PATHOPHYSIOLOGY
MMBD is characterized by increased resorption on bone formation[1]
[3]
[4]
[6]
[7]
[8] due to overexpression of the receptor activator of nuclear factor kappa B (RANK),
its ligand (RANKL) and osteoprotegerin (OPG), resulting in increased osteoclastic
activity,[3] that leads to development of lesions without evidence of typical replacement or
repair[6]
[7]
[8] and osteoporosis, bone pain, pathologic fractures, hypercalcemia, and spinal cord
compression.[3]
Increased Bone Resorption
In MM, bone destruction is mediated by osteoclasts and not by neoplastic cells. Osteoclasts
accumulate on resorptive surfaces adjacent to neoplastic cells, and their number is
not increased in areas not involved by the tumor. The increase in osteoclastic activity
is mediated by the release of osteoclast activating factors produced by neoplastic
cells or medullary stromal cells (BMSCs).[1]
Neoplastic cells adhere to BMSCs through a4b1 integrin, present on their surfaces,
to vascular cell adhesion molecule-1, expressed in stromal cells.[9] Adhesion of MM cells to BMSCs and osteoblasts increases the production of RANKL,
macrophage colony-stimulating factors, and other cytokines that activate osteoclasts,
such as IL-6, IL-11, IL-1β, tumor necrosis factors, and factor of basic fibroblastic
growth. At the same time, the production of OPG, which naturally occurs and antagonizes
the effects of RANKL, preserving bone integrity, is suppressed[1]
[9] - there is a decrease in OPG production by stromal cells, induced by neoplastic
cells, and OPG sequestration by neoplastic cells, which degrade it in their lysosomes;
both mechanisms may contribute to the local and systemic reduction of OPG in patients
with MM.[1] The RANKL/OPG ratio is determinant in the regulation of bone resorption. The interactive
network of cytokines and hormones involved in bone resorption and anti-resorption
converge in the RANKL/OPG system, which acts as a common end effector in the regulation
of osteoclastic formation from its bone marrow precursors and subsequent activation.[1]
RANK and RANKL play an important role in the development of osteoclasts - RANK is
expressed on the surface of these cells; RANKL is expressed on the surface of osteoblasts
and stromal cells, and, by binding to its receptor (RANK), it drives differentiation
and activation signals in osteoclastic precursors, promoting bone resorption.[1]
IL-1β is a potent stimulator of osteoclast formation, but its levels in patients with
MM are very low. This suggests that IL-1β is probably not a major mediator in MMBD.[1]
[9]
IL-6 stimulates the development of osteoclasts. The use of anti-IL-6 allowed demonstrating
the role of this cytokine in stimulating bone resorption in patients with MM.[1]
Other important factors are MIP-1α and MIP-1β chemokines. There is an overproduction
of MIP-1α in the bone marrow and both chemokines are secreted by neoplastic cells,
acting on the chemoattractiveness and activation of monocytes. Osteoclastic precursors
and stromal cells express receptors for MIP-1α and MIP-1β. The chemokine MIP-1α as
well as MIP-1β induce RANKL expression in stromal cells and, consequently, increase
bone resorptive activity. In addition to their inductive osteoclastic capacity, these
chemokines have relevant biological activities in determining other clinical characteristics
present in MM patients, acting as potent modulators of hematopoiesis: MIP-1α inhibits
early erythropoiesis and MIP-1β increases apoptosis in pre-B cells by suppressing
erythropoiesis, B lymphopoiesis, and immunoglobulin production.[1]
Decreased Bone Formation
Histomorphometric studies and biochemical indicators demonstrate that, although the
number and function of osteoclasts are increased in the MM, the determining condition
for the presence or absence of lytic lesions is lower osteoblastic activity.[1]
In the early stages of MMBD, bone formation is increased, reflecting the coupling
of resorption to formation. However, as the disease progresses, bone formation decreases,
with rapid bone loss, suggesting that neoplastic cells initially stimulate osteoblastic
function and then inhibit it, or there is cellular toxicity during tumor expansion.[1]
Even when MM is in remission, with no evidence of neoplastic cells in the marrow,
bone lesions persist. Treatment with bisphosphonates inhibits resorption without inducing
bone repair.
The clinical finding that patients with MM have decreased osteoblastic activity has
been confirmed in several in vitro and in vivo studies.[9] However, few inhibitory interactions between osteoblasts and MM have been described.
MM cells produce the protein dickkoppf 1 (DKK1), which inhibits osteoblasts. Indeed,
DKK1 overexpression in MM is associated with MMBD.[1] Possible candidates for osteoblast inhibitors in MM include DKK1 and other factors
that block the Wnt signaling pathway, along with IL-3 and IL-7.[9]
INTERNATIONAL MYELOMA WORKING GROUP (IMWG) RECOMMENDATIONS FOR THE TREATMENT OF MMBD[8]
Treatment with Diphosphonates
Diphosphonates are pyrophosphate analogues that bind to exposed areas of hydroxyapatite
crystals during the bone remodeling process. They are potent inhibitors of intracellular
farnesyl pyrophosphate synthase, leading to osteoclast apoptosis and prevention of
bone loss.
Indications
Diphosphonates (zoledronate or pamidronate) should be administered to all patients
with active MM, regardless of the presence or absence (only for zoledronate) of identifiable
MMBD in imaging studies.
Zoledronate (ZOL) is also indicated in the treatment of MM-related hypercalcemia and
is superior to pamidronate (PAM) in this setting.
Choice of Diphosphonate, Route of Administration and Dosing Schedule
In patients with symptomatic MM, 4 mg intravenous (IV) ZOL given over 15 min every
3-4 weeks. 30 or 90 mg IV PAM given every 3-4 weeks for 45 min (for 30 mg) or 2 h
(for 90 mg) is recommended for prevention of skeletal related events (SRE). Dose adjustments
are essential in case of renal impairment, both at diagnosis and during treatment.
In addition to more convenient administration, ZOL is preferred over PAM because of
the significant reduction in the mortality rate. ZOL is also preferred over clodronate
(CLO) due to its superiority in reducing SRE and improving survival, especially in
newly diagnosed patients and patients with multiple MMBD at diagnosis. Compared with
placebo or no treatment, only ZOL showed both progression-free survival and overall
survival benefits. PAM 90 mg IV monthly is not superior to PAM 30 mg IV monthly for
SRE prevention.
In outpatients, administration of IV ZOL is preferred over IV PAM or oral CLO. In
patients unable to receive outpatient care, home infusion may be an alternative; in
these cases, ZOL is preferable to PAM, due to the shorter infusion time.
Duration of Treatment
ZOL must be administered monthly for at least 12 months. If, after this period, a
very good or better partial response is achieved, one may consider decreasing the
frequency to every three months or, based on osteoporosis recommendations, every six
months or annually, or even discontinuing it. The decision to discontinue ZOL should
consider individualized assessment of fracture risk based on gender, age, ethnicity,
body mass index, fracture history, smoking, alcohol consumption, bone mineral density,
associated systemic disease (other than MM) to secondary osteoporosis, and daily and
cumulative dose of glucocorticoid, frequent in continuous anti-myeloma regimens. If,
after 12 months, a very good partial response has not been achieved, ZOL should be
continued monthly until this occurs; hence, one can decrease the frequency or stop
the treatment.
PAM should be administered to patients with MM who have active disease and can be
continued at clinical discretion, taking into account patient and disease-related
factors.
If discontinued, ZOL or PAM should be restarted on relapse to reduce the risk of new
SREs.
Adverse events
Calcium and vitamin D supplementation should be performed in all patients receiving
diphosphonates, but only after normalization of calcium concentration, in the case
of hypercalcemia. Creatinine clearance, serum electrolytes, and urinary albumin (in patients receiving PAM only) should
be monitored monthly, with dose adjustments accordingly.
A comprehensive dental examination and any necessary invasive treatment should be
performed prior to initiation of therapy. Diphosphonates should be discontinued when
osteonecrosis of the jaw is present, unless ongoing treatment is required (MMBD progression
or recurrent hypercalcemia). If possible, diphosphonates should be temporarily withheld
before and after any tooth extraction or invasive oral procedures, and periprocedural
antibiotic prophylaxis should be considered; after that, the treatment can be restarted
considering risk-benefit. Patient education is essential in adhering to oral hygiene
and supplement consumption, as well as in recognizing and reporting adverse events
early.
Treatment with Denosumab
Denosumab is a human monoclonal IgG2 antibody, highly specific against RANKL. This
drug mimics the physiological effect of OPG, inhibiting the interaction between RANKL
and RANK, decreasing bone resorption.
Indications
Denosumab is recommended in the treatment of newly diagnosed MM and in relapsed or
refractory cases with evidence of multiple MMBD. It has an effect equivalent to ZOL
in delaying the first SRE after the diagnosis of MM. Denosumab may prolong progression-free
survival in patients with newly diagnosed MM who are eligible for autologous stem
cell transplantation. Denosumab may be preferable to ZOL in the treatment of patients
with MM who have renal dysfunction, and may be considered in the treatment of patients
who have a creatinine clearance of less than 30 ml/min under close monitoring. Denosumab
can also be given to patients with MM-related hypercalcemia, especially those refractory
to ZOL.
Route of Administration, Dosage Schedule and Duration of Treatment
120 mg of denosumab should be administered subcutaneously (SC) at monthly intervals.
Home SC injection makes administration of denosumab more convenient than IV administration
of diphosphonates. Denosumab should be administered continuously until unacceptable
toxicity occurs. De-escalation, pause or discontinuation of the drug can only be considered
after 24 months if the patient achieves a very good or better partial response with
anti-myeloma treatment. A personalized assessment based on patient characteristics,
comorbidities and glucocorticoid use should also guide therapeutic decisions. Until
more data is available, a single dose of IV diphosphonate is recommended, at least
six months after the last dose of denosumab, to avoid a rebound effect; similarly,
the administration of denosumab every six months can be considered.
Adverse Events
Calcium and vitamin D supplementation is recommended for all patients, especially
those with renal impairment after normalization of serum calcium concentration, in
case of hypercalcemia. Calcium, vitamin D, phosphate and magnesium should be measured
regularly to assess the need for supplementation. Oral health should be assessed at
baseline and during treatment. Denosumab should be discontinued 30 days prior to invasive
dental or oral procedures until healing occurs, at which time it can be restarted.
Radiotherapy
MM cells are radiosensitive and many people with this disease will need radiotherapy
at some point, particularly in the treatment of symptomatic bone lesions[1] - radiotherapy is highly effective in relieving pain; up to 90% of patients achieve
pain control with this therapeutic approach.[17]
Spinal cord compression occurs in 10% to 20% of patients with MM. In cases where there
is no vertebral instability, the use of corticosteroids associated with radiotherapy
may prevent permanent neurological deficit.[1]
Radiation therapy may be followed by vertebroplasty/kyphoplasty to ensure vertebral
stabilization,[18]
[19] however, the treatment sequence does not seem to affect the improvement of pain.[19]
The IMWG recommends that radiotherapy should be considered when there is persistent
uncontrolled pain, associated with impending or ongoing spinal cord compression, or
pathological fractures; in these scenarios, low-dose radiotherapy (above 30 Gy) can
be used as a palliative treatment.[8]
Orthopedic Treatment
In general, the orthopedic approach to MMBD is surgical, reserving non-surgical treatment
(plastered immobilizations, braces, vests together with drug treatment and/or radiotherapy)
for minor injuries that affect the upper limbs ([Fig. 3A]) and the axial skeleton, accompanied or not by conservatively treatable bone pain
not associated with neurological deficits.
Fig. 3 Orthopedic approach in the treatment of bone lesions associated with MM with imminent
or ongoing fracture. (A) Nonsurgical treatment of fracture of the distal segment of the right humerus; (B) IMN in the treatment of metaphyseal fracture and distal diaphyseal bone lesion in
the right femur; (C) Modular megaprosthesis in the treatment of an extensive lesion affecting the proximal
segment of the right femur.
More than 90% of patients with MM develop lytic bone lesions that can be surgically
treated.[3] The objectives of surgical treatment are: to relieve pain[3]
[7]
[8]; maintain function[3]
[7]
[8]; improve quality of life[3]
[7]
[8] by addressing impending or existing pathological fractures, focal bone lesions associated
with refractory pain, medullary and radicular compression, and vertebral instability[3]
[7]
[8]; and, (4) need for percutaneous or open biopsy (in 6% of cases, the myelogram is
insufficient to establish the diagnosis).[12]
Extensive bone destruction is a surrogate marker of advanced disease and, in general,
surgical interventions in these patients may result in a greater number of perioperative
complications.[3] Most newly diagnosed patients demand immediate initiation of systemic treatment,
impairing immune function. They are usually elderly, many of whom have diabetes and
hypertension, in addition to presenting hypercalcemia, anemia, coagulopathies and
hypoproteinemia. In particular, care must be taken when correcting anemia; procedures
should not be performed until a hemoglobin concentration and platelet count of 10 g/l
and 80 × 109/l respectively have been achieved.[13] In this context, multidisciplinary management is considered essential.
Postoperative radiotherapy should be considered,[2]
[8] especially in long bone fractures, to obtain local control of the disease and prevent
failures in procedures involving implants. It is particularly important in those patients
who have minimal or no response to systemic treatment.[8]
Staging and prognostic estimation methods that allow categorically defining which
patients are eligible for surgical treatment have not yet been established.[6]
[12] MM should be staged pre- and postoperatively according to the Revised International
Staging System (R-ISS).[6]
[10]
[20] Neurological function should be graded using Frankel[12] or American Spinal Injury Association (ASIA) scores, along with assessment of bladder,
bowel, and sexual function. Pain should be assessed using the visual analogue scoring
system and function using the Karnofsky functional scale[12] or the Eastern Cooperative Oncology Group (ECOG) score.[4] All of these assessment systems are useful for estimating pre- and postoperative
therapeutic benefits.[9]
The Committee of Surgeons of the Chinese Myeloma Working Group (CMWG) contraindicates
surgical treatment when there is poor clinical condition, intractable cardiac, pulmonary
and renal dysfunctions, severe coagulation disorders - which are difficult to control,
and severe and uncontrollable infection.[12]
General anesthesia is often the approach of choice because intraspinal blocks and
other methods of anesthetic induction are invasive and can lead to bleeding[3]
[12] and infection.[12] Patients with MMBD are generally in poor physical condition - general anesthesia
allows better control of blood pressure, oxygen saturation and respiratory rate.[3]
[12]
The implants used should preferably be made of titanium alloys or be carbon fiber
reinforced as they generate significantly less artifacts than those made of stainless
steel. Although titanium alloy implants generate fewer artifacts, the difficulty in
properly planning radiotherapy remains, especially in identifying the target and evaluating
the amount of dose actually administered to the tissues. Carbon fiber reinforced implants
are chemically and biologically stable and allow for even better CT and MRI imaging
– these features facilitate monitoring of pathologic fracture healing, local recurrence,
progression, and response to treatment,[21] in addition to making it possible to outline an ideal radiotherapy strategy, as
the image quality provided during planning reduces discrepancies between late/delivered
and measured doses, generating more homogeneous dose distribution[22]; due to their low atomic number and similar radioactive properties to surrounding
tissues, they are inert to ionic irradiation and provide minimal disruption to their
distribution during radiotherapy.[21]
Pelvic and Periacetabular Injuries
Pelvic and periacetabular involvement in MM has unique characteristics in terms of
biomechanics, morbidity, overall survival and prognosis, reflecting on the quality
of life of affected individuals.[23] Periacetabular injuries are particularly challenging and are often associated with
severe pain, functional disability and pathological fractures; due to load transmission,
lesions that show progressive growth can compromise the stability of the pelvic ring.[24]
In MM, pelvic and periacetabular bone involvement occurs in about 6% of cases. The
Harrington classification (1981) is widely used in defining the treatment of BM of
carcinoma or MM that affect the acetabulum.[25] Group I comprises lesions that present intact subchondral bone; in group II, there
is destruction of the medial wall, but demonstrate an intact acetabular roof and lateral
wall; in group III, there is destruction of the medial wall, roof and lateral edge
of the acetabulum; group IV is defined by the presence of solitary lesions that can
be resected en bloc, with anticipation of healing.[24]
Operative treatment is indicated for patients with MM who have periacetabular bone
lesions whose non-operative treatment has failed, in pathological/imminent fractures,[24]
[26] in pelvic collapse, or when the symptoms are intolerable.[24] Expected survival should exceed surgical recovery time, allowing for a real improvement
in quality of life.[24] The surgical approach to these lesions has historically consisted of cementoplasty
for contained lesions and Harrington reconstructions for larger and more destructive
lesions.[24] In 1981, Harrington described a technique involving the use of threaded Steinmann
pins and polymethylmethacrylate for the reconstruction of acetabular defects, associated
with cemented total hip arthroplasty, allowing the transmission of load-bearing forces
to the intact segment of the pelvis.[24] Due to the limitations of these techniques, new surgical approaches, dictated by
the size and location of these lesions, have been created to manage this challenging
condition.[26] The use of adjuncts to the Harrington procedure, such as restricted overlays and
dual mobility bearings, has reduced historically high rates of prosthetic dislocation.[26] Despite functional improvements and pain control, these procedures are associated
with extensive surgical wounds and massive blood loss, leading to the development
of percutaneous approaches (including acetabular screw fixation and screw-associated
cementoplasty) to minimize surgical morbidity.[24] Antiprotrusion ring with medial wall cementation and acetabular impaction bone graft
combined with cementless acetabular components are other well-established methods
indicated for contained defects or when acetabular fixation is feasible.[25] Cages and porous tantalum implants are becoming increasingly common in the management
of large bone defects and destructive periacetabular injuries.[24] More recently, customized prostheses, developed from the analysis of three-dimensional
reconstruction imaging studies, have been used to replace pelvic segments in selected
cases.[24]
Spinal injuries
MM is the most common malignancy of the spine,[27] accounting for approximately 15% of all cases.[2] About 70% of patients with MM have spinal injuries,[18] which is the most frequent site for fractures[1] (> 50%)[27]–8 to 10% of patients develop neurological deficits.[2]
[12]
[27]
The surgical indication is based on the neurological, oncological, mechanical and
systemic (NOMS) decision-making framework, which includes the neurological status
(myelopathy, degree of epidural spinal cord compression), radio/chemosensitivity of
the tumor, mechanical instability, extension of the systemic disease and comorbidities.[28]
Vertebroplasty and kyphoplasty are indicated for patients with lytic lesions[3] and/or symptomatic compressive vertebral fractures[8] not associated with spinal cord compression.[1]
[11]
[12] These procedures provide immediate pain relief and stabilization of the vertebral
bodies.[1]
[12] It is essential to obtain tissue samples during the approach, seeking greater definition
or correction in the diagnosis.[12]
Vertebroplasty consists of the percutaneous injection of polymethylmethacrylate (PMMA)
into the affected vertebra, under radioscopic control. This procedure allows a significant
decrease in pain (up to 97%) but presents a (low) risk of cement leakage and pulmonary
embolism.[1]
Kyphoplasty provides vertebral stabilization, pain relief and restoration of vertebral
body height. This is possible by inserting a balloon into the affected vertebra which,
when inflated, creates a cavity in the vertebral body where PMMA is injected. The
frequency of cement leakage is lower with this procedure.[1]
The open approach to the spine is indicated when there is spinal instability, associated
or not with spinal cord compression.[3] The procedures are defined according to the number, location and size of the lesions.
Approaches include direct anterior, posterior, or combined approaches. The goals of
treatment are: removal of as much tumor as possible, decompression, reconstruction
and stabilization.[15]
[16] The implants (titanium alloy or carbon fiber reinforced) are chosen to meet the
specific requirements of each procedure, including plates, pedicle screw systems,
lateral mass screw fixation systems, artificial vertebral bodies and cages, as well
as filling material, such as PMMA and allograft. In addition to facilitating modeling,
PMMA has a local adjuvant function, due to the exothermic reaction, which destroys
tumor cells - it is therefore the first choice for filling bone defects after tumor
removal - autologous bone grafts are not recommended, because they are more prone
to resorption.[12]
Combinations of open and minimally invasive surgery are used in the treatment of patients
with multiple vertebral injuries, allowing to add advantages presented by both, reducing
the need for volume replacement and preventing other complications. Wide or radical
resection is unnecessary in the treatment of MM that affects the spine.[12]
Long Bone Injuries
In MM, long bone fractures are relatively less frequent than vertebral fractures,
but they usually require hospitalization for early intervention,[6] through fixation or replacement of the affected segment.[1]
Prophylactic surgery has become a reality with the increasingly early diagnosis of
MMBD. This approach provides early stability, providing less time for recovery of
function when compared to non-surgical treatment.[5] Mirels (1989)[29] developed a risk prediction score for pathological fractures in injuries located
in the appendicular skeleton.[6]
[29]
[30]
[31] This score is based on four characteristics, which are assigned progressive scores
from 1 to 3, added at the end: (1) lesion site; (2) nature of the injury; (3) lesion
size; and (4) pain ([Table 2]).[30]
[31] Based on this score, a recommendation for or against prophylactic surgery is given.
Lesions with a score equal to or greater than 9 constitute an indication for a surgical
approach.[29]
[30]
[31] Lesions with a score of 7 or less can be managed conservatively (observation, radiotherapy
and/or pharmacological treatment).[29]
[30]
[31] A score of 8 represents a dilemma - the probability of fracture is only 15%, it
is recommended to use clinical judgment for each situation, considering the benefits
of prophylactic surgery versus the probability of fracture - more detailed imaging
exams allow more accurate access to the dimension of the defect generated by the lesion.[6]
[29]
[30]
[31]
Table 2
|
|
Score
|
|
|
Component
|
1
|
2
|
3
|
|
Site
|
Upper limb
|
Lower limb
|
Pertrochanteric
|
|
Pain
|
Mild
|
Moderate
|
Severe
|
|
Lesion
|
Blastic
|
Mixed
|
Lytic
|
|
Size
|
< 1/3 of cortex
|
1/3–2/3 of cortex
|
> 2/3 of cortex
|
Pathological fractures of the long bones must be operated on as soon as possible,
particularly those in the lower limbs, due to load bearing.[6] Procedures include resection of the affected segment (“expendable” bones), filling
with PMMA, internal fixation (screws, plates or intramedullary rods in carbon fiber
reinforced or titanium implants)[6]
[7]
[11]
[12]
[24] or replacement with conventional prostheses[16] or megaprostheses.[1]
[7]
[11]
[15]
[16]
The choice of surgical procedure depends on the general condition and life expectancy
of the patient, previous response to chemotherapy, affected site, number, size and
location of lesions and extent of bone invasion.
If there are concomitant lesions in the distal and proximal segments of the same bone,
choose long plates or intramedullary nails (IMN). IMN ([Fig. 3B]) reinforce the affected bone with a definitive, durable and mechanically stable
implant, allowing for reduced pain and early discharge.[24]
[32] Reaming should only be performed when there is good bone quality. The rate of reoperation
due to infection, pseudarthrosis or loosening is substantially lower when using IMN,
compared to other methods, as it provides greater stability and vascular preservation
in bones affected by primary osteoporosis, or secondary to MMBD.[6] Diaphyseal and metaphyseal fractures of the femur and humerus usually require fixation
with IMN followed by radiotherapy.
In cases where there is more extensive bone destruction affecting the joint and/or
metaphyseal segment of the affected bone,[3] resection with replacement by megaprostheses may be considered ([Fig. 3C]).[1] Megaprostheses of the proximal segment of the femur provide good functional outcomes,
low incidence of complications and better quality of life in the medium term - patients
with pathological fracture of the proximal segment of the femur due to MM, confirmed
or imminent, treated by resection with replacement, have significantly longer survival.
Although different types of surgeries can provide pain relief and functional improvement
in different anatomical locations, the best results, with lower complication rates,
are observed in lesions located in the upper extremities[3]
[12] or diaphyseal segments of long bones.[12]
