Conditions: Multiple Myeloma
Keywords: Multiple Myeloma
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 40
Healthy volunteers: no

Brief summary:
This research study is evaluating a combination of four drugs -- lenalidomide, bortezomib, dexamethasone and elotuzumab -- as therapy for newly diagnosed multiple myeloma.

Detailed description:
This research study is a Phase II clinical trial testing the safety and effectiveness of an investigational drug (in this case elotuzumab) in combination with lenalidomide, bortezomib and dexamethasone to learn more about the side effects of this regimen and whether it is effective in newly diagnosed multiple myeloma.

"Investigational" means that the drug elotuzumab and the combination of this agent with lenalidomide, bortezomib, and dexamethasone are being studied. It also means that the the U.S. Food and Drug Administration (FDA) has not yet approved elotuzumab for the treatment of cancer. The drugs, lenalidomide, bortezomib, and dexamethasone are approved by the FDA. Participants in this trial will have the option to undergo autologous stem cell transplantation (ASCT) following initial therapy with elotuzumab, lenalidomide, bortezomib, and dexamethasone. ASCT is a standard of care in the treatment of multiple myeloma. All participants, including those who undergo ASCT and those who choose not to, will receive what is referred to as "maintenance therapy" - or continuous treatment - after the initial cycles of treatment with elotuzumab, lenalidomide, bortezomib, and dexamethasone. The specific maintenance regimen will be determined by risk category.

Arms:
arm 1: Participants will receive therapy with the combination of lenalidomide, bortezomib, and dexamethasone and elotuzumab (E-RVD). Induction cycles (1 to 8) are 21-day cycles.

* Elotuzumab will be administered by intravenous (IV) infusion
* Bortezomib as a subcutaneous injection
* Lenalidomide single daily oral dose
* Dexamethasone as oral tablets and IV infusion
* Stem cell mobilization will be performed for all subjects at the end of Cycle 4.

Subjects may elect to stop E-RVD at the end of Induction Cycle 4 and proceed to autologous SCT. Subjects who do not proceed to SCT may receive a full 8 cycles of induction therapy.

The maintenance schedule (28 days) will start after 8 cycles of induction regimen for subjects not proceeding with SCT, or after recovery from SCT for subjects proceeding with it.

Maintenance therapy with E-RVD will be administered to all patients, with the specific maintenance regimen determined by risk category.

Interventions: intervention 1: Lenalidomide intervention 2: Elotuzumab intervention 3: Bortezomib intervention 4: Dexamethasone intervention 5: Stem Cell Mobilization
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None intervention 4: None intervention 5: None

Protocol document:
Prot_SAP_000.pdf: 
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.