An Open-Label, Single Arm, Phase 2a Study of Bortezomib, Lenalidomide, Dexamethasone and Elotuzumab in Newly Diagnosed Multiple Myeloma
Phase: PHASE2
Conditions: Multiple Myeloma
Sponsor: Dana-Farber Cancer Institute

Title:  A n  O pe n- L a bel,  Si n gle Ar m,  P hase  2a St u d y of B ortez o mi b, Le nali d o mi de, 
De xa met has o n e  a n d El ot uz u ma b i n Ne wl y  Dia g n ose d M ulti ple  M yel o ma  
N C T  N um ber:  N C T 0 2 3 7 5 5 5 5 
I R B A p pr o v al D ate:  0 4 /0 8 / 2 02 1  

C O N FI D E N TI A L
T his d oc u me nt is c o nfi de ntial. D o n ot discl ose or use e xce pt as a ut h orize d.
E mail: 
A ge nts:  
Le nali d o mi de - Cel ge ne C or p orati o n - c o m mercial s u p pl y
B ortez o mi b  - Mille n ni u m P har mace uticals, I nc. – c o m mercial s u p pl y
De xa met has o ne  – c o m mercial s u p pl y 
El ot uz u ma b – Brist ol- M yer S q ui b b ( B M S) – i n vesti gati o nal s u p pl y

S h ort title: P h ase II st u d y of El ot uz u m a b pl us R V D i n Ne wl y Di a g n ose d M M
Versi o n D ate:      N o ve m ber 1 0, 2 0 2 0 
C O N FI D E N TI A L
T his d oc u me nt is c o nfi de ntial. D o n ot discl ose or use e xce pt as a ut h orize d.
S Y N O P SI S
Title
A n O pe n- La bel, Si n gle Ar m, P hase 2a St u d y of B ortez o mi b, Le nali d o mi de, De xa met has o ne a n d El ot uz u ma b i n Ne wl y Dia g n ose d 
M ulti ple M yel o ma
St u d y 
O bjecti ves
Ori gi n al Pri m ar y O bjecti ve

T o esti mate t he res p o nse rate after 4 c ycles i n s u bjects treate d wit h el ot uz u ma b pl us b ortez o mi b, le nali d o mi de a n d 
de xa met has o ne ( E- R V D).
Ori gi n al Sec o n d ar y O bjecti ves

T o esti mate t he pr o p orti o n of s u bjects wit h s uccessf ul ste m cell m o bilizati o n after recei vi n g 4 c ycles of treat me nt wit h E- R V D.

T o esti mate t he pr o p orti o n of s u bjects re q uiri n g d ose m o dificati o n of a n y st u d y dr u g d uri n g t he first f o ur c ycles of E- R V D 

T o c haracterize safet y i n s u bjects w h o recei ve E- R V D 

T o pr o vi de preli mi nar y i nf or mati o n o n t he acti vit y of E- R V D i ncl u di n g best res p o nse, o bjecti ve res p o nse rate ( O R R),  i ncl u di n g 
O R R at e n d of 8 c ycles f or patie nts t hat c o m plete 8 c ycles of i n d ucti o n t hera p y,  d urati o n of res p o nse, ti me t o res p o nse, 
pr o gressi o n free s ur vi val ( P F S) a n d ti me t o ne xt treat me nt.
Ori gi n al E x pl or at or y O bjecti ves

F or s u bjects w h o elect t o u n der g o a ut ol o g o us ste m cell tra ns pla nt ( A S C T), t o c haracterize e n graft me nt para meters 
T he ori gi nal o bjecti ves of t he st u d y ha ve n o w bee n met as of Oct o ber 2 0 2 0.   T he ne w pri mar y o bjecti ve will be safet y. T he 
f oll o wi n g i nf or mati o n will be c ollecte d: 

All S A Es.

All ≥Gra de  2 A Es.

Ne w pri mar y mali g na ncies.

A n y A E res ulti n g i n d ose m o dificati o n or disc o nti n uati o n of a n y st u d y dr u g.

A n y ot her A E t hat i n t he o pi ni o n of t he i n vesti gat or is a cli nicall y si g nifica nt e ve nt.
St u d y Desi g n
T his is a n o pe n-la bel P hase 2a st u d y of E- R V D. T he st u d y will treat a p pr o xi matel y 4 0 a ut ol o g o us ste m-cell tra ns pla nt ( A S C T)-eli gi ble 
s u bjects wit h ne wl y dia g n ose d m ulti ple m yel o ma ( M M).
I n d ucti o n C ycles 1 - 8: I n d ucti o n re gi me n will c o nsist of a treat me nt c ycle e ver y 2 1 da ys wit h:

El ot uz u ma b at 1 0 m g/ k g I V o n Da ys 1, 8, a n d 1 5 i n I n d ucti o n C ycles 1 a n d 2 a n d 1 0 m g/ k g I V o n Da ys 1 a n d 1 1 i n I n d ucti o n 
C ycles 3 t hr o u g h 8.

B ortez o mi b at 1. 3 m g/ m 2 s u bc uta ne o us ( S Q) i njecti o n o n Da ys 1, 4, 8, a n d 1 1 f oll o we d b y a 1 0- da y rest peri o d of c ycles 1 – 8.

S h ort title: P h ase II st u d y of El ot uz u m a b pl us R V D i n Ne wl y Di a g n ose d M M
Versi o n D ate:      N o ve m ber 1 0, 2 0 2 0 
C O N FI D E N TI A L
T his d oc u me nt is c o nfi de ntial. D o n ot discl ose or use e xce pt as a ut h orize d.

Le nali d o mi de as a si n gle dail y oral d ose of 2 5 m g o n Da ys 1 - 1 4 of C ycles 1 - 8 f oll o we d b y 7- da y rest peri o d.  ( Le nali d o mi de 
starti n g d ose t o be a dj uste d acc or di n g t o baseli ne re nal f u ncti o n acc or di n g t o Pac ka ge I nsert g ui deli ne).   

De xa met has o ne as a si n gle dail y oral d ose of 2 0 m g/ da y o n Da ys 2, 4, 5, 9, 1 1, a n d 1 2 d uri n g c ycles 1 a n d 2. 

De xa met has o ne  2 8 m g p o ( 3 – 2 4 h o urs bef ore el ot uz u ma b) a n d 8 m g I V ( 4 5- 9 0 mi n utes bef ore el ot uz u ma b) o n Da ys 1, 8, a n d 
1 5 of I n d ucti o n C ycles 1 a n d 2.  

De xa met has o ne as a si n gle oral d ose of 2 0 m g/ da y o n Da ys 2, 4, 5, 8, 9, a n d 1 2 d uri n g i n d ucti o n C ycles 3 a n d 4.

De xa met has o ne  2 8 m g p o ( 3 – 2 4 h o urs bef ore el ot uz u ma b) a n d 8 m g I V ( 4 5- 9 0 mi n utes bef ore el ot uz u ma b) o n Da ys 1 a n d 1 1 
of I n d ucti o n C ycles 3 a n d 4.  

De xa met has o ne 1 0 m g as a si n gle oral d ose of 1 0 m g o n Da ys 2, 4, 5, 8, 9, a n d 1 2 d uri n g i n d ucti o n C ycles 5 t hr o u g h 8.

De xa met has o ne  2 8 m g p o ( 3 – 2 4 h o urs bef ore el ot uz u ma b) a n d 8 m g I V ( 4 5- 9 0 mi n utes bef ore el ot uz u ma b) o n Da ys 1 a n d 1 1 
of i n d ucti o n C ycles 5 t hr o u g h 8.    
Ste m cell m o biliz ati o n: Ste m cell m o bilizati o n will be perf or me d f or all s u bjects at t he e n d of I n d ucti o n C ycle 4.  Ste m cell m o bilizati o n 
will be perf or me d wit h eit her c ycl o p h os p ha mi de 2 5 0 0 m g/ m 2 a n d fil grasti m or fil grasti m wit h or wit h o ut pleri xaf or acc or di n g t o 
i nstit uti o nal g ui deli nes.  If ste m cell m o bilizati o n usi n g t his a p pr oac h is u ns uccessf ul, a sec o n d atte m pt at c ollecti o n ca n be u n derta ke n 
wit hi n o ne m o nt h of t he first atte m pt at m o bilizati o n.  S u bjects w h o attai n at least a partial res p o nse ( P R) ma y elect t o st o p E- R V D at t he 
e n d of I n d ucti o n C ycle 4 a n d pr ocee d t o a ut ol o g o us S C T as per t he i nstit uti o nal g ui deli nes. S u bjects w h o d o n ot pr ocee d t o S C T ma y 
recei ve a f ull 8 c ycles of t he i n d ucti o n t hera p y.
T he decisi o n w het her s u bjects will pr ocee d t o S C T will be ma de o n t he basis of treati n g p h ysicia n rec o m me n dati o ns a n d patie nt prefere nce. 
P h ysicia n rec o m me n dati o ns are t y picall y base d o n disease res p o nse a n d o n h o w well s u bjects are t olerati n g treat me nt. T he ki n d of decisi o n 
ma ki n g pr ocess relate d t o S C T is c o nsi dere d n o wa da ys sta n dar d of care i n t he m ulti ple m yel o ma fiel d.
M ai nte n a nce:  S u bjects w h o recei ve 8 c ycles of t he i n d ucti o n re gi me n will be all o we d t o c o nti n ue treat me nt o n a mai nte na nce sc he d ule, 
if t he y ha ve at least sta ble disease a n d are eli gi ble t o recei ve mai nte na nce treat me nt. A d diti o nall y, s u bjects w h o recei ve d S C T at t he e n d 
of I n d ucti o n C ycle 4 will f ore g o C ycles 5 t o 8 of t hera p y a n d will be all o we d t o c o nti n ue treat me nt directl y o n a mai nte na nce sc he d ule 
after rec o ver y fr o m S C T.
Mai nte na nce t hera p y will c o nti n ue u ntil disease rela pse, u nacce pta ble t o xicit y, wit h dra wal of c o nse nt or u ntil t he treati n g p h ysicia n 
deter mi nes treat me nt disc o nti n uati o n is i n t he best i nterest of t he patie nt.   S u bjects u na ble t o t olerate a n y of t he i n di vi d ual dr u gs 
(e g, el ot uz u ma b, le nali d o mi de, b ortez o mi b or de xa met has o ne) d uri n g t he mai nte na nce p hase ma y st o p t h ose i n di vi d ual dr u gs a n d c o nti n ue 
o n t he re mai ni n g dr u gs, at t he i n vesti gat or’s discreti o n. 
Mai nte na nce t hera p y will be a d mi nistere d t o all patie nts, wit h t he s pecific mai nte na nce re gi me n deter mi ne d b y ris k cate g or y.  Eac h 
Mai nte na nce c ycle is 2 8 da ys.

S h ort title: P h ase II st u d y of El ot uz u m a b pl us R V D i n Ne wl y Di a g n ose d M M
Versi o n D ate:      N o ve m ber 1 0, 2 0 2 0 
C O N FI D E N TI A L
T his d oc u me nt is c o nfi de ntial. D o n ot discl ose or use e xce pt as a ut h orize d.
P atie nts u n der g oi n g A S C T w h o are I S S st a ge III a n d/ or h a ve hi g h-ris k c yt o ge netics  i ncl u di n g t( 4; 1 4), t( 1 4; 1 6); or del 1 7 p will recei ve 
mai nte na nce wit h:

El ot uz u ma b 2 0 m g/ k g o n Da y 1 of eac h 2 8 da y c ycle; 

Le nali d o mi de 1 0 m g Da ys 1 – 2 1; 

B ortez o mi b 1. 3 m g/ m 2 Da ys 1 a n d 1 5 S Q;

I V de xa met has o ne 8 m g o n Da y 1( 4 5- 9 0 mi n utes bef ore el ot uz u ma b). 
P atie nts u n der g oi n g A S C T w h o are I S S I or II wit h o ut hi g h-ris k  c yt o ge netics will recei ve mai nte na nce wit h:

El ot uz u ma b 2 0 m g/ k g Da y 1 of eac h 2 8 da y c ycle; 

Le nali d o mi de 1 0 m g Da ys 1 – 2 1; a n d 

I V de xa met has o ne 8 m g o n Da y 1( 4 5- 9 0 mi n utes bef ore el ot uz u ma b).  
P atie nts o pti n g n ot t o pr ocee d wit h A S C T f oll o wi n g 8 c ycles of i n d ucti o n w h o are I S S st a ge II or III a n d/ or h a ve hi g h-ris k 
c yt o ge netics  i ncl u di n g t( 4; 1 4), t( 1 4; 1 6); or del 1 7 p will recei ve mai nte na nce wit h:

El ot uz u ma b 2 0 m g/ k g o n Da y 1 of eac h 2 8 da y c ycle; 

Le nali d o mi de at t he d ose t olerate d d uri n g i n d ucti o n Da ys 1 – 2 1; 

B ortez o mi b 1. 3 m g/ m 2 Da ys 1 a n d 1 5 S Q; a n d 

I V de xa met has o ne 8 m g o n Da y 1( 4 5- 9 0 mi n utes bef ore el ot uz u ma b).
P atie nts o pti n g n ot t o pr ocee d wit h A S C T f oll o wi n g 8 c ycles of i n d ucti o n w h o are I S S st a ge I wit h o ut hi g h-ris k c yt o ge netics  will 
recei ve mai nte na nce wit h:

El ot uz u ma b 2 0 m g/ k g Da y 1 of eac h 2 8 da y c ycle; 

 Le nali d o mi de at t he d ose t olerate d d uri n g i n d ucti o n Da ys 1 – 2 1; a n d

I V de xa met has o ne 8 m g o n Da y 1( 4 5- 9 0 mi n utes bef ore el ot uz u ma b). 
St u d y 
Pr oce d ures
I nstit uti o ns will re gister eli gi ble partici pa nts wit h t he D F/ H C C Q ualit y Ass ura nce Office f or Cli nical Trials ( O D Q) ce ntral re gistrati o n 
s yste m. Re gistrati o n m ust occ ur pri or t o t he i nitiati o n of t hera p y. A n y partici pa nt n ot re gistere d t o t he pr ot oc ol bef ore treat me nt be gi ns 
will be c o nsi dere d i neli gi ble a n d re gistrati o n will be de nie d.  See Secti o n 4 of t he pr ot oc ol f or details.
P artici p a nt 
S a m ple
4 1 partici pa nts ha ve bee n e nr olle d o n t his pr ot oc ol. 

S h ort title: P h ase II st u d y of El ot uz u m a b pl us R V D i n Ne wl y Di a g n ose d M M
Versi o n D ate:      N o ve m ber 1 0, 2 0 2 0 
C O N FI D E N TI A L
T his d oc u me nt is c o nfi de ntial. D o n ot discl ose or use e xce pt as a ut h orize d.
Tre at me nt a n d 
D os a ge
I n d ucti o n ( C ycles 1 - 8): 

El ot uz u ma b at 1 0 m g/ k g I V o n Da ys 1, 8, a n d 1 5 i n I n d ucti o n C ycles 1 a n d 2 a n d 1 0 m g/ k g o n Da ys 1 a n d 1 1 i n I n d ucti o n C ycles 3 
t hr o u g h 8.

B ortez o mi b at 1. 3 m g/ m 2/ S Q i njecti o n o n Da ys 1, 4, 8, a n d 1 1 of  C ycles 1 - 8, f oll o we d b y a 1 0- da y rest peri o d.

Le nali d o mi de as a si n gle dail y oral d ose of 2 5 m g o n Da ys 1 - 1 4 of C ycles 1 - 8 f oll o we d b y 7- da y rest peri o d.  ( Le nali d o mi de starti n g 
d ose t o be a dj uste d acc or di n g t o baseli ne re nal f u ncti o n acc or di n g t o Pac ka ge I nsert g ui deli ne).   

De xa met has o ne as a si n gle dail y oral d ose of 2 0 m g/ da y o n Da ys 2, 4, 5, 9, 1 1, a n d 1 2 d uri n g C ycles 1 a n d 2. 

De xa met has o ne  2 8 m g p o ( 3 – 2 4 h o urs bef ore el ot uz u ma b) a n d 8 m g I V ( 4 5- 9 0 mi n utes bef ore el ot uz u ma b) o n Da ys 1, 8, a n d 1 5 i n 
d uri n g I n d ucti o n C ycles 1 a n d 2.  

De xa met has o ne as a si n gle oral d ose of 2 0 m g/ da y o n Da ys 2, 4, 5, 8, 9, a n d 1 2 d uri n g i n d ucti o n C ycles 3 a n d 4.

De xa met has o ne  2 8 m g p o ( 3 – 2 4 h o urs bef ore el ot uz u ma b) a n d 8 m g I V ( 4 5- 9 0 mi n utes bef ore el ot uz u ma b) o n Da ys 1 a n d 1 1 of 
I n d ucti o n C ycles 3 a n d 4.  

De xa met has o ne 1 0 m g as a si n gle oral d ose of 1 0 m g o n Da ys 2, 4, 5, 8, 9, a n d 1 2 d uri n g i n d ucti o n C ycles 5 t hr o u g h 8.

De xa met has o ne  2 8 m g p o ( 3 – 2 4 h o urs bef ore el ot uz u ma b) a n d 8 m g I V ( 4 5- 9 0 mi n utes bef ore el ot uz u ma b) o n Da ys 1 a n d 1 1 of 
i n d ucti o n C ycles 5 t hr o u g h 8.    
M ai nte n a nce:  T he mai nte na nce sc he d ule will start after c o m pleti o n of 8 c ycles of t he i n d ucti o n re gi me n or after rec o ver y fr o m S C T
Mai nte na nce t hera p y will be a d mi nistere d t o all patie nts, wit h t he s pecific mai nte na nce re gi me n deter mi ne d b y ris k cate g or y.  
P atie nts u n der g oi n g A S C T w h o are I S S st a ge III a n d/ or h a ve hi g h-ris k c yt o ge netics  i ncl u di n g t( 4; 1 4), t( 1 4; 1 6); or del 1 7 p will recei ve 
mai nte na nce wit h:

El ot uz u ma b 2 0 m g/ k g o n da y 1 of eac h 2 8 da y c ycle; 

Le nali d o mi de 1 0 m g Da ys 1 – 2 1; 

B ortez o mi b 1. 3 m g/ m 2 Da ys 1 a n d 1 5 S Q;

I V de xa met has o ne 8 m g o n Da y 1. 
P atie nts u n der g oi n g A S C T w h o are I S S I or II wit h o ut hi g h-ris k  c yt o ge netics will recei ve mai nte na nce wit h:

El ot uz u ma b 2 0 m g/ k g Da y 1 of eac h 2 8 da y c ycle; 

 Le nali d o mi de 1 0 m g Da ys 1 – 2 1; a n d 

S h ort title: P h ase II st u d y of El ot uz u m a b pl us R V D i n Ne wl y Di a g n ose d M M
Versi o n D ate:      N o ve m ber 1 0, 2 0 2 0 
C O N FI D E N TI A L
T his d oc u me nt is c o nfi de ntial. D o n ot discl ose or use e xce pt as a ut h orize d.

I V de xa met has o ne 8 m g o n da y 1 ( 4 5- 9 0 mi n utes bef ore el ot uz u ma b).  
P atie nts o pti n g n ot t o pr ocee d wit h A S C T f oll o wi n g 8 c ycles of i n d ucti o n w h o are I S S st a ge II or III a n d/ or h a ve hi g h-ris k 
c yt o ge netics  i ncl u di n g t( 4; 1 4), t( 1 4; 1 6); or del 1 7 p will recei ve mai nte na nce wit h:

El ot uz u ma b 2 0 m g/ k g o n Da y 1 of eac h 2 8 da y c ycle; 

Le nali d o mi de at t he d ose t olerate d d uri n g i n d ucti o n Da ys 1 – 2 1; 

B ortez o mi b 1. 3 m g/ m 2 Da ys 1 a n d 1 5 S Q; a n d 

I V de xa met has o ne 8 m g o n Da y 1( 4 5- 9 0 mi n utes bef ore el ot uz u ma b).
P atie nts o pti n g n ot t o pr ocee d wit h A S C T f oll o wi n g 8 c ycles of i n d ucti o n w h o are I S S st a ge I wit h o ut hi g h-ris k c yt o ge netics  will 
recei ve mai nte na nce wit h:

El ot uz u ma b 2 0 m g/ k g Da y 1 of eac h 2 8 da y c ycle; 

 Le nali d o mi de at t he d ose t olerate d d uri n g i n d ucti o n Da ys 1 – 2 1; a n d

I V de xa met has o ne 8 m g o n Da y 1( 4 5- 9 0 mi n utes bef ore el ot uz u ma b).  
D ur ati o n of t he 
St u d y
Partici pa nts w h o ha ve sta ble or res p o n di n g disease t o treat me nt a n d ha ve a n acce pta ble t o xicit y pr ofile will be all o we d t o c o nti n ue treat me nt 
u ntil disease rela pses, u nacce pta ble t o xicit y de vel o ps, t he patie nt wit h dra ws c o nse nt  or u ntil t he treati n g p h ysicia n deter mi nes treat me nt 
disc o nti n uati o n is i n t he best i nterest of t he patie nt.   
S afet y 
P ar a meters
Pri or t o e nr oll me nt eac h partici pa nt will ha ve t heir me dical hist or y d oc u me nte d.  T he hist or y will be u p date d at baseli ne ( C ycle 1, Da y 1), 
a n d t hr o u g h o ut partici pati o n i n t he st u d y as i n dicate d b y cli nical s y m pt o ms.   Partici pa nts will u n der g o p h ysical e xa mi nati o n (t o i ncl u de 
vital si g ns), q uer y f or a d verse e ve nts a n d c o nc o mita nt me dicati o n use, a n d cli nical la b orat or y testi n g, acc or di n g t o t he details o utli ne d i n 
Secti o n 9.    Assess me nt of peri p heral ne ur o pat h y will occ ur o n Da y 1 of eac h c ycle.  C o m pleti o n of t he peri p heral ne ur o pat h y q uesti o n naire 
( F A C T/ G O G Nt x) will occ ur o n Da y 1 of o d d c ycles.  A d verse e x perie nces, i ncl u di n g cli nical la b orat or y a n d vital si g n a b n or malities, will 
be gra de d usi n g C T E P Versi o n 4. 0 3 of t he N CI C o m m o n Ter mi n ol o g y f or A d verse E ve nts ( C T C A E).  B o d y s urface area will be calc ulate d 
pri or t o eac h c ycle of b ortez o mi b.
T he effect of el ot uz u ma b has bee n st u die d e xte nsi vel y i n c o m bi nati o n wit h Le nali d o mi de a n d B ortez o mi b, a n d d osa ges of 1 0 m g/ k g I V are 
use d i n all p hase III a n d ra n d o mize d p hase II st u dies t o date. N o net heless, t he f o ur dr u g c o m bi nati o n pr o p ose d i n t his st u d y has n ot yet 
bei n g e val uate d i n h u ma ns. T heref ore, after t he e nr oll me nt of 1 0 s u bjects i n t he st u d y, f urt her s u bject e nr oll me nt will be place d o n h ol d t o 
e val uate safet y/t o xicit y data pertai ni n g t he 4 dr u g c o m bi nati o n, a n d s pecificall y re gar di n g El ot uz u ma b.
Effic ac y 
P ar a meters
It is rec o m me n de d t hat disease assess me nts are perf or me d per sta n dar d of care.

S h ort title: P h ase II st u d y of El ot uz u m a b pl us R V D i n Ne wl y Di a g n ose d M M
Versi o n D ate:      N o ve m ber 1 0, 2 0 2 0 
C O N FI D E N TI A L
T his d oc u me nt is c o nfi de ntial. D o n ot discl ose or use e xce pt as a ut h orize d.
T A B L E O F C O N T E N T S 
1 
I N T R O D U C TI O N ( B A C K G R O U N D)............................................................................................................ 9
1. 1  
M ulti ple M yel o m a ( M M) .......................................................................................................................... 9
1. 2 
El ot uz u m a b De vel o p me nt B ac k gr o u n d................................................................................................. 1 2
2  
O BJ E C TI V E S................................................................................................................................................. 2 3
2. 1  
Rese arc h H y p ot hesis................................................................................................................................ 2 3
2. 2  
Ori gi n al Pri m ar y O bjecti ves .................................................................................................................. 2 3
2. 3  
Ori gi n al Sec o n d ar y O bjecti ves............................................................................................................... 2 3
3 
P A R TI CI P A N T S E L E C TI O N ....................................................................................................................... 2 4
3. 1 
Eli gi bilit y Criteri a.................................................................................................................................... 2 4
3. 2 
E xcl usi o n Criteri a.................................................................................................................................... 2 5
3. 3 
I ncl usi o n of W o me n, Mi n orities a n d Ot her U n derre prese nte d P o p ul ati o ns..................................... 2 7
3. 4 
Scree ni n g Pr oce d ures.............................................................................................................................. 2 7
4 
R E GI S T R A TI O N P R O C E D U R E S................................................................................................................ 2 8
4. 1  
Ge ner al G ui deli nes f or All I nstit uti o ns.................................................................................................. 2 8
4. 2  
Re gistr ati o n Pr ocess ................................................................................................................................ 2 8
5 
T R E A T M E N T P L A N .................................................................................................................................... 2 9
5. 1 
Pre-tre at me nt Criteri a ............................................................................................................................ 3 0
5. 2 
Tre at me nt................................................................................................................................................. 3 1
5. 3  
A ge nt A d mi nistr ati o n.............................................................................................................................. 3 3
5. 4 
Le n ali d o mi de............................................................................................................................................ 3 8
5. 5  
Ge ner al C o nc o mit a nt Me dic ati o n a n d S u p p orti ve C are G ui deli nes.................................................. 4 1
5. 6  
D ur ati o n of T her a p y................................................................................................................................ 4 4
5. 7 
S ur ger y a n d R a di ati o n............................................................................................................................ 4 5
5. 8  
D ur ati o n of F oll o w U p............................................................................................................................. 4 5
5. 9  
Criteri a f or Re m o v al fr o m St u d y........................................................................................................... 4 5
6 
E X P E C T E D T O XI CI TI E S A N D D O SI N G D E L A Y S/ D O S E M O DI FI C A TI O N S...................................... 4 5
6. 1  
A ntici p ate d T o xicities.............................................................................................................................. 4 5
6. 2 
T o xicit y M a n a ge me nt.............................................................................................................................. 4 7
6. 3  
D ose M o dific ati o n/ Del a ys........................................................................................................................ 5 0
6. 4 
I niti ati o n of Ne w C ycle of E- R V D T her a p y ( D a y 1)............................................................................. 5 3
6. 5 
I niti ati o n of I n d ucti o n C ycle 5 p ost Ste m Cell M o biliz ati o n............................................................... 5 4
7  
D R U G F O R M U L A TI O N A N D A D MI NI S T R A TI O N ................................................................................. 5 5
7. 1 
Le n ali d o mi de ( R E V LI MI D ®)................................................................................................................ 5 5

S h ort title: P h ase II st u d y of El ot uz u m a b pl us R V D i n Ne wl y Di a g n ose d M M
Versi o n D ate:      N o ve m ber 1 0, 2 0 2 0 
C O N FI D E N TI A L
T his d oc u me nt is c o nfi de ntial. D o n ot discl ose or use e xce pt as a ut h orize d.
7. 2 
B ortez o mi b ( V E L C A D E ®)..................................................................................................................... 5 6
7. 3  
De x a met h as o ne ........................................................................................................................................ 5 8
7. 4 
El ot uz u m a b .............................................................................................................................................. 5 8
8 
C O R R E L A TI V E/ S P E CI A L S T U DI E S.......................................................................................................... 6 1
9 
S T U D Y A S S E S S M E N T S A N D P R O C E D U R E S ......................................................................................... 6 2
T a bl e 9. 1
Fl o w C h art/ Ti m e a n d E v e nt s S c h e d ul e ........................................................................................... 6 2
1 0  
M E A S U R E M E N T O F E F F E C T.................................................................................................................... 6 7
1 0. 1  
A ntit u m or Effect – S oli d T u m ors............................................................................................................ 6 7
1 0. 2  
A ntit u m or Effect – He m at ol o gic T u m ors.............................................................................................. 6 7
1 0. 3  
Ot her Res p o nse P ar a meters ................................................................................................................... 7 0
1 1  
A D V E R S E E V E N T R E P O R TI N G R E Q UI R E M E N T S................................................................................ 7 0
1 1. 1  
Defi niti o ns................................................................................................................................................. 7 0
1 1. 2 
E x pecte d ness ............................................................................................................................................ 7 3
1 1. 3 
Pr oce d ures f or A E a n d S A E Rec or di n g a n d Re p orti n g....................................................................... 7 3
1 1. 4  
M o nit ori n g of A d verse E ve nts a n d Peri o d of O bser v ati o n.................................................................. 7 7
1 2  
D A T A A N D S A F E T Y M O NI T O RI N G ........................................................................................................ 7 8
1 2. 1  
D at a Re p orti n g......................................................................................................................................... 7 8
1 2. 2 
T he D F CI C T O will m o nit or a n d m a n a ge t he d at a o n a n o n g oi n g b asis, usi n g a ris k- b ase d 
m o nit ori n g a p pr o ac h t h at i nc or p or ates re m ote d at a re vie w as well as o ne o nsite m o nit ori n g visit per ye ar f or 
sites wit h acti ve p atie nts S afet y Meeti n gs.................................................................................................................. 7 8
1 2. 3  
M o nit ori n g................................................................................................................................................ 7 8
1 3 
R E G U L A T O R Y C O N SI D E R A TI O N S ......................................................................................................... 7 8
1 3. 1 
Pr ot oc ol Re vie w a n d A me n d me nts ........................................................................................................ 7 8
1 3. 2 
I nf or me d C o nse nt.................................................................................................................................... 7 9
1 3. 3 
Et hics......................................................................................................................................................... 7 9
1 3. 4 
St u d y D oc u me nt ati o n.............................................................................................................................. 7 9
1 3. 5  
Rec or ds Rete nti o n.................................................................................................................................... 8 0
1 3. 6  
M ulti-ce nter G ui deli nes........................................................................................................................... 8 0
1 3. 7  
C o o per ati ve Rese arc h a n d De vel o p me nt A gree me nt/ Cli nic al Tri als A gree me nt ( C T A)................. 8 0
1 4 
S T A TI S TI C A L C O N SI D E R A TI O N S........................................................................................................... 8 0
1 4. 1 
E n d p oi nts.................................................................................................................................................. 8 0
1 4. 2 
S a m ple Size/ Accr u al R ate....................................................................................................................... 8 2
1 4. 3 
Str atific ati o n F act ors............................................................................................................................... 8 2
1 4. 4  
A n al ysis..................................................................................................................................................... 8 3
1 5 
P U B LI C A TI O N P L A N.................................................................................................................................. 8 4

S h ort title: P h ase II st u d y of El ot uz u m a b pl us R V D i n Ne wl y Di a g n ose d M M
Versi o n D ate:      N o ve m ber 1 0, 2 0 2 0 
C O N FI D E N TI A L
T his d oc u me nt is c o nfi de ntial. D o n ot discl ose or use e xce pt as a ut h orize d.
1 6 
R E F E R E N C E S............................................................................................................................................... 8 5
1 7  
A P P E N DI C E S................................................................................................................................................ 8 9
A p pe n di x I:  Perf or ma nce Stat us Criteria..................................................................................................................... 8 9
A p pe n di x II:  D u B ois F or m ula f or B o d y S urface Area................................................................................................ 9 0
1D u B ois D, D u B ois E F. A f or m ula t o esti mate t he a p pr o xi mate s urface area if hei g ht a n d wei g ht be k n o w n. Arc h 
I nter n Me dici ne. 1 9 1 6; 1 7: 8 6 3- 7 1................................................................................................................................ 9 0
A p pe n di x III:  T he Ne w Y or k Heart Ass ociati o n Classificati o n of Car diac Disease................................................... 9 1
T he f oll o wi n g ta ble prese nts t he N Y H A classificati o n of car diac disease:.................................................................. 9 1
A p pe n di x I V:   I nter nati o nal M yel o ma F o u n dati o n 2 0 0 3 Dia g n ostic Criteria:............................................................ 9 2
. 
9 2
A p pe n di x V:  F A C T/ G O G- Ne ur ot o xicit y Q uesti o n naire, Versi o n 4. 0........................................................................ 9 3
A p pe n di x VI 
 Li nes of T hera p y............................................................................................................................. 9 4
A p pe n di x VII 
 Pre parati o n a n d a d mi nistrati o n of el ot uz u ma b ............................................................................... 9 5
A P P E N DI X VIII   Da na- Far ber/ Har var d Ca ncer Ce nter M ulti- Ce nter Data a n d Safet y M o nit ori n g Pla n.................. 9 8
2. 3  
D F/ H C C O D Q a n d M ulti ple M yel o m a Rese arc h C o ns orti u m ( M M R C)........................ 1 0 3............. 9 8
1. 0 
I N T R O D U C TI O N........................................................................................................................................ 1 0 5
1. 1 
P ur p ose................................................................................................................................................... 1 0 5
1. 2  
M ulti- Ce nter D at a a n d S afet y M o nit ori n g Pl a n Defi niti o ns ............................................................. 1 0 5
2. 0  
G E N E R A L R O L E S A N D R E S P O N SI BI LI TI E S........................................................................................ 1 0 6
2. 1  
D F/ H C C S p o ns or................................................................................................................................... 1 0 6
2. 2  
C o or di n ati n g Ce nter.............................................................................................................................. 1 0 7
2. 3  
D F/ H C C O D Q a n d M ulti ple M yel o m a Rese arc h C o ns orti u m ( M M R C)......................................... 1 0 7
2. 4 
P artici p ati n g I nstit uti o n........................................................................................................................ 1 0 8
3. 0  
D F/ H C C R E Q UI R E M E N T S F O R M U L TI- C E N T E R P R O T O C O L S........................................................ 1 0 9
3. 1 
Pr ot oc ol Distri b uti o n............................................................................................................................. 1 0 9
3. 2 
Pr ot oc ol Re visi o ns a n d Cl os ures.......................................................................................................... 1 0 9
3. 3 
I nf or me d C o nse nt Re q uire me nts......................................................................................................... 1 1 0
3. 4 
I R B D oc u me nt ati o n............................................................................................................................... 1 1 0
3. 5 
I R B Re- A p pr o v al................................................................................................................................... 1 1 0
3. 6 
P artici p a nt C o nfi de nti alit y a n d A ut h oriz ati o n St ate me nt ................................................................ 1 1 1
3. 7  
D F/ H C C M ulti- Ce nter Pr ot oc ol Re gistr ati o n P olic y ......................................................................... 1 1 1
3. 7. 1 
P artici p a nt Re gistr ati o n........................................................................................................................ 1 1 1

S h ort title: P h ase II st u d y of El ot uz u m a b pl us R V D i n Ne wl y Di a g n ose d M M
Versi o n D ate:      N o ve m ber 1 0, 2 0 2 0 
C O N FI D E N TI A L
T his d oc u me nt is c o nfi de ntial. D o n ot discl ose or use e xce pt as a ut h orize d.
3. 7. 2 
I niti ati o n of T her a p y............................................................................................................................. 1 1 1
3. 7. 3 
Eli gi bilit y E xce pti o ns............................................................................................................................. 1 1 2
3. 7. 4  
Verific ati o n of Re gistr ati o n, D ose Le vels, a n d Ar m Desi g n ati o n...................................................... 1 1 2
3. 8  
D F/ H C C Pr ot oc ol C ase N u m ber.......................................................................................................... 1 1 2
3. 8. 1 
Pr ot oc ol De vi ati o ns, E xce pti o ns a n d Vi ol ati o ns ................................................................................. 1 1 2
3. 8. 2  
Defi niti o ns............................................................................................................................................... 1 1 2
3. 8. 3  
Re p orti n g Pr oce d ures............................................................................................................................ 1 1 3
3. 9 
S afet y Assess me nts a n d T o xicit y M o nit ori n g...................................................................................... 1 1 3
3. 9. 1  
G ui deli nes f or Re p orti n g Seri o us A d verse E ve nts ............................................................................. 1 1 3
3. 9. 2  
G ui deli nes f or Pr ocessi n g I N D S afet y Re p orts................................................................................... 1 1 4
4. 
R E Q UI SI TI O NI N G I N V E S TI G A TI O N A L D R U G.................................................................................... 1 1 4
5.  
M O NI T O RI N G: Q U A LI T Y C O N T R O L..................................................................................................... 1 1 4
5. 1  
O n g oi n g M o nit ori n g of Pr ot oc ol C o m pli a nce..................................................................................... 1 1 4
5. 2  
M o nit ori n g Re p orts............................................................................................................................... 1 1 5
5. 3  
Accr u al M o nit ori n g............................................................................................................................... 1 1 5
6  
A U DI TI N G: Q U A LI T Y A S S U R A N C E...................................................................................................... 1 1 5
6. 1  
A u dit Pl a n: D F/ H C C S p o ns ore d Tri als............................................................................................... 1 1 6
6. 2  
A u dit N otific ati o n.................................................................................................................................. 1 1 6
6. 3  
A u dit Re p orts......................................................................................................................................... 1 1 6
6. 4 
P artici p ati n g I nstit uti o n Perf or m a nce................................................................................................. 1 1 6
6. 4. 1  
C orrecti ve Acti o ns................................................................................................................................. 1 1 6

S h ort title: P h ase II st u d y of El ot uz u m a b pl us R V D i n Ne wl y Di a g n ose d M M
Versi o n D ate:      N o ve m ber 1 0, 2 0 2 0 
C O N FI D E N TI A L
T his d oc u me nt is c o nfi de ntial. D o n ot discl ose or use e xce pt as a ut h orize d.
A b bre vi ati o n
Defi niti o n
C
de grees Celsi us
F
De grees Fare n heit
A D L
Acti vities of dail y li vi n g
A E
a d verse e ve nt
A L T
ala ni ne a mi n otra nsferase
A N C
a bs ol ute ne utr o p hil c o u nt
A P L 
ac ute pr o m yel oc ytic le u ke mia
A S T
as partate a mi n otra nsferase
A T R A
All tra ns-reti n oic aci d
B M
B o ne marr o w
B p m
beats per mi n ute
B S A
b o d y s urface area
B M S C
B o ne marr o w str o mal cells
B U N
Bl o o d urea nitr o ge n
C B C
C o m plete bl o o d c o u nt
C H F
C o n gesti ve heart fail ure
C m
Ce nti meter
C R
C o m plete Res p o nse
C R F
Case re p ort f or m
C R P
C-reacti ve pr otei n
C T
C o m p ute d t o m o gra p h y
C T C A E
( N CI) C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nts
C T E P
Ca ncer T hera p y E val uati o n Pr o gra m
D A R
Dr u g acc o u nta bilit y rec or d
D F/ H C C
Da na- Far ber/ Har var d Ca ncer Ce nter
d L
Deciliter
D L T
D ose Li miti n g T o xicit y
D N A
de o x yri b o n ucleic aci d
D S M C
Data Safet y M o nit ori n g C o m mittee
D V T
Dee p vei n t hr o m b osis
E B M T
E ur o pea n Gr o u p f or Bl o o d & Marr o w Tra ns pla nt
E C G
Electr ocar di o gra p h y
E C H O
Ec h ocar di o gra m

S h ort title: P h ase II st u d y of El ot uz u m a b pl us R V D i n Ne wl y Di a g n ose d M M
Versi o n D ate:      N o ve m ber 1 0, 2 0 2 0 
C O N FI D E N TI A L
T his d oc u me nt is c o nfi de ntial. D o n ot discl ose or use e xce pt as a ut h orize d.
A b bre vi ati o n
Defi niti o n
E C M
E xtracell ular matri x
E C O G
Easter n C o o perati ve O nc ol o g y Gr o u p
E R K
E xtracell ular si g nal-re g ulate d ki nase
F A C T/ G O G- N T X
F u ncti o nal Assess me nt of Ca ncer T hera p y/ G y nec ol o gic O nc ol o g y Gr o u p- Ne ur ot o xicit y
F C B P
Fe males of c hil d beari n g p ote ntial
F D A
F o o d a n d Dr u g A d mi nistrati o n
FI S H
Fl u oresce nce i n sit u H y bri dizati o n
F L C
Free li g ht c hai n
G
Gra m
G C P
G o o d Cli nical Practice
G- C S F
Gra n ul oc yte c ol o n y sti m ulati n g fact or
G G T
Ga m ma- gl uta m yltra nsferase
GI
Gastr oi ntesti nal
HI V
H u ma n i m m u n o deficie nc y vir us
Ht
Hei g ht
I C H
I nter nati o nal C o nfere nce o n Har m o nizati o n
I g
I m m u n o gl o b uli n
I G F- 1
I ns uli n-li ke gr o wt h fact or
I L- 6
I nterle u ki n- 6
I M W G
I nter nati o nal M yel o ma W or ki n g Gr o u p
I N R
I nter nati o nal N or malize d Rati o
I N D
I n vesti gati o nal Ne w Dr u g
I R B
I nstit uti o nal Re vie w B oar d
I S S
I nter nati o nal Sta gi n g S yste m 
I V
I ntra ve n o us
K g
Kil o gra m
L bs
P o u n ds
L
Liters
L D H
Lactate de h y dr o ge nase
L L N
L o wer li mit of n or mal
m 2
s q uare meters
m m 3
C u bic milli meter
Me d D R A
Me dical Dicti o nar y f or Re g ulat or y Acti vities

S h ort title: P h ase II st u d y of El ot uz u m a b pl us R V D i n Ne wl y Di a g n ose d M M
Versi o n D ate:      N o ve m ber 1 0, 2 0 2 0 
C O N FI D E N TI A L
T his d oc u me nt is c o nfi de ntial. D o n ot discl ose or use e xce pt as a ut h orize d.
A b bre vi ati o n
Defi niti o n
M g
Milli gra ms
Ml
Milliliter
M M
M ulti ple m yel o ma
m- pr otei n
M o n ocl o nal pr otei n
M R
Mi ni mal res p o nse
M RI
Ma g netic res o na nce i ma gi n g
Msec
Millisec o n d
M T D
Ma xi m u m t olerate d d ose
M U G A
M ulti- gate d ac q uisiti o n sca n
N C
N o c ha n ge
N CI
Nati o nal Ca ncer I nstit ute
n C R
near c o m plete res p o nse
N F- B
n uclear fact or- B
N g
Na n o gra m
N K cell
Nat ural killer cell
n M
Na n o m ole
N Y H A
Ne w Y or k Heart Ass ociati o n
O H R S
Office of H u ma n Researc h St u dies
p 2 1
p 2 1(ras) far nes yl- pr otei n tra nsferase
p 5 3
t u m or s u p press or pr otei n wit h m olec ular wei g ht of 5 3 k Da
P B M C
Peri p heral bl o o d m o n o n uclear cell
P C
Plas ma cells
P C P
P ne u m oc ystis car nii p ne u m o nia
P D
Pr o gressi ve disease
P E
P ul m o nar y e m b olis m
P F S
Pr o gressi o n-free s ur vi val
P K
P har mac o ki netics
P R
Partial res p o nse
O D Q
Q ualit y Ass ura nce f or Cli nical Trials
Q O W
E ver y ot her wee k

S h ort title: P h ase II st u d y of El ot uz u m a b pl us R V D i n Ne wl y Di a g n ose d M M
Versi o n D ate:      N o ve m ber 1 0, 2 0 2 0 
C O N FI D E N TI A L
T his d oc u me nt is c o nfi de ntial. D o n ot discl ose or use e xce pt as a ut h orize d.
A b bre vi ati o n
Defi niti o n
Q W
E ver y wee k
R N A
Ri b o n ucleic aci d
R R 
Res p o nse rate
S A E
s C R
seri o us a d verse e ve nt
Stri n ge nt C o m plete Res p o nse
S C T
Ste m cell tra ns pla ntati o n
S D
Sta ble disease
S G O T
ser u m gl uta mic o xal oacetic tra nsa mi nase
S G P T
ser u m gl uta mic p yr u vic tra nsa mi nase
SJ S
Ste ve ns-J o h ns o n s y n dr o me
S O C 
S yste m or ga n class
S U S A R
s us pecte d u ne x pecte d seri o us a d verse reacti o n
S W O G
S Q
S o ut h west O nc ol o g y Gr o u p
S u bc uta ne o us
T E N
T o xic e pi der mal necr osis
T F R
T u m or flare reacti o n
TI W
T hree ti mes a wee k
T L S
T u m or l ysis s y n dr o me
T S H
T h yr oi d-sti m ulati n g h or m o ne
T T R
Ti me-t o-res p o nse
U L N
U p per li mit of n or mal
U S P
U nite d States P har mac o peia
V E G F
Vasc ular e n d ot helial gr o wt h fact or
V G P R
Ver y g o o d partial res p o nse
W B C
W hite bl o o d cells
Wt
Wei g ht

S h ort title: P h ase II st u d y of El ot uz u m a b pl us R V D i n  Ne wl y Di a g n ose d M M
                         Versi o n D ate:     N o ve m ber 1 0, 2 0 2 0 
C O N FI D E N TI A L
T his d oc u me nt is c o nfi de ntial. D o n ot discl ose or use e xce pt as a ut h orize d.
9
1 
I N T R O D U C TI O N ( B A C K G R O U N D)
1. 1
M ulti ple M yel o m a ( M M)
1. 1. 1 E pi de mi ol o g y a n d p at h o ge nesis
M M is a B-cell ne o plas m c haracterize d b y t he pr oliferati o n of cl o nal plas ma cells a n d ass ociate d 
wit h a variet y of cli nical 
ma nifestati o ns s uc h as l ytic b o ne lesi o ns, h y percalce mia, re nal 
i m pair me nt, a n d a ne mia.  It acc o u nts f or 1 0- 1 5 % of he mat ol o gic mali g na ncies a n d 2 0 % of deat hs 
relate d t o ca ncers of t he bl o o d a n d b o ne marr o w ( Mc Ke n na, 2 0 0 8).  T he hi g h de gree of 
i m m u n o gl o b uli n (I g) hea v y c hai n ge ne h y per m utati o n prese nt i n M M cells s u g gests t hat t u m or 
cells deri ve fr o m a p ost- ger mi nal ce nter B-cell ( Ba k k us, 1 9 9 2).  
M ore o ver, it is li kel y t hat 
m utati o ns occ urri n g d uri n g I g rece pt or h y per- m utati o n a n d class s witc h are i n v ol ve d i n t he 
pat h o ge nesis of 
M M.  I n dee d a s u bsta ntial perce nta ge of 
M M patie nts ha ve c hr o m os o mal 
a berrati o ns i n v ol vi n g t he I g hea v y c hai n ge ne at l oc us 1 4 q 3 2 ( F o nseca, 2 0 0 3).  Part ner ge nes i n 
tra nsl ocati o ns i n v ol vi n g t he I g hea v y c hai n i ncl u de c ycli n D 1 (c hr o m os o me 1 1 q 1 3), c ycli n D 3 
(c hr o m os o me 6 p 2 1), F G F R 3/ M M S E T (c hr o m os o me 4 p 1 6), a n d C- M A F (c hr o m os o me 1 6 q 2 3).  It 
is belie ve d t hat s uc h m utati o ns lea d t o d ysre g ulate d gr o wt h of t he affecte d cl o ne.  C- M A F, f or 
e xa m ple, a p pears t o a u g me nt M M cell pr oliferati o n a n d bi n di n g t o s urr o u n di n g b o ne marr o w 
str o mal cells ( B M S Cs) ( H urt, 2 0 0 4). I n hi biti o n of F G F R 3, mea n w hile, has bee n s h o w n t o pr o m ote 
plas ma cell differe ntiati o n a n d i n d uce a p o pt osis ( C ha u ha n, 1 9 9 5).  Gai n or l oss of s pecific 
c hr o m os o mal re gi o ns is als o fre q ue ntl y o bser ve d, i ncl u di n g m o n os o m y or partial deleti o n of 
c hr o m os o me 1 3, l oss of t he s h ort ar m of c hr o m os o me 1 7 (site of t he t u m or-s u p press or ge ne T P 5 3), 
a n d gai ns or a m plificati o n of c hr o m os o mal re gi o n 1 q ( Ha na m ura, 2 0 0 6).  
T he pat h o ge nesis of M M is als o dri ve n b y i nteracti o ns bet wee n M M cells a n d t he b o ne marr o w 
micr oe n vir o n me nt, w hic h is c o m p ose d of e xtracell ular matri x pr otei ns s uc h as fi br o necti n, 
c olla ge n, a n d la mi ni n, al o n g wit h cell ular ele me nts s uc h as he mat o p oietic ste m cells, i m m u ne 
cells, b o ne marr o w e n d ot helial cells, a n d b o ne marr o w str o mal cells ( B M S Cs).  A d hesi o n of M M 
cells t o E C M pr otei ns a n d access or y cells lea ds t o i ncrease d e x pressi o n of fact ors s uc h as I L- 6, 
i ns uli n-li ke gr o wt h fact or (I G F- 1), a n d vasc ular e n d ot helial gr o wt h fact or ( V E G F), w hic h i n t ur n 
f urt her sti m ulates gr o wt h a n d s ur vi val of t he mali g na nt cl o ne ( C ha u ha n, 1 9 9 5; P o dar, 2 0 0 1).  
Vari o us i ntracell ular pat h wa ys are i n v ol ve d i n t his res p o nse, i ncl u di n g t he Ras- Raf- M A P K ki nase, 
( M E K)-e xtracell ular si g nal-re g ulate d ki nase ( E R K), p h os p hati d yli n osit ol 3- ki nase ( PI 3 K)- A kt, 
a n d t he Ja n us ki nase 2-si g nal tra ns d ucer a n d acti vat or of tra nscri pti o n 3 ( S T A T 3) pat h wa ys 
( Hi des hi ma, 2 0 0 7).  
1. 1. 2 St a gi n g
Si nce 1 9 7 5, t he D urie- Sal m o n classificati o n s yste m has bee n wi del y use d f or disease dia g n osis 
a n d sta gi n g. Sta ges I, II a n d III are defi ne d b y criteria f or b o ne lesi o n stat us, he m o gl o bi n, ser u m 
calci u m, a n d m o n ocl o nal pr otei n ( M- pr otei n) le vels a n d s u bcate g orize d as A or B o n t he basis of 
re nal f u ncti o n. A clear c orrelati o n bet wee n disease sta ge a n d s ur vi val d urati o n has bee n 
de m o nstrate d ( D urie, 1 9 8 6).  T he I nter nati o nal Sta gi n g S yste m (I S S) was esta blis he d m ore 
rece ntl y ( Grei p p, 2 0 0 5), a n d is base d o n t he le vels of ser u m β 2 M  a n d al b u mi n a m o n g M M patie nts 
at dia g n osis. T he I S S has bee n vali date d as a pre dict or of o verall s ur vi val f or M M patie nts.  

C O N FI D E N TI A L
T his d oc u me nt is c o nfi de ntial. D o n ot discl ose or use e xce pt as a ut h orize d.
1 0
S h ort title: P h ase II st u d y of El ot uz u m a b pl us R V D i n Ne wl y Di a g n ose d M M
Versi o n D ate: N o ve m ber 1 0, 2 0 2 0 
1. 1. 3 Tre at me nt
Patie nts 
wit h earl y sta ge, as y m pt o matic 
M M are t y picall y o bser ve d 
wit h o ut s yste mic 
c he m ot hera p y ( Ale xa nia n, 1 9 8 0; K yle, 1 9 8 0).  S uc h patie nts are caref ull y m o nit ore d wit h 
a p pr o priate cli nical assess me nt, i ncl u di n g la b orat or y st u dies, e ver y t w o t o t hree 
m o nt hs.  
Treat me nt is i n dicate d w he n si g nifica nt disease-relate d s y m pt o ms or or ga n d ysf u ncti o n de vel o p.  
Hist oricall y, patie nts i neli gi ble f or ste m cell tra ns pla ntati o n ( S C T) ha ve bee n treate d wit h t he 
c o m bi nati o n of mel p hala n a n d pre d nis o ne ( M P) ( Ale xa nia n, 1 9 6 9), w hile t h ose eli gi ble f or S C T 
recei ve d t he t hree- dr u g c o m bi nati o n of vi ncristi ne, d o x or u bici n, a n d de xa met has o ne ( Sa ms o n, 
1 9 8 9).  M P pr o d uce d a partial res p o nse ( P R) i n a p pr o xi matel y 5 0 % of patie nts, a n d a c o m plete 
res p o nse ( C R) i n 3- 5 %.  Eff orts t o a u g me nt c he m ot hera p y se nsiti vit y a n d i m pr o ve patie nt 
o utc o mes le d t o t he e val uati o n of vari o us 
m ulti dr u g c o m bi nati o ns, i ncl u di n g vi ncristi ne, 
car m usti ne, mel p hala n, c ycl o p h os p ha mi de, a n d pre d nis o ne ( V B M C P) ( Lee, 1 9 7 4); car m usti ne, 
mel p hala n, c ycl o p h os p ha mi de, a n d pre d nis o ne ( B M C P) ( C o o per, 1 9 8 6); a n d vi ncristi ne, 
d o x or u bici n, a n d de xa met has o ne ( V A D) ( Sa ms o n, 1 9 8 9).  H o we ver, w hile t hese a ge nts pr o d uce d 
hi g her rates of res p o nse t ha n M P, t he y di d n ot le n gt he n re missi o n or pr ol o n g o verall s ur vi val.  
O ver t he past deca de, t he ma na ge me nt of M M has c ha n ge d dra maticall y wit h t he i ntr o d ucti o n of 
ne w a n d m ore acti ve t hera pies.  T hese i ncl u de t he i m m u n o m o d ulat or y a ge nts, t hali d o mi de a n d 
le nali d o mi de, as well as t he pr oteas o me i n hi bit or b ortez o mi b.  T hali d o mi de, t he first of t hese dr u gs 
t o be de vel o pe d cli nicall y, e xerts its a nti- M M acti vit y t hr o u g h vari o us mec ha nis ms, i ncl u di n g 
e nc ha nce me nt of T-cell a n d N K-cell me diate d i m m u n ol o gical res p o nse, alterati o n of t he b o ne 
marr o w 
micr oe n vir o n me nt, i n d ucti o n of cas pase- 8 
me diate d a p o pt osis, a n d i n hi biti o n of 
a n gi o ge nesis ( D’ A mat o, 1 9 9 4).  I nitial cli nical e val uati o n of t hali d o mi de de m o nstrate d t he a ge nt’s 
si g nifica nt acti vit y e ve n i n hea vil y pretreate d patie nts wit h rela pse d a n d refract or y disease 
( Si n g hal, 1 9 9 9).  I n t he setti n g of ne wl y dia g n ose d M M, t hali d o mi de pl us M P has pr o ve n t o be 
s u peri or t o 
M P al o ne i n ter ms of b ot h res p o nse a n d me dia n o verall s ur vi val ( Fac o n, 2 0 0 7; 
Pal u m b o, 2 0 0 6).  
Le nali d o mi de, a n a nal o g ue of t hali d o mi de, has m ore p ote nt a nti- M M acti vit y t ha n its pare nt 
c o m p o u n d a n d a m ore fa v ora ble t o xicit y pr ofile.  F oll o wi n g a series of earl y p hase cli nical trials, 
t he cli nical acti vit y of le nali d o mi de i n rela pse d M M was c o nfir me d i n t w o lar ge p hase III trials 
c o m pari n g le nali d o mi de pl us de xa met has o ne t o de xa met has o ne al o ne ( We ber, 2 0 0 7; Di m o p o ul os, 
2 0 0 7).  Se veral le nali d o mi de- base d c o m bi nati o ns, i ncl u di n g le nali d o mi de pl us de xa met has o ne 
a n d le nali d o mi de pl us M P ha ve pr o ve n t o be effecti ve i n t he treat me nt of patie nts wit h ne wl y 
dia g n ose d M M ( Raj k u mar, 2 0 0 9; Pal u m b o, 2 0 0 9).  
B ortez o mi b is a pr oteas o me i n hi bit or t hat i n hi bits N F K B, i n d uces cas pase- 8/ 9 me diate d a p o pt osis, 
a n d disr u pts I L- 6 i n d uce d i ntracell ular si g nali n g pat h wa ys ( Hi des hi ma, 2 0 0 3).  I n a la n d mar k 
p hase III trial, b ortez o mi b was s u peri or t o hi g h d ose de xa met has o ne i n rela pse d M M ( Ric har ds o n, 
2 0 0 5).  T he a ge nt has als o bee n ass ociate d wit h pr o misi n g res ults i n patie nts wit h ne wl y dia g n ose d 
disease.  I n t his setti n g t he c o m bi nati o n of b ortez o mi b pl us M P was s u peri or t o M P al o ne wit h 
res pect t o res p o nse, re missi o n d urati o n, a n d o verall s ur vi val ( Sa n Mi g uel, 2 0 0 8).  M ore rece ntl y, 
s u bc uta ne o us (s. q.) b ortez o mi b was c o m pare d t o i ntra ve n o us (i. v.) b ortez o mi b i n a ra n d o mize d, 
p hase III n o n-i nferi orit y st u d y i n v ol vi n g patie nts wit h rela pse d disease a n d f o u n d t o be e q ui vale nt 

C O N FI D E N TI A L
T his d oc u me nt is c o nfi de ntial. D o n ot discl ose or use e xce pt as a ut h orize d.
1 1
S h ort title: P h ase II st u d y of El ot uz u m a b pl us R V D i n Ne wl y Di a g n ose d M M
Versi o n D ate: N o ve m ber 1 0, 2 0 2 0 
i n ter ms pri mar y efficac y e n d p oi nts wit h si g nifica ntl y less t hera p y-i n d uce d peri p heral ne ur o pat h y 
( M orea u, 2 0 1 1).  
Precli nical e vi de nce of s y ner g y bet wee n le nali d o mi de a n d b ortez o mi b pr o vi de d rati o nale f or 
c o m bi nati o n t hera p y wit h le nali d o mi de a n d b ortez o mi b.  A p hase I m ultice nter st u d y esta blis he d 
t he M T D of t he re gi me n at le nali d o mi de 1 5 m g/ d Da ys 1- 1 4 a n d i. v. b ortez o mi b 1 m g/ m2 Da ys 1, 
4, 8, a n d 1 1 of a 2 1 da y c ycle ( Ric har ds o n, 2 0 0 9).  De xa met has o ne at eit her 2 0 or 4 0 m g o n t he 
da y of a n d da y f oll o wi n g b ortez o mi b was a d de d f or pr o gressi ve disease after t w o c ycles of 
treat me nt.  St u d y partici pa nts ha d recei ve d a me dia n of 5 pri or li nes of t hera p y, a n d 6 1 % ha d 
pre vi o usl y u n der g o ne eit her a ut ol o g o us or all o ge neic S C T.  D L Ts i ncl u de d gra de 3 h y p o natre mia 
a n d her pes z oster reacti vati o n, as well as gra de 4 ne utr o pe nia.  T he m ost c o m m o n gra de 3/ 4 
t o xicities were ne utr o pe nia, t hr o m b oc yt o pe nia, a ne mia, a n d le uc o pe nia.  T he c o m bi nati o n 
de m o nstrate d si g nifica nt acti vit y, wit h 6 1 % of patie nts ac hie vi n g a mi ni mal res p o nse ( M R) or 
better, a n d 3 1 % ac hie vi n g at least a P R.  
1. 1. 4 El ot uz u m a b: Mec h a nis m of Acti o n 
El ot uz u ma b is a h u ma nize d I g G 1 m A b tar gete d a gai nst Si g nalli n g L y m p h oc yte Acti vati o n 
M olec ule ( S L A M F 7, als o calle d C S 1), a gl yc o pr otei n e x presse d o n m yel o ma a n d Nat ural Killer 
cells b ut n ot o n n or mal tiss ues.  El ot uz u ma b bi n di n g t o S L A M F 7 directl y acti vates N K cells, b ut 
n ot m yel o ma cells. El ot uz u ma b b o u n d t o m yel o ma cells via S L A M F 7 f urt her acti vates N K cells 
via a C D 1 6 me diate d pat h wa y t here b y e na bli n g selecti ve killi n g of m yel o ma cells wit h mi ni mal 
effects o n n or mal tiss ue. S L A M F 7 e x pressi o n is restricte d t o mali g na nt m yel o ma a n d n or mal 
plas ma cells a n d s u bsets of n or mal le u k oc ytes i n h u ma ns ( N K, N K-li ke T-cells [ N K T], a s u bset 
of C D 8 p ositi ve T-cells a n d tiss ue plas ma cells).
T hr o u g h b ot h direct acti vati o n a n d e n ga ge me nt of Nat ural Killer cells, El ot uz u ma b selecti vel y 
tar gets a n d kills S L A M F 7 e x pressi n g m yel o ma cells. W hile a nal ysis of m R N A i n dicates t hat C S 1 
has a si milar e x pressi o n patter n i n n o n h u ma n pri mates T-cells a n d tiss ue plas ma cells).
1. 1. 5 C o m bi n ati o n of el ot uz u m a b wit h le n ali d o mi de, b ortez o mi b a n d de x a met h as o ne
Le nali d o mi de is a n oral i m m u n o m o d ulat or y a ge nt, a deri vati ve of t hali d o mi de wit h a disti nct si de 
effect pr ofile. C urre ntl y, it is a p pr o ve d i n c o m bi nati o n wit h de xa met has o ne f or t he treat me nt of 
rela pse d M M. T he a nti- m yel o ma acti vit y of le nali d o mi de is me diate d b y m ulti ple mec ha nis ms of 
acti o n, w hic h tar get b ot h t he mali g na nt cell a n d its micr oe n vir o n me nt. T his dr u g has als o bee n 
s h o w n t o i n d uce i m m u ne res p o nses, e n ha nce acti vit y of i m m u ne cells, a n d i n hi bit i nfla m mati o n. 
F or i nsta nce, le nali d o mi de ma y e n ha nce t he acti vati o n of T cells a n d N K cells, i n d uce pr o d ucti o n 
of i nterle u ki n- 2, a n d i n hi bit pr o-i nfla m mat or y c yt o ki nes, s uc h as t u m or necr osis fact or-al p ha a n d 
i nterle u ki n 1- beta. Si nce le nali d o mi de ma y e n ha nce t he acti vit y of N K cells, w hic h are ce ntral t o 
t he mai n bi ol o gical acti vit y of el ot uz u ma b, t he t w o dr u gs u n der we nt precli nical testi n g i n 
c o m bi nati o n t o deter mi ne t he e xte nt of p ote ntial s y ner g y. El ot uz u ma b- me diate d A D C C a gai nst 

C O N FI D E N TI A L
T his d oc u me nt is c o nfi de ntial. D o n ot discl ose or use e xce pt as a ut h orize d.
1 2
S h ort title: P h ase II st u d y of El ot uz u m a b pl us R V D i n Ne wl y Di a g n ose d M M
Versi o n D ate: N o ve m ber 1 0, 2 0 2 0 
pri mar y m yel o ma cells was si g nifica ntl y e n ha nce d w he n t he P B M C effect or cells ( w hic h i ncl u de 
N K cells) fr o m t he sa me s u bject were pretreate d wit h le nali d o mi de (I n vesti gat or Br oc h ure – 
El ot uz u ma b).
De xa met has o ne, a gl uc oc ortic oi d t hat is use d e xte nsi vel y f or t he treat me nt of M M i n c o m bi nati o n 
wit h le nali d o mi de, as well as wit h m ost ot her a nti- m yel o ma t hera pies, has bee n s h o w n t o directl y 
i n d uce a p o pt osis of 
m yel o ma cells b y acti vati o n of cas pases. T he effect of c o m bi ni n g 
de xa met has o ne wit h el ot uz u ma b was als o teste d usi n g a n i n vi v o h u ma n m yel o ma xe n o graft 
m o del. Res ults i n dicate d a n a d diti ve a nti-t u m or effect i n c o m bi nati o n wit h el ot uz u ma b.
B ortez o mi b is a s mall- m olec ule pr oteas o me i n hi bit or a p pr o ve d f or t he treat me nt of M M as well 
as f or ma ntle-cell n o n- H o d g ki n l y m p h o ma after at least o ne pri or treat me nt. B ortez o mi b a p pears 
t o ha ve a nti-t u m or acti vit y a gai nst a wi de s pectr u m of h u ma n ne o plas ms a n d its mec ha nis m of 
acti o n ma y var y de pe n di n g o n t u m or t y pe. I n M M i n hi biti o n of n uclear fact or B  ( N F B)  a n d 
atte n uati o n of i nterle u ki n- 6- me diate d gr o wt h a p pear t o be a m o n g t he pri mar y mec ha nis ms of 
acti o n, p ossi bl y f urt her a u g me nte d b y a n a nti a n gi o ge nic effect. I n a d diti o n, a d o w n- m o d ulati o n 
of cell-s urface e x pressi o n of 
M H C Class 1 —a n i n hi bit or of N K f u ncti o n — was rece ntl y 
de m o nstrate d f oll o wi n g b ortez o mi b treat me nt of m yel o ma cells. T his fi n di n g le n ds f urt her s u p p ort 
t o t he h y p ot hesis t hat treat me nt of m yel o ma cells wit h b ortez o mi b ma y re n der t he m m ore 
s usce pti ble t o el ot uz u ma b- me diate d A D C C.
I n vitr o testi n g of t he b ortez o mi b/el ot uz u ma b c o m bi nati o n usi n g A D C C assa ys s h o we d e n ha nce d 
el ot uz u ma b- me diate d A D C C a gai nst O P M 2 cells usi n g N K effect or cells fr o m healt h y d o n ors. I n 
se parate e x peri me nts, patie nt- deri ve d N K cells i n d uce d a p pr o xi matel y 2 0 % s pecific l ysis of 
a ut ol o g o us m yel o ma cells i n t he prese nce of el ot uz u ma b ( 1 0 μ g/ m L)  al o ne at a rati o of 3 0 N K 
cells t o 1 M M cell wit h a d ose- de pe n de nt i ncrease i n s pecific l ysis wit h t he a d diti o n of b ortez o mi b.
I n vi v o e x peri me nts wit h O P M 2 t u m or- beari n g mice de m o nstrate d pr of o u n d re d ucti o n i n t he rate 
of t u m or gr o wt h fr o m t he a d diti o n of b ortez o mi b t o el ot uz u ma b a n d acti vit y t hat was si g nifica ntl y 
s u peri or t o b ortez o mi b or el ot uz u ma b al o ne.
1. 2 
El ot uz u m a b De vel o p me nt B ac k gr o u n d
N o n-cli nical as well as cli nical st u dies, as re vie we d i n s u bse q ue nt secti o ns of t his pr ot oc ol, ha ve 
pr o vi de d e vi de nce f or s y ner gistic a ntit u m or acti vit y bet wee n el ot uz u ma b, b ortez o mi b, a n d 
le nali d o mi de. F urt her m ore, el ot uz u ma b- base d c o m bi nati o ns ha ve bee n s h o w n t o be safe a n d well 
t olerate d. I n t he c urre nt pr ot oc ol, t he c o m bi nati o n of b ortez o mi b, le nali d o mi de, a n d 
de xa met has o ne (als o referre d t o as R V D) is use d at d oses a d o pte d f or P hase 3 de vel o p me nt, w hic h 
were f o u n d t o be hi g hl y effecti ve a n d safe i n t he P hase 1/ 2 setti n g ( Ric har ds o n 2 0 1 0).  T his R V D 
tri plet is a d mi nistere d i n c o m bi nati o n wit h el ot uz u ma b ( E- R V D). I n vie w of t he de m o nstrate d 
efficac y of t he R V D re gi me n —a c urre nt sta n dar d of care wit h a re p orte d res p o nse rate of 7 4 % at 
1 2 wee ks ( Ric har ds o n 2 0 1 0) —a n d e vi de nce f or s y ner g y bet wee n its c o m p o ne nts a n d el ot uz u ma b, 
a ra pi d res p o nse t o t his re gi me n is e x pecte d i n at least 9 0 % of s u bjects.
I n a d diti o n t o assessi n g t he efficac y of E- R V D, t his st u d y will e x pl ore t he a bilit y of s u bjects treate d 
wit h f o ur c ycles of E- R V D as i n d ucti o n t hera p y t o u n der g o s uccessf ul ste m cell m o bilizati o n. T his 

C O N FI D E N TI A L
T his d oc u me nt is c o nfi de ntial. D o n ot discl ose or use e xce pt as a ut h orize d.
1 3
S h ort title: P h ase II st u d y of El ot uz u m a b pl us R V D i n Ne wl y Di a g n ose d M M
Versi o n D ate: N o ve m ber 1 0, 2 0 2 0 
sec o n dar y o bjecti ve re mai ns criticall y i m p orta nt c o nsi deri n g t he i m p orta nt r ole of a ut ol o g o us ste m 
cell tra ns pla nt ( A S C T) i n t he ma na ge me nt of s u bjects wit h M M w h o are eli gi ble f or t he pr oce d ure.
1. 2. 1 N o n-cli nic al T o xic ol o g y
El ot uz u ma b o nl y rec o g nizes h u ma n S L A M F 7 1 pr otei n a n d d oes n ot a p pear t o bi n d S L A M F 7 fr o m 
ot her s pecies, i ncl u di n g c hi m pa nzee, c y n o m ol g us m o n ke y, d o g, mi ni- pi g, m o use, ra b bit, rat, a n d 
r hes us m o n ke y. D ue t o t he lac k of s pecies-s pecific cr oss-reacti vit y, t here are n o rele va nt a ni mal 
s pecies i n w hic h t o c o n d uct t o xic ol o gical st u dies. T heref ore, t he n o ncli nical st u dies c o nsiste d 
pri maril y of i n vitr o safet y assess me nts a n d i n vi v o bi ol o gical acti vit y e val uati o n t o a d dress t he 
selecti vit y of el ot uz u ma b a n d p ote ntial t o xicities.
El ot uz u ma b ( 1 0 0 a n d 2 0 0 mc g/ m L) i n vitr o ha d n o effect o n l y m p h oc ytes, C D 3 +, C D 4 +, C D 8 +, 
a n d B cell c o u nts i n bl o o d sa m ples fr o m healt h y d o n ors. N K cell c o u nts were decrease d o n a vera ge 
b y 2 0 % at b ot h d oses of el ot uz u ma b. T he o bser ve d decli ne was varia ble bet wee n d o n ors a n d 
ra n ge d bet wee n 0 % a n d 4 5 %.
El ot uz u ma b at c o nce ntrati o ns u p t o 5 0 0 mc g/ m L di d n ot a d versel y affect t he a bilit y of b o ne 
marr o w- deri ve d he mat o p oietic ste m cells t o differe ntiate d o w n t he er yt hr oi d a n d m yel oi d 
pat h wa ys.
1. 2. 2 Cli nic al E x perie nce wit h El ot uz u m a b i n M ulti ple M yel o m a
1. 2. 2. 1
H u L u c 6 3- 1 7 0 1, a P h as e 1 El ot u z u m a b M o n ot h e r a p y St u d y
I n t his P hase 1 st u d y, escalati n g d oses ( 0. 5 - 2 0 m g/ k g) of el ot uz u ma b m o n ot hera p y were 
a d mi nistere d I V e ver y 2 wee ks f or a t otal of 4 d oses i n s u bjects wit h a d va nce d M M ( Z o n der 2 0 1 2). 
S u bjects wit h sta ble disease or better ha d t he o pti o n t o recei ve a d diti o nal d oses of el ot uz u ma b. As 
of 0 3-J ul- 2 0 0 9, t he st u d y is c o m plete. A t otal of 3 5 s u bjects were e nr olle d: 3 i n t he 0. 5 m g/ k g 
c o h ort, 4 i n t he 1. 0 m g/ k g c o h ort, 6 i n t he 2. 5 m g/ k g c o h ort, 4 i n t he 5. 0 m g/ k g c o h ort, 4 i n t he 1 0 
m g/ k g c o h ort, a n d 1 4 i n t he 2 0 m g/ k g c o h ort. O ne ( 1) s u bject i n t he 1 0 m g/ k g c o h ort di d n ot 
recei ve st u d y dr u g. T he pri mar y o bjecti ve of t his st u d y was t o deter mi ne t he M T D.
I n t he 2. 5 m g/ k g c o h ort, 1 o ut of t he first 3 s u bjects d ose d e x perie nce d a d ose-li miti n g t o xicit y of 
( D L T) Gra de 3 i ncrease i n bl o o d creati ni ne le vels lea di n g t o Gra de 4 ac ute re nal fail ure a n d t hat 
c o h ort was t he n e x pa n de d t o i ncl u de a n ot her 3 s u bjects. N o f urt her D L Ts occ urre d i n t he 2. 5 m g/ k g 
c o h ort a n d d osi n g c o nti n ue d u p t o t he 2 0 m g/ k g c o h ort. I n t he 2 0- m g/ k g c o h ort, 1 o ut of 1 4 s u bjects 
e x perie nce d a D L T of Gra de 3 h y perse nsiti vit y. T heref ore, t he M T D was n ot reac he d i n t his st u d y. 
A t otal of 3 1 S A Es were re p orte d i n 1 5 s u bjects. Si x ( 6) of t he S A Es were assesse d as relate d t o 
el ot uz u ma b w hic h i ncl u de d Gra de 4 ac ute re nal fail ure, Gra de 2 c hills, Gra de 2 p yre xia, Gra de 3 
h y perse nsiti vit y, Gra de 2 bra d ycar dia, a n d Gra de 2 c hest disc o mf ort. T he m ost c o m m o n treat me nt-
e mer ge nt A Es ( T E A E) o verall d uri n g t he st u d y were c hills ( 1 3 [ 3 8. 2 %] s u bjects), fati g ue ( 1 3 
[ 3 8. 2 %] s u bjects), p yre xia ( 1 3 [ 3 8. 2 %] s u bjects), c o u g h ( 1 0 [ 2 9. 4 %] s u bjects), hea dac he ( 1 0 
[ 2 9. 4 %] s u bjects), a n d a ne mia ( 9 [ 2 6. 5 %] s u bjects). T he m ost c o m m o n treat me nt-relate d A Es 
were c hills ( 1 1 [ 3 2. 4 % s u bjects), p yre xia ( 6 [ 1 7. 6 %] s u bjects), a n d fl us hi n g ( 4 [ 1 1. 8 % s u bjects). 
T here was n o a p pare nt d ose res p o nse relati o ns hi p wit h res pect t o t he i nci de nce of A Es o verall or 
treat me nt relate d T E A Es. M ost T E A Es a n d treat me nt-relate d T E A Es were Gra de 1 or Gra de 2.

C O N FI D E N TI A L
T his d oc u me nt is c o nfi de ntial. D o n ot discl ose or use e xce pt as a ut h orize d.
1 4
S h ort title: P h ase II st u d y of El ot uz u m a b pl us R V D i n Ne wl y Di a g n ose d M M
Versi o n D ate: N o ve m ber 1 0, 2 0 2 0 
A sec o n dar y o bjecti ve of t his st u d y was assess me nt f or preli mi nar y acti vit y. Ni ne ( 9) s u bjects ha d 
a best res p o nse of sta ble disease. Alt h o u g h n o s u bject ha d a c o nfir me d res p o nse, t his st u d y was 1) 
c o n d ucte d i n hea vil y pre-treate d s u bjects 
wit h li kel y c o m pr o mise d i m m u ne s yste ms (ie, 
c o m pr o mise d N K cell f u ncti o n), 2) di d n ot i ncl u de b ortez o mi b or i m m u ne acti vati n g m yel o ma 
t hera pies s uc h as le nali d o mi de; a n d 3) half of t he s u bjects were treate d at d oses l o wer t ha n t he 
P hase 3 d ose of 1 0 m g/ k g of el ot uz u ma b.
1. 2. 2. 2  
H u L u c 6 3- 1 7 0 2, a P h as e 1 El ot u z u m a b + B o rt e z o mi b St u d y
T his is a P hase 1 st u d y of el ot uz u ma b i n c o m bi nati o n wit h b ortez o mi b ( pl us de xa met has o ne if 
a p plica ble) i n s u bjects wit h 
M M w h o ha ve ha d 1 t o 3 pri or t hera pies (Ja k u b o wia k 2 0 1 2). 
Escalati n g d oses ( 2. 5 - 2 0 m g/ k g) of el ot uz u ma b ( d ose d Da ys 1 a n d 1 1) are a d mi nistere d i n 
c o m bi nati o n wit h 1. 3 m g/ m 2 b ortez o mi b ( d ose d Da ys 1, 4, 8, a n d 1 1) i n a 2 1- da y c ycle. S u bjects 
wit h disease pr o gressi o n at t he e n d of C ycle 2 or 3 als o recei ve d a n oral d ose of 2 0 m g 
de xa met has o ne o n Da ys 1, 2, 4, 5, 8, 9, 1 1, a n d 1 2 of eac h c ycle t hereafter.
Data are preli mi nar y as of 2 5- Mar- 2 0 1 1, 2 8 s u bjects wit h rela pse d a n d rela pse d a n d refract or y 
M M ha ve bee n treate d; 3 eac h at 2. 5, 5, a n d 1 0 m g/ k g a n d 1 9 at 2 0 m g/ k g of el ot uz u ma b 
res pecti vel y. T we nt y-ei g ht ( 2 8) s u bjects i n t he i nte nt-t o-treat (I T T) p o p ulati o n recei ve d at least 1 
d ose of el ot uz u ma b a n d all 2 8 s u bjects ( 1 0 0 %) e x perie nce d at least 1 A E. N o D L T was o bser ve d 
i n t he st u d y a n d M T D was n ot esta blis he d u p t o t he pla n ne d hi g hest d ose of 2 0 m g/ k g. T here were 
2 3 ( 8 2. 1 %) s u bjects wit h a n el ot uz u ma b relate d A E. T he m ost c o m m o n A Es (i n 4 5 % or hi g her, 
re gar dless of ca usalit y) i ncl u de Gra de 1 t o 3 fati g ue, diarr hea, a ne mia, t hr o m b oc yt o pe nia, na usea, 
h y per gl yce mia, l y m p h o pe nia, le u k o pe nia, ne utr o pe nia, c o nsti pati o n, a n d peri p heral ne ur o pat h y.
Gra de 3 or hi g her A Es occ urre d i n 2 2 ( 7 8. 6 %) s u bjects of w h o m 7 ( 2 5 %) s u bjects e x perie nce d 
Gra de 3 or hi g her A Es assesse d as relate d t o el ot uz u ma b (l y m p h o pe nia, t hr o m b oc yt o pe nia, 
gastr oe nteritis, c hest pai n, fati g ue, a n d h y perse nsiti vit y). S A Es occ urre d i n 1 0 ( 3 5. 7 %) s u bjects.
A d diti o nall y, 6 ( 2 1. 4 %) s u bjects, 2 i n t he 5. 0 m g/ k g a n d 4 i n t he 2 0. 0 m g/ k g c o h orts, wit h dre w 
fr o m treat me nt d ue t o a n A E ( ne ur o pat h y peri p heral [ 2 s u bjects], ac ute m y ocar dial i nfarcti o n, 
gastr oe nteritis, se psis a n d pai n i n e xtre mit y [ 1 s u bject eac h]). N o deat hs ha ve bee n re p orte d d ue t o 
A Es. O verall t here d oes n ot a p pear t o be a d ose relati o ns hi p wit h t he i nci de nce of A Es.
As of 2 5- Mar- 2 0 1 1, t he best cli nical res p o nse ( ≥ mi ni mal [ mi n or] res p o nse [ M R]) a n d t he best 
res p o nse rate ( ≥ partial res p o nse ( P R)) b y t he c o m bi ne d E ur o pea n Gr o u p f or Bl o o d a n d Marr o w 
Tra ns pla ntati o n a n d u nif or m criteria ( Bla de 1 9 9 8) i n 2 7 res p o nse e val ua ble s u bjects c o m pare 
fa v ora bl y t o t he hist orical, P hase 3 cli nical trial of b ortez o mi b m o n ot hera p y ( A P E X) i n a si milar 
p o p ulati o n ( Ric har ds o n 2 0 0 5).  T he cli nical res p o nse rate was 6 3 % i n St u d y 1 7 0 2 c o m pare d t o 
4 6 % i n A P E X a n d t he o bjecti ve res p o nse rate was 4 8 % i n St u d y 1 7 0 2 c o m pare d t o 3 8 % i n A P E X. 
Fi nall y, t he me dia n ti me t o pr o gressi o n ( T T P) was 9. 5 m o nt hs c o m pare d t o 6. 2 m o nt hs i n A P E X.
1. 2. 2. 3
H u L u c 6 3- 1 7 0 3, a P h as e 1/ 2 L e n ali d o mi d e/ d e x a m et h as o n e + El ot u z u m a b ( L d E) 
St u d y
T his P hase 1 b/ 2, m ultice nter, o pe n-la bel, d ose-escalati o n st u d y is e val uati n g t he c o m bi nati o n of 
el ot uz u ma b wit h le nali d o mi de a n d de xa met has o ne i n s u bjects wit h rela pse d M M. El ot uz u ma b was 
a d mi nistere d b y I V i nf usi o n at escalati n g d ose le vels i n a 3 pl us 3 desi g n, ra n gi n g fr o m 5 t o 2 0 

C O N FI D E N TI A L
T his d oc u me nt is c o nfi de ntial. D o n ot discl ose or use e xce pt as a ut h orize d.
1 5
S h ort title: P h ase II st u d y of El ot uz u m a b pl us R V D i n Ne wl y Di a g n ose d M M
Versi o n D ate: N o ve m ber 1 0, 2 0 2 0 
m g/ k g i n c o m bi nati o n wit h orall y a d mi nistere d d oses of 2 5 m g le nali d o mi de pl us 4 0 m g 
de xa met has o ne ( L o nial 2 0 1 2) .
T he pri mar y o bjecti ve of t he P hase 1 p orti o n of t he st u d y was t o i de ntif y t he M T D of el ot uz u ma b 
gi ve n i n c o m bi nati o n wit h le nali d o mi de a n d de xa met has o ne i n s u bjects wit h M M w h o ha ve at 
least 1 pri or rela pse. As n o M T D was esta blis he d, t he P hase 1 c o h ort defi ni n g t he hi g hest d ose 
st u die d ( 2 0 m g/ k g) i ncl u de d 7 s u bjects, t o w hic h a n a d diti o nal 1 5 s u bjects were a d de d as part of 
t he e x pa nsi o n p hase.
T he P hase 2 p orti o n of t his st u d y is o n g oi n g, a n d has ra n d o mize d s u bjects wit h meas ura ble disease 
w h o ha ve ha d 1 t o 3 pri or rela pses a n d 1 t o 3 pri or t hera pies t o 1 0 vers us 2 0 m g/ k g el ot uz u ma b i n 
c o m bi nati o n wit h le nali d o mi de a n d l o w- d ose de xa met has o ne. T he pri mar y o bjecti ve of t his p hase 
is t o c o m pare efficac y a n d safet y bet wee n 1 0 a n d 2 0 m g/ k g el ot uz u ma b a n d deter mi ne a d ose f or 
t he P hase 3 st u dies.
S u bjects recei ve el ot uz u ma b, le nali d o mi de, a n d de xa met has o ne i n 2 8- da y c ycles u nless 
disc o nti n ue d earlier d ue t o disease pr o gressi o n. S u bjects recei ve el ot uz u ma b o n Da ys 1, 8, 1 5, a n d 
2 2 f or t he first 2 treat me nt c ycles a n d o n Da ys 1 a n d 1 5 f or s u bse q ue nt c ycles. Le nali d o mi de is 
gi ve n orall y o nce dail y o n Da ys 1 t hr o u g h 2 1 f oll o we d b y a 7- da y rest peri o d f or eac h c ycle. 
De xa met has o ne is gi ve n o n Da ys 1, 8, 1 5, a n d 2 2 of eac h c ycle. S u bjects are e val uate d at 3 0 a n d 
6 0 da ys after t he last d ose of st u d y dr u g.
I n P hase 1 of t he st u d y, as of 0 8-J ul- 2 0 1 1, data are a vaila ble f or 2 9 s u bjects. D uri n g P hase 1, 2 8 
of t he 2 9 s u bjects were d ose d: 3 i n t he 5- m g/ k g c o h ort, 3 i n t he 1 0- m g/ k g c o h ort, a n d 2 2 i n t he 2 0-
m g/ k g c o h ort. O ne a d diti o nal s u bject i n t he 5- m g/ k g c o h ort di d n ot recei ve treat me nt. T he st u d y 
p o p ulati o n c o nsists of 1 5 w o me n a n d 1 4 me n, a ge d 4 1 t o 8 3 years. I n P hase 2, as of 1 5- A u g- 2 0 1 1, 
data are a vaila ble f or 7 3 s u bjects. All 7 3 s u bjects ha ve bee n d ose d: 3 6 i n t he 1 0- m g/ k g c o h ort a n d 
3 7 i n t he 2 0- m g/ k g c o h ort. T he st u d y p o p ulati o n c o nsists of 3 0 w o me n a n d 4 3 me n, a ge d 3 9 t o 8 2 
years.
N o D L Ts ha ve bee n o bser ve d b y a n y s u bject treate d wit h el ot uz u ma b. T here was o ne deat h i n 
P hase 1 of t he st u d y, d ue t o a n a d verse e ve nt i n t he 1 0 m g/ k g c o h ort. T here ha ve bee n n o deat hs 
re p orte d i n P hase 2 of t he st u d y as of data c ut off.
Of t he 2 9 s u bjects e nr olle d i n P hase 1 of t he trial as of 0 8-J ul- 2 0 1 1, 2 8 recei ve d st u d y dr u g. All 
2 8 treate d s u bjects ( 1 0 0 %) re p orte d at least 1 A E, a n d 2 3 ( 8 2. 1 %) ha d A Es wit h a t o xicit y of Gra de 
3 or hi g her.
T E A Es relate d t o el ot uz u ma b t hat occ urre d i n at least 2 s u bjects are prese nte d i n decreasi n g 
fre q ue nc y i n Ta ble 1. 2. 2. 3 A. T he m ost c o m m o n el ot uz u ma b-relate d T E A Es (as deter mi ne d b y t he 
i n vesti gat or) were a ne mia ( 3 5. 7 %), fati g ue ( 2 8. 6 %), na usea ( 2 1. 4 %), a n d ne utr o pe nia ( 2 1. 4 %). 
T he 
m ost c o m m o n Gra de ≥ 3 el ot uz u ma b-relate d T E A Es were ne utr o pe nia ( 1 4. 3 %) a n d 
t hr o m b oc yt o pe nia ( 1 0. 7 %).
T he i nteri m safet y a nal ysis re veale d a ke y safet y si g nal of el ot uz u ma b-ass ociate d i nf usi o n 
reacti o ns. T hese A Es i ncl u de d m ostl y Gra de 1 a n d 2 na usea, d ys p nea, c hills, a n d hea dac he. T w o 
( 2) s u bjects i n t he 2 0 m g/ k g c o h ort disc o nti n ue d d ue t o i nf usi o n reacti o ns, o ne Gra de 4 S A E of 
a na p h yla xis (relate d t o el ot uz u ma b) a n d 
o ne 
Gra de 
3 
S A E 
of stri d or (relate d t o 

C O N FI D E N TI A L
T his d oc u me nt is c o nfi de ntial. D o n ot discl ose or use e xce pt as a ut h orize d.
1 6
S h ort title: P h ase II st u d y of El ot uz u m a b pl us R V D i n Ne wl y Di a g n ose d M M
Versi o n D ate: N o ve m ber 1 0, 2 0 2 0 
el ot uz u ma b/ de xa met has o ne). S u bse q ue nt t o t hese e ve nts, a ne w pre me dicati o n re gi me n f or t he 
w h ole pr o gra m has bee n i nstit ute d t o mi ni mize i nf usi o n reacti o ns.
T a ble 1. 2. 2. 3 A: 
St u d y H u L uc 6 3- 1 7 0 3 P h ase 1 Tre at me nt-e mer ge nt Rel ate d 
A d verse E ve nts i n  2 D ose d S u bjects b y Preferre d Ter m a n d 
C o h ort
D ose ( m g/ k g) ( n u m ber of s u bjects) 
A n y Gr a de: 
T ot al N o. S u bjects 
( N = 2 8) 
N o. E ve nts 
Gr a de 3, 4, or 
5 
Preferre d Ter m 
5 ( n = 3) 
1 0 ( n = 3) 
2 0 ( n = 2 2) 
A ne mia
1 ( 3 3. 3 %)
2 ( 6 6. 7 %)
7 ( 3 1. 8 %)
1 0 ( 3 5. 7 %)
1 ( 3. 6 %) a
Fati g ue
0
0
8 ( 3 6. 4 %)
8 ( 2 8. 6 %)
0
Na usea
0
1 ( 3 3. 3 %)
5 ( 2 2. 7 %)
6 ( 2 1. 4 %)
0
Ne utr o pe nia
2 ( 6 6. 7 %)
2 ( 6 6. 7 %)
2 ( 9. 1 %)
6 ( 2 1. 4 %)
4 ( 1 4. 3 %) a
C hills
2 ( 6 6. 7 %)
2 ( 6 6. 7 %)
0
4 ( 1 4. 3 %)
0
C o nsti pati o n
0
0
4 ( 1 8. 2 %)
4 ( 1 4. 3 %)
0
T hr o m b oc yt o pe nia
1 ( 3 3. 3 %)
1 ( 3 3. 3 %)
2 ( 9. 1 %)
4 ( 1 4. 3 %)
3 ( 1 0. 7 %) b
Diarr h oea
0
1 ( 3 3. 3 %)
2 ( 9. 1 %)
3 ( 1 0. 7 %)
0
Hea dac he
1 ( 3 3. 3 %)
0
2 ( 9. 1 %)
3 ( 1 0. 7 %)
0
I ns o m nia
1 ( 3 3. 3 %)
1 ( 3 3. 3 %)
1 ( 4. 5 %)
3 ( 1 0. 7 %)
0
Art hral gia
0
1 ( 3 3. 3 %)
1 ( 4. 5 %)
2 ( 7. 1 %)
0
Dee p Vei n 
T hr o m b osis
1 ( 3 3. 3 %)
0
1 ( 4. 5 %)
2 ( 7. 1 %)
1 ( 3. 6 %) a
Le u k o pe nia
1 ( 3 3. 3 %)
0
1 ( 4. 5 %)
2 ( 7. 1 %)
0
Pr urit us
1 ( 3 3. 3 %)
0
1 ( 4. 5 %)
2 ( 7. 1 %)
0
Ras h
0
0
2 ( 9. 1 %)
2 ( 7. 1 %)
0
Urticaria
0
0
2 ( 9. 1 %)
2 ( 7. 1 %)
0
a Gra de 3
b  Gra de 3, 4
S o urce: preli mi nar y data as of 0 8-J ul- 2 0 1 1
Of t he 7 3 s u bjects e nr olle d i n t he P hase 2 p orti o n of t he trial as of 2 6- Oct- 2 0 1 1, all ha d bee n treate d 
wit h el ot uz u ma b a n d ha ve data a vaila ble. At least 1 A E was re p orte d i n 1 0 0 % of s u bjects, a n d 
7 2. 6 % e x perie nce d A Es wit h a t o xicit y of Gra de 3 or Gra de 4. A E re p orts were si milar bet wee n 
t he 2 d oses of el ot uz u ma b wit h n u mericall y sli g htl y hi g her rates of diarr hea, fati g ue, na usea, u p per 
res pirat or y tract i nfecti o n, le u k o pe nia, ne utr o pe nia, t hr o m b oc yt o pe nia, l y m p h o pe nia, a ne mia, 
peri p heral e de ma, a n d bac k pai n at 1 0 m g/ k g, a n d n u mericall y sli g htl y hi g her rates of m uscle 
s pas ms, c o nsti pati o n, i ns o m nia, h y per gl yce mia, a n d h y p o kale mia at 2 0 m g/ k g. Gi ve n t he sa m ple 
size a n d i nteri m stat us of t his a nal ysis, t he rates of A Es a p pear t o be ge nerall y si milar bet wee n t he 

C O N FI D E N TI A L
T his d oc u me nt is c o nfi de ntial. D o n ot discl ose or use e xce pt as a ut h orize d.
1 7
S h ort title: P h ase II st u d y of El ot uz u m a b pl us R V D i n Ne wl y Di a g n ose d M M
Versi o n D ate: N o ve m ber 1 0, 2 0 2 0 
2 d oses.
Of t he 7 3 s u bjects e nr olle d, 5 1 ( 6 9. 9 %) s u bjects re p orte d at least o ne el ot uz u ma b-relate d T E A E 
(as assesse d b y t he i n vesti gat or). T E A Es relate d t o el ot uz u ma b t hat occ urre d i n at  2 5 % of d ose d 
s u bjects are prese nte d i n decreasi n g fre q ue nc y i n Ta ble 1. 2. 2. 3 B. T he m ost c o m m o n  ( 4 0 %) 
el ot uz u ma b-relate d 
T E A Es 
were 
m uscle s pas ms ( 5 5 %), diarr hea ( 5 3 %, fati g ue ( 4 8 %), 
c o nsti pati o n ( 4 5 %), na usea ( 4 2 %), a n d u p per res pirat or y tract i nfecti o n ( 4 1 %). T he m ost c o m m o n 
 Gra de 3 el ot uz u ma b-relate d T E A Es were l y m p h o pe nia, ne utr o pe nia, a n d t hr o m b oc yt o pe nia 
( 1 6 % eac h).
T a ble 1. 2. 2. 3 B: 
St u d y H u L uc 6 3- 1 7 0 3 P h ase 2 Tre at me nt- E mer ge nt Rel ate d 
A d verse E ve nts i n  2 5 % of D ose d S u bjects or Gr a de 3/ 4 
 5 % b y Preferre d Ter m a n d C o h ort
El ot uz u m a b D ose ( m g/ k g) 
( n u m ber of s u bjects) 
T ot al N o. S u bjects ( N = 7 3) 
1 0 
( N = 3 6) 
2 0 
( N = 3 7) 
A n y Gr a de
Gr a de 3/ 4
Preferre d Ter m
n ( %)
M uscle s pas ms
1 9 ( 5 3)
2 1 ( 5 7)
4 0 ( 5 5)
2 ( 3)
Diarr hea
2 0 ( 5 6)
1 9 ( 5 1)
3 9 ( 5 3)
4 ( 5)
Fati g ue
1 9 ( 5 3)
1 6 ( 4 3)
3 5 ( 4 8)
5 ( 7)
C o nsti pati o n
1 4 ( 3 9)
1 9 ( 5 1)
3 3 ( 4 5)
0
Na usea
1 6 ( 4 4)
1 5 ( 4 1)
3 1 ( 4 2)
1 ( 1)
U p per res pirat or y 
tract i nfecti o n
1 7 ( 4 7)
1 3 ( 3 5)
3 0 ( 4 1)
2 ( 3)
P yre xia
1 4 ( 3 9)
1 4 ( 3 8)
2 8 ( 3 8)
1 ( 1)
A ne mia
1 3 ( 3 6)
1 0 ( 2 7)
2 3 ( 3 2)
8 ( 1 1)
I ns o m nia
9 ( 2 5)
1 3 ( 3 5)
2 2 ( 3 0)
1 ( 1)
Peri p heral e de ma
1 2 ( 3 3)
9 ( 2 4)
2 1 ( 2 9)
1 ( 1)
Bac k pai n
1 1 ( 3 1)
8 ( 2 2)
1 9 ( 2 6)
2 ( 3)
H y per gl yce mia
7 ( 1 9)
1 2 ( 3 2)
1 9 ( 2 6)
7 ( 1 0)
Ne utr o pe nia
1 1 ( 3 1)
8 ( 2 2)
1 9 ( 2 6)
1 2 ( 1 6)
T hr o m b oc yt o pe nia
1 1 ( 3 1)
7 ( 1 9)
1 8 ( 2 5)
1 2 ( 1 6)
L y m p h o pe nia
1 0 ( 2 8)
7 ( 1 9)
1 7 ( 2 3)
1 2 ( 1 6)
Le u k o pe nia
7 ( 1 9)
5 ( 1 4)
1 2 ( 1 6)
6 ( 8)
H y p o kale mia
5 ( 1 4)
6 ( 1 6)
1 1 ( 1 5)
4 ( 5)

C O N FI D E N TI A L
T his d oc u me nt is c o nfi de ntial. D o n ot discl ose or use e xce pt as a ut h orize d.
1 8
S h ort title: P h ase II st u d y of El ot uz u m a b pl us R V D i n Ne wl y Di a g n ose d M M
Versi o n D ate: N o ve m ber 1 0, 2 0 2 0 
Fift y- o ne S A Es ha ve bee n re p orte d i n s u bjects treate d i n P hase 2 of st u d y H u L uc 6 3- 1 7 0 3 as of 1 5-
A u g- 2 0 1 1. Seri o us A Es t hat occ urre d i n m ore t ha n 1 s u bject are s h o w n i n Ta ble 1. 2. 2. 3 C. Seri o us 
A Es of p ne u m o nia re p orte d i n 4 ( 5. 5 %) s u bjects; b o ne pai n, br o nc hitis, fe brile ne utr o pe nia, 
ne utr o pe nia, p ul m o nar y e m b olis m, se psis, s y nc o pe, a n d tra nsie nt isc hae mic attac k were re p orte d 
i n 2 ( 2. 7 %) s u bjects eac h; all ot her S A Es ha ve bee n re p orte d i n o nl y 1 ( 1. 4 %) s u bject eac h.
T a ble 1. 2. 2. 3 C: 
St u d y H u L uc 6 3- 1 7 0 3 P h ase 2 Seri o us A d verse E ve nts b y 
Preferre d Ter m a n d C o h ort f or All Tre at me nt C ycles 
C o m bi ne d Occ urri n g i n M ore t h a n O ne S u bject
El ot uz u m a b D ose ( m g/ k g) 
( n u m ber of s u bjects) 
1 0 
( N = 3 6) 
2 0 
( N = 3 7) 
T ot al N o. S u bjects 
( N = 7 3) 
Preferre d Ter m
n ( %)
Gr a de
P ne u m o nia 
2 ( 5. 6 %) 
2 ( 5. 4 %) 
4 ( 5. 5 %) 
1 Gra de 2 
3 Gra de 3 
B o ne Pai n 
2 ( 5. 6 %) 
0 
2 ( 2. 7 %) 
3 
Br o nc hitis 
1 ( 2. 8 %) 
1 ( 2. 7 %) 
2 ( 2. 7 %) 
1 Gra de 2 
1 Gra de 3 
Fe brile Ne utr o pe nia 
1 ( 2. 8 %) 
1 ( 2. 7 %) 
2 ( 2. 7 %) 
3 
Ne utr o pe nia 
1 ( 2. 8 %) 
1 ( 2. 7 %) 
2 ( 2. 7 %) 
4 
P ul m o nar y E m b olis m 
1 ( 2. 8 %) 
1 ( 2. 7 %) 
2 ( 2. 7 %) 
1 Gra de 2 
1 Gra de 3 
Se psis 
2 ( 5. 6 %) 
0 
2 ( 2. 7 %) 
1 Gra de 2 
1 Gra de 3 
S y nc o pe 
2 ( 5. 6 %) 
0 
2 ( 2. 7 %) 
3 
Tra nsie nt Isc he mic 
Attac k 
1 ( 2. 8 %) 
1 ( 2. 7 %) 
2 ( 2. 7 %) 
3 
O ne of t he sec o n dar y o bjecti ves of St u d y H u L uc 6 3- 1 7 0 3 was t o e val uate t he efficac y of 
el ot uz u ma b w he n gi ve n i n c o m bi nati o n wit h le nali d o mi de a n d l o w- d ose de xa met has o ne ( L d). 
Ta ble 1. 4. 2. 3 D prese nts t he P hase 1 res p o nse rates i n treate d s u bjects. T he o verall res p o nse rate 
( O R R) ( P R) was assesse d usi n g I M W G criteria at 8 2. 1 % i n all treate d s u bjects w h o recei ve d 
el ot uz u ma b/ L d a n d 9 3. 8 % i n s u bjects w h o recei ve d pri or t hali d o mi de. I n t he s u bset a nal ysis of 
s u bjects wit h n o pri or le nali d o mi de ( n = 2 2), t he O R R was 9 5. 5 %.

C O N FI D E N TI A L
T his d oc u me nt is c o nfi de ntial. D o n ot discl ose or use e xce pt as a ut h orize d.
1 9
S h ort title: P h ase II st u d y of El ot uz u m a b pl us R V D i n Ne wl y Di a g n ose d M M
Versi o n D ate: N o ve m ber 1 0, 2 0 2 0 
T a ble 1. 2. 2. 3 D:  
Res p o nse R ates i n St u d y H u L uc 6 3- 1 7 0 3 P h ase 1 ( S afet y 
P o p ul ati o n)
Effic ac y 
P ar a meter 
All E v al u a ble 
( N = 2 8) 
N o Pri or 
Le n ali d o mi de 
( N = 2 2) 
Pri or 
Le n ali d o mi de
( N = 6) 
Pri or 
T h ali d o mi de 
( N = 1 6) 
Refr act or y t o 
M ost Rece nt 
Li ne of 
T her a p y 
( N = 1 2) 
O R R ( ≥ P R) 
2 3 ( 8 2. 1 %) 
2 1 ( 9 5. 5 %) 
2 ( 3 3. 3 %) 
1 5 ( 9 3. 8 %) 
1 0 ( 8 3. 3 %) 
≥ V G P R 
1 2 ( 4 2. 9 %) 
1 1 ( 5 0. 0 %) 
1 ( 1 6. 7 %) 
7 ( 4 3. 8 %) 
5 ( 4 1. 7 %) 
s C R 
0 
0 
0 
0 
0 
C R 
1 ( 3. 6 %) 
1 ( 4. 5 %) 
0 
0 
0 
V G P R 
1 1( 3 9. 3 %) 
1 0 ( 4 5. 5 %) 
1 ( 1 6. 7 %) 
7 ( 4 3. 8 %) 
5 ( 4 1. 7 %) 
P R 
1 1 ( 3 9. 3 %) 
1 0 ( 4 5. 5 %) 
1 ( 1 6. 7 %) 
8 ( 5 0. 0 %) 
5 ( 4 1. 7 %) 
N o 
C o nfir me d 
Res p o nse 
5 ( 1 7. 9 %) 
1 ( 4. 5 %) 
4 ( 6 6. 7 %) 
1 ( 6. 3 %) 
2 ( 1 6. 7 %) 
P h ase 2 
Res p o nse rates i n t he P hase 2 p orti o n of t his st u d y are s h o w n i n Ta ble 1. 4. 2. 3 E. As of t he efficac y 
data c ut off of 2 6- Oct- 2 0 1 1, t he O R R (  P R) usi n g I M W G criteria a n d i n all 7 3 s u bjects was 8 2 %. 
Alt h o u g h t he st u d y is n ot c o m plete, t he i nteri m data a nal ysis de m o nstrates 9 2 % O R R at 1 0 m g/ k g 
a n d 7 3 % O R R at 2 0 m g/ k g. A m o n g t he 1 6 s u bjects wit h 1 pri or t hera p y w h o recei ve d t he 1 0 m g/ k g 
d ose of el ot uz u ma b, t he O R R was 1 0 0 %. T his O R R is base d o n a me dia n of 1 5 c ycles. Res p o nses 
were ra pi d, wit h a me dia n ti me t o res p o nse of a p pr o xi matel y 1 m o nt h i n e val ua ble s u bjects.
T a ble 1. 2. 2. 3 E:  
Res p o nse R ates i n St u d y H u L uc 6 3- 1 7 0 3 P h ase 2 ( Res p o nse 
E v al u a ble P o p ul ati o n - I M W G Criteri a)
Treat me nt Gr o u p ( m g/ k g) 
1 0 
( N = 3 6) 
2 0 
( N = 3 7) 
T otal N o. S u bjects 
( N = 7 3)
Efficac y Para meter 
n ( %)
O R R ( ≥ P R) 
3 3 ( 9 2 %) 
2 7 ( 7 3 %) 
6 0 ( 8 2 %) 
C R/s C R 
5 ( 1 4 %) 
4 ( 1 1 %) 
9 ( 1 2 %) 
V G P R 
1 4 ( 3 9 %) 
1 1 ( 3 0 %) 
2 5 ( 3 4 %) 
P R 
1 4 ( 3 9 %) 
1 1 ( 3 0 %) 
2 5 ( 3 4 %) 
< P R
3 ( 8 %) 
1 0 ( 2 7 %) 
1 3 ( 1 8 %) 

C O N FI D E N TI A L
T his d oc u me nt is c o nfi de ntial. D o n ot discl ose or use e xce pt as a ut h orize d.
2 0
S h ort title: P h ase II st u d y of El ot uz u m a b pl us R V D i n Ne wl y Di a g n ose d M M
Versi o n D ate: N o ve m ber 1 0, 2 0 2 0 
T he P hase II c o h ort was re p orte d at A S C O 2 0 1 3 ( L o nial 2 0 1 3), t he o bjecti ve res p o nse rate ( O R R) 
was 8 4 %; 9 2 % wit h 1 0 m g/ k g ( n = 3 6) a n d 7 6 % wit h 2 0 m g/ k g ( n = 3 7). At a me dia n f oll o w- u p of 
2 0. 8 m o nt hs, me dia n pr o gressi o n free s ur vi val ( P F S) was n ot reac he d ( 1 0 m g/ k g) a n d was 1 8. 6 
m o ( 2 0 m g/ k g).
1. 2. 2. 4
I nf usi o n R e a cti o ns
First- d ose el ot uz u ma b i nf usi o n reacti o ns a n d ot her peri-i nf usi o nal A Es ha ve bee n o bser ve d i n 
a p pr o xi matel y 5 0 % of s u bjects i n cli nical trials. Seri o us i nf usi o n reacti o ns ha ve bee n o bser ve d 
wit h el ot uz u ma b; t hese ha ve occ urre d o n t he first da y of el ot uz u ma b d osi n g or wit h s u bse q ue nt 
el ot uz u ma b i nf usi o ns.
T he m ost fre q ue nt el ot uz u ma b peri-i nf usi o nal A Es t hat occ urre d i n  1 0 % of s u bjects acr oss all 
P hase 1 or P hase 1/ 2 st u dies, re gar dless of ca usalit y, i ncl u de na usea, v o miti n g, c hills, i nf usi o n-
relate d reacti o n, fl us hi n g, d ys p nea, c o u g h, hea dac he, dizzi ness, a n d ras h.
T he maj orit y of peri-i nf usi o nal A Es were Gra de 1 or 2 a n d res ol ve d wit h little or n o treat me nt. 
T here was n o a p pare nt d ose-relati o ns hi p f or i nf usi o n reacti o ns or peri-i nf usi o nal A Es.
Se ve n ( 7) s u bjects acr oss all 3 st u dies e x perie nce d  Gra de 3 el ot uz u ma b relate d peri-i nf usi o nal 
A Es (see Ta ble 1. 2. 2. 4 A).
I n St u d y 1 7 0 1, 1 s u bject de vel o pe d Gra de 3 h y perse nsiti vit y ( 2 0 m g/ k g, first i nf usi o n).
I n St u d y 1 7 0 2, 1 s u bject de vel o pe d Gra de 3 h y perse nsiti vit y ( 1 0 m g/ k g, f oll o wi n g a t hir d d ose.
I n P hase 1 of St u d y 1 7 0 3, 3 s u bjects de vel o pe d  Gra de 3 e ve nts; stri d or ( 2 0 m g/ k g, f oll o wi n g t he 
t hir d a n d f o urt h i nf usi o ns), a na p h yla xis ( 2 0 m g/ k g, f oll o wi n g a f o urt h i nf usi o n) a n d i nfl ue nza-li ke 
ill ness ( 2 0 m g/ k g).
I n P hase 2 of St u d y 1 7 0 3, 2 s u bjects de vel o pe d  Gra de 3 e ve nts; 1 s u bject de vel o pe d Gra de 3 
ras h, d uri n g el ot uz u ma b i nf usi o n ( 1 0 m g/ k g); a n d 1 s u bject de vel o pe d Gra de 3 na usea ( 2 0 m g/ k g, 
assesse d b y t he i n vesti gat or as u nrelate d t o el ot uz u ma b).
T a ble 1. 2. 2. 4 A: 
El ot uz u m a b-rel ate d Peri-I nf usi o n al A Es: S A Es a n d Se vere 
A Es Gr a de Gre ater t h a n or E q u al t o 3 Acr oss 3 St u dies
St u d y 
S u bject
C o h ort
Ver b ati m Ter m
Se verit y 
( C T C A E)
C o m me nts
1 7 0 1
S u bject 3
2 0 m g/ k g
H y perse nsiti vit y
3
Gra de 3 fe ver. Res ol ve d sa me 
da y. Disc o nti n ue d fr o m st u d y
1 7 0 2
S u bject 4
1 0 m g/ k g
H y perse nsiti vit y
3
E ve nt res ol ve d t he sa me da y
1 7 0 3 P h 1
S u bject 6
2 0 m g/ k g
A na p h yla xis
4
C ycle 1 Da y 2 2
S u bject was wit h dra w n

C O N FI D E N TI A L
T his d oc u me nt is c o nfi de ntial. D o n ot discl ose or use e xce pt as a ut h orize d.
2 1
S h ort title: P h ase II st u d y of El ot uz u m a b pl us R V D i n Ne wl y Di a g n ose d M M
Versi o n D ate: N o ve m ber 1 0, 2 0 2 0 
T a ble 1. 2. 2. 4 A: 
El ot uz u m a b-rel ate d Peri-I nf usi o n al A Es: S A Es a n d Se vere 
A Es Gr a de Gre ater t h a n or E q u al t o 3 Acr oss 3 St u dies
St u d y 
S u bject
C o h ort
Ver b ati m Ter m
Se verit y 
( C T C AE)
C o m me nts
1 7 0 3 P h 1
S u bject 7
2 0 m g/ k g
Stri d or
3
C ycle 1 Da ys 1 5 a n d 2 2
S u bject re-c halle n ge d a n d 
e x perie nce d i nf usi o n reacti o n 
a gai n. S u bject was wit h dra w n 
1 7 0 3 P h 1
S u bject
2 0 m g/ k g
I nfl ue nza Li ke 
Ill ness 
3
1 7 0 3 P h 2
S u bject 8 
1 0 m g/ k g
Ras h
3
Be ga n C ycle 2 Da y 8 S u bject 
rec halle n ge d a n d rec urre d eac h 
treat me nt. S u bject disc o nti n ue d 
C ycle 3 Da y 1 5
1 7 0 3 P h 2
S u bject 9
2 0 m g/ k g
Na usea
3
I n vesti gat or assesse d as u nrelate d 
t o el ot uz u ma b i nf usi o n
T o miti gate i nf usi o n reacti o ns, all o n g oi n g el ot uz u ma b st u dies were a me n de d f or all s u bjects t o recei ve pre me dicati o n 
wit h I V c ortic oster oi ds, a nti hista mi nes ( di p he n h y dra mi ne or h y dr o x yzi ne) a n d aceta mi n o p he n pri or t o eac h 
el ot uz u ma b i nf usi o n. I n t he st u d y 1 7 0 3 pr ot oc ol, H 2 a nti hista mi nes were als o a d de d as a pre me dicati o n.
I n t he P hase 2 p orti o n of t he St u d y 1 7 0 3, i n vesti gat or- desi g nate d i nf usi o n reacti o ns occ urre d i n a 
t otal of 9 o ut of 7 3 s u bjects ( 1 2 %). O nl y a si n gle s u bject e x perie nce d a Gra de 3 ras h des pite t he 
pre me dicati o n re gi me n ( See Ta ble 1. 2. 2. 4 B).
T a ble 1. 2. 2. 4 B: 
St u d y H u L uc 6 3- 1 7 0 3 P h ase 2 I n vesti g at or- Desi g n ate d 
I nf usi o n Re acti o ns
Tre at me nt Gr o u p ( m g/ k g) 
1 0
( N = 3 6) 
2 0
( N = 3 7) 
T ot al N o. S u bjects
( N = 7 3)
P ar a meter 
n ( %)
A n y A E
5 ( 1 4)
4 ( 1 1)
9 ( 1 2)
Gra de 1
3 ( 8)
2 ( 5)
5 ( 7)
Gra de 2
1 ( 3)
2 ( 5)
3 ( 4)
Gra de 3 a
1 ( 3)
0
1 ( 1)
a
S u bject e x perie nce d a Gra de 3 ras h des pite pre me dicati o n re gi me n.
Si nce t he i m ple me ntati o n of a m ore stri n ge nt pre me dicati o n re gi me n, el ot uz u ma b i nf usi o ns ha ve 
bee n ass ociate d wit h pre d o mi na ntl y Gra de 1 or 2 peri-i nf usi o nal A Es. All i nf usi o n reacti o ns ha ve 
bee n ma na ge d b y i nf usi o n rate c ha n ges, a n d/ or me dicati o ns a n d res ol ve d t he sa me da y or wit hi n 

C O N FI D E N TI A L
T his d oc u me nt is c o nfi de ntial. D o n ot discl ose or use e xce pt as a ut h orize d.
2 2
S h ort title: P h ase II st u d y of El ot uz u m a b pl us R V D i n Ne wl y Di a g n ose d M M
Versi o n D ate: N o ve m ber 1 0, 2 0 2 0 
2 4 h o urs, a n d i n m ost cases, s u bjects ha ve c o nti n ue d wit h t he st u d y. S u bjects pre me dicate d wit h 
H 1 a n d H 2 a nti hista mi nes (s uc h as di p he n h y dra mi ne), ra niti di ne, aceta mi n o p he n, a n d I V 
c ortic oster oi ds pri or t o all d oses of el ot uz u ma b ha ve n ot e x perie nce d seri o us i nf usi o n reacti o ns. 
Usi n g t he u p date d pre me dicati o n re gi me n acr oss all o n g oi n g el ot uz u ma b st u dies has re d uce d t he 
i nci de nce of a n y- gra de peri-i nf usi o n A E. Treat me nt wit h t hera pe utic m o n ocl o nal a nti b o dies is 
ass ociate d wit h i nf usi o n reacti o ns wit h varia ble ti me of o nset a n d var yi n g le vels of i nci de nce a n d 
se verit y. T here was n o a p pare nt d ose relati o ns hi p f or i nf usi o n reacti o n.
I n s u m mar y, el ot uz u ma b i nf usi o ns ha ve bee n ass ociate d wit h pre d o mi na ntl y Gra de 1 or 2 i nf usi o n 
reacti o ns. All i nf usi o n reacti o ns were ma na ge d b y i nf usi o n rate c ha n ges a n d/ or me dicati o ns a n d 
res ol ve d t he sa me da y or wit hi n 2 4 h o urs. I n m ost cases, s u bjects ha ve bee n a ble t o c o nti n ue o n 
st u d y. O nl y 1 s u bject pre me dicate d wit h di p he n h y dra mi ne, aceta mi n o p he n, a n d I V c ortic oster oi ds 
pri or t o all d oses of el ot uz u ma b de vel o pe d a Gra de 3 i nf usi o n reacti o n relate d t o el ot uz u ma b a n d 
disc o nti n ue d st u d y treat me nt.
1. 2. 3  
O ver all Ris k/ Be nefit Assess me nt
M ulti ple m yel o ma acc o u nts f or 1 % of all ne o plas ms a n d 1 0 % of he mat ol o gic mali g na ncies i n t he 
U nite d States wit h a n esti mate d a n n ual i nci de nce of 2 0, 5 2 0 a n d esti mate d a n n ual disease-s pecific 
m ortalit y of al m ost 1 1, 0 0 0. I n s pite of rece nt i m pr o ve me nt i n treat me nt o pti o ns it re mai ns lar gel y 
i nc ura ble a n d is ass ociate d wit h ver y si g nifica nt m or bi dit y.
T he maj orit y of patie nts wit h ne wl y dia g n ose d M M will re q uire s yste mic t hera p y a n d ma n y will 
be referre d f or A S C T as well. A c o m bi nati o n of de xa met has o ne wit h b ortez o mi b, a n I Mi D or b ot h 
has bec o me o ne of t he m ost c o m m o nl y rec o m me n de d t hera pies i n t he first li ne setti n g. T he c h oice 
of a s pecific re gi me n ofte n de pe n ds o n patie nt or p h ysicia n prefere nce, eli gi bilit y f or A S C T or 
cli nical trial a n d percei ve d ris k base d o n esta blis he d pr o g n ostic fact ors, s uc h as sta ge a n d 
c yt o ge netics. T he c o m bi nati o n of B L D has bee n s h o w n t o be hi g hl y acti ve a n d is n o w 
rec o m me n de d as a sta n dar d of care b y wi del y acce pte d treat me nt g ui deli nes ( N C C N G ui deli nes). 
El ot uz u ma b as m o n ot hera p y or i n c o m bi nati o n wit h b ortez o mi b or le nali d o mi de/ de xa met has o ne 
is well t olerate d. T o date, t he ke y el ot uz u ma b safet y si g nal has bee n i nf usi o n reacti o n A Es w hic h 
ha ve bee n s uccessf ull y ma na ge d b y a p pr o priate cli nical i nter ve nti o n res ulti n g i n e ve nt res ol uti o n 
i n less t ha n 2 4 h o urs. T he maj orit y of i nf usi o n reacti o ns occ ur i n t he first c ycle wit h decreasi n g 
i nci de nce t hr o u g h C ycle 4. F oll o wi n g t he i m ple me ntati o n of a n u p date d pre me dicati o n sc he me 
wit h H 1 bl oc ker, H 2 bl oc ker, aceta mi n o p he n, a n d I V c ortic oster oi ds, t he i nci de nce of a n y gra de, 
a n d se vere ( Gra de 3 a n d 4) el ot uz u ma b i nf usi o n reacti o n A Es ha ve decrease d. F or e xa m ple, i n t he 
P hase 2 p orti o n of St u d y 1 7 0 3 ( n = 7 3), t here was o nl y 1 Gra de 3 i nf usi o n ass ociate d reacti o n: 
ras h ( 1 0 m g/ k g).
T he el ot uz u ma b d ose of 1 0 m g/ k g was selecte d base d o n acc u m ulate d safet y, p har mac o ki netic a n d 
p har mac o d y na mic data. T he safet y pr ofile of el ot uz u ma b d oes n ot a p pear t o be d ose de pe n de nt, 
wit h rates a n d se verit y of ge neral A Es/ S A Es a n d i nf usi o n relate d A Es/ S A Es bei n g si milar at 1 0 
a n d 2 0 m g/ k g d oses. P har mac o ki netic a nal ysis s u g gests t hat tr o u g h ser u m a nti b o d y c o nce ntrati o ns 
of el ot uz u ma b are a b o ve t he tar get le vels deter mi ne d fr o m n o n-cli nical m o dels i n al m ost all 
s u bjects treate d at 2 0 m g/ k g as well as 1 0 m g/ k g. M ore o ver, el ot uz u ma b a d mi nistrati o n at d oses 

C O N FI D E N TI A L
T his d oc u me nt is c o nfi de ntial. D o n ot discl ose or use e xce pt as a ut h orize d.
2 3
S h ort title: P h ase II st u d y of El ot uz u m a b pl us R V D i n Ne wl y Di a g n ose d M M
Versi o n D ate: N o ve m ber 1 0, 2 0 2 0 
≥ 1 0 m g/ k g res ulte d i n near-c o m plete sat urati o n of tar get sites o n b o ne marr o w plas ma cells i n 
st u dies 1 7 0 2 a n d 1 7 0 3.
Base d o n pri or cli nical e x perie nce, t he d ose a n d sc he d ule of el ot uz u ma b i n t his st u d y is a ntici pate d 
t o be well t olerate d. T he ris k of i nf usi o n reacti o n or ot her el ot uz u ma b-relate d t o xicit y is n ot d ose 
de pe n de nt. A 2 0 m g/ k g d ose of el ot uz u ma b was t olerate d i n all st u dies t o date a n d wit h o ut d ose 
li miti n g t o xicit y.
Alt h o u g h el ot uz u ma b as a m o n ot hera p y di d n ot ha ve si g nifica nt acti vit y i n rela pse d/refract or y 
m yel o ma, t he c o m bi nati o ns of el ot uz u ma b wit h eit her b ortez o mi b or le nali d o mi de/ de xa met has o ne 
a p pear t o be acti ve a n d well t olerate d. Gi ve n t he pre vi o usl y de m o nstrate d efficac y of t he B L D 
re gi me n, it is e x pecte d t hat t he c o m bi nati o n of B L D a n d el ot uz u ma b will be hi g hl y acti ve.
 
2  
O B J E C TI V E S
2. 1  
Rese arc h H y p ot hesis
T he researc h h y p ot hesis is t hat t he c o m bi nati o n of el ot uz u ma b pl us le nali d o mi de, b ortez o mi b, a n d 
de xa met has o ne will res ult i n a hi g h le vel of a nti- M M acti vit y a n d will be well t olerate d.  
2. 2  
Ori gi n al Pri m ar y O bjecti ves
T o esti mate t he res p o nse rate after 4 c ycles of i n d ucti o n t hera p y i n s u bjects treate d wit h E- R V D.
2. 3  
Ori gi n al Sec o n d ar y O bjecti ves 
•
T o esti mate t he pr o p orti o n of s u bjects wit h a s uccessf ul ste m cell m o bilizati o n after recei vi n g 
f o ur c ycles of treat me nt wit h E- R V D
•
T o esti mate t he pr o p orti o n of s u bjects re q uiri n g d ose m o dificati o n of a n y st u d y dr u g d uri n g t he 
first f o ur c ycles of E- R V D 

T o c haracterize safet y i n s u bjects w h o recei ve E- R V D

T o pr o vi de preli mi nar y i nf or mati o n o n t he acti vit y of E- R V D i ncl u di n g best res p o nse, o bjecti ve 
res p o nse rate ( O R R), i ncl u di n g O R R at e n d of 8 c ycles f or patie nts t hat c o m plete 8 c ycles of 
i n d ucti o n t hera p y, d urati o n of res p o nse, ti me t o res p o nse, pr o gressi o n free s ur vi val ( P F S) a n d 
ti me t o ne xt treat me nt
2. 4
Ori gi n al E x pl or at or y O bjecti ves
•
T o pr o vi de preli mi nar y i nf or mati o n o n t he e val uati o n of mi ni mal resi d ual disease ( M R D)
F or s u bjects w h o elect t o u n der g o ste m cell tra ns pla nt ( S C T), t o c haracterize e n graft me nt 
para meters 
T he ori gi nal o bjecti ves f or t his st u d y ha ve bee n met as of Oct o ber 2 0 2 0. T he ne w o bjecti ve of t he 
st u d y is safet y. 

C O N FI D E N TI A L
T his d oc u me nt is c o nfi de ntial. D o n ot discl ose or use e xce pt as a ut h orize d.
2 4
S h ort title: P h ase II st u d y of El ot uz u m a b pl us R V D i n Ne wl y Di a g n ose d M M
Versi o n D ate: N o ve m ber 1 0, 2 0 2 0 
T he f oll o wi n g i nf or mati o n will be c ollecte d:

All S A Es.

All ≥Gra de  2 A Es.

Ne w pri mar y mali g na ncies.

A n y A E res ulti n g i n d ose m o dificati o n or disc o nti n uati o n of a n y st u d y dr u g.

A n y ot her A E t hat i n t he o pi ni o n of t he i n vesti gat or is a cli nicall y si g nifica nt e ve nt
3 
P A R TI CI P A N T S E L E C TI O N
3. 1 
Eli gi bilit y Criteri a 
3. 1. 1
P ati e nt s m u st m e et t h e f oll o wi n g crit eri a o n s cr e e ni n g e x a mi n ati o n t o b e 
eli gi bl e t o p arti ci p at e i n t h e st u d y.  All l a b or at or y a s s e s s m e nt s s h o ul d b e 
p erf or m e d wit hi n 2 1 d a y s of i niti ati o n of pr ot o c ol t h er a p y u nl e s s ot h er wi s e 
s p e cifi e d . B o n e m arr o w bi o p s y s h o ul d b e p erf or m e d wit hi n 3 0 d a y s of 
i niti ati o n of pr ot o c ol t h er a p y. S u bj e ct is, i n t h e i n v esti g at or’s o pi ni o n, willi n g a n d 
a bl e t o c o m pl y wit h t h e pr ot o c ol r e q uir e m e nts.
3. 1. 2
S u bj e ct h as gi v e n v ol u nt ar y si g n e d writt e n i nf or m e d c o ns e nt b ef or e p erf or m a n c e of a n y 
st u d y-r el at e d pr o c e d ur e t h at is n ot p art of n or m al m e di c al c ar e, wit h t h e u n d erst a n di n g 
t h at c o ns e nt m a y b e wit h dr a w n b y t h e s u bj e ct at a n y ti m e wit h o ut pr ej u di c e t o t h eir f ut ur e 
m e di c al c ar e. 
3. 1. 3
E ast er n C o o p er ati v e O n c ol o g y Gr o u p ( E C O G) p erf or m a n c e st at us  2 (s e e A p p e n di x 1).
3. 1. 4
S u bj e ct is a c a n di d at e f or hi g h- d os e t h er a p y a n d a ut ol o g o us S C T b as e d o n st a n d ar d 
crit eri a at t h e i nstit uti o n w h er e t his tr e at m e nt will b e a d mi nist er e d.
3. 1. 5
            
            Partici pa nts m ust ha ve a dia g n osis of M M acc or di n g Re vise d I nter nati o nal M yel o ma 
W or ki n g Gr o u p dia g n ostic criteria ( Raj k u mar 2 0 1 4), w hic h re q uire t he f oll o wi n g 
fi n di n gs,
Cl o nal b o ne marr o w plas ma cells ≥1 0 %  or bi o ps y- pr o ve n b o n y or e xtra me d ullar y
plas mac yt o ma a n d a n y o ne or m ore of t he f oll o wi n g m yel o ma defi ni n g e ve nts:

E n d or ga n da ma ge t hat ca n be attri b ute d t o t he u n derl yi n g plas ma cell
pr oliferati ve dis or der, s pecificall y:
• H y percalce mia: ser u m calci u m > 0. 2 5 m m ol/ L ( > 1 m g/ d L) hi g her t ha n t he
u p per li mit of n or mal or > 2. 7 5 m m ol/ L ( > 1 1 m g/ d L)
• Re nal i ns ufficie nc y: creati ni ne cleara nce < 4 0 m L per mi n or ser u m creati ni ne
> 1 7 7 μ m ol/ L  ( > 2 m g/ d L)
• A ne mia: he m o gl o bi n val ue of > 2 0 g/ L bel o w t he l o wer li mit of n or mal, or a
he m o gl o bi n val ue < 1 0 0 g/ L
• B o ne lesi o ns: o ne or m ore oste ol ytic lesi o ns o n s keletal ra di o gra p h y, C T, or
P E T- C T

O ne or m ore of t he f oll o wi n g bi o mar kers of mali g na nc y:

C O N FI D E N TI A L
T his d oc u me nt is c o nfi de ntial. D o n ot discl ose or use e xce pt as a ut h orize d.
2 5
S h ort title: P h ase II st u d y of El ot uz u m a b pl us R V D i n Ne wl y Di a g n ose d M M
Versi o n D ate: N o ve m ber 1 0, 2 0 2 0 
• Cl o nal b o ne marr o w plas ma cell perce nta ge ≥6 0 %
• I n v ol ve d: u ni n v ol ve d ser u m free li g ht c hai n rati o ≥1 0 0
• > 1 f ocal lesi o ns o n M RI st u dies
3. 1. 6   Partici pa nts m ust als o ha ve meas ura ble disease acc or di n g t o t he Sta n dar d Dia g n ostic 
Criteria ( Raj k u mar 2 0 0 9):

S er u m I g G, I g A, or I g M M- pr ot ei n ≥ 0. 5 g/ d L, or

S er u m I g D M- pr ot ei n ≥ 0. 0 5 g/ d L, or

Uri n ar y M- pr ot ei n e x cr eti o n of m or e t h a n 2 0 0 m g/ 2 4 h o urs, or

Ser u m free li g ht c hai ns of at least 1 0 0 m g/ L wit h a n a b n or mal F L C rati o
3. 1. 7
S u bj e ct a gr e es t o r efr ai n fr o m bl o o d d o n ati o ns d uri n g t h er a p y o n st u d y a n d f or 8 w e e ks 
aft er t h er a p y is c o m pl et e d.
3. 1. 8
M e n a n d w o m e n, a g e ≥ 1 8 y e ars or l e g al a g e of c o ns e nt p er l o c al r e g ul ati o ns ( w hi c h e v er 
is gr e at er).
3. 1. 9
F e m al es of c hil d b e ari n g p ot e nti al ( F C B P) † m ust h a v e a n e g ati v e s er u m or uri n e 
pr e g n a n c y t est wit h a s e nsiti vit y of at l e ast 5 0 mI U/ m L wit hi n 1 0 – 1 4 d a ys pri or t o a n d 
a g ai n wit hi n 2 4 h o urs of st arti n g L e n ali d o mi d e a n d m ust eit h er c o m mit t o c o nti n u e d 
a bsti n e n c e fr o m h et er os e x u al i nt er c o urs e or b e gi n T W O a c c e pt a bl e m et h o ds of birt h 
c o ntr ol, o n e hi g hl y eff e cti v e m et h o d a n d o n e a d diti o n al eff e cti v e m et h o d A T T H E S A M E 
TI M E, at l e ast 2 8 d a ys b ef or e s h e st arts t a ki n g L e n ali d o mi d e t hr o u g h 9 0 d a ys aft er t h e 
l ast d os e of st u d y dr u g.  F C B P m ust als o a gr e e t o o n g oi n g pr e g n a n c y t esti n g.  M e n m ust 
a gr e e t o us e a l at e x c o n d o m d uri n g s e x u al c o nt a ct wit h a F C B P e v e n if t h e y h a v e h a d a 
v as e ct o m y fr o m t h e ti m e of si g ni n g t h e i nf or m e d c o ns e nt f or m t hr o u g h 9 0 d a ys aft er t h e 
l ast d os e of st u d y dr u g.  All p ati e nts m ust b e r e gist er e d i n a n d m ust c o m pl y wit h all 
r e q uir e m e nts of t h e R e vli mi d R E M S ™ pr o gr a m.  
3. 2 
E xcl usi o n Criteri a 
P arti ci p a nts w h o e x hi bit a n y of t h e f oll o wi n g c o n diti o ns at s cr e e ni n g will n ot b e eli gi bl e f or 
a d missi o n i nt o t h e st u d y.   
3. 2. 1   Dia g n ose d wit h s m ol deri n g M M, m o n ocl o nal ga m m o pat h y of u n deter mi ne d si g nifica nce,
  
Wal de nstr o m's 
macr o gl o b uli ne mia, 
Plas ma cell le u ke mia, 
P O E M S s y n dr o me or 
a m yl oi d osis.
3. 2. 2   P arti ci p a nt h as ≥ Gr a d e 2 p eri p h er al n e ur o p at h y o n cli ni c al e x a mi n ati o n wit hi n 2 1 
d a ys b ef or e i niti ati o n of pr ot o c ol t h er a p y.
3. 2. 3
R e n al i ns uffi ci e n c y, d efi n e d as cr e ati ni n e cl e ar a n c e < 3 0 m L/ mi n ( eit h er a ct u al or 
c al c ul at e d v al u e), wit hi n 2 1 d a ys of i niti ati o n of pr ot o c ol t h er a p y. T h e C o c k gr oft-
G a ult f or m ul a s h o ul d b e us e d f or c al c ul ati n g cr e ati ni n e cl e ar a n c e v al u es:

C O N FI D E N TI A L
T his d oc u me nt is c o nfi de ntial. D o n ot discl ose or use e xce pt as a ut h orize d.
2 6
S h ort title: P h ase II st u d y of El ot uz u m a b pl us R V D i n Ne wl y Di a g n ose d M M
Versi o n D ate: N o ve m ber 1 0, 2 0 2 0 
( 1 4 0- a g e) x B o d y m ass ( k g)   x 0. 8 5 (f e m al e) or 1. 0 ( m al e)
s er u m cr e at ( m g/ d L) x 7 2 
* I d e al b o d y w ei g ht (I B W) s h o ul d b e us e d if a ct u al b o d y w ei g ht is > 2 0 % a b o v e I B W
3. 2. 4
Pl at el et c o u nt < 7 5, 0 0 0 c ells/ m m 3 at ti m e of s cr e e ni n g e v al u ati o n. Tr a nsf usi o n m a y 
n ot b e us e d t o m e et pl at el et eli gi bilit y crit eri a wit hi n 7 d a ys of o bt ai ni n g s cr e e ni n g 
e v al u ati o n.
3. 2. 5
Partici pa nts wit h a n a bs ol ute ne utr o p hil c o u nt ( A N C) < 1 0 0 0 cells/ m m 3 at ti me of 
scree ni n g e val uati o n.  Gr o wt h f act or m ay n ot  be use d t o meet A N C eli gi bilit y criteri a 
wit hi n 1 4 d a ys of o bt ai ni n g scree ni n g e v al u ati o n.  
3. 2. 6
Partici pa nts wit h he m o gl o bi n le vel < 8. 0 g/ d L, at ti me of scree ni n g. Tra nsf usi o n ma y n ot 
be use d t o meet eli gi bilit y criteria wit hi n 7 da ys of o btai ni n g scree ni n g e val uati o n.
3. 2. 7
Partici pa nts wit h he patic i m pair me nt, defi ne d as bilir u bi n > 1. 5 x i nstit uti o nal u p per li mit 
of n or mal ( U L N) or A S T ( S G O T), A L T ( S G P T), or al kali ne p h os p hatase > 3 x i nstit uti o nal 
U L N, wit hi n 2 1 da ys of i nitiati o n of pr ot oc ol t hera p y
3. 2. 8
Ot her o n g oi n g or pri or a nti- m yel o ma t hera p y.  Patie nts ma y be recei vi n g c o nc o mita nt 
t hera p y wit h bis p h os p h o nates a n d l o w d ose c ortic oster oi ds (e. g., pre d nis o ne u p t o b ut n o 
m ore t ha n 1 0 m g p. o. q. d. or its e q ui vale nt) f or s y m pt o m ma na ge me nt a n d c o m or bi d 
c o n diti o ns. D oses of c ortic oster oi d s h o ul d be sta ble f or at least 7 da ys pri or t o st u d y 
treat me nt.)  T he d ose of c ortic oster oi ds f or t he treat me nt of t heir m yel o ma recei ve d b y t he  
partici pa nt   s h o ul d   n ot  e xcee d  t he  e q ui vale nt  of  1 6 0  m g  of de xa met has o ne o ver a 
t w o- wee k  peri o d bef ore i nitiati o n of  pr ot oc ol t hera p y
3. 2. 9    K n o w n si g nifica nt car diac a b n or malities i ncl u di n g:   

C o n gesti ve heart fail ure, N Y H A class III or I V

U nc o ntr olle d a n gi na, arr h yt h mia or h y perte nsi o n

M y ocar dial i nfarcti o n wit hi n t he past si x m o nt hs

A n y ot her u nc o ntr olle d or se vere car di o vasc ular c o n diti o n

Pri or cere br o vasc ular e ve nt wit h resi d ual ne ur ol o gic deficit
3. 2. 1 0 Seri o us, i nterc urre nt ill ness i ncl u di n g, b ut n ot li mite d t o, cli nicall y rele va nt acti ve 
i nfecti o n, k n o w n acti ve he patitis B or C viral i nfecti o n, k n o w n 
HI V i nfecti o n, 
u nc o ntr olle d dia betes mellit us, or seri o us c o- m or bi d me dical c o n diti o ns s uc h as c hr o nic 
restricti ve p ul m o nar y disease, a n d cirr h osis.
3. 2. 1 1
A n y c o n diti o n, i ncl u di n g la b orat or y a b n or malities, t hat i n t he o pi ni o n of t he i n vesti gat or 
places t he s u bject at u nacce pta ble ris k if he/s he were t o partici pate i n t he st u d y.

C O N FI D E N TI A L
T his d oc u me nt is c o nfi de ntial. D o n ot discl ose or use e xce pt as a ut h orize d.
2 7
S h ort title: P h ase II st u d y of El ot uz u m a b pl us R V D i n Ne wl y Di a g n ose d M M
Versi o n D ate: N o ve m ber 1 0, 2 0 2 0 
3. 2. 1 2 Pri or mali g na nc y ( wit hi n t he last 5 years) e xce pt f or a de q uatel y treate d basal cell or 
s q ua m o us cell s ki n ca ncer, or i n sit u cer vical ca ncer
3. 2. 1 3
K n o w n h y perse nsiti vit y t o ac ycl o vir or si milar a nti- viral dr u g
3. 2. 1 4
K n o w n i nt olera nce t o ster oi d t hera p y
3. 2. 1 5
C o ntrai n dicati o n or pri or i nt olera nce t o t hr o m b oe m b olic pr o p h yla xis wit h as piri n, warfari n 
or l o w- m olec ular wei g ht he pari n
3. 2. 1 6 Partici pa nts wit h k n o w n brai n metastases. 
3. 2. 1 7 P o or t olera bilit y or k n o w n aller g y t o a n y of t he st u d y dr u gs or c o m p o u n ds of si milar 
c he mical or bi ol o gic c o m p ositi o n t o de xa met has o ne, b or o n or ma n nit ol.  
3. 2. 1 8 Fe male partici pa nts pre g na nt or breast-fee di n g.  
3. 2. 1 9 Partici pa nts w h o ha ve u n der g o ne maj or s ur ger y ≤ 4 wee ks pri or t o starti n g st u d y dr u g or 
w h o ha ve n ot rec o vere d fr o m si de effects of t he s ur ger y.
3. 2. 2 0 Partici pa nts wit h a n y si g nifica nt hist or y of n o n-c o m plia nce t o me dical re gi me ns or 
u n willi n g or u na ble t o c o m pl y wit h t he i nstr ucti o ns gi ve n t o hi m/ her b y t he st u d y staff.
3. 3 
I ncl usi o n of W o me n, Mi n orities a n d Ot her U n derre prese nte d P o p ul ati o ns
W o me n, 
mi n orities a n d 
me m bers of ot her u n derre prese nte d p o p ulati o ns 
will ha ve e q ual 
c o nsi derati o n f or partici pati o n i n t his trial.  Please n ote, h o we ver, t hat t he pre vale nce of M M is 
m ore c o m m o n a m o n g me n t ha n w o me n, occ urs m ore fre q ue ntl y wit h i ncreasi n g a ge, a n d de vel o ps 
t wice as ofte n a m o n g blac k i n di vi d uals t ha n a m o n g w hite i n di vi d uals.  I ncl usi o n a n d e xcl usi o n 
criteria are n ot e x pecte d t o ha ve a ne gati ve effect o n recr uit me nt or rete nti o n of t hese 
u n derre prese nte d p o p ulati o ns.  
3. 4 
Scree ni n g Pr oce d ures
T he I n vesti gat or is res p o nsi ble f or kee pi n g a rec or d of all partici pa nts scree ne d f or e ntr y i nt o t he 
st u d y a n d s u bse q ue ntl y e xcl u de d.  T he reas o n(s) f or e xcl usi o n m ust als o be rec or de d.  T he 
f oll o wi n g scree ni n g pr oce d ures m ust be perf or me d wit hi n 2 1 da ys of i nitiati o n of pr ot oc ol t hera p y, 
u nless ot her wise sti p ulate d i n t he St u d y Cale n dar ( Secti o n 9):

Partici pa nts w h o are p ote ntiall y eli gi ble f or st u d y partici pati o n m ust si g n a n i nf or me d c o nse nt f or m 
pri or t o t he u n derta ki n g of scree ni n g pr oce d ures f or t his st u d y t hat are n ot a part of sta n dar d me dical 
care.

I ncl usi o n a n d e xcl usi o n criteria re vie we d.

M M dia g n osis will be c o nfir me d  

C o m plete me dical hist or y will be o btai ne d t o i ncl u de d oc u me ntati o n of all c o nc o mita nt me dicati o ns 
use d i n t he pri or 3 wee ks.  

Baseli ne S y m pt o m Assess me nt

C O N FI D E N TI A L
T his d oc u me nt is c o nfi de ntial. D o n ot discl ose or use e xce pt as a ut h orize d.
2 8
S h ort title: P h ase II st u d y of El ot uz u m a b pl us R V D i n Ne wl y Di a g n ose d M M
Versi o n D ate: N o ve m ber 1 0, 2 0 2 0 

P h ysical e xa mi nati o n t o i ncl u de meas ure me nt of vital si g ns, hei g ht, wei g ht a n d calc ulati o n of b o d y 
s urface area ( B S A).

E C O G perf or ma nce stat us will be e val uate d ( A p pe n di x I)

1 2-lea d E C G (see St u d y Cale n dar f or details)

2 D Ec h ocar di o gra m or M U G A

A ne ur ol o gic assess me nt will be perf or me d i ncl u di n g ( F A C T/ G O G Nt x).

He mat ol o g y: he m o gl o bi n, he mat ocrit, w hite bl o o d cell ( W B C) c o u nt a n d differe ntial, a n d platelet 
c o u nt.

Cli nical la b orat or y tests: Bl o o d c he mistr y [s o di u m, p otassi u m, c hl ori de, C O 2, calci u m, ma g nesi u m, 
p h os p h or o us, bl o o d urea nitr o ge n ( B U N), creati ni ne, gl uc ose, al b u mi n, t otal pr otei n, al kali ne 
p h os p hatase, t otal bilir u bi n, A S T/ S G O T, A L T/ S G P T, lactate de h y dr o ge nase ( L D H), uric aci d, beta 2-
micr o gl o b uli n.

T h yr oi d f u ncti o n t o i ncl u de T S H a n d T 4

C oa g ulati o n tests

Uri nal ysis, i ncl u di n g micr osc o pic a nal ysis a n d c ol or

B 2 micr o gl o b uli n

M c o m p o ne nt q ua ntificati o n b y i m m u n oelectr o p h oresis (I E P) fr o m ser u m a n d uri ne a n d 2 4 h o ur uri ne 
c ollecti o n f or para pr otei n meas ure me nt

Ser u m sa m ple f or Free Lite T M  testi n g

Ser u m or uri ne pre g na nc y test (se nsiti vit y of at least 5 0 mI U/ m L), f or F C B P m ust be c o m plete d.  T he 
first test s h o ul d be perf or me d wit hi n 1 0- 1 4 da ys, a n d t he sec o n d test wit hi n 2 4 h o urs pri or t o i nitiati o n 
of le nali d o mi de. All patie nts m ust re gister i nt o t he Re vli mi d R E M S pr o gra m. 

S keletal s ur ve y (i ncl u di n g c hest X-ra y) f or q ua ntificati o n of b o ne lesi o ns, wit h ma g netic res o na nce 
i ma gi n g ( M RI) a n d C T sca ns as cli nicall y i n dicate d. 

I ma gi n g of e xtra me d ullar y plas mac yt o mas if prese nt 

B o ne marr o w as pirati o n a n d bi o ps y t o be e val uate d f or m or p h ol o g y a n d f or c yt o ge netics b y sta n dar d 
ba n di n g a n d FI S H, i ncl u di n g marr o w kar y ot y pe if p ossi ble.  S u g geste d pr o bes i ncl u de, at a mi ni m u m 
del 1 3 q 1 4, t( 4: 1 4), t( 1 1; 1 4), t( 1 4: 1 6), a n d del 1 7 p. 
4  
R E GI S T R A TI O N P R O C E D U R E S
4. 1  
Ge ner al G ui deli nes f or All I nstit uti o ns
Eli gi ble partici pa nts fr o m all i nstit uti o ns will be re gistere d wit h t he D F/ H C C Q ualit y Ass ura nce 
Office f or Cli nical Trials ( O D Q). Re gistrati o ns m ust occ ur pri or t o t he i nitiati o n of pr ot oc ol 
t hera p y. A n y partici pa nt n ot re gistere d t o t he pr ot oc ol bef ore treat me nt be gi ns will be c o nsi dere d 
i neli gi ble a n d re gistrati o n will be de nie d. A n i n vesti gat or will c o nfir m eli gi bilit y criteria a n d a 
me m ber of t he st u d y tea m will c o m plete t he O D Q pr ot oc ol-s pecific eli gi bilit y c hec klist. F oll o wi n g 
re gistrati o n, partici pa nts ma y be gi n pr ot oc ol treat me nt. Iss ues t hat w o ul d ca use treat me nt dela ys 
s h o ul d be disc usse d wit h t he O verall Pri nci pal I n vesti gat or ( PI). If a partici pa nt d oes n ot recei ve 
pr ot oc ol t hera p y f oll o wi n g re gistrati o n, t he partici pa nt’s re gistrati o n o n t he st u d y ma y be ca ncele d. 
N otif y t he pr oject ma na ger at t he c o or di nati n g site, w h o will i nf or m t he O D Q Re gistrar of 
re gistrati o n ca ncellati o ns, as s o o n as p ossi ble.  
4. 2  
Re gistr ati o n Pr ocess
4. 2. 1 Re gistr ati o n Pr ocess f or D F/ H C C p artici p ati n g sites a n d All I nstit uti o ns

C O N FI D E N TI A L
T his d oc u me nt is c o nfi de ntial. D o n ot discl ose or use e xce pt as a ut h orize d.
2 9
S h ort title: P h ase II st u d y of El ot uz u m a b pl us R V D i n Ne wl y Di a g n ose d M M
Versi o n D ate: N o ve m ber 1 0, 2 0 2 0 
T he re gistrati o n pr oce d ures are as f oll o ws:
1.
O btai n writte n i nf or me d c o nse nt fr o m t he partici pa nt pri or t o t he perf or ma nce of a n y st u d y 
relate d pr oce d ures or assess me nts. 
2.
C o m plete t he O D Q pr ot oc ol-s pecific eli gi bilit y c hec klist usi n g t he eli gi bilit y assess me nt 
d oc u me nte d i n t he partici pa nt’s me dical rec or d a n d/ or researc h c hart. T o be eli gi ble f or 
re gistrati o n t o t he pr ot oc ol, t he partici pa nt m ust meet all i ncl usi o n a n d e xcl usi o n criteri o n as 
descri be d i n t he pr ot oc ol a n d reflecte d o n t he eli gi bilit y c hec klist.
3. E- mail all t he f oll o wi n g d oc u me nts t o A C T O nc ol o g y at El o R V D @act o nc ol o g y.c o m
a.
C o p y of all scree ni n g tests a n d pr oce d ures 
b. Si g ne d i nf or me d c o nse nt f or m
c.
HI P A A a ut h orizati o n f or m (if se parate fr o m t he i nf or me d c o nse nt d oc u me nt)
d. Eli gi bilit y C hec klist
4. A C T O nc ol o g y will re vie w t he re gistrati o n d oc u me nts f or c o m plete ness a n d f oll o w u p wit h t he 
site if a n y clarificati o n is re q uire d or if a n y a d diti o nal s o urce d oc u me nts are nee de d.  O nce all 
d oc u me nts are verifie d t o be i n or der, A C T O nc ol o g y will pr o vi de c o nfir mati o n b y e- mail t o 
t he st u d y c o or di nat or at t he site, t he o verall st u d y PI, a n d a desi g nee of D F CI tea m. O nce t he 
st u d y PI, or his desi g nee, a p pr o ves t he s u bject f or e nr oll me nt, he/s he will se n d a n a p pr o val e-
mail bac k t o A C T a n d t he site tea m.   A desi g nee at D F CI ( or D F/ H C C st u d y c o or di nat or f or 
D F/ H C C sites) will pr ocee d t o re gister t he partici pa nt wit h t he O D Q Re gistrar.
5.
F oll o wi n g t he re gistrati o n, a n e mail c o nfir mi n g t he s u bject is o n st u d y will be se nt t o t he O verall 
PI, site PI a n d st u d y c o or di nat or(s), fr o m t he Lea d Site.
T he re gistrati o n pr ocess is s u m marize d as f oll o ws:
Site ( D F CI or Ot her I n vesti g ati ve Site) → A C T O nc ol o g y → D F CI C o or di n ati n g Ce nter PI 
→ A p pr o v al t o A C T 
O nc ol o g y a n d site → D F CI C o or di n ati n g Ce nter ( or D F/ H C C 
c o or di n at or f or D F/ H C C ce nters) will e nr oll p artici p a nts  a n d will c o nfir m s u bject 
re gistr ati o n o n st u d y
N ote: Sa me da y treat me nt re gistrati o ns will o nl y be acce pte d wit h pri or n otice a n d disc ussi o n wit h 
t he D F/ H C C Lea d I nstit uti o n.
A partici pa nt ca n n ot i nitiate st u d y treat me nt u ntil t he Partici pati n g I nstit uti o n recei ves a n e- mail 
C o nfir mati o n of O D Q Re gistrati o n a n d C o nfir mati o n of Re gistrati o n wit h A C T O nc ol o g y. 
5 
T R E A T M E N T P L A N  
Treat me nt will be a d mi nistere d o n a n o ut patie nt basis.  E x pecte d t o xicities a n d p ote ntial ris ks as 
well as d ose m o dificati o ns f or le nali d o mi de, b ortez o mi b, de xa met has o ne a n d el ot uz u ma b are 

C O N FI D E N TI A L
T his d oc u me nt is c o nfi de ntial. D o n ot discl ose or use e xce pt as a ut h orize d.
3 0
S h ort title: P h ase II st u d y of El ot uz u m a b pl us R V D i n Ne wl y Di a g n ose d M M
Versi o n D ate: N o ve m ber 1 0, 2 0 2 0 
descri be d i n Secti o n 6 ( E x pecte d T o xicities a n d 
D osi n g 
Dela ys/ D ose 
M o dificati o n). 
N o 
i n vesti gati o nal or c o m mercial a ge nts or t hera pies ot her t ha n t h ose descri be d bel o w ma y be 
a d mi nistere d wit h t he i nte nt t o treat t he partici pa nt’s mali g na nc y.
Tre at me nt D ose a n d Sc he d ule
Tre at me nt 
C ycle
1 a n d 2
3 a n d 4
5 t hr o u g h 8
M ai nte n a nce
El ot uz u m a b I V
1 0 m g/ k g I V
Da ys 1, 8, & 1 5
1 0 m g/ k g I V
Da ys 1 & 1 1
1 0 m g/ k g I V
Da ys 1, & 1 1
2 0 m g/ k g I V
Da y 1
B ortez o mi b S q
1. 3 m g/ m 2
Da ys 1, 4, 8, 1 1 S Q
1. 3 m g/ m 2
Da ys 1, 4, 8, 1 1 S Q
1. 3 m g/ m 2
Da ys 1, 4, 8, 1 1 S Q
1. 3 m g/ m 2
Da ys 1 & 1 5 S Q
Le n ali d o mi de 
P O
2 5 m g p o
Da ys 1 - 1 4
2 5 m g p o
Da ys 1 - 1 4
2 5 m g p o
Da ys 1 - 1 4
 1 0 m g p o
Da ys 1 – 2 1 * O R 
d ose t olerate d 
d uri n g i n d ucti o n 
Da ys 1 – 2 1 * *
De x a met h as o ne 
P O
2 0 m g p o
D 2, 4, 5, 9, 1 1 & 1 2
2 8 m g p o ( 3 - 2 4 h) pre 
El o * * *
2 0 m g p o  
D 2, 4, 5, 8, 9 & 1 2
  2 8 m g p o ( 3  -
2 4 h) pre El o * * * 
1 0 m g p o  
D 2, 4, 5, 8, 9, & 1 2
 2 8  m g p o ( 3 - 2 4 h) 
pre El o * * *
  
-
De x a met h as o ne 
I V
8 m g I V ( 4 5 –  9 0 mi n 
pre El o)
D 1, 8 a n d 1 5
8 m g I V  ( 4 5-   
9 0 mi n pre El o)  
 D 1,  a n d 1 1
8 m g I V ( 4 5 –   
9 0 mi n pre El o) 
D 1 & 1 1
8 m g I V
( 4 5- 9 0 mi ns pre 
El o) D 1
a Ris k base d see secti o n 5. 4. 4. 2
* F or patie nts u n der g oi n g A S C T w h o are I S S sta ge III a n d/ or ha ve hi g h-ris k c yt o ge netics a n d f or f or patie nts u n der g oi n g 
A S C T w h o are I S S I or II wit h o ut hi g h-ris k c yt o ge netics
* * F or patie nts o pti n g n ot t o pr ocee d wit h A S C T f oll o wi n g 8 c ycles of i n d ucti o n w h o are I S S sta ge I wit h o ut hi g h-ris k 
c yt o ge netics a n d f or patie nts o pti n g n ot t o pr ocee d wit h A S C T f oll o wi n g 8 c ycles of i n d ucti o n w h o are I S S sta ge II or III 
a n d/ or ha ve hi g h-ris k c yt o ge netics
* * * At t he discreti o n of t he i n vesti gat or, t he 2 8 m g oral de xa met has o ne c o m p o ne nt ma y be gi ve n as a s plit d ose: 1 2 m g P O ( 1 2 
– 2 4 h o urs pri or t o el ot uz u ma b) A N D 1 6 m g P O ( 3 h o urs pri or t o el ot uz u ma b)
Dr u g a d mi nistrati o n g ui deli nes, pretreat me nt rec o m me n dati o ns a n d c o nc o mita nt me dicati o ns are 
o utli ne d t hr o u g h o ut t his secti o n. 
5. 1 
Pre-tre at me nt Criteri a
Patie nts m ust meet all t he eli gi bilit y criteria i ncl u di n g pre-treat me nt assess me nts pri or t o i nitiati o n 
of t hera p y.  Refer t o Secti o n 9 st u d y cale n dar f or all pre-treat me nt st u d y pr oce d ures.  
Pre-treat me nt c o nc o mita nt me dicati o ns a n d pr oce d ures t hat are re q uire d a n d or rec o m me n de d a n d 
t h ose t o be a v oi de d are detaile d i n Secti o n 5. 5: Ge neral C o nc o mita nt me dicati o ns a n d S u p p orti ve 
Care G ui deli nes.

C O N FI D E N TI A L
T his d oc u me nt is c o nfi de ntial. D o n ot discl ose or use e xce pt as a ut h orize d.
3 1
S h ort title: P h ase II st u d y of El ot uz u m a b pl us R V D i n Ne wl y Di a g n ose d M M
Versi o n D ate: N o ve m ber 1 0, 2 0 2 0 
All patie nts s h o ul d be e val uate d f or a d verse e ve nts pri or t o c o nti n uati o n of t hera p y be y o n d C ycle 
1, da y 1 i ncl u di n g i ntra-c ycle d osi n g a n d i nitiati o n of s u bse q ue nt c ycles.   D ose m o dificati o ns a n d 
g ui deli nes f or i nitiati o n of a ne w c ycle of t hera p y are o utli ne d i n Secti o n 6.
5. 2 
Tre at me nt
5. 2. 1 I n d ucti o n ( C ycles 1 - 8): I n d ucti o n re gi me n will c o nsist of a tre at me nt c ycle e ver y 
2 1 d a ys wit h:

El ot uz u ma b at 1 0 m g/ k g o n Da ys 1, 8, a n d 1 5 d uri n g I n d ucti o n C ycles 1 a n d 2 a n d 1 0 m g/ k g 
o n Da ys 1 a n d 1 1 d uri n g I n d ucti o n C ycles 3 t hr o u g h 8.

B ortez o mi b at 1. 3 m g/ m 2  S Q o n Da ys 1, 4, 8, a n d 1 1 of  C ycles 1 - 8, f oll o we d b y a 1 0- da y 
rest peri o d.

Le nali d o mi de as a si n gle dail y oral d ose of 2 5 m g o n Da ys 1 - 1 4 of  C ycles 1 - 8, f oll o we d b y 
7- da y rest peri o d. ( Le nali d o mi de starti n g d ose t o be a dj uste d acc or di n g t o baseli ne re nal 
f u ncti o n acc or di n g t o Pac ka ge I nsert g ui deli ne).  

De xa met has o ne as a si n gle dail y oral d ose of 2 0 m g/ da y o n Da ys 2, 4, 5, 9, 1 1, a n d 1 2 d uri n g 
C ycles 1 a n d 2. 

De xa met has o ne  2 8 m g p o ( 3 – 2 4 h o urs bef ore el ot uz u ma b) a n d 8 m g I V ( 4 5- 9 0 mi n utes 
bef ore el ot uz u ma b) o n Da ys 1, 8, a n d 1 5 i n d uri n g I n d ucti o n C ycles 1 a n d 2.  

De xa met has o ne as a si n gle oral d ose of 2 0 m g/ da y o n Da ys 2, 4, 5, 8, 9, a n d 1 2 d uri n g i n d ucti o n 
C ycles 3 a n d 4.

De xa met has o ne  2 8 m g p o ( 3 – 2 4 h o urs bef ore el ot uz u ma b) a n d 8 m g I V ( 4 5- 9 0 mi n utes 
bef ore el ot uz u ma b) o n Da ys 1 a n d 1 1 of I n d ucti o n C ycles 3 a n d 4.  

De xa met has o ne 1 0 m g as a si n gle oral d ose of 1 0 m g o n Da ys 2, 4, 5, 8, 9, a n d 1 2 d uri n g 
i n d ucti o n C ycles 5 t hr o u g h 8.

De xa met has o ne  2 8  m g p o ( 3 – 2 4 h o urs bef ore el ot uz u ma b) a n d 8 m g I V ( 4 5- 9 0 mi n utes 
bef ore el ot uz u ma b) o n Da ys 1 a n d 1 1 of i n d ucti o n C ycles 5 t hr o u g h 8.    
5. 2. 2 Ste m cell m o biliz ati o n:
Ste m cell m o bilizati o n will be perf or me d f or all  s u bjects at t he e n d of I n d ucti o n C ycle 4. Ste m cell 
m o bilizati o n will be perf or me d wit h eit her c ycl o p h os p ha mi de 2 5 0 0 m g/ m 2 a n d fil grasti m or 
fil grasti m wit h or wit h o ut pleri xaf or.  If ste m cell m o bilizati o n usi n g t his a p pr oac h is u ns uccessf ul, 
a sec o n d atte m pt at c ollecti o n ca n be u n derta ke n wit hi n o ne m o nt h of t he first atte m pt at 
m o bilizati o n. S u bjects w h o attai n at least a P R ma y elect t o st o p E- R V D at t he e n d of I n d ucti o n 
C ycle 4 a n d pr ocee d t o a ut ol o g o us S C T as per t he i nstit uti o nal g ui deli nes. T he decisi o n w het her 
s u bjects will pr ocee d t o S C T will be ma de o n t he basis of treati n g p h ysicia n rec o m me n dati o ns a n d 
patie nt prefere nce. P h ysicia n rec o m me n dati o ns are t y picall y base d o n disease res p o nse a n d o n 
h o w well s u bjects are t olerati n g treat me nt. T he ki n d of decisi o n ma ki n g pr ocess relate d t o S C T is 
c o nsi dere d n o wa da ys sta n dar d of care i n t he m ulti ple m yel o ma fiel d.  S u bjects w h o d o n ot pr ocee d 
t o S C T ma y recei ve a f ull 8 c ycles of t he i n d ucti o n t hera p y. H o we ver, pri or t o c o nti n ui n g t o 

C O N FI D E N TI A L
T his d oc u me nt is c o nfi de ntial. D o n ot discl ose or use e xce pt as a ut h orize d.
3 2
S h ort title: P h ase II st u d y of El ot uz u m a b pl us R V D i n Ne wl y Di a g n ose d M M
Versi o n D ate: N o ve m ber 1 0, 2 0 2 0 
I n d ucti o n C ycle 5, all ste m cell har vest-relate d t o xicities m ust ha ve res ol ve d or i m pr o ve d t o 
C T C A E Gra de  1 a n d s u bjects m ust meet t he f oll o wi n g ste m cell har vest rec o ver y criteria:
a)
E C O G  2;
b)
A bs ol ute ne utr o p hil c o u nt > 1 0 0 0 cells/ m m 3;
c)
Platelet c o u nt  7 5, 0 0 0 cell/ m m3  ( 7 5 x 1 09/ L);
d)
He m o gl o bi n  8 g/ d L at m ost rece nt meas ure me nt;
e)
T otal bilir u bi n < 1. 5 x u p per li mit of n or mal ( U L N);
f)
As partate a mi n otra nsferase ( A S T) or ala ni ne a mi n otra nsferase ( A L T) < 3 x U L N;
g)
A ble t o u n der g o f urt her treat me nt i n t he j u d g me nt of t he i n vesti gat or.
I n t he e ve nt t hat t hera p y is dela ye d d ue t o ste m cell m o bilizati o n, c ollecti o n, or tra ns pla nt, t he 
treati n g p h ysicia n will deter mi ne o pti mal ti mi n g of treat me nt re-i nitiati o n. I n t he e ve nt t hat 
d uri n g t his peri o d off treat me nt m yel o ma-relate d para meters (i.e. ser u m m o n ocl o nal pr otei n, 
uri ne m o n ocl o nal pr otei n a n d/ or i n v ol ve d free li g ht c hai n) i ncrease a n d meet criteria f or 
pr o gressi o n, patie nts ma y c o nti n ue o n t hera p y if t he i ncrease i n t hese para meters is felt t o be 
relate d t o dela y i n t hera p y a n d t here c o ul d be cli nical be nefit ass ociate d wit h f urt her t hera p y. 
T his deter mi nati o n will be ma de b y t he treati n g p h ysicia n i n c o ns ultati o n wit h t he o verall st u d y 
PI.  
5. 2. 3
M ai nte n a nce:
S u bjects w h o recei ve 8 c ycles of t he i n d ucti o n re gi me n will be all o we d t o c o nti n ue treat me nt o n a 
mai nte na nce sc he d ule, if t he y ha ve at least sta ble disease a n d are eli gi ble t o recei ve mai nte na nce 
treat me nt. A d diti o nall y, s u bjects w h o recei ve d S C T at t he e n d of I n d ucti o n C ycle 4 will f ore g o 
C ycles 5 t o 8 of t hera p y a n d  will be all o we d t o c o nti n ue treat me nt directl y o n a mai nte na nce sc he d ule 
after rec o ver y fr o m S C T pr o vi de d t hat all S C T-relate d t o xicities ha ve res ol ve d or i m pr o ve d t o 
C T C A E Gra de  1 a n d t he y meet t he ste m cell har vest rec o ver y criteria defi ne d i n Secti o n 5. 2. 2.
Mai nte na nce t hera p y will c o nti n ue u ntil disease rela pse, u nacce pta ble t o xicit y, wit h dra wal of 
c o nse nt or n o f urt her cli nical be nefit is e x perie nce d. S u bjects u na ble t o t olerate a n y of t he 
i n di vi d ual dr u gs (e g, el ot uz u ma b, le nali d o mi de or b ortez o mi b) d uri n g t he mai nte na nce p hase ma y 
st o p t h ose i n di vi d ual dr u gs a n d c o nti n ue o n t he re mai ni n g dr u gs, wit h or wit h o ut de xa met has o ne, 
at t he i n vesti gat or’s discreti o n. 
Mai nte na nce t hera p y will be a d mi nistere d t o all patie nts, wit h t he s pecific mai nte na nce re gi me n 
deter mi ne d b y ris k cate g or y.  Eac h c ycle of mai nte na nce t hera p y is 2 8 da ys.
P atie nts u n der g oi n g A S C T w h o are I S S st a ge III a n d/ or h a ve hi g h-ris k c yt o ge netics  
i ncl u di n g t( 4; 1 4), t( 1 4; 1 6); or del 1 7 p will recei ve mai nte na nce wit h:

El ot uz u ma b 2 0 m g/ k g o n Da y 1 of eac h 2 8 da y c ycle; 

Le nali d o mi de 1 0 m g Da ys 1 – 2 1; 

B ortez o mi b 1. 3 m g/ m 2 Da ys 1 a n d 1 5 S Q;

C O N FI D E N TI A L
T his d oc u me nt is c o nfi de ntial. D o n ot discl ose or use e xce pt as a ut h orize d.
3 3
S h ort title: P h ase II st u d y of El ot uz u m a b pl us R V D i n Ne wl y Di a g n ose d M M
Versi o n D ate: N o ve m ber 1 0, 2 0 2 0 

I V de xa met has o ne 8 m g o n Da y 1 ( 4 5- 9 0 mi n utes bef ore el ot uz u ma b). 
P atie nts u n der g oi n g A S C T w h o are I S S I or II wit h o ut hi g h-ris k  c yt o ge netics will recei ve 
mai nte na nce wit h:

El ot uz u ma b 2 0 m g/ k g Da y 1 of eac h 2 8 da y c ycle; 

 Le nali d o mi de 1 0 m g Da ys 1 – 2 1; a n d 

I V de xa met has o ne 8 m g o n Da y 1 ( 4 5- 9 0 mi n utes bef ore el ot uz u ma b).
P atie nts o pti n g n ot t o pr ocee d wit h A S C T f oll o wi n g 8 c ycles of i n d ucti o n w h o are I S S st a ge 
II or III a n d/ or h a ve hi g h-ris k c yt o ge netics i ncl u di n g t( 4; 1 4), t( 1 4; 1 6); or del 1 7 p will recei ve 
mai nte na nce wit h:

El ot uz u ma b 2 0 m g/ k g o n Da y 1 of eac h 2 8 da y c ycle; 

Le nali d o mi de at t he d ose t olerate d d uri n g i n d ucti o n Da ys 1 – 2 1; 

B ortez o mi b 1. 3 m g/ m 2 Da ys 1 a n d 1 5 S Q; a n d 

I V de xa met has o ne 8 m g o n Da y 1 ( 4 5- 9 0 mi n utes bef ore el ot uz u ma b).
P atie nts o pti n g n ot t o pr ocee d wit h A S C T f oll o wi n g 8 c ycles of i n d ucti o n w h o are I S S st a ge 
I wit h o ut hi g h-ris k c yt o ge netics will recei ve mai nte na nce wit h:

El ot uz u ma b 2 0 m g/ k g Da y 1 of eac h 2 8 da y c ycle; 

Le nali d o mi de at t he d ose t olerate d d uri n g i n d ucti o n Da ys 1 – 2 1; a n d

I V de xa met has o ne 8 m g o n Da y 1 ( 4 5- 9 0 mi n utes bef ore el ot uz u ma b).
5. 2. 4 T u m or assess me nts: 
It is rec o m me n de d t hat disease assess me nts are perf or me d per sta n dar d of care. 
5. 3  
A ge nt A d mi nistr ati o n
5. 3. 1 El ot uz u m a b
N ote: a d mi nister el ot uz u ma b 3 0 t o 9 0 mi n utes f oll o wi n g b ortez o mi b w he n b ot h dr u gs are gi ve n 
o n t he sa me da y. El ot uz u ma b will be a d mi nistere d t o eac h s u bject as a n I V i nf usi o n, usi n g a n 
a ut o mate d i nf usi o n p u m p set at t he a p pr o priate rate acc or di n g t o t he i nstr ucti o ns pr o vi de d i n 
Secti o n 7. 4. 4 a n d A p pe n di x VII.
5. 3. 2 I n d ucti o n C ycles 1 a n d 2
El ot uz u ma b will be a d mi nistere d at a d ose of 1 0 m g/ k g I V o n Da ys 1, 8, a n d 1 5 i n 2 1- da y c ycles 
i n I n d ucti o n C ycles 1 a n d 2. T he d osi n g wi n d o w f or el ot uz u ma b is - 1/ + 3 da ys f or I n d ucti o n C ycles 
1 a n d 2.

C O N FI D E N TI A L
T his d oc u me nt is c o nfi de ntial. D o n ot discl ose or use e xce pt as a ut h orize d.
3 4
S h ort title: P h ase II st u d y of El ot uz u m a b pl us R V D i n Ne wl y Di a g n ose d M M
Versi o n D ate: N o ve m ber 1 0, 2 0 2 0 
5. 3. 3 I n d ucti o n C ycles 3 – 8
El ot uz u ma b will be a d mi nistere d at a d ose of 1 0 m g/ k g I V o n Da ys 1 a n d 1 1 i n 2 1- da y c ycles i n 
I n d ucti o n C ycles 3 – 8. T he d osi n g wi n d o w f or el ot uz u ma b is - 3/ + 7 f or I n d ucti o n C ycles 3 t hr o u g h 
8.
5. 3. 4
M ai nte n a nce C ycles
El ot uz u ma b will be a d mi nistere d at a d ose of 2 0 m g/ k g I V o n Da y 1 i n 2 8- da y c ycles. T he d osi n g 
wi n d o w f or el ot uz u ma b is - 3/ + 7 da ys be gi n ni n g wit h Mai nte na nce C ycle 1.
See A p pe n di x VII f or i nstr ucti o ns re gar di n g pre parati o n a n d a d mi nistrati o n of el ot uz u ma b. T he 
first i nf usi o n is e x pecte d t o re q uire a p pr o xi matel y 3 h o urs.
5. 3. 5 Vit al Si g ns, P h ysic al Me as ure me nts, a n d P h ysic al E x a mi n ati o n
Vital si g ns ( b o d y te m perat ure, res pirat or y rate, seate d bl o o d press ure a n d heart rate) will be 
rec or de d as o utli ne d i n Secti o n 9, Ta ble 9. 1. Bl o o d press ure, res pirat or y rate a n d heart rate s h o ul d 
be meas ure d after t he s u bject has bee n seate d q uietl y f or at least 5 mi n utes pri or t o d osi n g. S u bjects 
will ha ve vital si g ns meas ure d as f oll o ws:

Pri or t o pre- me dicati o n a d mi nistrati o n

Pri or t o t he start of t he el ot uz u ma b i nf usi o n

T hirt y mi n utes after t he start of i nf usi o n

At t he e n d of t he i nf usi o n

T hirt y a n d 1 2 0 mi n utes p ost c o m pleti o n of t he el ot uz u ma b i nf usi o n f or I n d ucti o n C ycles 1 a n d 
2

I n d ucti o n C ycle 3 a n d be y o n d p ost i nf usi o n vital si g ns will be meas ure d at 3 0 mi n utes

S u bjects w h o e x perie nce a n i nf usi o n reacti o n re q uire vital si g ns t o be m o nit ore d e ver y 3 0 
mi n utes d uri n g a n d f or 2 h o urs after t he e n d of t he el ot uz u ma b i nf usi o n
Hei g ht will be rec or de d at scree ni n g. Wei g ht will be meas ure d at st u d y visits as i n dicate d i n Ta bles 
9.
A f ull p h ysical e xa mi nati o n will be perf or me d at t he scree ni n g visit, w hereas a tar gete d e xa m will 
occ ur as i n dicate d i n Secti o n 9, Ta ble 9. 1. Tar gete d p h ysical e xa mi nati o n ma y be perf or me d b y a 
q ualifie d pr ofessi o nal g ui de d b y t he e xa mi ner’s o bser vati o ns a n d/ or s u bject c o m plai nts o n ne w or 
c ha n ge d c o n diti o ns, s y m pt o ms, or c o ncer ns. Tar gete d p h ysical e xa mi nati o n i ncl u des assess me nt 
of heart, l u n g, a n d a b d o me n.
5. 3. 6 Perf or m a nce St at us

C O N FI D E N TI A L
T his d oc u me nt is c o nfi de ntial. D o n ot discl ose or use e xce pt as a ut h orize d.
3 5
S h ort title: P h ase II st u d y of El ot uz u m a b pl us R V D i n Ne wl y Di a g n ose d M M
Versi o n D ate: N o ve m ber 1 0, 2 0 2 0 
Perf or ma nce assess me nt will be perf or me d acc or di n g t o Secti o n 9, Ta ble 9. 1 as descri be d i n 
A p pe n di x 1. T he assess me nt s h o ul d be c o m plete d pri or t o a n y st u d y-relate d pr oce d ures, treat me nt 
or cli nicia n assess me nt.
5. 3. 7 El ot uz u m a b Pre me dic ati o n
5. 3. 7. 1
El ot u z u m a b P r e m e di c ati o n R e gi m e n i n S u bj e cts wit h o ut a P ri o r I nf usi o n 
R e a cti o n
O n da ys of el ot uz u ma b i nf usi o n, t he de xa met has o ne d ose will be s plit i nt o a p o a n d I V 
a d mi nistrati o n ( descri be d i n Secti o n 5. 4. 5 w hic h will als o ser ve as pre me dicati o n f or el ot uz u ma b).
I ntra ve n o us a n d p o de xa met has o ne d oses are calc ulate d t o pr o vi de a t otal d ose t hat is bi oe q ui vale nt 
t o t he 2 0 m g oral d ose d uri n g I n d ucti o n C ycles 1 - 4 a n d 1 0 m g oral d ose d uri n g I n d ucti o n C ycles 
5 - 8 a n d d uri n g mai nte na nce ( de xa met has o ne 8 m g I V is a p pr o xi matel y bi oe q ui vale nt t o 1 1 m g 
p o).
I n a d diti o n, t he f oll o wi n g m ust als o be a d mi nistere d 4 5 t o 9 0 mi n utes bef ore i nitiati n g t he 
el ot uz u ma b:
H 1 bl oc ker: di p he n h y dra mi ne ( 2 5 - 5 0 m g p o or I V) or e q ui vale nt ( 4 5- 9 0 mi ns pri or t o t he start of 
i nf usi o n)
H 2 bl oc ker: ra niti di ne ( 5 0 m g I V) or e q ui vale nt
Aceta mi n o p he n ( 6 5 0 - 1 0 0 0 m g p o).
C o ns ult t he PI f or f urt her g ui da nce re gar di n g alter nati ve pre- me dicati o ns f or s u bjects aller gic or 
i nt olera nt t o a n y pre me dicati o n or t o deter mi ne if l ocall y use d e q ui vale nt me dicati o ns are 
acce pta ble.
5. 3. 7. 2
El ot u z u m a b P r e m e di c ati o n R e gi m e n i n S u bj e cts wit h a P ri o r I nf usi o n R e a cti o n
T o be re-treate d wit h el ot uz u ma b, s u bjects wit h pri or i nf usi o n reacti o n m ust recei ve H 1 a n d H 2 
bl oc kers a n d aceta mi n o p he n at n o 
m ore t ha n t he 
ma xi m u m d oses s pecifie d (e g: 5 0 m g 
di p he n h y dra mi ne, 5 0 m g ra niti di ne [ or e q ui vale nt], a n d 1 0 0 0 m g aceta mi n o p he n) 4 5 t o 9 0 mi n utes 
bef ore i nitiati n g t he el ot uz u ma b.
D oses of I V de xa met has o ne a b o ve 1 0 
m g re q uire a decrease i n t he p o de xa met has o ne. 
Rec o m me n de d de xa met has o ne d osi n g is s u m marize d i n Ta ble 5. 3. Decisi o ns t o use m ore 

C O N FI D E N TI A L
T his d oc u me nt is c o nfi de ntial. D o n ot discl ose or use e xce pt as a ut h orize d.
3 6
S h ort title: P h ase II st u d y of El ot uz u m a b pl us R V D i n Ne wl y Di a g n ose d M M
Versi o n D ate: N o ve m ber 1 0, 2 0 2 0 
a g gressi ve pre me dicati o n sc he mes i n s u bjects wit h o nl y pri or Gra de 1 or o nl y o ne pri or Gra de 2 
i nf usi o n reacti o n m ust be a p pr o ve d b y t he Pri nci pal I n vesti gat or.
T a ble 5. 3: C ortic oster oi d Pre me dic ati o n a 
Pri or I nf usi o n Re acti o n
C ortic oster oi d Pre me dic ati o n b  Bef ore El ot uz u m a b
N o ne or
O nl y Gra de 1 i nf usi o n reacti o n c
I n d ucti o n C ycles 1 – 8: 
2 8 m g p o de xa met has o ne ( 3 - 2 4 hrs. bef ore el ot uz u ma b) e A N D
8 m g I V de xa met has o ne at least 4 5- 9 0  mi n bef ore el ot uz u ma b 
M ai nte n a nce: 
8 m g I V de xa met has o ne at least 4 5- 9 0  mi n bef ore el ot uz u ma b
Pri or Gra de 2 i nf usi o n reacti o n d
I n d ucti o n c ycles a n d M ai nte n a nce: 
2 8 m g p o de xa met has o ne ( 3 - 2 4 hrs. bef ore el ot uz u ma b e A N D
1 0 m g I V de xa met has o ne at least 4 5 - 9 0 mi n bef ore el ot uz u ma b 
Pri or Gra de 3 or rec urre nt 
Gra de 2 i nf usi o n reacti o n
I n d ucti o n c ycles a n d M ai nte n a nce: 
8 m g p o de xa met has o ne ( 1 2 - 2 4 hrs. bef ore el ot uz u ma b) A N D
8 m g p o de xa met has o ne (at least 3 hrs. bef ore el ot uz u ma b, o n t he 
sa me da y as t he i nf usi o n) A N D
1 8 m g I V de xa met has o ne at least 4 5 – 9 0 mi n bef ore el ot uz u ma b
a
F or pri or i nf usi o n reacti o ns, use ma xi m u m d oses H 1, H 2 bl oc kers a n d aceta mi n o p he n as descri be d i n Secti o n 
5. 3. 6. 2
b
At t he discreti o n of t he i n vesti gat or, t he oral de xa met has o ne c o m p o ne nt ma y be gi ve n as a s plit d ose 1 2 - 2 4 a n d 3 
h o urs bef ore el ot uz u ma b f or pri or Gra de 1 a n d 2 i nf usi o n reacti o ns.
c
S u bjects wit h pri or Gra de 1 i nf usi o n reacti o n ma y be pre me dicate d as per Gra de 2 i nf usi o n reacti o ns if a p pr o ve d 
b y t he me dical m o nit or.
d
S u bjects wit h pri or Gra de 2 i nf usi o n reacti o n ma y be pre me dicate d as per Gra de 3 i nf usi o n reacti o ns if a p pr o ve d 
b y t he me dical m o nit or.
e At t he discreti o n of t he i n vesti gat or, t he 2 8 m g oral de xa met has o ne c o m p o ne nt ma y be gi ve n as a s plit d ose: 1 2 m g 
P O ( 1 2 – 2 4 h o urs pri or t o el ot uz u ma b) A N D 1 6 m g P O ( 3 h o urs pri or t o el ot uz u ma b).
If a s u bject wit h a pri or Gra de 2 t o 3 i nf usi o n reacti o n als o re q uires d ose re d ucti o n of 
de xa met has o ne, t he de xa met has o ne d ose o n t he da ys of el ot uz u ma b i nf usi o n s h o ul d be n o l o wer 
t ha n 8 m g I V ( o n t he da y of el ot uz u ma b i nf usi o n at least 4 5 – 9 0 mi n utes bef ore el ot uz u ma b).
S u bjects wit h Gra de 4 i nf usi o n reacti o n are n ot eli gi ble t o recei ve a d diti o nal el ot uz u ma b. T hese 
s u bjects ma y c o nti n ue t o recei ve le nali d o mi de, b ortez o mi b, a n d de xa met has o ne.
If a s u bject is u na ble t o t olerate pre me dicati o ns, t he st u d y PI s h o ul d be ma de a ware.
F or patie nts w h o ha ve n ot e x perie nce d a n i nf usi o n reacti o n, t he 2 8 m g d ose of de xa met has o ne ca n 
be re d uce d first t o 2 0 m g a n d sec o n dl y t o 1 2 m g.  T he 8 m g I V d ose ca n be re d ucte d t o o ne le vel, 

C O N FI D E N TI A L
T his d oc u me nt is c o nfi de ntial. D o n ot discl ose or use e xce pt as a ut h orize d.
3 7
S h ort title: P h ase II st u d y of El ot uz u m a b pl us R V D i n Ne wl y Di a g n ose d M M
Versi o n D ate: N o ve m ber 1 0, 2 0 2 0 
t o 4 m g.  St u d y partici pa nts w h o ha ve e x perie nce d a pri or i nf usi o n reacti o n will n ot be a ble t o 
re d uce t he de xa met has o ne pre- me dicati o n d ose.
5. 3. 8 G ui deli nes f or El ot uz u m a b I nf usi o n i n S u bjects wit h I nf usi o n Re acti o ns
5. 3. 8. 1
G r a d e 1 I nf usi o n R e a cti o n
F or Gra de 1 el ot uz u ma b i nf usi o n-relate d reacti o ns, c o nsi der te m p orar y i nterr u pti o n of i nf usi o n or 
sl o wi n g of i nf usi o n rate a n d treat me nt wit h s u p p orti ve meas ures, as cli nicall y i n dicate d. U nless 
s y m pt o ms w orse n, t he i nf usi o n ca n res u me or c o nti n ue as pla n ne d.
5. 3. 8. 2
G r a d e 2- 3 I nf usi o n R e a cti o n
I nf usi o n re acti o ns d uri n g t he el ot uz u m a b i nf usi o n: F or a Gra de  2 el ot uz u ma b i nf usi o n-relate d 
reacti o n, t he i nf usi o n m ust be i nterr u pte d. T he s u bject s h o ul d be treate d as cli nicall y i n dicate d 
wit h o ne or m ore of t he f oll o wi n g me dicati o ns or i nter ve nti o ns: a nti-e metics, a nti hista mi nes, 
a nal gesics, 
c ortic oster oi ds, 
le u k otrie ne 
i n hi bit ors, 
o x y ge n 
i n halati o n, 
e pi ne p hri ne, 
br o nc h o dilat ors, or ot her s u p p orti ve meas ures. 
F or Gra de 2 i nf usi o n reacti o ns, o nce t he el ot uz u ma b i nf usi o n-relate d reacti o n has res ol ve d t o 
Gra de  1, t he i nf usi o n ca n be restarte d at t he sa me rate of i nf usi o n at w hic h t he i nf usi o n reacti o n 
occ urre d. If s y m pt o ms d o n ot rec ur after 3 0 mi n utes, t he i nf usi o n rate ma y be i ncrease d i n a 
ste p wise fas hi o n ( acc or di n g t o Ta ble 2, A p pe n di x VII). F or Gra de 3 i nf usi o n reacti o ns, o nce t he 
el ot uz u ma b i nf usi o n-relate d reacti o n has res ol ve d t o Gra de  1, t he i nf usi o n ca n be restarte d at 
o ne le vel l o wer t ha n t he rate of i nf usi o n at w hic h t he i nf usi o n reacti o n occ urre d (refer t o Ta ble 2, 
A p pe n di x VII). If s y m pt o ms d o n ot rec ur after 3 0 mi n utes, t he i nf usi o n rate ma y be i ncrease d i n a 
ste p wise fas hi o n ( Ta ble 2, A p pe n di x VII). H o we ver, fi nal deter mi nati o n a b o ut t he rate of i nf usi o n 
will be deter mi ne d b y t he treati n g p h ysicia n a n d ma y be c o nsi dere d o n a case- b y-case basis. 
S u bjects w h o e x perie nce a n i nf usi o n reacti o n re q uire vital si g ns t o be m o nit ore d e ver y 3 0 mi n utes 
d uri n g a n d f or 2 h o urs after t he e n d of t he el ot uz u ma b i nf usi o n. If t he el ot uz u ma b i nf usi o n reacti o n 
rec urs, t he i nf usi o n m ust be st o p pe d a n d n ot restarte d o n t hat da y. A p pr o priate t hera p y s h o ul d be 
a d mi nistere d t o a d dress t he s u bject’s si g ns a n d s y m pt o ms. T he i nf usi o n ca n be reatte m pte d at t he 
ne xt pr ot oc ol defi ne d i nf usi o n ti me p oi nt at t he i n vesti gat or’s discreti o n wit h a d diti o nal 
pre me dicati o n as descri be d i n Ta ble 5. 3.
I nf usi o n re acti o ns after t he c o m pleti o n of el ot uz u m a b i nf usi o n: S h o ul d a Gra de  2 i nf usi o n 
reacti o n occ ur f oll o wi n g c o m pleti o n of a n el ot uz u ma b i nf usi o n, t he s u bject s h o ul d be treate d as 
cli nicall y i n dicate d 
wit h o ne or 
m ore of t he f oll o wi n g 
me dicati o ns or i nter ve nti o ns: 
di p he n h y dra mi ne, aceta mi n o p he n, h y dr oc ortis o ne, H 2 i n hi bit or, le u k otrie ne i n hi bit or, o x y ge n 
i n halati o n, e pi ne p hri ne, br o nc h o dilat ors, or ot her s u p p orti ve meas ures as i n dicate d.
S u bse q ue nt el ot uz u m a b i nf usi o n after a pri or Gr a de 2 or 3 i nf usi o n re acti o n : S u bjects wit h 
pri or Gra de 2 i nf usi o n reacti o ns s h o ul d ha ve t he s u bse q ue nt i nf usi o n starte d at t he sa me rate of 
i nf usi o n at w hic h t he i nf usi o n reacti o n occ urre d a n d t he i nf usi o n rate ma y be escalate d i n a 
ste p wise fas hi o n ( Ta ble 2, A p pe n di x VII) t o a ma xi m u m of 5 m L per mi n ute. S u bjects wit h 
pri or Gra de 3 i nf usi o n reacti o ns s h o ul d ha ve t he s u bse q ue nt i nf usi o n starte d at o ne le vel l o wer 

C O N FI D E N TI A L
T his d oc u me nt is c o nfi de ntial. D o n ot discl ose or use e xce pt as a ut h orize d.
3 8
S h ort title: P h ase II st u d y of El ot uz u m a b pl us R V D i n Ne wl y Di a g n ose d M M
Versi o n D ate: N o ve m ber 1 0, 2 0 2 0 
t ha n t he rate of i nf usi o n at w hic h t he i nf usi o n reacti o n occ urre d. See A p pe n di x VII f or g ui deli nes 
re gar di n g escalati o n of t he i nf usi o n rate.
5. 3. 8. 3
G r a d e 4 I nf usi o n R e a cti o n
El ot uz u ma b m ust be per ma ne ntl y disc o nti n ue d. S u bjects ma y c o nti n ue wit h le nali d o mi de, 
b ortez o mi b, a n d de xa met has o ne per pr ot oc ol.
5. 4 
Le n ali d o mi de 
5. 4. 1 I n d ucti o n C ycles
Le nali d o mi de * * 2 5 m g p o will be a d mi nistere d o n Da ys 1 t hr o u g h 1 4 f oll o we d b y 7 da ys rest i n 
2 1 da y c ycles. O n t he da ys of el ot uz u ma b a d mi nistrati o n, t he d ose of le n ali d o mi de is t o be 
a d mi nistere d at le ast 2 h o urs after c o m pleti o n of el ot uz u m a b d osi n g. 
* *( Le n ali d o mi de st arti n g d ose t o be a dj uste d acc or di n g t o b aseli ne re n al f u ncti o n acc or di n g 
t o P ac k a ge I nsert g ui deli ne).   
5. 4. 2
M ai nte n a nce C ycles
Mai nte na nce t hera p y will be a d mi nistere d t o all patie nts, wit h t he s pecific mai nte na nce re gi me n 
deter mi ne d b y ris k cate g or y.  Eac h mai nte na nce c ycles is 2 8 da ys.
P atie nts u n der g oi n g A S C T w h o are I S S st a ge III a n d/ or h a ve hi g h-ris k c yt o ge netics  
i ncl u di n g t( 4; 1 4), t( 1 4; 1 6); or del 1 7 p will recei ve mai nte na nce wit h:

Le nali d o mi de 1 0 m g da ys 1 – 2 1 of eac h 2 8 da y c ycle; 
P atie nts u n der g oi n g A S C T w h o are I S S I or II wit h o ut hi g h-ris k  c yt o ge netics will recei ve 
mai nte na nce wit h:

Le nali d o mi de 1 0 m g Da ys 1 – 2 1 of eac h 2 8 da y C ycle 1 – 2 1; a n d 
P atie nts o pti n g n ot t o pr ocee d wit h A S C T  w h o are I S S st a ge II or III a n d/ or h a ve hi g h-ris k 
c yt o ge netics  i ncl u di n g t( 4; 1 4), t( 1 4; 1 6); or del 1 7 p will recei ve mai nte na nce f oll o wi n g 8 c ycles 
of  i n d ucti o n wit h:

Le nali d o mi de at t he d ose t olerate d d uri n g i n d ucti o n Da ys 1 – 2 1 of eac h 2 8 da y c ycle; 
P atie nts o pti n g n ot t o pr ocee d wit h A S C T w h o are I S S st a ge I wit h o ut hi g h-ris k c yt o ge netics  
will recei ve mai nte na nce f oll o wi n g 8 c ycles of i n d ucti o n wit h:

Le nali d o mi de at t he d ose t olerate d d uri n g i n d ucti o n da ys 1 – 2 1 of eac h 2 8 da y c ycle
5. 4. 3 A L L C ycles
O nl y e n o u g h le nali d o mi de f or 1 c ycle of t hera p y ma y be pr o vi de d t o t he partici pa nt eac h c ycle. 
 
Le nali d o mi de ca ps ules s h o ul d be s wall o we d w h ole, a n d s h o ul d n ot be br o ke n, c he we d or o pe ne d.  
A d mi nistrati o n of le nali d o mi de will be at a p pr o xi matel y t he sa me ti me eac h da y.  H o we ver, t he 
d ose of le n ali d o mi de is t o be a d mi nistere d at le ast 2 h o urs after c o m pleti o n of el ot uz u m a b 
d osi n g.   Dr u g ma y be ta ke n wit h or wit h o ut f o o d.  If a d ose of le nali d o mi de is misse d a n d it has 

C O N FI D E N TI A L
T his d oc u me nt is c o nfi de ntial. D o n ot discl ose or use e xce pt as a ut h orize d.
3 9
S h ort title: P h ase II st u d y of El ot uz u m a b pl us R V D i n Ne wl y Di a g n ose d M M
Versi o n D ate: N o ve m ber 1 0, 2 0 2 0 
bee n less t ha n 1 2 h o urs si nce t he i nte n de d sc he d ule d d ose ti me, t he s u bject s h o ul d ta ke t he misse d 
d ose as s o o n as he/s he re me m bers. If it has bee n m ore t ha n 1 2 h o urs, t his le nali d o mi de d ose s h o ul d 
n ot be ta ke n. D o n ot ta ke 2 d oses at t he sa me ti me.  If it is misse d f or t he e ntire da y or v o mite d, 
t he d ose s h o ul d n ot be ma de u p a n d t he partici pa nt s h o ul d c o nti n ue wit h t he re g ular sc he d ule of 
t he dr u g at t he ne xt d ose. A dr u g diar y will be pr o vi de d t o partici pa nts t o rec or d oral a d mi nistrati o n 
of d oses.  
Partici pa nts w h o ta ke m ore t ha n t he prescri be d d ose of le nali d o mi de s h o ul d be i nstr ucte d t o see k 
e mer ge nc y me dical care if nee de d a n d c o ntact st u d y staff i m me diatel y.  Partici pa nts e x perie nci n g 
a d verse e ve nts ma y nee d st u d y treat me nt m o dificati o ns (see Secti o n 6).
Le nali d o mi de will be pr o vi de d i n acc or da nce wit h t he Re vli mi d R E M S ® pr o gra m of Cel ge ne 
C or p orati o n.  Per sta n dar d Re vli mi d R E M S ® re q uire me nts, all p h ysicia ns w h o prescri be 
le nali d o mi de f or researc h s u bjects e nr olle d i nt o t his trial m ust be re gistere d i n a n d m ust c o m pl y 
wit h all re q uire me nts of t he Re vli mi d R E M S ® pr o gra m.  Prescri pti o ns m ust be fille d wit hi n 7 
da ys.  O nl y e n o u g h le nali d o mi de f or o ne c ycle of t hera p y will be s u p plie d t o t he patie nt eac h c ycle.  
A dr u g diar y will be pr o vi de d t o partici pa nts t o rec or d oral a d mi nistrati o n of d oses.
All st u d y partici pa nts are re q uire d t o re gister i n a n d c o m pl y wit h t he Re vli mi d R E M S ® pr o gra m.
5. 4. 4 B ortez o mi b  
B ortez o mi b will be a d mi nistere d S Q u n der t he s u per visi o n of t he i n vesti gat or or i de ntifie d s u b-
i n vesti gat or(s).  Partici pa nts ma y be treate d o n a n o ut- patie nt basis, if p ossi ble.  T he a m o u nt (i n 
m g) of b ortez o mi b t o be a d mi nistere d will be deter mi ne d base d o n B S A.  B S A is t o be calc ulate d 
base d o n b o d y wei g ht usi n g t he D u B ois f or m ula ( A p pe n di x II) a n d i n acc or da nce wit h i nstit uti o nal 
sta n dar ds.  At a mi ni m u m, t he d ose will be calc ulate d o n Da y 1 of eac h c ycle.  At l e ast 7 0- 7 2 
h o urs 
m ust el a ps e b et w e e n b ort e z o mi b d os es. If t he patie nt de vel o ps t o xicit y i ncl u di n g 
ne ur o pat h y, less t ha n 7 2 h o urs bet wee n d oses is n ot rec o m me n de d, b ut n ot pr o hi bite d. B ort e z o mi b 
s h o ul d n ot b e a d mi nist er e d i n p arti ci p a nts w h o h a v e a k n o w n all er g y t o b ort e z o mi b, b or o n or 
m a n nit ol.  
5. 4. 4. 1
I n d u cti o n C y cl es 1 t o 8
B ortez o mi b ( 1. 3 m g/ m 2 ) S Q i njecti o n will be a d mi nistere d o n Da ys 1, 4, 8, a n d 1 1 i n 2 1- da y 
c ycles. T he d osi n g wi n d o w f or b ortez o mi b is  1 da y w he n b ortez o mi b is a d mi nistere d t wice per 
wee k; at least 7 2 h o urs m ust ela pse bet wee n c o nsec uti ve d oses of b ortez o mi b. H o we ver, d osi n g at 
a n i nter val of 7 0 h o urs is per mitte d f or sc he d uli n g reas o ns, s u bject c o n ve nie nce, or har ds hi p.
5. 4. 4. 2
M ai nt e n a n c e C y cl es
Mai nte na nce t hera p y will be a d mi nistere d t o all patie nts, wit h t he s pecific mai nte na nce re gi me n 
deter mi ne d b y ris k cate g or y.  Eac h mai nte na nce c ycle is 2 8 da ys.
P atie nts u n der g oi n g A S C T w h o are I S S st a ge III a n d/ or h a ve hi g h-ris k c yt o ge netics a n d 
p atie nts o pti n g n ot t o pr ocee d wit h A S C T f oll o wi n g 8 c ycles of i n d ucti o n w h o are I S S st a ge 
II or III a n d/ or h a ve hi g h-ris k c yt o ge netics i ncl u di n g t( 4; 1 4), t( 1 4; 1 6); or del 1 7 p will recei ve 
mai nte na nce wit h:

C O N FI D E N TI A L
T his d oc u me nt is c o nfi de ntial. D o n ot discl ose or use e xce pt as a ut h orize d.
4 0
S h ort title: P h ase II st u d y of El ot uz u m a b pl us R V D i n Ne wl y Di a g n ose d M M
Versi o n D ate: N o ve m ber 1 0, 2 0 2 0 

B ortez o mi b 1. 3 m g/ m 2 da ys 1 a n d 1 5 S Q
P atie nts u n der g oi n g A S C T w h o are I S S I or II wit h o ut hi g h-ris k  a n d  p atie nts o pti n g n ot t o 
pr ocee d wit h A S C T f oll o wi n g 8 c ycles of i n d ucti o n w h o are I S S st a ge I wit h o ut hi g h-ris k 
c yt o ge netics  will 

B ortez o mi b will n ot be a d mi nistere d i n t he mai nte na nce c ycles
5. 4. 5 De x a met h as o ne
5. 4. 5. 1
I n d u cti o n C y cl es 1 a n d 2
De xa met has o ne 2 0 m g p o will be a d mi nistere d o n Da ys 2, 4, 5, 9, 1 1 a n d 1 2 i n 2 1- da y c ycles.
O n da ys of el ot uz u ma b i nf usi o n ( Da ys 1, 8, a n d 1 5), de xa met has o ne will be a d mi nistere d as a s plit 
d ose of:

2 8 m g p o ( bet wee n 3 - 2 4 h o urs bef ore t he start of el ot uz u ma b i nf usi o n) A N D

8 m g I V ( o n t he da y of el ot uz u ma b i nf usi o n at least 9 0 - 4 5 mi n utes bef ore t he start of 
el ot uz u ma b i nf usi o n).
If el ot uz u ma b d osi n g is s ki p pe d or disc o nti n ue d, de xa met has o ne will be a d mi nistere d orall y.
At t he discreti o n of t he i n vesti gat or, t he 2 8 m g oral de xa met has o ne c o m p o ne nt ma y be gi ve n as a 
s plit d ose: 1 2 m g P O ( 1 2 – 2 4 h o urs pri or t o el ot uz u ma b) A N D 1 6 m g P O ( 3 h o urs pri or t o 
el ot uz u ma b).
Refer t o ta ble 5. 3 f or clarificati o n o n de xa met has o ne a d mi nistrati o n i n t he e ve nt of i nf usi o n 
reacti o ns or i n a bse nce of reacti o ns. 
5. 4. 5. 2
I n d u cti o n C y cl es 3 a n d 4
De xa met has o ne 2 0 m g p o will be a d mi nistere d o n Da ys 2, 4, 5, 8, 9, a n d 1 2 i n 2 1- da y c ycles.
O n da ys of el ot uz u ma b i nf usi o n ( Da ys 1 a n d 1 1), de xa met has o ne will be a d mi nistere d as a s plit 
d ose of:

2 8 m g p o ( bet wee n 3 - 2 4 h o urs bef ore t he start of el ot uz u ma b i nf usi o n) A N D

8 m g I V ( o n t he da y of el ot uz u ma b i nf usi o n at least 9 0 - 4 5 mi n utes bef ore t he start of 
el ot uz u ma b i nf usi o n).
If el ot uz u ma b d osi n g is s ki p pe d or disc o nti n ue d, de xa met has o ne will be a d mi nistere d orall y.
At t he discreti o n of t he i n vesti gat or, t he 2 8 m g oral de xa met has o ne c o m p o ne nt ma y be gi ve n as a 
s plit d ose: 1 2 m g P O ( 1 2 – 2 4 h o urs pri or t o el ot uz u ma b) A N D 1 6 m g P O ( 3 h o urs pri or t o 
el ot uz u ma b).
Refer t o ta ble 5. 3 f or clarificati o n o n de xa met has o ne a d mi nistrati o n i n t he e ve nt of i nf usi o n 
reacti o ns or i n a bse nce of reacti o ns. 

C O N FI D E N TI A L
T his d oc u me nt is c o nfi de ntial. D o n ot discl ose or use e xce pt as a ut h orize d.
4 1
S h ort title: P h ase II st u d y of El ot uz u m a b pl us R V D i n Ne wl y Di a g n ose d M M
Versi o n D ate: N o ve m ber 1 0, 2 0 2 0 
5. 4. 5. 3
I n d u cti o n C y cl es 5 - 8
De xa met has o ne 1 0 m g p o will be a d mi nistere d o n Da ys 2, 4, 5, 8, 9, a n d 1 2 i n 2 1- da y c ycles.
O n da ys of el ot uz u ma b i nf usi o n ( Da ys 1 a n d 1 1), de xa met has o ne will be a d mi nistere d as a s plit 
d ose of:

2 8 m g p o ( bet wee n 3 - 2 4 h o urs bef ore t he start of el ot uz u ma b i nf usi o n) A N D

8 m g I V ( o n t he da y of el ot uz u ma b i nf usi o n at least 9 0 - 4 5 mi n utes bef ore t he start of 
i nf usi o n).
If el ot uz u ma b d osi n g is s ki p pe d or disc o nti n ue d, de xa met has o ne will be a d mi nistere d orall y.
At t he discreti o n of t he i n vesti gat or, t he 2 8 m g oral de xa met has o ne c o m p o ne nt ma y be gi ve n as a 
s plit d ose: 1 2 m g P O ( 1 2 – 2 4 h o urs pri or t o el ot uz u ma b) A N D 1 6 m g P O ( 3 h o urs pri or t o 
el ot uz u ma b).
Refer t o ta ble 5. 3 f or clarificati o n o n de xa met has o ne a d mi nistrati o n i n t he e ve nt of i nf usi o n 
reacti o ns or i n a bse nce of reacti o ns. 
F or all c ycles, eac h de xa met has o ne d ose s h o ul d be ta ke n wit h f o o d a n d at t he sa me ti me eac h da y. 
If a d ose is misse d or v o mite d, t he d ose s h o ul d n ot be ma de u p a n d t he partici pa nt s h o ul d c o nti n ue 
wit h re g ular sc he d ule of t he dr u g.
5. 4. 5. 4
M ai nt e n a n c e C y cl es
O n t he da y of t he el ot uz u ma b i nf usi o n, de xa met has o ne will be a d mi nistere d as a d ose of:

8 m g I V ( o n t he da y of el ot uz u ma b i nf usi o n at least 9 0 - 4 5 mi n utes bef ore t he start of 
i nf usi o n).
If el ot uz u ma b d osi n g is s ki p pe d or disc o nti n ue d, de xa met has o ne will be a d mi nistere d orall y.
Refer t o ta ble 5. 3 f or clarificati o n o n de xa met has o ne a d mi nistrati o n i n t he e ve nt of i nf usi o n 
reacti o ns or i n a bse nce of reacti o ns. 
5. 5  
Ge ner al C o nc o mit a nt Me dic ati o n a n d S u p p orti ve C are G ui deli nes
5. 5. 1 Re q uire d C o nc o mit a nt T her a p y
It is re q uire d t hat partici pa nts recei ve pr o p h yla xis a gai nst her pes z oster usi n g oral ac ycl o vir ( 4 0 0 
m gs t wice dail y) or valac ycl o vir ( 5 0 0 m gs t wice dail y) or e q ui vale nt a nti viral t hera p y per 
i nstit uti o nal g ui deli nes a n d at t he discreti o n of t he site i n vesti gat or, u nless t he partici pa nt de vel o ps 
a h y perse nsiti vit y t o t he a ge nts.  T he d ose will be a dj uste d base d u p o n ser u m creati ni ne le vels 
acc or di n g t o pac ka ge i nsert.

C O N FI D E N TI A L
T his d oc u me nt is c o nfi de ntial. D o n ot discl ose or use e xce pt as a ut h orize d.
4 2
S h ort title: P h ase II st u d y of El ot uz u m a b pl us R V D i n Ne wl y Di a g n ose d M M
Versi o n D ate: N o ve m ber 1 0, 2 0 2 0 
S u bjects m ust c o m plete ste m cell m o bilizati o n. Treat me nts a n d pr oce d ures necessar y f or ste m cell 
m o bilizati o n a n d S C T (if a p plica ble) are per mitte d at t he discreti o n of t he i n vesti gat or a n d 
acc or di n g t o t he sta n dar ds of partici pati n g i nstit uti o ns.
Pre-treat me nt wit h de xa met has o ne I V (at least 9 0 - 4 5 mi n utes pri or t o el ot uz u ma b o n t he da y of 
i nf usi o n), a n d di p he n h y dra mi ne ( or e q ui vale nt H 1 bl oc ker [e g, h y dr o x yzi ne] if aller gic t o 
di p he n h y dra mi ne), a n H 2 bl oc ker (ra niti di ne or e q ui vale nt), a n d aceta mi n o p he n 3 0 t o 9 0 mi n utes 
pri or t o el ot uz u ma b i nf usi o ns is re q uire d i n all s u bjects ( See Secti o ns 5. 3. 7). If persiste nt 
i nt olera nce de vel o ps wit h o ne or 
m ore of t hese 
me dicati o ns, c o ns ult wit h t he Pri nci pal 
I n vesti gat or.
Le nali d o mi de i ncreases t he ris k of t hr o m b otic e ve nts i n patie nts w h o are at hi g h ris k or wit h a 
hist or y of t hr o m b osis, i n partic ular w he n c o m bi ne d wit h ot her dr u gs k n o w n t o ca use t hr o m b osis.  
W he n le nali d o mi de is c o m bi ne d wit h ot her a ge nts s uc h as ster oi ds (e. g. de xa met has o ne, 
pre d nis o ne), a nt hrac ycli nes ( D o xil, A dria m yci n) a n d er yt hr o p oieti n t he ris k of t hr o m b osis is 
i ncrease d.  
T hera p y t o re d uce t he ris k of t hr o m b otic e ve nts ass ociate d wit h le nali d o mi de, is re q uire d f or all 
partici pa nts.  Partici pa nts s h o ul d recei ve dail y as piri n a d mi nistrati o n ( 8 1 or 3 2 5 m g) t o decrease 
t he ris k of t hr o m b oe m b olic c o m plicati o ns, h o we ver, ca uti o n s h o ul d be use d i n partici pa nts w h o 
de vel o p t hr o m b oc yt o pe nia.  Patie nts at hi g h-ris k f or t hr o m b oe m b olic disease, s uc h as t h ose wit h 
pri or h/ o D V T, s h o ul d recei ve a ntic oa g ulati o n wit h l o w m olec ular wei g ht he pari n or warfari n.  It 
is rec o m me n de d t hat if t he platelet c o u nt falls bel o w 5 0, 0 0 0/ m m3, t hr o m b o pr o p h yla xis be hel d t o 
mi ni mize t he ris k of blee di n g a n d t he n res u me d w he n platelet c o u nts are e q ual t o or a b o ve t his 
le vel. 
5. 5. 2 Rec o m me n de d C o nc o mit a nt T her a p y 
It is rec o m me n de d t hat partici pa nts recei ve p ne u m oc ystis cari nii p ne u m o nia ( P C P) pr o p h yla xis 
usi n g a p pr o priate t hera p y acc or di n g t o i nstit uti o nal g ui deli nes a n d at t he discreti o n of t he 
i n vesti gat or.
It is als o rec o m me n de d t hat t he f oll o wi n g a dj u ncti ve a p pr oac hes be c o nsi dere d t o pre ve nt 
ne ur o pat h y at t he discreti o n of t he site i n vesti gat or:

M ulti- B C o m ple x Vita mi ns, o nce dail y: wit h B 1, B 1 2, B 6 at R D A.  B 6 d ose s h o ul d n ot 
e xcee d 1 0 0 m g.

F olic aci d 1 m g/ dail y

Vita mi n E a n d Vita mi n D: U p t o 4 0 0 I U dail y

Acet yl L- Car niti ne: 5 0 0 m g t wice a da y wit h f o o d A N D

Al p ha- Li p oic Aci d: 5 0 0 m g a da y wit h f o o d O R

A c o m bi nati o n pill of: Al p ha li p oic aci d 2 0 0 m g + Acet yl- L- Car niti ne 5 0 0 m g: ta ke O N E 
t wice a da y wit h f o o d.
Ple ase n ote  t hat all a b o ve s u p ple me nts s h o ul d n ot be ta ke n o n da ys of b ortez o mi b a d mi nistrati o n.

C O N FI D E N TI A L
T his d oc u me nt is c o nfi de ntial. D o n ot discl ose or use e xce pt as a ut h orize d.
4 3
S h ort title: P h ase II st u d y of El ot uz u m a b pl us R V D i n Ne wl y Di a g n ose d M M
Versi o n D ate: N o ve m ber 1 0, 2 0 2 0 
At t he discreti o n of t he site i n vesti gat or, c oc oa b utter, w hic h is ric h i n Vita mi n E, xa nt hi nes a n d 
nat ural ser ot o ni ns, ca n als o be use d. It is ge nerall y a p plie d t o e xtre mities t wice a da y wit h ge ntle 
massa ge. Me nt h ol- base d crea ms ca n als o be use d f or areas of n u m b ness as nee de d.
Ot her rec o m me n de d t her a p y: 

C o nc o mita nt bis p h os p h o nate t hera p y, acc or di n g t o i n di vi d ual i nstit uti o n g ui deli nes.  

Dili ge nt de ntal/ m o ut h care is rec o m me n de d.

All s u p p orti ve meas ures c o nsiste nt wit h o pti mal partici pa nt care will be gi ve n t hr o u g h o ut t he 
st u d y.
5. 5. 3 Pr o hi bite d C o nc o mit a nt T her a p y
I n ge neral, t he use of a n y c o nc o mita nt me dicati o n/t hera pies dee me d necessar y f or t he care of t he 
patie nt are all o we d, i ncl u di n g dr u gs gi ve n pr o p h ylacticall y (e. g. a ntie metics) wit h t he f oll o wi n g 
e xce pti o ns:

N o ot her i n vesti gati o nal t hera p y s h o ul d be gi ve n t o patie nts

N o a ntica ncer a ge nts ot her t ha n t he st u d y me dicati o ns a d mi nistere d as part of t his st u d y 
pr ot oc ol s h o ul d be gi ve n t o patie nts. If s uc h a ge nts are re q uire d f or a patie nt t he n t he patie nt 
m ust first be wit h dra w n fr o m t he st u d y.

C o nc o mita nt s yste mic c ortic oster oi ds, ot her t ha n as part of t he pr ot oc ol-s pecifie d t hera pe utic 
re gi me n, or t o pical c ortic oster oi d wit h o ut s yste mic a bs or pti o n, are pr o hi bite d. L o w d ose 
ster oi ds ( pre d nis o ne 1 0 m g or e q ui vale nt) f or treat me nt of c o- m or bi d c o n diti o ns or st u d y 
relate d t o xicities, partic ularl y ras h, is all o we d. Ot her t ha n st u d y me dicati o ns, a d mi nistrati o n of 
a n y t hera pe utic or dia g n ostic i n vesti gati o nal a ge nt (f or a n y i n dicati o n) is pr o hi bite d w hile o n 
st u d y. G ui deli nes f or selecti o n a n d use of ot her c o nc o mita nt me dicati o ns s h o ul d be deri ve d 
fr o m t he le nali d o mi de, b ortez o mi b, a n d de xa met has o ne prescri bi n g i nf or mati o n.
5. 5. 4 Per mitte d at I n vesti g at or’s Discreti o n

A d diti o nal gl uc oc ortic oi ds, a nti hista mi nes, a n d a nal gesics, f or t he ma na ge me nt of i nf usi o n 
reacti o ns. A d diti o nal s u p p orti ve meas ures s h o ul d be pr o vi de d as i n dicate d i ncl u di n g o x y ge n 
i n halati o n, e pi ne p hri ne, a n d br o nc h o dilat ors

A nti micr o bial (i ncl u di n g a nti-f u n gal) or a nti viral pr o p h yla xis

Pr o p h ylactic a ntic oa g ulati o n (as piri n, warfari n or l o w m olec ular wei g ht he pari n) t o pre ve nt 
t hr o m b oe m b olic e ve nts)

A nti-e metics

Er yt hr o p oieti n ( E P O) or dar be p oeti n (acc or di n g t o t he pac ka ge i nsert a n d i nstit uti o nal 
g ui deli nes).  N ote: Er yt hr o p oieti n ca n n ot be use d wit hi n 7 da ys of scree ni n g e val uati o ns t o 
meet eli gi bilit y criteria

Re d bl o o d cell or platelet tra nsf usi o n

Pr o p h ylactic a d mi nistrati o n of G- C S F i n a s u bject w h o is e x perie nci n g rec urre nt diffic ulties 
wit h ne utr o pe nia, or t hera pe utic use i n s u bjects wit h seri o us ne utr o pe nic c o m plicati o ns (s uc h 
as tiss ue i nfecti o n, se psis s y n dr o me or f u n gal i nfecti o n) 
ma y be c o nsi dere d at t he 

C O N FI D E N TI A L
T his d oc u me nt is c o nfi de ntial. D o n ot discl ose or use e xce pt as a ut h orize d.
4 4
S h ort title: P h ase II st u d y of El ot uz u m a b pl us R V D i n Ne wl y Di a g n ose d M M
Versi o n D ate: N o ve m ber 1 0, 2 0 2 0 
i n vesti gat or's discreti o n, c o nsiste nt wit h A merica n S ociet y of Cli nical O nc ol o g y g ui deli nes 
( A S C O 2 0 0 6). N O T E: G C S F ca n n ot be use d wit hi n 1 4 da ys of scree ni n g e val uati o ns t o meet 
eli gi bilit y criteria.  

Bis p h os p h o nates acc or di n g t o t he A S C O 2 0 0 7 Cli nical Practice G ui deli nes. ( K yle 2 0 0 7) 

Ge neral s u p p orti ve i nter ve nti o ns, i ncl u di n g b ut n ot li mite d t o i ntra ve n o us fl ui ds a n d oral or 
pare nteral electr ol yte s u p ple me ntati o n.

A b o wel re gi me n t o pre ve nt c o nsti pati o n, acc or di n g t o l ocal practice, is hi g hl y rec o m me n de d.
5. 6  
D ur ati o n of T her a p y
D urati o n of t hera p y will de pe n d o n res p o nse t o t hera p y, e vi de nce of disease pr o gressi o n, a n d 
t olera nce. Partici pa nts w h o ha ve sta ble or res p o n di n g disease t o treat me nt a n d ha ve a n acce pta ble 
t o xicit y pr ofile will be all o we d t o c o nti n ue 
mai nte na nce treat me nt u ntil disease rela pse, 
u nacce pta ble t o xicit y or u ntil o ne of t he f oll o wi n g criteria a p plies:

Wit h dra wal of i nf or me d c o nse nt (s u bject’s decisi o n t o wit h dra w f or a n y reas o n)

A n y cli nical A E, la b orat or y a b n or malit y or i nterc urre nt ill ness w hic h, i n t he o pi ni o n of t he 
i n vesti gat or, i n dicates t hat c o nti n ue d partici pati o n i n t he st u d y is n ot i n t he best i nterest of t he 
s u bject

Pre g na nc y ( m ust disc o nti n ue all st u d y dr u gs u n der t his pr ot oc ol)

Ter mi nati o n of t he st u d y b y t he S p o ns or/I n vesti gat or

L oss of a bilit y t o freel y pr o vi de c o nse nt t hr o u g h i m pris o n me nt or i n v ol u ntar y i ncarcerati o n f or 
treat me nt of eit her a ps yc hiatric or p h ysical (e g, i nfecti o us disease) ill ness

Pr o gressi ve Disease (see Ta ble 1 0. 2. 4. 1 f or defi niti o n of pr o gressi ve disease).

S u bjects w h o recei ve a n y n o n- pr ot oc ol s pecifie d s yste mic a nti- m yel o ma t hera p y ( ot her t ha n 
ste m cell m o bilizati o n a n d S C T) bef ore d oc u me nte d pr o gressi o n will be disc o nti n ue d fr o m all 
st u d y treat me nt (i ncl u di n g el ot uz u ma b, b ortez o mi b, le nali d o mi de, a n d de xa met has o ne), 
h o we ver, t u m or assess me nts m ust c o nti n ue u ntil pr o gressi o n

S u bjects e x perie nci n g a Gra de 4 i nf usi o n reacti o n t o el ot uz u ma b m ust disc o nti n ue t he 
el ot uz u ma b. S u bjects ma y c o nti n ue b ortez o mi b, le nali d o mi de, a n d de xa met has o ne.

S u bjects w h o e x perie nce Gra de 2 ne ur o pat h y wit h pai n or  Gra de 3 ne ur o pat h y relate d t o 
b ortez o mi b f oll o wi n g d ose dela y a n d d ose re d ucti o n m ust disc o nti n ue t he b ortez o mi b. 
S u bjects ma y c o nti n ue t he el ot uz u ma b, le nali d o mi de, a n d de xa met has o ne.

S u bjects e x perie nci n g a n gi oe de ma, Gra de 4 ras h, e xf oliati ve or b ull o us ras h, Ste ve ns-J o h ns o n 
s y n dr o me, or t o xic e pi der mal necr ol ysis relate d t o le nali d o mi de 
m ust disc o nti n ue 
le nali d o mi de. S u bjects ma y c o nti n ue b ortez o mi b, de xa met has o ne, a n d el ot uz u ma b.

S u bjects e x perie nci n g a treat me nt dela y of m ore t ha n 2 1 da ys i n all st u d y dr u gs ( b ortez o mi b, 
le nali d o mi de, de xa met has o ne a n d el ot uz u ma b) d ue t o a n A E relate d t o st u d y dr u g m ust be 
disc o nti n ue d fr o m st u d y dr u gs. S u bjects e x perie nci n g dela ys u nrelate d t o st u d y dr u g, f or 
e xa m ple d ue t o ra diati o n t hera p y, ma y dela y st u d y dr u g u p t o 4 2 da ys. Dela ys m ore t ha n 
2 1 da ys m ust be disc usse d wit h t he PI wit h t he e xce pti o ns detaile d i n Secti o n 6. 2. 1 a n d relate d 
t o ste m cell m o bilizati o n, har vest, a n d/ or tra ns pla nt.

C O N FI D E N TI A L
T his d oc u me nt is c o nfi de ntial. D o n ot discl ose or use e xce pt as a ut h orize d.
4 5
S h ort title: P h ase II st u d y of El ot uz u m a b pl us R V D i n Ne wl y Di a g n ose d M M
Versi o n D ate: N o ve m ber 1 0, 2 0 2 0 
5. 7 
S ur ger y a n d R a di ati o n


L ocalize d ra di ot hera p y ca n be gi ve n pre-st u d y wit h a 2 wee k brea k pri or t o t he start of s yste mic 
treat me nt, as l o n g as t his ra diati o n t hera p y is t o a site of pre-e xisti n g disease a n d t here is 
res ol uti o n of he mat ol o gic or gastr oi ntesti nal t o xicit y t hat ma y be relate d t o ra diati o n.

If t he s u bject de vel o ps a defi nite i ncrease i n t he size of e xisti n g b o ne lesi o ns or s oft tiss ue 
plas mac yt o mas t hat meets t he criteria f or disease pr o gressi o n, treat me nt m ust be disc o nti n ue d 
f or pr o gressi ve disease re gar dless of w het her ra diati o n t hera p y is i nitiate d. K y p h o plast y, 
verte br o plast y or e mer ge nc y ort h o pe dic s ur ger y is per mitte d.
5. 8 
    D ur ati o n of F oll o w U p  
D uri n g t hera p y patie nts are f oll o we d e ver y treat me nt c ycle. 
5. 9  
Criteri a f or Re m o v al fr o m St u d y 
Partici pa nts will be re m o ve d fr o m st u d yif t he patie nt wit h dra ws c o nse nt f or f oll o w- u p or i n t he e ve nt 
of deat h. Please see Secti o n 5. 6 f or c o m plete list of reas o ns f or re m o val fr o m st u d y..
I n t h e e v e nt of u n us u al or lif e-t hr e at e ni n g c o m pli c ati o ns, p arti ci p ati n g i n v esti g at ors m ust 
i m m e di at el y n otif y t h e st u d y Pri n ci p al I n v esti g at or ( PI): J a c o b L a u b a c h at 
 
(t el e p h o n e) or 
.  
Partici pa nts will be i nf or me d t hat t he y ha ve t he ri g ht t o wit h dra w fr o m t he st u d y at a n y ti me f or 
a n y reas o n, wit h o ut prej u dice t o t heir me dical care.
6 
E X P E C T E D T O XI CI TI E S A N D D O SI N G D E L A Y S/ D O S E M O DI FI C A TI O N S 
D ose dela ys a n d m o dificati o ns will be ma de usi n g t he f oll o wi n g rec o m me n dati o ns. T o xicit y 
assess me nts will be d o ne usi n g t he C T E P Versi o n 4. 0 3 of t he N CI C o m m o n Ter mi n ol o g y Criteria 
f or A d verse E ve nts ( C T C A E) w hic h is i de ntifie d a n d l ocate d o n t he C T E P we bsite at: 
htt p://e vs. nci. ni h. g o v/ft p 1/ C T C A E/ C T C A E _ 4. 0 3 _ 2 0 1 0- 0 6- 1 4 _ Q uic k Refere nce _ 5 x 7. p df
T he f oll o wi n g a d verse e ve nts will be c ollecte d:

All S A Es.

All ≥Gra de  2 A Es.

Ne w pri mar y mali g na ncies.

A n y A E res ulti n g i n d ose m o dificati o n or disc o nti n uati o n of a n y st u d y dr u g.

A n y ot her A E t hat i n t he o pi ni o n of t he i n vesti gat or is a cli nicall y si g nifica nt e ve nt
6. 1  
A ntici p ate d T o xicities 
A list of t he a d verse e ve nts a n d p ote ntial ris ks ass ociate d wit h t he a ge nts a d mi nistere d i n t his 
st u d y a p pear bel o w a n d will deter mi ne w het her d ose dela ys a n d m o dificati o ns will be ma de or 
w het her t he e ve nt re q uires e x pe dite d re p orti n g i n a d diti o n t o r o uti ne re p orti n g.

C O N FI D E N TI A L
T his d oc u me nt is c o nfi de ntial. D o n ot discl ose or use e xce pt as a ut h orize d.
4 6
S h ort title: P h ase II st u d y of El ot uz u m a b pl us R V D i n Ne wl y Di a g n ose d M M
Versi o n D ate: N o ve m ber 1 0, 2 0 2 0 
6. 1. 1 C A E P Rs f or C T E P- S u p plie d I n vesti g ati o n al A ge nt(s)
T his secti o n is n ot a p plica ble t o t he st u d y.
6. 1. 2 A d v e rs e E v e nts List f o r L e n ali d o mi d e
T he f oll o wi n g is a list of a d verse e ve nts t hat are ass ociate d wit h t he use of le nali d o mi de.
E ve nts t h at h a ve occ urre d i n > 1 0 % of i n di vi d u als tre ate d wit h le n ali d o mi de
Ne utr o pe nia
A ne mia
T hr o m b oc yt o pe nia
Fati g ue
Ras h
Diarr hea 
C o nsti pati o n
Na usea
L oss of a p petite
Itc hi n g
Dr y s ki n
M uscle cra m ps 
Lac k or l oss of stre n gt h
Dizzi ness
I ns o m nia
S welli n g of t he e xtre mities
Hea dac he
Bac k a n d j oi nt pai n
Fe ver
C o u g h
U p per res pirat or y i nfecti o n
D ys p nea
E ve nts t h at h a ve occ urre d i n < 1 0 % of i n di vi d u als tre ate d wit h le n ali d o mi de
Ris k of D V T
P E a n d bl o o d cl ots t hat c o ul d 
lea d t o str o ke
Heart attac k, or or ga n fail ure
Fe brile ne utr o pe nia 
Atrial fi brillati o n
P ne u m o nia or l u n g i nfecti o ns
Se psis
De h y drati o n
Re nal fail ure 
Ot her r are e ve nts t h at h a ve occ urre d i n i n di vi d u als tre ate d wit h le n ali d o mi de
A n gi oe de ma, seri o us s ki n reacti o ns i ncl u di n g Ste ve ns-J o h ns o n s y n dr o me ( SJ S) a n d t o xic 
e pi der mal necr ol ysis ( T E N) or a n aller gic s ki n reacti o n si milar t o t hat see n wit h t hali d o mi de.
T u m or l ysis s y n dr o me ( T L S), t u m or flare reacti o n ( T F R), a n d r ha b d o m y ol ysis. 
I n a d diti o n, le nali d o mi de has bee n s h o w n t o i ncrease t he le vel of di g o xi n i n t he bl o o d i n s o me 
patie nts.
Partici pa nts will be i nstr ucte d t o i nf or m t heir d oct or if ta ki n g di g o xi n. 
T here ma y be a n i ncrease d ris k of sec o n d ca ncers i n partici pa nts w h o are o n le nali d o mi de 
mai nte na nce t hera p y after a b o ne marr o w tra ns pla nt.
 
6. 1. 3
A d verse E ve nts List f or B ortez o mi b
T he f oll o wi n g is a list of a d verse e ve nts t hat are ass ociate d wit h t he use of b ortez o mi b.
E ve nts t h at h a ve occ urre d i n > 1 0 % of i n di vi d u als tre ate d wit h b ortez o mi b
Fati g ue
L oss of stre n gt h
Na usea
Diarr hea
C o nsti pati o n
L oss of a p petite
Ner ve i nj ur y
V o miti n g
Decrease d bl o o d c o u nts
E de ma
M uscle or j oi nt pai n
S h ort ness of breat h
C o u g h
Hea dac he
Ras h
H y p ote nsi o n
S hi n gles
E ve nts t h at h a ve occ urre d i n < 1 0 % of i n di vi d u als tre ate d wit h b ortez o mi b

C O N FI D E N TI A L
T his d oc u me nt is c o nfi de ntial. D o n ot discl ose or use e xce pt as a ut h orize d.
4 7
S h ort title: P h ase II st u d y of El ot uz u m a b pl us R V D i n Ne wl y Di a g n ose d M M
Versi o n D ate: N o ve m ber 1 0, 2 0 2 0 
C o n gesti ve heart fail ure 
Dizzi ness.
R are or less fre q ue nt e ve nts t h at h a ve occ urre d i n i n di vi d u als tre ate d wit h b ortez o mi b
T u m or l ysis s y n dr o me ( T L S), 
H y perte nsi o n,
I nterstitial l u n g disease, 
Pericar ditis 
Arr h yt h mia, 
A n gi oe de ma, 
H y p o natre mia, 
H y p o ma g nese mia,
H y p o p h os p hate mia, 
H y p o gl yce mia
Her pes me ni n g o ge n p halitis
6. 1. 4
A d verse E ve nts List f or De x a met h as o ne
E ve nts t h at h a ve occ urre d i n > 1 0 % of i n di vi d u als tre ate d wit h de x a met h as o ne
I ncrease d a p petite
Wei g ht gai n
Slee p dist ur ba nce
H y perte nsi o n
Fl ui d rete nti o n
A n kle s welli n g
Br uisi n g
I nfecti o n
M o o d c ha n ges
Sl o w w o u n d heali n g
De pressi o n
H y per gl yce mia, w hic h ma y 
lea d t o fati g ue, wei g ht l oss, 
e xcessi ve t hirst, a n d fre q ue nt 
uri nati o n
E ve nts t h at h a ve occ urre d i n < 1 0 % of i n di vi d u als tre ate d wit h de x a met h as o ne i ncl u de
L oss of a p petite
M uscle t witc hi n g
I ncrease d t hirst
Fre q ue nt uri nati o n
I ncrease d pers pirati o n
Diarr hea
Na usea
Hea dac he
S pi nal fract ure or fract ure of 
b o nes
Tac h ycar dia 
F u n gal i nfecti o ns.
E ve nts t h at h a ve occ urre d i n < 1 % of i n di vi d u als tre ate d wit h de x a met h as o ne
Bl urre d visi o n
Pers o nalit y c ha n ges 
St o mac h ulcers wit h blee di n g 
t hat ma y ca use he mate mesis
Bl o o d i n t he st o ol 
A b d o mi nal pai n.
Ot her, less fre q ue nt, e ve nts t h at m a y occ ur i n i n di vi d u als tre ate d wit h de x a met h as o ne
B o wel perf orati o n
Irritati o n a n d blee di n g of t he 
es o p ha g us
Heart fail ure
Aller gic reacti o n t hat ma y 
lea d t o facial re d ness
S h ort ness of breat h
A b d o mi nal cra m ps
H y p ote nsi o n
C o n v ulsi o ns
Brai n s welli n g
Dizzi ness
Cataracts
Gla uc o ma a n d i ncrease d 
bl o o d press ure i n t he e ye 
De vel o p me nt of dia betes
Pa ncreatic i nfla m mati o n
A b d o mi nal s welli n g
H y p o kale mia
D V T or P E
Malaise
S welli n g a n d/ or re d ness of 
s ki n
Aller gic s ki n reacti o ns
Itc hi n g
Hirs utis m
M uscle wea k ness or l oss of 
m uscle mass
R u pt ure of te n d o ns
Me nstr ual c ycle dist ur ba nces
Hicc u ps.
6. 1. 5
A d verse E ve nts List f or El ot uz u m a b 
Refer t o t he c urre nt I n vesti gati o nal dr u g br oc h ure f or El ot uz u ma b f or listi n gs of treat me nt 
e mer ge nt a d verse e ve nts. 
6. 2 
T o xicit y M a n a ge me nt

C O N FI D E N TI A L
T his d oc u me nt is c o nfi de ntial. D o n ot discl ose or use e xce pt as a ut h orize d.
4 8
S h ort title: P h ase II st u d y of El ot uz u m a b pl us R V D i n Ne wl y Di a g n ose d M M
Versi o n D ate: N o ve m ber 1 0, 2 0 2 0 
B ef or e e a c h dr u g d os e, t h e p arti ci p a nt will b e e v al u at e d f or p ossi bl e t o xi citi es t h at m a y h a v e 
o c c urr e d aft er t h e pr e vi o us d os e(s).  T o xi citi es ar e t o b e ass ess e d a c c or di n g t o t h e N CI C o m m o n 
T er mi n ol o g y C T E P Versi o n 4. 0 3 of t he N CI C T C A E. D os e m o difi c ati o ns or d el a ys will b e 
p erf or m e d b as e d o n t h e t o xi cit y e x p eri e n c e d d uri n g a c y cl e of t h er a p y or n e wl y e n c o u nt er e d o n 
d a y 1 of e a c h c y cl e.  R e d u cti o n a n d/ or t e m p or ar y s us p e nsi o n of o n e a g e nt a n d n ot t h e ot h er is 
a p pr o pri at e if t o xi cit y is r el at e d pri m aril y t o o n e of t h e a g e nts.  T h e p arti ci p a nt m a y c o nti n u e o n 
t h er a p y if t h e t o xi cit y c a n b e m a n a g e d a c c or di n g t o t h e d os e m o difi c ati o n g ui d eli n es as o utli n e d 
b el o w.  
O nce a treat me nt d ose is re d uce d f or t o xicit y, n o re-escalati o n of t hat treat me nt will be all o we d.  
Dr u g ma y be hel d f or n o m ore t ha n 2 1 da ys t o all o w res ol uti o n of t o xicit y fr o m t he i nte n de d da y 
of t he ne xt sc he d ule d d ose, t he n t he patie nt m ust be disc o nti n ue d fr o m t he st u d y. If h o we ver t he 
patie nt was clearl y be nefiti n g fr o m t hera p y, t he patie nt ma y be a ble t o c o nti n ue treat me nt wit h a 
d ose re d ucti o n at t he I n vesti gat or discreti o n a n d i n c o ns ultati o n wit h t he Pri nci pal I n vesti gat or, 
after res ol uti o n of t he a d verse e ve nt. T he d ose re d ucti o n ste ps are detaile d bel o w.
If t h e d os e of o n e dr u g i n t h e r e gi m e n (i e, l e n ali d o mi d e, b ort e z o mi b, d e x a m et h as o n e, or 
el ot u z u m a b) is d el a y e d, i nt err u pt e d, or dis c o nti n u e d, t h e tr e at m e nt wit h t h e ot h er dr u gs s h o ul d 
c o nti n u e as s c h e d ul e d. H o w e v er, if eit h er p o or I V d e x a m et h as o n e is d el a y e d or dis c o nti n u e d, 
dis c uss o n g oi n g el ot u z u m a b a d mi nistr ati o n wit h t h e Pri n ci p al I n v esti g at or.
S u bj e cts e x p eri e n ci n g a 2 1 d a y d el a y i n all st u d y dr u gs (l e n ali d o mi d e, b ort e z o mi b, 
d e x a m et h as o n e, a n d el ot u z u m a b) d u e t o a n A E(s) r el at e d t o st u d y dr u g m ust b e dis c o nti n u e d 
fr o m st u d y dr u g. S u bj e cts e x p eri e n ci n g d el a ys u nr el at e d t o st u d y dr u g, f or e x a m pl e d u e t o 
r a di ati o n t h er a p y m a y d el a y st u d y dr u g u p t o 4 2 d a ys. D el a ys gr e at er t h a n 2 1 d a ys m ust b e 
dis c uss e d wit h t h e Pri n ci p al I n v esti g at or wit h t h e e x c e pti o ns d et ail e d b el o w.
T h e eff e ct of el ot u z u m a b h as b e e n st u di e d e xt e nsi v el y i n c o m bi n ati o n wit h L e n ali d o mi d e a n d 
B ort e z o mi b, a n d d os a g es of 1 0 m g/ k g I V ar e us e d i n all p h as e III a n d r a n d o mi z e d p h as e II st u di es 
t o d at e. N o n et h el ess, t h e f o ur dr u g c o m bi n ati o n pr o p os e d i n t his st u d y h as n ot y et b ei n g 
e v al u at e d i n h u m a ns. T h er ef or e, aft er t h e e nr oll m e nt of 1 0 s u bj e cts i n t h e st u d y, f urt h er s u bj e ct 
e nr oll m e nt will b e pl a c e d o n h ol d t o e v al u at e s af et y/t o xi cit y d at a p ert ai ni n g t o t h e 4 dr u g 
c o m bi n ati o n, a n d s p e cifi c all y r e g ar di n g El ot u z u m a b will b e r e vi e w e d i n or d er t o m a k e tri al 
c o n d u ct r e c o m m e n d ati o ns b as e d o n a n a n al ysis of ris k vs. b e n efit.
6. 2. 1 Per mitte d tre at me nt del a ys
1) U p t o 4 w e e ks f or st e m c ell m o bili z ati o n a n d r e c o v er y (if c y cl o p h os p h a mi d e is us e d, a n 
a d diti o n al 3 w e e ks f or r e c o v er y [t ot al 7 w e e ks] is all o w e d); s u bj e cts e x p eri e n ci n g d el a ys gr e at er 
t h a n 4 w e e ks ( 7 w e e ks f or s u bj e cts r e c ei vi n g c y cl o p h os p h a mi d e) m ust b e dis c o nti n u e d fr o m 
st u d y tr e at m e nt b ut ar e f oll o w e d f or pr o gr essi o n.
2) S u bj e cts u n d er g oi n g S C T ar e all o w e d a 1 2 w e e k p eri o d of r e c o v er y fr o m d a y 0 b ef or e 
i niti ati o n of p ost tr a ns pl a nt m ai nt e n a n c e t h er a p y; s u bj e cts e x p eri e n ci n g d el a ys gr e at er t h a n 1 2 
w e e ks m ust b e dis c o nti n u e d fr o m st u d y tr e at m e nt.

C O N FI D E N TI A L
T his d oc u me nt is c o nfi de ntial. D o n ot discl ose or use e xce pt as a ut h orize d.
4 9
S h ort title: P h ase II st u d y of El ot uz u m a b pl us R V D i n Ne wl y Di a g n ose d M M
Versi o n D ate: N o ve m ber 1 0, 2 0 2 0 
6. 2. 1. 1
El ot u z u m a b
I n I n d ucti o n C ycles 1 a n d 2, el ot uz u ma b d oses t hat fall o utsi de of t he pres pecifie d wi n d o w of -
1/ + 3 da ys m ust be s ki p pe d.
Be gi n ni n g wit h I n d ucti o n C ycle 3 a n d d uri n g mai nte na nce c ycles, t he el ot uz u ma b d osi n g wi n d o w 
is - 3/ + 7 da ys, a n d d oses t hat fall o utsi de of t his wi n d o w m ust be s ki p pe d.
6. 2. 1. 2
L e n ali d o mi d e
If a d ose of le nali d o mi de is misse d a n d it has bee n less t ha n 1 2 h o urs si nce t he i nte n de d sc he d ule d 
d ose ti me, t he s u bject s h o ul d ta ke t he misse d d ose as s o o n as he/s he re me m bers. If it has bee n 
m ore t ha n 1 2 h o urs, t his le nali d o mi de d ose s h o ul d n ot be ta ke n. D o n ot ta ke 2 d oses at t he sa me 
ti me.
6. 2. 1. 3
D e x a m et h as o n e
De xa met has o ne dela y s h o ul d be perf or me d as cli nicall y i n dicate d at t he discreti o n of t he 
i n vesti gat or. O n t he wee ks of treat me nt wit h el ot uz u ma b, t he de xa met has o ne d ose m ust be 
a d mi nistere d as part of t he pre me dicati o n f or el ot uz u ma b per t he g ui da nce i n Secti o n 5. 4. 5
6. 2. 1. 4
B o rt e z o mi b
Treat me nt wit h b ortez o mi b ma y be dela ye d f or rec o ver y fr o m a n y A E/ S A Es as descri be d i n 
Secti o n 4. 3. 5. T he treat me nt wi n d o w f or b ortez o mi b d uri n g I n d ucti o n C ycles 1 - 8 is  1 da y, b ut 
t he i nter val bet wee n c o nsec uti ve d oses of b ortez o mi b m ust be at least 7 2 h o urs. Be gi n ni n g wit h 
Mai nte na nce C ycle 1, t he wi n d o w f or b ortez o mi b is  3 da ys. 
6. 2. 2 D ose Re d ucti o n Ste ps 
6. 2. 2. 1    D os e R e d u cti o n St e ps f o r L e n ali d o mi d e
St arti n g d ose of le n ali d o mi de
Da ys 1 – 1 4 e ver y 2 1 da ys C ycles 1 - 8
* Mai nte na nce t hera p y Da ys 1 - 2 1
1 S T  D ose
Re d ucti o n
2 N D  D ose
Re d ucti o n
3 R D  D ose
Re d ucti o n
4 T H  D ose
Re d ucti o n
2 5 m g
1 5 m g
1 0 m g
5 m g
Disc o nti n ue 
le nali d o mi de
6. 2. 2. 2
D os e R e d u cti o n St e ps f o r B o rt e z o mi b 
St arti n g D ose of b ortez o mi b
S Q) 
Da ys 1, 4, 8 a n d 1 1 i n C ycles 1- 8 
* Mai nte na nce t hera p y Da ys 1 a n d 8 
1 S T  
D ose Re d ucti o n
2 N D  
D ose Re d ucti o n
3 R D  
D ose Re d ucti o n
4 T H  D ose
Re d ucti o n
1. 3 m g/ m 2
1 m g/ m 2
0. 7 m g/ m 2
0. 7 m g/ m 2 da ys 1 a n d 8
Disc o nti n ue 
b ortez o mi b

C O N FI D E N TI A L
T his d oc u me nt is c o nfi de ntial. D o n ot discl ose or use e xce pt as a ut h orize d.
5 0
S h ort title: P h ase II st u d y of El ot uz u m a b pl us R V D i n Ne wl y Di a g n ose d M M
Versi o n D ate: N o ve m ber 1 0, 2 0 2 0 
* D os e r e d u cti o ns d uri n g t h e m ai nt e n a n c e t h er a p y s h o ul d f oll o w t h e s a m e st e ps of 1. 3 m g/ m 2 t o 
1. 0 m g/ m 2 t o 0. 7 m g/ m2 wit h o ut f urt h er c h a n g e i n s c h e d ul e ( D a ys 1 a n d 1 5).  D os e r e d u cti o ns 
b el o w 0. 7 m g/ m 2 d a ys 1 a n d 8, d uri n g i n d u cti o n a n d or 1 a n d 1 5 d uri n g m ai nt e n a n c e, will r e q uir e 
pri or st u d y PI p er missi o n a n d d o c u m e nt ati o n.  
6. 2. 2. 3
D os e R e d u cti o ns St e ps f o r D e x a m et h as o n e
De x a met h as o ne D ose Re d ucti o ns 
St arti n g D ose of 
De x a met h as o ne
 
1 S T  
D ose 
Re d ucti o n
2 N D  
D ose Re d ucti o n
2 0 m g P O
1 2 m g P O
0 m g P O
6. 2. 2. 4
D os e R e d u cti o n St e ps f o r El ot u z u m a b
N o d ose re d ucti o ns are per mitte d f or el ot uz u ma b
6. 3  
D ose M o dific ati o n/ Del a ys
E a c h A d v ers e E v e nt s h o ul d b e attri b ut e d t o a s p e cifi c st u d y dr u g if p ossi bl e s o t h at d os e 
m o difi c ati o ns c a n b e m a d e a c c or di n gl y.  F urt h er cl arifi c ati o n c a n b e o bt ai n e d i n c o ns ult ati o n 
wit h t h e st u d y PI. If m ulti pl e t o xi citi es ar e n ot e d, t h e d os e a dj ust m e nt s h o ul d b e m a d e a c c or di n g 
t o t h e m ost s e v er e t o xi cit y.  Dr u g m a y b e h el d f or n o m or e t h a n 2 1 d a ys t o all o w r es ol uti o n of 
t o xi cit y.  T h e s a m e d os e m o difi c ati o n g ui d eli n es will a p pl y t o m ai nt e n a n c e c y cl es u nl ess 
ot h er wis e n ot e d.
P arti ci p a nts w h o dis c o nti n u e o n e st u d y dr u g f or t o xi cit y m a y c o nti n u e t o b e tr e at e d o n pr ot o c ol 
wit h t h e r e m ai ni n g st u d y dr u gs.
6. 3. 1 Dr u g Rel ate d A d verse E ve nt D ose M o dific ati o n G ui deli nes f or Le n ali d o mi de a n d 
B ortez o mi b  D uri n g a C ycle.

C O N FI D E N TI A L
T his d oc u me nt is c o nfi de ntial. D o n ot discl ose or use e xce pt as a ut h orize d.
5 1
S h ort title: P h ase II st u d y of El ot uz u m a b pl us R V D i n Ne wl y Di a g n ose d M M
Versi o n D ate: N o ve m ber 1 0, 2 0 2 0 
W orst T o xicit y
D ose M o dificati o n G ui deli nes
At a n y ti me d uri n g a c ycle of t her a p y 
(i ncl u di n g i nte n de d da y of d osi n g)
H E M A T O L O GI C A L T O XI CI TI E S
T hr o m b oc yt o pe nia
Platelet c o u nt < 1 0, 0 0 0 or Gra de 4 
( < 2 5 x 1 09/ L) wit h blee di n g.
Te m p oraril y disc o nti n ue t hera p y i ncl u di n g 
a ntie m b olic pr o p h yla xis. M o nit or C B C o n 
Da ys 4, 8 a n d 1 1 d uri n g i n d ucti o n C ycles 1 
– 8 a n d Da ys 1 a n d 1 5 d uri n g mai nte na nce.
Res u me d osi n g if res ol ve d t o ≥ 
2 5, 0 0 0/ m m 3  wit h: 
O ne le vel d ose re d ucti o n of le nali d o mi de
a n d / or
O ne le vel d ose re d ucti o n of b ortez o mi b 
D ose re d ucti o n of o ne dr u g a n d n ot t he 
ot hers is per mitte d at t he i n vesti gat ors 
discreti o n.   If n o ot her t o xicit y re q uires a 
d ose re d ucti o n a n d t hr o m b oc yt o pe nia ca n 
be ma na ge d wit h t he use of platelet 
tra nsf usi o ns, n o d ose re d ucti o ns are 
re q uire d. 
Use of plt tra nsf usi o n is per mitte d o n t he 
da y of d osi n g.
Ne utr o pe nia ( A N C)
Gra de 4 ( A N C < 0. 5 x 1 0 9/ L) or
Fe brile ne utr o pe nia
( A N C < 1. 0 x 1 09/ L, fe ver ≥ 
3 8. 5° C)
Te m p oraril y disc o nti n ue t hera p y.  M o nit or 
C B C o n Da ys 4, 8 a n d 1 1 d uri n g i n d ucti o n 
C ycles 1 – 8 a n d Da ys 1 a n d 1 5 d uri n g 
mai nte na nce. Use of G- C S F is all o we d a n d 
rec o m me n de d a n d is all o we d o n da y of 
d osi n g. 
Res u me d osi n g if res ol ve d t o ≥ 7 5 0/ m m3 
wit h: 
O ne le vel d ose re d ucti o n of le nali d o mi de
a n d / or
O ne le vel d ose re d ucti o n of b ortez o mi b 
D ose re d ucti o n of o ne dr u g a n d n ot t he 
ot her is per mitte d at t he i n vesti gat ors 
discreti o n.   If n o ot her t o xicit y re q uires a 
d ose re d ucti o n a n d ne utr o pe nia ca n be 
ma na ge d wit h t he use of G- C S F, n o d ose 
re d ucti o ns are re q uire d. 
 
N O N- H E M A T O L O GI C A L T O XI CI TI E S

C O N FI D E N TI A L
T his d oc u me nt is c o nfi de ntial. D o n ot discl ose or use e xce pt as a ut h orize d.
5 2
S h ort title: P h ase II st u d y of El ot uz u m a b pl us R V D i n Ne wl y Di a g n ose d M M
Versi o n D ate: N o ve m ber 1 0, 2 0 2 0 
Her pes Z oster reacti vati o n
A n y Gra de
H ol d b ortez o mi b u ntil lesi o ns are dr y.  
I ncrease a nti viral pr o p h yla xis t o 
t hera pe utic d ose u ntil lesi o ns are heali n g 
a n d dr y.
Peri p heral ne ur o pat h y
≥ Gra de 3 or Gra de 2 wit h pai n
See Secti o n 6. 3. 1. 1 f or b ortez o mi b d ose 
re d ucti o ns.  C o nsi derati o n f or d ose 
re d ucti o n of le nali d o mi de ma y be gi ve n 
after re d ucti o n of b ortez o mi b.  
Ot her dr u g relate d n o n 
he mat ol o gic t o xicit y
≥ Gra de 3
Deter mi ne attri b uti o n of t o xicit y if p ossi ble 
a n d h ol d a p pr o priate t hera p y.  F oll o w at 
least wee kl y.  If t o xicit y res ol ves t o ≤ 
Gra de 2 res u me t hera p y wit h o ne le vel 
d ose re d ucti o n of a p pr o priate dr u g.
6. 3. 1. 1
D os e m o difi c ati o ns f o r B o rt e z o mi b- R el at e d N e u r o p at hi c P ai n a n d/ o r P e ri p h e r al 
S e ns o r y N e u r o p at h y
T he ne ur ot o xicit y- directe d q uesti o n naire ( A p pe n di x VI) is a usef ul t o ol f or deter mi ni n g t he 
prese nce a n d i nte nsit y of ne ur o pat hic pai n a n d/ or peri p heral ne ur o pat h y fr o m t he partici pa nt’s 
pers pecti ve.  Ne ur o pat hic s y m pt o ms are m ore pr o mi ne nt t ha n a b n or malities o n t he cli nical 
e xa mi nati o n.  After t he partici pa nt c o m pletes t he Ne ur ot o xicit y- directe d q uesti o n naire, t he 
q uesti o n naire s h o ul d be re vie we d t o assist wit h t he e val uati o n of t he o nset a n d i nte nsit y of 
peri p heral ne ur o pat h y a n d ot her ne ur ot o xicities t hat ma y p ossi bl y re q uire i nter ve nti o n or d ose 
m o dificati o n.
Rec o m me n de d D ose M o dific ati o n f or B ortez o mi b- Rel ate d Ne ur o p at hic P ai n a n d/ or Peri p her al Se ns or y 
Ne ur o p at h y
Se verit y of Peri p her al Ne ur o p at h y Si g ns a n d S y m pt o ms
M o dific ati o n of D ose a n d Re gi me n 
Gra de 1 ( parest hesias, wea k ness, a n d/ or l oss of refle xes) 
wit h o ut pai n or l oss of f u ncti o n
N o acti o n
Gra de 1 wit h pai n or Gra de 2 (i nterferi n g wit h f u ncti o n b ut 
n ot wit h acti vities of dail y li vi n g)
Re d uce b y o ne d ose le vel.  If a sec o n d d ose 
re d ucti o n is necessar y, b ortez o mi b will be 
gi ve n o nce wee kl y  d uri n g i n d ucti o n o n Da ys 1 
a n d 8  at 0. 7 m g/ m 2 or Da ys 1 a n d 1 5 d uri n g 
mai nte na nce
Gra de 2 wit h pai n or Gra de 3 (i nterferi n g wit h acti vities of 
dail y li vi n g)
H ol d b ortez o mi b u ntil t o xicit y res ol ves t o < 
gra de 2. W he n t o xicit y res ol ves, rei nitiate at 
o ne le vel d ose re d ucti o n. If a sec o n d d ose 
re d ucti o n is necessar y, b ortez o mi b will be 
gi ve n o nce wee kl y d uri n g i n d ucti o n o n Da ys 1 
a n d 8 at 0. 7 m g/ m 2 or Da ys 1 a n d 1 5 d uri n g 
mai nte na nce
Gra de 4 (se ns or y ne ur o pat h y w hic h is disa bli n g or m ot or 
ne ur o pat h y t hat is life-t hreate ni n g or lea ds t o paral ysis)
Disc o nti n ue b ortez o mi b

C O N FI D E N TI A L
T his d oc u me nt is c o nfi de ntial. D o n ot discl ose or use e xce pt as a ut h orize d.
5 3
S h ort title: P h ase II st u d y of El ot uz u m a b pl us R V D i n Ne wl y Di a g n ose d M M
Versi o n D ate: N o ve m ber 1 0, 2 0 2 0 
Gra di n g base d o n C T E P Versi o n 4. 0 3 of t he N CI C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nts 
( C T C A E): htt p://cte p.ca ncer. g o v/ pr ot oc ol De vel o p me nt/electr o nic a p plicati o ns/ctc. ht m . 
A D L = acti vities of dail y li vi n g
6. 3. 2 De x a met h as o ne D ose M o dific ati o ns
De x a met h as o ne d ose m o dific ati o ns 
D ys pe psia, gastric or d u o de nal 
ulcer, gastritis Gra de 1- 2 
(re q uiri n g me dical 
ma na ge me nt) 
Treat wit h H 2 bl oc kers, s ucralfate, or o me praz ole.  If 
s y m pt o ms persist des pite a b o ve meas ures, decrease 
de xa met has o ne d ose b y 1 d ose le vel
> Gra de 3 (re q uiri n g 
h os pitalizati o n or s ur ger y)
H ol d de xa met has o ne u ntil s y m pt o ms a de q uatel y 
c o ntr olle d. W he n t he e ve nt gra de is ≤ 2, restart a n d 
decrease o ne d ose le vel of c urre nt d ose al o n g wit h 
c o nc urre nt t hera p y wit h H 2 bl oc kers, s ucralfate, or 
o me praz ole,.  If s y m pt o ms persist des pite a b o ve meas ures, 
disc o nti n ue de xa met has o ne a n d d o n ot res u me.
Gastr oi ntesti nal
Ac ute pa ncreatitis
Disc o nti n ue de xa met has o ne a n d d o n ot res u me.
Car di o vasc ular
E de ma
> Gra de 3 (li miti n g f u ncti o n 
a n d u nres p o nsi ve t o t hera p y or 
a nasarca)
Di uretics as nee de d, a n d decrease de xa met has o ne d ose b y 
1 d ose le vel; if e de ma persists des pite a b o ve meas ures, 
decrease d ose a n ot her d ose le vel.  Disc o nti n ue 
de xa met has o ne a n d d o n ot res u me if s y m pt o ms persist 
des pite sec o n d re d ucti o n.
Ne ur ol o g y
C o nf usi o n or M o o d alterati o n
> Gra de 2 (i nterferi n g wit h 
f u ncti o n +/- i nterferi n g wit h 
acti vities of dail y li vi n g)
H ol d de xa met has o ne u ntil s y m pt o ms res ol ve t o gra de < 2. 
Restart wit h o ne d ose le vel re d ucti o n. If s y m pt o ms persist 
des pite a b o ve meas ures, disc o nti n ue de xa met has o ne a n d 
d o n ot res u me
M usc ul os keletal
M uscle wea k ness
> Gra de 2 (s y m pt o matic a n d 
i nterferi n g wit h f u ncti o n +/- 
i nterferi n g wit h acti vities of 
dail y li vi n g
Decrease de xa met has o ne b y o ne d ose le vel. If wea k ness 
persists des pite a b o ve meas ures decrease d ose b y o ne 
le vel. Disc o nti n ue de xa met has o ne a n d d o n ot res u me if 
s y m pt o ms persist.
Meta b olic
H y per gl yce mia
> Gra de 3 or hi g her
Treat me nt wit h i ns uli n or oral h y p o gl yce mics as nee de d. If 
u nc o ntr olle d des pite a b o ve meas ures, decrease d ose b y o ne 
d ose le vel u ntil le vels are satisfact or y ( gra de < 3).
D ose re d ucti o n f or persiste nt Gra de 2 or Gra de  3 A Es belie ve d t o be relate d t o de xa met has o ne 
a n d n ot liste d a b o ve are per mitte d. T he A E m ust be d oc u me nte d i n t he C R F. 
M ore a g gressi ve d ose re d ucti o ns f or l o wer gra de t o xicit y t ha n t h ose liste d a b o ve m ust first be 
disc usse d wit h t he Pri nci pal I n vesti gat or
6. 4 
I niti ati o n of Ne w C ycle of E- R V D T her a p y ( D a y 1)
A d diti o n al criteri a f or i niti ati o n of C ycle 5 f oll o wi n g ste m cell m o biliz ati o n are det aile d i n 
secti o n 6. 5

C O N FI D E N TI A L
T his d oc u me nt is c o nfi de ntial. D o n ot discl ose or use e xce pt as a ut h orize d.
5 4
S h ort title: P h ase II st u d y of El ot uz u m a b pl us R V D i n Ne wl y Di a g n ose d M M
Versi o n D ate: N o ve m ber 1 0, 2 0 2 0 
A ne w c o urse of treat me nt ma y be gi n o n t he sc he d ule d Da y 1 of a ne w c ycle of E- R V D if t he 
f oll o wi n g criteria are met:

A N C > 1, 0 0 0/ m m 3 ( gr o wt h fact or s u p p ort is per mitte d; it is all o we d o n t he sa me da y as 
treat me nt a d mi nistrati o n) platelet c o u nt > 5 0, 0 0 0/ m m3 ( platelet s u p p ort is per mitte d; it is 
all o we d o n t he sa me da y as treat me nt a d mi nistrati o n). 

A n y ot her le nali d o mi de, b ortez o mi b, de xa met has o ne or el ot uz u ma b relate d a d verse e ve nt t hat 
ma y ha ve occ urre d has res ol ve d t o < gra de 2 se verit y ( or acc or di n g t o t he d ose m o dificati o n 
ta ble).  

Her pes Z oster lesi o ns are dr y
If t here are d ose m o dificati o ns or dela ys i n t he pre vi o us c ycle, t hese g ui deli nes s h o ul d be f oll o we d 
f or t he i nitiati o n of a ne w c ycle.
If t here are n o ot her t o xicities t hat re q uire a d ose re d ucti o n a n d t hr o m b oc yt o pe nia a n d/ or 
ne utr o pe nia ca n be ma na ge d b y t he use of platelet tra nsf usi o ns or G- C S F, n o d ose re d ucti o ns are 
re q uire d b ut 
ma y be 
ma de at t he i n vesti gat ors discreti o n.   C o ns ultati o n wit h t he PI is 
rec o m me n de d.

If le nali d o mi de was hel d d uri n g t he pre vi o us c ycle a n d restarte d at a re d uce d d ose le vel, 
wit h o ut i nterr u pti o n f or t he re mai n der of t he c ycle, t he n t he re d uce d d ose le vel will be i nitiate d 
o n Da y 1 of t he ne w c ycle.

If le nali d o mi de d osi n g was o mitte d f or t he re mai n der of t he pre vi o us c ycle or if a ne w c ycle 
is dela ye d d ue t o le nali d o mi de-relate d t o xicit y ne wl y e nc o u ntere d o n t he sc he d ule d Da y 1, 
t he n t he ne w c ycle will be starte d wit h o ne-le vel d ose re d ucti o n.

If a n y t w o or m ore d oses of b ortez o mi b were hel d d uri n g t he c ycle (eit her c o nsec uti vel y or 
t w o or m ore i n o ne c ycle), t he n t he ne w c ycle will be starte d wit h o ne le vel d ose re d ucti o n.

If t he ne w c ycle is dela ye d d ue t o b ortez o mi b-relate d t o xicit y ne wl y e nc o u ntere d o n t he 
sc he d ule d Da y 1, t he n t he ne w c ycle will be starte d wit h a o ne-le vel d ose re d ucti o n.
D ose m o dificati o ns f or t o xicit y are per mitte d acc or di n g t o secti o n 6. T he ma xi m u m a m o u nt of 
ti me f or w hic h a dr u g ma y be hel d d ue t o t o xicit y is 2 1 da ys.  If st u d y dr u g is hel d f or m ore t ha n 
2 1 da ys d ue t o t o xicit y t he partici pa nt will be re m o ve d fr o m t he st u d y. If h o we ver t he patie nt was 
clearl y be nefiti n g fr o m t hera p y, t he patie nt ma y be a ble t o c o nti n ue treat me nt wit h a d ose re d ucti o n 
at t he I n vesti gat or discreti o n a n d i n c o ns ultati o n wit h t he Pri nci pal I n vesti gat or, after res ol uti o n of 
t he a d verse e ve nt.
6. 5 
I niti ati o n of I n d ucti o n C ycle 5 p ost Ste m Cell M o biliz ati o n
Pri or t o c o nti n ui n g t o I n d ucti o n C ycle 5, all ste m cell har vest-relate d t o xicities m ust ha ve res ol ve d 
or i m pr o ve d t o C T C A E Gra de ≤ 1 a n d s u bjects m ust meet t he f oll o wi n g ste m cell har vest rec o ver y 
criteria:
a) 
E C O G ≤ 2;
b)  
A bs ol ute ne utr o p hil c o u nt > 1 0 0 0 cells/ m m 3;
c) 
Platelet c o u nt ≥ 7 5, 0 0 0 cell/ m m 3 ( 7 5 x 1 0 9/ L);
d)  
He m o gl o bi n ≥ 8 g/ d L at m ost rece nt meas ure me nt;
e) 
T otal bilir u bi n < 1. 5 x u p per li mit of n or mal ( U L N);

C O N FI D E N TI A L
T his d oc u me nt is c o nfi de ntial. D o n ot discl ose or use e xce pt as a ut h orize d.
5 5
S h ort title: P h ase II st u d y of El ot uz u m a b pl us R V D i n Ne wl y Di a g n ose d M M
Versi o n D ate: N o ve m ber 1 0, 2 0 2 0 
f)  
As partate a mi n otra nsferase ( A S T) a n d ala ni ne a mi n otra nsferase ( A L T) < 3 x U L N;
g)  
A ble t o u n der g o f urt her treat me nt i n t he j u d g me nt of t he i n vesti gat or.
7  
D R U G F O R M U L A TI O N A N D A D MI NI S T R A TI O N 
7. 1 
Le n ali d o mi de ( R E V LI MI D ®)
7. 1. 1 Descri pti o n
Le nali d o mi de ( R E V LI MI D ® ), a t hali d o mi de a nal o g ue, is a n i m m u n o m o d ulat or y a ge nt wit h 
a ntia n gi o ge nic pr o perties. T he c he mical na me is 3-( 4-a mi n o- 1- o x o 1, 3- di h y dr o - 2 H -is oi n d ol- 2-
yl) pi peri di ne- 2, 6- di o ne a n d it has t he f oll o wi n g c he mical str uct ure:
3-( 4-a mi n o- 1- o x o 1, 3- di h y dr o- 2 H -is oi n d ol- 2- yl) pi peri di ne- 2, 6- di o ne
T he e m pirical f or m ula f or le nali d o mi de is C 1 3H 1 3N 3O 3, a n d t he gra m m olec ular wei g ht is 2 5 9. 3.
7. 1. 2 F or m
Le nali d o mi de is off- w hite t o pale- yell o w s oli d p o w der. Le nali d o mi de is s ol u ble i n or ga nic 
s ol ve nt/ water mi xt ures, a n d b uffere d a q ue o us s ol ve nts. It is m ore s ol u ble i n or ga nic s ol ve nts a n d 
l o w p H s ol uti o ns. S ol u bilit y was si g nifica ntl y l o wer i n less aci dic b uffers, ra n gi n g fr o m a b o ut 0. 4 
t o 0. 5 m g/ ml. Le nali d o mi de has a n as y m metric car b o n at o m a n d ca n e xist as t he o pticall y acti ve 
f or ms S(-) a n d R( +), a n d is pr o d uce d as a race mic mi xt ure wit h a net o ptical r otati o n of zer o.
7. 1. 3 St or a ge a n d St a bilit y
Le nali d o mi de is c o m merciall y a vaila ble a n d will be dis pe nse d b y a p har macist re gistere d i n t he 
Re vli mi d R E M S ® pr o gra m. L e n ali d o mi d e s h o ul d b e st or e d at r o o m t e m p er at ur e a w a y fr o m 
dir e ct s u nli g ht a n d pr ot e ct e d fr o m e x c essi v e h e at a n d c ol d.
7. 1. 4 H a n dli n g
Fe males of c hil d beari n g p ote ntial s h o ul d n ot ha n dle or a d mi nister le nali d o mi de u nless t he y are 
weari n g gl o ves.
7. 1. 5 A v ail a bilit y
Le nali d o mi de is c o m merciall y a vaila ble a n d will be dis pe nse d b y a p har macist re gistere d i n t he 
Re vli mi d R E M S ® pr o gra m.

C O N FI D E N TI A L
T his d oc u me nt is c o nfi de ntial. D o n ot discl ose or use e xce pt as a ut h orize d.
5 6
S h ort title: P h ase II st u d y of El ot uz u m a b pl us R V D i n Ne wl y Di a g n ose d M M
Versi o n D ate: N o ve m ber 1 0, 2 0 2 0 
7. 1. 6 Or deri n g
L e n ali d o mi d e will b e pr o vi d e d as c o m m er ci al s u p pl y i n a c c or d a n c e wit h t h e R e vli mi d R E M S ® 
pr o gr a m of C el g e n e C or p or ati o n.  P er st a n d ar d R e vli mi d R E M S ® r e q uir e m e nts all p h ysi ci a ns 
w h o pr es cri b e l e n ali d o mi d e f or r es e ar c h s u bj e cts e nr oll e d i nt o t his tri al, a n d all r es e ar c h 
s u bj e cts e nr oll e d i nt o t his tri al, m ust b e r e gist er e d i n a n d m ust c o m pl y wit h all r e q uir e m e nts 
of t h e R e vli mi d R E M S ® pr o gr a m.  Pr es cri pti o ns m ust b e fill e d wit hi n 1 4 d a ys, u nl ess t h e 
p ati e nt is a f e m al e of c hil d b e ari n g p ot e nti al, i n w hi c h c as e t h e pr es cri pti o n m ust b e fill e d 
wit hi n 7 d a ys.  O nl y e n o u g h l e n ali d o mi d e f or o n e c y cl e of t h er a p y will b e s u p pli e d t o t h e 
p ati e nt e a c h c y cl e.
7. 1. 7 Acc o u nt a bilit y
L e n ali d o mi d e is c o m m er ci all y a v ail a bl e t h er ef or e, n o dr u g a c c o u nt a bilit y r e c or ds ar e r e q uir e d. 
T h e i n v esti g at or is r es p o nsi bl e f or m o nit ori n g p ati e nt c o m pli a n c e b y m o nit ori n g p ati e nt di ar y 
a n d or pill c o u nt.
7. 1. 8 Destr ucti o n a n d Ret ur n
P arti ci p a nts will b e i nstr u ct e d t o r et ur n e m pt y b ottl es or u n us e d c a ps ul es vi a t h e R e vli mi d 
R E M S ® pr o gr a m.
7. 2 
B ortez o mi b ( V E L C A D E ®)
7. 2. 1 Descri pti o n
B ortez o mi b f or I njecti o n is a s mall m olec ule pr oteas o me i n hi bit or de vel o pe d b y Mille n ni u m as a 
n o vel a ge nt t o treat h u ma n mali g na ncies.  B y i n hi biti n g a si n gle m olec ular tar get, t he pr oteas o me, 
b ortez o mi b affects m ulti ple si g nali n g pat h wa ys. T he a nti- ne o plastic effect of b ortez o mi b li kel y 
i n v ol ves se veral disti nct mec ha nis ms, i ncl u di n g i n hi biti o n of cell gr o wt h a n d s ur vi val pat h wa ys, 
i n d ucti o n of a p o pt osis, a n d i n hi biti o n of e x pressi o n of ge nes t hat c o ntr ol cell ular a d hesi o n, 
mi grati o n a n d a n gi o ge nesis. B ortez o mi b is t h o u g ht t o be efficaci o us i n m ulti ple m yel o ma via its 
i n hi biti o n of N F- κ B  acti vati o n, its atte n uati o n of I L- 6- me diate d cell gr o wt h, a direct a p o pt otic 
effect, a n d p ossi bl y a nti-a n gi o ge nic a n d ot her effects.
7. 2. 2 F or m
B ort e z o mi b f or I nj e cti o n is a st eril e l y o p hili z e d p o w d er f or r e c o nstit uti o n a n d is s u p pli e d i n 
st eril e, si n gl e us e vi als c o nt ai ni n g b ort e z o mi b a n d m a n nit ol at a 1: 1 0 r ati o.  F or e x a m pl e, vi als 
c o nt ai ni n g 3. 5 m g of b ort e z o mi b c o nt ai n 3 5 m g of m a n nit ol.  B ort e z o mi b is c o m m er ci all y 
a v ail a bl e a n d will n ot b e s u p pli e d as p art of t his cli ni c al tri al.
7. 2. 3 St or a ge a n d St a bilit y
Vi als c o nt ai ni n g l y o p hili z e d b ort e z o mi b f or I nj e cti o n s h o ul d b e st or e d a c c or di n g t o l a b el 
r e q uir e m e nts.  St or e at U S P C o ntr oll e d R o o m T e m p er at ur e w hi c h is 2 5◦C ( 7 7 ◦F); e x c ursi o ns 
p er mitt e d fr o m 1 5 t o 3 0 ◦C ( 5 9 t o 8 6 ◦F).  

C O N FI D E N TI A L
T his d oc u me nt is c o nfi de ntial. D o n ot discl ose or use e xce pt as a ut h orize d.
5 7
S h ort title: P h ase II st u d y of El ot uz u m a b pl us R V D i n Ne wl y Di a g n ose d M M
Versi o n D ate: N o ve m ber 1 0, 2 0 2 0 
7. 2. 4 H a n dli n g
B ortez o mi b is c yt ot o xic. As wit h all c yt ot o xic dr u gs, ca uti o n is re q uire d w he n pre pari n g a n d 
ha n dli n g b ortez o mi b s ol uti o ns.  C yt ot o xic dr u gs s h o ul d o nl y be ha n dle d b y staff s peciall y trai ne d 
i n t he safe ha n dli n g of s uc h pre parati o ns.  T he use of gl o ves a n d ot her a p pr o priate pr otecti ve 
cl ot hi n g is rec o m me n de d.  I n case of s ki n c o ntact, was h t he affecte d area i m me diatel y a n d 
t h or o u g hl y wit h s oa p a n d water f or at least 1 5 mi n utes.  If pr o d uct c o ntacts e ye, i m me diatel y 
fl us h e ye t h or o u g hl y wit h water f or at least 1 5 mi n utes.  Al wa ys c o ntact a p h ysicia n after a n y 
f or m of b o d y c o ntact.  All materials t hat ha ve bee n use d f or pre parati o n s h o ul d be dis p ose d of 
acc or di n g t o sta n dar d practices.  
7. 2. 5 A v ail a bilit y
C o m mercial s u p plies of b ortez o mi b will be use d f or t his st u d y.
7. 2. 6 Pre p ar ati o n
E a c h vi al of b ort e z o mi b s h o ul d b e r e c o nstit ut e d u n d er a l a mi n ar fl o w bi ol o gi c al c a bi n et ( h o o d) 
wit hi n ei g ht h o urs b ef or e d osi n g wit h n or m al ( 0. 9 %) s ali n e, S o di u m C hl ori d e I nj e cti o n U S P. 
Pri or t o r e c o nstit uti o n t h e vi als s h o ul d r e m ai n i n t h e c art o ns t o pr ot e ct t h e m fr o m li g ht.  
Diss ol uti o n is c o m pl et e d i n a p pr o xi m at el y 1 0 s e c o n ds.  T h e r e c o nstit ut e d s ol uti o n is cl e ar a n d 
c ol orl ess, wit h a fi n al p H of 5 t o 6.  T h e r e c o nstit ut e d s ol uti o n s h o ul d b e a d mi nist er e d pr o m ptl y 
a n d i n n o c as e m or e t h a n 8 h o urs aft er r e c o nstit uti o n.  All m at eri als t h at h a v e b e e n us e d f or 
pr e p ar ati o n s h o ul d b e dis p os e d of a c c or di n g t o st a n d ar d pr a cti c es.    C a uti o n s h o ul d b e us e d 
w h e n c al c ul ati n g t h e r e c o nstit uti n g v ol u m e a n d t h e fi n al c o n c e ntr ati o n f or a d mi nistr ati o n.  
Rec o nstit uti o n V ol u mes a n d Fi n al C o nce ntr ati o n f or 
S u bc ut a ne o us A d mi nistr ati o n
R o ute of
a d mi nistr ati o n
B ortez o mi b
( m g/ vi al)
Dil ue nt
( 0. 9 % S o di u m
C hl ori de)
Fi n al B ortez o mi b
c o nce ntr ati o n
( m g/ m L)
S u bc uta ne o us
3. 5 m g
 1. 4 m L
 2. 5 m g/ m L
W h e n a d mi nist er e d s u b c ut a n e o usl y, sit es f or e a c h i nj e cti o n (t hi g h or a b d o m e n) s h o ul d b e 
r ot at e d.  N e w i nj e cti o ns s h o ul d b e gi v e n at l e ast o n e i n c h fr o m a n ol d sit e a n d n e v er i nt o ar e as 
w h er e t h e sit e is t e n d er, br uis e d, er yt h e m at o us, or i n d ur at e d. 
R ef er t o t h e P a c k a g e I ns ert f or c o m pl et e d et ails.
7. 2. 7 Or deri n g
C o m mercial s u p plies of b ortez o mi b will be use d f or t his trial.  
7. 2. 8 Acc o u nt a bilit y

C O N FI D E N TI A L
T his d oc u me nt is c o nfi de ntial. D o n ot discl ose or use e xce pt as a ut h orize d.
5 8
S h ort title: P h ase II st u d y of El ot uz u m a b pl us R V D i n Ne wl y Di a g n ose d M M
Versi o n D ate: N o ve m ber 1 0, 2 0 2 0 
C o m mercial s u p plies of b ortez o mi b will be use d f or t his trial, t heref ore n o dr u g acc o u nta bilit y 
rec or ds are re q uire d.
7. 3  
De x a met h as o ne
7. 3. 1 Descri pti o n
De xa met has o ne is a s y nt hetic a dre n oc ortical ster oi d. C ortic oster oi ds are nat urall y- occ urri n g 
c he micals pr o d uce d b y t he a dre nal gla n ds l ocate d a b o ve t he ki d ne ys. C ortic oster oi ds affect t he 
f u ncti o n of ma n y cells wit hi n t he b o d y a n d s u p press t he i m m u ne s yste m. C ortic oster oi ds als o bl oc k 
i nfla m mati o n a n d are use d i n a wi de variet y of i nfla m mat or y diseases affecti n g ma n y or ga ns.  T he 
m olec ular wei g ht f or de xa met has o ne is 3 9 2. 4 7.  It is desi g nate d c he micall y as 9-fl u or o- 1 1 β, 1 7, 2 1-
tri h y dr o x y- 1 6 α- met h yl pre g na- 1, 4- die ne- 3, 2 0- di o ne. De xa met has o ne is sta ble i n air a n d al m ost 
i ns ol u ble i n water.  T he e m pirical f or m ula is C2 2H 2 9F O 5 a n d t he str uct ural f or m ula is:
7. 3. 2 A v ail a bilit y
De xa met has o ne s u p pl y will be o btai ne d t hr o u g h c o m mercial s u p pl y.  
7. 3. 3 Or deri n g
T h e i n v esti g at or or d esi g n e e will or d er dr u g s u p pl y fr o m c o m m er ci al s u p pl y. 
7. 4 
El ot uz u m a b
7. 4. 1 Descri pti o n
El ot uz u ma b f or i njecti o n has bee n de vel o pe d t o be use d as a n i ntra ve n o us (I V) i nf usi o n f or t he
cli nical st u dies. Dr u g pr o d uct is a n o n- p yr o ge nic l y o p hilize d p o w der w hic h is w hite t o off- w hite
c o ntai ne d i n 2 0-cc T y pe I glass vials, cl ose d wit h 2 0- m m st o p pers a n d seale d wit h al u mi n u m
seals. Eac h vial of dr u g pr o d uct c o ntai ns t he la bele d a m o u nt of B M S- 9 0 1 6 0 8 dr u g s u bsta nce,
s ucr ose, s o di u m citrate di h y drate, citric aci d, a n d p ol ys or bate 8 0. A 1 0 % o verfill is i ncl u de d i n
eac h vial t o acc o u nt f or vial, nee dle, s yri n ge ( V N S) h ol d u p. T he dr u g pr o d uct will be
rec o nstit ute d pri or t o a d mi nistrati o n.
Pri or t o a d mi nistrati o n t he dr u g pr o d uct m ust be rec o nstit ute d wit h Sterile Water f or I njecti o n, 
U S P, a n d t he n f urt her dil ute d i n 0. 9 % s o di u m c hl ori de n or mal sali ne, U S P, as per t he i nstr ucti o ns 
i n A p pe n di x VII 

C O N FI D E N TI A L
T his d oc u me nt is c o nfi de ntial. D o n ot discl ose or use e xce pt as a ut h orize d.
5 9
S h ort title: P h ase II st u d y of El ot uz u m a b pl us R V D i n Ne wl y Di a g n ose d M M
Versi o n D ate: N o ve m ber 1 0, 2 0 2 0 
7. 4. 2 St or a ge a n d St a bilit y
El ot uz u ma b f or i njecti o n s h o ul d be st ore d refri gerate d at 2° t o 8° C ( 3 6° - 4 6° F) wit h pr otecti o n
fr o m li g ht. D o n ot freeze or s ha ke.
Rec o nstit ute d a n d dil ute d s ol uti o n of el ot uz u ma b f or i njecti o n is sta ble f or u p t o 2 4 h o urs, u n der
refri gerate d c o n diti o ns, 2° t o 8° C ( 3 6° - 4 6° F). T he dr u g s ol uti o n s h o ul d be e q uili brate d t o r o o m
te m perat ure a n d t he c o ntai ner m ust be ge ntl y i n verte d t o mi x well bef ore a d mi nistrati o n. D o n ot
use t he accelerate d war mi n g met h o d. After t he d ose is dil ute d i n n or mal sali ne, it m ust be f ull y 
a d mi nistere d wit hi n 8 h o urs if st ore d at r o o m te m perat ure.
7. 4. 3 A v ail a bilit y
El ot uz u ma b f or i njecti o n will be s u p plie d b y B M S.
7. 4. 4 Pre p ar ati o n a n d A d mi nistr ati o n
T he d ose of el ot uz u ma b t o be a d mi nistere d t o a s u bject will be calc ulate d b y m ulti pl yi n g t he 
s u bject’s wei g ht ( k g) b y 1 0 m g/ k g f or I n d ucti o n C ycles a n d 2 0 m g/ k g f or Mai nte na nce C ycles.   
D ose calc ulati o ns a n d re-calc ulati o ns will be base d o n t he site’s i nstit uti o nal sta n dar d.
Pri or t o a d mi nistrati o n t he dr u g pr o d uct m ust be rec o nstit ute d wit h Sterile Water f or I njecti o n, 
U S P, a n d t he n f urt her dil ute d i n 0. 9 % s o di u m c hl ori de n or mal sali ne, U S P, as per t he i nstr ucti o ns 
i n A p pe n di x VII. After t he d ose is dil ute d i n n or mal sali ne, t he i nf usi o n m ust be c o m plete d wit hi n 
8 h o urs if st ore d at r o o m te m perat ure. If a dela y is a ntici pate d, t he pre pare d d ose ma y be 
refri gerate d at 2° t o 8° C f or u p t o 2 4 h o urs. If st ore d u n der refri gerate d c o n diti o ns, t he pre pare d 
st u d y dr u g s ol uti o n s h o ul d be e q uili brate d t o r o o m te m perat ure ( pr ocess ta kes 2 - 2. 5 h o urs) a n d 
t he c o ntai ner m ust be ge ntl y i n verte d t o mi x well bef ore a d mi nistrati o n. D o n ot use t he accelerate d 
war mi n g met h o d. If a d mi nistrati o n is dela ye d be y o n d t he s pecifie d ti me, t he pre pare d d ose 
s ol uti o n m ust be discar de d, a n d t he reas o n d oc u me nte d b y t he p har macist i n st u d y dr u g 
acc o u nta bilit y rec or ds. 
T he first d ose of el ot uz u ma b will be a d mi nistere d f oll o wi n g pre me dicati o ns t o eac h s u bject as a n 
I V i nf usi o n, usi n g a n a ut o mate d i nf usi o n p u m p set at a n i nitial rate of 0. 5 m L per mi n ute ( 3 0 
m L/ h o ur).  If t he s u bject d oes n ot ha ve a n i nf usi o n reacti o n wit hi n 3 0 mi n utes, escalate t he 
i nf usi o n rate b y 0. 5 m L per mi n ute.  If t he s u bject still d oes n ot ha ve a n i nf usi o n reacti o n wit hi n 
3 0 mi n utes, escalate t he i nf usi o n rate t o a ma xi m u m of 2 m L per mi n ute ( 1 2 0 m L/ h o ur). 
T he sec o n d d ose of el ot uz u ma b s h o ul d be i nitiate d at a n i nf usi o n rate of 3 m L per mi n ute if n o 
i nf usi o n reacti o ns were re p orte d wit h t he first el ot uz u ma b i nf usi o n.  If t he s u bject d oes n ot 
e x perie nce a n i nf usi o n reacti o n d uri n g t he first 3 0 mi n utes of t he sec o n d d ose of el ot uz u ma b, 
escalate t he i nf usi o n rate b y 1. 0 m L per mi n ute t o a ma xi m u m i nf usi o n rate of 4 m L per mi n ute.
T he t hir d d ose of el ot uz u ma b s h o ul d be i nitiate d at a n i nf usi o n rate of 5 m L per mi n ute if n o 
i nf usi o n reacti o ns were re p orte d wit h pre vi o us el ot uz u ma b i nf usi o ns.

C O N FI D E N TI A L
T his d oc u me nt is c o nfi de ntial. D o n ot discl ose or use e xce pt as a ut h orize d.
6 0
S h ort title: P h ase II st u d y of El ot uz u m a b pl us R V D i n Ne wl y Di a g n ose d M M
Versi o n D ate: N o ve m ber 1 0, 2 0 2 0 
If n o i nf usi o n reacti o ns were o bser ve d d uri n g t he first c ycle of el ot uz u ma b, t he sec o n d c ycle ca n 
c o m me nce at a rate of 5 m L per mi n ute (see Ta ble 2 A p pe n di x VII).
F urt her i nstr ucti o ns o n t he escalati o n of t he i nf usi o n rate a n d i n case of i nf usi o n reacti o ns, are 
pr o vi de d i n A p pe n di x VII.
7. 4. 5 Or deri n g 
Eac h partici pati n g i nstit uti o n will or der El ot uz u ma b directl y fr o m t he s u p plier Brist ol M yers 
S q ui b b P har mace uticals ( B M S). A partici pati n g site ma y or der t he a ge nt(s) o nl y after t he i nitial 
I R B a p pr o val f or t he site has bee n f or war de d b y t he C o or di nati n g Ce nter t o B M S. 
7. 4. 6 Acc o u nt a bilit y
T h e i n v esti g at or, or a r es p o nsi bl e p art y d esi g n at e d b y t h e i n vesti gat or, m ust mai ntai n a caref ul 
rec or d of t he i n ve nt or y a n d dis p ositi o n of t he a ge nt (i n vesti gati o nal or free of c har ge) usi n g t he 
N CI Dr u g Acc o u nta bilit y Rec or d or a n ot her c o m para ble dr u g acc o u nta bilit y f or m. ( See t he C T E P 
we bsite at 
htt p://cte p.ca ncer. g o v/ pr ot oc ol De vel o p me nt  f or t he “ P olic y a n d 
G ui deli nes f or 
Acc o u nta bilit y a n d St or a g e of I n v esti g ati o n al A g e nts ” or t o o bt ai n a c o p y of t h e dr u g 
a c c o u nt a bilit y f or m.)
7. 4. 7 Destr ucti o n a n d Ret ur n 
F or t his st u d y, st u d y dr u gs (t h ose s u p plie d b y B M S or s o urce d b y t he i n vesti gat or) s uc h as 
partiall y use d st u d y dr u g c o ntai ners, vials a n d s yri n ges ma y be destr o ye d o n site.
A n y u n use d st u d y dr u gs ca n o nl y be destr o ye d after bei n g i ns pecte d a n d rec o ncile d b y t he 
res p o nsi ble D F CI St u d y M o nit or or desi g nee u nless st u d y dr u g c o ntai ners m ust be i m me diatel y 
destr o ye d as re q uire d f or safet y, or t o meet l ocal re g ulati o ns (e g, c yt ot o xics or bi ol o gics).
O n-site destr ucti o n is all o we d pr o vi de d t he f oll o wi n g mi ni mal sta n dar ds are met:

O n-site dis p osal practices m ust n ot e x p ose h u ma ns t o ris ks fr o m t he dr u g.

O n-site dis p osal practices a n d pr oce d ures are i n a gree me nt wit h a p plica ble la ws a n d 
re g ulati o ns, i ncl u di n g a n y s pecial re q uire me nts f or c o ntr olle d or hazar d o us s u bsta nces.

Writte n pr oce d ures f or o n-site dis p osal are a vaila ble a n d f oll o we d. T he pr oce d ures m ust be 
file d wit h t he site’s S O Ps a n d a c o p y pr o vi de d t o B M S u p o n re q uest.

Rec or ds are mai ntai ne d t hat all o w f or tracea bilit y of eac h c o ntai ner, i ncl u di n g t he date 
dis p ose d of, q ua ntit y dis p ose d, a n d i de ntificati o n (I D) of t he pers o n dis p osi n g t he c o ntai ners. 
T he met h o d of dis p osal, (e g, i nci nerat or, lice nse d sa nitar y la n dfill, or lice nse d waste dis p osal 
ve n d or) m ust be d oc u me nte d.

Acc o u nta bilit y a n d dis p osal rec or ds are c o m plete, u p-t o- date, a n d a vaila ble f or t he M o nit or t o 
re vie w t hr o u g h o ut t he cli nical trial peri o d.

C O N FI D E N TI A L
T his d oc u me nt is c o nfi de ntial. D o n ot discl ose or use e xce pt as a ut h orize d.
6 1
S h ort title: P h ase II st u d y of El ot uz u m a b pl us R V D i n Ne wl y Di a g n ose d M M
Versi o n D ate: N o ve m ber 1 0, 2 0 2 0 
If c o n diti o ns f or destr ucti o n ca n n ot be met t he res p o nsi ble St u d y M o nit or will ma ke arra n ge me nts 
f or ret ur n of st u d y dr u g.
It is t he i n vesti gat or’s res p o nsi bilit y t o arra n ge f or dis p osal of all e m pt y c o ntai ners, pr o vi de d t hat 
pr oce d ures f or pr o per dis p osal ha ve bee n esta blis he d acc or di n g t o a p plica ble fe deral, state, l ocal, 
a n d i nstit uti o nal g ui deli nes a n d pr oce d ures, a n d pr o vi de d t hat a p pr o priate rec or ds of dis p osal are 
ke pt.
If st u d y dr u g will n ot be destr o ye d u p o n c o m pleti o n or ter mi nati o n of t he st u d y, all u n use d a n d/ or 
partiall y use d st u d y dr u g t hat was s u p plie d b y B M S m ust be ret ur ne d t o B M S. T he ret ur n of st u d y 
dr u g will be arra n ge d b y t he res p o nsi ble St u d y M o nit or.
8  
C O R R E L A TI V E/ S P E CI A L S T U DI E S
 N ot a p plica ble. 

S h ort title: P h ase II st u d y of El ot uz u m a b pl us R V D i n  Ne wl y Di a g n ose d M M
                         Versi o n D ate:     N o ve m ber 1 0, 2 0 2 0 
C O N FI D E N TI A L
T his d oc u me nt is c o nfi de ntial. D o n ot discl ose or use e xce pt as a ut h orize d.
6 2
9 
S T U D Y A S S E S S M E N T S A N D P R O C E D U R E S
T a bl e 9. 1
Fl o w C h art/ Ti m e a n d E v e nt s S c h e d ul e

C O N FI D E N TI A L
T his d oc u me nt is c o nfi de ntial. D o n ot discl ose or use e xce pt as a ut h orize d.
6 3
S h ort title: P h ase II st u d y of El ot uz u m a b pl us R V D i n Ne wl y Di a g n ose d M M
Versi o n D ate: N o ve m ber 1 0, 2 0 2 0 
Pr oce d ure 
Scree ni n g 1
( wit hi n 2 1 
da ys pri or t o 
C 1 D 1)
I n d ucti o n C ycle 11  t o 4
Eac h c ycle is 2 1 da ys
P ost C ycle 4 
a n d pre- ste m 
cell c ollecti o n
I n d ucti o n C ycle 5 – 8
Eac h c ycle is 2 1 da ys
Mai nte na nce 
C ycles 9 +
Eac h c ycle is 2 8 
da ys
E n d of 
St u d y 3 0
 
 
 
 
Da y 1
Da y 4
Da y  8
Da y 1 1 Da y 1 5
Da y 1
Da y 4
Da y 8
Da y 1 1
Da y 1
Da y 1 5
I nf or me d c o nse nt
X
I ncl usi o n/ E xcl usi o n criteria
X
C o m plete Me dical Hist or y
X
Dia g n osis & hist or y of M M
X
Vital si g ns, hei g ht, wei g ht/ B S A 2
X
X 1, 2
X 2
X 2
X 2
X 2
X 2
X 2
X 2
X 2
X 2
X 2
X
P h ysical e xa mi nati o n
X
X 1
X
X
X
X
E C O G perf or ma nce stat us
X
X 1
X
X
X
X
1 2- Lea d E C G 3
X
C hest X-ra y 4
X
 Ec h ocar di o gra m or M U G A
X
He mat ol o g y 5, 6, 7
X
X
X
X
X
X 7
X
X
X
X
X
X
X
X
C oa g ulati o n 8
X
Bi oc he mistr y 9, 1 0
X
X 1, 9
X
X 9
X 9
X
Uri nal ysis 1 1
X
X
Calc ulate d Creati ni ne Cleara nce
X
X
X
X

C O N FI D E N TI A L
T his d oc u me nt is c o nfi de ntial. D o n ot discl ose or use e xce pt as a ut h orize d.
6 4
S h ort title: P h ase II st u d y of El ot uz u m a b pl us R V D i n Ne wl y Di a g n ose d M M
Versi o n D ate: N o ve m ber 1 0, 2 0 2 0 
Ser u m/ Uri ne Pre g na nc y test 1 2, 1 3  
X
X
X 1 2
X 1 2
X
X
X Da y 
1 5 1 2
X
X 1 2
X 1 2
T h yr oi d f u ncti o n 1 4
X
Patie nt Re p orte d O utc o mes 
( F A C T G O G- N T X)/ Se ns or y 2 8
Ne ur o pat h y gra di n g 2 8
  
 
 
X
X 2 8
X 2 8
X 2 8
X
Disease Assess me nt
X
X 3 2
X 3 2
X 3 2
X
Ser u m M- pr otei n ( S- P E P) 1 5, 1 7
X
X 1 5, 1 6
X
X 1 5
X
X
Uri ne M- pr otei n ( U- P E P) 1 5, 1 7, 1 8
X
X 1 5, 1 6
X
X 1 5
X
X
Ser u m Free li g ht c hai n ( F L C) 1 5
X
X 2 1
X
X
X
X
Ser u m I m m u n ofi xati o n (sI F) 1 5
X
X
X
X
X
Uri ne I m m u n ofi xati o n ( uI F) 1 5, 1 8
X
X
X
X
X
S keletal s ur ve y 1 9
X
E val uati o n of s oft tiss ue 
plas mac yt o mas 2 0
X
X 2 0
X
X 2 0
X 2 0
B o ne Marr o w f or plas ma cell 
c o u nt 2 2
X 2 1
X 2 2
Ste m Cell M o bilizati o n
X 3 3
A ut ol o g o us Ste m Cell tra ns pla nt
X 3 4
B ortez o mi b 3 1
X
X
X
X
X
X
X
X
X
X
Le nali d o mi de oral d osi n g 3 1
Dail y da ys 1- 1 4
Dail y da ys 1- 1 4
Dail y da ys 1- 2 1 

C O N FI D E N TI A L
T his d oc u me nt is c o nfi de ntial. D o n ot discl ose or use e xce pt as a ut h orize d.
6 5
S h ort title: P h ase II st u d y of El ot uz u m a b pl us R V D i n Ne wl y Di a g n ose d M M
Versi o n D ate: N o ve m ber 1 0, 2 0 2 0 
1.   
Assess me nts re q uire d at scree ni n g visit, e xce pt f or he mat ol o g y, d o n ot ha ve t o be re peate d if perf or me d ≤ 7 da ys pri or t o C ycle 1 Da y 1 u nless ot her wise 
s pecifie d. T o ta ke i nt o acc o u nt sc he d uli n g c o nflicts (e. g., o ver p u blic h oli da ys), a 3 da y +/- wi n d o w will be all o we d f or all assess me nts, u nless ot her wise 
s pecifie d. F oll o wi n g C ycle 2, a 7 da y + wi n d o w is per mitte d bet wee n c ycles. H o we ver e ver y eff ort m ust be ma de t o f oll o w t he sc he d ule o utli ne d i n t he 
a b o ve ta ble.  
2.    
Hei g ht re q uire d at baseli ne o nl y. B S A is t o be calc ulate d base d o n b o d y wei g ht usi n g t he D u B ois f or m ula ( A p pe n di x II) a n d i n acc or da nce wit h i nstit uti o nal 
sta n dar ds.  At a mi ni m u m, t he d ose will be calc ulate d o n Da y 1 of eac h c ycle. Vital si g ns t o be meas ure d pri or t o el ot uz u ma b pre- me dicati o n, pre-
el ot uz u ma b i nf usi o n, 3 0 mi n utes after t he start of t he i nf usi o n, at t he e n d of t he i nf usi o n a n d 3 0 a n d 1 2 0 mi n utes after c o m pleti o n of t he i nf usi o n ( 1 2 0 mi n 
f or C 1 a n d 2 o nl y). S u bjects w h o e x perie nce a n i nf usi o n reacti o n re q uire vital si g ns t o be m o nit ore d e ver y 3 0 mi n utes d uri n g a n d f or 2 h o urs after t he 
e n d of t he el ot uz u ma b i nf usi o n. Vital si g ns t o be meas ure d pri or t o b ortez o mi b o n da ys n ot a d mi nistere d wit h el ot uz u ma b. 
3.    
E C G 1 2 lea d at baseli ne a n d as cli nicall y i n dicate d. 
4.  
A C hest X-ra y is re q uire d t o pr o vi de a baseli ne refere nce i n t he e ve nt t hat t he patie nt de vel o ps car diac or p ul m o nar y s y m pt o ms d uri n g t he st u d y. T he 
c hest X-ra y ma y be i ncl u de d i n t he s keletal s ur ve y assess me nt.
5.  
He mat ol o g y i ncl u des t he f oll o wi n g para meters: c o m plete bl o o d c o u nt c o nsisti n g of a t otal w hite bl o o d cell c o u nt wit h differe ntial (t otal ne utr o p hil 
[i ncl u di n g ba n ds], l y m p h oc yte, m o n oc yte, e osi n o p hil, a n d bas o p hil c o u nts); he m o gl o bi n; he mat ocrit a n d platelet c o u nt. He mat ol o g y assess me nts s h o ul d 
be perf or me d o n t he sc he d ule d da y or u p t o t hree da ys pri or, e ve n if st u d y me dicati o n is bei n g hel d. M ore fre q ue nt e xa mi nati o ns ma y be perf or me d at t he 
I n vesti gat or’s discreti o n, if me dicall y i n dicate d. He mat ol o g y assess me nt o n da y 1 5 is o nl y re q uire d bef ore C 1 a n d 2, a n d i n mai nte na nce w he n b ortez o mi b 
will be a d mi nistere d o n da y 1 5.
6.   
Baseli ne he mat ol o g y a n d bi oc he mistr y la bs ma y be re peate d o nce, if nee de d, t o o btai n acce pta ble val ues bef ore t he patie nt w o ul d scree n fail, h o we ver n o 
G- C S F or platelet tra nsf usi o ns are all o we d t o c orrect val ues.
7.   
He mat ol o g y res ults are re q uire d pri or t o B T Z d osi n g o n I n d ucti o n C ycle 1- 8 da ys 1, 4, 8, a n d 1 1 a n d mai nte na nce c ycles Da ys 1 a n d 1 5 f or t otal ne utr o p hils 
[i ncl u di n g ba n ds] a n d platelet c o u nts. He mat ol o g y res ults are als o re q uire d pri or t o El ot uz u ma b a d mi nistrati o n o n da y 1 5 of C ycle 1 a n d 2.
8.    
C oa g ulati o n pr ofile i ncl u des pr ot hr o m bi n ti me ( P T) or i nter nati o nal n or malize d rati o (I N R), acti vate d partial t hr o m b o plasti n ti me (a P T T), a n d fi bri n o ge n. 
E val uati o n s h o ul d be perf or me d at scree ni n g visit a n d ma y be re peate d at t he I n vesti gat or’s discreti o n, if me dicall y i n dicate d. If patie nt is recei vi n g 
c o u ma di n or ot her a ntic oa g ula nt t hera p y, t he n c oa g ulati o n para meters s h o ul d be m o nit ore d m ore fre q ue ntl y, per i n vesti gat or’s discreti o n
9.    
Res ults of bi oc he mistr y assess me nts nee d t o be a vaila ble pri or t o d osi n g o n Da y 1 of eac h c ycle.
1 0. 
Bi oc he mistr y i ncl u des t he f oll o wi n g para meters: Urea or B U N, creati ni ne, s o di u m, p otassi u m, gl uc ose, t otal calci u m (c orrecte d f or ser u m al b u mi n) or 
i o nize d calci u m, al b u mi n, t otal pr otei n, t otal bilir u bi n, lactate de h y dr o ge nase, al kali ne p h os p hatase, A S T/ S G O T, A L T/ S G P T, p h os p h or o us, ma g nesi u m, 
c hl ori de, C O 2( H C O 3), , a n d uric aci d. If t otal bilir u bi n > U L N, direct a n d i n direct bilir u bi n s h o ul d be perf or me d. Bi oc he mistr y assess me nts s h o ul d be 
De xa met has o ne d osi n g 3 1
Refer t o secti o n 5. 4. 5 
Refer t o secti o n 5. 4. 5 
X 
El ot uz u ma b- Pre me dicati o n 3 1
X
X
C ycles 1 
a n d 2
X
C ycles 3 
a n d 4
X
C ycl
es 1 
 
X
X
X
El ot uz u ma b d osi n g 3 1
X
X
C ycles 1 
a n d 2 
X
C ycles 3 
a n d 4
X
C ycl
es 1 
 
X
X
X
A d verse E ve nts 2 3
C o nti n u o us

C O N FI D E N TI A L
T his d oc u me nt is c o nfi de ntial. D o n ot discl ose or use e xce pt as a ut h orize d.
6 6
S h ort title: P h ase II st u d y of El ot uz u m a b pl us R V D i n Ne wl y Di a g n ose d M M
Versi o n D ate: N o ve m ber 1 0, 2 0 2 0 
perf or me d o n t he sc he d ule d da y e ve n if st u d y me dicati o n is bei n g hel d. M ore fre q ue nt e xa mi nati o ns ma y be perf or me d at t he I n vesti gat or’s discreti o n, if 
me dicall y i n dicate d. β- 2  Micr o gl o b uli n t o be i ncl u de d at scree ni n g a n d da y 1 of eac h c ycle.
1 1.  
Uri nal ysis i ncl u des di pstic k a n d micr osc o pic e xa ms. Di pstic k e xa mi nati o n i ncl u des: pr otei n, gl uc ose, bl o o d, a n d s pecific gra vit y. Micr osc o pic e xa mi nati o n 
( o nl y re q uire d if macr o is a b n or mal) i ncl u des: W B C/ H P F, R B C/ H P F, a n d a n y a d diti o nal fi n di n gs. Baseli ne la bs ma y be re peate d, if nee de d, t o o btai n 
acce pta ble val ues bef ore t he patie nt w o ul d scree n fail. E val uati o n ma y be re peate d w hile t he patie nt is o n st u d y, w here cli nicall y i n dicate d.
1 2 
Pre g na nc y tests (se nsiti vit y of at least 5 0 mI U/ m L), m ust occ ur wit hi n 1 0 – 1 4 da ys a n d a gai n wit hi n 2 4 h o urs pri or t o i nitiati o n of le nali d o mi de. Fe males 
of c hil d beari n g p ote ntial wit h re g ular or n o me nstr uati o n m ust ha ve a pre g na nc y test wee kl y f or t he first 2 8 da ys, t he n e ver y 2 8 da ys (i ncl u di n g brea ks i n 
t hera p y); at disc o nti n uati o n of le nali d o mi de a n d at Da y 2 8 p ost t he last d ose of le nali d o mi de. Fe males wit h irre g ular me nstr uati o n m ust ha ve a pre g na nc y 
test wee kl y f or t he first 2 8 da ys a n d t he n e ver y 1 4 da ys w hile o n t hera p y (i ncl u di n g brea ks i n t hera p y), at disc o nti n uati o n of le nali d o mi de a n d at Da y 1 4 
a n d Da y 2 8 p ost t he last d ose of le nali d o mi de. 
1 3.  
All patie nts m ust e nr oll i n t he Re vli mi d R E M S ®  pr o gra m. 
1 4. 
T h yr oi d F u ncti o n i ncl u des T h yr oi d Sti m ulati n g H or m o ne ( T S H) a n d free T 4 (t h yr o xi ne).
1 5.  
Disease assess me nts are rec o m me n de d t o be d o ne per sta n dar d of care. 
1 6.  
T he “ 7 da ys” ti me wi n d o w (f o ot n ote 1 a b o ve) d oes n ot a p pl y f or sa m pli n g of Ser u m M- pr otei n ( S- P E P) a n d Uri ne M- pr otei n ( U- P E P) o n C ycle 1 Da y 1.
1 7.  
I M W G criteria will be use d t o assess res p o nse. Disease assess me nts are rec o m me n de d t o be d o ne per sta n dar d of care.  
1 8.  
 Disease assess me nts are rec o m me n de d t o be d o ne per sta n dar d of care.
1 9. 
S keletal s ur ve y s h o ul d be perf or me d at scree ni n g. If res ults of a s keletal s ur ve y perf or me d wit hi n 8 wee ks pri or t o scree ni n g visit are a vaila ble, a n d if 
t here is n o cli nical i n dicati o n t o re peat, t he n s keletal s ur ve y nee ds n ot t o be re peate d at scree ni n g visit. B o ne X-ra ys nee d t o be perf or me d o n st u d y o nl y 
if cli nicall y i n dicate d (e. g. b o ne pai n).
2 0.  
S oft tiss ue plas mac yt o ma: If prese nt m ust be assesse d b y cli nical e xa mi nati o n a n d M RI or C T at scree ni n g. Assess me nt of t he lesi o n(s) b y M RI or C T is 
als o re q uire d at t he e n d of I n d ucti o n C ycle 4, at ti me of co m plete res p o nse ( C R) if it is ac hie ve d, a n d w he n me dicall y i n dicate d d uri n g treat me nt
2 1.         Scree ni n g b o ne marr o w bi o ps y s h o ul d be perf or me d wit hi n 3 0 da ys of C 1 D 1. 
2 2.  
B o ne marr o w as pirati o n a n d bi o ps y t o be e val uate d f or m or p h ol o g y a n d f or c yt o ge netics b y sta n dar d ba n di n g a n d FI S H, i ncl u di n g marr o w kar y ot y pe if 
p ossi ble.  S u g geste d pr o bes i ncl u de, at a mi ni m u m del 1 3 q 1 4, t( 4: 1 4), t( 1 1; 1 4), t( 1 4: 1 6), a n d del 1 7 p. After Baseli ne, b o ne marr o w sa m pli n g f or plas ma 
cell c o u nt is re q uire d t o q ualif y C R a n d at t he e n d of c ycle 4 f or all patie nts.
2 3. 
 Patie nts m ust be i nstr ucte d t o n otif y t he I n vesti gat or of a n y u n desira ble s y m pt o ms or si de effects w hile o n st u d y. 
2 8 
F A C T G O G- N T X q uesti o n naire s h o ul d be a d mi nistere d at scree ni n g a n d o n da y 1 of eac h o d d c ycle a n d at t he st u d y c o m pleti o n visit. Se ns or y ne ur o pat h y 
gra di n g sc ores will als o be e val uate d at t hese visits.
3 0.  
E n d of  st u d y visit s h o ul d occ ur wit hi n 2 8 da ys of disc o nti n uati o n of treat me nt.
3 1  
Refer t o Secti o n 5 f or dr u g a d mi nistrati o n, d osi n g a n d sc he d ule a n d secti o n 6 f or d ose m o dificati o n g ui deli nes.
3 2  
 Disease assess me nts are rec o m me n de d t o be d o ne as per sta n dar d of care. 
3 3  
Re q uire d f or all patie nts at t he e n d of I n d ucti o n C ycle 4.  T o be perf or me d per i nstit uti o nal g ui deli nes.
3 4  
A S C T is o pti o nal a n d per i nstit uti o nal; g ui deli nes after I n d ucti o n C ycle 4. 

S h ort title: P h ase II st u d y of El ot uz u m a b pl us R V D i n  Ne wl y Di a g n ose d M M
                         Versi o n D ate:     N o ve m ber 1 0, 2 0 2 0 
C O N FI D E N TI A L
T his d oc u me nt is c o nfi de ntial. D o n ot discl ose or use e xce pt as a ut h orize d.
6 7
1 0
M E A S U R E M E N T O F E F F E C T  
I n t his st u d y, patie nts m ust ha ve meas ura ble disease (see Secti o n 1 0. 2. 2). T he disease res p o nse 
will be assesse d usi n g criteria base d o n t he m o difie d I nter nati o nal 
W or ki n g Gr o u p U nif or m 
Res p o nse Criteria ( Raj k u mar 2 0 1 1) i n Secti o n 1 0. 2. 4. 1. If t he o nl y meas ura ble para meter is ser u m 
i m m u n o gl o b uli ns free li g ht c hai n ( F L C), t he partici pa nt will be f oll o we d b y Free Lite ™ Disease 
Res p o nse Criteria pr o vi de d i n Secti o n 1 0. 2. 4. 2. 
T he s a me met h o d of assess me nt a n d tec h ni q ue s h o ul d be use d f or dise ase me as ure me nt at 
b aseli ne, d uri n g t he st u d y a n d f oll o w- u p.  
1 0. 1  
A ntit u m or Effect – S oli d T u m ors
T his secti o n is n ot a p plica ble t o t his st u d y.
1 0. 2  
A ntit u m or Effect – He m at ol o gic T u m ors
1 0. 2. 1
Defi niti o ns
E val ua ble f or t o xicit y: All partici pa nts w h o recei ve at least o ne d ose of st u d y treat me nt will be 
e val ua ble f or t o xicit y fr o m t he ti me of t heir first treat me nt.
E val ua ble f or res p o nse: All patie nts w h o recei ve st u d y t hera p y a n d at least o ne f oll o w- u p 
assess me nt will be i ncl u de d i n a res p o nse e val uati o n.   Res p o nses will be classifie d acc or di n g t o 
t he defi niti o ns state d bel o w. ( N ote: Partici pa nts w h o e x hi bit disease pr o gressi o n or die pri or t o 
t he e n d of c ycle 1 will als o be c o nsi dere d e val ua ble.)
1 0. 2. 2
Dise ase P ar a meters
M e as ur a bl e dis e as e: Meas ura ble disease is disease t hat ca n be meas ure d eit her b y ser u m or 
uri nar y e val uati o n of t he m o n ocl o nal c o m p o ne nt or b y ser u m assa y of F L C a n d is defi ne d b y at 
least o ne of t he f oll o wi n g t hree meas ure me nts:  

S er u m I g G, I g A, or I g M M- pr ot ei n ≥ 0. 5 g/ d L, or

S er u m I g D M- pr ot ei n ≥ 0. 0 5 g/ d L

Uri ne M- pr otei n > 2 0 0 m g/ 2 4 h

Ser u m F L C assa y: I n v ol ve d F L C le vel > 1 0 m g/ dl ( > 1 0 0 m g/l) pr o vi de d ser u m F L C rati o is 
a b n or mal.
1 0. 2. 3
Met h o ds f or E v al u ati o n of Me as ur a ble Dise ase
All baseli ne e val uati o ns s h o ul d be perf or me d o n C ycle 1, Da y 1 of t hera p y.  Res p o nse will be 
assesse d b y M- pr otei n q ua ntificati o n, pr otei n electr o p h oresis a n d i m m u n ofi xati o n fr o m ser u m a n d 
a 2 4- h o ur uri ne c ollecti o n.  A ser u m sa m ple f or Free Lite T M  testi n g will be o btai ne d.  I n a d diti o n, 

C O N FI D E N TI A L
T his d oc u me nt is c o nfi de ntial. D o n ot discl ose or use e xce pt as a ut h orize d.
6 8
S h ort title: P h ase II st u d y of El ot uz u m a b pl us R V D i n Ne wl y Di a g n ose d M M
Versi o n D ate: N o ve m ber 1 0, 2 0 2 0 
b o ne marr o w as pirati o n will be perf or me d t o c o nfir m res p o nse a n d t o differe ntiate bet wee n C R 
a n d stri n ge nt C R.  
T he s a me met h o d of assess me nt a n d tec h ni q ue s h o ul d be use d f or dise ase me as ure me nt at 
b aseli ne a n d d uri n g f oll o w- u p.
1 0. 2. 4
Res p o nse Criteri a 
Disease res p o nse will be assesse d usi n g t he u p date d I nter nati o nal M yel o ma 
W or ki n g Gr o u p 
Res p o nse Criteria (I M W G) ( Raj k u mar 2 0 1 1). A si x- wee k c o nfir mati o n meas ure me nt f or disease 
res p o nse assess me nts is re q uire d i n t his pr ot oc ol. 
1 0. 2. 4. 1  I nter n ati o n al M yel o m a W or ki n g Gr o u p Res p o nse Criteri a 
R e s p o n s e
I M W G crit eri a 
s C R
C R as defi ne d bel o w pl us: 

n or mal F L C rati o a n d 

a bse nce of cl o nal cells i n b o ne marr o w  b y i m m u n o hist oc he mistr y or 2 – 
4 c ol or fl o w c yt o metr y
C R

Ne gati ve i m m u n ofi xati o n o n t he ser u m a n d uri ne a n d 

disa p peara nce of a n y s oft tiss ue plas mac yt o mas a n d 

< 5 % plas ma cells i n b o ne marr o w.  

I n patie nts wit h o nl y F L C disease, a n or mal F L C rati o of 0. 2 6 – 1. 6 5 is 
re q uire d. 
V G P R

Ser u m a n d uri ne M- pr otei n detecta ble b y i m m u n ofi xati o n b ut n ot o n 
electr o p h oresis or

> 9 0 % re d ucti o n i n ser u m M- pr otei n pl us uri ne M- pr otei n le vel < 1 0 0 
m g/ 2 4 h.  

I n patie nts wit h o nl y F L C disease, > 9 0 % decrease i n t he differe nce 
bet wee n i n v ol ve d a n d u ni n v ol ve d F L C le vels is re q uire d.
P R

5 0 % re d ucti o n of ser u m M- pr otei n a n d re d ucti o n i n 2 4 h o urs uri nar y M-
pr otei n b y > 9 0 % or t o < 2 0 0 m g/ 2 4 h

If t he ser u m a n d uri ne M- pr otei n are u n meas ura ble,3 a > 5 0 % decrease i n 
t he differe nce bet wee n i n v ol ve d a n d u ni n v ol ve d F L C le vels is re q uire d i n 
place of t he M- pr otei n criteria

If ser u m a n d uri ne M- pr otei n are n ot mea s ura ble, a n d ser u m free li g ht 
assa y is als o n ot meas urea ble, > 5 0 % re d ucti o n i n plas ma cells is re q uire d 
i n place of M- pr otei n, pr o vi de d baseli ne b o ne marr o w plas ma cell 
perce nta ge was > 3 0 %

I n a d diti o n t o t he a b o ve liste d criteria, if prese nt at baseli ne, a > 5 0 % 
re d ucti o n i n t he size of s oft tiss ue plas mac yt o mas is als o re q uire d
St a bl e Di s e a s e

N ot meeti n g criteria f or C R, V G P R, P R or pr o gressi ve disease
Pr o gr e s si v e 
di s e a s e
I ncrease of > 2 5 % fr o m l o west res p o nse val ue i n a n y o ne of t he f oll o wi n g:

C O N FI D E N TI A L
T his d oc u me nt is c o nfi de ntial. D o n ot discl ose or use e xce pt as a ut h orize d.
6 9
S h ort title: P h ase II st u d y of El ot uz u m a b pl us R V D i n Ne wl y Di a g n ose d M M
Versi o n D ate: N o ve m ber 1 0, 2 0 2 0 

Ser u m M-c o m p o ne nt (t he a bs ol ute i ncrease m ust be > 0. 5 g/ d L) 4 a n d/ or 

Uri ne M-c o m p o ne nt (t he a bs ol ute i ncrease m ust be > 2 0 0 m g/ 2 4 h) a n d/ or 

O nl y i n patie nts wit h o ut meas ura ble ser u m a n d uri ne M- pr otei n, t he 
differe nce bet wee n i n v ol ve d a n d u ni n v ol ve d F L C le vels. T he a bs ol ute 
i ncrease m ust be > 1 0 m g/ d L

O nl y i n patie nts wit h o ut meas ura ble ser u m a n d uri ne M- pr otei n a n d wit h o ut 
meas ura ble disease b y F L C le vels, b o ne marr o w plas ma cell perce nta ge 
(a bs ol ute % m ust be ≥ 1 0 %) 

Defi nite de vel o p me nt of ne w b o ne lesi o ns or s oft tiss ue plas mac yt o mas or 
defi nite i ncrease i n t he size of e xisti n g b o ne lesi o ns or s oft tiss ue 
plas mac yt o mas

De vel o p me nt of h y percalce mia (c orrecte d ser u m calci u m > 1 1. 5 m g/ d L ) t hat 
ca n be attri b ute d s olel y t o t he plas ma cell pr oliferati ve dis or der
All res p o nse cate g ories (s C R, C R, V G P R, P R, a n d P D) re q uire 2 c o nsec uti ve assess me nts ma de at a n y 
ti me bef ore t he i nstit uti o n of a n y ne w t hera p y; s C R, C R, V G P R, P R, a n d S D cate g ories als o re q uire n o 
k n o w n e vi de nce of pr o gressi ve or ne w b o ne lesi o ns if ra di o gra p hic st u dies were perf or me d. V G P R a n d 
C R cate g ories re q uire ser u m a n d uri ne st u dies re gar dless of w het her disease at baseli ne was meas ura ble 
o n ser u m, uri ne, b ot h, or neit her. Ra di o gra p hic st u dies are n ot re q uire d t o satisf y t hese res p o nse 
re q uire me nts. B o ne marr o w assess me nts nee d n ot be c o nfir me d. F or P D, ser u m M-c o m p o ne nt i ncreases 
of m ore t ha n or e q ual t o 1 g/ d L are s ufficie nt t o defi ne rela pse if starti n g M-c o m p o ne nt is 5 g/ d L.
1 0. 2. 4. 1 A d diti o n al r es p o ns e c rit e ri a f o r s p e cifi c dis e as e st at es 
Mi n or r es p o ns e i n p ati e nts wit h r el a ps e d a n d 
r efr act or y m y el o m a a d a pt e d fr o m t h e E M B T 
crit eri a 3
≥ 2 5 % b ut < 4 9 % r e d ucti o n of s er u m M pr ot ei n a n d  
r e d ucti o n i n 2 4 h o ur uri n e M pr ot ei n b y 5 0 – 8 9 %, 
w hic h still exc e e ds 2 0 0 m g/ 2 4 hrs.
I n a d diti o n t o a b o v e; if pr es e nt at b as eli n e, 2 5- 4 9 % 
r e d ucti o n i n t h e siz e of s oft tiss u e pl as m ac yt o m as is 
als o r e q uir e d
N o i ncr e as e i n siz e or n u m b er of l ytic b o n e l esi o ns 
( d ev el o p m e nt of c o m pr essi o n fr act ur es d o es n ot 
excl u d e r es p o ns e)
1 0. 2. 4. 2 D u r ati o n of R es p o ns e a n d E n d p oi nt D efi niti o ns
D urati o n of o verall res p o nse: T he d urati o n of o verall res p o nse is meas ure d as t he ti me fr o m 
i nitiati o n of first res p o nse t o first d oc u me ntati o n of disease pr o gressi o n or deat h. Patie nts w h o 
ha ve n ot pr o gresse d or die d are ce ns ore d at t he date last k n o w n pr o gressi o n-free.
D urati o n of o verall c o m plete res p o nse: T he d urati o n of o verall C R is meas ure d as t he ti me fr o m 
i nitiati o n of C R t o first d oc u me ntati o n of disease pr o gressi o n or deat h. Patie nts w h o ha ve n ot 
pr o gresse d or die d are ce ns ore d at t he date last k n o w n pr o gressi o n-free.

C O N FI D E N TI A L
T his d oc u me nt is c o nfi de ntial. D o n ot discl ose or use e xce pt as a ut h orize d.
7 0
S h ort title: P h ase II st u d y of El ot uz u m a b pl us R V D i n Ne wl y Di a g n ose d M M
Versi o n D ate: N o ve m ber 1 0, 2 0 2 0 
1 0. 2. 4. 3 P r o g r essi o n- F r e e S u r vi v al
Pr o gressi o n- Free S ur vi val ( P F S):  P F S is defi ne d as t he ti me fr o m ra n d o mizati o n t o t he disease 
pr o gressi o n or deat h fr o m a n y ca use.  Patie nts w h o ha ve n ot pr o gresse d or die d are ce ns ore d at t he 
date last k n o w n pr o gressi o n-free. 
1 0. 2. 5
Res p o nse Re vie w
Ce ntral re vie w of disease res p o nse assess me nts is n ot pla n ne d f or t his trial. Disease res p o nse 
assess me nts will be perf or me d l ocall y o n t he f oll o wi n g disease res p o nse meas ures: M- pr otei n 
q ua ntificati o n a n d i m m u n ofi xati o n fr o m ser u m a n d a 2 4- h o ur uri ne c ollecti o n, a n d ser u m 
Free Lite T M  testi n g.  
1 0. 3  
Ot her Res p o nse P ar a meters
T his secti o n is n ot a p plica ble t o t his st u d y.
1 1
A D V E R S E E V E N T R E P O R TI N G R E Q UI R E M E N T S
1 1. 1  
Defi niti o ns
1 1. 1. 1
A d verse E ve nt ( A E)
A n a d verse e ve nt ( A E) is a n y u n desira ble si g n, s y m pt o m or me dical c o n diti o n or e x perie nce t hat 
de vel o ps or w orse ns i n se verit y after t he date of i nf or me d c o nse nt si g nat ure or a n y pr oce d ure 
s pecifie d i n t he pr ot oc ol, e ve n if t he e ve nt is n ot c o nsi dere d t o be relate d t o t he st u d y. 
A b n or mal la b orat or y val ues or dia g n ostic test res ults c o nstit ute a d verse e ve nts o nl y if t he y i n d uce 
cli nical si g ns or s y m pt o ms or re q uire treat me nt or f urt her dia g n ostic tests. 
A n A E ca n t heref ore be a n y u nfa v ora ble a n d u ni nte n de d si g n (i ncl u di n g a n a b n or mal la b orat or y 
fi n di n g, f or e xa m ple), s y m pt o m, or disease te m p orall y ass ociate d wit h t he use of i n vesti gati o nal 
pr o d uct, w het her or n ot c o nsi dere d relate d t o t he i n vesti gati o nal pr o d uct.
1 1. 1. 2
Seri o us a d verse e ve nt ( S A E)
A seri o us a d verse e ve nt ( S A E) is a n y a d verse e ve nt, occ urri n g at a n y d ose a n d re gar dless of 
ca usalit y t hat: 

Res ults i n deat h

Is life-t hreate ni n g. Life-t hreate ni n g mea ns t hat t he pers o n was at i m me diate ris k of deat h 
fr o m t he reacti o n as it occ urre d, i.e., it d oes n ot i ncl u de a reacti o n w hic h h y p ot heticall y mi g ht 
ha ve ca use d deat h ha d it occ urre d i n a m ore se vere f or m.

Re q uires or pr ol o n gs i n patie nt h os pitalizati o n (i.e., t he e ve nt re q uire d at least a 2 4- h o ur 
h os pitalizati o n or pr ol o n ge d a h os pitalizati o n be y o n d t he e x pecte d le n gt h of sta y). 
H os pitalizati o n a d missi o ns a n d/ or s ur gical o perati o ns sc he d ule d t o occ ur d uri n g t he st u d y 
peri o d, b ut pla n ne d pri or t o st u d y e ntr y are n ot c o nsi dere d S A Es if t he ill ness or disease 
e xiste d bef ore t he pers o n was e nr olle d i n t he trial, pr o vi de d t hat it di d n ot deteri orate i n a n 
u ne x pecte d ma n ner d uri n g t he trial (e. g., s ur ger y perf or me d earlier t ha n pla n ne d).

C O N FI D E N TI A L
T his d oc u me nt is c o nfi de ntial. D o n ot discl ose or use e xce pt as a ut h orize d.
7 1
S h ort title: P h ase II st u d y of El ot uz u m a b pl us R V D i n Ne wl y Di a g n ose d M M
Versi o n D ate: N o ve m ber 1 0, 2 0 2 0 

Res ults i n persiste nt or si g nifica nt disa bilit y/i nca pacit y. Disa bilit y is defi ne d as a s u bsta ntial 
disr u pti o n of a pers o n’s a bilit y t o c o n d uct n or mal life f u ncti o ns.

Is a c o n ge nital a n o mal y or birt h defect; or

Is a n i m p orta nt me dical e ve nt w he n, base d u p o n a p pr o priate me dical j u d g me nt, it ma y 
je o par dize t he partici pa nt a n d re q uire me dical or s ur gical i nter ve nti o n t o pre ve nt o ne of t he 
o utc o mes liste d a b o ve. E xa m ples of s uc h me dical e ve nts i ncl u de aller gic br o nc h os pas m 
re q uiri n g i nte nsi ve treat me nt i n a n e mer ge nc y r o o m or at h o me; bl o o d d yscrasias or 
c o n v ulsi o ns t hat d o n ot res ult i n i n patie nt h os pitalizati o n, or t he de vel o p me nt of dr u g 
de pe n de nc y or dr u g a b use.

P ote ntial dr u g-i n d uce d li ver i nj ur y ( DI LI) is als o c o nsi dere d a n i m p orta nt me dical e ve nt--
see t he DI LI secti o n bel o w f or a defi niti o n of a p ote ntial DI LI e ve nt.

S us pecte d tra ns missi o n of a n i nfecti o us a ge nt (e g, pat h o ge nic or n o n- pat h o ge nic) via t he 
st u d y dr u g is a n S A E.

O ver d ose

Sec o n dar y mali g na nc y
P ote nti al dr u g-i n d uce d li ver i nj ur y ( DI LI)
W here ver p ossi ble, ti mel y c o nfir mati o n of i nitial li ver-relate d la b orat or y a b n or malities s h o ul d 
occ ur pri or t o t he re p orti n g of a p ote ntial DI LI e ve nt. All occ urre nces of p ote ntial DI LIs meeti n g 
t he defi ne d criteria m ust be re p orte d as S A Es.
P ote ntial dr u g i n d uce d li ver i nj ur y is defi ne d as 

A T ( A L T or A S T) ele vati o n > 3 ti mes u p per li mit of n or mal ( U L N)
A N D

T otal bilir u bi n > 2 ti mes U L N, wit h o ut i nitial fi n di n gs of c h olestasis (ele vate d ser u m 
al kali ne p h os p hatase),
A N D

N o ot her i m me diatel y a p pare nt p ossi ble ca uses of A T ele vati o n a n d h y per bilir u bi ne mia, 
i ncl u di n g, b ut n ot li mite d t o, viral he patitis, pre-e xisti n g c hr o nic or ac ute li ver disease, or 
t he a d mi nistrati o n of ot her dr u g(s) k n o w n t o be he pat ot o xic.
O ver d ose 
A n o ver d ose is defi ne d as t he acci de ntal or i nte nti o nal a d mi nistrati o n of a n y d ose of a pr o d uct t hat 
is c o nsi dere d b ot h e xcessi ve a n d me dicall y i m p orta nt. All occ urre nces of o ver d ose m ust be 
re p orte d as S A Es.
1 1. 1. 3
Pre g n a nc y
Pre g na ncies a n d s us pecte d pre g na ncies occ urri n g w hile t he partici pa nt is o n st u d y dr u g or wit hi n 
2 8 da ys of t he partici pa nt’s last d ose of st u d y dr u g s h o ul d be re p orte d i m me diatel y u p o n 
i n vesti gat or’s k n o wle d ge. If t he partici pa nt is o n st u d y dr u g, t he st u d y dr u g is t o be disc o nti n ue d 
i m me diatel y a n d t he partici pa nt is t o be i nstr ucte d t o ret ur n a n y u n use d p orti o n of t he st u d y dr u g 
t o t he I n vesti gat or. T he pre g na nc y, s us pecte d pre g na nc y, or p ositi ve pre g na nc y test m ust be 

C O N FI D E N TI A L
T his d oc u me nt is c o nfi de ntial. D o n ot discl ose or use e xce pt as a ut h orize d.
7 2
S h ort title: P h ase II st u d y of El ot uz u m a b pl us R V D i n Ne wl y Di a g n ose d M M
Versi o n D ate: N o ve m ber 1 0, 2 0 2 0 
re p orte d i m me diatel y of t he I n vesti gat or’s k n o wle d ge of t he pre g na nc y b y p h o ne a n d e- mail / 
facsi mile t o Da na- Far ber Ca ncer I nstit ute usi n g t he Pre g na nc y Re p orti n g F or m. I m me diatel y u p o n 
recei pt of t his re p ort, Da na- Far ber will i nf or m B M S Safet y De part me nt, a n d Cel ge ne as re q uire d 
b y t he Re vli mi d R E M S ® pr o gra m. T he patie nt s h o ul d be referre d t o a n o bstetricia n/ g y nec ol o gist 
e x perie nce d i n re pr o d ucti ve t o xicit y f or f urt her e val uati o n a n d c o u nseli n g.  
T he I n vesti gat or will f oll o w t he partici pa nt u ntil c o m pleti o n of t he pre g na nc y, a n d m ust n otif y 
Da na- Far ber Ca ncer I nstit ute of t he o utc o me of t he pre g na nc y (i ncl u di n g n otificati o n of false-
p ositi ve tests) wit hi n 2 4 b usi ness h o urs of ha vi n g k n o wle d ge of t he e ve nt b y e mail / facsi mile 
usi n g t he F oll o w- U p Pre g na nc y Re p orti n g F or m.  I m me diatel y u p o n recei pt of t his re p ort, Da na-
Far ber will i nf or m B M S a n d Cel ge ne as re q uire d b y t he Re vli mi d R E M S ® pr o gra m usi n g t he 
F oll o w- U p Pre g na nc y Re p orti n g F or m.
If t he o utc o me of t he pre g na nc y meets t he criteria f or i m me diate classificati o n as a S A E (i.e., 
s p o nta ne o us a b orti o n [a n y c o n ge nital a n o mal y detecte d i n a n a b orte d fet us is t o be d oc u me nte d], 
still birt h, ne o natal deat h, or c o n ge nital a n o mal y [i ncl u di n g t hat i n a n a b orte d fet us]), t he 
I n vesti gat or s h o ul d f oll o w t he pr oce d ures f or re p orti n g S A Es (i.e., re p ort t he e ve nt t o Da na- Far ber 
Ca ncer I nstit ute wit h 2 4 b usi ness h o urs of t he I n vesti gat or’s k n o wle d ge of t he e ve nt b y e- mail or 
facsi mile.  I m me diatel y u p o n recei pt of t his re p ort, Da na- Far ber will i nf or m B M S a n d Cel ge ne as 
re q uire d b y t he Re vli mi d R E M S ® pr o gra m). 
All ne o natal deat hs t hat occ ur wit hi n 2 8 da ys of birt h s h o ul d be re p orte d, wit h o ut re gar d t o 
ca usalit y, as S A Es. I n a d diti o n, a n y i nfa nt deat h after 2 8 da ys t hat t he I n vesti gat or s us pects is 
relate d t o t he i n uter o e x p os ure t o t he st u d y dr u g s h o ul d als o be re p orte d t o Da na- Far ber wit hi n 2 4 
b usi ness h o urs of t he I n vesti gat or’s k n o wle d ge of t he e ve nt b y e- mail or facsi mile.  I m me diatel y 
u p o n recei pt of t his re p ort, Da na- Far ber will i nf or m B M S a n d Cel ge ne as re q uire d b y t he Re vli mi d 
R E M S ® pr o gra m. I n t he case of a li ve “ n or mal” birt h, Da na- Far ber Ca ncer I nstit ute s h o ul d be 
a d vise d as s o o n as t he i nf or mati o n is a vaila ble.  Da na- Far ber will i nf or m B M S, a n d Cel ge ne as 
re q uire d b y t he Re vli mi d R E M S ® pr o gra m. 
If t he patie nt is f o u n d n ot t o be pre g na nt, a n y deter mi nati o n re gar di n g t he partici pa nt’s c o nti n ue d 
partici pati o n i n t he st u d y will be deter mi ne d b y t he I n vesti gat or.
A fe male part ner of a male ta ki n g i n vesti gati o nal pr o d uct s h o ul d be a d vise d t o call t heir healt hcare 
pr o vi der i m me diatel y if t he y get pre g na nt.  T he male partici pa nt s h o ul d n otif y t he i n vesti gat or of 
his part ner’s pre g na nc y a n d her healt hcare pr o vi der i nf or mati o n.  T he i n vesti gat or will t he n 
pr o vi de t he i nf or mati o n t o Da na- Far ber Ca ncer I nstit ute f or f oll o w- u p as necessar y.  Da na- Far ber 
will i nf or m B M S, a n d Cel ge ne as re q uire d b y t he Re vli mi d R E M S ® pr o gra m. 
1 1. 1. 4 
E ve nts n ot c o nsi dere d t o be seri o us a d verse e ve nts are h os pit aliz ati o ns f or:

R o uti ne treat me nt or m o nit ori n g of t he st u die d i n dicati o n, n ot ass ociate d wit h a n y 
deteri orati o n i n c o n diti o n, or f or electi ve pr oce d ures

Electi ve or pre- pla n ne d treat me nt f or a pre-e xisti n g c o n diti o n t hat di d n ot w orse n

E mer ge nc y o ut patie nt treat me nt f or a n e ve nt n ot f ulfilli n g t he seri o us criteria o utli ne d 
a b o ve a n d n ot res ulti n g i n i n patie nt a d missi o n

C O N FI D E N TI A L
T his d oc u me nt is c o nfi de ntial. D o n ot discl ose or use e xce pt as a ut h orize d.
7 3
S h ort title: P h ase II st u d y of El ot uz u m a b pl us R V D i n Ne wl y Di a g n ose d M M
Versi o n D ate: N o ve m ber 1 0, 2 0 2 0 

Res pite care
1 1. 2 
E x pecte d ness
A d v ers e e v e nts c a n b e ' E x p e ct e d' or ' U n e x p e ct e d.' 
1 1. 2. 1
E x pecte d a d verse e ve nt
E x pecte d a d verse e ve nts are t h ose t hat ha ve bee n pre vi o usl y i de ntifie d as res ulti n g fr o m 
a d mi nistrati o n of t he a ge nt. F or t he p ur p oses of t his st u d y, a n a d verse e ve nt is c o nsi dere d e x pecte d 
w he n it a p pears i n t he c urre nt a d verse e ve nt list of t he I n vesti gat or’s Br oc h ure or t he pac ka ge 
i nsert, a n d s h o ul d be i ncl u de d i n t he i nf or me d c o nse nt d oc u me nt as a p ote ntial ris k.  
R ef er t o S e cti o n 6. 1 f or a listi n g of e x p e ct e d a d v ers e e v e nts ass o ci at e d wit h t h e st u d y a g e nts.
1 1. 2. 2
U ne x pecte d a d verse e ve nt
F or t he p ur p oses of t his st u d y, a n a d verse e ve nt is c o nsi dere d u ne x pecte d w he n it varies i n nat ure, 
i nte nsit y or fre q ue nc y fr o m i nf or mati o n pr o vi de d i n t he c urre nt a d verse e ve nt list, t he 
I n vesti gat or’s Br oc h ure, t he pac ka ge i nsert or o n g oi n g I N D safet y letters. 
1 1. 2. 3
Attri b uti o n
Attri b uti o n is t he relati o ns hi p bet wee n a n a d verse e ve nt or seri o us a d verse e ve nt a n d t he st u d y 
treat me nt. Attri b uti o n will be assi g ne d as f oll o ws:
Defi nite – T he A E is clearl y relate d  t o t he st u d y treat me nt.
Pr o ba ble – T he A E is li kel y relate d  t o t he st u d y treat me nt.
P ossi ble – T he A E ma y be relate d  t o t he st u d y treat me nt. 
U nli kel y - T he A E is d o u btf ull y relate d  t o t he st u d y treat me nt.
U nr el at e d - T h e A E is cl e arl y N O T r el at e d  t o t h e st u d y tr e at m e nt.
A n e ve nt will be c o nsi dere d u nrelate d i n a sit uati o n w here, f or c hr o n ol o gical reas o ns, t he ca usal 
relati o ns hi p bet wee n t he A E a n d a d mi nistrati o n of t he st u d y dr u g is u nli kel y, or c o nc o mita nt use 
of ot her dr u gs or t hera pe utic i nter ve nti o ns or pree xisti n g c o n diti o ns pr o vi de s ufficie nt 
e x pla nati o ns f or t he o bser ve d e ve nt.
A n e ve nt will be c o nsi dere d p ossi bl y relate d i n a sit uati o n w here, f or c hr o n ol o gical reas o ns, t he 
ca usal relati o ns hi p bet wee n t he A E a n d a d mi nistrati o n of t he st u d y dr u g is p ossi ble, a n d 
c o nc o mita nt use of ot her dr u gs or t hera pe utic i nter ve nti o ns or pree xisti n g c o n diti o ns d o n ot 
pr o vi de s ufficie nt e x pla nati o ns f or t he o bser ve d e ve nt.
1 1. 3 
Pr oce d ures f or A E a n d S A E Rec or di n g a n d Re p orti n g

C O N FI D E N TI A L
T his d oc u me nt is c o nfi de ntial. D o n ot discl ose or use e xce pt as a ut h orize d.
7 4
S h ort title: P h ase II st u d y of El ot uz u m a b pl us R V D i n Ne wl y Di a g n ose d M M
Versi o n D ate: N o ve m ber 1 0, 2 0 2 0 
Re p orti n g Partici pati n g i n vesti gat ors will assess t he occ urre nce of A Es a n d S A Es at all partici pa nt 
e val uati o n ti me p oi nts d uri n g t he st u d y. 
. All A Es m ust be rec or de d i n t he partici pa nt’s me dical rec or d, stati n g t he d urati o n a n d i nte nsit y 
of t he e ve nt, acti o n ta ke n b y t he i n vesti gat or a n d o utc o me of t he e ve nt.  T he i n vesti gat or m ust 
e val uate t he ca usal relati o ns hi p bet wee n t he st u d y dr u g(s) a n d t he a d verse e ve nt as defi ne d i n 
secti o n 1 1. 2. 3.
W he ne ver p ossi ble, a dia g n osis or a si n gle s y n dr o me s h o ul d be re p orte d i nstea d of s y m pt o ms.  
T he I n vesti gat or s h o ul d s pecif y t he date of o nset, seri o us ness, i nte nsit y (se verit y), acti o n ta ke n 
wit h res pect t o st u d y treat me nt, c orrecti ve treat me nt/t hera p y gi ve n, dia g n ostic i n vesti gati o ns 
res ults, o utc o me, a n d t he I n vesti gat or’s o pi ni o n as t o w het her t here is a reas o na ble p ossi bilit y t hat 
t he A E was ca use d b y t he st u d y treat me nt or b y t he st u d y pr oce d ure(s).
T he i n vesti gat or m ust e val uate all a b n or mal la b orat or y res ults t o deter mi ne t he cli nical 
si g nifica nce.  All a b n or mal la b orat or y or test res ults t hat i n d uce cli nical si g ns or s y m pt o ms, or 
re q uire t hera p y, are c o nsi dere d cli nicall y si g nifica nt a n d are rec or de d as a d verse e ve nts. T he 
i n vesti gat or will be t he fi nal deter mi na nt of cli nical si g nifica nce.
T he descri pti o ns a n d gra di n g scales f o u n d i n t he C T E P Versi o n 4. 0 3 of t he N CI C T C A E will be 
utilize d f or A E re p orti n g. T he C T E P Versi o n 4 of t he C T C A E is i de ntifie d a n d l ocate d o n t he 
C T E P we bsite at: 
htt p://e vs. nci. ni h. g o v/ft p 1/ C T C A E/ C T C A E _ 4. 0 3 _ 2 0 1 0- 0 6- 1 4 _ Q uic k Refere nce _ 5 x 7. p df
1 1. 3. 1
Re p orti n g Re q uire me nts 
T he st u d y m ust be c o n d ucte d i n c o m plia nce wit h F D A re g ulati o ns, l ocal safet y re p orti n g 
re q uire me nts, a n d re p orti n g re q uire me nts of t he st u d y PI. All Seri o us A d verse E ve nts ( S A Es) t hat 
occ ur f oll o wi n g t he date of i nf or me d c o nse nt si g nat ure, d uri n g treat me nt, m ust be re p orte d.
T he f oll o wi n g m ust be re p orte d t o t he c o or di nati n g ce nter:

All S A Es.

All ≥Gra de  2 A Es.

Ne w pri mar y mali g na ncies.

A n y A E res ulti n g i n d ose m o dificati o n or disc o nti n uati o n of a n y st u d y dr u g.
A n y ot her A E t hat i n t he o pi ni o n of t he i n vesti gat or is a cli nicall y si g nifica nt e ve nt. Eac h a d verse e ve nt 
will be assesse d t o deter mi ne if it meets t he criteria f or S A E re p orti n g.  Eac h i n vesti gati ve site will 
be res p o nsi ble t o re p ort S A Es t hat occ ur at t hat i nstit uti o n t o t heir res pecti ve I R B. It is t he 
res p o nsi bilit y of eac h partici pati n g i n vesti gat or t o re p ort seri o us a d verse e ve nts t o t he st u d y PI, 
t he partici pati n g site’s I R B, a n d ot hers as descri be d bel o w. 
All S A Es m ust als o be re p orte d t o t he C o or di nati n g Ce nter i n or der t o c o m pl y wit h t he 
res p o nsi bilit y f or o versi g ht of t he pr oject a n d re p orti n g t o t he F D A. 
1 1. 3. 1. 1 S e ri o us A d v e rs e E v e nt R e p o rti n g  

C O N FI D E N TI A L
T his d oc u me nt is c o nfi de ntial. D o n ot discl ose or use e xce pt as a ut h orize d.
7 5
S h ort title: P h ase II st u d y of El ot uz u m a b pl us R V D i n Ne wl y Di a g n ose d M M
Versi o n D ate: N o ve m ber 1 0, 2 0 2 0 
W he n t he I n vesti gat or or his/ her desi g nee bec o mes a ware t hat a n S A E has occ urre d t he y will 
c o m plete t he M E D W A T C H F or m F D A 3 5 0 0 A ( Ma n dat or y Re p orti n g F or m f or i n vesti gati o nal 
a ge nts) f or all S A Es.  T he c o m plete d f or m will be e- maile d t o t he D F CI pr oject ma na ger at 
 All S A E re p orts t hat ha ve t he mi ni m u m data set f or re p orti n g 
s h o ul d be s u b mitte d t o t he c o or di nati n g ce nter, , e ve n if o nl y li mite d i nf or mati o n is a vaila ble. T his 
m ust occ ur wit hi n 2 4 b usi ness h o urs of lear ni n g of t he occ urre nce, re gar dless of t he relati o ns hi p 
of t he S A E t o ‘ St u d y Dr u g.’ I n t he e ve nt t hat t he partici pati n g i n vesti gat or d oes n ot bec o me a ware 
of t he seri o us a d verse e ve nt i m me diatel y (e. g., partici pa nt s o u g ht treat me nt else w here), t he 
partici pati n g i n vesti gat or is t o re p ort t he e ve nt wit hi n 2 4 b usi ness h o urs after lear ni n g of it a n d 
d oc u me nt t he ti me of his or her first a ware ness of t he a d verse e ve nt.
                      
T he I n vesti gat or is res p o nsi ble f or n otif yi n g t he I nstit uti o nal Re vie w B oar d (I R B) or I n de pe n de nt 
Et hics C o m mittee (I E C) i n acc or da nce wit h l ocal re g ulati o ns, of all S A Es. Eac h i n vesti gati ve site 
will re p ort S A Es t o t heir res pecti ve I R B acc or di n g t o t he l ocal I R B’s p olicies a n d pr oce d ures i n 
re p orti n g a d verse e ve nts. A c o p y of t he s u b mitte d i nstit uti o nal S A E f or m s h o ul d be f or war de d t o 
t he O verall PI ( wit hi n 5 cale n dar da ys if t he e ve nt is gra de 4, a n d wit hi n 2 4 h o urs f or gra de 5), 
w h o will s u b mit S A E re p orts fr o m o utsi de i nstit uti o ns t o t he D F CI O H R S acc or di n g t o D F CI I R B 
p olicies a n d pr oce d ures i n re p orti n g a d verse e ve nts. 
All S A Es re gar dless of relati o ns hi p t o st u d y dr u g m ust be f oll o we d t o res ol uti o n or t o sta bilizati o n 
if i m pr o ve me nt or res ol uti o n is n ot e x pecte d.  D F CI will s u b mit t o t he F D A after t he Lea d 
I n vesti gat or re vie w, if t he e ve nt meets re p orti n g re q uire me nts. 
T he i nitial re p ort m ust be as c o m plete as p ossi ble, i ncl u di n g details of t he c urre nt ill ness a n d 
(seri o us) a d verse e ve nt, a n d a n assess me nt of t he ca usal relati o ns hi p bet wee n t he e ve nt a n d t he 
i n vesti gati o nal pr o d uct(s). I nf or mati o n n ot a vaila ble at t he ti me of t he i nitial re p ort (e. g., a n e n d 
date f or t he a d verse e ve nt or la b orat or y val ues recei ve d after t he re p ort) m ust be d oc u me nte d b y 
e- maili n g a f oll o w u p M E D W A T C H f or m t o t he c o or di nati n g ce nter. .
Wit hi n t he f oll o wi n g 2 4 b usi ness h o urs, t he partici pati n g i n vesti gat or m ust pr o vi de f oll o w- u p 
i nf or mati o n o n t he seri o us a d verse e ve nt. F oll o w- u p i nf or mati o n s h o ul d descri be w het her t he 
e ve nt has res ol ve d or c o nti n ues, if a n d h o w t he e ve nt was treate d, a n d w het her t he partici pa nt will 
c o nti n ue or disc o nti n ue st u d y partici pati o n.  T he i n vesti gat or m ust kee p c o pies of all A E 
i nf or mati o n, i ncl u di n g c orres p o n de nce wit h B M S a n d Da na- Far ber Ca ncer I nstit ute a n d I R B, o n 
file. 
1 1. 3. 1. 2 N o n- S e ri o us A d v e rs e E v e nt R e p o rti n g 
N o n-seri o us a d verse e ve nts will state  t he d urati o n a n d i nte nsit y of t he e ve nt, acti o n ta ke n b y t he 
i n vesti gat or a n d o utc o me of t he e ve nt.  T he i n vesti gat or m ust e val uate t he ca usal relati o ns hi p 
bet wee n t he st u d y a n d t he a d verse e ve nt.  
N o n seri o us a d verse e ve nts will be re p orte d t o t he c o or di nati n g ce nter. All a p plica ble e ve nts, i ncl u di n g 
e ve nt ter m, gra de, attri b uti o n, e x pecte d ness, a n d start a n d st o p dates m ust be re p orte d. T his will be 

C O N FI D E N TI A L
T his d oc u me nt is c o nfi de ntial. D o n ot discl ose or use e xce pt as a ut h orize d.
7 6
S h ort title: P h ase II st u d y of El ot uz u m a b pl us R V D i n Ne wl y Di a g n ose d M M
Versi o n D ate: N o ve m ber 1 0, 2 0 2 0 
re p orte d via a s prea ds heet. T he c o m plete d s prea ds heet will be e maile d t o t he D F CI pr oject ma na ger, 
.  A d verse e ve nts will be re p orte d wit hi n 1 4 da ys after 
a partici pa nt’s da y 1 mai nte na nce visit. 
 
1 1. 3. 2
Re p orti n g t o Brist ol M yers S q ui b b
D F CI, t he C o or di nati n g Ce nter, is res p o nsi ble f or re p orti n g S A Es t o B M S. T he Lea d Pri nci pal 
I n vesti gat or or Pr oject Ma na ger ma y re q uest a d diti o nal s o urce d oc u me ntati o n pertai ni n g t o t he 
S A E.  If a s u bject is per ma ne ntl y wit h dra w n fr o m t he st u d y beca use of a S A E, t his i nf or mati o n 
m ust be i ncl u de d i n t he i nitial or f oll o w- u p S A E re p ort f or m. 
D F CI s h o ul d re p ort t he S A Es, as defi ne d i n Secti o n 1 1. 1. 2, t o B M S wit hi n 2 4 hrs of bec o mi n g 
a ware of t he e ve nt.  T he Me d Watc h f or m, or a n ot her f or m pre vi o usl y a p pr o ve d b y B M S, ca n be 
use d t o re p ort t he e ve nt.
D F CI will s u b mit t he S A Es t o: 
 or via fa x at 
.
All seri o us a d verse e ve nts t hat occ ur d uri n g treat me nt m ust be re p orte d.  
1 1. 3. 3
Re p orti n g t o t he I nstit uti o n al Re vie w B o ar d (I R B) 
I n vesti gati ve sites wit hi n D F/ H C C will re p ort all seri o us a d verse e ve nts directl y t o t he D F CI 
Office f or H u ma n Researc h St u dies ( O H R S).
Ot her i n vesti gati ve sites s h o ul d re p ort seri o us a d verse e ve nts t o t heir res pecti ve I R B acc or di n g t o 
t he l ocal I R B p olicies a n d pr oce d ures i n re p orti n g a d verse e ve nts. A c o p y of t he s u b mitte d 
i nstit uti o nal A E f or m s h o ul d be f or war de d t o t he O verall PI wit hi n t he ti mefra mes detaile d i n 
bel o w.  

Gra de 2 ( m o derate) a n d Gra de 3 (se vere) e ve nts t hat are u ne x pecte d a n d at least p ossi bl y 
relate d/ass ociate d wit h t he i nter ve nti o n.

All u ne x pecte d Gra de 4 (life-t hreate ni n g or disa bli n g) e ve nts. 

All Gra de 5 (fatal) e ve nts w hile t he partici pa nt is e nr olle d a n d acti vel y partici pati n g i n t he 
trial O R w he n t he e ve nt occ urs wit hi n 3 0 da ys of t he last st u d y i nter ve nti o n
T he Pri nci pal I n vesti gat or will s u b mit S A E re p orts fr o m o utsi de i nstit uti o ns t o t he D F CI Office 
f or H u ma n Researc h St u dies ( O H R S) acc or di n g t o D F CI I R B p olicies a n d pr oce d ures i n re p orti n g 
a d verse e ve nts.
1 1. 3. 4
Re p orti n g t o t he F o o d a n d Dr u g A d mi nistr ati o n ( F D A)

C O N FI D E N TI A L
T his d oc u me nt is c o nfi de ntial. D o n ot discl ose or use e xce pt as a ut h orize d.
7 7
S h ort title: P h ase II st u d y of El ot uz u m a b pl us R V D i n Ne wl y Di a g n ose d M M
Versi o n D ate: N o ve m ber 1 0, 2 0 2 0 
T he O verall PI will re p ort t o t he F D A, re gar dless of t he site of occ urre nce, a n y a d verse e ve nt t hat 
is seri o us, u ne x pecte d a n d reas o na bl y relate d (i.e., p ossi ble, pr o ba ble, defi nite) t o t he 
i n vesti gati o nal a ge nt or pr o d uct.   
U ne x pecte d fatal or life-t hreate ni n g e x perie nces ass ociate d wit h t he use of t he i n vesti gati o nal 
pr o d uct will be re p orte d t o F D A as s o o n as p ossi ble b ut i n n o e ve nt later t ha n 7 cale n dar da ys after 
i nitial recei pt of t he i nf or mati o n.
All ot her seri o us u ne x pecte d e x perie nces ass ociate d wit h t he use of t he i n vesti gati o nal pr o d uct 
will be re p orte d t o F D A as s o o n as p ossi ble b ut i n n o e ve nt later t ha n 1 5 cale n dar da ys after i nitial 
recei pt of t he i nf or mati o n.  A clear descri pti o n of t he s us pecte d reacti o n s h o ul d be pr o vi de d al o n g 
wit h a n assess me nt as t o w het her t he e ve nt is dr u g or disease relate d.
I N D S Rs will be re p orte d t o t he F D A b y tele p h o ne ( 1- 8 0 0- F D A- 1 0 8 8) or b y 
mail usi n g 
M E D W A T C H F or m F D A 3 5 0 0 A. 
1 1. 3. 5
Re p orti n g t o t he NI H Office of Bi otec h n ol o g y Acti vities ( O B A)
T his secti o n is n ot a p plica ble t o t his st u d y.
1 1. 3. 6
Re p orti n g t o t he I nstit uti o n al Bi os afet y C o m mittee (I B C)
T his secti o n is n ot a p plica ble t o t his st u d y.
1 1. 3. 7
Re p orti n g t o H os pit al Ris k M a n a ge me nt
Partici pati n g i n vesti gat ors will re p ort t o t heir l ocal Ris k Ma na ge me nt office a n y s u bject safet y 
re p orts or se nti nel e ve nts t hat re q uire re p orti n g acc or di n g t o i nstit uti o nal p olic y.
1 1. 4  
M o nit ori n g of A d verse E ve nts a n d Peri o d of O bser v ati o n
All a d verse e ve nts, b ot h seri o us a n d n o n-seri o us, a n d deat hs t hat are e nc o u ntere d fr o m t he date of 
i nf or me d c o nse nt si g nat ure, t hr o u g h o ut t he st u d y, a n d wit hi n 3 0 da ys of t he last st u d y i nter ve nti o n 
s h o ul d be f oll o we d t o t heir res ol uti o n, or u ntil t he partici pati n g i n vesti gat or assesses t he m as 
sta ble, or t he partici pati n g i n vesti gat or deter mi nes t he e ve nt t o be irre versi ble, or t he partici pa nt is 
l ost t o f oll o w- u p. T he prese nce a n d res ol uti o n of A Es a n d S A Es ( wit h dates) s h o ul d be d oc u me nte d 
i n t he partici pa nt’s me dical rec or d t o facilitate s o urce data verificati o n. 
F or s o me S A Es, t he st u d y s p o ns or or desi g nee ma y f oll o w- u p b y tele p h o ne, fa x, a n d/ or m o nit ori n g 
visit t o o btai n a d diti o nal case details dee me d necessar y t o a p pr o priatel y e val uate t he S A E re p ort 
(e. g., h os pital disc har ge s u m mar y, c o ns ulta nt re p ort, or a ut o ps y re p ort). 
Partici pa nts s h o ul d be i nstr ucte d t o re p ort a n y seri o us p ost-st u d y e ve nt(s) t hat mi g ht reas o na bl y 
be relate d t o partici pati o n i n t his st u d y. Partici pati n g i n vesti gat ors s h o ul d n otif y t he st u d y PI a n d 
t heir res pecti ve I R B of a n y u na ntici pate d deat h or a d verse e ve nt occ urri n g after a partici pa nt has 
disc o nti n ue d or ter mi nate d st u d y partici pati o n t hat ma y reas o na bl y be relate d t o t he st u d y.  

C O N FI D E N TI A L
T his d oc u me nt is c o nfi de ntial. D o n ot discl ose or use e xce pt as a ut h orize d.
7 8
S h ort title: P h ase II st u d y of El ot uz u m a b pl us R V D i n Ne wl y Di a g n ose d M M
Versi o n D ate: N o ve m ber 1 0, 2 0 2 0 
1 2
D A T A A N D S A F E T Y M O NI T O RI N G
1 2. 1  
D at a Re p orti n g
1 2. 1. 1
Met h o d 
1 2. 2 
T he D F CI C T O will m o nit or a n d m a n a ge t he d at a o n a n o n g oi n g b asis, usi n g a ris k-
b ase d m o nit ori n g a p pr o ac h t h at i nc or p or ates re m ote d at a re vie w as well as o ne o nsite 
m o nit ori n g visit per ye ar f or sites wit h acti ve p atie nts S afet y Meeti n gs
T he D F/ H C C Data a n d Safet y M o nit ori n g C o m mittee ( D S M C) will re vie w a n d m o nit or t o xicit y 
a n d accr ual data fr o m t his trial. T he c o m mittee is c o m p ose d of cli nical s pecialists wit h e x perie nce 
i n o nc ol o g y a n d w h o ha ve n o direct relati o ns hi p wit h t he st u d y. I nf or mati o n t hat raises a n y 
q uesti o ns a b o ut partici pa nt safet y will be a d dresse d wit h t he st u d y PI a n d st u d y tea m.
T he D S M C will meet q uarterl y a n d/ or m ore ofte n if re q uire d t o re vie w t o xicit y a n d accr ual data.  
I nf or mati o n t o be pr o vi de d t o t he c o m mittee ma y i ncl u de:  u p-t o- date partici pa nt accr ual; c urre nt 
d ose le vel i nf or mati o n; D L T i nf or mati o n; all gra de 2 or hi g her u ne x pecte d a d verse e ve nts t hat 
ha ve bee n re p orte d; s u m mar y of all deat hs occ urri n g wit hi n 3 0 da ys of c o m pleti o n of t hera p y; a n y 
res p o nse i nf or mati o n; a u dit res ults, a n d a s u m mar y pr o vi de d b y t he st u d y tea m. Ot her i nf or mati o n 
(e. g. sca ns, la b orat or y val ues) will be pr o vi de d u p o n re q uest. 
1 2. 3  
M o nit ori n g 
S pecifie d data will be m o nit ore d f or ti meli ness of s u b missi o n, c o m plete ness, a n d a d here nce t o 
pr ot oc ol re q uire me nts. M o nit ori n g will be gi n at t he ti me of partici pa nt re gistrati o n a n d will 
c o nti n ue d uri n g pr ot oc ol perf or ma nce a n d c o m pleti o n. See Secti o n 5. 1 of D S M P f or a d diti o nal 
details.
D uri n g t he c o urse of t he st u d y, c o m m u nicati o n bet wee n t he C o or di nati n g Ce nter a n d 
partici pati n g sites will occ ur via re g ular e- mail c orres p o de nce.  Telec o nfere nces will be 
sc he d ule d as nee de d. 
1 3
R E G U L A T O R Y C O N SI D E R A TI O N S
1 3. 1 
Pr ot oc ol Re vie w a n d A me n d me nts
T his pr ot oc ol, t he pr o p ose d i nf or me d c o nse nt a n d all f or ms of partici pa nt i nf or mati o n relate d t o 
t he st u d y (e. g., a d vertise me nts use d t o recr uit partici pa nts) a n d a n y ot her necessar y d oc u me nts 
m ust be s u b mitte d, re vie we d a n d a p pr o ve d b y a pr o perl y c o nstit ute d I R B g o ver ni n g eac h st u d y 
l ocati o n. 
A n y c ha n ges ma de t o t he pr ot oc ol m ust be s u b mitte d as a me n d me nts a n d m ust be a p pr o ve d b y t he 
I R B pri or t o i m ple me ntati o n. A n y c ha n ges i n st u d y c o n d uct m ust be re p orte d t o t he I R B.  T h e 
st u d y PI ( or Pr ot o c ol C h air) 
will diss e mi n at e pr ot o c ol a m e n d m e nt i nf or m ati o n t o all 
p arti ci p ati n g i n v esti g at ors. C ha n ges t o t he pr ot oc ol will re q uire writte n I R B a p pr o val/fa v ora ble 
o pi ni o n pri or t o i m ple me ntati o n, e xce pt w he n t he m o dificati o n is nee de d t o eli mi nate a n 
i m me diate hazar d(s) t o partici pa nts.

C O N FI D E N TI A L
T his d oc u me nt is c o nfi de ntial. D o n ot discl ose or use e xce pt as a ut h orize d.
7 9
S h ort title: P h ase II st u d y of El ot uz u m a b pl us R V D i n Ne wl y Di a g n ose d M M
Versi o n D ate: N o ve m ber 1 0, 2 0 2 0 
All decisi o ns of t he I R B c o ncer ni n g t he c o n d uct of t he st u d y m ust be ma de i n writi n g.
1 3. 2 
I nf or me d C o nse nt
All partici pa nts m ust be pr o vi de d a c o nse nt f or m descri bi n g t his st u d y a n d pr o vi di n g s ufficie nt 
i nf or mati o n f or partici pa nts t o ma ke a n i nf or me d decisi o n a b o ut t heir partici pati o n i n t his st u d y. 
T he f or mal c o nse nt of a partici pa nt, usi n g t he I R B a p pr o ve d c o nse nt f or m, m ust be o btai ne d 
bef ore t he partici pa nt is i n v ol ve d i n a n y st u d y-relate d pr oce d ure. T he c o nse nt f or m m ust be 
si g ne d a n d date d b y t he partici pa nt or t he partici pa nt’s le gall y a ut h orize d re prese ntati ve, a n d b y 
t he pers o n o btai ni n g t he c o nse nt. T he partici pa nt m ust be gi ve n a c o p y of t he si g ne d a n d date d 
c o nse nt d oc u me nt. T he ori gi nal si g ne d c o p y of t he c o nse nt d oc u me nt m ust be retai ne d i n t he 
me dical rec or d or researc h file.  T he met h o d of o btai ni n g a n d d oc u me nti n g t he i nf or me d c o nse nt 
a n d t he c o nte nts of t he c o nse nt will c o m pl y wit h I C H- G C P a n d all a p plica ble re g ulat or y 
re q uire me nt(s).
1 3. 3 
Et hics 
T his st u d y is t o be c o n d ucte d acc or di n g t o t he f oll o wi n g c o nsi derati o ns, w hic h re prese nt g o o d 
a n d s o u n d researc h practice:

U S C o de of Fe deral Re g ulati o ns ( C F R) g o ver ni n g cli nical st u d y c o n d uct a n d 
et hical pri nci ples t hat ha ve t heir ori gi n i n t he Declarati o n of Helsi n ki
o
Title 2 1 Part 5 0 – Pr otecti o n of H u ma n S u bjects 
w w w.access. g p o. g o v/ nara/cfr/ waisi d x 0 2/ 2 1cfr 5 0 0 2. ht ml  
o
Title 2 1 Part 5 4 – Fi na ncial Discl os ure b y Cli nical I n vesti gat ors 
w w w.access. g p o. g o v/ nara/cfr/ waisi d x _ 0 2/ 2 1cfr 5 4 _ 0 2. ht ml  
o
Title 2 1 Part 5 6 – I nstit uti o nal Re vie w B oar ds 
w w w.access. g p o. g o v/ nara/cfr/ waisi d x _ 0 2/ 2 1cfr 5 6 _ 0 2. ht ml  
o
Title 2 1 Part 3 1 2 – I n vesti gati o nal Ne w Dr u g A p plicati o n 
w w w.access. g p o. g o v/ nara/cfr/ waisi d x _ 0 2/ 2 1cfr 3 1 2 _ 0 2. ht ml  

State la ws

D F/ H C C researc h p olicies a n d pr oce d ures        
htt p:// w w w. df hcc. har var d.e d u/cli nical-researc h-s u p p ort/cli nical-researc h- u nit-
cr u/ p olicies-a n d- pr oce d ures/  
It is u n derst o o d t hat de viati o ns fr o m t he pr ot oc ol s h o ul d be a v oi de d, e xce pt w he n necessar y t o 
eli mi nate a n i m me diate hazar d t o a researc h partici pa nt. I n s uc h case, t he de viati o n m ust be 
re p orte d t o t he I R B acc or di n g t o t he l ocal re p orti n g p olic y. 
1 3. 4 
St u d y D oc u me nt ati o n

C O N FI D E N TI A L
T his d oc u me nt is c o nfi de ntial. D o n ot discl ose or use e xce pt as a ut h orize d.
8 0
S h ort title: P h ase II st u d y of El ot uz u m a b pl us R V D i n Ne wl y Di a g n ose d M M
Versi o n D ate: N o ve m ber 1 0, 2 0 2 0 
T he i n vesti gat or m ust pre pare a n d mai ntai n a de q uate a n d acc urate case hist ories desi g ne d t o rec or d 
all o bser vati o ns a n d ot her data perti ne nt t o t he st u d y f or eac h researc h partici pa nt. T his i nf or mati o n 
e na bles t he st u d y t o be f ull y d oc u me nte d a n d t he st u d y data t o be s u bse q ue ntl y verifie d.
Ori gi nal s o urce d oc u me nts s u p p orti n g e ntries i n t he case re p ort f or ms i ncl u de b ut are n ot li mite d 
t o h os pital rec or ds, cli nical c harts, la b orat or y a n d p har mac y rec or ds, rec or de d data fr o m a ut o mate d 
i nstr u me nts, micr ofic hes, p h ot o gra p hic ne gati ves, micr ofil m or ma g netic me dia, a n d/ or x-ra ys. 
1 3. 5  
Rec or ds Rete nti o n
All st u d y-r el at e d d o c u m e nts m ust b e r et ai n e d f or t h e m a xi m u m p eri o d r e q uir e d b y a p pli c a bl e 
f e d er al r e g ul ati o ns a n d g ui d eli n es or i nstit uti o n al p oli ci es. 
1 3. 6  
M ulti-ce nter G ui deli nes 
T his pr ot oc ol will a d here t o t he p olicies a n d re q uire me nts of t he D F/ H C C M ulti- Ce nter Data a n d 
Safet y M o nit ori n g Pla n.  T he s pecific res p o nsi bilities of t he O verall PI, C o or di nati n g Ce nter, a n d 
Partici pati n g I nstit uti o ns a n d t he pr oce d ures f or a u diti n g are prese nte d i n A p pe n di x VIII

T he O verall PI/ C o or di nati n g Ce nter is res p o nsi ble f or distri b uti n g all I N D Acti o n Letters or 
Safet y Re p orts t o all partici pati n g i nstit uti o ns f or s u b missi o n t o t heir i n di vi d ual I R Bs f or 
acti o n as re q uire d.

Mec ha nis ms will be i n place t o e ns ure q ualit y ass ura nce, pr ot oc ol c o m plia nce, a n d a d verse 
e ve nt re p orti n g at eac h site.

E xce pt i n ver y u n us ual circ u msta nces, eac h partici pati n g i nstit uti o n will or der t he st u d y 
a ge nt(s) directl y fr o m s u p plier.  A partici pati n g site ma y or der t he a ge nt(s) o nl y after t he 
i nitial I R B a p pr o val f or t he site has bee n f or war de d t o t he C o or di nati n g Ce nter.
1 3. 7  
C o o per ati ve Rese arc h a n d De vel o p me nt A gree me nt/ Cli nic al Tri als A gree me nt ( C T A) 
T his is n ot a C T E P-s u p p ort e d st u d y, t h er ef or e, t his s e cti o n is n ot a p pli c a bl e.
1 4
S T A TI S TI C A L C O N SI D E R A TI O N S 
1 4. 1 
E n d p oi nts
1 4. 1. 1
Ori gi n al Pri m ar y E n d p oi nt
T he pri mar y e n d p oi nt is res p o nse rate at Wee k 1 2, w hic h is defi ne d as t he pr o p orti o n of  s u bjects 
w h o ac hie ve d a res p o nse of P R or better (s C R, C R, or V G P R) at Wee k 1 2 after first d ose of 
st u d y dr u g. Res p o nse will be deter mi ne d b y m o difie d I M W G criteria.
1 4. 1. 2
Ori gi n al Sec o n d ar y E n d p oi nts

C O N FI D E N TI A L
T his d oc u me nt is c o nfi de ntial. D o n ot discl ose or use e xce pt as a ut h orize d.
8 1
S h ort title: P h ase II st u d y of El ot uz u m a b pl us R V D i n Ne wl y Di a g n ose d M M
Versi o n D ate: N o ve m ber 1 0, 2 0 2 0 
T he pr o p orti o n of s u bjects wit h s uccessf ul ste m cell m o bilizati o n after 1 2 wee ks. A s uccessf ul 
ste m cell m o bilizati o n is defi ne d as t he a bilit y t o c ollect a t otal of at least 2 x 1 0 6 C D 3 4 + 
cells/ k g. 
T he pr o p orti o n of s u bjects re q uiri n g at least o ne d ose m o dificati o n (ie, d ose re d ucti o n, d ose hel d, 
or d ose n ot gi ve n) of a n y st u d y dr u g d uri n g I n d ucti o n C ycles 1 - 4.
T he e x pl orat or y e n d p oi nts f or t his st u d y are liste d as t he f oll o wi n g:
1 4. 1. 2. 1 B est R es p o ns e O n- St u d y a n d O bj e cti v e R es p o ns e R at e
Best res p o nse o n-st u d y refers t o t he best res p o nse pri or t o disc o nti n uati o n of all st u d y t hera p y. T he 
O bjecti ve res p o nse rate ( O R R) is defi ne d as t he pr o p orti o n of treate d s u bjects w h o ac hie ve a best 
res p o nse of C R, s C R, V G P R, or P R usi n g t he I M W G criteria (see Secti o n 1 0. 2. 4. 1 f or defi niti o ns 
of C R, s C R, V G P R a n d P R res p o nse). T he pr o p orti o n of s u bjects w h o c o m plete 8 c ycles of t hera p y 
t hat ac hie ve d a res p o nse of P R or better (s C R, C R, or V G P R) at Wee k 2 4 after first d ose of st u d y 
dr u g will als o be re p orte d.
1 4. 1. 2. 2 Ti m e t o R es p o ns e a n d D u r ati o n of R es p o ns e
Ti me t o res p o nse is defi ne d as t he ti me fr o m first d ose of st u d y dr u g t o t he first d oc u me ntati o n of 
res p o nse P R or better. T his a nal ysis will be restricte d t o s u bjects w h ose best res p o nse is P R or 
better.
D urati o n of res p o nse ( D O R) is t he ti me fr o m first res p o nse ( P R or better) u ntil a pr o gressi o n e ve nt 
( d oc u me nte d pr o gressi o n or deat h). O nl y s u bjects w h o e ver ac hie ve d a res p o nse of P R or better 
will be c o nsi dere d. S u bjects w h o neit her pr o gress n or die will be ce ns ore d o n t he date of t heir last 
t u m or assess me nt.
1 4. 1. 2. 3 P r o g r essi o n- F r e e S u r vi v al ( P F S)
Pr o gressi o n- Free S ur vi val ( P F S) is defi ne d as t he ti me fr o m first d ose u ntil d oc u me nte d 
pr o gressi o n or deat h. A s u bject w h o neit her pr o gresses n or dies will be ce ns ore d o n t he date of his 
or her last t u m or assess me nts.
1 4. 1. 2. 4 Ti m e t o n e xt t r e at m e nt
T he ti me t o s u bse q ue nt m yel o ma t hera p y is defi ne d as t he i nter val fr o m ra n d o mizati o n t o earliest 
start date of s u bse q ue nt m yel o ma t hera p y. S u bjects w h o d o n ot recei ve a n y s u bse q ue nt m yel o ma 
t hera p y will be ce ns ore d at t he date of t heir last f oll o w- u p visit. S u bjects wit h n o f oll o w- u p visits 
will be ce ns ore d at t heir last date of st u d y me dicati o n.
1 4. 1. 2. 5 S af et y E n d p oi nts

C O N FI D E N TI A L
T his d oc u me nt is c o nfi de ntial. D o n ot discl ose or use e xce pt as a ut h orize d.
8 2
S h ort title: P h ase II st u d y of El ot uz u m a b pl us R V D i n Ne wl y Di a g n ose d M M
Versi o n D ate: N o ve m ber 1 0, 2 0 2 0 
Safet y e n d p oi nts are seri o us a n d n o n-seri o us A Es, cli nical la b orat or y tests ( he mat ol o g y, c he mistr y, 
uri nal ysis, c oa g ulati o n pa nel), vital si g n meas ure me nts, a n d p h ysical e xa mi nati o n wit h assess me nt 
of E C O G P S
1 4. 1. 3
E x pl or at or y E n d p oi nts
Assess me nt of mi ni mal resi d ual disease
T he ac hie ve me nt of mi ni mal resi d ual disease will be e val uate d a n d re p orte d o n patie nts t hat 
ac hie ve a c o m plete res p o nse
1 4. 1. 3. 1 E n g r aft m e nt P a r a m et e rs
E n graft me nt para meters will be c ollecte d a n d re p orte d o nl y a m o n g s u bjects w h o pr ocee d t o S C T. 
Ne utr o p hil e n graft me nt is defi ne d as a n a bs ol ute ne utr o p hil c o u nt > 5 0 0/ µ L f or t w o c o nsec uti ve 
da ys a n d platelet e n graft me nt is defi ne d as platelets > 2 0, 0 0 0/ µ L f or t w o c o nsec uti ve da ys wit h o ut 
platelet i nf usi o n wit hi n t he pre vi o us wee k.
1 4. 2 
S a m ple Size/ Accr u al R ate
T his is a si n gle ar m, o pe n-la bel st u d y t o esti mate t he res p o nse rate at Wee k 1 2. A p pr o xi matel y 4 0 
s u bjects will be treate d. Wit h a n o bser ve d res p o nse rate of 9 0 % a n d 4 0 s u bjects, t he l o wer b o u n d 
of t he 9 5 % c o nfi de nce i nter val ( CI) w o ul d be i n e xcess of 7 5 %, w hic h was t he res p o nse rate at 
Wee k 1 2 i n a rece nt P hase 2 st u d y of s u bjects treate d wit h B L D.
6 T he ta ble bel o w gi ves t w o-si de d, 
9 5 %, e xact ( Cl o p per a n d Pears o n) CIs f or a ra n ge of res p o nse rates, base d o n a sa m ple size of 4 0.
T a ble 1 4. 2  
U p per b o u n ds ( %) of Cl o p per- Pe ars o n i nter v al f or a r a n ge of 
o bser ve d e ve nt r ates ( S a m ple Size E q u als 4 0)
N u m ber of Res p o nses
Res p o nse R ate
9 5 % C o nfi de nce I nter v al
3 8
9 5 %
( 8 3. 3 %, 9 9. 4 %)
3 6
9 0 %
( 7 6. 3 %, 9 7. 2 %)
3 4
8 5 %
( 7 0. 2 %, 9 4. 3 % )
3 2
8 0 %
( 6 4. 4 %, 9 0. 0 %)
3 0
7 5 %
( 5 8. 8 %, 8 7. 3) )
2 8
7 0 %
( 5 3. 5 %, 8 3. 4 %)
Patie nts w h o are e nr olle d o n st u d y b ut d o n ot recei ve a n y st u d y treat me nt ma y be re place d.
As of Oct o ber 2 0 2 0, t he ori gi nal e n d p oi nts ha ve bee n met. 
1 4. 3 
Str atific ati o n F act ors
T here are n o stratificati o n fact ors pla n ne d i n t his trial.  Patie nts will be e nr olle d i nt o a gi ve n c o h ort 
base d o n se q ue nce of e nteri n g t he trial a n d c o h ort a vaila bilit y.  

C O N FI D E N TI A L
T his d oc u me nt is c o nfi de ntial. D o n ot discl ose or use e xce pt as a ut h orize d.
8 3
S h ort title: P h ase II st u d y of El ot uz u m a b pl us R V D i n Ne wl y Di a g n ose d M M
Versi o n D ate: N o ve m ber 1 0, 2 0 2 0 
1 4. 4  
A n al ysis 
T he pri mar y a n d sec o n dar y e n d p oi nts a nal ysis will be base d o n all treate d s u bjects. T he a nal ysis 
f or s u bject dis p ositi o n will be base d o n e nr olle d s u bjects. All ot her efficac y a n d safet y a nal ysis 
will be base d o n all treate d s u bjects. A d diti o nal e x pl orat or y a nal yses will be i ncl u de d i n t he 
statistical a nal ysis pla n.
1 4. 4. 1
De m o gr a p hics a n d B aseli ne C h ar acteristics
S u bject c haracteristics i ncl u di n g de m o gra p hic c haracteristics, disease c haracteristics, baseli ne 
E C O G perf or ma nce stat us, a n d rele va nt ge netic c haracteristics, will be s u m marize d usi n g 
descri pti ve statistics. N u m ber of scree ni n g fail ures will als o be s u m marize d.
1 4. 4. 2
Effic ac y A n al yses
1 4. 4. 2. 1
W e e k 1 2 A n al ys es:
A 9 5 %, t w o-si de d, e xact CI f or t he res p o nse rate at 
Wee k 1 2, t he pri mar y e n d p oi nt, will be 
c o m p ute d usi n g t he Cl o p per a n d Pears o n met h o d. De pt h of res p o nse at 
Wee k 1 2 will be 
s u m marize d b y pr o p orti o n of s u bjects w h o ac hie ve s C R, C R, V G P R, P R, M R, S D a n d P D.
T he pr o p orti o n of a n d t w o-si de d, 9 5 % CI f or t he s uccessf ul har vest rate at Wee k 1 2, t he sec o n dar y 
e n d p oi nt, will be c o m p ute d usi n g t he Cl o p per a n d Pears o n met h o d.
1 4. 4. 2. 2 Effi c a c y B as e d o n t h e E nti r e St u d y D u r ati o n
T he efficac y a nal yses descri be d bel o w will be d o ne o n all treate d s u bjects a n d als o b y t he f oll o wi n g 
s u b gr o u ps: s u bjects w h o recei ve d S C T a n d s u bjects w h o di d n ot recei ve S C T.
A n esti mate of best O R R d uri n g t he st u d y, al o n g wit h its 9 5 % CI usi n g t he Cl o p per- Pears o n 
met h o d, will be c o m p ute d.  T he t u m or res p o nse data will be liste d b y visits f or eac h s u bject.
T he distri b uti o ns of d urati o n res p o nse, P F S, a n d o verall s ur vi val will be a nal yze d usi n g t he 
Ka pla n- Meier pr o d uct-li mit met h o d.
1 4. 4. 3
S afet y A n al yses
Safet y will be assesse d b y t he nat ure, fre q ue nc y, a n d se verit y of A Es, a n d t he res ults of cli nical 
la b orat or y tests i ncl u di n g he mat ol o g y, bl o o d c he mistr y, a n d uri nal ysis. Safet y a nal yses will be 
d o ne o n all treate d s u bjects a n d als o b y t he f oll o wi n g s u b gr o u ps: s u bjects w h o recei ve d S C T a n d 
s u bjects w h o di d n ot recei ve S C T. Me dical hist or y, p h ysical e xa mi nati o ns, vital si g ns, a n d E C G 
will be dis pla ye d.
A d verse e ve nts will be cate g orize d usi n g t he latest versi o n of Me d D R A a n d t he se verit y will be 
gra de d usi n g C T C A E ( Versi o n 4. 0 3). A n y occ urre nce a n d se vere ( w orst gra de ≥ 3) A Es will be 
ta b ulate d b y S yste m Or ga n Class ( S O C) a n d Preferre d Ter m ( P T). All rec or de d A Es, S A Es a n d 
A Es lea di n g t o st u d y dr u g disc o nti n uati o n will be liste d a n d ta b ulate d b y S O C a n d P T. T he 
pr o p orti o n of s u bjects wit h at least o ne d ose m o dificati o n of a n y st u d y dr u g d uri n g t he first 4 

C O N FI D E N TI A L
T his d oc u me nt is c o nfi de ntial. D o n ot discl ose or use e xce pt as a ut h orize d.
8 4
S h ort title: P h ase II st u d y of El ot uz u m a b pl us R V D i n Ne wl y Di a g n ose d M M
Versi o n D ate: N o ve m ber 1 0, 2 0 2 0 
c ycles will be c o m p ute d. I n a d diti o n, a 9 5 % c o nfi de nce i nter val f or t he rate of d ose m o dificati o n 
will be c o m p ute d usi n g t he Cl o p per a n d Pears o n met h o d.
La b orat or y val ues will be gra de d usi n g N CI C T C. S hift fr o m baseli ne t o w orst o n-st u d y val ue will 
be dis pla ye d f or he mat ol o gic a n d bl o o d c he mistr y la b orat or y e xa mi nati o ns.
T he effect of el ot uz u ma b has bee n st u die d e xte nsi vel y i n c o m bi nati o n wit h Le nali d o mi de a n d 
B ortez o mi b, a n d d osa ges of 1 0 m g/ k g I V are use d i n all p hase III a n d ra n d o mize d p hase II st u dies 
t o date. N o net heless, t he f o ur dr u g c o m bi nati o n pr o p ose d i n t his st u d y has n ot yet bei n g e val uate d 
i n h u ma ns. T heref ore, after t he e nr oll me nt of 1 0 s u bjects i n t he st u d y, f urt her s u bject e nr oll me nt 
will be place d o n h ol d t o e val uate safet y/t o xicit y data pertai ni n g t o t he 4 dr u g c o m bi nati o n, a n d 
s pecificall y re gar di n g El ot uz u ma b.  
1 4. 4. 4
P h ar m ac o ki netic A n al yses
N ot a p plica ble.
1 4. 4. 5
Bi o m ar ker A n al yses
N ot a p plica ble
1 4. 4. 6
O utc o mes Rese arc h A n al yses
N ot a p plica ble.
1 4. 4. 7
Ot her A n al yses
1 4. 4. 7. 1 I m m u n o g e ni cit y A n al ys es
N ot A p plica ble.
1 4. 4. 8
I nteri m A n al yses
T here is n o i nteri m a nal ysis pla n ne d f or t his st u d y.
1 5
P U B LI C A TI O N P L A N
Data fr o m t his trial will be re p orte d o nce it is release d fr o m t he D S M C f or p u blicati o n.  T he fi nal 
res ults of t his st u d y will be p u blis he d i n ma n uscri pt f or m i n a maj or peer-re vie we d j o ur nal.  T he 
st u d y PI will be res p o nsi ble f or s u b mitti n g t he fi nal ma n uscri pt f or p u blicati o n.  T he fi nal 
ma n uscri pt will be re vie we d b y all parties i n v ol ve d.  A p pr o val will be o btai ne d fr o m t he pri mar y 
res p o nsi ble part y bef ore a n y i nf or mati o n ca n be use d or passe d o n t o a t hir d part y or s u b mitte d f or 
p u blicati o n.
C o-a ut h ors hi p of t his ma n uscri pt will be deter mi ne d acc or di n g t o t he le vel of partici pati o n i n t he 
st u d y as meas ure d b y accr ual fr o m eac h partici pati n g site, t here b y i ncl u di n g i n di vi d uals w h o ha ve 

C O N FI D E N TI A L
T his d oc u me nt is c o nfi de ntial. D o n ot discl ose or use e xce pt as a ut h orize d.
8 5
S h ort title: P h ase II st u d y of El ot uz u m a b pl us R V D i n Ne wl y Di a g n ose d M M
Versi o n D ate: N o ve m ber 1 0, 2 0 2 0 
bee n m ost i n v ol ve d i n t he desi g n, c o n d uct, a n d a nal ysis of t he st u d y.  A d diti o nal i n di vi d uals ma y 
recei ve ac k n o wle d ge me nt i n t he fi nal ma n uscri pt f or t heir s u p p ort of t he c o n d uct of t he st u d y, as 
well as t heir re vie w of t he ma n uscri pt.  
1 6
R E F E R E N C E S 
Ale xa nia n R, Ha ut A, K ha n A U, La ne M, Mc Kel ve y E M, Mi gli ore PJ, St uc ke y WJ Jr, Wils o n H E. 
Treat me nt f or m ulti ple m yel o ma. C o m bi nati o n c he m ot hera p y wit h differe nt mel p hala n d ose 
re gi me ns. J A M A. 1 9 6 9 J u n 2; 2 0 8( 9): 1 6 8 0- 5.
Ale xa nia n R. Treat me nt of m ulti ple m yel o ma. Acta Hae mat ol. 1 9 8 0; 6 3( 5): 2 3 7- 4 0.
A merica n S ociet y of Cli nical O nc ol o g y g ui deli nes. 2 0 0 6.
Ba k k us M H, Heir ma n C, Va n Riet I, Va n Ca m p B, T hiele ma ns K. E vi de nce t hat m ulti ple m yel o ma 
I g hea v y c hai n V DJ ge nes c o ntai n s o matic m utati o ns b ut s h o w n o i ntracl o nal variati o n. Bl o o d. 1 9 9 2 
N o v 1; 8 0( 9): 2 3 2 6- 3 5.
Bla de J, Sa ms o n D, Reece D, A p perle y J, Bj or kstra n d B, Ga hrt o n G et al. Criteria f or e val uati n g 
disease res p o nse a n d pr o gressi o n i n patie nts wit h m ulti ple m yel o ma treate d b y hi g h- d ose t hera p y 
a n d hae m o p oietic ste m cell tra ns pla ntati o n. M yel o ma S u bc o m mittee of t he E B M T. E ur o pea n Gr o u p 
f or Bl o o d a n d B o ne Marr o w Tra ns pla nt. Br J Hae mat ol 1 9 9 8; 1 0 2: 1 1 1 5- 1 1 2 3.
C ha u ha n D, Uc hi ya ma H, Uras hi ma M, Ya ma m ot o K, A n ders o n K C. Re g ulati o n of i nterle u ki n 6 i n 
m ulti ple m yel o ma a n d b o ne marr o w str o mal cells. Ste m Cells. 1 9 9 5 A u g; 1 3 S u p pl 2: 3 5- 9.
C o o per M R, McI nt yre O R, Pr o pert KJ, K oc h wa S, A n ders o n K, C ole ma n M, K yle R A, Pra ger D, 
Rafla S, Zi m m er B. Si n gle, se q ue ntial, a n d m ulti ple al k ylati n g a ge nt t hera p y f or m ulti ple m yel o ma: 
a C A L G B St u d y. J Cli n O nc ol. 1 9 8 6 Se p; 4( 9): 1 3 3 1- 9.
D' A mat o RJ, Li n C M, Fl y n n E, F ol k ma n J, Ha mel E. 2- Met h o x yestra di ol, a n e n d o ge n o us 
ma m malia n meta b olite, i n hi bits t u b uli n p ol y merizati o n b y i nteracti n g at t he c olc hici ne site. Pr oc 
Natl Aca d Sci U S A. 1 9 9 4 A pr 2 6; 9 1( 9): 3 9 6 4- 8.
Di m o p o ul os M, S pe ncer A, Attal M, et al.  Le nali d o mi de pl us de xa met has o ne f or rela pse d or 
refract or y m ulti ple m yel o ma.  N E n gl J Me d. 2 0 0 7; 3 5 7( 2 1): 2 1 2 3- 3 2.
D urie B G. Sta gi n g a n d ki netics of m ulti ple m yel o ma. Se mi n O nc ol. 1 9 8 6 Se p; 1 3( 3): 3 0 0- 9. Re vie w. 
D urie B G, et al. I nter nati o nal u nif or m res p o nse criteria f or m ulti ple m yel o ma. Le u ke mia 
2 0 0 6; 2 0: 1 4 6 7- 7 3

C O N FI D E N TI A L
T his d oc u me nt is c o nfi de ntial. D o n ot discl ose or use e xce pt as a ut h orize d.
8 6
S h ort title: P h ase II st u d y of El ot uz u m a b pl us R V D i n Ne wl y Di a g n ose d M M
Versi o n D ate: N o ve m ber 1 0, 2 0 2 0 
Fac o n T, Mar y J Y, H uli n C, et al.  Mel p hala n a n d pre d nis o ne pl us t hali d o mi de vers us mel p hala n a n d 
pre d nis o ne or re d uce d-i nte nsit y a ut ol o g o us ste m cell tra ns pla ntati o n i n el derl y patie nts wit h m ulti ple 
m yel o ma (I F M 9 9- 0 6): a ra n d o mize d trial.  La ncet. 2 0 0 7; 3 7 0: 1 2 0 9- 1 2 1 8.
Grei p p P R, Sa n Mi g uel J, D urie B G, Cr o wle y JJ, Barl o gie B, Bla de J, et al. I nter nati o nal sta gi n g 
s yste m f or m ulti ple m yel o ma.  J o ur nal of Cli nical O nc ol o g y. 2 0 0 5; 2 3( 2 5): 6 2 8 1.
Ha na m ura I, Ste wart J P, H ua n g Y, Z ha n F, Sa ntra M, Sa w yer J R, H oll mi g K, Za n garri M, Pi ne da-
R o ma n M, va n R hee F, Ca vall o F, B uri n gt o n B, Cr o wle y J, Tric ot G, Barl o gie B, S ha u g h ness y J D 
Jr. Fre q ue nt gai n of c hr o m os o me ba n d 1 q 2 1 i n plas ma-cell d yscrasias detecte d b y fl u oresce nce i n 
sit u h y bri dizati o n: i nci de nce i ncreases fr o m M G U S t o rela pse d m yel o ma a n d is relate d t o pr o g n osis 
a n d disease pr o gressi o n f oll o wi n g ta n de m ste m-cell tra ns pla ntati o n. Bl o o d. 2 0 0 6 Se p 1; 1 0 8( 5): 1 7 2 4-
- 3 2
Hi des hi ma T, Ric har ds o n P G, A n ders o n K C. Tar geti n g pr oteas o me i n hi biti o n i n he mat ol o gic 
mali g na ncies. Re v Cli n E x p He mat ol. 2 0 0 3 J u n; 7( 2): 1 9 1- 2 0 4. Re vie w.
Hi des hi ma T, Catle y L, Raje N, C ha u ha n D, P o dar K, Mitsia des C, Tai Y- T, Vallet S, Kizilte pe T, 
Oci o E, I ke da H, O ka wa Y, Hi des hi ma H, M u ns hi N, Yas ui H, Ric har ds o n P, A n ders o n K. 
I n hi biti o n of A kt i n d uces si g nifica nt d o w nre g ulati o n of s ur vi vi n a n d c yt ot o xicit y i n h u ma n m ulti ple 
m yel o ma cells. Britis h j o ur nal of hae mat ol o g y. 2 0 0 7; 1 3 8( 6): 7 8 3- 9 1.
I n vesti gat or Br oc h ure f or El ot uz u ma b.
Ja k u b o wia k A, Be ns o n D, Be nsi n ger W.; Pase I Trial of A nti- C S 1 M o n ocl o nal A nti b o d y El ot uz u ma b 
i n C o m bi nati o n Wit h B ortez o mi b i n t he Treat me nt of Rela pse d/ Refract or y M ulti ple M yel o ma. J Cli n 
O nc ol. 2 0 1 2  J u n 3 0 ( 1 6): 1 9 6 0- 1 9 6 5
K yle, R. A. & Grei p p, P. R. S m o ul deri n g m ulti ple m yel o ma. N. E n gl. J. Me d. 1 9 8 0; 3 0 2, 1 3 4 7.
K yle R A, Yee G C, S o merfiel d M R, Fl y n n PJ, Hala bi S, Ja ga n nat h S, Orl o ws ki R Z, R o o d ma n D G, 
T wil de P, A n ders o n K; A merica n S ociet y of Cli nical O nc ol o g y. A merica n S ociet y of Cli nical 
O nc ol o g y 2 0 0 7 cli nical practice g ui deli ne u p date o n t he r ole of bis p h os p h o nates i n m ulti ple 
m yel o ma. J Cli n O nc ol. 2 0 0 7 J u n 1 0; 2 5( 1 7): 2 4 6 4- 7 2.
Lee BJ, Sa ha kia n G, Clar ks o n B D, Kra k off I H. Pr ocee di n gs: C o m bi nati o n c he m ot hera p y of m ulti ple 
m yel o ma wit h al kera n, c yt o xa n, vi ncristi ne, pre d nis o ne, a n d B C N U. Ca ncer. 1 9 7 4 Fe b; 3 3( 2): 5 3 3- 8. 
L o nial S, Vij R, Har o ussea u J- L, et al: El ot uz u ma b i n C o m bi nati o n Wit h Le nali d o mi de a n d 
L o w- D ose De xa met has o ne i n Rela pse d or Refract or y M ulti ple M yel o ma. J Cli n O nc ol,  
2 0 1 2,J u n 3 0 ( 1 6): 1 9 5 3- 5 0. 
L o nial S, Ja ga n nat h S, M orea u P, et al. P hase ( P h) I/II st u d y of el ot uz u ma b ( El o) pl us 
le nali d o mi de/ de xa met has o ne ( Le n/ de x) i n rela pse d/refract or y m ulti ple m yel o ma ( R R M M): 
U p date d P h II res ults a n d P h I/II l o n g-ter m safet y. J Cli n O nc ol 3 1, 2 0 1 3 (s u p pl; a bstr 8 5 4 2)

C O N FI D E N TI A L
T his d oc u me nt is c o nfi de ntial. D o n ot discl ose or use e xce pt as a ut h orize d.
8 7
S h ort title: P h ase II st u d y of El ot uz u m a b pl us R V D i n Ne wl y Di a g n ose d M M
Versi o n D ate: N o ve m ber 1 0, 2 0 2 0 
Mc Ke n na, R W, K yle, R A, K ue hl, W M, Gr o ga n, T M, Harris, N L & C o u pla n d, R W. Plas ma cell 
ne o plas ms. I n: W H O Cl assific ati o n of T u m o urs of He m at o p oietic a n d Ly m p h oi d Tiss ues  (e d. b y 
S. H. S wer dl o w, E. Ca m p o, N. L. Harris, E. S.Jaffe, S. A. Pileri, H. Stei n, J. T hiele & J. W. Var di ma n). 
2 0 0 8; 2 0 0 – 2 1 3. 
N C C N treat me nt g ui deli nes, htt p:// w w w. ncc n. or g/ pr ofessi o nals/ p h ysicia n _ gls/ p df/ m yel o ma. p df
Pal u m b o A, Bri n g he n S, Cara vita T, et al.  Oral mel p hala n a n d pre d nis o ne c he m ot hera p y pl us 
t hali d o mi de c o m pare d wit h mel p hala n a n d pre d nis o ne al o ne i n el derl y patie nts wit h m ulti ple 
m yel o ma: ra n d o mize d c o ntr olle d trial.  La ncet. 2 0 0 6; 3 6 7: 8 2 5- 4 3 5.
Pal u m b o A, Raj k u mar S V. Treat me nt of ne wl y dia g n ose d m yel o ma. Le u ke mia. 2 0 0 9 
Mar; 2 3( 3): 4 4 9- 5 6. Re vie w.
Raj k u mar K R et al. Criteria f or dia g n osis, sta gi n g, ris k stratificati o n a n d res p o nse assess me nt of 
m ulti ple m yel o ma. Le u ke mia 2 0 0 9 2 3; 3- 9.
Raj k u mar S V ( 2 0 1 4) et al. I nter nati o nal m yel o ma w or ki n g gr o u p u p date d criteria f or t he dia g n osis 
of m ulti ple m yel o ma. La ncet. 2 0 1 4; 1 5: 5 3 8- 5 4 8. Raj k u mar S C, Sa n Mi g uel J, Har o ussea u J- L et al.  
G ui deli nes f or t he u nif or m re p orti n g of cli nical trials: Re p ort of t he 2 0 0 8 I nter nati o nal M yel o ma 
W or ks h o p C o nse ns us Pa nel I ( 1 3 p.), 2 0 0 9. A vaila ble via [ htt p:// w w w. m w- del hi 0 9.c o m]
Ric har ds o n P G, S o n ne vel d P, Sc h uster M, Ir wi n D, Sta dt ma uer E A, Fac o n T, Har o ussea u J, Be n-
Ye h u da D, L o nial S, G ol dsc h mi dt H, Reece D, Sa n- Mi g uel J, Bla de J, B occa d or o M, Ca ve na g h J, 
Dalt o n W, B oral A, Esselti ne D, P orter J B, Sc he n kei n D, A n ders o n K C. B ortez o mi b or Hi g h- D ose 
De xa met has o ne f or Rela pse d M ulti ple M yel o ma. N E n gl J Me d. 2 0 0 5; 3 5 2( 2 4): 2 4 8 7- 2 4 9 8.
Ric har ds o n P G, Weller E, Ja ga n nat h S, A vi ga n D E, Alsi na M, Sc hl oss ma n R L, Maz u m der A, 
M u ns hi N C, G h o brial I M, D oss D, Warre n D L, L u n de L E, Mc Ke n ne y M, Dela ne y C, Mitsia des 
C S, Hi des hi ma T, Dalt o n W, K ni g ht R, Esselti ne D L, A n ders o n K C. M ultice nter, p hase I, d ose-
escalati o n trial of le nali d o mi de pl us b ortez o mi b f or rela pse d a n d rela pse d/refract or y m ulti ple 
m yel o ma. J Cli n O nc ol. 2 0 0 9 Dec 1; 2 7( 3 4): 5 7 1 3- 9. 
Ric har ds o n P G et al. Le nali d o mi de, b ortez o mi b, a n d de xa met has o ne c o m bi nati o n t hera p y i n 
patie nts wit h ne wl y dia g n ose d m ulti ple m yel o ma. Bl o o d. 2 0 1 0; 1 1 6( 5): 6 7 9.
Sa ms o n D, Ga mi nara E, Ne wla n d A, Va n de Pette J, Kear ne y J, Mc Cart h y D, J o y ner M, Ast o n 
L, Mitc hell T, Ha m o n M, et al. I nf usi o n of vi ncristi ne a n d d o x or u bici n wit h oral de xa met has o ne 
as first-li ne t hera p y f or m ulti ple m yel o ma. La ncet. 1 9 8 9 Oct 1 4; 2( 8 6 6 8): 8 8 2- 5.
Sa n Mi g uel J, Sc hla g R, K u va ge va N, et al.  B ortez o mi b pl us mel p hala n a n d pre d nis o ne f or i nitial 
treat me nt of m yel o ma.  N E n gl J Me d. 2 0 0 8; 3 5 9: 9 0 6- 1 7.
Si n g hal S, Me hta J, Desi ka n R, A yers D, R o bers o n P, E d dle m o n P, M u ns hi N, A naissie E, Wils o n 
C, D h o da p kar M, Ze d dis J, Barl o gie B. A ntit u m or acti vit y of t hali d o mi de i n refract or y m ulti ple 

C O N FI D E N TI A L
T his d oc u me nt is c o nfi de ntial. D o n ot discl ose or use e xce pt as a ut h orize d.
8 8
S h ort title: P h ase II st u d y of El ot uz u m a b pl us R V D i n Ne wl y Di a g n ose d M M
Versi o n D ate: N o ve m ber 1 0, 2 0 2 0 
m yel o ma. N E n gl J Me d. 1 9 9 9 N o v 1 8; 3 4 1( 2 1): 1 5 6 5- 7 1. Errat u m i n: N E n gl J Me d 2 0 0 0 Fe b 
3; 3 4 2( 5): 3 6 4.
We ber D M, C he n C, Nies viz k y R, et al.  Le nali d o mi de pl us de xa met has o ne f or rela pse d  m ulti ple 
m yel o ma i n N ort h A merica.  N E n gl J Me d. 2 0 0 7; 3 5 7( 2 1): 2 1 3 3- 4 2.
Z o n der J, M o hr bac her A, Si n g hal S, et al.; A p hase 1, m ultice nter, o pe n-la bel, d ose escalati o n st u d y 
of el ot uz u ma b i n patie nts wit h a d va nce d m ulti ple m yel o ma. Bl o o d J ul 2 0 1 2, 1 2 0( 3) 5 5 2- 5 5 9

C O N FI D E N TI A L
T his d oc u me nt is c o nfi de ntial. D o n ot discl ose or use e xce pt as a ut h orize d.
8 9
S h ort title: P h ase II st u d y of El ot uz u m a b pl us R V D i n Ne wl y Di a g n ose d M M
Versi o n D ate: N o ve m ber 1 0, 2 0 2 0 
1 7
A P P E N DI C E S 
A p pe n di x I:  Perf or m a nce St at us Criteri a
E C O G Perf or m a nce St at us Sc ale
Gr a d e
D es cri pti o n
0
N or m al a cti vit y. F ull y a cti v e, a bl e t o c arr y o n all pr e- dis e as e p erf or m a n c e wit h o ut 
r estri cti o n.
1
S y m pt o ms, b ut a m b ul at or y. R estri ct e d i n p h ysi c all y str e n u o us a cti vit y, b ut a m b ul at or y a n d 
a bl e t o c arr y o ut w or k of a li g ht or s e d e nt ar y n at ur e ( e. g., li g ht h o us e w or k, offi c e w or k).
2
I n b e d < 5 0 % of t h e ti m e. A m b ul at or y a n d c a p a bl e of all s elf- c ar e, b ut u n a bl e t o c arr y o ut 
a n y w or k a cti viti es. U p a n d a b o ut m or e t h a n 5 0 % of w a ki n g h o urs.
3
I n b e d > 5 0 % of t h e ti m e. C a p a bl e of o nl y li mit e d s elf- c ar e, c o nfi n e d t o b e d or c h air m or e 
t h a n 5 0 % of w a ki n g h o urs.
4
1 0 0 % b e dri d d e n. C o m pl et el y dis a bl e d. C a n n ot c arr y o n a n y s elf- c ar e. T ot all y c o nfi n e d t o 
b e d or c h air.
5
D e a d.

C O N FI D E N TI A L
T his d oc u me nt is c o nfi de ntial. D o n ot discl ose or use e xce pt as a ut h orize d.
9 0
S h ort title: P h ase II st u d y of El ot uz u m a b pl us R V D i n Ne wl y Di a g n ose d M M
Versi o n D ate: N o ve m ber 1 0, 2 0 2 0 
A p pe n di x II:  D u B ois F or m ul a f or B o d y S urf ace Are a 
B o d y s urface area ( B S A) s h o ul d be calc ulate d usi n g t he D u B ois f or m ula t hat yiel ds t he 
f oll o wi n g res ult i n meters s q uare d ( m2):1
B S A ( m²) = Wt ( k g) 0. 4 2 5 x Ht (c m)0. 7 2 5 x 0. 0 0 7 1 8 4
1D u B ois D, D u B ois E F. A f or m ula t o esti mate t he a p pr o xi mate s urface area if hei g ht a n d wei g ht 
be k n o w n. Arc h I nter n Me dici ne. 1 9 1 6; 1 7: 8 6 3- 7 1.

C O N FI D E N TI A L
T his d oc u me nt is c o nfi de ntial. D o n ot discl ose or use e xce pt as a ut h orize d.
9 1
S h ort title: P h ase II st u d y of El ot uz u m a b pl us R V D i n Ne wl y Di a g n ose d M M
Versi o n D ate: N o ve m ber 1 0, 2 0 2 0 
A p pe n di x III:  T he Ne w Y or k He art Ass oci ati o n Cl assific ati o n of C ar di ac Dise ase
T he f oll o wi n g ta ble prese nts t he N Y H A classificati o n of car diac disease:
Cl ass
F u ncti o n al C a p acit y
O bjecti ve Assess me nt
I
Patie nts wit h car diac disease b ut wit h o ut res ulti n g li mitati o ns of 
p h ysical acti vit y.  Or di nar y p h ysical acti vit y d oes n ot ca use u n d ue 
fati g ue, pal pitati o n, d ys p nea, or a n gi nal pai n.
N o o bjecti ve e vi de nce 
of car di o vasc ular 
disease.
II
Patie nts wit h car diac disease res ulti n g i n sli g ht li mitati o n of p h ysical 
acti vit y.  T he y are c o mf orta ble at rest.  Or di nar y p h ysical acti vit y 
res ults i n fati g ue, pal pitati o n, d ys p nea, or a n gi nal pai n.
O bjecti ve e vi de nce of 
mi ni mal 
car di o vasc ular disease.
III
Patie nts wit h car diac disease res ulti n g i n mar ke d li mitati o n of 
p h ysical acti vit y.  T he y are c o mf orta ble at rest.  Less t ha n or di nar y 
acti vit y ca uses fati g ue, pal pitati o n, d ys p nea, or a n gi nal pai n.
O bjecti ve e vi de nce of 
m o deratel y se vere 
car di o vasc ular disease.
I V
Patie nts wit h car diac disease res ulti n g i n i na bilit y t o carr y o n a n y 
p h ysical acti vit y wit h o ut disc o mf ort.  S y m pt o ms of heart fail ure or 
t he a n gi nal s y n dr o me ma y be prese nt e ve n at rest.  If a n y p h ysical 
acti vit y is u n derta ke n, disc o mf ort is i ncrease d.
O bjecti ve e vi de nce of 
se vere car di o vasc ular 
disease.

S h ort title: P h ase II st u d y of El ot uz u m a b pl us R V D i n  Ne wl y Di a g n ose d M M
                         Versi o n D ate:     N o ve m ber 1 0, 2 0 2 0 
C O N FI D E N TI A L
T his d oc u me nt is c o nfi de ntial. D o n ot discl ose or use e xce pt as a ut h orize d.
9 2
A p pe n di x I V:   I nter n ati o n al M yel o m a F o u n d ati o n 2 0 0 3 Di a g n ostic Criteri a:
1 7. 1. 1
A di a g n osis of M M re q uires t h at all t hree of t he f oll o wi n g m ust be met:

M o n ocl o nal plas ma cells i n t he b o ne marr o w > 1 0 % a n d/ or prese nce of a bi o ps y-
pr o ve n plas mac yt o ma

M o n ocl o nal pr otei n ( M- pr otei n) prese nt i n t he ser u m a n d/ or uri ne .  If n o m o n ocl o nal 
pr otei n is detecte d ( n o n-secret or y) disease, t he n > 3 0 % m o n ocl o nal b o ne marr o w 
plas ma cells a n d/ or a bi o ps y- pr o ve n plas mac yt o ma

M yel o ma-relate d or ga n d ysf u ncti o n ( 1 or m ore) of t he f oll o wi n g.  A variet y of ot her 
t y pes of e n d- or ga n d ysf u ncti o n ca n occasi o nall y occ ur a n d lea d t o a nee d f or t hera p y.  
S uc h d ysf u ncti o n is s ufficie nt t o s u p p ort classificati o n of m yel o ma if pr o ve n t o be 
m yel o ma relate d.
[ C]  Calci u m ele vati o n i n t he bl o o d, defi ne d as ser u m calci u m >  1 0. 5 m g/ dl or 
u p per li mit of n or mal
[ R]  Re nal i ns ufficie nc y, defi ne d as ser u m creati ni ne > 2 m g/ dl
[ A]  A ne mia, defi ne d as he m o gl o bi n < 1 0 g/ dl or 2 g < n or mal
[ B] L ytic b o ne lesi o ns or oste o p or osis.  If a s olitar y ( bi o ps y- pr o ve n) 
plas mac yt o ma or oste o p or osis al o ne ( wit h o ut fract ures) are t he s ole 
defi ni n g criteria, t he n > 3 0 % plas ma cells are re q uire d i n t he b o ne marr o w .
.

S h ort title: P h ase II st u d y of El ot uz u m a b pl us R V D i n  Ne wl y Di a g n ose d M M
 Versi o n Date:       Fe br u ar y 6, 2 0 1 9
 
C O N FI D E N TI A L
T his d oc u me nt is c o nfi de ntial. D o n ot discl ose or use e xce pt as a ut h orize d.
9 3
A p pe n di x V:  F A C T/ G O G- Ne ur ot o xicit y Q uesti o n n aire, Versi o n 4. 0
B y circli n g o ne ( 1) n u m ber per li ne, please i n dicate h o w tr ue eac h state me nt has bee n f or y o u 
d uri n g t he past 7 da ys.
A D DI TI O N A L C O N C E R N S
N ot
at all
A little
bit
S o me-
w h at
Q uite
a bit
Ver y
m uc h
I ha ve n u m b ness or ti n gli n g i n m y ha n ds … … …
0
1
2
3
4
I ha ve n u m b ness or ti n gli n g i n m y feet … … … …
0
1
2
3
4
I feel disc o mf ort i n m y ha n ds … … … … … … ….
0
1
2
3
4
I feel disc o mf ort i n m y feet … … … … … … … …
0
1
2
3
4
I ha ve j oi nt pai n or m uscle cra m ps … … … … …
0
1
2
3
4
I feel wea k all o ver … … … … … … … … … … …
0
1
2
3
4
I ha ve tr o u ble heari n g … … … … … … … … … …
0
1
2
3
4
I get a ri n gi n g or b uzzi n g i n m y ears … … … …
0
1
2
3
4
I ha ve tr o u ble b utt o ni n g b utt o ns … … … … … …
0
1
2
3
4
I ha ve tr o u ble feeli n g t he s ha pe of s mall o bjects
w he n t he y are i n m y ha n d … … … … … … … … …
0
1
2
3
4
I ha ve tr o u ble wal ki n g … … … … … … … … … …
0
1
2
3
4
P artici p a nt Si g n at ure: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _      D ate: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
C ycle: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

9 4
S h ort title: P h ase II st u d y of El ot uz u m a b pl us R V D i n Ne wl y Di a g n ose d M M
 Versi o n D ate:       Fe br u ar y 6, 2 0 1 9
C O N FI D E N TI A L
T his d oc u me nt is c o nfi de ntial. D o n ot discl ose or use e xce pt as a ut h orize d.
A p pe n di x VI  Li nes of T her a p y
Acc or di n g t o t he I M W G C o nse ns us pa nel 1 o n u nif or m re p orti n g criteria i n cli nical trials 2, a li ne of 
t hera p y c o nsists of at least 1 or m ore c ycles of a pla n ne d treat me nt re gi me n.  T his ma y c o nsist of si n gle-
a ge nt or c o m bi nati o n t hera p y or a se q ue nce of treat me nts a d mi nistere d i n a pla n ne d ma n ner.   F or 
e xa m ple, a pla n ne d i n d ucti o n, f oll o we d b y A S C T f oll o we d b y mai nte na nce is c o nsi dere d o ne li ne of 
t hera p y.  A ne w li ne of t hera p y starts w he n a pla n ne d c o urse is m o difie d as a res ult of pr o gressi o n, 
rela pse or t o xicit y or w he n a pla n ne d peri o d of o bser vati o n is i nterr u pte d b y t he nee d f or a d diti o nal 
treat me nt of t he disease.   
M o dificati o n of dr u g d oses or res u mi n g t hera p y after h ol di n g will n ot be c o nsi dere d a ne w li ne of 
t hera p y pr o vi de d t hat t here was n o e vi de nce of pr o gressi o n of disease as defi ne d i n t he “ Res p o nse 
Criteria” secti o n of t his d oc u me nt.

9 5
S h ort title: P h ase II st u d y of El ot uz u m a b pl us R V D i n Ne wl y Di a g n ose d M M
 Versi o n D ate:       Fe br u ar y 6, 2 0 1 9
C O N FI D E N TI A L
T his d oc u me nt is c o nfi de ntial. D o n ot discl ose or use e xce pt as a ut h orize d.
A p pe n di x VII Pre p ar ati o n a n d a d mi nistr ati o n of el ot uz u m a b
D ose Pre p ar ati o n I nstr ucti o ns
After dil uti o n i n n or mal sali ne, t he i nf usi o n m ust be c o m plete d wit hi n 8 h o urs if ke pt at r o o m 
te m perat ure ( 2 5C). If a dela y is a ntici pate d after t he d ose has bee n dil ute d i n n or mal sali ne, t he 
pre pare d d ose ( pr o perl y i de ntifie d) ma y be refri gerate d at 2 C t o 8 C f or u p t o 2 4 h o urs. If st ore d 
u n der refri gerate d c o n diti o ns, t he st u d y dr u g s ol uti o n s h o ul d be e q uili brate d t o r o o m te m perat ure 
(ta kes a b o ut 2 t o 2. 5 h o urs), a n d t he c o ntai ner m ust be ge ntl y i n verte d t o t h or o u g hl y mi x t he 
c o nte nts bef ore a d mi nistrati o n. If t he st ora ge ti me li mit is e xcee de d, t he pre pare d d ose s ol uti o n 
m ust be discar de d a n d t he reas o n d oc u me nte d b y t he p har macist i n t he st u d y dr u g acc o u nta bilit y 
rec or ds.
El ot uz u ma b will be a d mi nistere d t o eac h s u bject as a n I V i nf usi o n, usi n g a n a ut o mate d i nf usi o n 
p u m p set at t he a p pr o priate rate acc or di n g t o t he d ose a d mi nistrati o n secti o n (see A d mi nistrati o n 
I nstr ucti o n secti o n bel o w) disc usse d bel o w. T he d ose of el ot uz u ma b will be calc ulate d usi n g t he 
s u bject’s pre d ose wei g ht o n Da y of treat me nt i n eac h c ycle, a n d t he n a d de d t o 0. 9 % sali ne f or 
i nf usi o n. D o n ot r o u n d u p or d o w n.
Rec o nstit ute el ot uz u ma b l y o p hilize d st u d y dr u g, as descri be d i n Ste ps 1 t o 5. Eac h 4 0 0 m g vial 
c o ntai ns 1 0 % o verfill f or a t otal of 4 4 0 m g of st u d y dr u g b ut is i nte n de d t o deli ver 4 0 0 m g of 
el ot uz u ma b. Sta n dar d ase ptic tec h ni q ue s h o ul d be utilize d.
Ste p 1: Re m o ve t he fli p-t o p fr o m el ot uz u ma b a n d Sterile Water f or I njecti o n ( S W FI) vials.
Ste p 2: Wit h dra w 1 7 m L of S W FI usi n g a n 1 8- ga u ge or s maller nee dle. Place t he el ot uz u ma b vial 
u pri g ht o n a flat s urface a n d i nsert t he s yri n ge nee dle i nt o t he vial t hr o u g h t he ce nter of t he r u b ber 
st o p per. Sl o wl y i nject t he S W FI al o n g t he si de of t he vial t o hel p pre ve nt b u b bli n g or f oa mi n g. 
Sl o wl y re m o ve t he s yri n ge nee dle o ut of t he vial.
Ste p 3: D O N O T S H A K E. A v oi d pr ol o n ge d or vi g or o us a gitati o n. H ol d t he vial u pri g ht a n d ge ntl y 
s wirl t he s ol uti o n b y r otati n g t he vial t o diss ol ve t he l y o p hilize d ca ke. T he n ge ntl y i n vert t he vial 
a fe w ti mes i n or der t o diss ol ve a n y p o w der t hat ma y be prese nt o n t o p of t he vial or t he st o p per. 
Fi nall y, h ol d t he vial u pri g ht a gai n a n d ge ntl y s wirl t he s ol uti o n a fe w m ore ti mes t o diss ol ve a n y 
re mai ni n g particles.
Ste p 4: After t he re mai ni n g s oli ds are c o m pletel y diss ol ve d, all o w t he rec o nstit ute d s ol uti o n t o 
sta n d f or 5 t o 1 0 mi n utes. T he fi nal v ol u me of t he rec o nstit ute d s ol uti o n is a p pr o xi matel y 1 7. 6 m L, 
f or a n a p pr o xi mate c o nce ntrati o n of 2 5 m g/ m L.
It is acce pta ble t o ha ve s mall b u b bles a n d/ or f oa m ar o u n d t he e d ge of t he vial. T he rec o nstit ute d 
pre parati o n res ults i n a c ol orless t o sli g htl y yell o w, clear t o sli g htl y o palesce nt s ol uti o n.
Ste p 5: O nce t he rec o nstit uti o n is c o m plete d, wit h dra w t he calc ulate d dr u g v ol u me a n d f urt her 
dil ute wit h n or mal sali ne i nt o a n i nf usi o n ba g (see Ta ble 1). Fi nal dr u g v ol u me will be calc ulate d 
base d o n d ose le vel a n d s u bject wei g ht: F or e xa m ple, a s u bject recei vi n g 1 0 m g/ k g el ot uz u ma b 
w h o wei g hs 8 0 k g o n Da y 1 ( pre d ose) will re q uire 8 0 0 m g of st u d y dr u g f or i nf usi o n. Wit h dra w 
3 2 m L of el ot uz u ma b ( 2 5 m g/ m L) fr o m 2 vials a n d a d d t o a n i nf usi o n ba g alrea d y c o ntai ni n g 2 3 0 

9 6
S h ort title: P h ase II st u d y of El ot uz u m a b pl us R V D i n Ne wl y Di a g n ose d M M
 Versi o n D ate:       Fe br u ar y 6, 2 0 1 9
C O N FI D E N TI A L
T his d oc u me nt is c o nfi de ntial. D o n ot discl ose or use e xce pt as a ut h orize d.
m L sali ne, f or a t otal of 2 6 2 m L t o be i nf use d. T he sa me s u bject recei vi n g 2 0 m g/ k g el ot uz u ma b 
will re q uire 1 6 0 0 m g of st u d y dr u g f or i nf usi o n. Wit h dra w 6 4 m L of el ot uz u ma b ( 2 5 m g/ m L) fr o m 
4 vials a n d a d d t o a n i nf usi o n ba g alrea d y c o ntai ni n g 3 4 0 m L sali ne, f or a t otal of 4 0 4 m L t o be 
i nf use d. Use a ne w sterile nee dle f or wit h dra wi n g s ol uti o n fr o m eac h vial.
T a ble 1 A p pe n di x VII:
D ose Le vel a n d Dil uti o n
D ose Le vel
V ol u me 0. 9 % N or m al S ali ne
1 0 m g/ k g
2 3 0 m L
2 0 m g/ k g
3 4 0 m L
A d mi nistr ati o n I nstr ucti o ns
D uri n g t he first c ycle, t he el ot uz u ma b i nf usi o n rate will be i ncrease d gra d uall y t o a ma xi m u m of 
5 m L/ mi n as prese nte d i n Ta ble 2 A p pe n di x VII. T he first d ose of el ot uz u ma b will be a d mi nistere d 
f oll o wi n g pre me dicati o ns ( descri be d i n Secti o n 5. 3. 7) t o eac h s u bject as a n I V i nf usi o n, usi n g a n 
a ut o mate d i nf usi o n p u m p set at a n i nitial rate of 0. 5 m L per mi n ute ( 3 0 m L/ h o ur). If t he s u bject 
d oes n ot ha ve a n i nf usi o n reacti o n wit hi n 3 0 mi n utes, escalate t he i nf usi o n rate b y 0. 5 m L per 
mi n ute. If t he s u bject still d oes n ot ha ve a n i nf usi o n reacti o n wit hi n 3 0 mi n utes, escalate t he 
i nf usi o n rate t o a ma xi m u m of 2 m L per mi n ute ( 1 2 0 m L/ h o ur). If a s u bject e x perie nces a 
Gra de  2 i nf usi o n reacti o n, t he i nf usi o n m ust be i nterr u pte d. Please refer t o Secti o n 5. 3. 8 f or 
detaile d i nf or mati o n o n t he ma na ge me nt of i nf usi o n reacti o n a n d re-i nitiati o n of i nf usi o n.
T he sec o n d d ose of el ot uz u ma b s h o ul d be i nitiate d at a n i nf usi o n rate of 3 m L per mi n ute if n o 
i nf usi o n reacti o ns were re p orte d wit h t he first el ot uz u ma b i nf usi o n. If t he s u bject d oes n ot 
e x perie nce a n i nf usi o n reacti o n d uri n g t he first 3 0 mi n utes of t he sec o n d d ose of el ot uz u ma b, 
escalate t he i nf usi o n rate b y 1. 0 m L per mi n ute t o a ma xi m u m i nf usi o n rate of 4 m L per mi n ute.
T he t hir d d ose of el ot uz u ma b s h o ul d be i nitiate d at a n i nf usi o n rate of 5 m L per mi n ute if n o 
i nf usi o n reacti o ns were re p orte d wit h pre vi o us el ot uz u ma b i nf usi o ns. If n o i nf usi o n reacti o ns were 
o bser ve d d uri n g t he first c ycle of el ot uz u ma b, t he sec o n d c ycle ca n c o m me nce at a rate of 5 m L 
per mi n ute (see Ta ble 2 A p pe n di x VII). If a s u bject e x perie nces a Gra de  2 i nf usi o n reacti o n, t he 
i nf usi o n m ust be i nterr u pte d. Please refer t o Secti o n 5. 3. 8 f or detaile d i nf or mati o n o n t he 
ma na ge me nt of i nf usi o n reacti o n a n d rei nitiati o n of i nf usi o n. If a s u bject e x perie nces a  Gra de 3 
el ot uz u ma b i nf usi o n reacti o n t hat has res ol ve d t o  Gra de 1, s u bse q ue nt i nf usi o n rate of 
el ot uz u ma b s h o ul d be escalate d i n a ste p wise fas hi o n ( see Ta ble 2 A p pe n di x VII).
A d mi nister t hr o u g h a l o w- pr otei n- bi n di n g 0. 2 2- micr o meter i n-li ne filter ( place d as pr o xi mal t o t he 
s u bject as is practical). Pri me t he i nf usi o n li ne wit h st u d y dr u g bef ore starti n g t he i nf usi o n.
Set t he I V p u m p t o deli ver t he i nf usi o n at t he rate of 0. 5 m L per mi n ute (i ncl u di n g t he dr u g i n t he 
li ne). T he t otal ti me of i nf usi o n will var y de pe n di n g u p o n t he ma xi m u m t olerate d m L/ mi n i nf usi o n 
rate as disc usse d a b o ve.
Rec or d e ver y ti me t he i nf usi o n is starte d a n d st o p pe d a n d t he reas o n w h y t he start a n d st o p 
occ urre d.

9 7
S h ort title: P h ase II st u d y of El ot uz u m a b pl us R V D i n Ne wl y Di a g n ose d M M
 Versi o n D ate:       Fe br u ar y 6, 2 0 1 9
C O N FI D E N TI A L
T his d oc u me nt is c o nfi de ntial. D o n ot discl ose or use e xce pt as a ut h orize d.
M o nit or t he I V set u p a n d t he s u bject’s I V site fre q ue ntl y d uri n g i nf usi o n, c hec ki n g f or t he c orrect 
i nf usi o n rate a n d I V site i nfiltrati o n.
E ns ure t hat t he f ull v ol u me of el ot uz u ma b is i nf use d. After el ot uz u ma b has bee n i nf use d fr o m t he 
li ne, disc o nti n ue t he i nf usi o n, disc o n nect t he I V t u bi n g, a n d dis p ose of materials a p pr o priatel y 
acc or di n g t o t he facilit y’s sta n dar d pr oce d ure.
T a ble 2 A p pe n di x VII:
El ot uz u m a b I nf usi o n R ate
I nf usi o n R ate
D ur ati o n of i nf usi o n
V ol u me deli vere d
V ol u me re m ai ni n g
C ycle 1 D ose 1
A p pr o xi m ate T ot al D ur ati o n: 2 hrs 5 0 mi n
2 6 2 m L *   
0. 5 m L/ mi n
3 0 mi n
1 5 m L
2 4 7 m L
1 m L/ mi n  
3 0 mi n
3 0 m L
2 1 7 m L
2 m L/ mi n  
1 1 0 mi n
2 1 7 m L
0 m L
C ycle 1 D ose 2
A p pr o xi m ate T ot al D ur ati o n: 1 hrs 1 3 mi n
2 6 2 m L
3 m L/ mi n  
3 0 mi n
9 0 m L
1 7 2 m L
4 m L/ mi n
4 3 mi n
1 7 2 m L
0 m L
C ycle 1 D ose 3
5 m L/ mi n
C ycle 2 +  
      
         A p pr o xi m ate T ot al D ur ati o n: 5 3 mi n
                   5 3 mi n                                         2 6 2 m L                   
         A p pr o xi m ate T ot al D ur ati o n: 5 3 mi n
0 m L
2 6 2 m L
5 m L/ mi n  
5 3 mi n
2 6 2 m L
0 m L
* V ol u me f or 8 0 k g s u bject. T otal v ol u me varies acc or di n g t o t he s u bject wei g ht.
Ple ase n ote t h at i nf usi o n r ate i ncre ase t o t he ne xt hi g her le vel are per mitte d o nl y if n o i nf usi o n re acti o ns are 
e nc o u ntere d .

9 8
S h ort title: P h ase II st u d y of El ot uz u m a b pl us R V D i n Ne wl y Di a g n ose d M M
 Versi o n D ate:       Fe br u ar y 6, 2 0 1 9
C O N FI D E N TI A L
T his d oc u me nt is c o nfi de ntial. D o n ot discl ose or use e xce pt as a ut h orize d.
A P P E N DI X VIII   D a n a- F ar ber/ H ar v ar d C a ncer Ce nter M ulti- Ce nter D at a a n d S afet y 
M o nit ori n g Pl a n
D a n a- F ar ber/ H ar v ar d C a ncer Ce nter M ulti- Ce nter D at a a n d S afet y M o nit ori n g Pl a n
T A B L E O F C O N T E N T S
1 
I N T R O D U C TI O N ( B A C K G R O U N D)............................................................................................................ 9
1. 1  
M ulti ple M yel o m a ( M M) .......................................................................................................................... 9
1. 1. 1 
E pi de mi ol o g y a n d pat h o ge nesis ............................................................................................................. 9
1. 1. 2 
Sta gi n g.................................................................................................................................................... 9
1. 1. 3 
Treat me nt.............................................................................................................................................. 1 0
1. 1. 4 
El ot uz u ma b: Mec ha nis m of Acti o n...................................................................................................... 1 1
1. 1. 5 
C o m bi nati o n of el ot uz u ma b wit h le nali d o mi de, b ortez o mi b a n d de xa met has o ne............................... 1 1
1. 2 
El ot uz u m a b De vel o p me nt B ac k gr o u n d................................................................................................. 1 2
1. 2. 1  
N o n-cli nical T o xic ol o g y....................................................................................................................... 1 3
1. 2. 2 
Cli nical E x perie nce wit h El ot uz u ma b i n M ulti ple M yel o ma............................................................... 1 3
1. 2. 3  
O verall Ris k/ Be nefit Assess me nt ......................................................................................................... 2 2
2  
O BJ E C TI V E S................................................................................................................................................. 2 3
2. 1  
Rese arc h H y p ot hesis................................................................................................................................ 2 3
2. 2  
Ori gi n al Pri m ar y O bjecti ves .................................................................................................................. 2 3
2. 3  
Ori gi n al Sec o n d ar y O bjecti ves............................................................................................................... 2 3
3 
P A R TI CI P A N T S E L E C TI O N ....................................................................................................................... 2 4
3. 1 
Eli gi bilit y Criteri a.................................................................................................................................... 2 4
3. 1. 1 
P ati e nts m ust m e et t h e f oll o wi n g crit eri a o n s cr e e ni n g e x a mi n ati o n t o b e eli gi bl e t o p arti ci p at e i n 
t h e st u d y.  All la b orat or y assess me nts s h o ul d be perf or me d wit hi n 2 1 da ys of i nitiati o n of pr ot oc ol t hera p y 
u nless ot her wise s pecifie d. B o n e m arr o w bi o ps y s h o ul d b e p erf or m e d wit hi n 3 0 d a ys of i niti ati o n of 
pr ot o c ol t h er a p y. S u bj e ct is, i n t h e i n v esti g at or’s o pi ni o n, willi n g a n d a bl e t o c o m pl y wit h t h e pr ot o c ol 
r e q uir e m e nts. ...................................................................................................................................................... 2 4
3. 1. 2 
S u bj e ct h as gi v e n v ol u nt ar y si g n e d writt e n i nf or m e d c o ns e nt b ef or e p erf or m a n c e of a n y st u d y-
r el at e d pr o c e d ur e t h at is n ot p art of n or m al m e di c al c ar e, wit h t h e u n d erst a n di n g t h at c o ns e nt m a y b e 
wit h dr a w n b y t h e s u bj e ct at a n y ti m e wit h o ut pr ej u di c e t o t h eir f ut ur e m e di c al c ar e..................................... 2 4
3. 1. 3 
E ast er n C o o p er ati v e O n c ol o g y Gr o u p ( E C O G) p erf or m a n c e st at us  2 (s e e A p p e n di x 1).............. 2 4
3. 1. 4 
S u bj e ct is a c a n di d at e f or hi g h- d os e t h er a p y a n d a ut ol o g o us S C T b as e d o n st a n d ar d crit eri a at t h e 
i nstit uti o n w h er e t his tr e at m e nt will b e a d mi nist er e d....................................................................................... 2 4
3. 1. 5..................................................................................................................................................................... 2 4

S er u m I g G, I g A, or I g M M- pr ot ei n ≥ 0. 5 g/ d L, or.................................................................................. 2 5

S er u m I g D M- pr ot ei n ≥ 0. 0 5 g/ d L, or...................................................................................................... 2 5

Uri n ar y M- pr ot ei n e x cr eti o n of m or e t h a n 2 0 0 m g/ 2 4 h o urs, or ............................................................ 2 5

Ser u m free li g ht c hai ns of at least 1 0 0 m g/ L wit h a n a b n or mal F L C rati o............................................... 2 5
3. 1. 7 
S u bj e ct a gr e es t o r efr ai n fr o m bl o o d d o n ati o ns d uri n g t h er a p y o n st u d y a n d f or 8 w e e ks aft er 
t h er a p y is c o m pl et e d........................................................................................................................................... 2 5
3. 1. 8  
M e n a n d w o m e n, a g e ≥ 1 8 y e ars or l e g al a g e of c o ns e nt p er l o c al r e g ul ati o ns ( w hi c h e v er is 
gr e at er). 2 5
3. 1. 9 
F e m al es of c hil d b e ari n g p ot e nti al ( F C B P) † m ust h a v e a n e g ati v e s er u m or uri n e pr e g n a n c y t est 
wit h a s e nsiti vit y of at l e ast 5 0 mI U/ m L wit hi n 1 0 – 1 4 d a ys pri or t o a n d a g ai n wit hi n 2 4 h o urs of st arti n g 

9 9
S h ort title: P h ase II st u d y of El ot uz u m a b pl us R V D i n Ne wl y Di a g n ose d M M
 Versi o n D ate:       Fe br u ar y 6, 2 0 1 9
C O N FI D E N TI A L
T his d oc u me nt is c o nfi de ntial. D o n ot discl ose or use e xce pt as a ut h orize d.
L e n ali d o mi d e a n d m ust eit h er c o m mit t o c o nti n u e d a bsti n e n c e fr o m h et er os e x u al i nt er c o urs e or b e gi n T W O 
a c c e pt a bl e m et h o ds of birt h c o ntr ol, o n e hi g hl y eff e cti v e m et h o d a n d o n e a d diti o n al eff e cti v e m et h o d A T 
T H E S A M E TI M E, at l e ast 2 8 d a ys b ef or e s h e st arts t a ki n g L e n ali d o mi d e t hr o u g h 9 0 d a ys aft er t h e l ast 
d os e of st u d y dr u g.  F C B P m ust als o a gr e e t o o n g oi n g pr e g n a n c y t esti n g.  M e n m ust a gr e e t o us e a l at e x 
c o n d o m d uri n g s e x u al c o nt a ct wit h a F C B P e v e n if t h e y h a v e h a d a v as e ct o m y fr o m t h e ti m e of si g ni n g t h e 
i nf or m e d c o ns e nt f or m t hr o u g h 9 0 d a ys aft er t h e l ast d os e of st u d y dr u g.  All p ati e nts m ust b e r e gist er e d i n 
a n d m ust c o m pl y wit h all r e q uir e m e nts of t h e R e vli mi d R E M S ™ pr o gr a m................................................... 2 5
3. 2 
E xcl usi o n Criteri a.................................................................................................................................... 2 5
3. 3 
I ncl usi o n of W o me n, Mi n orities a n d Ot her U n derre prese nte d P o p ul ati o ns..................................... 2 7
3. 4 
Scree ni n g Pr oce d ures.............................................................................................................................. 2 7
4 
R E GI S T R A TI O N P R O C E D U R E S................................................................................................................ 2 8
4. 1  
Ge ner al G ui deli nes f or All I nstit uti o ns.................................................................................................. 2 8
4. 2  
Re gistr ati o n Pr ocess ................................................................................................................................ 2 8
4. 2. 1 
Re gistrati o n Pr ocess f or D F/ H C C partici pati n g sites a n d All I nstit uti o ns ........................................... 2 8
5 
T R E A T M E N T P L A N .................................................................................................................................... 2 9
5. 1 
Pre-tre at me nt Criteri a ............................................................................................................................ 3 0
5. 2 
Tre at me nt................................................................................................................................................. 3 1
5. 2. 1 
I n d ucti o n ( C ycles 1 - 8): I n d ucti o n re gi me n will c o nsist of a treat me nt c ycle e ver y 2 1 da ys wit h: .... 3 1
5. 2. 2 
Ste m cell m o bilizati o n:......................................................................................................................... 3 1
5. 2. 3  
Mai nte na nce:......................................................................................................................................... 3 2
5. 2. 4 
T u m or assess me nts:.............................................................................................................................. 3 3
5. 3  
A ge nt A d mi nistr ati o n.............................................................................................................................. 3 3
5. 3. 1 
El ot uz u ma b........................................................................................................................................... 3 3
5. 3. 2 
I n d ucti o n C ycles 1 a n d 2....................................................................................................................... 3 3
5. 3. 3 
I n d ucti o n C ycles 3 – 8.......................................................................................................................... 3 4
5. 3. 4  
Mai nte na nce C ycles.............................................................................................................................. 3 4
5. 3. 5  
Vital Si g ns, P h ysical Meas ure me nts, a n d P h ysical E xa mi nati o n......................................................... 3 4
5. 3. 6 
Perf or ma nce Stat us............................................................................................................................... 3 4
5. 3. 7 
El ot uz u ma b Pre me dicati o n................................................................................................................... 3 5
5. 3. 8  
G ui deli nes f or El ot uz u ma b I nf usi o n i n S u bjects wit h I nf usi o n Reacti o ns........................................... 3 7
5. 4 
Le n ali d o mi de............................................................................................................................................ 3 8
5. 4. 1 
I n d ucti o n C ycles................................................................................................................................... 3 8
5. 4. 2  
Mai nte na nce C ycles.............................................................................................................................. 3 8
5. 4. 3  
A L L C ycles........................................................................................................................................... 3 8
5. 4. 4 
B ortez o mi b............................................................................................................................................ 3 9
5. 4. 5  
De xa met has o ne..................................................................................................................................... 4 0
5. 5  
Ge ner al C o nc o mit a nt Me dic ati o n a n d S u p p orti ve C are G ui deli nes.................................................. 4 1
5. 5. 1 
Re q uire d C o nc o mita nt T hera p y............................................................................................................ 4 1
5. 5. 2 
Rec o m me n de d C o nc o mita nt T hera p y................................................................................................... 4 2
5. 5. 3 
Pr o hi bite d C o nc o mita nt T hera p y.......................................................................................................... 4 3
5. 5. 4 
Per mitte d at I n vesti gat or’s Discreti o n .................................................................................................. 4 3
5. 6  
D ur ati o n of T her a p y................................................................................................................................ 4 4
5. 7 
S ur ger y a n d R a di ati o n............................................................................................................................ 4 5
5. 8  
D ur ati o n of F oll o w U p............................................................................................................................. 4 5
5. 9  
Criteri a f or Re m o v al fr o m St u d y........................................................................................................... 4 5

1 0 0
S h ort title: P h ase II st u d y of El ot uz u m a b pl us R V D i n Ne wl y Di a g n ose d M M
 Versi o n D ate:       Fe br u ar y 6, 2 0 1 9
C O N FI D E N TI A L
T his d oc u me nt is c o nfi de ntial. D o n ot discl ose or use e xce pt as a ut h orize d.
6 
E X P E C T E D T O XI CI TI E S A N D D O SI N G D E L A Y S/ D O S E M O DI FI C A TI O N S...................................... 4 5
6. 1  
A ntici p ate d T o xicities.............................................................................................................................. 4 5
6. 1. 1 
C A E P Rs f or C T E P- S u p plie d I n vesti gati o nal A ge nt(s)........................................................................ 4 6
6. 2 
T o xicit y M a n a ge me nt.............................................................................................................................. 4 7
6. 2. 1 
Per mitte d treat me nt dela ys.................................................................................................................... 4 8
6. 2. 2  
D ose Re d ucti o n Ste ps........................................................................................................................... 4 9
6. 3  
D ose M o dific ati o n/ Del a ys........................................................................................................................ 5 0
6. 3. 1  
Dr u g Relate d A d verse E ve nt D ose M o dificati o n G ui deli nes f or Le nali d o mi de a n d B ortez o mi b  
D uri n g a C ycle. ................................................................................................................................................... 5 0
6. 3. 2  
De xa met has o ne D ose M o dificati o ns.................................................................................................... 5 3
6. 4 
I niti ati o n of Ne w C ycle of E- R V D T her a p y ( D a y 1)............................................................................. 5 3
6. 5 
I niti ati o n of I n d ucti o n C ycle 5 p ost Ste m Cell M o biliz ati o n............................................................... 5 4
7  
D R U G F O R M U L A TI O N A N D A D MI NI S T R A TI O N ................................................................................. 5 5
7. 1 
Le n ali d o mi de ( R E V LI MI D ®)................................................................................................................ 5 5
7. 1. 1  
Descri pti o n............................................................................................................................................ 5 5
7. 1. 2 
F or m...................................................................................................................................................... 5 5
7. 1. 3 
St ora ge a n d Sta bilit y............................................................................................................................. 5 5
7. 1. 4  
Ha n dli n g................................................................................................................................................ 5 5
7. 1. 5  
A vaila bilit y ........................................................................................................................................... 5 5
7. 1. 6  
Or deri n g................................................................................................................................................ 5 6
7. 1. 7  
Acc o u nta bilit y....................................................................................................................................... 5 6
7. 1. 8  
Destr ucti o n a n d Ret ur n......................................................................................................................... 5 6
7. 2 
B ortez o mi b ( V E L C A D E ®)..................................................................................................................... 5 6
7. 2. 1  
Descri pti o n............................................................................................................................................ 5 6
7. 2. 2 
F or m...................................................................................................................................................... 5 6
7. 2. 3 
St ora ge a n d Sta bilit y............................................................................................................................. 5 6
7. 2. 4  
Ha n dli n g................................................................................................................................................ 5 7
7. 2. 5  
A vaila bilit y ........................................................................................................................................... 5 7
7. 2. 6 
Pre parati o n............................................................................................................................................ 5 7
7. 2. 7  
Or deri n g................................................................................................................................................ 5 7
7. 2. 8  
Acc o u nta bilit y....................................................................................................................................... 5 7
7. 3  
De x a met h as o ne ........................................................................................................................................ 5 8
7. 3. 1  
Descri pti o n............................................................................................................................................ 5 8
7. 3. 2  
A vaila bilit y ........................................................................................................................................... 5 8
7. 3. 3  
Or deri n g................................................................................................................................................ 5 8
7. 4 
El ot uz u m a b .............................................................................................................................................. 5 8
7. 4. 1  
Descri pti o n............................................................................................................................................ 5 8
7. 4. 2 
St ora ge a n d Sta bilit y............................................................................................................................. 5 9
7. 4. 3  
A vaila bilit y ........................................................................................................................................... 5 9
7. 4. 4 
Pre parati o n a n d A d mi nistrati o n............................................................................................................ 5 9
7. 4. 5  
Or deri n g................................................................................................................................................ 6 0
7. 4. 6  
Acc o u nta bilit y....................................................................................................................................... 6 0
7. 4. 7  
Destr ucti o n a n d Ret ur n......................................................................................................................... 6 0
8 
C O R R E L A TI V E/ S P E CI A L S T U DI E S.......................................................................................................... 6 1
9 
S T U D Y A S S E S S M E N T S A N D P R O C E D U R E S ......................................................................................... 6 2
T a bl e 9. 1
Fl o w C h art/ Ti m e a n d E v e nt s S c h e d ul e ........................................................................................... 6 2

1 0 1
S h ort title: P h ase II st u d y of El ot uz u m a b pl us R V D i n Ne wl y Di a g n ose d M M
 Versi o n D ate:       Fe br u ar y 6, 2 0 1 9
C O N FI D E N TI A L
T his d oc u me nt is c o nfi de ntial. D o n ot discl ose or use e xce pt as a ut h orize d.
1 0  
M E A S U R E M E N T O F E F F E C T.................................................................................................................... 6 7
1 0. 1  
A ntit u m or Effect – S oli d T u m ors............................................................................................................ 6 7
1 0. 2  
A ntit u m or Effect – He m at ol o gic T u m ors.............................................................................................. 6 7
1 0. 2. 1  
Defi niti o ns........................................................................................................................................ 6 7
1 0. 2. 2  
Disease Para meters .......................................................................................................................... 6 7

S er u m I g G, I g A, or I g M M- pr ot ei n ≥ 0. 5 g/ d L, or.................................................................................. 6 7

S er u m I g D M- pr ot ei n ≥ 0. 0 5 g/ d L ........................................................................................................... 6 7
1 0. 2. 3  
Met h o ds f or E val uati o n of Meas ura ble Disease.............................................................................. 6 7
1 0. 2. 4 
Res p o nse Criteria............................................................................................................................. 6 8
1 0. 2. 5 
Res p o nse Re vie w............................................................................................................................. 7 0
1 0. 3  
Ot her Res p o nse P ar a meters ................................................................................................................... 7 0
1 1  
A D V E R S E E V E N T R E P O R TI N G R E Q UI R E M E N T S................................................................................ 7 0
1 1. 1  
Defi niti o ns................................................................................................................................................. 7 0
1 1. 1. 1  
A d verse E ve nt ( A E)......................................................................................................................... 7 0
1 1. 1. 2 
Seri o us a d verse e ve nt ( S A E)............................................................................................................ 7 0
1 1. 1. 3 
Pre g na nc y......................................................................................................................................... 7 1
1 1. 1. 4 
E ve nts n ot c o nsi dere d t o be seri o us a d verse e ve nts are h os pitalizati o ns f or:.................................. 7 2
1 1. 2 
E x pecte d ness ............................................................................................................................................ 7 3
1 1. 2. 1 
E x pecte d a d verse e ve nt.................................................................................................................... 7 3
1 1. 2. 2  
U ne x pecte d a d verse e ve nt................................................................................................................ 7 3
1 1. 2. 3  
Attri b uti o n........................................................................................................................................ 7 3
1 1. 3 
Pr oce d ures f or A E a n d S A E Rec or di n g a n d Re p orti n g....................................................................... 7 3
1 1. 3. 1 
Re p orti n g Re q uire me nts .................................................................................................................. 7 4
1 1. 3. 2 
Re p orti n g t o Brist ol M yers S q ui b b.................................................................................................. 7 6
1 1. 3. 3 
Re p orti n g t o t he I nstit uti o nal Re vie w B oar d (I R B)......................................................................... 7 6
1 1. 3. 4 
Re p orti n g t o t he F o o d a n d Dr u g A d mi nistrati o n ( F D A).................................................................. 7 6
1 1. 3. 5 
Re p orti n g t o t he NI H Office of Bi otec h n ol o g y Acti vities ( O B A)................................................... 7 7
1 1. 3. 6 
Re p orti n g t o t he I nstit uti o nal Bi osafet y C o m mittee (I B C).............................................................. 7 7
1 1. 3. 7 
Re p orti n g t o H os pital Ris k Ma na ge me nt......................................................................................... 7 7
1 1. 4  
M o nit ori n g of A d verse E ve nts a n d Peri o d of O bser v ati o n.................................................................. 7 7
1 2  
D A T A A N D S A F E T Y M O NI T O RI N G ........................................................................................................ 7 8
1 2. 1  
D at a Re p orti n g......................................................................................................................................... 7 8
1 2. 1. 1  
Met h o d............................................................................................................................................. 7 8
1 2. 2 
T he D F CI C T O will m o nit or a n d m a n a ge t he d at a o n a n o n g oi n g b asis, usi n g a ris k- b ase d 
m o nit ori n g a p pr o ac h t h at i nc or p or ates re m ote d at a re vie w as well as o ne o nsite m o nit ori n g visit per ye ar f or 
sites wit h acti ve p atie nts S afet y Meeti n gs.................................................................................................................. 7 8
1 2. 3  
M o nit ori n g................................................................................................................................................ 7 8
1 3 
R E G U L A T O R Y C O N SI D E R A TI O N S ......................................................................................................... 7 8
1 3. 1 
Pr ot oc ol Re vie w a n d A me n d me nts ........................................................................................................ 7 8
1 3. 2 
I nf or me d C o nse nt.................................................................................................................................... 7 9
1 3. 3 
Et hics......................................................................................................................................................... 7 9
1 3. 4 
St u d y D oc u me nt ati o n.............................................................................................................................. 7 9
1 3. 5  
Rec or ds Rete nti o n.................................................................................................................................... 8 0
1 3. 6  
M ulti-ce nter G ui deli nes........................................................................................................................... 8 0

1 0 2
S h ort title: P h ase II st u d y of El ot uz u m a b pl us R V D i n Ne wl y Di a g n ose d M M
 Versi o n D ate:       Fe br u ar y 6, 2 0 1 9
C O N FI D E N TI A L
T his d oc u me nt is c o nfi de ntial. D o n ot discl ose or use e xce pt as a ut h orize d.
1 3. 7  
C o o per ati ve Rese arc h a n d De vel o p me nt A gree me nt/ Cli nic al Tri als A gree me nt ( C T A)................. 8 0
1 4 
S T A TI S TI C A L C O N SI D E R A TI O N S........................................................................................................... 8 0
1 4. 1 
E n d p oi nts.................................................................................................................................................. 8 0
1 4. 1. 1  
Ori gi nal Pri mar y E n d p oi nt............................................................................................................... 8 0
1 4. 1. 2  
Ori gi nal Sec o n dar y E n d p oi nts......................................................................................................... 8 0
1 4. 1. 3 
E x pl orat or y E n d p oi nts ..................................................................................................................... 8 2
1 4. 2 
S a m ple Size/ Accr u al R ate....................................................................................................................... 8 2
1 4. 3 
Str atific ati o n F act ors............................................................................................................................... 8 2
1 4. 4  
A n al ysis..................................................................................................................................................... 8 3
1 4. 4. 1  
De m o gra p hics a n d Baseli ne C haracteristics.................................................................................... 8 3
1 4. 4. 2 
Efficac y A nal yses ............................................................................................................................ 8 3
1 4. 4. 3 
Safet y A nal yses................................................................................................................................ 8 3
1 4. 4. 4 
P har mac o ki netic A nal yses............................................................................................................... 8 4
1 4. 4. 5 
Bi o mar ker A nal yses......................................................................................................................... 8 4
1 4. 4. 6  
O utc o mes Researc h A nal yses.......................................................................................................... 8 4
1 4. 4. 7  
Ot her A nal yses................................................................................................................................. 8 4
1 4. 4. 8 
I nteri m A nal yses.............................................................................................................................. 8 4
1 5 
P U B LI C A TI O N P L A N.................................................................................................................................. 8 4
1 6 
R E F E R E N C E S............................................................................................................................................... 8 5
1 7  
A P P E N DI C E S................................................................................................................................................ 8 9
A p pe n di x I:  Perf or ma nce Stat us Criteria..................................................................................................................... 8 9
A p pe n di x II:  D u B ois F or m ula f or B o d y S urface Area................................................................................................ 9 0
1D u B ois D, D u B ois E F. A f or m ula t o esti mate t he a p pr o xi mate s urface area if hei g ht a n d wei g ht be k n o w n. Arc h 
I nter n Me dici ne. 1 9 1 6; 1 7: 8 6 3- 7 1................................................................................................................................ 9 0
A p pe n di x III:  T he Ne w Y or k Heart Ass ociati o n Classificati o n of Car diac Disease................................................... 9 1
T he f oll o wi n g ta ble prese nts t he N Y H A classificati o n of car diac disease:.................................................................. 9 1
A p pe n di x I V:   I nter nati o nal M yel o ma F o u n dati o n 2 0 0 3 Dia g n ostic Criteria:............................................................ 9 2
1 7. 1. 1  
A dia g n osis of M M re q uires t hat all t hree of t he f oll o wi n g m ust be met:....................................... 9 2
. 
9 2
A p pe n di x V:  F A C T/ G O G- Ne ur ot o xicit y Q uesti o n naire, Versi o n 4. 0........................................................................ 9 3
A p pe n di x VI 
 Li nes of T hera p y............................................................................................................................. 9 4
A p pe n di x VII 
 Pre parati o n a n d a d mi nistrati o n of el ot uz u ma b ............................................................................... 9 5
A P P E N DI X VIII   Da na- Far ber/ Har var d Ca ncer Ce nter M ulti- Ce nter Data a n d Safet y M o nit ori n g Pla n.................. 9 8
1. 0 
I N T R O D U C TI O N........................................................................................................................................ 1 0 5
1. 1 
P ur p ose................................................................................................................................................... 1 0 5
1. 2  
M ulti- Ce nter D at a a n d S afet y M o nit ori n g Pl a n Defi niti o ns ............................................................. 1 0 5

1 0 3
S h ort title: P h ase II st u d y of El ot uz u m a b pl us R V D i n Ne wl y Di a g n ose d M M
 Versi o n D ate:       Fe br u ar y 6, 2 0 1 9
C O N FI D E N TI A L
T his d oc u me nt is c o nfi de ntial. D o n ot discl ose or use e xce pt as a ut h orize d.
2. 0  
G E N E R A L R O L E S A N D R E S P O N SI BI LI TI E S........................................................................................ 1 0 6
2. 1  
D F/ H C C S p o ns or................................................................................................................................... 1 0 6
2. 2  
C o or di n ati n g Ce nter.............................................................................................................................. 1 0 7
2. 3  
D F/ H C C O D Q a n d M ulti ple M yel o m a Rese arc h C o ns orti u m ( M M R C)......................................... 1 0 7
2. 4 
P artici p ati n g I nstit uti o n........................................................................................................................ 1 0 8
3. 0  
D F/ H C C R E Q UI R E M E N T S F O R M U L TI- C E N T E R P R O T O C O L S........................................................ 1 0 9
3. 1 
Pr ot oc ol Distri b uti o n............................................................................................................................. 1 0 9
3. 2 
Pr ot oc ol Re visi o ns a n d Cl os ures.......................................................................................................... 1 0 9
3. 3 
I nf or me d C o nse nt Re q uire me nts......................................................................................................... 1 1 0
3. 4 
I R B D oc u me nt ati o n............................................................................................................................... 1 1 0
3. 5 
I R B Re- A p pr o v al................................................................................................................................... 1 1 0
3. 6 
P artici p a nt C o nfi de nti alit y a n d A ut h oriz ati o n St ate me nt ................................................................ 1 1 1
3. 6. 1  
D F/ H C C M ulti- Ce nter Pr ot oc ol C o nfi de ntialit y ................................................................................ 1 1 1
3. 7  
D F/ H C C M ulti- Ce nter Pr ot oc ol Re gistr ati o n P olic y ......................................................................... 1 1 1
3. 7. 1 
P artici p a nt Re gistr ati o n........................................................................................................................ 1 1 1
3. 7. 2 
I niti ati o n of T her a p y............................................................................................................................. 1 1 1
3. 7. 3 
Eli gi bilit y E xce pti o ns............................................................................................................................. 1 1 2
3. 7. 4  
Verific ati o n of Re gistr ati o n, D ose Le vels, a n d Ar m Desi g n ati o n...................................................... 1 1 2
3. 8  
D F/ H C C Pr ot oc ol C ase N u m ber.......................................................................................................... 1 1 2
3. 8. 1 
Pr ot oc ol De vi ati o ns, E xce pti o ns a n d Vi ol ati o ns ................................................................................. 1 1 2
3. 8. 2  
Defi niti o ns............................................................................................................................................... 1 1 2
3. 8. 3  
Re p orti n g Pr oce d ures............................................................................................................................ 1 1 3
3. 9 
S afet y Assess me nts a n d T o xicit y M o nit ori n g...................................................................................... 1 1 3
3. 9. 1  
G ui deli nes f or Re p orti n g Seri o us A d verse E ve nts ............................................................................. 1 1 3
3. 9. 2  
G ui deli nes f or Pr ocessi n g I N D S afet y Re p orts................................................................................... 1 1 4
4. 
R E Q UI SI TI O NI N G I N V E S TI G A TI O N A L D R U G.................................................................................... 1 1 4
5.  
M O NI T O RI N G: Q U A LI T Y C O N T R O L..................................................................................................... 1 1 4
5. 1  
O n g oi n g M o nit ori n g of Pr ot oc ol C o m pli a nce..................................................................................... 1 1 4
5. 2  
M o nit ori n g Re p orts............................................................................................................................... 1 1 5
5. 3  
Accr u al M o nit ori n g............................................................................................................................... 1 1 5
6  
A U DI TI N G: Q U A LI T Y A S S U R A N C E...................................................................................................... 1 1 5
6. 1  
A u dit Pl a n: D F/ H C C S p o ns ore d Tri als............................................................................................... 1 1 6
6. 2  
A u dit N otific ati o n.................................................................................................................................. 1 1 6
6. 3  
A u dit Re p orts......................................................................................................................................... 1 1 6
6. 4 
P artici p ati n g I nstit uti o n Perf or m a nce................................................................................................. 1 1 6
6. 4. 1  
C orrecti ve Acti o ns................................................................................................................................. 1 1 6

1 0 4
S h ort title: P h ase II st u d y of El ot uz u m a b pl us R V D i n Ne wl y Di a g n ose d M M
 Versi o n D ate:       Fe br u ar y 6, 2 0 1 9
C O N FI D E N TI A L
T his d oc u me nt is c o nfi de ntial. D o n ot discl ose or use e xce pt as a ut h orize d.

1 0 5
S h ort title: P h ase II st u d y of El ot uz u m a b pl us R V D i n Ne wl y Di a g n ose d M M
 Versi o n D ate:       Fe br u ar y 6, 2 0 1 9
C O N FI D E N TI A L
T his d oc u me nt is c o nfi de ntial. D o n ot discl ose or use e xce pt as a ut h orize d.
1. 0
I N T R O D U C TI O N
T he Da na- Far ber/ Har var d Ca ncer Ce nter M ulti- Ce nter Data a n d Safet y M o nit ori n g Pla n 
( D F/ H C C D S M P) o utli nes t he pr oce d ures f or c o n d ucti n g a D F/ H C C M ulti- Ce nter researc h 
pr ot oc ol. T he D F/ H C C D S M P s h o ul d ser ve as a refere nce f or a n y sites e xter nal t o D F/ H C C 
t hat will be partici pati n g i n t he researc h pr ot oc ol.
1. 1 
P ur p ose
T o esta blis h sta n dar ds t hat will e ns ure t hat a Da na- Far ber/ Har var d Ca ncer Ce nter M ulti-
Ce nter pr ot oc ol will c o m pl y wit h Fe deral Re g ulati o ns, Healt h I ns ura nce P orta bilit y a n d 
Acc o u nta bilit y Act ( HI P A A) re q uire me nts a n d a p plica ble D F/ H C C Sta n dar d O perati n g 
Pr oce d ures. 
1. 2  
M ulti- Ce nter D at a a n d S afet y M o nit ori n g Pl a n  Defi niti o ns
D F/ H C C 
M ulti-ce nter Pr ot oc ol :  A researc h pr ot oc ol i n w hic h o ne  or m ore o utsi de 
i nstit uti o ns are c olla b orati n g wit h Da na- Far ber/ Har var d Ca ncer Ce nter w here  a D F/ H C C 
i n vesti gat or is t he s p o ns or. D F/ H C C i ncl u des Da na- Far ber/ Part ners Ca ncer Care ( D F/ P C C) 
Net w or k Cli nical Trial Affiliates. 
Le a d I nstit uti o n:  O ne of t he  Da na- Far ber/ Har var d Ca ncer Ce nter c o ns orti u m me m bers 
( Da na- Far ber Ca ncer I nstit ute ( D F CI), Massac h usetts Ge neral H os pital ( M G H), Bet h Israel 
Deac o ness Me dical Ce nter ( BI D M C), C hil dre n’s H os pital B ost o n ( C H B), Bri g ha m a n d 
W o me n’s H os pital ( B W H)) res p o nsi ble f or t he c o or di nati o n, de vel o p me nt, s u b missi o n, a n d 
a p pr o val of a pr ot oc ol as well as its s u bse q ue nt a me n d me nts per t he D F CI I R B a n d a p plica ble 
re g ulat or y g ui deli nes ( F o o d a n d Dr u g A d mi nistrati o n ( F D A),  etc.).  T he Lea d I nstit uti o n is 
t y picall y t he h o me of t he D F/ H C C S p o ns or. T he Lea d I nstit uti o n als o t y picall y ser ves as t he 
C o or di nati n g Ce nter f or t he D F/ H C C M ulti- Ce nter Pr ot oc ol.  
D F/ H C C S p o ns or:  T he  pers o n s p o ns ori n g t he s u b mitte d M ulti- Ce nter pr ot oc ol.  Wit hi n 
D F/ H C C, t his pers o n is t he O verall Pri nci pal I n vesti gat or w h o ta kes res p o nsi bilit y f or 
i nitiati o n, ma na ge me nt a n d c o n d uct of t he pr ot oc ol at all researc h l ocati o ns. I n a p plica ble 
pr ot oc ols, t he D F/ H C C S p o ns or will ser ve as t he si n gle liais o n wit h a n y re g ulat or y a ge ncies 
( F D A). T he D F/ H C C S p o ns or has ulti mate a ut h orit y o ver t he pr ot oc ol a n d is res p o nsi ble f or 
t he c o n d uct of t he st u d y at D F/ H C C a n d all Partici pati n g I nstit uti o ns. I n m ost cases t he 
D F/ H C C S p o ns or is t he sa me pers o n as t he D F/ H C C Pri nci pal I n vesti gat or; h o we ver, b ot h 
r oles ca n be fille d b y t w o differe nt pe o ple. 
P artici p ati n g I nstit uti o n:  A n i nstit uti o n t hat is o utsi de t he D F/ H C C a n d D F/ P C C 
c o ns orti u m t hat is c olla b orati n g wit h D F/ H C C o n a pr ot oc ol w here t he s p o ns or is a D F/ H C C 
I n vesti gat or.  T he Partici pati n g I nstit uti o n ac k n o wle d ges t he D F/ H C C S p o ns or as ha vi n g t he 
ulti mate a ut h orit y a n d res p o nsi bilit y f or t he o verall c o n d uct of t he st u d y.   
C o or di n ati n g Ce nter: T he e ntit y (i.e. Lea d I nstit uti o n, Me dical M o nit or, C o ntract Researc h 

1 0 6
S h ort title: P h ase II st u d y of El ot uz u m a b pl us R V D i n Ne wl y Di a g n ose d M M
 Versi o n D ate:       Fe br u ar y 6, 2 0 1 9
C O N FI D E N TI A L
T his d oc u me nt is c o nfi de ntial. D o n ot discl ose or use e xce pt as a ut h orize d.
Or ga nizati o n ( C R O), t hat pr o vi des a d mi nistrati ve s u p p ort t o t he D F/ H C C S p o ns or i n or der 
t hat he/s he ma y f ulfill t he res p o nsi bilities o utli ne d i n t he pr ot oc ol d oc u me nt a n d D S M P, a n d 
as s pecifie d i n a p plica ble re g ulat or y g ui deli nes . I n ge neral, t he Lea d I nstit uti o n is t he 
C o or di nati n g Ce nter f or t he D F/ H C C M ulti- Ce nter Pr ot oc ol. S h o ul d t he D F/ H C C S p o ns or 
deci de t o use a C R O, t he C R O will be dee me d t he C o or di nati n g Ce nter.  
D F/ H C C 
Q u alit y Ass ur a nce 
Office f or Cli nic al Tri als: A gr o u p wit hi n D F/ H C C 
res p o nsi ble f or re gisteri n g h u ma n s u bjects f or trials, e ns uri n g hi g h- q ualit y sta n dar ds are use d 
f or data c ollecti o n a n d t he o n g oi n g ma na ge me nt of cli nical trials, a u diti n g, a n d data a n d 
safet y m o nit ori n g. O D Q als o c o or di nates q ualit y ass ura nce eff orts relate d t o m ulti-ce nter 
cli nical researc h.
2. 0  
G E N E R A L R O L E S A N D R E S P O N SI BI LI TI E S
F or D F/ H C C M ulti- Ce nter Pr ot oc ols, t he D F/ H C C S p o ns or, t he C o or di nati n g Ce nter, a n d 
t he Partici pati n g I nstit uti o ns are e x pecte d t o a d here t o t he f oll o wi n g ge neral res p o nsi bilities: 
2. 1
D F/ H C C S p o ns or
T he D F/ H C C S p o ns or, Jac o b La u bac h  will acce pt res p o nsi bilit y f or all as pects of c o n d ucti n g 
a D F/ H C C M ulti- Ce nter pr ot oc ol w hic h i ncl u des b ut is n ot li mite d t o: 

O versee t he c o or di nati o n, de vel o p me nt, s u b missi o n, a n d a p pr o val of t he pr ot oc ol as 
well as s u bse q ue nt a me n d me nts. 

E ns ure t hat t he i n vesti gat ors, st u d y tea m me m bers, a n d Partici pati n g I nstit uti o ns are 
q ualifie d a n d a p pr o priatel y res o urce d t o c o n d uct t he pr ot oc ol.  

S u b mit t he M ulti- Ce nter Data a n d Safet y M o nit ori n g Pla n as a n a p pe n di x t o t he 
pr ot oc ol.

Ass ure all Partici pati n g I nstit uti o ns are usi n g t he c orrect versi o n of t he pr ot oc ol.

E ns ure t hat eac h partici pati n g i n vesti gat or a n d st u d y tea m recei ves a de q uate 
pr ot oc ol trai ni n g a n d/ or a Site I nitiati o n Visit pri or t o e nr olli n g partici pa nts a n d 
t hr o u g h o ut trial’s c o n d uct as nee de d.

E ns ure t he pr ot oc ol will be pr o vi de d t o eac h partici pati n g site i n a la n g ua ge 
u n dersta n da ble t o all site pers o n nel w he n E n glis h is n ot t he pri mar y la n g ua ge. 

M o nit or pr o gress a n d o verall c o n d uct of t he st u d y at all Partici pati n g I nstit uti o ns. 

E ns ure all D F CI I nstit uti o nal Re vie w B oar d (I R B), D F/ H C C a n d ot her a p plica ble 
(i.e.  F D A) re p orti n g re q uire me nts are met. 

Re vie w data a n d mai ntai n ti mel y s u b missi o n of data f or st u d y a nal ysis. 

Act as t he si n gle liais o n wit h t he F D A (i n vesti gat or- hel d I N D trials).

E ns ure c o m plia nce wit h all re q uire me nts as set f ort h i n t he C o de of Fe deral 
Re g ulati o ns, a p plica ble D F/ H C C re q uire me nts, HI P A A re q uire me nts, a n d t he 
a p pr o ve d pr ot oc ol.

C o m mit t o t he pr o visi o n t hat t he pr ot oc ol will n ot be re writte n or m o difie d b y 
a n y o ne ot her t ha n t he D F/ H C C S p o ns or.

I de ntif y a n d q ualif y Partici pati n g I nstit uti o ns a n d o btai n accr ual c o m mit me nts pri or 
t o e xte n di n g t he pr ot oc ol t o t hat site. 

1 0 7
S h ort title: P h ase II st u d y of El ot uz u m a b pl us R V D i n Ne wl y Di a g n ose d M M
 Versi o n D ate:       Fe br u ar y 6, 2 0 1 9
C O N FI D E N TI A L
T his d oc u me nt is c o nfi de ntial. D o n ot discl ose or use e xce pt as a ut h orize d.
2. 2
C o or di n ati n g Ce nter 
T he C o or di nati n g Ce nter will ass u me t he f oll o wi n g ge neral res p o nsi bilities:

Assist i n pr ot oc ol de vel o p me nt 

Mai ntai n c o pies of Fe deral Wi de Ass ura nce a n d I nstit uti o nal Re vie w B oar d (I R B) 
a p pr o vals fr o m all Partici pati n g I nstit uti o ns.

Mai ntai n F D A c orres p o n de nce, as a p plica ble.

Mai ntai n u p date d r oster of partici pa nts. 

Verif y eli gi bilit y.

Verif y res p o nse.

O versee t he data c ollecti o n pr ocess fr o m Partici pati n g I nstit uti o ns.

Mai ntai n d oc u me ntati o n of Seri o us A d verse E ve nt ( S A E) re p orts s u b mitte d b y 
Partici pati n g I nstit uti o ns a n d s u b mit t o D F/ H C C S p o ns or f or ti mel y re vie w.  

Distri b ute a d verse e ve nts re p orte d t o t he D F/ H C C S p o ns or t hat fall u n der t he D F CI 
I R B A d verse E ve nt Re p orti n g P olic y t o all partici pati n g i n vesti gat ors.

Pr o vi de Partici pati n g I nstit uti o ns wit h i nf or mati o n re gar di n g D F/ H C C re q uire me nts 
t hat t he y will be e x pecte d t o c o m pl y wit h.

M o nit or Partici pati n g I nstit uti o ns eit her b y o n-site or virt ual m o nit ori n g. 

Mai ntai n Re g ulat or y d oc u me nts of all Partici pati n g I nstit uti o ns. 

C o n d uct re g ular c o m m u nicati o ns wit h all Partici pati n g I nstit uti o ns (c o nfere nce 
calls, e mails, etc). 

Mai ntai n d oc u me ntati o n of all c o m m u nicati o ns.

E ns ure t hat eac h Partici pati n g I nstit uti o n has t he a p pr o priate ass ura nce o n file wit h 
t he Office of H u ma n Researc h Pr otecti o n ( O H R P).    
2. 3
D F/ H C C O D Q a n d M ulti ple M yel o m a Rese arc h C o ns orti u m ( M M R C)
I n a d diti o n t o t he D F/ H C C O D Q S p o ns or assista nce at t he C o or di nati n g Ce nter, t he 
f oll o wi n g s u p p ort ser vices will be dele gate d t o M ulti ple M yel o ma Researc h C o ns orti u m 
( M M R C).
L e a d B usi n ess U nit
O p er ati o n al T as ks  & Ass u m pti o ns                     
Cli n O ps
R e vi e w of fi n al st u d y m at eri als i n cl u di n g st u d y pr ot o c ol, I B, p h ar m a c y 
i nstr u cti o ns, E D C f or ms, a n d pr oj e ct pl a ns b y M M R C Cli ni c al O p er ati o ns 
st aff.    
Cli n O ps
Ki c k Off M e eti n g: I n cl u d es ti m e f or m e eti n g att e n d a n c e a n d 
pr e p ar ati o n.  Ass u m es att e n d a n c e b y Cli ni c al O p er ati o ns, L e g al.

1 0 8
S h ort title: P h ase II st u d y of El ot uz u m a b pl us R V D i n Ne wl y Di a g n ose d M M
 Versi o n D ate:       Fe br u ar y 6, 2 0 1 9
C O N FI D E N TI A L
T his d oc u me nt is c o nfi de ntial. D o n ot discl ose or use e xce pt as a ut h orize d.
Cli n O ps
R e vi e w Dr aft Cli ni c al Pr oj e ct Pl a ns: Ass u m es ti m e t o r e vi e w Pr oj e ct Pl a ns b y 
M M R C Cli ni c al O p er ati o ns.    
Cli n O ps
T e m pl at e C R F R e vi e w b y M M R C Cli ni c al O p er ati o ns.  
L e g al
Sit e I d e ntifi c ati o n: M M R C will pr o vi d e f e asi bilit y s ur v e y t o p ot e nti al M M R C 
sit es a n d c oll at e r es p o ns es. 
L e g al
Cli ni c al Tri al A gr e e m e nts:  Ass u m es M M R F L e g al pr e p ar ati o n of dr aft C T A, 
n e g oti ati n g a n d f a cilit ati n g si g n at ur es.  
Cli n O ps
R e vi e w I nf or m e d C o ns e nt F or ms: M M R C Cli ni c al O p er ati o ns a n d L e g al, if 
r e q uir e d, r e vi e w of t e m pl at e a n d m o difi c ati o ns t o I C F
Cli n O ps
T el e c o nf er e n c es - M o nt hl y m e eti n gs, o n e ( 1) h o ur i n l e n gt h wit h att e n d a n c e 
b y  cli ni c al O p er ati o ns a n d L e g al.        
Cli n O ps
Pr oj e ct M a n a g e m e nt: M M R C st aff t o pr o vi d e o v er all P M s u p p ort t o e ns ur e 
a d h er e n c e t o pr oj e ct pl a ns, ti m eli n es, a n d st u d y q u alit y. M M R C st aff s er v es 
as c e ntr al p oi nt of c o nt a ct f or all M M R C p arti ci p ati n g c e nt ers; o v ers e e 
p erf or m a n c e a n d dir e ctl y i m pl e m e nts a cti o n pl a ns / c o m m u ni c ati o ns t o 
e ns ur e M M R C i nt er n al st u d y st art- u p b e n c h m ar ks ar e m et a n d e nr oll m e nt 
t ar g ets ar e a c hi e v e d.  I niti at es a cti o n pl a ns t o o v er c o m e iss u es / d el a ys at 
sit es or wit h i n d ustr y p art n er.            
Cli n O ps
O n- Sit e Pr oj e ct M a n a g e m e nt a n d S u p p ort b y M M P Ms:  O n-sit e s u p p ort of 
r a pi d c o m pl eti o n of r e vi e w c o m mitt e e s u b missi o n p a c k a g es; dri v es 
b u d g et / C T A fi n ali z ati o n, a n d ess e nti al d o c u m e nt c oll e cti o n. Pr o vi d es 
o n g oi n g, d a y-t o- d a y o v ersi g ht t o assi g n e d st u d y st aff ( C R C, D M et c.) a n d 
s u p p orts r a pi d st u d y e nr oll m e nt t hr o u g h c h art r e vi e ws, p ati e nt D B s e ar c h es, 
a n d p ati e nt a p p oi nt m e nt s c h e d ul es.  C o n d u cts i nt er n al i n v esti g ati o n a n d 
r e p orts o ut c o m es f or iss u es / pr o bl e ms r el at e d t o e nr oll m e nt a g ai nst a c cr u al 
pl a n.
Fi n a n c e
Fi n a n ci al Pr oj e ct M a n a g e m e nt:  I n cl u d es a cti viti es ass o ci at e d wit h i n v oi c e 
pr o c essi n g, b u d g et f or e c asti n g, a n d p eri o di c st u d y fi n a n ci al r e c o n cili ati o n.   
A d mi n
A d mi nistr ati v e S u p p ort: Ass u m es M M R F a d mi nistr ati v e st aff pr o vi d e s u p p ort 
f or all M M R F p ers o n n el i n v ol v e d wit h t h e st u d y
2. 4
P artici p ati n g I nstit uti o n
Eac h Partici pati n g I nstit uti o n is e x pecte d t o c o m pl y wit h all a p plica ble Fe deral Re g ulati o ns 

1 0 9
S h ort title: P h ase II st u d y of El ot uz u m a b pl us R V D i n Ne wl y Di a g n ose d M M
 Versi o n D ate:       Fe br u ar y 6, 2 0 1 9
C O N FI D E N TI A L
T his d oc u me nt is c o nfi de ntial. D o n ot discl ose or use e xce pt as a ut h orize d.
a n d D F/ H C C re q uire me nts, t he pr ot oc ol a n d HI P A A re q uire me nts. All Partici pati n g 
I nstit uti o ns will pr o vi de a list of pers o n nel assi g ne d t o t he r ole f or o versi g ht of data 
ma na ge me nt at t heir site t o t he C o or di nati n g Ce nter. 
T he ge neral res p o nsi bilities f or eac h Partici pati n g I nstit uti o n are as f oll o ws:

C o m mit t o t he accr ual of partici pa nts t o t he pr ot oc ol.

S u b mit pr ot oc ol a n d/ or a me n d me nts t o t heir l ocal I R B.

Mai ntai n a re g ulat or y bi n der i n acc or da nce wit h D F/ H C C re q uire me nts.

Pr o vi de t he C o or di nati n g Ce nter wit h re g ulat or y d oc u me nts as re q ueste d.

Partici pate i n pr ot oc ol trai ni n g pri or t o e nr olli n g partici pa nts a n d t hr o u g h o ut t he trial 
as nee de d (i.e. telec o nfere nces).

U p date C o or di nati n g Ce nter wit h researc h staff c ha n ges o n a ti mel y basis.

Re gister partici pa nts t hr o u g h t he C o or di nati n g Ce nter. 

S u b mit s o urce d oc u me nts, researc h rec or ds, a n d C R Fs per pr ot oc ol s pecific 
s u b missi o n g ui deli nes t o t he C o or di nati n g Ce nter.

S u b mit Seri o us A d verse E ve nt ( S A E) re p orts t o l ocal I R B per l ocal re q uire me nts 
a n d t o t he C o or di nati n g Ce nter, i n acc or da nce wit h D F/ H C C re q uire me nts.

S u b mit pr ot oc ol de viati o ns a n d vi olati o ns t o l ocal I R B per l ocal re q uire me nts a n d 
t o t he D F/ H C C S p o ns or i n acc or da nce wit h D F/ H C C re q uire me nts.

Sec ure a n d st ore i n vesti gati o nal a ge nts a n d/ or ot her pr ot oc ol ma n date d dr u gs per 
fe deral g ui deli nes a n d pr ot oc ol re q uire me nts.

Ha ve office s pace, office e q ui p me nt, a n d i nter net access t hat meet HI P A A sta n dar ds.
F or pr ot oc ols usi n g i n vesti gati o nal a ge nts, t he Partici pati n g I nstit uti o n will or der t heir o w n 
i n vesti gati o nal a ge nts. 
3. 0
D F/ H C C R E Q UI R E M E N T S F O R M U L TI- C E N T E R P R O T O C O L S
 
T he f oll o wi n g secti o n will clarif y D F/ H C C Re q uire me nts a n d f urt her detail t he e x pectati o ns 
f or partici pati n g i n a D F/ H C C M ulti- Ce nter pr ot oc ol. 
3. 1 
Pr ot oc ol Distri b uti o n
T he C o or di nati n g Ce nter will distri b ute t he fi nal D F CI I R B a p pr o ve d pr ot oc ol a n d a n y 
s u bse q ue nt a me n de d pr ot oc ols t o all Partici pati n g I nstit uti o ns.   
3. 2 
Pr ot oc ol Re visi o ns a n d Cl os ures
T he Partici pati n g I nstit uti o ns will recei ve n otificati o n of pr ot oc ol re visi o ns a n d cl os ures fr o m 
t he C o or di nati n g Ce nter.  It is t he i n di vi d ual Partici pati n g I nstit uti o n’s res p o nsi bilit y t o 
n otif y its I R B of t hese re visi o ns.

N o n life-t hre ate ni n g re visi o ns:  Partici pati n g I nstit uti o ns will recei ve writte n 
n otificati o n of pr ot oc ol re visi o ns re gar di n g n o n life-t hreate ni n g e ve nts fr o m t he 
C o or di nati n g Ce nter. N o n-life-t hreate ni n g pr ot oc ol re visi o ns m ust be I R B a p pr o ve d 
a n d i m ple me nte d wit hi n 9 0 da ys fr o m recei pt of t he n otificati o n.

1 1 0
S h ort title: P h ase II st u d y of El ot uz u m a b pl us R V D i n Ne wl y Di a g n ose d M M
 Versi o n D ate:       Fe br u ar y 6, 2 0 1 9
C O N FI D E N TI A L
T his d oc u me nt is c o nfi de ntial. D o n ot discl ose or use e xce pt as a ut h orize d.

Re visi o ns f or life-t hre ate ni n g c a uses:  Partici pati n g I nstit uti o ns will recei ve 
i m me diate n otificati o n fr o m t he C o or di nati n g Ce nter c o ncer ni n g pr ot oc ol re visi o ns 
re q uire d t o pr otect li ves wit h f oll o w- u p b y fa x, mail, e- mail, etc.  Life-t hreate ni n g 
pr ot oc ol re visi o ns will be i m ple me nte d i m me diatel y f oll o we d b y I R B re q uest f or 
a p pr o val.

Pr ot oc ol cl os ures a n d te m p or ar y h ol ds:  Partici pati n g I nstit uti o ns will recei ve 
n otificati o n of pr ot oc ol cl os ures a n d te m p orar y h ol ds fr o m t he C o or di nati n g Ce nter. 
Cl os ures a n d h ol ds will be effecti ve i m me diatel y.  I n a d diti o n, t he C o or di nati n g 
Ce nter, will u p date t he Partici pati n g I nstit uti o ns o n a n o n g oi n g basis a b o ut pr ot oc ol 
accr ual data s o t hat t he y will be a ware of i m mi ne nt pr ot oc ol cl os ures.
3. 3 
I nf or me d C o nse nt Re q uire me nts
T he D F/ H C C a p pr o ve d i nf or me d c o nse nt d oc u me nt will ser ve as a te m plate f or t he i nf or me d 
c o nse nt f or Partici pati n g I nstit uti o ns. T he Partici pati n g I nstit uti o n c o nse nt f or m m ust f oll o w 
t he c o nse nt te m plate as cl osel y as p ossi ble a n d s h o ul d a d here t o s pecificati o ns o utli ne d i n 
t he D F/ H C C G ui da nce D oc u me nt o n M o del C o nse nt La n g ua ge f or PI-I nitiate d M ulti- Ce nter 
Pr ot oc ols.  T his d oc u me nt will be pr o vi de d se paratel y t o eac h Partici pati n g I nstit uti o n.
Partici pati n g I nstit uti o ns are t o se n d t heir versi o n of t he i nf or me d c o nse nt d oc u me nt a n d 
HI P A A a ut h orizati o n, if a se parate d oc u me nt, t o t he C o or di nati n g Ce nter f or re vie w a n d 
a p pr o val pri or t o s u b missi o n t o t heir l ocal I R B. T he a p pr o ve d c o nse nt f or m m ust als o be 
s u b mitte d t o t he C o or di nati n g Ce nter after a p pr o val b y t he l ocal I R B.
T he Pri nci pal I n vesti gat or ( PI) at eac h Partici pati n g I nstit uti o n will i de ntif y t he p h ysicia n 
me m bers of t he st u d y tea m w h o will be o btai ni n g c o nse nt a n d si g ni n g t he c o nse nt f or m f or 
t hera pe utic pr ot oc ols. Partici pati n g i nstit uti o ns m ust f oll o w t he D F/ H C C re q uire me nt t hat 
o nl y atte n di n g p h ysicia ns o btai n i nf or me d c o nse nt a n d re-c o nse nt t o i nter ve nti o nal trials (i.e. 
dr u g a n d/ or de vice trials).   
3. 4 
I R B D oc u me nt ati o n
T he f oll o wi n g m ust be o n file wit h t he D F/ H C C Lea d I nstit uti o n or desi g nee a n d m ust be 
s u b mitte d a n d a p pr o ve d b y t he D F CI I R B pri or t o partici pa nt re gistrati o n:

A p pr o val letter of t he Partici pati n g I nstit uti o n's I R B 

C o p y of t he I nf or me d C o nse nt F or m a p pr o ve d b y t he Partici pati n g I nstit uti o n’s I R B 

Partici pati n g I R B’s a p pr o val f or all a me n d me nts

A n n ual a p pr o val letters b y t he Partici pati n g I nstit uti o n's I R B.
3. 5 
I R B Re- A p pr o v al
Verificati o n of I R B re-a p pr o val fr o m t he Partici pati n g I nstit uti o ns is re q uire d i n or der t o 
c o nti n ue researc h acti vities.  T here is n o grace peri o d f or c o nti n ui n g a p pr o vals.

1 1 1
S h ort title: P h ase II st u d y of El ot uz u m a b pl us R V D i n Ne wl y Di a g n ose d M M
 Versi o n D ate:       Fe br u ar y 6, 2 0 1 9
C O N FI D E N TI A L
T his d oc u me nt is c o nfi de ntial. D o n ot discl ose or use e xce pt as a ut h orize d.
T he C o or di nati n g Ce nter will n ot re gister partici pa nts if a re-a p pr o val letter is n ot recei ve d 
fr o m t he Partici pati n g I nstit uti o n o n or bef ore t he a n ni versar y of t he pre vi o us a p pr o val date.  
3. 6 
P artici p a nt C o nfi de nti alit y a n d A ut h oriz ati o n St ate me nt
I n 1 9 9 6, c o n gress passe d t he first fe deral la w c o veri n g t he pri vac y of healt h i nf or mati o n 
k n o w n as t he Healt h I ns ura nce P orta bilit y a n d 
Acc o u nta bilit y 
Act ( HI P A A). 
A n y 
i nf or mati o n, relate d t o t he p h ysical or me ntal healt h of a n i n di vi d ual is calle d Pr otecte d 
Healt h I nf or mati o n ( P HI). HI P A A o utli nes h o w a n d u n der w hat circ u msta nces P HI ca n be 
use d or discl ose d. 
I n or der f or c o vere d e ntities t o use or discl ose pr otecte d healt h i nf or mati o n d uri n g t he c o urse 
of a st u d y, t he st u d y partici pa nt m ust si g n a n A ut h orizati o n.  T his A ut h orizati o n ma y or ma y 
n ot be se parate fr o m t he i nf or me d c o nse nt d oc u me nt.  T he C o or di nati n g Ce nter, wit h t he 
a p pr o val fr o m t he D F CI I R B, will pr o vi de a c o nse nt te m plate, w hic h c o vere d e ntities 
( D F/ H C C M ulti- Ce nter Pr ot oc ol Partici pati n g I nstit uti o ns) m ust use. 
T he D F/ H C C S p o ns or will use all eff orts t o li mit its use of pr otecte d healt h i nf or mati o n i n 
its trials.  H o we ver, beca use of t he nat ure of t hese trials, certai n pr otecte d healt h i nf or mati o n 
m ust be c ollecte d per N CI re q uire me nts. T hese are t he pri mar y reas o ns w h y D F/ H C C has 
c h ose n t o use A ut h orizati o ns, si g ne d b y t he partici pa nt i n t he trial, rat her t ha n li mite d data 
sets wit h data use a gree me nts.
3. 6. 1  D F/ H C C M ulti- Ce nter Pr ot oc ol C o nfi de nti alit y
All d oc u me nts, i n vesti gati ve re p orts, or i nf or mati o n relati n g t o t he partici pa nt are strictl y 
c o nfi de ntial. W he ne ver reas o na bl y feasi ble, a n y partici pa nt s pecific re p orts (i.e. Pat h ol o g y 
Re p orts, M RI Re p orts, O perati ve Re p orts, etc.) s u b mitte d t o t he C o or di nati n g Ce nter m ust 
ha ve t he partici pa nt’s f ull na me & s ocial sec urit y n u m ber “ blac ke d o ut” a n d t he assi g ne d 
D F/ H C C O D Q case n u m ber (as descri be d bel o w) a n d D F/ H C C pr ot oc ol n u m ber writte n i n 
( wit h t he e xce pti o n of t he si g ne d i nf or me d c o nse nt d oc u me nt). Partici pa nt i nitials ma y o nl y 
be i ncl u de d or retai ne d f or cr oss verificati o n of i de ntificati o n
3. 7  
D F/ H C C M ulti- Ce nter Pr ot oc ol Re gistr ati o n P olic y
 
3. 7. 1
P artici p a nt Re gistr ati o n 
Partici pa nt re gistrati o n is c o m plete d t hr o u g h O D Q b y t he Lea d I nstit uti o n.  Please refer t o 
Secti o n 4. 0 Re gistrati o n Pr oce d ures i n t he pr ot oc ol f or i nf or mati o n re gar di n g partici pa nt 
re gistrati o n. 
3. 7. 2 I niti ati o n of T her a p y

1 1 2
S h ort title: P h ase II st u d y of El ot uz u m a b pl us R V D i n Ne wl y Di a g n ose d M M
 Versi o n D ate:       Fe br u ar y 6, 2 0 1 9
C O N FI D E N TI A L
T his d oc u me nt is c o nfi de ntial. D o n ot discl ose or use e xce pt as a ut h orize d.
Partici pa nts 
m ust be re gistere d wit h t he D F/ H C C O D Q bef ore recei vi n g treat me nt.  
Treat me nt ma y n ot be i nitiate d u ntil t he Partici pati n g I nstit uti o n recei ves a fa xe d or e- maile d 
c o p y of t he partici pa nt’s re gistrati o n c o nfir mati o n me m o fr o m t he C o or di nati n g Ce nter. 
T hera p y m ust be i nitiate d per pr ot oc ol g ui deli nes.  T he D F/ H C C S p o ns or a n d D F CI I R B 
m ust be n otifie d of a n y e xce pti o ns t o t his p olic y.
3. 7. 3
Eli gi bilit y E xce pti o ns
T he D F/ H C C O D Q will ma ke n o e xce pti o ns t o t he eli gi bilit y re q uire me nts f or a pr ot oc ol 
wit h o ut D F CI I R B a p pr o val. T he D F/ H C C O D Q re q uires eac h i nstit uti o n t o f ull y c o m pl y 
wit h t his re q uire me nt.
3. 7. 4
Verific ati o n of Re gistr ati o n, D ose Le vels, a n d Ar m Desi g n ati o n
A re gistrati o n c o nfir mati o n me m o f or partici pa nts re gistere d t o D F/ H C C 
M ulti- Ce nter 
Pr ot oc ol will be fa xe d or e maile d t o t he re gisteri n g i nstit uti o n wit hi n o ne b usi ness da y of t he 
re gistrati o n.
  Treat me nt ma y n ot be i nitiate d u ntil t he site recei ves a fa xe d or e- maile d c o p y of t he   
re gistrati o n c o nfir mati o n me m o.                    
 
3. 8  
D F/ H C C Pr ot oc ol C ase N u m ber
O nce eli gi bilit y has bee n esta blis he d a n d t he partici pa nt s uccessf ull y re gistere d, t he 
partici pa nt is assi g ne d a fi ve di git pr ot oc ol case n u m ber.  T his n u m ber is u ni q ue t o t he 
partici pa nt o n t his trial a n d 
m ust be use d f or 
O D Q 
C R F/e C R F c o m pleti o n a n d 
c orres p o n de nce, a n d c orres p o n de nce wit h t he C o or di nati n g Ce nter.  
3. 8. 1
Pr ot oc ol De vi ati o ns, E xce pti o ns a n d Vi ol ati o ns
Fe deral Re g ulati o ns re q uire a n I R B t o re vie w pr o p ose d c ha n ges i n a researc h acti vit y t o 
e ns ure t hat researc hers d o n ot i nitiate c ha n ges i n a p pr o ve d researc h wit h o ut I R B re vie w a n d 
a p pr o val, e xce pt w he n necessar y t o eli mi nate a p pare nt i m me diate hazar ds t o t he partici pa nt. 
D F/ H C C re q uires all de part ures fr o m t he defi ne d pr oce d ures set f ort h i n t he I R B a p pr o ve d 
pr ot oc ol t o be re p orte d t o t he D F/ H C C S p o ns or, w h o i n t ur n is res p o nsi ble f or re p orti n g t o 
t he D F CI I R B.
F or re p orti n g p ur p oses, D F/ H C C uses t he ter ms “ vi olati o n”, “ de viati o n” a n d “e xce pti o n” t o 
descri be deri vati o ns fr o m a pr ot oc ol. All Partici pati n g I nstit uti o ns m ust a d here t o t hese 
re q uire me nts f or re p orti n g t o t he D F/ H C C S p o ns or a n d will f oll o w t heir i nstit uti o nal p olic y 
f or re p orti n g t o t heir l ocal I R B.
3. 8. 2
Defi niti o ns
Pr ot oc ol De viati o n: A n y de part ure fr o m t he defi ne d pr oce d ures set f ort h i n t he I R B-a p pr o ve d 
pr ot oc ol w hic h is pr os pectively a p pr ove d  pri or t o its i m ple me ntati o n.

1 1 3
S h ort title: P h ase II st u d y of El ot uz u m a b pl us R V D i n Ne wl y Di a g n ose d M M
 Versi o n D ate:       Fe br u ar y 6, 2 0 1 9
C O N FI D E N TI A L
T his d oc u me nt is c o nfi de ntial. D o n ot discl ose or use e xce pt as a ut h orize d.
Pr ot oc ol E xce pti o n:  A n y pr ot oc ol de viati o n t hat relates t o t he eli gi bilit y criteria, e. g.
e nr oll me nt of a partici pa nt w h o d oes n ot meet all i ncl usi o n/e xcl usi o n criteria.
Pr ot oc ol Vi olati o n: A n y pr ot oc ol de viati o n t hat was n ot pr os pectively a p pr ove d  b y t he I R B 
pri or t o its i nitiati o n or i m ple me ntati o n. 
3. 8. 3  Re p orti n g Pr oce d ures
D F/ H C C S p o ns or: is res p o nsi ble f or e ns uri n g t hat clear d oc u me ntati o n is a vaila ble i n t he 
me dical rec or d a n d/ or re g ulat or y d oc u me nts t o descri be all pr ot oc ol e xce pti o ns, de viati o ns 
a n d vi olati o ns. T he D F/ H C C S p o ns or will als o be res p o nsi ble f or e ns uri n g t hat all pr ot oc ol 
vi olati o ns/ de viati o ns are pr o m ptl y re p orte d per D F CI I R B g ui deli nes. 
Partici pati n g I nstit uti o ns: Pr ot oc ol de viati o ns re q uire pr os pecti ve a p pr o val fr o m t he D F CI 
I R B. T he Partici pati n g I nstit uti o n m ust s u b mit t he de viati o n re q uest t o t he C o or di nati n g 
Ce nter w h o will t he n s u b mit t he de viati o n re q uest t o t he D F CI I R B. U p o n D F CI I R B 
a p pr o val t he de viati o n is s u b mitte d t o t he Partici pati n g I nstit uti o n I R B, per i nstit uti o nal 
p olic y. A c o p y of t he Partici pati n g I nstit uti o n’s I R B re p ort a n d deter mi nati o n will be 
f or war de d t o t he C o or di nati n g Ce nter wit hi n 1 0 b usi ness da ys after t he ori gi nal s u b missi o n. 
All pr ot oc ol vi olati o ns m ust be se nt t o t he C o or di nati n g Ce nter i n a ti mel y ma n ner. 
C o or di nati n g Ce nter:  U p o n recei pt of t he vi olati o n/ de viati o n re p ort fr o m t he Partici pati n g 
I nstit uti o n, t he C o or di nati n g Ce nter will s u b mit t he re p ort t o t he D F/ H C C S p o ns or f or 
re vie w. S u bse q ue ntl y, t he Partici pati n g I nstit uti o n’s I R B vi olati o n/ de viati o n re p ort will be 
s u b mitte d t o t he D F CI I R B f or re vie w per D F CI I R B re p orti n g g ui deli nes. 
3. 9    S afet y Assess me nts a n d T o xicit y M o nit ori n g
T he st u d y tea ms at all partici pati n g i nstit uti o ns are res p o nsi ble f or pr otecti n g t he safet y, 
ri g hts a n d well- bei n g of st u d y partici pa nts. Rec or di n g a n d re p orti n g of a d verse e ve nts t hat 
occ ur d uri n g t he c o urse of a st u d y hel p e ns ure t he c o nti n ui n g safet y of st u d y partici pa nts. 
All partici pa nts recei vi n g i n vesti gati o nal a ge nts a n d/ or ot her pr ot oc ol ma n date d treat me nt 
will be e val uate d f or safet y.   T he safet y para meters i ncl u de all la b orat or y tests a n d 
he mat ol o gical a b n or malities, p h ysical e xa mi nati o n fi n di n gs, a n d s p o nta ne o us re p orts of 
a d verse e ve nts re p orte d b y partici pa nts.  All t o xicities e nc o u ntere d d uri n g t he st u d y will be 
e val uate d acc or di n g t o t he N CI criteria s pecifie d i n t he pr ot oc ol. Life-t hreate ni n g t o xicities 
m ust be re p orte d i m me diatel y t o t he D F/ H C C S p o ns or via t he C o or di nati n g Ce nter. 
A d diti o nal safet y assess me nts a n d t o xicit y m o nit ori n g will be o utli ne d i n t he pr ot oc ol.
3. 9. 1
G ui deli nes f or Re p orti n g Seri o us A d verse E ve nts 
G ui deli nes f or re p orti n g A d verse E ve nts ( A Es) a n d Seri o us A d verse E ve nts ( S A Es) are 
detaile d i n pr ot oc ol secti o n 1 1.

1 1 4
S h ort title: P h ase II st u d y of El ot uz u m a b pl us R V D i n Ne wl y Di a g n ose d M M
 Versi o n D ate:       Fe br u ar y 6, 2 0 1 9
C O N FI D E N TI A L
T his d oc u me nt is c o nfi de ntial. D o n ot discl ose or use e xce pt as a ut h orize d.
Partici pati n g I nstit uti o ns m ust re p ort t he A Es t o t he D F/ H C C S p o ns or a n d t he C o or di nati n g 
Ce nter f oll o wi n g t he D F CI I R B S A E Re p orti n g Re q uire me nts. 
T he C o or di nati n g Ce nter will 
mai ntai n d oc u me ntati o n of all Partici pati n g I nstit uti o n 
A d verse E ve nt re p orts a n d be res p o nsi ble f or c o m m u nicati n g t o all partici pati n g 
i n vesti gat ors, a n y o bser vati o ns re p orta ble u n der t he D F CI I R B Re p orti n g Re q uire me nts.  
Partici pati n g I n vesti gat ors will re vie w a n y distri b ute d A E re p orts, se n d a c o p y t o t heir I R B 
acc or di n g t o t heir l ocal I R B’s p olicies a n d pr oce d ures, a n d file a c o p y wit h t heir re g ulat or y 
d oc u me nts.
3. 9. 2
G ui deli nes f or Pr ocessi n g I N D S afet y Re p orts 
F D A re g ulati o ns re q uire s p o ns ors of cli nical st u dies t o n otif y t he F D A a n d all partici pati n g 
i n vesti gat ors of a n y a d verse e x perie nce ass ociate d wit h t he use of t he i n vesti gati o nal a ge nt 
t hat is b ot h seri o us a n d u ne x pecte d. T he D F/ H C C S p o ns or will re vie w all I N D Safet y 
Re p orts a n d e ns ure t hat all I N D Safet y Re p orts are distri b ute d t o t he Partici pati n g 
I nstit uti o ns.  
T he Partici pati n g I nstit uti o ns will re vie w a n d s u b mit t o t heir I R B acc or di n g t o t heir 
i nstit uti o nal p olicies a n d pr oce d ures.
4.
R E Q UI SI TI O NI N G I N V E S TI G A TI O N A L D R U G
T he or deri n g of i n vesti gati o nal a ge nt is s pecifie d i n Secti o n 7. 4. 5 of t he pr ot oc ol. 
If t he a ge nt is i n vesti gati o nal, e ns ure t hat t he p har mac y will be a ble t o recei ve a n d st ore t he 
a ge nt acc or di n g t o state a n d fe deral re q uire me nts. T he l ocal I R B s h o ul d be ke pt i nf or me d of 
w h o will s u p pl y t he a ge nt (i.e., N CI or a p har mace utical c o m pa n y) s o t hat a n y re g ulat or y 
res p o nsi bilities ca n be met i n a ti mel y fas hi o n. 
5.
M O NI T O RI N G: Q U A LI T Y C O N T R O L
T he q ualit y c o ntr ol pr ocess f or a cli nical trial re q uires verificati o n of pr ot oc ol c o m plia nce 
a n d data acc urac y. T he C o or di nati n g Ce nter, wit h t he ai d of t he D F CI C T O pr o vi des q ualit y 
c o ntr ol o versi g ht f or t he pr ot oc ol.
5. 1
O n g oi n g M o nit ori n g of Pr ot oc ol C o m pli a nce
Site i nitiati o ns will be c o n d ucte d as eit her a n o n-site visit or via we b telec o nfere nce. 
F oll o wi n g site i nitiati o n,  D F CI C T O will i m ple me nt o n-site as well as virt ual m o nit ori n g 
acti vities t o e ns ure t hat Partici pati n g I nstit uti o ns are c o m pl yi n g wit h re g ulat or y a n d pr ot oc ol 
re q uire me nts, data q ualit y, a n d s u bject safet y.  T he Partici pati n g I nstit uti o ns will be re q uire d 

1 1 5
S h ort title: P h ase II st u d y of El ot uz u m a b pl us R V D i n Ne wl y Di a g n ose d M M
 Versi o n D ate:       Fe br u ar y 6, 2 0 1 9
C O N FI D E N TI A L
T his d oc u me nt is c o nfi de ntial. D o n ot discl ose or use e xce pt as a ut h orize d.
t o s u b mit s o urce d oc u me nts t o t he C o or di nati n g Ce nter f or D F CI C T O m o nit ori n g.  Als o 
Partici pati n g I nstit uti o ns will be s u bject t o o n-site m o nit ori n g c o n d ucte d b y t he D F CI C T O.  
Virt ual or re m ote m o nit ori n g will be perf or me d o n a n o n g oi n g basis as re m ote Cli nical Data 
Re vie w wit h o n-site visits occ urri n g o nce per year i ncl u di n g a cl ose- o ut visit.  T he D F CI 
C T O site m o nit or will re q uest s o urce d oc u me nts f or data t hat re q uires s o urce d oc u me nt 
verificati o n ( S D V). T hese d oc u me nts s h o ul d be fa xe d or sca n ne d/e maile d t o t he C R A.  
M o nit ori n g practices ma y i ncl u de b ut are n ot li mite d t o; s o urce verificati o n, re vie w a n d 
a nal ysis of t he f oll o wi n g: eli gi bilit y re q uire me nts of all partici pa nts, i nf or me d c o nse nt 
pr oce d ures, a d verse e ve nts a n d all ass ociate d d oc u me ntati o n, st u d y dr u g a d mi nistrati o n / 
treat me nt, re g ulat or y rec or ds a n d site trial master files, pr ot oc ol de viati o ns, p har mac y 
rec or ds, res p o nse assess me nts, a n d data ma na ge me nt.  M o nit ori n g will occ ur bef ore t he 
cli nical p hase of t he pr ot oc ol be gi ns a n d will c o nti n ue d uri n g pr ot oc ol perf or ma nce t hr o u g h 
st u d y c o m pleti o n.   
Re g ulat or y a ut h orities ma y als o re q uest access t o s o urce d oc u me nts, data ca pt ure rec or ds, 
a n d ot her st u d y d oc u me ntati o n f or o n-site a u dit or i ns pecti o n. T he i n vesti gat or will n otif y 
D F CI i n t he e ve nt of a n a u dit re q uest. 
D uri n g t he c o urse of t he st u d y, c o m m u nicati o n bet wee n t he C o or di nati n g Ce nter a n d 
partici pati n g sites will occ ur via re g ular telec o nfere nce.  
5. 2  
M o nit ori n g Re p orts
T he D F/ H C C S p o ns or will re vie w all m o nit ori n g re p orts f or o n-site a n d virt ual m o nit ori n g 
of Partici pati n g I nstit uti o ns t o e ns ure pr ot oc ol c o m plia nce a n d a bilit y t o f ulfill 
res p o nsi bilities of partici pati n g i n t he st u d y. T he D F/ H C C S p o ns or ma y i ncrease t he 
m o nit ori n g acti vities at Partici pati n g I nstit uti o ns t hat are u na ble t o c o m pl y wit h t he 
pr ot oc ol, D F/ H C C S p o ns or re q uire me nts or fe deral a n d l ocal re g ulati o ns. Partici pati n g 
I nstit uti o ns ma y als o be s u bject t o a n a u dit as deter mi ne d b y t he D F/ H C C S p o ns or.
5. 3
  Accr u al M o nit ori n g
Pri or t o e xte n di n g a pr ot oc ol t o a n e xter nal site, t he D F/ H C C S p o ns or will esta blis h 
accr ual re q uire me nts f or eac h partici pati n g i nstit uti o n. Accr ual will be m o nit ore d f or eac h 
partici pati n g i nstit uti o n b y t he D F/ H C C S p o ns or or desi g nee. Sites t hat are n ot meeti n g 
t heir accr ual e x pectati o ns ma y be s u bject t o ter mi nati o n.
6  
A U DI TI N G: Q U A LI T Y A S S U R A N C E
A u diti n g is a met h o d of Q ualit y Ass ura nce. Its mai n f oc us is t o meas ure w het her sta n dar ds 
a n d pr oce d ures were f oll o we d. A u diti n g is t he s yste matic a n d i n de pe n de nt e xa mi nati o n of 
all trial relate d acti vities a n d d oc u me nts.  A u dits deter mi ne if e val uate d acti vities were 
a p pr o priatel y c o n d ucte d a n d w het her data was ge nerate d, rec or de d a n d a nal yze d, a n d 

1 1 6
S h ort title: P h ase II st u d y of El ot uz u m a b pl us R V D i n Ne wl y Di a g n ose d M M
 Versi o n D ate:       Fe br u ar y 6, 2 0 1 9
C O N FI D E N TI A L
T his d oc u me nt is c o nfi de ntial. D o n ot discl ose or use e xce pt as a ut h orize d.
acc uratel y re p orte d per t he pr ot oc ol, Sta n dar d O perati n g Pr oce d ures ( S O Ps), a n d t he C o de 
of Fe deral Re g ulati o ns ( C F R).
6. 1
A u dit Pl a n:  D F/ H C C S p o ns ore d Tri als
O ne a u dit o n-site will be sc he d ule b y t he O D Q ass u mi n g at least t hree s u bjects ha ve bee n 
treate d o n pr ot oc ol at t he site. A p pr o xi matel y 3- 4 s u bjects w o ul d be a u dite d at t he site o ver 
a 2 da y peri o d.  If vi olati o ns w hic h i m pact s u bject safet y or t he i nte grit y of t he st u d y are 
f o u n d, m ore s u bject rec or ds ma y be a u dite d. A d diti o nal a u dits ma y occ ur if e vi de nce of 
n o n-c o m plia nce is f o u n d d uri n g t he r o uti ne m o nit ori n g.
6. 2
A u dit N otific ati o n
It is t he Partici pati n g I nstit uti o n’s res p o nsi bilit y t o n otif y t he C o or di nati n g Ce nter of all 
sc he d ule d a u dit dates a n d re-a u dit dates (if a p plica ble), w hic h i n v ol ve t his pr ot oc ol. All 
i nstit uti o ns will f or war d a c o p y of fi nal a u dit a n d/ or re-a u dit re p orts a n d c orrecti ve acti o n 
pla ns (if a p plica ble) t o t he C o or di nati n g Ce nter, wit hi n 1 2 wee ks after t he a u dit date. 
6. 3
A u dit Re p orts 
T he D F/ H C C S p o ns or will re vie w all fi nal a u dit re p orts a n d c orrecti ve acti o n pla ns if 
a p plica ble. T he C o or di nati n g Ce nter, m ust f or war d t hese re p orts t o t he D F/ H C C O D Q per 
D F/ H C C p olic y f or re vie w b y t he D F/ H C C A u dit C o m mittee. Base d u p o n t he a u dit 
assess me nts t he D F/ H C C A u dit C o m mittee c o ul d acce pt or c o n diti o nall y acce pt t he a u dit 
rati n g a n d fi nal re p ort. C o n diti o nal a p pr o val c o ul d re q uire t he D F/ H C C S p o ns or t o 
i m ple me nt rec o m me n dati o ns or re q uire f urt her f oll o w- u p.  F or u nacce pta ble a u dits, t he 
D F/ H C C A u dit C o m mittee w o ul d f or war d t he fi nal a u dit re p ort a n d c orrecti ve acti o n pla n 
t o t he D F CI I R B as a p plica ble.
6. 4
P artici p ati n g I nstit uti o n Perf or m a nce
T he 
D F/ H C C S p o ns or is c har ge d 
wit h c o nsi deri n g t he t otalit y of a n i nstit uti o n’s 
perf or ma nce i n c o nsi deri n g i nstit uti o nal partici pati o n i n t he pr ot oc ol.
6. 4. 1 C orrecti ve Acti o ns
Partici pati n g I nstit uti o ns t hat fail t o meet t he perf or ma nce g oals of accr ual, s u b missi o n of 
ti mel y acc urate data, a d here nce t o pr ot oc ol re q uire me nts, a n d c o m plia nce wit h state a n d 
fe deral re g ulati o ns, 
will be rec o m me n de d f or a si x- m o nt h pr o bati o n peri o d. S uc h 
i nstit uti o ns m ust res p o n d wit h a c orrecti ve acti o n pla n a n d m ust de m o nstrate d uri n g t he 
pr o bati o n peri o d t hat deficie ncies ha ve bee n c orrecte d, as e vi de nce d b y t he i m pr o ve d 
perf or ma nce 
meas ures. Partici pati n g I nstit uti o ns t hat fail t o de m o nstrate si g nifica nt 
i m pr o ve me nt will be c o nsi dere d b y t he D F/ H C C S p o ns or f or re v ocati o n of partici pati o n.

1 1 7
S h ort title: P h ase II st u d y of El ot uz u m a b pl us R V D i n Ne wl y Di a g n ose d M M
 Versi o n D ate:       Fe br u ar y 6, 2 0 1 9
C O N FI D E N TI A L
T his d oc u me nt is c o nfi de ntial. D o n ot discl ose or use e xce pt as a ut h orize d.