Multiple Myeloma Final

7/26/2019 Multiple Myeloma Final

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MULTIPLE

MYELOMA


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Multiple Myeloma

Multiple myeloma is a disseminated

malignancy of monoclonal plasma cells

that accounts for 15% of all hematologic

cancers. Multiple myeloma is a disease with a wide

clinical spectrum, ranging from the

condition known as MGUS to the most

aggressive form, plasma cell leukemia .


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Monoclonal Gammopathy ofUnknown Signicance (MGUS)

haracteri!ed "y an accumulation of "one marrow

plasma cells derived from a single a"normal clone .

M#$rotien in Serum &'g(). and(or

*one marrow colonal plasma cells+1'%.

o related organ or tissue impairment-no end organdamage,or impairment or symptoms.


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Monoclonal Gammopathy ofUnknown Signicance (MGUS)

*enign or a premalignant condition .

/he risk of transformation has "een estimated at

1% per year /he long period of sta"ility supports annual

monitoring with serum electrophoresis and "lood

counts.


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Smoldering AsymptomaticMyeloma

M#$rotien in Serum 0 &'g().

and(or

*one marrow colonal plasma cells 1'%. o related organ or tissue impairment -no end

organ damage or impairment or symptoms.


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Smoldering AsymptomaticMyeloma

2ntermediate form of myeloma . 3isk of transformation to multiple myeloma is much

higher than in MGUS -5#1'% per year.


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Multiple Myeloma

M#$rotien in Serum 0 &'g().

and(or

*one marrow colonal plasma cells 1'%.

$lus re4uires one of following -CRABriteria.

Calcium levation -11.5g(dl.

Renal insufficiency -reatinine 6mg(dl.

Anemia -7". + 1'g(dl or 6g(dl+normal.

Bone disease -)ytic or 8steopenic.


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Solitary lasmacytoma of !one"

Solitary "one lesion due to plasma cell tumor.

ormal Skeletal Survey.

ormal *one marrow plasmacytosis. o 9nemia, 7ypercalcemia or 3enal disease.

$reserved levels of uninvolved immunoglo"ulins.


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lasma cell leukemia

$lasma cell leukemia is a very rare variant of multiple

myeloma, where the proliferation of plasma cells is

not confined to the "one marrow "ut may "e detectedin the peripheral "lood.

arries a very poor prognosis with median survival of

only & to : months.


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#pidemiology

Gender

Men are affected more fre4uently than women

-1.;imately ::years.

Race

More common in *lacks.


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#tiology and $isk %actors

o predisposing factors for the development of

multiple myeloma have "een confirmed.

Environment

o Radiation exposure

o Occupational exposure -agricultural, chemical,

metallurgical, ru""erplant, pulp, wood and paper

workers, and leather tanners.o Chemical exposure to formaldehyde,

epichlorohydrin,


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&he 'nitial orkup

CBCwith differential count and platelet count.

Routine serum chemistry -e.g., calcium, "lood urea nitrogen,

creatinine,al"umin.

Bone marrow aspirate and trephine biopsyor biopsy of mass if

solitary lesion

lonality, immunophenotype and cytogenetic studies, plasma cell

la"eling inde>to assess plasmacytosis.

M-Protien Assessment

erum protein electrophoresis and immunofi!ation to defineprotein type.

erum free light chain"

#$-hour urine protein% electrophoresis% and immunofi!ation "

&uantitative serum 'g levels"


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&he 'nitial orkup

(eletal survey

Prognostic )actors

? Beta-#-microglobulin "

? erum albumin"

? C reactive protein *CRP+"

? ,actate dehydrogenase *,.+ levels"

/hole-body 01 )-fluorodeo!yglucose *)G+positron emissiontomography *PE2+3C2 scan"

MR' is an e!cellent tool for evaluation of spinal

cord compression3impingement


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eripheral *lood

/he peripheral "lood smear may reveal a

normocytic, normochromic anemia with

rouleau> formation.

$lasma cells may also "e seen.


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ormal plasma cells help

protect the "ody from germs

and other harmful

su"stances

Myeloma cells make

anti"odies called M proteins

and other proteins. /hese

proteins can collect in the

"lood, urine, and organs


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!one Marrow *one marrow e>amination usually reveals an

increased number of plasma cells*4056+"

2mmaturity of the plasma cells is evident with the

presence of prominent nucleoli -@myeloma cellsA.

/hese cells are strongly positive for C71% C071,

and cytoplasmic immunoglobulin.

/he pattern of "one marrow involvement in plasma

cell myeloma may "e macrofocal. 9s a result, plasmacell count may "e normal when an aspirate misses the

focal aggregates of plasma cells that are "etter

visuali!ed radiographically or on direct needle "iopsy.


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Monoclonal roteins

2gG -:'%.

2g9 -6'%.

2gB -6%.

2g -+ '.1%.

light#chain C or D only -1E%.

*i#clonal + 1% of patients.

on#secretory disease + 5%.


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+steolytic ,esions

Multiple osteolytic lesions ='%. Single osteolytic lesions or diffuse osteoporosis 15%.

ormal skeletal radiographs in 15%.

)esions are most commonly seen in the Skull

Ferte"rae

3i"s

$elvis

$ro>imal long "ones.

/he use of M32 indicates that skeletal a"normalities

e>ist in nearly all patients with myeloma.


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-ypercalcemia

lassified "ased on total serum and ioni!ed

calcium levels, as followscision is an indication for radical

3/, which can significantly reduce local recurrence

rates. )ocal lymph nodes are only included in the

target volume if they are clinically involved.


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Multiple Myeloma&reatment

/he main options for therapy includeamethasone -F9B was the standard induction

therapy in upfront patients who were candidates for 7B/.

2n the last 1' years, induction regimens dramatically

changed following the onset of thalidomide, "orte!omi",

and lenalidomide.

Melphalan is not usually recommended for people who

are canidate for renal transplant. /his is "ecause it is

often difficult to collect a sufficient number of

healthy stem cellsfor transplantation


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&halidomime4e0amethasone

2halidomide was the first @novelA agent to "e

tested in frontline setting. /he use of thalidomide

plus de>amethasone -2hal-e! has "een studied

in four randomi!ed trials.

9ll studies have demonstratedthat /hal#Be>

regimen was superior to ?=6 ;RR.


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Bortezomib-Based Induction Regimens

2n the last 5 years, "orte!omi" also

reached the frontline setting and various

phase 22 and phase 222 clinical trials were

conducted -7arousseau et al. 6'':,6''ER 3osinol et al. 6''=. /he 833

ranges from :'% to E5% with 15% to

6'% 3s.


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,enalidimide4e0amethasone

,enalidomide-3ev is also undergoing first lineevaluation. 3ev#Be> regimen was studied in

attempt to improve the /hal#Be> regimen,"ased

on the assumption that lenalidomide is more

effective and less neuroto>ic than thalidomide.

/wo large randomi!ed trials, one conducted "y

8G -3akumar et al. 6'1' and the other "y

SN8G -Tonder et al. 6''=,have shown that themaority of patients respond to induction with

3ev(Be> -;RR of 1# and 196 with a 3 rate of

;O66%, respectively.


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&hree4rug $egimens

2hree-rug Regimens

9s all new drugs have shown e>cellent feasi"ility

and efficacy com"ined with Be> as inductiontherapy.

/he most promising three#drug induction regimen

might "e the com"ination of borte@omib with

Rev3e! *


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&ypes of &ransplant

#utologous transplantation< the stem cells areo"tained from the individual with multiple myeloma.

Most commonly recommended.

#llogeneic transplantation< the stem cells or "one

marrow are o"tained from a donor with a tissue typematching that of the patient. /his type of transplantation

carries very high risks and is not recommendedfor most

individuals with multiple myeloma.;'% mortality rate.

"$ngeneic transplantation< the stem cells or "one

marrow are o"tained from an identical twin of the

individual. /his is the optimal form of transplantation

although few people with multiple myeloma have an

identical twin who can serve as a donor.


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rocedure

'nitial therapy with a regimen such as len(de>a or thali(de>a given for three tofour months.

Granulocyte colony-stimulating factor-G#S are given to stimulate the

production of stem cells.

Stem cell are collected thru plasmaphoresis .

.arvested

Cryopreserved


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rocedure

9fter an individual recovers from the stem cell

collection, he or she is given high-dose

chemotherapywith melphalan -6''mg(m6to killas many of the malignant plasma cells as possi"le.

$reviously collected stem cells are thawed and

returnedto the patient.


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4elayed &ransplantation"

9lternatively, after stem cell collection standard

chemotherapy with melphalan -or similar drugs

given to achieve a plateau phase"

At the time of relapse, high doses of melphalan

-or similar drugs are given.

/he previously collected stem cells are returned to

the patient.


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&andem &ransplant

Bou"le autologous transplantation -two

consecutive autologous

transplantations may "e more effective

than single autologous transplantation ifthe first transplant has not produced

a complete or near complete

response"/he second transplantation

is usually performed within si> months of

the first.


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#5ecti/eness

9"out 0 to # percent of individuals die

from complications related to

transplantation. 7owever, compared

with chemotherapy alone, autologousstem cell transplantation is more likely to

produce a response, and is associated

with 0#-month longer survival

compared to chemotherapy alone"

-appro>imately 5= versus ;; months

ti t 3 t #li i*l f A t l


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atients 3ot #ligi*le for AutologousStem .ell &ransplantation

:ewer regimens for the treatment of MM.

2halidomide3 de!amethasone

9 dose of 1'' mg $8 daily at night is as effective, "ut

with fewer neuropathic effects, than higher doses. MP2 -cycle fre4uency is every ; weeks

? Melphalan< ; mg(m6 daily on days 1 through =

? $rednisone< ;' mg(m6 daily on days 1 through =

? /halidomide< 1'' mg daily at night

Rev3e!-cycle fre4uency is every ; weeks

? 3evlimid -lenalidomide< 65 mg $8

? Be>amethasone< ;' mg $8 weekly


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&he doselimiting side e5ects

:eurologic-somnolence, peripheral

neuropathy for thalidomide .

.ematosuppression-mainly throm"ocytopenia

for lenalidomide.

*oth agents are teratogenicand

thrombophilic.


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6elcade (*orte7omi*) regimens


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4oselimiting sidee5ects

Bose#limiting side effects of "orte!omi" are

Peripheral neuropathy -predominantly sensory .

.ematosuppression-esp. throm"ocytopenia.

+lder chemotherapy regimens for


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+lder chemotherapy regimens forMM

MP-cycle fre4uency is ; to : weeks

? Melphalan< 1' mg(m6 $8 on days 1 through ;

? $rednisone< :' mg(m6 $8 on days 1 through ;


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lateau phase

hemotherapy is usually continued until multiple

myeloma enters a stable *plateau+ phase"

/he plateau phase is reached when the myeloma

"ecomes sta"le and shows no signs ofprogressing.

9lthough this phase is usually temporary, it typically

lasts si! months or longer.

;ccurs in about one half of individuals after

chemotherapy.

9chieving this phase usually reuires at least si!

or more cycles of treatment.


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$emission maintenance &herapy

"teroi!s for maintenance

/wo large, randomi!ed trials have shown that

glucocorticoid maintenance prolongs the

duration of remission and improves life

e!pectancy"

/he SN8G used prednisone -5' mg every other

day. /he 2 anadain trial contained de>amethasone

-;' mg daily for ; days every ; weeks.


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$emission maintenance &herapy

hali!omi!e

/he 2M #': study evaluated maintenance

therapy with thalidomide plus pamidronate

-9redia compared with pamidronate alone orwith o"servation only following tandem

autologous transplantation. uperior event-

free survival and overall survival were

reported in the cohort receiving thalidomideplus pamidronate.

Borte@omib

urrently under study as a maintenance


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Refractory and relapsed, refractory disease

9ppro>imately 1'% to 15% of patients

with newly diagnosed multiple myeloma

are unresponsive to induction therapy.

Moreover, virtually all patients whorespond initially will relapse.


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&reatment +ptions

Con&entional chemotherap$

Al(ylating agents% alone or in combination,

have "een effective in appro>imately one#third of

patients with F9B#refractory disease.

hali!omi!e

/halidomide has an esta"lished role in therapy for

refractory(relapsed multiple myeloma, with 756 ofpatients achieving at least 956 reduction in

paraprotein levels. 3emissions o"tained are

dura"le


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&reatment +ptions

'igh!ose chemotherap$

7igh#dose melphalan and stem cell

rescue should "e offered to patients who

have deferred the transplant initially.:ovel agents

enali!omi!e

)enalidomide has greater potency thandoes thalidomide.

Borte@omib


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Supporti/e care

Bedrestis often necessary "ecause of the painful "ony

lesions or fractures. *edrest, however, further promotes

"one deminerali!ation, which may lead to hypercalcemia.

Bisphosphonates $amidronate, ' mg 2F over 6 hours, or Toledronic acid,

; mg 2F over 15 minutes given monthly are indicated for

all patients with stage 22 or 222 MM -and perhaps stage 2 as

well./hese agents have significantly decreased the incidence

of skeletal complications in this disease.

2t is important to recogni!e that these agents occasionally

are associated with renal dysfunction.


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Supporti/e care

ental procedures, such as root canal or

e>traction of teeth, may "e associated

with infection or destruction of the aw

-osteonecrosis in patients treated withintravenous bisphosphonates.

9ccordingly, patients should avoid such

procedures, if possi"le, while taking these

agentsR any needed dental proceduresshould "e performed beforethese agents

are started.


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Supporti/e care

Calcium and vitamin deficiencies

occur in many patients with myeloma and

serum calcium levels may also be

reduced with bisphosphonate treatment./hus, oral calcium -1,''' mg daily and

vitamin B -E'' 2U daily is recommended.

Monitoring of serum calcium is necessary,

however, "ecause occasionally patient maydevelop hypercalcemia.


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Supporti/e care

.ydration" $atients must "e repeatedly reminded

to drink # to 7 , of liuids daily to promote

urinary e>cretion of light chains, calcium, and uric

acid. /his simple reminder has "een shown toimprove survival greatly in some studies.

'nfections are the foremost cause of death in

patients with MM-Bue to lack of opsoni!ation.2nfections must "e investigated and treated

urgently. 2F2G therapy should "e considered in

cases of recurrent, life#threatening infections


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Supporti/e care

Renal failure /he treatment of impaired kidney function is aimed at the

specific underlying cause"

/reatment usually includes intravenous fluids.

Prednisonecan indirectly lower "lood calcium levels.

Allopurinol, a drug that can lower "lood levels of uric acid.

$atients are advised to stay well-hydratedand should drink

enough fluid to produce three liters of urine daily if they have

*ence ones proteinuria .

/hey should also avoid using :A's and contrast media

Some patients may "e candidates for hemodialysis treatment


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$egimes Used 'n $enal %ailure

/halidomide(Be>a

F9B

Falcade (Be>a )inilidamide(Be>a


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$ole of #!$&

/he most common use of 3/ in the

management of plasma cell tumors is for

palliative treatment of "ony disease -relief

of compression of spinal cord cranialnerves, or peripheral nerves.

2t has "een estimated that appro>imately

;'% of patients with multiple myeloma will

re4uire palliative 3/ for "one pain at sometime during the course of their disease


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$ole of #!$&

Nhen 3/ is given for pain due to

disease involving a long "one, a local

field suffices. 2t is unnecessary to treat

the entire "one . Boses of 1' to 6' Gy -in five to 1'

fractions are effective, although the pain

relief is often partial .

Documents

Multiple Myeloma Final