Current Role of Radiation Therapy for Multiple Myeloma

Abstract

Radiation therapy (RT) is a treatment modality traditionally used in patients with multiple myeloma (MM), but little is known regarding the role and effectiveness of RT in the era of novel agents, i.e., immunomodulatory drugs and proteasome inhibitors.
We retrospectively reviewed data from 449 consecutive MM patients seen at our institute in 2010-2012 to assess indications for RT as well as its effectiveness. Pain response was scored similarly to RTOG 0631 and used the Numerical Rating Pain Scale.
Among 442 evaluable patients, 149 (34%) patients and 262 sites received RT. The most common indication for RT was palliation of bone pain (n = 109, 42%), followed by prevention/treatment of pathological fractures (n = 73, 28%), spinal cord compression (n = 26, 10%), and involvement of vital organs/extramedullary disease (n = 25, 10%). Of the 55 patients evaluable for pain relief, complete and partial responses were obtained in 76.4 and 7.2%, respectively. Prior RT did not significantly decrease the median number of peripheral blood stem cells collected for autologous transplant, even when prior RT was given to both the spine and pelvis. Inadequacy of stem cell collection for autologous stem cell transplant (ASCT) was not significantly different and it occurred in 9 and 15% of patients receiving no RT and spine/pelvic RT, respectively. None of the three cases of therapy-induced acute myelogenous leukemia/MDS occurred in the RT group.
Despite the introduction of novel effective agents in the treatment of MM, RT remains a major therapeutic component for the management in 34% of patients, and it effectively provides pain relief while not interfering with successful peripheral blood stem cell collection for ASCT.

Full text

ORIGINAL RESEARCH ARTICLE
published: 18 February 2015
doi: 10.3389/fonc.2015.00040
Current role of radiation therapy for multiple myeloma
GiampaoloTalamo*, Christopher Dimaio, Kamal K. S. Abbi , Manoj K. Pandey, Jozef Malysz,
Michael H. Creer, Junjia Zhu, Muhammad A. Mir and John M.Varlotto
Penn State Milton S. Hershey Medical Center, Hershey, PA, USA
Edited by:
Soren M. Bentzen, University of
Maryland School of Medicine, USA
Reviewed by:
Valdir Carlos Colussi, University
Hospitals Seidman Case Medical
Center, USA
Nitin Ohri, Albert Einstein College of
Medicine, USA
*Correspondence:
Giampaolo Talamo, Penn State Milton
S. Hershey Medical Center, 500
University Drive, P.O. Box 850,
Hershey, PA 17033, USA
e-mail: gtalamo@hmc.psu.edu
Background: Radiation therapy (RT) is a treatment modality traditionally used in patients
with multiple myeloma (MM), but little is known regarding the role and effectiveness of RT
in the era of novel agents, i.e., immunomodulatory drugs and proteasome inhibitors.
Methods: We retrospectively reviewed data from 449 consecutive MM patients seen at
our institute in 2010–2012 to assess indications for RT as well as its effectiveness. Pain
response was scored similarly to RTOG 0631 and used the Numerical Rating Pain Scale.
Results: Among 442 evaluable patients, 149 (34%) patients and 262 sites received RT.
The most common indication for RT was palliation of bone pain (n=109, 42%), followed
by prevention/treatment of pathological fractures (n=73, 28%), spinal cord compression
(n=26, 10%), and involvement of vital organs/extramedullary disease (n=25, 10%). Of
the 55 patients evaluable for pain relief, complete and partial responses were obtained in
76.4 and 7.2%, respectively. Prior RT did not significantly decrease the median number
of peripheral blood stem cells collected for autologous transplant, even when prior RT
was given to both the spine and pelvis. Inadequacy of stem cell collection for autologous
stem cell transplant (ASCT) was not significantly different and it occurred in 9 and 15%
of patients receiving no RT and spine/pelvic RT, respectively. None of the three cases of
therapy-induced acute myelogenous leukemia/MDS occurred in the RT group.
Conclusion: Despite the introduction of novel effective agents in the treatment of MM,
RT remains a major therapeutic component for the management in 34% of patients, and it
effectively provides pain relief while not interfering with successful peripheral blood stem
cell collection for ASCT.
Keywords: multiple myeloma, radiation therapy, palliative therapy, pathologic fractures, stem cell collection
INTRODUCTION
Multiple myeloma (MM) is a rare cancer, representing 1% of
all malignancies, with an annual incidence of approximately 4-
5/100,000 (1). In the past, the traditional treatment of MM con-
sisted of corticosteroids and conventional chemotherapy, with or
without stem cell transplantation (SCT). However, systemic ther-
apy was often inadequate, and previous studies have shown that
the majority of MM patients -approximately two-thirds- required
the use of radiation therapy (RT) during the course of the disease
(2–4). The goal of RT is to deprive cancer cells of their multi-
plication potential by targeting their DNA and damaging it with
irreparable double strand breaks, either by direct interaction or
indirectly, after generation of free radicals. Neoplastic cells are
killed by a variety of mechanisms, including apoptosis, mitotic
catastrophe, necrosis, senescence, and autophagy, but the main
cell-death mechanism following RT is considered apoptosis (5–7).
RT was recognized as an effectiveanti-MM ther apyas ear lyas 1931,
when it was found to ameliorate symptoms and, in certain cases,
to provide a lasting disease control (8). Plasmacytomas are exquis-
itely radiosensitive neoplasms (9), and RT has a potentially curative
effect for both solitary plasmacytoma of bone and extramedullary
plasmacytomas (10,11). However, the role of RT in the treatment
of MM is only palliative. Traditional indications for RT in MM are
pain control for large osteolytic lesions, prophylactic treatment of
impending pathological fractures, post-fracture pain, spinal cord
compression, and treatment of extramedullary disease (3,12–14).
Palliation of symptoms is a major goal of therapy in MM, because
skeletal-related events (SREs), such as painful lytic lesions and
pathologic fractures, represent major causes of morbidity in this
cancer (15). In fact, MM patients often require potent analgesic
drugs to control bone pain and improve their quality of life, and
SREs may still develop despite a therapeutic response to effec-
tive systemic therapy (16,17), due to the slow repair of osteolytic
lesions. The efficacy of RT in palliating pain is very high, and sev-
eral studies have reported a 75–100% range of pain control with
a relatively short course of RT (2–4,14,18). Most MM patients
achieve significant pain relief with a local RT dose of 3,000 cGy
given in 10–15 fractions (14).
In the last few years, the introduction in clinical practice of
several novel agents, i.e., the three immunomodulatory drugs
(IMiDs) thalidomide, lenalidomide, and pomalidomide, and the
two proteasome inhibitors (PIs) bortezomib and carfilzomib, has
produced significant disease responses and survival advantage in
MM patients, revolutionizing the therapy of MM in all phases of
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Talamo et al. Radiation therapy in multiple myeloma
treatment, i.e., induction therapy, maintenance, and in the set-
ting of relapsed/refractory disease (19). The role of RT in the era
of the novel biological agents has not been adequately assessed.
In this study, we retrospectively evaluated the current role of RT
in the treatment of MM, with particular attention to indications,
impact on survival, and effect on collection of blood stem cells for
autologous SCT.
MATERIALS AND METHODS
After permission from our Institutional Review Board, we per-
formed a systematic retrospective review of medical charts of 449
consecutive MM patients seen in 2010–2012 followed at our insti-
tute, either directly or as consultants for community oncologists.
Because a range of radiation doses were given, all dosing regimens
were converted into biologic effective doses using an alpha beta
ratio =10 for myeloma cells (20).
For assessing the pain response after RT, we measured pain lev-
els on an 11-point scale 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, according
to the Numerical Rating Pain Scale (NRPS) (21), both at baseline
(within 1 week from the beginning of RT) and 3 months after RT
(±1 week). We adopted the criteria used in the protocol RTOG
0631 (22): “complete pain relief”: pain score of 0 at 3 months
post-treatment; “partial pain relief ”: improvement of at least three
points from the baseline NRPS (without increase in the level
of narcotic pain medication); “stable response”: post-treatment
pain score the same as or within two points of the baseline pain
score (with no increase in narcotic pain medication);“progressive
response”: post-treatment increase of at least three points from
the baseline pain score.
Clinical characteristics of cases and controls were compared
with the unpaired two-sample student’s t-test for numerical vari-
ables, and χ2test for categorical variables (but if any expected
frequency was <2 or if >20% of the expected frequencies were
<5, we used the Fisher’s exact test). Survival curves were obtained
with the Kaplan-Meier method, and compared with the log-rank
test. We used the Cox proportional hazard regression model to
analyze the effect of several risk factors on survival. All pval-
ues were two-tailed, and values <0.05 were considered significant.
Overall survival (OS) was calculated from diagnosis to last follow-
up or death. The time of diagnosis was defined as the day of
the initial bone marrow biopsy. Statistical analysis was performed
using the program SAS® software, version 9.3 (SAS Institute, Cary,
NC, USA).
RESULTS
In our original dataset of 449 consecutive MM patients, 14 patients
received RT for reasons different from MM, i.e., cancers of the
prostate (n=4), lung (3), skin (3), breast (1), uterus (1), esophagus
(1), and pituitary adenoma (1). Seven of these 14 patients received
RT only for reasons other than MM,and they were excluded from
the analysis. Of the remaining 442 patients, 293 (66%) did not
receive RT for MM (Group A,“RT-naive”), and 149 patients (34%)
did (Group B, “RT-treated”). Table 1 shows the characteristics of
the two groups. A statistically significant difference was found
between the two groups regarding age, but not sex and race. At
the time of diagnosis, patients in group B were more likely to
have non-secretory MM, lower infiltration of plasma cells in BM
Table 1 | Characteristics of 442 consecutive patients with multiple
myeloma (MM), divided in two groups, depending on whether or not
they received radiation therapy.
Group A
(RT-naive)
n= 293
Group B
(RT-treated)
n= 149
p
Age at diagnosis
Mean, years (range) 64.4 (37−92)62.3 (21−86)0.043
Sex, male 170 (58%)83 (56%)0.64
Race, Caucasian 249 (86%)132 (89%)0.30
Paraprotein
IgG, IgA 233 (80%)98 (66%)<0.001
κor λlight chain 55 (19%)39 (26%)
Non-secretory/other 5 (2%)12 (8%)
Osteolytic lesions on X-rays 142 (57%)103 (79%)<0.001
ISS
Stage I 82/241 (34%)59/112 (53%)0.002
Stage II 61/241 (25%)25/112 (22%)
Stage III 98/241 (41%)28/112 (25%)
Plasma cells in BM aspirate
Mean (±SD) 49% (±28%)37% (±32%)<0.001
High-risk cytogeneticsa59/205 (29%)22/103 (21%)0.16
Initial diagnosis of SP 0 12 (8%)<0.001
Treatment
Thalidomide 89 (31%)52 (35%)0.33
Lenalidomide 212 (72%)120 (81%)0.06
Bortezomib 244 (84%)132 (89%)0.13
Pomalidomide/carfilzomib 17 (6%)14 (9%)0.16
Stem cell transplant 172 (59%)104 (70%)0.018
Bisphosphonates IV 226 (83%)139 (96%)<0.001
Secondary malignanciesb11 (4%)4(3%)0.78
p levels <0.05 are shown in bold font.
BM, bone marrow; ISS, International Staging System; IV, intravenous; SP, solitary
plasmacytoma.
Percentages may not total 100 due to rounding.
aDefined as: hypodiploidy/complex karyotype or chromosome 13 abnormalities
at metaphase cytogenetics, or translocations t(4;14), t(14;16), or del(17p) at FISH.
bBasocellular and squamocellular carcinomas of the skin are not included.
aspirate, early ISS stage, and osteolytic lesions on skeletal sur-
veys. They were more likely to receive treatment with autologous
SCT and IV bisphosphonates, either pamidronate or zoledronic
acid.
In both groups, median follow-up was 28months (range, 0–
184). Median OS was 108 months (95% CI 69–162) and 85 months
(95% CI 49–98) in group A and B, respectively (p=0.052 at
Log-rank test; Figure 1). The OS between the two groups was
re-examined in a multivariate Cox proportional hazard regres-
sion model by controlling for ISS stage (I, II, and III), cytogenetic
status (high-risk vs. standard-risk), and presence of lytic lesions
at skeletal survey. The results show that OS for group A patients
is still significantly higher than that for group B patients (haz-
ard ratio 0.43, 95% CI 0.21–0.72, p=0.009). Hazard ratios were
0.59 (95% CI 0.28–1.05) for stage I vs. stage III (p=0.10), 3.17
(95% CI 2.13–4.96) for high-risk cytogenetics (p<0.001), and
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Talamo et al. Radiation therapy in multiple myeloma
FIGURE 1 | Kaplan–Meier estimates of overall survival in 442 patients
with multiple myeloma, divided in “RT-naive” (Group A, n=293 -solid
line) and “RT-treated” (Group B, n=149 -dotted line). Survival is
calculated from the time of diagnosis.
1.35 (95% CI 0.86–1.59) for presence of lytic lesions at skeletal
survey (p=0.39).
Table 2 shows indications, sites of RT, and time to RT after
the diagnosis of MM. A total of 262 sites were irradiated. The
median dose of RT was 30 Gy (SD 7.4, range 0.8–50.0 Gy). The
median number of fractions was 10 (SD 4.8, range 1–25), with
30 Gy given in 10 fraction being the most commonly used sched-
ule (26.5% of RT courses). The most common indication for RT
was palliation of pain, which accounted for 42% of all RT courses.
A properly documented assessment of pain response according to
the NRPS scale was available in only 55 patients: complete,partial,
stable, and progressive responses were observed in 42 (76.4%), 4
(7.2%), 9 (16.4%), and 0 patients, respectively. The median bio-
logical effective dose (BED) was 37.5, 36, and 39Gy in patients
with complete response, partial response, and stable pain level,
respectively, and ANOVA test found no significant dose/response
relationship between BED and response (p=0.76).
The second most common indication for RT were pathologic
fractures (28%), either for their prevention before an impend-
ing fracture (13%), or as “consolidation” RT after surgery for the
fracture (15%). Another frequent reason for RT were neurological
complications (16%), such as spinal cord compression (10%), or
impingement of cranial nerves, spinal neural foramina, or cauda
equina syndrome (6%). Other less common indications included
involvement of bones adjacent to vital organs (e.g., the sphenoid
bone in the cranium; 10%), extramedullary disease (4%), and
esthetic reasons (e.g., the development of a painless bony pro-
tuberance in the skull with deformity of the cranium; 5%). The
most common site of RT was the spine (36%), and spine and pelvis
constituted almost half of the radiated sites. In 51% of cases, RT
was administered at the time of diagnosis of MM, either before
or soon after (within 2 months) the initiation of systemic therapy.
In 42% of cases, RT was given later during the course of the dis-
ease, more than 1 year after the initial diagnosis of MM. Only nine
Table 2 | Indications, sites of treatment, and time to treatment of 262
radiotherapy courses in 149 patients with multiple myeloma.
No. of
RT-treated
sites
% of
RT-treated
sitesa
Indications for RT
Palliation of bone pain 109 42
Spinal cord compression 26 10
Involvement of cranial nerves, neural
foramina, cauda equina
17 6
Pathological fracture
Prophylaxis of impending fracture 33 13
Post-fracture RT 40 15
Involvement near vital organs/EMD 25 10
Esthetic reasons (painless bony
protuberance)
12 5
Sites for RT
Skull/facial bones 26 10
Clavicle/scapula 20 8
Humerus/radius 20 8
Ribs/sternum 17 6
Spine
Cervical spine 16 6
Thoracic spine 47 18
Lumbar spine 32 12
Sacrum/pelvis 29 11
Femur/tibia 41 16
Soft tissues/EMD 14 5
Time to RT
Within 2 months of diagnosis 134 51
3–12months from diagnosis 18 7
>1 year from diagnosis 110 42
aPercentages may not total 100 due to rounding.
EMD, extramedullary disease.
patients (6%) required a second course of RT for relapsed disease
in a previously radiated site.
The median number of peripheral blood stem cells collected
for autologous SCT, expressed as CD34+cells ×106/Kg, was 6.3
and 6.8 in group A (189 pts) and B (111 pts), respectively. The dif-
ference is not significant according to non-parametric Wilcoxon
Rank-Sum t-test (p=0.84). In group B, 48 pts underwent stem
cell collection after RT to lumbar spine and pelvis, with a median
dose of 45 Gy. Their median number of CD34+cells ×106/Kg
collected was 5.2, and only seven of them (15%) failed stem cell
collection. Seventeen of 189 patients (9%) in Group A failed stem
cell collection (p=0.41).
Finally, we scrutinized our cohort of 442 patients for second
malignancies, developed after the diagnosis of MM (Figure 2). We
found 11 and 4 cases in Groups A and B, respectively (p=0.78
by Fisher’s exact test). There were three cases of secondary acute
myelogenous leukemia (AML), but they were not related to RT:
these patients belonged to group A, and their AML was presum-
ably attributed to the previous exposure to high-dose melphalan
used as conditioning regimen for SCT.
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Talamo et al. Radiation therapy in multiple myeloma
0 12 24 36 48 60 72 84
0
20
40
60
80
100
Months
Probability of second malignancy (%)
RT
No
Yes
FIGURE 2 | Cumulative probability of second malignancy. Time to
develop a second malignancy is calculated from the initial diagnosis of MM.
DISCUSSION
Our study of 449 consecutive MM patients shows that RT
continues to play a prominent role in the treatment of MM,
despite the availability of effective novel agents, such as thalido-
mide, lenalidomide, pomalidomide, bortezomib, and carfilzomib.
Approximately one-third of patients required the use of RT dur-
ing the course of their disease. While RT can produce definitive
cures in solitary plasmacytomas, its role in MM is only palliative.
Although RT was associated with a survival decrement (Figure 1),
we feel that this survival difference was due to patient selection.
To our knowledge, only one study specifically assessed the effect
of RT on the prognosis of MM patients, and no OS improvement
was observed in a cohort of 162 patients (13), in accordance with
our results.
The most common indication for RT in MM was pain pallia-
tion, and its efficacy in this setting was excellent: according to our
data, a partial (7.2%) or complete (76.4%) response of pain to RT
was achieved in 84% of patients, and no progressive pain/failure of
RT was observed. Interestingly, the pain response seems to be more
effective in this era of IMiDs and PIs, because previously complete
and partial responses were reported in 21.6–30 and 69.8–71% of
MM patients, respectively (2,4,14). Due to the retrospective nature
of our study, we cannot be sure whether this improvement reflects
only the benefit from RT, or the use of better types or higher doses
of analgesics.
As expected, RT was mostly needed either at the time of diag-
nosis, when a clinical manifestation requires urgent intervention
(e.g., spinal cord compression), or later during the course of the
disease, when MM progresses. Its use is rarely required when the
disease is in remission, during the induction chemotherapy. In
fact, according to our data, only 7% of MM patients required
RT between 2 and 12 months of initiation of systemic therapy,
presumably due to the effectiveness of modern chemotherapy reg-
imens. Initial diagnosis and refractory disease at progression are
critical moments in the course of MM, because they may require
RT for rapid local tumor reduction and “debulking” of focal
lesions. The excellent activity of RT against MM has been known
for decades. In 1971, Bergsagel observed that a single RT dose of
10 Gy can produce a 3 log cell kill, whereas drugs such as melphalan
and prednisone produce <1 log cell kill (23). In vitro determina-
tions of radiosensitivity in MM cell lines supported Bergsagel’s
hypothesis (24,25).
We found that the two most common indications for RT were
pain palliation and pathological fractures, either for their pre-
vention, or as “consolidation” therapy after surgery. This was
expected, as RT is known to be an effective treatment modal-
ity in reducing the incidence of new fractures and focal lesions
in irradiated bones of MM patients with vertebral lesions (18).
In our series, other indications for RT included neurologic com-
plications (such as spinal cord compression, cauda equina syn-
drome, and involvement of cranial nerves), extramedullary dis-
ease, and esthetical reasons, for example painless disfiguring bony
prominences in the skull. Although spine and pelvis represented
almost half of the RT sites, many other bones of both axial and
appendicular skeleton were radiated, as shown in Table 2. In
our patients, we never administered alkylating drugs (e.g., mel-
phalan) and lenalidomide during the course of RT, because we
feared their myelosuppressive effect. However, we have adopted
the concomitant use of RT with corticosteroids, thalidomide,
and bortezomib without significant problems (data not shown),
when patients needed systemic cytoreduction at the same time
of RT.
The baseline characteristics of our RT-treated and RT-naive
groups were balanced for sex, race, and rates of high-risk cyto-
genetics. The statistical difference in age could theoretically be
due to the fact that some very old patients have problems that
prevent the administration of RT (e.g., poor performance status,
comorbidities, dementia). ISS stage was significantly lower in the
RT-treated group. This is probably due to a combination of fac-
tors: first, all MM patients who initially presented with a solitary
plasmacytoma -clinically a more indolent plasma cell neoplasm
than MM - received RT. Secondly, ISS stage III is defined by a
serum level of beta-2 microglobulin >5.5 mg/dL, a finding that
reflects not only high tumor load in the bones (which may need
RT), but also renal insufficiency (which does not need RT). For
reasons unknown to us, patients in the RT-treated group were
more likely to have non-secretory disease. We can speculate that
these patients come to medical attention for skeletal complica-
tions and require RT more frequently than patients with secretory
MM, because the latter have useful tumor markers that may
detect progressive disease at an earlier stage, or because they may
present with MM manifestations that do not require RT, such as
hyperviscosity syndrome due to IgG or IgA paraproteins, or cast
nephropathy due to free light chain secretion (26). The associ-
ation between RT and IV bisphosphonate use can be explained
by the need for concomitant use of both treatments in a sce-
nario of painful bone lesions and/or pathologic fractures. In fact,
presence of osteolytic lesions at skeletal survey was more likely in
the RT-treated group.
We found that a median dose of 30 Gy was administered for
successful palliation. Studies done in the prior era of treatment
reported that even lower doses, e.g., 10–20 Gy over 1–2 weeks, can
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Talamo et al. Radiation therapy in multiple myeloma
provide adequate pain relief (2,27). In the past, some investiga-
tions demonstrated worse response (14) or similar effectiveness
with re-treatment (4). Since our data include only nine patients
who required a second course of RT for relapsed disease in a pre-
viously radiated site, we cannot make meaningful conclusions on
the palliative role of re-treatment. Of note, the significance of our
findings regarding the palliative effect of RT in patients with MM
is limited by two factors: the retrospective nature of our study,
which predisposes it to a collection bias, and the limited number
of evaluable cases: in fact, a properly documented assessment of
pain response according to the NRPS scale was available in only
55 patients.
An important issue of RT in MM is its feasibility in transplant-
eligible patients. Many MM experts avoid the use of RT - especially
if directed to lumbar spine and pelvis – when they anticipate the
need for collection of peripheral blood stem cells for autologous
SCT, fearing toxicity of RT upon the hematopoietic stem cells.
Published data on this subject remain controversial (28–30). In
our analysis, RT did not induce a statistically significant reduc-
tion of the number of stem cells harvested, and it did not increase
the number of patients who failed stem cell collection. Although
we cannot make definitive conclusions, due to the retrospective
nature of our study, it seems that palliative RT to the axial skele-
ton, if indicated, should not be denied based solely on fears of
toxicity to the hematopoietic system.
Finally,regarding the development of secondary leukemias after
RT, it is reassuring that we found no increased incidence of sec-
ondary malignancies among 149 RT-treated patients, albeit our
median follow-up of 28 months is relatively short. Of note, all three
cases of treatment-related AML observed in this time interval were
found in patients who did not receive RT.
In conclusion, despite the use of novel effective systemic agents
and SCT, RT continues to play a prominent role in the pallia-
tive treatment of MM. In our series, approximately one-third of
patients required the use of RT during the course of their dis-
ease, most commonly for pain control and prophylaxis/treatment
of fractures and neurological complications. Radiation provided
effective pain control in greater than 80% of patients. Exposure
to RT did not compromise the feasibility of peripheral blood
SCT, and it did not seem to increase the frequency of secondary
malignancies.
ACKNOWLEDGMENTS
We thank Derek C. Hathaway, O.B.E., for his financial support of
this scientific research. We also thank Lisa Hand, B.S., C.T.R., of
the Cancer Registry at the Penn State Hershey Cancer Institute for
her assistance in data collection.
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Conflict of Interest Statement: The authors declare that the researchwas conducted
in the absence of any commercial or financial relationships that could be construed
as a potential conflict of interest.
Received: 06 November 2014; accepted: 04 February 2015; published online: 18
February 2015.
Citation: Talamo G, Dimaio C, Abbi KKS, Pandey MK, Malysz J, Creer MH, Zhu
J, Mir MA and Varlotto JM (2015) Current role of radiation therapy for multiple
myeloma. Front. Oncol. 5:40. doi: 10.3389/fonc.2015.00040
This article was submitted to Radiation Oncology, a section of the journal Frontiers in
Oncology.
Copyright © 2015 Talamo, Dimaio, Abbi, Pandey, Malysz , Creer, Zhu, Mir and Var-
lotto. This is an open-access article distributed under the ter ms of the CreativeCommons
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permitted, provided the original author(s) or licensor are credited and that the origi-
nal publication in this journal is cited, in accordance with accepted academic practice.
No use, distribution or reproduction is permitted which does not comply with these
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Frontiers in Oncology | Radiation Oncology February 2015 | Volume 5 | Article 40 | 6