Multiple Myeloma Overview

8/18/2019 Multiple Myeloma Overview

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Practice Essential

Multiple myeloma (MM) is a debilitating malignancy that is part of a spectrum of

diseases ranging from monoclonal gammopathy of unknown signicance (MGUS) to

plasma cell leukemia. First described in !"!# MM is characteri$ed by a proliferation

of malignant plasma cells and a subse%uent o&erabundance of monoclonal

paraprotein (M protein). See the image below.

'one marrow aspirate demonstrating plasma cells of multiple myeloma. ote theblue cytoplasm# eccentric nucleus# and perinuclear pale $one (or halo). ll images

and te*t are (c) +,,+ by the merican Society of -ematology. ll rights reser&ed.

Signs and symptoms

he presentation of MM can range from asymptomatic to se&erely symptomatic#

with complications re%uiring emergent treatment. Systemic ailments include

bleeding# infection# and renal failure/ pathologic fractures and spinal cord

compression may occur.

0resenting symptoms of MM include the following1

'one pain

0athologic fractures

2eakness# malaise

'leeding# anemia

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3nfection (often pneumococcal)

-ypercalcemia

Spinal cord compression

4enal failure

europathies

See 0resentation for more detail.

Diagnosis

MM is often disco&ered through routine blood screening when patients are being

e&aluated for unrelated problems. 3n one third of patients# the condition is

diagnosed after a pathologic fracture occurs# usually in&ol&ing the a*ial skeleton.

5*amination for MM may re&eal the following1

-55 e*amination1 5*udati&e macular detachment# retinal hemorrhage# or cotton6

wool spots

7ermatologic e&aluation1 0allor from anemia# ecchymoses or purpura from

thrombocytopenia/ e*tramedullary plasmacytomas (most commonly in

aerodigesti&e tract but also orbital# ear canal# cutaneous# gastric# rectal# prostatic#

retroperitoneal areas)

Musculoskeletal e*amination1 'ony tenderness or pain without tenderness

eurologic assessment1 Sensory le&el change (ie# loss of sensation below a

dermatome corresponding to a spinal cord compression)# neuropathy# myopathy#

positi&e inel sign# or positi&e 0halen sign

bdominal e*amination1 -epatosplenomegaly

8ardio&ascular e&aluation1 8ardiomegaly

3n patients with MM and amyloidosis# the characteristic e*amination ndings include

the following1

Shoulder pad sign

Macroglossia

ypical skin lesions

0ostprotoscopic peripalpebral purpura

8arpal tunnel syndrome

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Subcutaneous nodules

esting

he 3nternational Myeloma 2orkshop guidelines for standard in&estigati&e workup in

patients with suspected MM include the following9: 1

Serum and urine assessment for monoclonal protein (densitometer tracing and

nephelometric %uantitation/ immuno*ation for conrmation)

Serum free light chain assay (in all patients with newly diagnosed plasma cell

dyscrasias)

'one marrow aspiration and;or biopsy

Serum beta+6microglobulin# albumin# and lactate dehydrogenase measurement

Standard metaphase cytogenetics

Fluorescence in situ hybridi$ation

Skeletal sur&ey

M43

4outine laboratory tests include the following1

8omplete blood count and di


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Simple radiography for the e&aluation of skeleton lesions/ skeletal sur&ey# including

the skull# long bones# and spine

M43 for detecting thoracic and lumbar spine lesions# paraspinal in&ol&ement# and

early cord compression

05 scanning in con>unction with M43 potentially useful

See 2orkup for more detail.

Management

here is currently no cure for MM. -owe&er# ad&ances in therapy# such as

autologous stem cell transplantation# radiation# and surgical care in certain cases#

ha&e helped to lessen the occurrence and se&erity of ad&erse e


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'orte$omib;de*amethasone

'orte$omib;cyclophosphamide;de*amethasome

'orte$omib;lenalidomide;de*amethasone (category )

Denalidomide;low6dose de*amethasone (category )

Melphalan;prednisone;borte$omib (M0') (category )

Melphalan;prednisone;lenalidomide (M0D) (category )

Melphalan;prednisone;thalidomide (M0) (category )

0atients with refractory disease or relapse may be treated with the following1

ny of the agents not pre&iously used

'orte$omib plus cyclophosphamide and de*amethasone

9+# ?:

8arl$omib (yprolis)

halidomide

Denalidomide plus cyclophosphamide and de*amethasone 9+:

0omalidomide 9B# !:

See reatment and Medication for more detail.

Multiple myeloma (MM) is a debilitating malignancy that is part of a spectrum of diseases

ranging from monoclonal gammopathy of unknown significance (MGUS) to plasma cell

leukemia. First described in 1!" MM is characteri#ed by a proliferation of malignant plasma

cells and a subse$uent o%erabundance of monoclonal paraprotein (M protein). &n intriguing

feature of MM is that the antibody'forming cells (ie" plasma cells) are malignant and" therefore"

may cause unusual manifestations.

he proliferation of plasma cells in MM may interfere with the normal production of blood cells"

resulting in leukopenia" anemia" and thrombocytopenia. he cells may cause soft'tissue masses

(plasmacytomas) or lytic lesions in the skeleton. Feared complications of MM are bone pain"

hypercalcemia" renal failure" and spinal cord compression.

he aberrant antibodies that are produced lead to impaired humoral immunity" and patients ha%e

a high pre%alence of infection" especially with encapsulated organisms such as Pneumococcus.

he o%erproduction of these antibodies may lead to hyper%iscosity" amyloidosis" and renal

failure. yper%iscosity syndrome (*S) refers to the clinical se$uelae of increased blood

%iscosity. +ncreased serum %iscosity usually results from increased circulating serum

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immunoglobulins and can be seen in such diseases as ,aldenstr-m macroglobulinemia and

multiple myeloma. *S can also result from increased cellular blood components (typically

white or red blood cells) in hyperproliferati%e states such as the leukemias" polycythemia" and

the myeloproliferati%e disorders.

he clinical presentation in *S consists principally of the triad of mucosal bleeding" %isual

changes" and neurologic symptoms.1/ 0onstitutional symptoms and cardiorespiratory symptoms

may also occur.

he diagnosis of *S is confirmed by measurement of ele%ated serum %iscosity in a patient with

characteristic clinical manifestations of *S. o e2act diagnostic cut'off e2ists for serum

%iscosity" howe%er" as different patients will ha%e symptoms at different %alues.

3lasmapheresis is the treatment of choice for initial management and stabili#ation of *S from

ele%ated immunoglobulin le%els.4/ 5eukapheresis" plateletpheresis" and phlebotomy are indicated

for *S from leukostasis" thrombocytosis" and polycythemia" respecti%ely.

6efiniti%e treatment of *S is treatment of the underlying disorder (eg" chemotherapy). +f the

underlying disease process is left untreated" the hyper%iscosity will recur.

he &merican 0ancer Society (&0S) estimates that about 78"778 new cases of MM (19":88 in

men and 14"!78 in women) will be diagnosed in 481;. +n the United States" the lifetime risk of

getting MM is one in 1!7 (8.9


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pathogenesis of myelomas.9A: his information has resulted in the e*pansion of

treatment options.

'one marrow aspiratedemonstrating plasma cells of multiple myeloma. ote the blue cytoplasm#

eccentric nucleus# and perinuclear pale $one (or halo). ll images and te*t are (c)

+,,+ by the merican Society of -ematology. ll rights reser&ed.

'one marrow biopsy

demonstrating sheets of malignant plasma cells in multiple myeloma. ll images


he malignant cells of MM# plasma cells# and plasmacytoid lymphocytes are the

most mature cells of '6lymphocytes. '6cell maturation is associated with a

programmed rearrangement of 7 se%uences in the process of encoding the

structure of mature immunoglobulins. 3t is characteri$ed by o&erproduction of

monoclonal immunoglobulin G (3gG)# immunoglobulin (3g)# and;or light chains#

which may be identied with serum protein electrophoresis (S050) or urine protein

electrophoresis (U050).


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he role of cytokines in the pathogenesis of MM is an important area of research.

3nterleukin (3D)H? is also an important factor promoting the in &itro growth of

myeloma cells. Ither cytokines are tumor necrosis factor and 3D6b.

he pathophysiologic basis for the clinical se%uelae of MM in&ol&es the skeletal#

hematologic# renal# and ner&ous systems# as well as general processes (see below).

Skeletal processes

0lasma6cell proliferation causes e*tensi&e skeletal destruction with osteolytic

lesions# anemia# and hypercalcemia. Mechanisms for hypercalcemia include bony

in&ol&ement and# possibly# humoral mechanisms. 3solated plasmacytomas (which

a


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confusion# &ertigo# sei$ure). 8ryoglobulinemia causes 4aynaud phenomenon#

thrombosis# and gangrene in the e*tremities.

he precise etiology of MM has not yet been established. @oles ha%e been suggested for a

%ariety of factors" including genetic causes" en%ironmental or occupational causes" MGUS"

radiation" chronic inflammation" and infection.

EtiologiGenetic causes

MM has been reported in two or more first'degree relati%es and in identical twins" although no

e%idence suggests a hereditary basis for the disease. & study by the Mayo clinic found MM ineight siblings from a group of !!8 patients? these eight siblings had different hea%y chains but

the same light chains.

Some studies ha%e shown that abnormalities of certain oncogenes" such as c-myc" are associated

with de%elopment early in the course of plasma cell tumors and that abnormalities of oncogenessuch as N-ras and K-ras are associated with de%elopment after bone marrow relapse.

&bnormalities of tumor suppressor genes" such as TP53" ha%e been shown to be associated with

spread to other organs.:/

Angoing research is in%estigating whether human leukocyte antigen (5&)'0w= or 5&'0w4may play a role in the pathogenesis of multiple myeloma.

5n&ironmental or occupational causes

0ase'controlled studies ha%e suggested a significant risk of de%eloping MM in indi%iduals with

significant e2posures in the agriculture" food" and petrochemical industries. &n increased risk has been reported in farmers" especially in those who use herbicides and insecticides" and in people

e2posed to ben#ene and other organic sol%ents. 5ong'term (B48 y) e2posure to hair dyes has been tied to an e2cessi%e risk of de%eloping MM.

MGUS;Smoldering Multiple Myeloma (SMM)

Monoclonal gammopathy of undetermined significance (MGUS) is defined by the presence ofthree criteriaC

• Serum monoclonal M protein (M'protein) concentration D 7 gEd5

• one marrow plasma cell concentration D 18<

• o e%idence of end organ damage

MGUS is seen in 4'7< of the elderly 0aucasian population. +t is di%ided into the following three

subtypesC

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• on +gM MGUS

• +gM MGUS

• 5ight chain MGUS

3atients with non'+gM MGUS ha%e a risk of progression to MM at rate of 1< per year. For these

patients" risk factors for progression to MM are as followsC

• M protein concentration B 1.= gEd5

• on'+gG isotype

• &n abnormal free light chain (F50) ratio

3atients with +gM MGUS ha%e a risk of progression to ,aldenstrom macroglobulinemia and lessfre$uently lymphoma or amyloid light chain (&5) amyloidosis. +gM MGUS rarely progresses

into MM. 5ight chain MGUS has a tendency to progress to light chain MM" &5 amyloidosis" or

light chain deposition disease.

& study by ,adhera et al e2amined secondary MGUS that de%eloped in patients with MM. Af1:!4 patients with MM" 14 (;.;


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@adiation may play a role in some patients. &n increased risk has been reported in atomic'bomb

sur%i%ors e2posed to more than =8 GyC +n 18:"888 sur%i%ors of the atomic bombing of agasaki

during ,orld ,ar ++" 4: died from multiple myeloma between 1:=8 and 1:9;. Some more recentstudies" howe%er" do not confirm that these sur%i%ors ha%e an increased risk of de%eloping

multiple myeloma.

& study of workers at the Aak @idge 6iffusion 3lant in eastern ennessee showed only a weak

correlation of risk of multiple myeloma to uranium e2posure.19/

8hronic in@ammation

& relationship between MM and pree2isting chronic inflammatory diseases has been suggested.

owe%er" a case'control study pro%ides no support for the role of chronic antigenic stimulation.

3nfection

uman herpes%irus () infection of bone marrow dendritic cells has been found in patientswith MM and in some patients with MGUS.

Epidemiologi

MM accounts for 18< of all hematologic cancers.1" 1:/ he age'adusted annual incidence of MM

is !.7 cases per 188"888 white men" 7 cases per 188"888 white women" :.; cases per 188"888

black men" and ;.9 cases per 188"888 black women.

he &merican 0ancer Society estimates that in the United States" appro2imately 78"778 new

cases of MM (19":88 in men and 14"!78 in women) will be diagnosed in 481;. he lifetime risk

of getting MM is one in 1!7 (8.9


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Prognosis

MM is a heterogeneous disease" with sur%i%al ranging from 1 year to more than 18 years. Mediansur%i%al in unselected patients with MM is 7 years. he ='year relati%e sur%i%al rate is !;.;


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Patient Education

3atient education is %ery important in the management of MM. he +nternational MyelomaFoundation (+MF) offers educational resources" a $uarterly newsletter" and conferences. 3atients

or physicians can contact the +MF by phone at (88) !=4'0U@> (88'!=4'497) in the United

States and 0anada or on the ,eb at +nternational Myeloma Foundation.

3atient education should address" at a minimum" the following $uestionsC

• ,hat is MM" and how does it affect the bodyJ

• ,hat are the causes of MMJ

• ,hat is the treatment for MMJ

• ,hat are the ad%erse effects of medicineJ (&s an e2ample" patients should be informed of

the risk of osteonecrosis of the aw" which has been associated with bisphosphonate

therapy in MM.)

• ,hat are some of the complications of MMJ

• ,here can additional information be foundJ

For patient education information" see lood and 5ymphatic System 0enter " as well as Myeloma.

PresentationHistory

3resenting symptoms of multiple myeloma (MM) include bone pain" pathologic fractures"

weakness" anemia" infection (often pneumococcal)" hypercalcemia" spinal cord compression" or

renal failure. he diagnosis is incidental in 78< of cases. MM is often disco%ered through

routine blood screening when patients are being e%aluated for unrelated problems. ypically" a

large gap between the total protein and the albumin le%els obser%ed on an automated chemistry

panel suggests a problem (ie" protein minus albumin e$uals globulin).

+n one third of patients" MM is diagnosed after a pathologic fracture occurs? such fracturescommonly in%ol%e the a2ial skeleton. wo thirds of patients complain of bone pain" commonly

with lower back pain. his bone pain is fre$uently located in the back" long bones" skull" andEor

pel%is.

3atients may also complain of nonspecific constitutional symptoms related to hyper%iscosity and

hypercalcemia.

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'one pain

one pain is the most common presenting symptom in MM. Most case series report that 98< of

patients ha%e bone pain at presentation. he lumbar spine is one of the most common sites of

pain.

0athologic fractures and bone lesions

3athologic fractures are %ery common in MM? :7< of patients ha%e more than one site of bony

in%ol%ement. & se%ere bony e%ent is a common presenting issue.

Spinal cord compression

he symptoms that should alert physicians to consider spinal cord compression are back pain"

weakness" numbness" or dysesthesias in the e2tremities. ecause spinal cord compressions in

MM occur at multiple le%els" comprehensi%e e%aluation of the spine is warranted. 3atients who

are ambulatory at the start of therapy ha%e the best likelihood of preser%ing function and

a%oiding paralysis.

'leeding

Accasionally" a patient may come to medical attention for bleeding resulting from

thrombocytopenia. @arely" monoclonal protein may absorb clotting factors and lead to bleeding.

-ypercalcemia

0onfusion" somnolence" bone pain" constipation" nausea" and thirst are the presenting symptoms

of hypercalcemia. his complication may be present in as many as 78< of patients with MM at

presentation. +n most solid malignancies" hypercalcemia carries an ominous prognosis" but in

MM" its occurrence does not ad%ersely affect sur%i%al.

3nfection

&bnormal humoral immunity and leukopenia may lead to infection. 3neumococcal organisms are

commonly in%ol%ed" but shingles (ie" herpes #oster) and Haemophilus infections are also more

common among patients with MM.

-yper&iscosity

yper%iscosity may be associated with a number of symptoms" including" generali#ed malaise"

infection" fe%er" paresthesia" sluggish mentation" and sensory loss. 3atients may report headaches

and somnolence" and they may bruise easily and ha%e ha#y %ision. 3atients with MM typically

e2perience these symptoms when their serum %iscosity is greater than ! times that of normal

serum.


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>pista2is may be a presenting symptom of MM with a high tumor %olume. Accasionally" patients

may ha%e such a high %olume of monoclonal protein that their blood %iscosity increases"

resulting in complications such as stroke" myocardial ischemia" or infarction.

eurologic symptoms

0arpal tunnel syndrome is a common complication of myeloma. Meningitis (especially that

resulting from pneumococcal or meningococcal infection) is more common in patients with MM.

Some peripheral neuropathies ha%e been attributed to MM. 5ong'term neurologic function is

directly related to the rapidity of the diagnosis and the institution of appropriate therapy for MM.

nemia

&nemia" which may be $uite se%ere" is the most common cause of weakness in patients with

MM.

Physical Examination

An head" ears" eyes" nose" and throat (>>) e2amination" the eyes may show e2udati%emacular detachment" retinal hemorrhage" or cotton'wool spots. 3allor from anemia may be

present. >cchymoses or purpura from thrombocytopenia may be e%ident.

ony tenderness is not uncommon in MM" resulting from focal lytic destructi%e bone lesions or

pathologic fracture. 3ain without tenderness is typical. 3athologic fractures may be obser%ed. +ngeneral" painful lesions that in%ol%e at least =8< of the cortical diameter of a long bone or

lesions that in%ol%e the femoral neck or calcar femorale are at high (=8%en a small cortical defect can decrease torsional strength by as much as ;8< (stress riser

effect).

eurologic findings may include a sensory le%el change (ie" loss of sensation below a

dermatome corresponding to a spinal cord compression)" neuropathy" myopathy" a inel sign" ora 3halen sign due to carpel tunnel compression secondary to amyloid deposition.

>2tramedullary plasmacytomas" which consist of soft'tissue masses of plasma cells" are not

uncommon. 3lasmacytomas ha%e been described in almost e%ery site in the body. &lthough the

aerodigesti%e tract is the most common location" reports also describe orbital" ear canal"

cutaneous" gastric" rectal" prostatic" and retroperitoneal lesions.

An e%aluation of the abdomen" hepatosplenomegaly may be disco%ered. 0ardio%ascular system

e2amination may re%eal cardiomegaly secondary to immunoglobulin deposition.

&myloidosis may de%elop in some patients with MM. he characteristic physical e2aminationfindings that suggest amyloidosis include the followingC

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• Shoulder pad sign

• Macroglossia

• ypical skin lesions

• 3ostprotoscopic peripalpebral purpura

he shoulder pad sign is defined by bilateral swelling of the shoulder oints secondary to

amyloid deposition. 3hysicians describe the swelling as hard and rubbery. &myloidosis may also

be associated with carpal tunnel syndrome and subcutaneous nodules.

Macroglossia may occur secondary to amyloid deposition in the tongue and is a common finding

in patients with amyloidosis (see the image below).

&myloidosis infiltrating the tongue inmultiple myeloma. &ll images and te2t are (c) 4884 by the &merican Society of ematology. &ll

rights reser%ed.

Skin lesions that ha%e been described as wa2y papules or nodules may occur on the torso" ears"

or lips.

3ostprotoscopic peripalpebral purpura strongly suggests amyloidosis. 3atients may de%elop

raccoonlike dark circles around their eyes following any procedure that parallels a prolonged

*alsal%a maneu%er. he capillary fragility associated with amyloidosis may account for this

obser%ation. +n the past" this correlation was obser%ed when patients underwent rectal biopsies tomake the diagnosis.


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@enal failure and insufficiency are seen in 4=< of patients with MM"4!/ including the following

manifestationsC

• Myeloma kidney syndrome with multiple etiologies

• &myloidosis with light chains

• ephrocalcinosis due to hypercalcemia

&nemia" neutropenia" or thrombocytopenia is due to bone marrow infiltration of plasma cells.hrombosis and @aynaud phenomenon due to cryoglobulinemia may be present.

one disease may result in the followingC

• Se%ere bone pain" pathologic fracture due to lytic lesionsC 5ytic disease or fracture may

be obser%ed on plain radiographs.

• +ncreased bone resorption leading to hypercalcemia

• Spinal cord compressionC his is one of the most se%ere ad%erse effects of MM. @eports

indicate that as many as 48< of patients de%elop spinal cord compression at some pointduring the course of their disease. Symptoms typically include back pain" weakness or

paralysis in the legs" numbness" or dysesthesias in the lower e2tremities. owe%er"

depending on the le%el of in%ol%ement" patients may present with upper'e2tremitysymptoms.

@adiculopathy andEor cord compression may occur because of skeletal destruction and ner%e

compression.

acterial infection may de%elop? it is the leading cause of death in patients with myeloma. he

highest risk is in the first 4'7 months of chemotherapy.

3urpura" retinal hemorrhage" papilledema" coronary ischemia" sei#ures" and confusion may occur

as a result of hyper%iscosity syndrome.

ypercalcemia may cause polyuria and polydipsia" muscle cramps" constipation" and a change in

the patientKs mental status.

Complication

@enal failure and insufficiency are seen in 4=< of patients with MM"4!/ including the following

manifestationsC

• Myeloma kidney syndrome with multiple etiologies


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• &myloidosis with light chains

• ephrocalcinosis due to hypercalcemia

&nemia" neutropenia" or thrombocytopenia is due to bone marrow infiltration of plasma cells.

hrombosis and @aynaud phenomenon due to cryoglobulinemia may be present.

one disease may result in the followingC

• Se%ere bone pain" pathologic fracture due to lytic lesionsC 5ytic disease or fracture may

be obser%ed on plain radiographs.

• +ncreased bone resorption leading to hypercalcemia

• Spinal cord compressionC his is one of the most se%ere ad%erse effects of MM. @eports

indicate that as many as 48< of patients de%elop spinal cord compression at some point

during the course of their disease. Symptoms typically include back pain" weakness or paralysis in the legs" numbness" or dysesthesias in the lower e2tremities. owe%er"

depending on the le%el of in%ol%ement" patients may present with upper'e2tremity

symptoms.

@adiculopathy andEor cord compression may occur because of skeletal destruction and ner%ecompression.

acterial infection may de%elop? it is the leading cause of death in patients with myeloma. he

highest risk is in the first 4'7 months of chemotherapy.

3urpura" retinal hemorrhage" papilledema" coronary ischemia" sei#ures" and confusion may occur as a result of hyper%iscosity syndrome.

ypercalcemia may cause polyuria and polydipsia" muscle cramps" constipation" and a change in

the patientKs mental status.

Dierential Diagnosishe most widely accepted schema for the diagnosis of multiple myeloma (MM) uses particular

combinations of laboratory" imaging" and procedure findings as diagnostic criteria. (See

,orkup.) he findings are as followsC

• 3 J 0lasmacytoma on tissue biopsy

• 33 J 'one marrow with greater than A, plasma cells

• 333 J Monoclonal globulin spike on serum protein electrophoresis# with animmunoglobulin (3g) G peak of greater than A.C g;dD or an 3g peak of greater

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than + g;dD# or urine protein electrophoresis (in the presence of amyloidosis)result of greater than g;+" h

• a J 'one marrow with ,6A, plasma cells

• b J Monoclonal globulin spike present but less than category 333

• c J Dytic bone lesions

• d J 4esidual 3gM le&el less than C, mg;dD# 3g le&el less than ,, mg;dD# or3gG le&el less than ?,, mg;dD

he following combinations of findings are used to make the diagnosis of MMC

• 3 plus b# c# or d

• 33 plus b# c# or d

• 333 plus a# c# or d

• a plus b plus c

• a plus b plus d

0riteria for the diagnosis of acti%e (symptomatic) MM are as follows4/ C

• 8lonal bone marrow plasma cells K, or

• 'iopsy6pro&en bony or e*tramedullary plasmacytoma and

• Ine or more myeloma6dening e&ents

Myeloma'defining e%ents include the following4/ C

• Serum calcium le&el L,.+C mmol;D (L mg;dD) higher than the upper limit ofnormal or L+.BC mmol;D (L mg;dD)

• 4enal insufficiency (creatinine L+ mg;dD 9LBB mol;D: or creatinineclearance N", mD;min)

• nemia (hemoglobin N, g;dD or hemoglobin L+ g;dD below the lower limit of normal)

• Ine or more osteolytic bone lesions on skeletal radiography# 8# or 0568

• 8lonal bone marrow plasma cells K?,


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• bnormal serum free light chain (FD8) ratio K,, (in&ol&ed kappa) or N,.,(in&ol&ed lambda)

• Ine or more focal LC mm lesions on M43 scans

&cti%e disease may also be indicated by repeated infections" amyloidosis" or hyper%iscosity.

+ndolent MM is a subset of MM with the following featuresC

• 'one disease absent (or &ery limited)

• 0erformance status greater than B,

• -emoglobin le&el greater than , g;dD

• Serum calcium le&el within the reference range

• 8reatinine le&el N+ mg;dD

• o infections

• Dow M protein le&els (ie# NB g;dD for 3gG# NC g;dD for 3g)

Smoldering (asymptomatic) MM is similar to indolent MM. 6iagnostic criteria for smoldering

MM are as follows4/ C

• Serum monoclonal protein1 3gG or 3g KA g;dD# or

• 'ence6=ones protein KC,, mg;+" h and/or

• 8lonal bone marrow plasma cells ,H?, and

• bsence of myeloma6dening e&ents or amyloidosis

he 00 recommends that a patient whose bone sur%ey is negati%e should be assessed for

bone disease with whole'body M@+ or 3>E0.4/

3olyneuropathy" organomegaly" endocrinopathy" monoclonal gammopathy" and skin changes

(3A>MS) syndrome is a rare syndrome consisting of polyneuropathy" organomegaly"endocrinopathy" M protein de%iations" and skin changes.

&myloidosis is often secondary to MM" but it may de%elop without MM. 3atients with

amyloidosis typically lack sufficient numbers of plasma cells in the bone marrow or sufficiently

high le%els of M protein to meet the diagnostic criteria for MM.


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Dierential Diagnoses

• Malignant 5ymphoma

• Metastatic one 6isease

• Monoclonal Gammopathies of Undetermined Significance

• ,aldenstrom Macroglobulinemia

WOR!P

"pproach Consideration

he +nternational Myeloma ,orkshop de%eloped guidelines for standard in%estigati%e workup in

patients suspected to ha%e multiple myeloma. hese guidelines include the followingC1/

• Serum and urine assessment for monoclonal protein (densitometer tracing and

nephelometric $uantitation? immunofi2ation for confirmation)

• Serum'free light chain assay (in all patients with newly diagnosed plasma cell dyscrasias)

• one marrow aspiration andEor biopsy

• Serum beta'4 microglobulin" albumin" and lactate dehydrogenase measurement

• Standard metaphase cytogenetics

• Fluorescent in situ hybridi#ation

• Skeletal sur%ey

• Magnetic resonance imaging

0onsider the risk of renal failure" especially in the setting of contrast medium inection for

imaging studies. ake care to limit patientsK e2posure and maintain hydration.

#lood Studies

3erform a complete blood count (00) to determine if the patient has anemia"thrombocytopenia" or leukopenia. he 00 and differential may show pancytopenia. he

reticulocyte count is typically low. 3eripheral blood smears may show rouleau formation.

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he erythrocyte sedimentation rate (>S@) is typically increased. 0oagulation studies may yield

abnormal results.

Abtain a comprehensi%e metabolic panel to assess le%els of the followingC

•otal protein" albumin" and globulin

• lood urea nitrogen (U) and creatinine

• Uric acid (will be ele%ated if the patient has high cell turno%er or is dehydrated

!rine CollectionIbtain a +"6hour urine collection for %uantication of the 'ence =ones protein (ie#

lambda light chains)# protein# and creatinine clearance. Ouantication of proteinuria

is useful for the diagnosis of MM (L g of protein in +" h is a ma>or criterion) and for

monitoring the response to therapy. 8reatinine clearance can be useful for dening

the se&erity of the patientPs renal impairment.

Electrophoresis and $mmunofxation

Serum protein electrophoresis (S3>3) is used to determine the type of each protein present and

may indicate a characteristic cur%e (ie" where the spike is obser%ed). Urine protein

electrophoresis (U3>3) is used to identify the presence of the ence Hones protein in urine.

+mmunofi2ation is used to identify the subtype of protein (ie" +g& lambda).

he 481= ational 0omprehensi%e 0ancer etwork (00) 0linical 3ractice Guidelines also

recommend the use of serum free light chain assay and fluorescence in situ hybridi#ation (F+S)

for del 17" del 19p17" t(!?1!)" t(11?1!)" 1$41 amplification as part of the initial diagnostic

workup.4/

0hemical screening" including calcium and creatinine S3>3" immunofi2ation" and

immunoglobulin $uantitation" may show a#otemia" hypercalcemia" an ele%ated alkaline

phosphatase le%el" and hypoalbuminemia. & high lactate dehydrogenase (56) le%el is

predicti%e of an aggressi%e lymphomalike course.

S3>3 is a useful screening test for detecting M proteins. &n M component is usually detected by

means of high'resolution S3>3. he kappa'to'lambda ratio has been recommended as a

screening tool for detecting M'component abnormalities. &n M'component serum concentration

of 78 gE5 is a minimal diagnostic criterion for MM. +n about 4=< of patients" M protein cannot

be detected by using S3>3.

@outine urinalysis may not indicate the presence of ence Hones proteinuria. herefore" a 4!'

hour urinalysis by means of U3>3 or immunoelectrophoresis may be re$uired. U3>3 or

immunoelectrophoresis can also be used to detect an M component and kappa or lambda light


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chains. he most important means of detecting MM is electrophoretic measurement of

immunoglobulins in both serum and urine.

%uantitati&e $mmunoglo'ulin (e&els )$g*+ $g"+ $gM,

Suppression of nonmyelomatous immunoglobulin is a minor diagnostic criterion for MM. he

le%el of MM protein (ie" M protein le%el)" as documented by the immunoglobulin le%el" can be

useful as a marker to assess the response to therapy.

#eta-. Microglo'ulin and C-Reacti&e Protein

eta'4 microglobulin is a surrogate marker for the o%erall body tumor burden. he le%el of beta'

4 microglobulin is increased in patients with renal insufficiency without MM" which is one

reason that it is a useful prognosticator in MM.41/ (See 3rognosis.) he prognosis of patients with

MM and impaired renal function is reduced.

0'reacti%e protein (0@3) is a surrogate marker of interleukin (+5)'; acti%ity. +5'; is often

referred to as the plasma cell growth factor. 5ike beta'4 microglobulin" 0@3 is useful for

prognostication.41/ (See 3rognosis.)

Serum /iscosity

0heck the serum %iscosity in patients with central ner%ous system (0S) symptoms" nosebleeds"

or %ery high M protein le%els. hese findings may indicate hyper%iscosity syndrome.

Radiography

Simple radiography is indicated for the e%aluation of skeleton lesions" and a skeletal sur%ey is

performed when myeloma is in the differential diagnosis. 3lain radiography remains the goldstandard imaging procedure for staging newly diagnosed and relapsed myeloma patients"

according to an +nternational Myeloma ,orking Group consensus statement.4=/

3erform a complete skeletal series at diagnosis of MM" including the skull (a %ery common site

of bone lesions in persons with MM? see the image below)" the long bones (to look for

impending fractures)" and the spine.



24/52

4adiograph of the skull

demonstrating a typical lytic lesion in multiple myeloma. ll images and te*t are (c)


0on%entional plain radiography can usually depict lytic lesions. Such lesions appear as multiple"

rounded" punched'out areas found in the skull" %ertebral column" ribs" andEor pel%is. 5ess

common but not rare sites of in%ol%ement include the long bones. 3lain radiographs can be

supplemented by computed tomography (0) scanning to assess cortical in%ol%ement and risk of

fracture. 6iffuse osteopenia may suggest myelomatous in%ol%ement before discrete lytic lesions

are apparent.

Findings from this e%aluation may be used to identify impending pathologic fractures" allowing

physicians the opportunity to repair debilities and pre%ent further morbidity.

Magnetic Resonance $maging

Magnetic resonance imaging (M@+) is useful in detecting thoracic and lumbar spine lesions"

paraspinal in%ol%ement" and early cord compression. Findings from M@+ of the %ertebrae are

often positi%e when plain radiographs are not. M@+ can depict as many as !8< of spinal

abnormalities in patients with asymptomatic gammopathies in whom radiographic studies are

normal. For this reason" e%aluate symptomatic patients with M@+ to obtain a clear %iew of the

spinal column and to assess the integrity of the spinal cord.

Positron Emission 0omography

0omparati%e studies ha%e suggested the possible utility of positron emission tomography (3>)

scanning in the e%aluation of MM.4;" 49/ For e2ample" a comparison study of 3> scanning and

whole'body M@+ in patients with bone marrow biopsy'pro%en multiple myeloma found that

although M@+ had higher sensiti%ity and specificity than 3> in the assessment of disease


25/52

acti%ity" when used in combination and with concordant findings" the 4 modalities had a

specificity and positi%e predicti%e %alue of 188

scanning has not yet been integrated into standard practice. he +nternational Myeloma ,orking

Group notes the potential usefulness of 3> scanning in selected patients but suggests that such

studies ideally should be performed in the conte2t of a clinical trial. 4=/

& study by Lamagni et al found that 1'F fluorodeo2yglucose (F6G) 3>E0 scan findings were

reliable predictors of prognosis among patients with multiple myeloma who had undergone

thalidomide'de2amethasone induction therapy and double autotransplantation.4/

#one Scan

6o not use bone scans to e%aluate MM. 0ytokines secreted by MM cells suppress osteoblast

acti%ity? therefore" typically" no increased uptake is obser%ed. An technetium bone scanning"

more than =8< of lesions can be missed.

"spiration and #iopsy

MM is characteri#ed by an increased number of bone marrow plasma cells. 3lasma cells show

low proliferati%e acti%ity" as measured by using the labeling inde2. his inde2 is a reliable

parameter for the diagnosis of MM. igh %alues are strongly correlated with progression of the

disease.

Abtain bone marrow aspirate and biopsy samples from patients with MM to calculate the percentage of plasma cells in the aspirate (reference range" up to 7


26/52

'one marrow aspirate

demonstrating plasma cells of multiple myeloma. ote the blue cytoplasm#

eccentric nucleus# and perinuclear pale $one (or halo). ll images and te*t are (c)


Many MM cells ha%e characteristic" but not diagnostic" cytoplasmic inclusions" usually

containing immunoglobulin. he %ariants include Mott cells" @ussell bodies" grape cells" and

morula cells. one marrow e2amination re%eals plasma cell infiltration" often in sheets or clumps

(see the image below). his infiltration is different from the lymphoplasmacytic infiltration

obser%ed in patients with ,aldenstrom macroglobulinemia.

'one marrow biopsy

demonstrating sheets of malignant plasma cells in multiple myeloma. ll images


&nalysis of bone biopsy specimens may re%eal plasmacytic" mi2ed cellular" or plasmablastic

histologic findings. &ppro2imate median sur%i%al by histologic type is as followsC

• 0lasmacytic 6 AQ.B months

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• Mi*ed cellular 6 ?. months

• 0lasmablastic 6 Q.! month

Cytogenetic "nalysis

0ytogenetic analysis of the bone marrow may contribute significant prognostic information inmultiple myeloma. he most significant cytogenetic abnormality appears to be deletion of

19p17. his abnormality is associated with shorter sur%i%al" more e2tramedullary disease" and

hypercalcemia. his locus is the site of the TP53 tumor suppressor gene. 0hromosome 1

abnormalities and c-myc defects are also significant prognostic factors in multiple myeloma.

&lthough not as well defined as in other hematologic malignancies" such as acute leukemia" risk'

adapted therapy based on cytogenetic abnormalities is at the forefront of myeloma research.

Staging

Staging is a cumulati%e e%aluation of all of the diagnostic information garnered and is a usefultool for stratifying the se%erity of patientsK disease. 0urrently" two staging systems for multiple

myeloma are in useC the Salmon'6urie system" which has been widely used since 1:9=? and the

+nternational Staging System" de%eloped by the +nternational Myeloma ,orking Group and

introduced in 488=.4:" 78/

Salmon67urie staging system

he Salmon'6urie classification of MM is based on three stages and additional

subclassifications.

+n stage +" the MM cell mass is less than 8.; 1814 cellsEm4" and all of the following are presentC

• -emoglobin &alue greater than , g;dD

• Serum calcium &alue less than + mg;dD (normal)

• ormal bone structure (scale ,) or only a solitary bone plasmacytoma onradiographs

• Dow M6component production rates (3gG &alue less than C g;dD# 3g &alue less

than A g;dD# urine light6chain M component on electrophoresis less than "g;+" h)

+n stage ++" the MM cell mass is 8.;'1.4 1814 cellsEm4. he other %alues fit neither those of stage

+ nor those of stage +++.

+n stage +++" the MM cell mass is greater than 1.4 1814 cellsEm4" and all of the following are

presentC


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• -emoglobin &alue e%ual to !.C g;dD

• Serum calcium &alue greater than + mg;dD

• d&anced lytic bone lesions (scale A) on radiographs

• -igh M6component production rates (3gG &alue greater than B g;dD# 3g &aluegreater than C g;dD# urine light6chain M component on electrophoresis greaterthan + g;+" h)

Subclassification & includes relati%ely normal renal function (serum creatinine %alue D 4 mgEd5)"

whereas subclassification includes abnormal renal function (serum creatinine %alue B 4 mgEd5)

Median sur%i%al is as followsC

• Stage 3# L?, months

• Stage 33# " months

• Stage 333# +A months

6isease in subclassification has a significantly worse outcome (eg" 4'14 mo sur%i%al in !

separate series).

3nternational Staging System

he +nternational Staging System of the +nternational Myeloma ,orking Group is also based on

three stages.

Stage + consists of the followingC

• 'eta6+ microglobulin less than or e%ual to A.C g;dD and albumin KA.C g;dD

• 840 K"., mg;dD

• 0lasma cell labeling inde* N

• bsence of chromosome A deletion

• Dow serum 3D6? receptor

• Dong duration of initial plateau phase

Stage ++ consists of the followingC

• 'eta6+ microglobulin le&el KA.C to N C.C g;dD# or


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• 'eta6+ microglobulin N A.C g;dD and albumin N A.C g;dD

Stage +++ consists of the followingC

• 'eta6+ microglobulin of C.C g;dD or more

Median sur%i%al is as followsC

• Stage 3# ?+ months

• Stage 33# "" months

• Stage 333# +Q months

0reatment

"pproach Considerations

3hysicians must understand both the natural history of multiple myeloma (MM) and the

limitations of current therapy in the treatment of the disease. he obecti%e in therapy is to obtain

the deepest response in the first round by choosing the appropriate regimen? this should lead to

better o%erall sur%i%al in both transplant and non'transplant patients. +n situations with no

definite data on therapeutic choices" participation in clinical trials should be encouraged. For a

summary of treatment approaches to MM" see Multiple Myeloma reatment 3rotocols.

0rogression of disease and timing of treatment

&n important study by 6imopoulos and associates e%aluated the risk of disease progression in

asymptomatic subects with MM.71/ his study e%aluated ;7 consecuti%e untreated subects with

MM. Af these subects" := were asymptomatic and were not treated until their M protein %alue

rose to greater than = gEd5. hese subects de%eloped increased bone disease or symptoms of

bone disease.

he indi%iduals in this group were designated as either low risk (ie" no bone disease" M protein

le%el D7 gEd5" or ence Hones protein le%el D= gE4! h) or high risk (ie" lytic bone disease and

serum M protein le%el B7 gEd5 or ence Hones protein le%el B= gE4! h). +ntermediate'risk

subects did not ha%e bone disease or an M protein le%el greater than 7 gEd5 or a ence Hones protein le%el greater than = gE4! h. he patients were e%aluated e%ery 4 months.

he median time for disease progression was 18 months in the high'risk group" 4= months in the

intermediate'risk group" and ;1 months in the low'risk group.71/ &t the time of progression"

subects were treated with standard chemotherapy. heir response rates did not significantly

differ from those of unselected populations. Median sur%i%al time from the institution of

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chemotherapy did not differ among the groups. hus" asymptomatic subects did not benefit from

early treatment" and delayed treatment did not affect treatment efficacy (ie" sur%i%al).

& systematic re%iew by e et al demonstrated a reduction in %ertebral compressions and time to

progression with early systemic treatment for asymptomatic patients" but this study also re%ealed

an increase in acute leukemia in the early treatment group.74/ he failure to demonstrate

impro%ed sur%i%al may be due to the small number of patients studied.

he 488: +nternational Myeloma ,orkshop concluded that detection of any cytogenic

abnormality suggests higher'risk disease" including chromosomal 17 or 17$ deletion" t(!?1!)" and

del19p and fluorescence in situ hybridi#ation detection of t(!?1!)" t(1!?1;)" and del19p.77/

Fluorescence in situ hybridi#ation detection of 17$ deletion alone is not considered a high'risk

feature. +nternational Staging System stages ++ and ++ and high serum beta(4)'microglobulin

le%els are suggesti%e of higher risk disease.

& study by Ilein et al determined that the prognostic significance of t(!?1!) may be eliminated

or lessened among patients who recei%e lenalidomide and de2amethasone? howe%er" del(19p17)

and N1$41 are still associated with a dismal o%erall sur%i%al.7!/ & study by eben et al concludes

that long'term administration of borte#omib in patients with del(19p17) may result in better

o%erall and progression'free sur%i%al.7=/

8urrent therapeutic approaches

A%erall" the care of patients with MM is comple2 and should focus on treatment of the disease

process and any associated complications.7" !" =/ &lthough MM remains incurable" se%eral drug

therapies are %aluable in the treatment of patients with MM" as are autologous stem cell

transplantation" radiation" and surgical care in certain cases.

Se%eral studies are e%aluating the role of treatment in patients with high'risk smoldering multiple

myeloma (SMM). 3re%ious smaller studies e%aluating thalidomide did not show a clear e%idence

of benefit with treatment in patients with SMM? howe%er" these included patients with all risk

le%els of SMM.

+n a phase +++ trial that was restricted to patients with high'risk SMM" the 3>>M& group

found e%idence of benefit from treatment with lenalidomide %ersus obser%ation. &fter a median

follow'up of !8 months" study patients who were randomi#ed to lenalidomide and

de2amethasone induction followed by lenalidomide maintenance demonstrated significantly

prolonged median time to progression (median not reached %s 41 months) and higher 7'year

sur%i%al rate (:!< %s. 8


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3atients with MM for whom therapy is indicated typically recei%e chemotherapy. Greater

understanding of the cell biology of MM and the ability to identify prognostic factors has led to

the increasing indi%iduali#ation of treatment for affected patients. 3hysicians treat many patients

with high'dose therapy and peripheral blood or bone marrow stem cell transplantation.

he 481; ational 0omprehensi%e 0ancer etwork (00) guidelines for MM list the

following combinations as preferred regimens for primary induction therapy in patients who are

not transplant candidates4/ C

• 'orte$omib;de*amethasone

• 'orte$omib;cyclophosphamide;de*amethasome

• 'orte$omib;lenalidomide;de*amethasone (category )

• Denalidomide;low6dose de*amethasone (category )

• Melphalan;prednisone;borte$omib (M0') (category )

• Melphalan;prednisone;lenalidomide (M0D) (category )

• Melphalan;prednisone;thalidomide (M0) (category )

3atients should be assessed for response after two cycles of one of the abo%e regimens.

3atients with MM who are treated with lenalidomide or thalidomide are at significantly increased

risk for thrombotic e%ents" and many physicians incorporate anticoagulation strategies in theirmanagement. & study by 3alumbo et al determined that aspirin and low'dose warfarin had

similar efficacy in reducing serious thromboembolic e%ents" acute cardio%ascular e%ents" and

sudden deaths in patients with myeloma recei%ing thalidomide'based regimens compared with

low'molecular weight heparin" e2cept in elderly patients.79/

&s monotherapy or in combination" interferon alfa'4b and prednisone modestly prolong the

disease'free inter%al.

& study by the Southwest Ancology Group compared lenalidomide plus de2amethasone to

placebo plus de2amethasone in patients with newly diagnosed myeloma.7/

he study determinedthat lenalidomide plus de2amethasone had superior 1'year progression'free sur%i%al" o%erall

response rate" and %ery good partial response rate" suggesting that it is safe and effecti%e as initial

therapy for patients with newly diagnosed myeloma. +n February 481=" the F6& appro%ed an

e2panded indication for MM to included newly diagnosed patients. he original indication was

for patients who had recei%ed at least 1 prior therapy.



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& phase +++ randomi#ed" open'label trial of 11: patients with high'risk smoldering MM found

that early treatment with lenalidomide plus de2amethasone" followed by maintenance therapy

with lenalidomide" delayed progression to symptomatic disease and increased o%erall sur%i%al.7:"

!8/

&duncti%e therapy for MM includes radiation therapy to target areas of pain" impending

pathologic fracture" or e2isting pathologic fracture. isphosphonate therapy ser%es as

prophyla2is (ie" primary" secondary) against skeletal e%ents (eg" hypercalcemia" spinal cord

compression" pathologic fracture" need for surgery" need for radiation). >%idence suggests that it

may be effecti%e in treating bone pain and in decreasing the likelihood of lesion recurrence.!1" !4"

!7/

&duncti%e therapy may also include any of the following" as appropriateC

• 5rythropoietin

• 8orticosteroids

• Surgical inter&ention

• 0lasmapheresis

'one disease guidelines

+n May 4817" the +nternational Myeloma ,orking Group released practice guidelines for the

management of MM'related bone disease.!!/ he recommendations" which were based on a

re%iew of the literature through &ugust 4814 and a consensus of an interdisciplinary panel ofe2perts" include the followingC

• 8onsideration of bisphosphonates ('0s) in all patients with MM recei&ing rst6line antimyeloma therapy# regardless of presence of osteolytic bone lesionson con&entional radiography

• 3ntra&enous (3E) $oledronic acid or pamidronate for pre&enting skeletal6related e&ents in patients with MM

• 'ecause of its potential antimyeloma e


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• yphoplasty should be considered for symptomatic &ertebral compressionfractures

• Irthopedic consultation should be sought for long6bone fractures# spinal cordcompression# and &ertebral column instability

• Dow6dose radiation therapy can be used for palliation of uncontrolled pain#impending pathologic fracture# or spinal cord compression

Chemotherapy and $mmunosuppression

+n patients with symptomatic MM" chemotherapy is re$uired. +n asymptomatic patients with

MM" treatment is delayed until disease clinically progresses or until serum or urine le%els of M

protein substantially increase.

he M'component le%el in serum andEor urine is an indicator of the tumor burden? its reduction

after chemotherapy is used as a sign of response. & =8< reduction in M'component is considered

a good clinical response (according to the 0hronic 5eukemia'Myeloma ask Force). M3 induces

a response in =8';8< of patients with MM. 6isappearance of the M component on

electrophoresis occurs in only 7< of patients" and cure is e2traordinarily rare.

he first step before starting therapy in MM is to determine whether a patient is a candidate for

an autologous stem cell transplant. >ligibility depends primarily on the patientKs age and

comorbidities. ypically an age of ;= years is used as a cut'off point for transplant eligibility.

hus" treatment for MM is best looked at in terms of the following three categories of patientsC

• oung# newly diagnosed patients who are potential transplant candidates

• -igh6risk patients who are potential transplant candidates

• ewly diagnosed elderly patients who are not transplant candidates

oung# newly diagnosed patients who are potential transplant candidates

0on%entionally" *&6 (%incristine" do2orubicin &driamycin/" and de2amethasone)

chemotherapy has been used to decrease the tumor burden in MM as preparation for

transplantation. *&6 is administered as a !'day continuous intra%enous infusion of %incristine

and do2orubicin" with ! daily oral doses of de2amethasone. 3atients re$uire a central %enous

catheter for deli%ery of the infusion. +n selected patients" this therapy can be performed in an

outpatient setting.

Many researchers feel that the high'dose steroid component of *&6 accounts for much of its

efficacy. +n some patients" high'dose de2amethasone alone may produce significant clinical

responses.


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Significant concerns with the use of infusion therapy include the risk of soft'tissue inury if the

chemotherapy agent infiltrates" the risk of cardiac inury from the do2orubicin" and the risk of

infection or hyperglycemia from the high'dose steroids. Some patients also e2perience ad%erse

central ner%ous system (0S) effects from the high'dose steroids. Gi%en these risks" and the

higher response rates of new agents (thalidomide" lenalidomide" and borte#omib)" *&6 is now

considered suboptimal treatment.

halidomide has pro%ed effecti%e against MM. he superiority of induction regimens containing

thalidomide was demonstrated in randomi#ed trials that compared *&6 with thalidomide plus

de2amethasone!=/ ? thalidomide and do2orubicin plus de2amethasone!;/ ? and thalidomide plus

*&6.!9/

halidomide has a well'established role as first'line therapy" either as a single agent or in

combination with steroids in patients with MM. he to2icity of this drug is predominantly

sensory neuropathy" and because of the drugKs teratogenicity" close monitoring is re$uired to

a%oid inad%ertent administration during pregnancy.

&n analogue of thalidomide" lenalidomide (@e%limid) is now a standard component of MM

therapy. +n Huly 4817" 0elgene 0orp announced that a phase +++ trial of lenalidomide (@e%limid)

met the main goal of impro%ing progression'free sur%i%al in patients with newly diagnosed MM.!/ he drug was already appro%ed for use in pre%iously treated MM" mantle cell lymphoma" and

transfusion'dependent anemia caused by myelodysplastic syndromes.

+n the late'stage study" treatment with lenalidomide combined with de2amethasome in patients

with newly diagnosed MM resulted in a significant impro%ement in sur%i%al without the cancerworsening" compared to treatment with a regimen consisting of melphalan" prednisone and

thalidomide (M3).!/ >%aluation of safety and efficacy is ongoing.

+n a randomi#ed" double'blind" placebo'controlled trial" lenalidomide plus high'dose

de2amethasone pro%ed superior to high'dose de2amethasone alone as treatment for newly

diagnosed MM.!=/ he o%erall response rate was !< in the lenalidomide plus high'dose

de2amethasone group %ersus =7< in the high'dose de2amethasone group" with 44< of patients

achie%ing complete remission in the lenalidomide plus high'dose de2amethasone arm.

3rogression'free sur%i%al and o%erall sur%i%al fa%ored lenalidomide plus high'dosede2amethasone" but 14'month sur%i%al for both arms was B:8


35/52

the o%erall response rate for 56 was superior (4


36/52

de2amethasone arm" in which patients went on to recei%e tandem autologous stem cell

transplantation.=!/ &s in other studies" response was independent of ad%erse prognostic risk

factors.

he phase +++ *elcade as initial standard therapy in MM (*+S&) trial found the combined

treatment of borte#omib" melphalan" and prednisone (*M3) significantly prolongs o%erall

sur%i%al compared with melphalan and prednisone (M3) after lengthy follow'up and e2tensi%e

subse$uent antimyeloma therapy.==/

& study by arousseau et al confirms the role of borte#omib in the initial nonintensi%e

management of MM.=;/

& study by Sher et al found that a combination of borte#omib (*)" pegylated liposomal

do2orubicin (6)" and thalidomide ()" known as the *6 regimen" had o%erall response rate and

complete response plus near complete response rates of 9< and 7=


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schema does not o%ercome the negati%e prognosis associated with high'risk cytogenetic

abnormalities.;8/

A%erall" the data on these no%el agents are %ery encouraging and promising. e%ertheless"

oncologists will need further studies to help define the e2act timing and role of no%el agents in

the treatment of MM.

-igh6risk patients who are potential transplant candidates

igh'risk MM patients are those with ad%anced'stage disease (stage +++ according to the

+nternational Staging System)? those with poor cytogenetics" such as t (!C1!)" t (1!C1;)" and t

(1!C48)" deletion of chromosome 17" inacti%ation of TP53? and those with a comple2 karyotype.

3atients with %ery high proliferati%e rates are also included in this classification.

his group represents about 4=< of those with newly diagnosed MM" with an e2pected median

sur%i%al of 4 years or less. &lthough they respond to traditional therapies for induction" theseindi%iduals tend to relapse rapidly. herefore" no%el agents should be considered up front for

these patients.

he ad%ent of thalidomide" lenalidomide" and borte#omib has substantially impro%ed outcomes

in these high'risk groups. +n fact" these no%el agents appear to o%ercome the influence

contributed by high'risk cytogenetics.;1" ;4/ Ance a response has been achie%ed" then these

patients can be brought to autologous stem cell transplantation.

ewly diagnosed elderly patients who are not transplant candidates

&ll of the abo%e regimens may be used in patients who are not being considered for autologous

stem cell transplantation. he following" howe%er" can only be used in patients not going for

transplantation" as they impair stem cell reser%e.

he gold standard has been the M3 regimen as far back as the 1:=8s. his regimen typically

consists of melphalan : mgEm4 and prednisone 188 mg gi%en on days 1'!" with courses repeated

at !' to ;'week inter%als for at least 1 year. & meta'analysis of !:78 patients from 48 randomi#ed

trials compared M3 to other drug combinations and showed a significantly higher response rate

(;8


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complete response rate was significantly better in the M3 plus thalidomide and the

transplantation arms than in the M3 arm.;!/

M3 plus thalidomide is now recommended as first'line treatment. M3 plus lenalidomide has also

shown promise.;=/

ulin et al conducted a randomi#ed" placebo'controlled" phase +++ trial to in%estigate the efficacy

of adding thalidomide to M3 in 44: elderly patients (B 9= y) newly diagnosed with MM.;;/

6uring each ;'week cycle" melphalan 8.4 mgEkgEd plus prednisone 4 mgEkgEd was gi%en to all

patients on days 1'! for 14 cycles. +n addition" patients were randomly assigned to recei%e

thalidomide 188 mgEd 3A (n O 117) or placebo (n O 11;)" continuously for 94 weeks.

A%erall sur%i%al was significantly longer in the group that recei%ed thalidomide (median" !! mo)

compared with placebo (median" 4:.1 mo).;;/ 3rogression'free sur%i%al was also significantly

prolonged in the thalidomide group (median" 4!.1 mo) relati%e to the placebo group (median"

1.= mo). owe%er" the in%estigators noted peripheral neuropathy and neutropenia were

significantly increased in the thalidomide group.;;/

& randomi#ed" controlled trial e%aluated the addition of thalidomide to standard M3

chemotherapy in elderly patients with pre%iously untreated MM. &lthough no impact on sur%i%al

was obser%ed" more patients in the thalidomide group achie%ed an obecti%e response. Af note"

thromboembolic e%ents did not increase in the thalidomide group. ;9/

& separate study by Fayers et al concluded that thalidomide added to M3 therapy impro%ed

o%erall sur%i%al and progression'free sur%i%al in pre%iously untreated elderly patients with

multiple myeloma" e2tending the mean sur%i%al time by an a%erage of 48


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Fi%e large phase +++ studies ha%e looked at role of thalidomide maintenance after autologous stem

cell transplant (&S0). hree initial studies showed an impro%ement in both progression'free

sur%i%al (3FS) and AS.91" 94" 97/ owe%er" two subse$uent studiesPincluding one large study with

1:98 patientsPdid not show an impro%ement in AS with thalidomide maintenance.9!" 9=/ 5ong'

term use of thalidomide is also associated with significant neuropathy" thus limiting its use in

maintenance therapy.

Gi%en its fa%orable to2icity profile and efficacy at low doses" lenalidomide has also been studied

for maintenance therapy. wo large trials" 0&5G 18818! and +FM 8='84" ha%e e%aluated the

role of lenalidomide in maintenance therapy" using slightly different protocols and ha%ing

somewhat different outcomes.9;" 99/ 3atients in both studies recei%ed induction treatment followed

by &S0. +n the +FM 8='84 study" howe%er" all patients recei%ed 4 months of consolidation

treatment with lenalidomide before being randomi#ed to lenalidomide or placebo.

oth studies showed a significant impro%ement in time to progression (!; %s 49 months in

0&5G study and !1 %s 47 months in +FM study). owe%er" 0&5G 18818! study showed

significant impro%ement in AS (= < %s 99


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• 3*a$omib;lenalidomide;de*amethasone

• 5lotu$umab;lenalidomide;de*amethasone

orte#omib has a well'established role as sal%age therapy" based on a phase +++ randomi#ed trial

showing a response rate of 7< %ersus 1< in patients recei%ing de2amethasone only.=4/

Median progression'free sur%i%al was ;.44 months in the borte#omib arm %ersus 7.!: months in the

de2amethasone'only group.

3anobinostat (Farydak) is a histone deacetylase (6&c) inhibitor appro%ed in February 481=. +t

is indicated in combination with borte#omib and de2amethasone for treatment of MM in patients

who ha%e recei%ed at least two prior regimens" including borte#omib and an immunomodulatory

agent. he F6& appro%al was based on efficacy and safety data in a prespecified subgroup

analysis of the phase +++ 3&A@&M&'1 (3&obinostat A@&l in Multiple Myelom&) trial" in

which patients treated with panobinostat (n O :!) had a median progression'free sur%i%al of 18.;

months" compared with =. months for patients in the placebo arm (nO ::) (ha#ard ratioO 8.=4:=< confidence inter%alC 8.7;" 8.9;/).4/

+n 4814" the F6& appro%ed carfil#omib (Iyprolis) for the treatment of patients with MM who

ha%e recei%ed at least two prior therapies including borte#omib and an immunomodulatory agent"

and ha%e demonstrated disease progression on or within ;8 days of therapy completion. he

appro%al was based on a phase 4b" single'arm" multicenter clinical study of 4;; patients with

relapsed multiple myeloma with other therapies. he study assessed for o%erall response rate

(A@@)" which was 44.:< o%er a median duration of 9. months.7/

+n 481=" the F6& e2panded carfil#omibKs indication for multiple myeloma based on data from

the &S3+@> study. +n this study" carfil#omib was combined with lenalidomide and

de2amethasone (I@d) for patients with relapsed multiple myeloma who had recei%ed 1'7 prior

lines of therapy. he study showed a significant impro%ement in progression'free sur%i%al (3FS)

for patients treated in the I@d arm compared with those treated with lenalidomide and low'dose

de2amethasone (@d) alone. he median 3FS was 4;.7 months in the I@d arm compared to 19.;

months in the @d arm.!/

+n Hanuary 481;" the F6& appro%ed carfil#omib in combination with de2amethasone for relapsed

or refractory multiple myeloma in patients who ha%e recei%ed 1'7 prior lines of therapy.

&ppro%al was based on the >6>&*A@ study (nO:4:) where a statistically significant

impro%ement in median progression'free sur%i%al was obser%ed with carfil#omib plus

de2amethasone compared with borte#omib plus de2amethasone in patients with relapsed

multiple myeloma (4;.7 mo %s 19.; mo? pO8.8881). A%erall sur%i%al data are not yet a%ailable.=/

he following three new drugs were appro%ed in o%ember 481=C


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• 7aratumumab (7ar$ale*)

• 3*a$omib (inlaro)

• 5lotu$umab (5mpliciti)

6aratumumab gained accelerated appro%al from the F6& for patients with MM who had

recei%ed at least three prior treatments" including a proteasome inhibitor (3+) and an

immunomodulatory agent (+Mi6)" or whose disease is refractory to both a 3+ and an +Mi6. he

appro%al was based on the phase ++ MMR4884 (S+@+US) study that showed treatment with

single'agent daratumumab resulted in an A@@ of 4:.4< in patients who recei%ed a median of

fi%e prior lines of therapy" including a 3+ and an +Mi6.;/

Stringent complete response (s0@) was reported in 4.'MM1 trial" an international" randomi#ed" double'blind clinical trial of 944

patients with treatment'refractory or recurrent multiple myeloma. +t compared i2a#omib with

placebo the patients who also recei%ed lenalidomide and de2amethasone. Median progression'free sur%i%al was impro%ed by 7=< with i2a#omib compared with placebo (48.; %s 1!.9 months?

3 O 8.814)./

>lotu#umab is a humani#ed +gG1 monoclonal antibody that specifically targets the S5&MF9

(signaling lymphocytic acti%ation molecule family member 9) protein. S5&MF9 is e2pressed on

myeloma cells and natural killer cells and plasma cells. >lotu#mab facilitates the interaction with

natural killer cells to mediate the killing of myeloma cells through antibody'dependent cellular

cytoto2icity. +t is indicated for use in combination with lenalidomide and de2amethasone for MM

in patients who ha%e recei%ed 1'7 prior therapies.

&ppro%al was based on the >5AU>'4 trial" a randomi#ed" open'label clinical study that

included ;!; participants with multiple myeloma who had e2perienced relapse or who had not

responded to pre%ious treatment. he addition of elotu#umab to the combination of lenalidomide

and de2amethasone e2tended progression' free sur%i%al to 1:.! months" as compared with 1!.:

months seen in patients treated with lenalidomide and de2amethasone (3D8.881). &dditionally"


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the o%erall response rate (including complete and partial responses) was 9.=


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use otherwise lethal doses of total body irradiation and chemotherapy and then Trescue the

patient by reinfusing the har%ested cells. his process of myeloablati%e therapy" followed by the

reinfusion of stem cells" is termed autologous stem cell transplantation.

his se$uence of therapy allows physicians to use melphalan at an appro2imately 18'48 times

higher dose than is used in standard therapy.!;/ +n autologous transplantation" the reinfused stem

cells or bone marrow act as a support to the patient but do not offer additional anticancer effects.

andem autologous transplantation has been proposed as a way of o%ercoming the incomplete

response to a single transplant. & 4'arm trial of single %ersus tandem transplantation re%ealed no

difference in o%erall sur%i%al at =! months.:;/

&nother two'arm study that compared single %ersus tandem transplants for newly diagnosed MM

showed that whereas double autologous stem cell transplantation effected superior complete or

near'complete response rates" relapse'free sur%i%al" and e%ent'free sur%i%al (>FS)" it failed to

significantly prolong o%erall sur%i%al.:9/ enefits offered by double autologous stem cell

transplantation were particularly e%ident among patients who failed to achie%e at least a near'

complete response after one autotransplantation.

& re%iew of long'term outcomes of se%eral autotransplantation trials for MM found that tandem

transplantations were superior to both single transplantations and standard therapies and that

tandem transplantations with thalidomide were superior to trials without thalidomide.:/

owe%er" postrelapse sur%i%al (3@S) was superior when initial >FS e2ceeded 148 days and

when tandem transplantations had been administered" whereas 3@S was shorter when >FS lasted

87 days or less and when trials had included thalidomide and borte#omib.

:/

wo randomi#ed prospecti%e studies compared standard chemotherapy with high'dose

autologous transplantation. +n the first study of 488 subects" researchers obser%ed better

response rates (ie" 1< for the transplantation group %s =9< for the con%entionally treated

group) and better ='year e%ent'free sur%i%al rates (ie" 4< %s 18


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cancer (ie" graft %s myeloma effect). Unfortunately" the donorKs immune system may also attack

the recipientKs body (ie" graft %s host effect).

3hysicians use allogeneic transplantation less often than autologous transplantation in MM

patients" for se%eral reasons. First" the risks of complications and death from allogeneic

transplantation increase with age" and most patients with multiple myeloma are older than the

ideal age for allogeneic transplantation.

Second" the transplantation'related mortality rate is $uite high in patients with MM who undergo

allogeneic transplantation. he death rate within 188 days of transplantation ranges from 18< to

=;< in different case series.

hird" although some sur%i%ors e2perience long'term disease'free results after allogeneic

transplantation" a retrospecti%e case'matched analysis of allogeneic %ersus autologous

transplantation showed a median sur%i%al of 7! months for the autologous transplantation group

and 1 months for the allogeneic group.

he e2ception to this rule is the rare patient with a twin donor. +n a limited study of 4=

transplantations in%ol%ing twins" outcomes with syngeneic transplantations were superior" with

reduced transplantation'related mortality.

he de%elopment of a nonmyeloablati%e preparati%e regimen for MM allogeneic transplantation

is changing the e$uation. & republished report of =4 high'risk patients who underwent

nonmyeloablati%e transplants described a 19< mortality rate.188/ 3rogression'free sur%i%al at 1

months was roughly 78


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#isphosphonate 0herapy

isphosphonates are specific inhibitors of osteoclastic acti%ity and are used to treat bone

resorption. hey also ha%e a role in the secondary pre%ention of bony complications in MM"

including hypercalcemia" pathologic fracture" and spinal cord compression. +ntra%enous (+*)

pamidronate (&redia) has been shown to be effecti%e in pre%enting skeletal complications?

#oledronic acid (Lometa) may be significantly more potent than pamidronate. & study by Morgan

et al found that the early use of #oledronic acid was superior to clodronic acid in pre%enting

skeletal'related e%ents among patients with newly diagnosed MM" irrespecti%e of bone disease

status at baseline.!1/

& randomi#ed placebo'controlled trial of pamidronate in subects with MM who had e2perienced

one skeletal e%ent demonstrated that the medication reduced the likelihood of a second skeletal

e%ent from !1< to 4!< after : months of therapy.!4/ he in%estigators also noted impro%ements

in pain" narcotic usage" and $uality of life scores.

& 4889 systematic re%iew of the use of bisphosphonates in MM confirmed a number'needed'to'

treat () of 18 for the pre%ention of %ertebral fractures" although no impact on mortality was

seen.!7/

he &merican Society of 0linical Ancology (&S0A) issued a clinical practice guideline

go%erning bisphosphonate therapy for MM patients who ha%e lytic destruction of bone or

compression fracture of the spine from osteopenia.!7/ &S0A recommends +* pamidronate" :8

mg deli%ered o%er at least 4 hours" or #oledronic acid" ! mg deli%ered o%er at least 1= minutes

e%ery 7'! weeks. ecause the risk for osteonecrosis of the aw is :.='fold greater with #oledronic

acid than with pamidronate" patients may prefer pamidronate.!7/

Loledronic acid doses should be reduced in patients with pree2isting mild to moderate renal

impairment (estimated creatinine clearance" 78';8 m5Emin)? the drug is not recommended for

use in patients with se%ere renal impairment.!7/ &ll patients recei%ing pamidronate or #oledronic

acid therapy should be screened e%ery 7'; months for albuminuria. +f une2plained albuminuria

(B=88 mgE4! hours) is found" &S0A recommends discontinuation of the drug until the renal

problems resol%e.!7/

& study by Morgan et al re%ealed the anticancer properties of #oledronic acid in addition to its

ability to reduce skeletal'related e%ents in MM.111/

Isteonecrosis of the >aw

Asteonecrosis of the aw is a rare but se%ere ad%erse effect of bisphosphonate therapy. 5e%el 1

e%idence (ie" systematic re%iews or randomi#ed controlled trials) indicate that appro2imately 1<

of cancer patients e2posed to #olendronic acid de%elop osteonecrosis of the aw.114/ 6ental

e2tractions appear to be a risk factor" and guidelines recommend a%oiding this where possible.


48/52

& position paper by the &merican &ssociation of Aral and Ma2illofacial Surgeons describes the

differential diagnosis" pre%ention" and treatment of medication'related osteonecrosis of the aw.

0onsultation with an appropriate dental professional is ad%ised before prescribing a

bisphosphonate.114/

"d3uncti&e 0herapy 2or Complications3otential complications of MM include the followingC

• Skeletal complications (eg# pain# hypercalcemia# pathologic fracture# spinalcord compression)

• 3nfection

• nemia

• 4enal failure

• myloidosis

reatment for myeloma'induced hypercalcemia is the same as that for other malignancy'

associated hypercalcemia? howe%er" the dismal outcome obser%ed with hypercalcemia in solid

tumors is not obser%ed in MM.

o treat pathologic fractures" physicians should orthopedically stabili#e (ie" typically pin) and

irradiate these lesions. 0areful attention to a patientKs bony symptoms" intermittent radiographic

sur%eys" and the use of bisphosphonates may be useful to pre%ent fractures.117" 11!" 11=/ (See

Surgical 0are and isphosphonate herapy.)

Spinal cord compression is one of the most se%ere ad%erse effects of MM. he dysfunction may

be re%ersible" depending on the duration of the cord compression? howe%er" once established" the

dysfunction is only rarely fully re%ersed. 3atients who may ha%e spinal cord compression need a

rapid e%aluation" which may necessitate urgent transfer to a center e$uipped with M@+ for

diagnosis or a center with a radiation oncologist for urgent therapy.

3atients with spinal cord compression due to MM should begin corticosteroid therapy

immediately to reduce swelling. Urgent arrangements must be made for radiation therapy in

order to restore or stabili#e neurologic function. Surgery may be indicated. (See Surgical 0are.)

>rythropoietin may ameliorate anemia resulting from either MM alone or from chemotherapy

and has been shown to impro%e $uality of life.11;/ & systematic re%iew failed to demonstrate a

sur%i%al ad%antage for the use of erythropoietin agents in the treatment of patients with cancer'

related anemia.119/



49/52

&cute renal impairment related to MM is typically managed with plasmapheresis to rapidly

lower circulating abnormal proteins. 6ata about this approach are limited" but a small

randomi#ed study showed a sur%i%al ad%antage with the use of apheresis.1=/ ydration (to

maintain a urine output of B7 5Ed)" management of hypercalcemia" and a%oidance of

nephroto2ins (eg" intra%enous contrast media" antibiotics) are also key factors. 0on%entional

therapy may take weeks to months to show a benefit.

@enal impairment resulting from MM is associated with a %ery poor prognosis. & case series

demonstrated that patients with renal failure from myeloma may benefit from autologous stem

cell transplants" and as many as one third may demonstrate impro%ement in their renal function

with this approach.11/ & report by 5udwig et suggests that borte#omib'based therapy may restore

renal function in MM patients with renal failure.1!/

Guidelines on the management of multiple myeloma complications by the >uropean Myeloma

etwork include the following recommendations11:/ C

• 2hole body low6dose computed tomography is more sensiti&e thancon&entional radiography in depicting osteolytic disease and thus isrecommended as the no&el standard for the detection of lytic lesions inmyeloma.

• Myeloma patients with ade%uate renal function and bone disease at diagnosisshould be treated with $oledronic acid or pamidronate.

• Symptomatic patients without lytic lesions on con&entional radiography canbe treated with $oledronic acid# but its ad&antage is not clear for patien t s

with no bone in&ol&ement on computed tomography or magnetic resonanceimaging.

• 3n asymptomatic myeloma# bisphosphonates are not recommended.

• Roledronic acid should be gi&en continuously# but it is not clear if patientswho achie&e at least a &ery good partial response benet from its continuoususe.

• reatment with erythropoietic6stimulating agents may be initiated in patientswith persistent symptomatic anemia (hemoglobin N,g;dD) in whom othercauses of anemia ha&e been e*cluded.

• 5rythropoietic agents should be stopped after ?6! wk if no ade%uatehemoglobin response is achie&ed.

• For renal impairment# borte$omib6based regimens are the current standard of care.


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• For the management of treatment6induced peripheral neuropathy# drugmodication is needed.

• Eaccination against in@uen$a is recommended/ &accination againstStreptococcus pneumoniae and Haemophilus infuenzae is appropriate# buteTcacy is not guaranteed due to suboptimal immune response.

• 0rophylactic acyclo&ir (or &alacyclo&ir) is recommended for patients recei&ingproteasome inhibitors# or autologous or allogeneic transplantation

Surgical Care

Surgical therapy for MM is limited to aduncti%e therapy. +t consists of prophylactic fi2ation of

pending fractures" decompression of the spinal cord when indicated" and treatment of pathologic

fractures.

3rophylactic treatment of impending fractures and the treatment of pathologic fractures may

in%ol%e bracing. +n general" bracing is not effecti%e for the long bones" though it may be effecti%efor treating spinal in%ol%ement without neurologic compromise.

+ntramedullary fi2ation is the procedure of choice when surgery is necessary. +f the metaphysis or

oint surface is in%ol%ed" resection of the diseased bone and reconstruction with a total oint or"

more typically" a hemiarthroplasty is indicated. Modular implants may be re$uired. Se%ere

destruction of the diaphysis may re$uire reconstruction with combinations of

methylmethacrylate" intramedullary nails" or resection and prosthetic replacement.

&lthough surgical decompression of the spinal cord is sometimes appropriate" posterior

laminectomy in this population has been reported to ha%e a mortality

Documents

Multiple Myeloma Overview