Supportive Care in Multiple Myeloma
31
Simit Mahesh Doshi, Tom T. Noff, and G. David Roodman
Myeloma Bone Disease
Multiple myeloma (MM) is the second most common hema-
tologic malignancy, affecting more than 60,000 patients in
the United States with 30,000 patients diagnosed in 2016
[1, 2]. Multiple myeloma (MM) is the most frequent cancer
to involve bone with almost 70% of patients presenting with
bone lesions at diagnosis [3]. Twenty percent of patients
present with a pathologic fracture at diagnosis and until
recently up to 60% of patients developed a pathologic frac-
ture over the course of their disease [7]. This is extremely
important since pathologic fractures increase mortality of
MM patients by 20% [8]. In addition, MM bone disease can
cause excruciating bone pain that remains undertreated in
many patients, and hypercalcemia that can be life threaten-
ing, as well as require surgery and/or radiation to bone to
control bone pain, treat impending or repair fractures, and
relieve spinal cord compression. Further, in the vast majority
of patients, MM bone lesions rarely heal even when patients
are in long-term remission [10], and MM patients continue
to suffer from the sequelae of their bone disease, even when
their MM is under excellent control. Tremendous progress
has been made in the treatment of MM, with a median sur-
vival of patients increasing to more than 6.1 years in the last
decade and a much better overall survival for patients over
the age of 65 [9]. Thus, treatment and repair of MM bone
disease are increasingly important, both for enhancing the
quality of life of patients, increasing their survival, preven-
S.M. Doshi, M.D., M.P.H.
Department of Nephrology, IUH University Hospital,
950 W Walnut Street, Indianapolis, IN 46202, USA
T.T. Noff, M.D.
Department of Neurology, University of Indiana School of
Medicine, 355 W 16th Street, Indianapolis, IN 46202, USA
G. David Roodman, M.D., Ph.D. (*)
Department of Hematology and Oncology, Indiana University
School of Medicine, 980 W Walnut Street, Suite C312,
Indianapolis, IN 46202, USA
e-mail: groodman@iu.edu
© Springer International Publishing AG 2018
P.H. Wiernik et al. (eds.), Neoplastic Diseases of the Blood, DOI 10.1007/978-3-319-64263-5_31
tion of hypercalcemia or fracture, and suppressing the growth
of MM cells in the bone marrow.
Pathophysiology of Myeloma Bone Disease
During the normal bone-remodeling process, osteoclastic bone
resorption is coupled to osteoblastic bone formation, so that
bone removal and formation are balanced (Fig. 31.1). However,
in MM the normal bone-remodeling process is essentially
uncoupled, with markedly increased bone resorption at sites of
MM and absent or severely decreased bone formation. This is
due to suppression of osteoblast differentiation that can persist
even when patients are in long-term remission [10]. Thus, little
or no repair of lytic lesions occurs in the vast majority of
patients with MM, although there have been anecdotal reports
of healing of bone lesions in patients receiving bortezomib-
based therapy. However, once a patient’s bone density is below
the fracture threshold, the patient continues to be at an increased
risk of fracture and experience persistent bone pain.
A multiplicity of osteoclast stimulating factors are produced
by MM cells and induced by MM cells in the bone marrow
microenvironment [10]. These factors include MM cell pro-
duction of Rank ligand, a highly potent osteoclast-­stimulating
factor, or induction of Rank ligand production by marrow stro-
mal cells and osteocytes in the MM microenvironment.
Furthermore, production of MIP-1 α by MM cells, interleukin
3 production by both MM cells and T-lymphocytes in the MM
microenvironment, and IL-6 production by marrow stromal
cells, osteoclasts, and other cells in the bone microenvironment
also occur [10]. In addition, osteoclastic bone resorption and
increased osteoclast numbers enhance the growth of MM cells.
This process has been described as the vicious cycle hypothe-
sis, in which MM cells induce osteoclastic bone resorption, and
the bone resorption process releases growth factors, such as
IGF1 and TGF-beta from bone matrix, which in turn stimulate
the growth of MM cells (Fig. 31.2). In addition, MM cells
induce polarization of T cells in the tumor microenvironment,
which reverses the ratio of Th17 to Th1 T cells to 10:1 com-
595
596 S.M. Doshi et al.

Fig. 31.1  Bone remodeling

is uncoupled in myeloma. The
normal bone-remodeling
process in which bone
resorption is followed by new
bone at the same site is
uncoupled in myeloma with
increased bone resorption
followed by little or no bone
formation. Adapted by
permission from Macmillan
Publishers Ltd: Hattner R
et al. Nature. 1965;206:489

Fig. 31.2  Reciprocal interactions between myeloma cells and bone
microenvironment contribute to progression of myeloma. Myeloma
cells colonize the marrow and some of the cells engage the endosteal
niche and become dormant, while other cells remain active myeloma
cells. Active myeloma cells produce factors and induce factors by
cells in the bone microenvironment to increase osteoclast formation
and resorption. The increased bone resorption in turn releases growth
factors from bone matrix to stimulate the growth of myeloma cells.
Myeloma cells also suppress osteoblast differentiation to block new
bone formation. In addition, myeloma cells directly interact with
osteocytes in the bone matrix and these interactions increase myeloma
cell growth and osteoclast formation as well as block osteoblast dif-
ferentiation. Finally, osteoclastic resorption also releases dormant
myeloma cells to become active myeloma cells, further contributing
to myeloma progression. Adapted from Roodman GD. N Engl J Med.
2004;350(16):1655–1664. Copyright © 2004 Massachusetts Medical
Society. Reprinted with permission

pared to the normal ratio of 1:10. Th17 cells produce IL17 that
induces dendritic cell differentiation toward the osteoclast lin-
eage, as well as enhance induction of Rank ligand.
MM cells, osteoclasts, and marrow stromal cells in the
microenvironment also produce angiogenic factors that fur-
ther increase the growth of MM cells [11]. In addition, the
increased numbers of osteoclasts directly support MM
growth. Yaccoby and coworkers demonstrated that primary
MM cells from patients can be passaged over feeder layers of
osteoclasts for long periods of time [12]. Abe and coworkers
found that osteoclasts support the growth of primary MM
cells through the production of IL-6 and osteopontin [13].
31  Supportive Care in Multiple Myeloma
Finally, direct interactions between osteoclasts and osteo-
cytes enhance bidirectional Notch signaling between the
cells to increase the growth of MM cells, induce osteocyte
apoptosis, and increase production of sclerostin and Rank
ligand by osteocytes that suppresses osteoblast differentia-
tion and stimulates osteoclastogenesis [14]. In addition,
osteoclasts produce Annexin II, BAFF, and April that sup-
port MM cell growth [15, 16].
Recently, osteoclastic bone resorption has also been shown
to play an important role in activating dormant MM cells in
the MM microenvironment to active MM cells. Activation of
dormant MM cells results in increased tumor burden, bone
destruction, and distant colonization of bones. Lawson et al.
recently showed by intravital imaging that treatment of mice
with Rank ligand increases osteoclast numbers and decreases
the numbers of dormant MM cells colonizing the osteoblast
niche [17]. Thus, osteoclasts play multiple roles in progres-
sion of MM, including activation of dormant MM cells, bone
destruction that results in release of matrix-bound growth fac-
tors to stimulate tumor growth, and enhancement of MM
growth by factors derived from osteoclasts.
Studies in preclinical models of MM found that blocking
osteoclastic bone resorption decreases tumor burden in addi-
tion to bone destruction [18]. However, until recently this
phenomenon has not been demonstrated in patients. The
MM IX trial showed that treating newly diagnosed MM
patients with zoledronate, a potent bisphosphonate that
blocks osteoclastic bone resorption, rather than with clodro-
nate, a weaker bisphosphonate, enhances survival of MM
patients. This increase in survival occurred regardless if the
patients had detectable bone disease at diagnosis [19].
However, the greatest benefit in survival was seen in patients
with detectable bone disease. Based on preclinical and clini-
cal studies, the International Myeloma Working Group
(IMWG) guidelines now support targeting osteoclastic bone
resorption in all patients with MM [20].
Osteoblast Suppression in Myeloma
As noted above, bone formation is markedly suppressed in
patients with MM and persists even when the MM is under
excellent control. This explains why bone scans, which mea-
sure reactive bone formation, frequently under-represent
bone disease in MM patients, making bone scans inappropri-
ate for imaging bone disease in MM patients [21]. Multiple
factors produced by MM cells or induced by MM cells in the
MM microenvironment block osteoblast precursor differen-
tiation to mature osteoblasts. A large number of inhibitors of
osteoblast differentiation have been identified in MM
patients, including TNFα, MIP-1 α, IL-3, activin A, scleros-
tin, DKK1, hepatocyte growth factor, TGF-beta, and IL7
[22]. All these factors can directly suppress osteoblast dif-
ferentiation and are potential therapeutic targets for treating
597
MM bone disease (see below). However, none of these fac-
tors can explain why osteoblast suppression persists in
patients even in the absence of MM cells. The mechanisms
responsible for the long-term suppression of osteoblast dif-
ferentiation in MM are just beginning to be understood.
D’Souza and all demonstrated that epigenetic changes in the
Runx2 promoter in pre-osteoblasts, the master gene control-
ling osteoblast differentiation, are induced by MM cells [23].
These changes in the Runx2 promoter result from induction
of Gfi1 in pre-osteoblastic marrow stromal cells exposed to
MM cells. Gfi1 acts as a transcriptional repressor of Runx2
and blocks osteoblast differentiation. Increased expression
of Gfi1 persists in marrow stromal cells from MM patients,
even when the stromal cells are passaged for long periods of
time in the absence of MM cells. Furthermore, knockdown
of Gfi1 in marrow stromal cells from MM patients allows
them to undergo osteoblast differentiation. These insights
into the mechanisms responsible for long-term suppression
of osteoblast differentiation have provided potential new
therapeutic targets for repairing bone lesions in MM patients.
Furthermore, Li and coworkers reported that mature osteo-
blasts could suppress MM cell growth through the produc-
tion of decorin [24]. These results suggest that in addition to
repairing bone lesions, inducing osteoblast differentiation
may also suppress the growth of MM cells in patients.
Imaging of Myeloma Bone Disease
Imaging of MM bone disease has become increasingly impor-
tant with the development of new criteria for the diagnosis of
active MM. These criteria include presence of at least one
lytic lesion detected by conventional radiography, whole-
body low-dose CT or PET/CT, or presence of more than one
focal bone marrow lesion greater than or equal to 5 mm on
MRI studies [25]. Skeletal surveys have been the gold stan-
dard for detecting MM bone disease. The lesions appear as
punched-out lytic bone lesions with the absence of reactive
new bone formation and can occur in any bone. However,
conventional radiographs are relatively insensitive for detect-
ing bone disease in MM, since more than 30% of bone must
be removed before a lesion is detectable. Conventional radio-
graphs are also not useful for following disease progression
or response to therapy, because lytic lesions rarely heal in
these patients and enumerating new lesions can frequently be
difficult in patients with extensive bone disease. In addition, it
is often difficult to distinguish between osteoporotic and
MM-induced vertebral fractures. Finally, skeletal surveys
take a great deal of time to perform, which can be difficult for
patients who have severe bone pain.
Low-dose whole-body CT has been recently shown to be
superior to conventional radiographs for detecting osteolytic
lesions in MM patients, and is especially useful for detecting
lesions in the spine or pelvis [26]. Low-dose whole-body CT
598
can take less than 5 min to perform, and has the advantage that
it can also demonstrate extraosseous lesions. Because of these
advantages, low-dose whole-body CT is becoming the stan-
dard screening method for MM bone disease in Europe.
However, although low-dose whole-body CT exposes the
patients to a higher dose of radiation than standard skeletal
surveys, the higher resolution and speed of the examination
outweigh the disadvantages. Many experts predict that low-­
dose whole-body CT will replace skeletal surveys as the new
gold standard for detecting MM bone disease [26].
Magnetic resonance imaging (MRI) is also more sensitive
than standard skeletal radiographs for detecting MM bone dis-
ease, and also detects bone marrow infiltration by MM cells. A
large study from the University of Arkansas showed that MRI
detected focal lesions in 74% of MM patients, compared to
56% of patients who were examined with whole-body radio-
graphs [27]. MRI is particularly useful for distinguishing
between asymptomatic smoldering MM and symptomatic
MM. Patients who were thought to have smoldering MM but
had more than one focal lesion on MRI had a 70% probability
of progression to active MM within 2 years [28]. These results
form the basis for adding the presence of more than one focal
criteria on MRI to the updated criteria for active MM [25]. The
International Myeloma Working Group recommends, at a min-
imum, MRI examination of the spine and pelvis as part of the
evaluation for smoldering MM, if whole-body MRI cannot be
done [29]. However, MRI limited to the spine and pelvis will
not detect lesions in the peripheral skeleton that occur in 10%
of patients who present with focal lesions [30].
PET/CT is a very useful albeit expensive imaging technique
for assessing MM bone disease. PET detects the hypermeta-
bolic activity of MM cells in both intraosseous and extramedul-
lary sites, while CT detects bone-destructive lesions. PET/CT
has a similar sensitivity to that of MRI, and is better than MRI
at detecting bony lesions. More importantly, PET/CT can be
used to assess response to therapy [31]. Further, the presence of
extramedullary lesions or an SUV Max greater than 4.21 on a
PET/CT performed at diagnosis, persistence of FDG uptake
following autologous stem cell transplantation for MM, or
detection of extramedullary disease are all associated with a
poor prognosis for patients. However, it is unclear if PET/CT or
MRI is better for determining if patients with solitary plasma-
cytoma have disease restricted to one site or multiple sites.
PET/CT is also useful for following patients with non-secre-
tory MM [32]. However, PET/CT may also detect false-posi-
tive findings in patients following radiotherapy or infections.
Treatment of MM Bone Disease
The landmark studies of Berenson and coworkers in 1996
demonstrated that the nitrogen- containing bisphosphonate,
pamidronate, decreased skeletal related events (surgery to
S.M. Doshi et al.
bone, fractures, radiation to bone, and spinal cord compres-
sion) and bone pain in patients with MM bone disease [33].
Pamidronate and zoledronic acid are the cornerstone of treat-
ment for MM bone disease. Bisphosphonates are non-­
hydrolyzable pyrophosphate analogues that block
osteoclastic bone resorption and inhibit osteoclast formation
through their capacity to inhibit protein prenylation by inhib-
iting farnesyl diphosphate synthase required for normal
osteoclast activity [34]. Pamidronate is usually administered
as a 90 mg intravenous infusion over 2 h, while its more
potent analogue, zoledronic acid, is administered as 4 mg
intravenously over 15 min. Both bisphosphonates have simi-
lar efficacy for treating MM bone disease and are routinely
given every 3–4 weeks. Bisphosphonates are very safe drugs
and their major toxicity is their potential deleterious effects
on renal function. Therefore, serum creatinine levels must be
measured prior to infusion. If creatinine levels in patients
receiving these agents increase more than 10% from their
baseline values, pamidronate or zoledronic acid should be
withheld until the serum creatinine returns to within 10% of
the previous baseline value. In patients who present with
impaired renal function, the infusion time for pamidronate
can be increased or the dose of zoledronate can be reduced,
since renal toxicity of bisphosphonates is related to peak
dose [35]. In patients who present with severe renal failure,
initial therapy with bortezomib-based regimens should be
started prior to initiation of bisphosphonate therapy (see
below).
Multiple organizations have developed guidelines for use
of bisphosphonates in MM. Each of these guidelines state
that bisphosphonates can be given intravenously every 3–4
weeks for patients with MM bone disease that is identified
by plain radiographs or MRI. More recent IMWG recom-
mendations for treatment of MM-related bone disease state
that bisphosphonate therapy should be considered for all
patients with MM, regardless of the presence of osteolytic
bone disease by conventional radiography [20]. These rec-
ommendations are based on the results of the MM IX trial
that compared clodronate to zoledronic acid therapy in more
than 1000 newly diagnosed patients receiving treatment for
MM (see above). This study found that patients receiving
zoledronate achieved a 5-month survival benefit compared to
patients receiving clodronate [19]. This survival advantage
occurred regardless if the patient had demonstrable bone
­disease at diagnosis. A subsequent secondary analysis of this
study showed that the major impact on survival occurred in
patients with bone disease [36]. However, it’s unclear how
long patients should continue to receive bisphosphonate
therapy. This question became a major concern with the rec-
ognition that some MM patients receiving bisphosphonates
develop bisphosphonate-associated osteonecrosis of the jaw
(BRONJ). This complication of bisphosphonate therapy was
first recognized by Marx et al. [37]. The occurrence of
31  Supportive Care in Multiple Myeloma
BRONJ is usually dependent on the duration and dose of
bisphosphonate therapy, undergoing invasive dental proce-
dures, age of the patient, and treatment with glucocorticoids.
BRONJ occurs more frequently in patients receiving zole-
dronate than pamidronate [37]. Because of concern for
development of BRONJ, most guidelines recommend treat-
ment with bisphosphonates for approximately 2 years, unless
active MM persists, and then stopping or increasing the
interval between administration of bisphosphonates should
be considered. However, with the regular institution of close
dental monitoring, dental prophylaxis, and performing most
dental procedures prior to initiating bisphosphonate therapy,
the incidence of BRONJ has markedly decreased.
Another question that often occurs is should bisphospho-
nate therapy should be stopped prior to invasive dental pro-
cedures. The American Dental Association recently
recommended not stopping bisphosphonates or other bone-­
targeted agents when patients undergo dental procedures,
and states that the decision to withhold bisphosphonate ther-
apy should be based primarily on the patient’s risk of devel-
oping a skeletal related event [38]. In contrast, the IMWG
recommends stopping bisphosphonates for 90 days before
and after invasive dental procedures, such as tooth extrac-
tion, dental implants, and surgery to the jaw [20].
Several studies assessed if bone resorption markers are
useful for determining the interval between bisphosphonate
administration in patients with MM bone disease. Patel and
coworkers found in patients who had received bisphospho-
nate therapy for at least a year and had stable disease that the
level of bone resorption markers could be used to determine
when to administer bisphosphonate therapy [39]. However,
other studies show that bone resorption markers are not suf-
ficiently sensitive to guide bisphosphonate therapy [40].
Importantly, the MM IX trial demonstrated that extending
bisphosphonate treatment beyond 2 years continued to have
beneficial effects on skeletal related events [36]. However,
only small numbers of patients received long-term bisphos-
phonate therapy in that study. Another consideration with
bisphosphonate therapy is whether bisphosphonate therapy
can be restarted in patients who developed BRONJ. A retro-
spective analysis of over 100 MM patients demonstrated that
about 50% of patients who developed BRONJ healed their
lesions and 50% of those who restarted bisphosphonates did
not develop new lesions [41]. These results suggest that
patients who have active MM and have healed their osteone-
crosis of the jaw can receive bisphosphonate therapy but
should be monitored closely for a reoccurrence of BRONJ.
In addition to bisphosphonates, denosumab, a human
monoclonal antibody that targets Rank ligand, has been
developed, and potently inhibits osteoclast formation and
bone resorption. Multiple large phase 3 studies of deno-
sumab versus zoledronate treatment for patients with bone
metastasis found that denosumab has either a non-inferior or
599
a superior effect on skeletal related events compared with
zoledronate, and patients treated with denosumab who had
breast cancer bone metastasis had a survival advantage [42].
A large phase 3 study compared denosumab to zoledronic
acid treatment in patients with bone metastasis that did not
have prostate cancer or breast cancer, and also included 200
MM patients. This study found a similar decrease in skeletal
related events in the MM patients with either treatment, but a
post hoc analysis found a decreased survival for MM patients
receiving denosumab [43]. Further analysis of this trial found
that the baseline characteristics of the MM patients receiving
zoledronic acid or denosumab were not balanced, and that
the patients receiving zoledronic acid treatment had more
early withdrawals from the study compared to those treated
with denosumab [43]. A large phase 3 study comparing
denosumab to zoledronic acid treatment in newly diagnosed
patients with MM bone disease has just been completed, and
the results of this trial should be reported soon. It is impor-
tant to note that the incidence of ONJ is similar in patients
receiving denosumab or zoledronic acid so that similar den-
tal screening, routine dental prophylaxis, and follow-up are
also required for patients receiving denosumab. Finally, nei-
ther denosumab nor zoledronic acid increases bone forma-
tion in patients with MM, so there is still a great need for
bone anabolic agents that can increase bone formation and
are safe for MM patients.
Recently, several agents have been developed to enhance
bone formation in patients with MM. These include an anti-
body to DKK1, BHQ880, and sotatercept, an activin recep-
tor antagonist [22]. A phase 1B clinical trial of anti-DKK1 in
patients with MM did not show any benefit for MM bone
disease [44], although the anti-DKK1 did show some bone
anabolic effects in a phase 2 trial of patients with smoldering
MM. No anti-MM activity was found in MM patients or
smoldering MM patients receiving anti-DKK1 therapy.
Sotatercept is in clinical trial for MM but can also increase
hemoglobin levels significantly [45]. Thus, its utility as a
bone anabolic agent of MM is still unclear. Most recently an
anti-sclerostin antibody has been developed and is in clinical
trial for patients with osteoporosis [46]. Anti-sclerostin anti-
body had potent bone anabolic effects and was well tolerated
by the patients. Preclinical studies demonstrated that anti-­
sclerostin antibody treatment of murine models of MM can
increase bone formation and may affect tumor burden.
Several agents used to treat MM also have effects on bone.
Bortezomib has been reported to have bone anabolic effects
in patients with MM whose MM responded to bortezomib
therapy [47], and transient increases in alkaline phosphatase
activity have been shown in patients receiving bortezomib
therapy. In addition there have been anecdotal reports of
bone healing in patients receiving bortezomib-based thera-
pies [48]. Furthermore, in preclinical studies, immunomodu-
latory agents such as pomalidomide can block osteoclast
600
differentiation [47]. Finally, the role of parathyroid hormone
as an anabolic agent for MM bone disease remains unclear.
Several groups reported the presence of the PTH receptor 1
on MM cells and found that parathyroid hormone-related
protein, which activates the PTH receptor, can increase MM
cell growth [49]. Other investigators failed to demonstrate
PTH receptors on MM cells and preclinical studies have
shown an anabolic effect of PTH in SCID-hu mouse model
of MM [50].
 adiation Therapy and Surgery for Myeloma
R survival in MM patients compared to patients not receiving
Bone Disease
Radiation therapy is frequently used to treat painful bone
lesions in myeloma. However, it must be used sparingly
because of its myelosuppressive effects. Thus, radiation
therapy is used primarily to treat painful lesions, impend-
ing fracture and spinal cord compression [20]. Similarly,
vertebroplasty and kyphoplasty are used to treat painful
vertebral fractures in patients with myeloma [51]. In a ran-
domized study for painful vertebral fractures in patients with
myeloma, kyphoplasty was shown to be superior to conser-
vative management, so that kyphoplasty is currently recom-
mended by the IMWG guidelines.
Thromboprophylaxis for Myeloma Patients
Patients with MM have an increased risk of a thrombotic
event during the course of their disease. In the original clini-
cal trial of thalidomide for treatment of patients with MM, a
30% incidence of DVT was reported in patients receiving tha-
lidomide [52]. Subsequent studies using combination chemo-
therapy regimens containing thalidomide also found a high
rate of deep venous thrombosis (DVT) in these patients.
Lenalidomide and pomalidomide are also associated with
increased risk of DVT [52]. These results led to the develop-
ment of thromboprophylaxis guidelines for patients receiving
immunomodulatory agents [6]. These guidelines suggest that
patients should receive thromboprophylaxis for at least the
first four cycles of immunomodulatory agent-based therapy
because the risk of DVT or pulmonary embolism (PE) is
greatly increased during that time. The type of DVT prophy-
laxis is based on individual risk factors (e.g., age, obesity
immobilization, history of DVT). Patients who have no or
only one risk factor should receive prophylaxis with low-­dose
or standard-dose aspirin (81–325 mg per day) and patients
with two or more risk factors should receive low-­molecular-­
weight heparin or the equivalent or full-dose warfarin therapy
to maintain the INR at 2–3. A recent abstract at the American
society of clinical oncology found that the risk of VTE persis-
tently changes throughout the disease process [53]. Lipe and
S.M. Doshi et al.
coworkers found that VTE can occur in MM patients at a
median time from diagnosis of 952 days, much longer than
the IMWG guidelines recommend for thromboprophylaxis.
Importantly, Lipe et al. found that of 60% of patients at high
risk for thrombosis, only 16% ever received the recommended
prophylactic therapy. These results suggest that VTE may
occur later in MM than was previously thought, and that
guidelines for thromboprophylaxis in MM may need to be
adjusted. Finally, the use of erythropoiesis-­stimulating agents
(ESAs) also increases the risk of thrombosis in patients with
MM. Katodritou and coworkers reported that ESAs reduced
ESAs (and increased the risk of thrombosis in patients with
MM) [54]. Thus, ESAs should be used with caution in patients
with MM.
Neuropathy in Myeloma
Neurological complications in MM range from peripheral
neuropathy to compression of the nerve roots or spinal cord.
Compression of the nerve roots and spinal cord is an onco-
logical emergency and can result from compression by verte-
bral and extramedullary plasmacytomas, respectively. Early
recognition and treatment of spinal cord or nerve root com-
pression are more important than the type of treatment in
improving outcomes.
Radiculopathy
Compression of the nerve root by vertebral plasmacytomas,
neuroforaminal stenosis, or vertebral fracture usually pres-
ents with back pain and a unilateral radiculopathy that may
progress to sensory loss and weakness. At least 5% of MM
patients suffer from spinal cord or cauda equina compres-
sion, and MM is responsible for 15% of hospitalization for
malignant spinal cord compression [55]. Spinal cord com-
pression often presents with progressively worsening back
pain and may have a symmetric radiculopathy. The thoracic
cord is most commonly affected and is associated with a
sensory-level deficit. Bowel and bladder dysfunction is a
late complication of spinal cord compression and is often
preceded by symmetric pain and weakness. Unilateral
­complaints are rare but may be seen with lateralized cord
compression. Complete spinal MRI with contrast is the pre-
ferred method of evaluating spinal cord compression, as CT
does not clearly demonstrate the spinal cord or epidural
space. Immediate treatment with corticosteroids, followed
by radiation therapy, is the mainstay of treatment. MRI
screening of MM patients for cord compression has not
been found to be beneficial for detecting spinal cord com-
pression [56].
31  Supportive Care in Multiple Myeloma
Clinically detectable peripheral neuropathy is uncommon
in MM at diagnosis and presents as a mild and slowly pro-
gressive symmetric neuropathy. Occurrence rates vary from
2% [5] to approximately 50% [57] of patients. Peripheral
neuropathy in MM is often caused by accompanying amyloi-
dosis or chemotherapy, and is a major presenting feature of
POEMS syndrome. Cranial nerve involvement is rare and is
usually a sign of progressive disease. Chemotherapy-induced
peripheral neuropathy is a serious and potentially reversible
side effect of treatment. The dose and duration of treatment
are commonly affected by the neurotoxic profiles of these
medications, which in severe cases may result in discontinu-
ation of treatment. The clinical history and neurological
examination are crucial for distinguishing CIPN from neuro-
pathic involvement from direct nerve compression by
MM. Neuropathy is a frequent complication of thalidomide-
and bortezomib-based therapies.
Thalidomide is a potent antiangiogenic therapy that has
been used for MM since 1998. Severe peripheral neuropathy
occurs in approximately 30% of patients who were treated
with doses of thalidomide greater than 200 mg/day [58].
Thalidomide-induced peripheral neuropathy presents as a
symmetric distal loss of light touch and temperature that is
painful. The neurotoxic effects of thalidomide are cumula-
tive and dose dependent. In approximately 60% of patients,
neuropathy results in lowering the dose or discontinuation of
treatment [59]. Reduced starting doses of thalidomide of
100 mg/day for patients greater than 75 years old, and
200 mg/day for patients less than 75 years old, have reduced
the incidence of severe peripheral neuropathy to less than
10%. However, there has been an overall increase in the inci-
dence of mild-to-moderate peripheral neuropathy at these
thalidomide doses. Although peripheral neuropathy is par-
tially reversible with discontinuation of thalidomide, the
long-term reversibility of neuropathy with discontinuation of
thalidomide requires further long-term studies [60, 61]. The
pathogenesis of thalidomide-induced peripheral neuropathy
is poorly understood but antiangiogenic and inflammatory
insults to the dorsal root ganglia may be the cause. This may
explain the reduced sensory nerve action potentials with rel-
ative sparing of compound motor action potentials found in
thalidomide-treated patients [62]. Other neurotoxic side
effects of thalidomide include tremor (in up to 30%) and
somnolence.
Bortezomib-associated peripheral neuropathy was recog-
nized as an early side effect in the initial phase I trials. The
incidence of bortezomib-induced peripheral neuropathy
(BIPN) in phase II and phase III trials was 30–64%, and
occurred in up to 46% of patients treated for newly diag-
nosed MM [62, 63]. BIPN is a subacute predominately sen-
sory neuropathy of the feet and hands that is often painful.
Small unmyelinated fibers are affected, causing prominent
neuropathic pain in 25–80% of cases [64]. BIPN occurs in
601
21% and 37% of patients at the onset of treatment at doses of
1.0 mg/m2, and 1.3 mg/m2, respectively. The severity typi-
cally plateaus by the fifth cycle, with an approximate cumu-
lative dose of 30 mg/m2 [65]. The pathogenesis of BIPN
remains unclear. The involvement of satellite and Schwann
cells in BIPN in animal models supports the involvement of
the dorsal root ganglia in the pathogenesis of the pain.
Although the autonomic nervous system is also innervated
by unmyelinated fibers, it is very rarely affected. The clinical
presentation of a symmetric distal peripheral neuropathy
with a temporal correlation to recent bortezomib treatment is
suggestive of BIPN. Electrodiagnostic studies can provide
objective evidence to aid in the diagnosis. However, the diag-
nosis can usually be made clinically. The neurologic exami-
nation is very important for distinguishing the cause of
peripheral neuropathy. If signs of motor weakness are pres-
ent, nerve root compression is more likely, since BIPN is
primarily a sensory neuropathy. In patients with BIPN, nerve
conduction studies show reduced sensory and motor action
potentials, with mild slowing of the distal sensory and motor
nerve velocities with increased distal motor latencies.
Bortezomib neurotoxicity is a potentially reversible com-
plication that must be recognized early. Currently, there is no
accepted proven treatment for BIPN. The mainstay of treat-
ment remains bortezomib dose modification or discontinua-
tion and neuropathic pain medication. Subcutaneous
administration of bortezomib has dramatically reduced the
incidence of neuropathy, and newer proteasome antagonists
(carfilzomib and ixazomib) are less neurotoxic and better
tolerated. Severe peripheral neuropathy was reported in less
than 1% of patients in phase II trials of carfilzomib who were
treated previously with bortezomib [66, 67]. There is a lack
of evidence to support prevention of BIPN with neuroprotec-
tive agents [65].
Neurologic involvement is a hallmark of POEMS syn-
drome, a rare osteoscerotic form of MM, and is a major cri-
terion for diagnosis. Approximately 50% of patients present
with a distal symmetric neuropathy that ascends proximally.
Eventually the vast majority of POEMS patients suffer from
prominent sensorimotor neuropathy. Severe neuropathy has
been reported in up to 76% of patients [68, 69]. Ocular
involvement is common in approximately 2/3 of patients.
Papilledema occurs in approximately half of those patients,
and patients with papilledema have a worse prognosis [70].
There is also an increased risk of thromboembolic disease
and cerebral infarction in POEMS patients. In a retrospective
cohort study of 208 POEMS patients 19 (9%) developed
cerebral infarction at a relatively young age [71]. The risk of
cerebral infarction increased with the degree of thrombocy-
tosis, and of plasma cell proliferation in the BM was also
associated with increased stroke risk [71]. Electrodiagnostic
studies are important to distinguish neuropathy due to
POEMS from CIDP; in contrast to CIDP, prominent axonal
602
loss in the lower limbs rather than slow conduction of the
distal nerve segments with conduction block occurs with
POEMS. Polyneuropathy is commonly the initial presenting
symptom of POEMS with up to 60% of patients with POEMS
initially misdiagnosed with CIDP. Thus, distinguishing
between CIDP and POEMS is critically important for treat-
ment and prognosis. Nerve conduction studies in POEMS
show predominate slowing of the nerve trunk when com-
pared to distal nerve involvement.
Renal Dysfunction in Multiple Myeloma
The characteristic M paraprotein in MM, specifically the light-
chain component, is nephrotoxic to the kidney, and frequently
the kidney is the major target organ in MM. Up to 50% of
patients have evidence of renal impairment at the time of diag-
nosis and about 10–15% of patients require renal replacement
therapy [72]. Multiple studies found that renal impairment
alone is a strong negative predictor of overall survival (OS) [4,
73]. In one study, the difference in median OS between patients
with and without renal impairment was as high as 8.6 vs. 34.5
months (P < 0.001) The same study also showed markedly
improved OS if renal impairment was reversible [4]. The
Nordic MM study group also found that severity of renal
impairment was a determinant of OS MM [73]. Hypercalcemia,
lower proteinuria (<1 g/day), and low serum creatinine were
positive prognostic factors. Thus, early detection of
MM-induced kidney disease is extremely important.
The IMWG defines renal injury as either an elevation of
serum creatinine >2 mg/dL or a reduced creatinine clearance
(CrCl) of <40 mL/min/1.73m2, due to MM [74]. CrCl should
be assessed using the Modification of Diet in Renal Disease
(MDRD) formula or the Chronic Kidney Disease Epidemiology
Collaboration (CKD-EPI) equation as these most accurately
predict the clearance obtained from inulin-­based glomerular
filtration rate (GFR) estimation [75, 76]. The CKD-EPI group
further suggests that an equation based on creatinine and cys-
tatin C, which also reflects tumor burden, is more accurate, but
this remains to be validated in larger studies [75]. The use of
eGFR should be restricted to stable patients and not for those
presenting with an acute kidney injury (AKI). RIFLE (Risk,
Injury, Failure, Loss and End-Stage Kidney Disease) criteria
and Acute Kidney Injury Network classification should be
used for assessing the severity of AKI [77].
I nitial Diagnostic Workup of Renal Injury
in Myeloma
All patients with symptomatic MM should have an initial
laboratory panel that includes serum creatinine, GFR estima-
tion, electrolytes, serum free light chains (SFLC), and 24-h
S.M. Doshi et al.
urine collection for proteinuria and urine electrophoresis.
The presence of selective proteinuria composed almost
entirely of light chains can be attributed to myeloma cast
nephropathy (MCN), whereas the presence of significant
albuminuria suggests alternative diagnoses that require fur-
ther investigation [78]. A renal biopsy should be considered
to exclude monoclonal immunoglobulin deposition disease,
amyloidosis, or other underlying causes of renal impairment
in the presence of nonselective proteinuria [78–80]. If amy-
loidosis is strongly suspected, a fat pad aspirate should be
done prior to kidney biopsy, since a diagnosis of amyloidosis
can be obtained in about 70% of cases with the less invasive
procedure [80].
Pathogenesis of Myeloma Kidney Disease
Free light chains circulating as monomers (predominantly Κ,
25KD) or dimers (predominantly λ, 50KD) are freely filtered
by the glomerulus. In the proximal tubule cells (PTC) they
are reabsorbed by receptor-mediated endocytosis [81]. This
glycoprotein receptor cubilin-mediated endocytosis incites a
proinflammatory response that induces release of IL-6, IL-8,
and monocyte chemoattractant protein 1 (MCP-1) via activa-
tion of nuclear factor kappa light-chain enhancer of activated
B-cells (NF-kB) in the PTC [82]. Similar to other proteinuric
diseases, excess light chains induce factors that promote
interstitial injury and fibrosis, as well as direct DNA injury
and induction of apoptosis [83].
Once the PTC is injured, LCs overflow into the distal
lumen and interact with the Tamm-Horsfall protein (THP)
secreted by the thick ascending limb (TAL). This leads to
formation of the MM cast that is responsible for the presen-
tation of MCN. The variability in cast formation by this
interaction can be explained by the variation in the
complementarity-­determining region 3 (CDR3) of different
LCs [84]. While urinary light chains are required for the for-
mation of casts, the type or quantity of LC does not correlate
with the severity of cast formation. Urinary LC quantity,
however, is predictive of response to therapy and risk for
renal failure. Tubular solute composition and flow rates are
other factors that also influence cast formation. Obstructed
tubules in turn induce an intense inflammatory response
probably related to urine leak into the interstitium [85].
 ommon Patterns of Renal Insufficiency
C
in Myeloma
Myeloma cast nephropathy (MCN) is the most common his-
tologic finding with autopsy studies reporting rates between
30 and 50% of all MM patients with renal failure [86–88].
MCN almost always occurs in the presence of high free LC
31  Supportive Care in Multiple Myeloma
burden and typically when serum FLC levels are >100 mg/
dL [74, 89]. Almost all MM patients with significant renal
impairment will also have high urine FLC levels [90]. The
serum and urine FLC levels can be prognostic indicators in
MCN [91, 92]. The hallmark of MCN is tubular obstruction
due to formation of LC casts, as described previously, from
the interaction of Tamm-Horsfall protein (THP) and mono-
clonal LCs. Factors that can influence formation of casts
include urinary concentration of THP, sodium, calcium, pH,
urine flow rate, and diuretic use [85].
MCN typically presents with acute renal failure; however,
oliguric AKI is a feature in about half of the cases even with
very high levels of serum creatinine [93]. The progression of
AKI is rapid [94], with volume depletion and hypercalcemia
being the most common precipitating factors. Other common
risk factors for AKI MM include use of IV contrast media,
presence of infection, and nonsteroidal anti-inflammatory
drugs (NSAIDs) used for bone pain. One of the initial indica-
tors for MCN is the presence of heavy proteinuria that is dis-
proportionate to the albuminuria detected on a urine dipstick.
The median amount of proteinuria is about 2 g/24 h and is
almost exclusively Bence Jones protein with albuminuria
contributing <10%.
Early identification of MCN is essential for the treat-
ment of MCN since delay in decreasing light-chain burden
is associated with lower kidney recovery rates [92].
Treatment is focused on elimination of the precipitating
agent and rapid reduction of the paraprotein. This can be
achieved with chemotherapy or extracorporeal removal via
therapeutic plasma exchange (TPE). While renal replace-
ment therapy (RRT) may be required in certain cases, the
indication for initiation of RRT is similar to other AKI
states. Role of TPE in the management of MCN and reduc-
tion of FLC burden remains controversial. Three random-
ized controlled trials have published conflicting results
[95–97]. The largest trial showed no benefit but was limited
by the absence of histologic diagnosis of MCN. A meta-
analysis of the three trials showed higher rates of dialysis
independence at 6 months for patients when TPE was com-
bined with chemotherapy but no change in overall survival
with use of TPE [98]. Arguments against using TPE include
the absence of FLC monitoring in previous randomized tri-
als and introduction of newer chemotherapeutic agents
with high response rates that did not significantly improve
with addition of TPE [99, 100].
The role of high-cutoff hemodialysis (HCO-HD) in treat-
ment of patients with renal insufficiency is being evaluated
in two large randomized controlled trials: EuLITE study
(European Trial of Free Light Chain Removal by Extended
Hemodialysis in Cast Nephropathy; NCT00700531)
and the French MYRE study (Studies in Patients with
MM and Renal Failure Due To MM Cast Nephropathy;
NCT01208818). Both these trials include patients on a
603
bortezomib-­based regimen. A prior study examining the
use of HCO-HD in combination with chemotherapy in 67
MM patients showed encouraging results, with a sustained
reduction in FLCs by day 12 in 67% of patients and dialysis
independency in 63% [101]. However, sustained reduction
in FLC requires effective chemotherapy. The choice of regi-
men is oftentimes guided by the presence of renal failure
and nonrenally cleared drugs like bortezomib and thalido-
mide are preferred.
 eneral Principles of Treatment Renal
G
Insufficiency in Myeloma
Initial treatment should include administration of intrave-
nous fluids to achieve high urine, reduction of calcium lev-
els in patients with hypercalcemia, treatment of infection,
and avoidance of nephrotoxic agents. However, there is no
established role for urine alkalization in treatment of RI
[102]. Bisphosphonates can be used for hypercalcemia;
however, pamidronate and zoledronic acid should be
avoided in patients with CrCl <30 mL/min. Pamidronate
has been associated with development of collapsing variant
of focal and segmental glomerulosclerosis [103], whereas
zoledronic acid is associated with development of ATN
[104]. Denosumab may be helpful in this subgroup with
close monitoring of serum calcium levels. The role of
mechanical treatments, which include therapeutic plasma
exchange (TPE) or high-cutoff hemodialysis (HCO-HD),
in treatment of MM is limited to MM cast nephropathy
(MCN) (see above).
Systemic chemotherapy should be started immediately
to reduce FLC burden and provides the best chance of renal
recovery, with bortezomib in combination with dexametha-
sone usually employed [72]. Bortezomib-based therapy has
significantly higher rates of renal recovery (≥partial renal
response) compared to thalidomide- or lenalidomide-based
regimens (77% vs. 55% vs. 43%, respectively) in a large
retrospective analysis of 133 patients [105]. Carfilzomib, a
second-generation proteasome inhibitor, has shown good
safety and efficacy when used in patients with RI, and
progression-­free survival was better with carfilzomib when
compared to bortezomib [106]. High-dose corticosteroids
(equivalent to dexamethasone 160 mg or greater over 4
days) can be effective for rapid recovery of renal function
regardless of the initial chemotherapy regimen [105]. High-
dose steroids should be used in the initial month of therapy
for MM. Thalidomide can be used in renal insufficiency
without dose adjustment; however there have been reports
of hyperkalemia in patients receiving dialysis [107, 108].
The renal recovery rates with use of thalidomide have been
as high as 75% in newly diagnosed MM and up to 60% in
patients with relapse/refractory disease [105, 107, 109].
604
Lenalidomide requires dose adjustment in renal insufficiency
and response to treatment is not as robust. Autologous stem
cell transplant (ASCT) can be used in MM even in presence
of severe RI requiring dialysis but requires dose adjustment
of the high-­dose melphalan [110]. RI at the time of trans-
plantation, however, is associated with higher risk of trans-
plant-related mortality (4% vs. <1%) [110, 111].
References
AL Amyloidosis
Amyloidosis represents the most common glomerular
lesion in MM. AL amyloidosis is a systemic disease with
deposition of congophilic fibrils in soft tissue. The fibrils
are composed of light chains (AL), heavy chains (AH), or
intact immunoglobulins (ALH) [112]. AL amyloidosis is
the most common subtype accounting for >95% of cases.
Autopsy studies report rates of 5–15% for AL amyloido-
sis [86–88]. MM is diagnosed in <10% of cases of AL
amyloidosis. About 50% of patients present with renal
failure. Proteinuria is present in >70% of the cases while
about a fourth of the cases present with nephrotic syn-
drome [113]. As opposed to MCN, the proteinuria is pre-
dominantly albumin [78]. Rarely, amyloidosis will
present with renal dysfunction in the absence of protein-
uria as in vascular limited amyloidosis or diabetes insipi-
dus. Kidney involvement can at times be the only
presentation of amyloidosis. A fat pad biopsy can pro-
vide a diagnosis in about 70% of cases, whereas the
remaining will require kidney biopsy [78]. Kidney
response in amyloidosis is predictive of OS [114, 115].
Kidney transplantation can be considered in combination
with chemotherapy and ASCT as one of the therapeutic
options in patients with AL amyloidosis [116].
Kidney Transplantation in Myeloma
Kidney transplantation is challenging in patients with
MM since the transplantation and ensuing use of immuno-
suppressive medications are thought to portend a high risk
for disease recurrence and infections. Most centers require
a treatment-free remission period of 3–5 years. The initial
lesion can be predictive of graft survival and recurrence.
Patients with MCN have a lower risk of graft recurrence if
MM stays in remission [117]. In patients with AL amyloi-
dosis, specifically those without significant cardiac
involvement, kidney transplantation in combination with
chemotherapy and ASCT has shown favorable outcomes
[116]. Renal transplantation in patients with MIDD is not
recommended unless complete response is noted, as
recurrence rates are about 80% in patients who do not
have a complete response to treatment [118].
S.M. Doshi et al.
Conclusion
Thus, supportive care for MM patients becomes increas-
ingly important, if MM patients are to enjoy a higher
quality of life. MM patients are living longer, receiving
more intensive therapy, and are potentially curable.
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