation of renal function should be
undertaken prior to initiating RT that may include the kidneys, and blood
counts should be evaluated prior to treating a large volume of bone marrow in
the spine or pelvis. Reirradiation of vertebral metastases is possible, but
careful evaluation of all prior RT records is required to ensure that the
tolerance of the spinal cord is not excee-ded.
