Lenalidomide Plus Melphalan as a Preparative Regimen for Autologous Stem Cell Transplantation in Relapsed Multiple Myeloma: A Phase 1 / 2 Study
Phase: PHASE1
Conditions: Multiple Myeloma
Sponsor: Weill Medical College of Cornell University

 
TI T L E: Le nali d o mi de pl us Mel p hala n as a Pre parati ve Re gi me n f or A ut ol o g o us Ste m Cell 
Tra ns pla ntati o n i n Rela pse d or Refract or y M ulti ple M yel o ma: A P hase 1 / 2 St u d y  
 
Pri nci p al I n vesti g at or: R o ger Pearse, M D  
Weill C or nell Me dici ne  
4 2 5 E. 6 1 st Street, 8 t h Fl o or  
P h o ne: 6 4 6- 9 6 2- 6 5 0 0  
Fa x: 2 1 2- 7 4 6- 8 9 6 1  
E mail: r n p 2 0 0 1 @ me d.c or nell.e d u  
 
N C T 0 1 0 5 4 1 9 6  
C urr e nt Pr ot oc ol A m e n d m e nt Versi o n ( 8):  0 5. 2 7. 2 0 2 1  
Pri or v ersi o ns : 
Pr ot oc ol A( 7) cl e a n 0 4. 1 4. 1 7  
Pr ot oc ol A( 6) d at e d 5. 2 5. 1 6  
Pr ot oc ol A( 5) d at e d 9. 1 1. 1 3  
Pr ot oc ol A( 4) d at e d 8. 1. 1 2  
Pr ot oc ol A( 3) d at e d 4. 7. 1 1  
 

Cel ge  C 
I R B Pr ot oc ol  N u m ber:  0 9 0 9 0 1 0 6 2 3 
A me n d me nt  8, Re visi o n  Date:  Ma y 2 7 t h , 2 0 2 1 
Cel ge ne Trac ki n g N u m ber: R V -M M -PI -0 4 5 8  
 
 
 
 
 
 
TI T L E: Le nali d o mi de pl us Mel p hala n  as a Pre parati ve Re gi me n  f or A ut ol o g o us  Ste m Cell  
Tra ns pla ntati o n  i n Rela pse d  or Refract or y  M ulti ple  M yel o ma:  A P hase 1 / 2 St u d y 
 
 
Pri nci p al  I n vesti g at or: 
R o ger  Pearse,  M D  
Weill C or nell  Me dici ne  
4 2 5 E. 6 1 st Street, 8 t h Fl o or    
P h o ne:  6 4 6 -9 6 2 -6 5 0 0  
Fa x:  2 1 2 -7 4 6 -8 9 6 1  
E mail:  r n p 2 0 0 1 @ me d.c or nell.e d u 
 
 
 
 
 
St atistici a n:  
Pa ul  C hrist os,  Dr P H,  M S  Weill  C or nell  Me dical  C olle ge  
Di visi o n  of  Bi ostatistics  a n d E pi de mi ol o g y  Ne w  Y or k,  N Y 1 0 0 6 5  
P h o ne:  6 4 6 -9 6 2 -8 0 1 8  
Fa x:  6 4 6 -9 6 2 -0 2 8 1  
E mail:  pac 2 0 0 1 @ me d.c or nell.e d u  
 
 
 
 
 
 
 
 
 
 

T R E A T M E N T S C H E M A  
 
 
Tra ns pla nt  P hase:  
 
 
 
 
Pla n ne d  d ose  le vels of  le nali d o mi de i n P hase  1 p orti o n  of  st u d y: 
 
D ose  Le vel  
 
Le n ali d o mi de D ose  / Sc he d ule  
 
-1  
2 5 m g  dail y  x  5 da ys  
 
1  
2 5 m g  t wice dail y  x  5 da ys  
 
2  
2 5 m g  q A M, 5 0 m q q P M x  5 da ys  
 
3  
5 0 m g  q A M, 7 5 m g  q P M x  5 da ys  
 
4  
7 5 m g  q A M, 1 0 0 m g  q P M x  5 da ys  
 
5  
1 0 0 m g  q A M, 1 5 0 m g  q P M x  5 da ys  
 
6  
1 5 0 m g  q A M, 2 0 0 m g  q P M x  5 da ys  
 
 
 
Mai nte na nce  P hase:  
Starti n g  Da y  + 1 0 0 ( p ost ste m cell i nf usi o n): 
Start  2 5 m g of Le nali d o mi de dail y  f or da ys  1- 2 1 of a 2 8- da y c ycle u ntil pr o gressi o n  of disease.  
As piri n 8 1 m g  dail y  c o nti n u o usl y d uri n g t he mai nte na nce p hase.  
 
 
 
 
 
 
 
 
 
 
 
 
 
i 

ii 
 
T A B L E O F  C O N T E N T S  
 
Pa ge  
S C H E M A  ........................................................................................................................................... i 
1.  O B J E C TI V E S  .......................................................................................................................... 1 
1. 1  
O bjecti ves  ........................................................................................................................ 1 
1. 2  
P hase 1 St u d y E n d p oi nts ............................................................................................... 1 
1. 3  
P hase 2 St u d y E n d p oi nts ............................................................................................... 1 
2.  B A C K G R O U N D  ........................................................................................................................ 1 
2. 1  
Disease  ............................................................................................................................. 1 
2. 2  
I n vesti gati o nal A ge nts  ..................................................................................................... 2 
2. 3  
Rati o nale  .......................................................................................................................... 4 
3.  P A TI E N T  S E L E C TI O N  ........................................................................................................... 5 
3. 1  
I ncl usi o n Criteria  ........................................................................................................... 5 
3. 2  
E xcl usi o n Criteria  ............................................................................................................ 6 
4.  R E GI S T R A TI O N  P R O C E D U R E S  .......................................................................................... 7 
5.  T R E A T M E N T P L A N  ................................................................................................................ 8 
5. 1  
St u d y Desi g n/ A ge nt  A d mi nistrati o n  .............................................................................. 8 
5. 2  
Ge neral  C o nc o mita nt  Me dicati o n  a n d S u p p orti ve Care  G ui deli nes  ............................ 1 0 
5. 3  
D urati o n  of T hera p y a n d Criteria  f or Re m o val  fr o m St u d y ......................................... 1 1 
5. 4  
Earl y  Ter mi nati o n  of St u d y .......................................................................................... 1 1 
5. 5  
D urati o n  of F oll o w  U p  .................................................................................................. 1 1 
6.  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  ................................................................... 1 1 
7.  A D V E R S E  E V E N T S:  LI S T A N D  R E P O R TI N G  R E Q UI R E M E N T S  ............................. 1 3 
7. 1  
St u d y A ge nt  / Met h o d  Ris ks  ........................................................................................ 1 3 
7. 2  
A d verse  E ve nt C haracteristics  ....................................................................................... 1 7 
7. 3  
Rec or di n g  of A d verse E ve nts ....................................................................................... 1 7 
7. 4  
Seri o us  A d verse  E ve nt ( S A E) Re p orti n g  ...................................................................... 1 7 
8.  P H A R M A C E U TI C A L  I N F O R M A TI O N ............................................................................. 2 1 
8. 1  
Cli nical  P har mac ol o g y  .................................................................................................. 2 1 
8. 2  
Dr u g  S u p pl y a n d D osa ge  ............................................................................................... 2 3 
8. 3  
Le nali d o mi de Or deri n g a n d Pac ka gi n g  ......................................................................... 2 3 
8. 4  
Le nali d o mi de Acc o u nta bilit y  ....................................................................................... 2 4 
9.  S T U D Y  E V A L U A TI O N S  ....................................................................................................... 2 4 
St u d y C ale n d ar  ............................................................................................................ 2 4 
9. 1  
Baseli ne E val uati o n ...................................................................................................... 2 5 
9. 2  
Da y  + 2 8  a n d Da y  + 5 6  visits  ......................................................................................... 2 6 
9. 3  
D a y  + 1 0 0  visit  .............................................................................................................. 2 7 

ii 
 
9. 4 
Da y  + 1 0 8,  1 1 5, 1 2 2 visits ............................................................................................ 2 7 
9. 5  
Mai nte na nce P hase, Da y  1 of c ycle a n d e n d- of-st u d y visit  ......................................... 2 7 
9. 6  
P ost st u d y f oll o w- u p .................................................................................................... 2 8 
9. 7  
Criteria  f or re m o val fr o m st u d y ................................................................................... 2 8 
1 0.  M E A S U R E M E N T  O F  E F F E C T  ............................................................................................ 2 9 
1 1. 1  
Disease Res p o nse  .......................................................................................................... 2 9 
1 1. 2  
D urati o n  of Res p o nse  .................................................................................................... 2 9 
1 1. 3  
O verall  S ur vi val  ............................................................................................................ 2 9 
1 1. 4  
Q ualit y  of  Life  ............................................................................................................... 2 9 
1 1.  D A T A  R E P O R TI N G  / R E G U L A T O R Y C O N SI D E R A TI O N S  ........................................ 2 9 
1 1. 2 
Data  C ollecti o n  .............................................................................................................. 2 9 
1 1. 2 
Re g ulat or y  C o nsi derati o ns ............................................................................................. 2 9 
1 2.  S T A TI S TI C A L  C O N SI D E R A TI O N S  ................................................................................... 3 0 
1 2. 1  
St u d y Desi g n  / E n d p oi nts ............................................................................................. 3 0 
1 2. 2  
Sa m ple Size  / Accr ual  rate ........................................................................................... 3 1 
1 2. 3  
A nal ysis  of Sec o n dar y E n d p oi nts ................................................................................ 3 1 
1 2. 4  
Re p orti n g  a n d E xcl usi o ns ............................................................................................ 3 1 
1 3.  P R O T O C O L  A M M E N D M E N T S  A N D  D E VI A TI O N S  ..................................................... 3 1 
1 4.  R E G U L A T O R Y C O N SI D E R A TI O N S  ................................................................................ 3 2 
1 4. 1  
I nstit uti o nal Re vie w  B oar d/ Et hics  C o m mittee A p pr o val  ............................................. 3 2 
1 4. 2  
I nf or me d C o nse nt Pr oce d ures  ....................................................................................... 3 2 
1 4. 3  
Pr otecti n g  Pri vac y  a n d C o nfi de ntialit y  ........................................................................ 3 3 
1 4. 4  
St u d y Rec or ds Re q uire me nts  ........................................................................................ 3 3 
1 4. 5  
Pr otecti o n  of H u ma n  Ri g hts ......................................................................................... 3 3 
1 4. 6  
Pre mat ure Disc o nti n uati o n of St u d y ............................................................................ 3 3 
1 4. 7  
Be nefits  of t he Pr ot oc ol  ................................................................................................. 3 4 
1 4. 8  
Ris ks i n Relati o n  t o A ntici pate d  Be nefit  ...................................................................... 3 4 
1 4. 9  
Alter nati ve Treat me nts  .................................................................................................. 3 4 
1 4. 1 0  I nce nti ves ....................................................................................................................... 3 4 
1 4. 1 1  C osts  ............................................................................................................................. 3 4 
R E F E R E N C E S  ............................................................................................................................... 3 5 
A P P E N DI C E S  
A P P E N DI X A  
Perf or ma nce Stat us Criteria  ................................................................................................. 3 8 
A P P E N DI X B  

4  
 
W C M C  S A E  Re p orti n g  F or ms  ............................................................................................ 3 9 
A P P E N DI X C  
I nter nati o nal U nif or m M ulti ple M yel o ma Res p o nse Criteria  ............................................. 4 0 
A P P E N DI X D  
Ris ks of Fetal  E x p os ure,  Pre g na nc y  Testi n g  G ui deli nes, a n d Acce pta ble  Birt h  C o ntr ol 
Met h o ds  ................................................................................................................................ 4 1 
A P P E N DI X E  
F A C T -B M T  ( Versi o n 4) .................................................................................................... 4 5 

1.  O B J E C TI V E S  
 
1. 1.  
Pri m ar y  O bjecti ves  
 
A)  P hase 1: T o  deter mi ne  t he ma xi mal t olerate d d ose ( M T D) of le nali d o mi de t hat ca n be safel y 
a d de d t o hi g h -d ose mel p hala n pri or  t o a ut ol o g o us ste m cell tra ns pla ntati o n ( A S C T). 
 
B)  P hase  2: T o deter mi ne  w het her  t he a d diti o n of hi g h -d ose le nali d o mi de t o A S C T f oll o we d b y  
mai nte na nce sta n dar d-d ose  le nali d o mi de i m pr o ves t he res p o nse rate a n d d urati o n of res p o nse f or 
rela pse d or refract or y m ulti ple m yel o ma ( R M M) as c o m pare d t o hist orical  data  f or sta n dar d 
A S C T usi n g  mel p hala n  c o n diti o ni n g al o ne. 
 
1. 2  
P h ase 1 St u d y E n d p oi nts  
 
•  Ma xi m u m T olerate d  D ose of Le nali d o mi de pri or t o a ut ol o g o us ste m cell 
tra ns pla ntati o n 
 
1. 3  
P h ase 2 St u d y E n d p oi nts  
Pri m ar y:  
•  D urati o n  of res p o nse ( D O R) 
 
Sec o n d ar y:  
•  Res p o nse  rate 
•  Deter mi nati o n  of re gi me n t o xicities 
•  O verall  S ur vi val  ( O S) 
•  Q ualit y  of  Life  
 
2.  B A C K G R O U N D  
 
2. 1  
Dise ase  
 
M ulti ple  m yel o ma ( M M) is a us uall y fatal ne o plas m of t he plas ma cell  t hat is c urre ntl y t he 
sec o n d m ost c o m m o n he mat ol o gic  mali g na nc y  i n t he U nite d  States,  wit h a n i nci de nce of 
a p pr o xi matel y 1 9, 0 0 0 ne w cases per year. 1M M  is c haracterize d b y  t he secreti o n of a m o n ocl o nal  
i m m u n o gl o b uli n, t he M-pr otei n,  i nt o t he bl o o d a n d is c o m plicate d b y t he de vel o p me nt  of e n d- 
or ga n  da ma ge,  i ncl u di n g l ytic lesi o ns of t he s kelet o n, re nal fail ure, a n d b o ne marr o w  
s u p pressi o n.2 F or  ma n y years,  t he tra diti o nal t hera pies f or m ulti ple  m yel o ma c o nsiste d  of 
al k ylati n g a ge nts, m ost c o m m o nl y  mel p hala n, c o m bi ne d wit h c ortic oster oi ds. W hile  t he res p o nse 
rate t o t hese t hera pies ra n ge d at a b o ut 5 0 %,  t he a vera ge s ur vi val of M M re mai ne d u nc ha n ge d  at 
3- 5 years. 3 M M is u ni q uel y se nsiti ve t o mel p hala n  i n a d ose -res p o nse relati o ns hi p, h o we ver  t he 
ma xi mal effecti ve d ose c o ul d n ot be safel y use d,  d ue t o t he se vere m yel os u p pressi o n a n d 
pa nc yt o pe nia t hat hi g h-d ose  mel p hala n  c o ul d i n d uce.4T he  de vel o p me nt  of t he tec h n ol o g y f or 
a ut ol o g o us ste m cell tra ns pla nt ( A S C T) i n t he 1 9 8 0’s  all o we d hi g h  d ose mel p hala n t o be use d  as 
a c o n diti o ni n g re gi me n i n M M a n d was  t he first t hera p y s h o w n t o i m pr o ve s ur vi val vs. 
tra diti o nal c he m ot hera p y. 5, 6  T he  s uccess ac hie ve d wit h hi g h -d ose mel p hala n a n d A S C T ma de  
t his re gi me n t he sta n dar d of care f or all patie nts  wit h M M w h o c o ul d t olerate t he ri g ors of 

2  
 
tra ns pla ntati o n. 
T he  a d ve nt of t he i m m u n o m o d ulat or y dr u gs  (I Mi D ® c o m p o u n ds) a n d pr oteas o me  i n hi biti o n 
wit h b ortez o mi b i n t he  late 1 9 9 0s o nce a gai n re v ol uti o nize d treat me nt f or M M.  T hali d o mi de,  
t he first I Mi D use d, was  s h o w n t o i n d uce res p o nses i n rela pse d R M M ( R M M), a  state of 
a d va nce d disease t hat is t y picall y resista nt t o tra diti o nal c he m ot hera p y (i ncl u di n g hi g h- d ose 
mel p hala n),  a n d is ass ociate d wit h hi g h  m or bi dit y a n d m ortalit y. 7W hile t he mec ha nis m  of acti o n 
of t hali d o mi de is n ot e ntirel y k n o w n, it is p ost ulate d  t hat it tar gets t he b o ne marr o w  e n vir o n me nt 
t hr o u g h a c o m bi nati o n of a n gi o ge nesis i n hi biti o n, T-cell sti m ulati o n, a n d c yt o ki ne 
m o d ulati o n. 8Le nali d o mi de is a sec o n d ge nerati o n  I Mi D t hat has bee n  s h o w n t o be directl y  t o xic 
t o m yel o ma cells a n d se veral t h o usa n d-f ol d ti mes m ore p ote nt t ha n t hali d o mi de f or certai n 
mec ha nis ms  of acti o n. 9Le nali d o mi de has  bee n  s h o w n i n t w o lar ge p hase t hree st u dies t o i m pr o ve 
t he i m pr o ve t he disease -free a n d o verall s ur vi val i n R M M. 1 0, 1 1  
Rece nt  trials of t he c o m bi nati o n of t he I Mi D ® c o m p o u n ds wit h tra diti o nal  c he m ot hera p y ha ve 
de m o nstrate d  a re mar ka ble s y ner g y i n a nti-m yel o ma efficac y. I n el derl y patie nts w h o are n ot 
c o nsi dere d t o be ca n di dates f or A S C T, t he  c o m bi nati o n of t hali d o mi de wit h  tra diti o nal 
mel p hala n  a n d pre d nis o ne treat me nt ( M P T) was s h o w n t o be s u peri or t o M P, wit h i ncreases i n 
b ot h disease res p o nse rate ( 7 6 % vs. 4 7. 6 %) a n d o verall  s ur vi val at t hree years  ( 8 0 % vs. 6 4 %). 1 2  
T he  c o m bi nati o n of le nali d o mi de wit h  mel p hala n  pl us pre d nis o ne ( R M P) has  s h o w n t o be 
si milarl y, if n ot sli g htl y m ore,  effecti ve i n preli mi nar y trials.1 3  
Le nali d o mi de has  a d ose -res p o nse relati o ns hi p i n its a nti-m yel o ma efficac y t hat is li mite d b y 
m yel os u p pressi o n  t hat hear ke ns  t he mel p hala n e x perie nce. I n a p hase I trial of le nali d o mi de, t he 
d ose -li miti n g t o xicit y of m yel os u p pressi o n  was  see n i n nearl y all patie nts  w h o were treate d  wit h  
5 0 m g dail y  of le nali d o mi de after 2 8 da ys,  ma ki n g  2 5  m g  dail y  t he ma xi mal t olerate d d ose a n d 
t he refere nce f or f ut ure trials.1 4Yet, i n t his st u d y nearl y  all patie nts  treate d wit h 5 0 m g 
le nali d o mi de dail y  ha d  a dra matic  i m pr o ve me nt i n t heir M M, wit h a  res p o nse rate of 8 5 %  t o t he 
si n gle a ge nt. T his res ult s u g gests t hat t he 5 0 m g d ose ma y  be m ore acti ve, al beit m ore  t o xic t o t he 
b o ne marr o w.  
T he  maj orit y  of  p atie nts recei vi n g first li ne treat me nt f or m yel o ma will ha ve  a dr o p i n t he M- 
pr otei n  a n d at least a partial re missi o n; h o we ver,  disease rela pse is t he r ule. As wit h  m ost 
mali g na ncies,  w he n  M M  pr o gresses  after eac h s uccessi ve t hera p y, t he treat me nt res p o nse wa nes,  
a n d t h us t here is a c o nti n ui n g nee d t o disc o ver  n o vel effecti ve t hera pies  f or patie nts wit h  R M M.  
Alt h o u g h  t he n o vel  a ge nts le nali d o mi de, t hali d o mi de, a n d b ortez o mi b  ha ve  all pr o vi de d  ne w  
h o pe f or t h o usa n ds of patie nts wit h R M M, ne w  strate gies are nee de d t o hel p ma na ge a n d  del a y 
disease pr o gressi o n  a n d m or bi dit y.  
 
2. 2  
I n vesti g ati o n al A ge nts  
Le n ali d o mi de  
Le nali d o mi de ( Re vli mi d ® ) is a n a nal o g of t hali d o mi de  wit h greater  p ote nc y t o acti vate 
i m m u n o m o d ulat or y effects a n d i n hi bit a n gi o ge nesis w he n  c o m pare d t o t hali d o mi de. B ot h  
le nali d o mi de a n d t hali d o mi de are me m bers of  t he Cel ge ne  C or p orati o n’s  pr o prietar y  class of 
c o m p o u n ds calle d I Mi Ds® w hic h  are c haracterize d b y  t heir i m m u n o m o d ulat or y a n d a nti- 
a n gi o ge nic acti vit y. 

3  
 
Le nali d o mi de differs str uct urall y fr o m t hali d o mi de b y  t he a d diti o n of a n a mi n o gr o u p, ma ki n g it 
a 4-a mi n o-gl uta m yl  a nal o g of t hali d o mi de.9It was  i nitiall y de vel o pe d wit h  t he f oc us o n f urt her  
i n hi biti o n of T N F -α secreti o n, a n d it d oes  s o 5 0, 0 0 0 ti mes m ore  effecti vel y t ha n t hali d o mi de i n 
vitr o a n d 2 0 0 0 ti mes m ore p ote ntl y i n acti vate d m o n oc ytes.  M ore o ver,  le nali d o mi de has als o 
bee n  s h o w n t o be directl y  c yt ot o xic t o M M cell li nes a n d patie nt  cells i n c ult ure. 1 5  
 
Le nali d o mi de ac hie ves  a pea k  plas ma  c o nce ntrati o n i n M M patie nts  bet wee n  0. 5 t o 4 h o urs after 
oral  a d mi nistrati o n.  A d mi nistrati o n  wit h f o o d d oes  n ot affect t he A U C  (t otal e x p os ure ti me) t o 
t he dr u g,  b ut it d oes re d uce t he ma xi m u m ser u m c o nce ntrati o n b y  a p pr o xi matel y  o ne-t hir d. T he  
maj orit y  of le nali d o mi de is e xcrete d via t he ki d ne y a n d t he half-life of t he  dr u g is a p pr o xi matel y 
3 h o urs.  Ser u m  c o nce ntrati o n a n d A U C  is affecte d b y  var yi n g  de grees  of re nal i ns ufficie nc y, 
w hic h  ca n affect t he ris k of a d verse effects  w he n ta ki n g le nali d o mi de.1 6  
 
P hase  I st u dies of hea vil y pretreate d  s u bjects wit h  rela pse d or refract or y m ulti ple m yel o ma was  
c o n d ucte d t o i de ntif y t he M T D a n d t o e val uate t he safet y of oral  le nali d o mi de.1 7M yel os u pressi o n  
was  f o u n d t o be t he D L T  a n d t he M T D was  deter mi ne d t o be 2 5 m g/ da y.   N o si g nifica nt 
s o m n ole nce, c o nsti pati o n, or ne ur o pat h y was o bser ve d.   Se ve ntee n  ( 7 1 %) of 2 4 e val ua ble 
patie nts  ac hie ve d > 2 5 % re d ucti o n  of t he m yel o ma para pr otei n  a n d 2 0 % of patie nts  ac hie ve d a > 
5 0 % para pr otei n  re d ucti o n (res p o n ders recei ve d 2 5- 5 0 m g/ da y).  T he  res ults fr o m p hase II trials 
of le nali d o mi de gi ve n at 3 0 m g per da y  f or 2 1 da ys  e ver y 2 8 da ys  s u g gest t hat oral  le nali d o mi de 
is acti ve i n a d va nce d m ulti ple m yel o ma a n d  well  t olerate d.  Of 4 6  e val ua ble s u bjects wit h  
rela pse d or refract or y M M, 3 9 ( 8 5 %) ac hie ve d at least sta ble disease,  i ncl u di n g 2 s u bjects wit h  
c o m plete res ol uti o n of para pr otei n. 1 7  
 
T w o  ra n d o mize d, p hase  III st u dies ha ve bee n c o n d ucte d t o i n vesti gate t he effecti ve ness a n d 
safet y of le nali d o mi de at 2 5 m g c o m bi ne d wit h hi g h- d ose de xa met has o ne  c o m pare d t o hi g h- d ose 
de xa met has o ne t o treat patie nts wit h rela pse d or refract or y m ulti ple m yel o ma. 1 0 -1 1  T he  res ults of 
t hese st u d y re veale d 5 9. 4 % of hea vil y  pretreate d  patie nts  wit h rela pse d / refract or y m ulti ple  
m yel o ma res p o n de d  t o t he c o m bi nati o n of 2 5 m g le nali d o mi de a n d hi g h-d ose  de xa met has o ne  
c o m pare d t o a 2 1. 1 % res p o nse rate t o hi g h-d ose de xa met has o ne al o ne. F urt her m ore,  a s ur vi val 
be nefit  was  see n i n t he le nali d o mi de-c o ntai ni n g ar m. T his data le d t o t he a p pr o val of 
le nali d o mi de i n c o m bi nati o n wit h de xa met has o ne i n patie nts wit h rela pse d / refract or y m ulti ple  
m yel o ma i n 2 0 0 6. 
 
Le nali d o mi de ( Re vli mi d ® ) will  be pr o vi de d  t o researc h s u bjects f or t he d urati o n of t heir 
partici pati o n  i n t his trial at n o c har ge t o t he m or t heir i ns ura nce pr o vi ders.  Le nali d o mi de will be  
pr o vi de d  i n acc or da nce wit h t he  Re v Assist ® pr o gra m  of Cel ge ne C or p orati o n. Per sta n dar d 
Re v Assist ® 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, a n d all 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 v Assist ® 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 n ali d o mi de f or o ne  c ycle of t her a p y (eit her  i n t he ste m cell 
tr a ns pl a nt c o n diti o ni n g  p h ase  or t he l ater m ai nte n a nce p h ase)  will be  s u p plie d t o t he 
p atie nt  e ac h c ycle. 
 
Mel p h al a n  
 
Mel p hala n  is c o m merciall y a vaila ble a n d is t he pri mar y a ge nt use d  f or c o n diti o ni n g i n 

4  
 
a ut ol o g o us ste m cell tra ns pla ntati o n f or m ulti ple  m yel o ma.  It is a deri vati ve  of nitr o ge n  m ustar d  
a n d classifie d as a n al k ylati n g a ge nt. Mel p hala n  i ntercalates wit hi n ri b o n ucleic aci d base  pairs  
a n d t h us i nterferes wit h D N A  re plicati o n a n d tra nscri pti o n of R N A,  lea di n g t o deat h i n acti vel y 
re plicati n g cells. W he n use d f or A S C T, it is gi ve n  i ntra ve n o usl y. Mel p hala n is i nc o m pletel y  a n d 
erraticall y a bs or be d, has a pr ol o n ge d  plas ma  half-life, a n d is e xcrete d lar gel y u nc ha n ge d  i n t he 
uri ne.  I ntra ve n o us mel p hala n res ults i n ver y hi g h  plas ma  le vels f oll o we d b y  a n i nitial ra pi d 
deca y  c ur ve ( half-life 3 0- 6 0 mi n utes).  M ost of t he  a d mi nistere d d ose is rec o vere d u nc ha n ge d  i n 
t he uri ne  a n d t he dr u g d oes n ot nee d  t o be meta b olize d t o be acti ve. T he  pea k c o nce ntrati o n 
ac hie ve d i n t he plas ma is  directl y  relate d t o creati ni ne cleara nce ( Cr Cl) a n d t h us t he d ose is 
us uall y re d uce d i n t h ose patie nts  wit h a Cr Cl <  7 0 cc/ mi n. 
 
T he  maj or  t o xicit y of  mel p hala n  is m yel os u p pressi o n,  w hic h  is d ose-relate d. Ot her  t o xicities 
w hic h  m a y  occ ur at hi g h -d oses i ncl u de na usea a n d  v o miti n g,  m uc ositis, a n d diarr hea.  
A ntie metics  are t heref ore r o uti nel y gi ve n  pri or t o a n d after a d mi nistrati o n, al o n g wit h oral care  
t o pre ve nt  a n d a meli orate m uc ositis, a n d a nti-diarr heals  as nee de d.  F urt her  details  of acti o n a n d 
p har mac ol o g y  ca n be f o u n d i n t he pac ka ge i nsert.  
 
Mel p hala n’s  efficac y  w he n use d  i n hi g h  d oses as a pre parati ve re gi me n  for a ut ol o g o us  ste m cell 
tra ns pla ntati o n was  esta blis he d b y  t he la n d mar k st u d y of Attal, et al. i n 1 9 9 6, i n w hic h  2 0 0 
patie nts  wit h M M were  ra n d o mize d t o recei ve eit her hi g h- d ose mel p hala n  wit h a ut ol o g o us ste m 
cell s u p p ort vers us  sta n dar d c o m bi nati o n c he m ot hera p y. 5T he  sta n dar d c o m bi nati o n t hera p y 
c o nsiste d of alter nati n g c ycles  of V C M P  ( Vi ncristi ne, C ycl o p h os p ha mi de,  oral  Mel p hala n,  
Pre d nis o ne) a n d  B V A P  ( Car m usti ne, Vi ncristi ne,  A dria m yci n,  Pre d nis o ne)  e ver y t hree wee ks  f or 
a t otal of 1 8 c ycles.  T he  A S C T c o n diti o ni n g re gi me n c o nsiste d of f o ur t o si x c ycles of V C M P  
a n d B V A P,  f oll o we d b y  1 4 0 m g/ m2 of i ntra ve n o us  mel p hala n  pl us 8 G y of  t otal b o d y irra diati o n. 
T he  res ults were  clearl y fa v ora ble f or t he A S C T  ar m, wit h a n i m pr o ve me nt i n e ve nt-free s ur vi val 
( 2 8 % vs. 1 0 %) a n d o verall s ur vi val at fi ve years  ( 5 2 % vs. 1 2 %).   A sec o n d lar ger ra n d o mize d 
st u d y of c o n ve nti o nal c he m ot hera p y vers us hi g h- d ose mel p hala n  c o nfir me d a s ur vi val be nefit of 
a p pr o xi matel y o ne year  wit h A S C T. 6F urt her m ore,  t his st u d y s h o we d t hat t he be nefit  was  
ac hie va ble wit h 1) o mitti n g  t he t otal b o d y  irra diati o n a n d i ncreasi n g t he d ose of mel p hala n  t o 
2 0 0 m g/ m 2  a n d 2) usi n g peri p heral  bl o o d ste m cells ( P B S C) i nstea d of b o ne marr o w.  F oll o wi n g 
t he res ults of t hese t w o trials, a n d ot her si milar st u dies, a ut ol o g o us ste m cell tra ns pla ntati o n 
bec o me  t he g ol d  sta n dar d treat me nt f or m ulti ple  m yel o ma i n patie nts dee me d fit f or i nte nsi ve 
t hera p y. 
 
2. 3  
R at i o n ale 
 
Patie nts  wit h R R M M ha ve us uall y u n der g o ne se veral pri or li nes of  t hera p y a n d te n d t o res p o n d 
p o orl y t o f urt her treat me nt. T h us, patie nts wit h R R M M  are partic ularl y  v ul nera ble  t o t heir 
disease a n d  t here is a nee d t o de vel o p  ne w treat me nt strate gies t o i m pr o ve t heir disease  res p o nse 
a n d s ur vi val.  T he  use of A S C T has  all o we d t he effecti ve a n d safe deli ver y of hi g h- d ose 
mel p hala n  a n d has  s h o w n t o ha ve a p ositi ve  i m pact o n s ur vi val i n M M. Si milarl y,  le nali d o mi de 
ma y  ha ve greater  efficac y i n hi g her d oses a n d has  bee n  s h o w n t o ha ve s y ner gistic acti vit y w he n  
c o m bi ne d wit h mel p hala n.  T he use of A S C T  s u p p ort is t he l o gical ne xt ste p t o all o w t he safe 
i nc or p orati o n of hi g h-d ose  le nali d o mi de wit h hi g h -d ose mel p hala n  c o n diti o ni n g pri or t o A S C T. 
T his ne w pr o p ose d  t hera p y s h o ul d pr o vi de  greater  a nti-m yel o ma efficac y c o m pare d t o hi g h- d ose 
mel p hala n  al o ne, es peciall y  i n t he R R M M setti n g.  If t here is si g nifica nt i m pr o ve me nt i n M M 

5  
 
cli nical o utc o mes  see n i n patie nts  wit h R R M M, t his treat me nt ma y  be e xte n de d t o t he u p -fr o nt 
treat me nt of ne wl y  dia g n ose d M M as well  a n d p ote ntiall y i m pr o ve t he q ualit y a n d le n gt h of t he 
li ves t h o usa n ds of patie nts  a year.  
 
3.  P A TI E N T  S E L E C TI O N  
 
3. 1 
I ncl usi o n Criteri a  
 
3. 1. 1 
Patie nts  m ust ha ve hist ol o gicall y  c o nfir me d m ulti ple m yel o ma t hat is eit her 
refract or y t o or has rela pse d f oll o wi n g at least o ne  pri or  li ne of t hera p y. Per t he  
I nter nati o nal M yel o ma  W or ki n g Gr o u p  C o nse ns us Pa nel  1, rela pse d m yel o ma is  
defi ne d  as pre vi o usl y treate d m yel o ma  t hat pr o gresses  a n d re q uires t he i nitiati o n of 
sal va ge t hera p y b ut d oes n ot meet  criteria f or eit her “ pri mar y  refract or y m yel o ma” or 
“rela pse d-a n d-refract or y m yel o ma” . Pri mar y  refract or y m yel o ma is defi ne d  as 
disease t hat is n o n -res p o nsi ve i n patie nts  w h o ha ve ne ver  ac hie ve d a mi ni mal 
res p o nse ( M R) or better  wit h a n y t hera p y. It i ncl u des patie nts  w h o ne ver ac hie ve M R  
or better  i n w h o m  t here is n o si g nifica nt c ha n ge i n M-pr otei n  a n d n o e vi de nce of 
cli nical pr o gressi o n,  as well as pri mar y  refract or y/ pr o gressi ve disease  w here  patie nts  
meet  criteria f or tr ue pr o gressi ve disease.   Rela pse d  a n d refract or y m yel o ma is  
defi ne d  as disease  t hat is n o n -res p o nsi ve w hile o n sal va ge t hera p y, or pr o gresses 
wit hi n 6 0 da ys  of last t hera p y, i n patie nts w h o ha ve ac hie ve d M R or better  at s o me 
p oi nt bef ore t he n pr o gressi n g.  
 
3. 1. 2   A ge > 1 8  years.  
 
3. 1. 3  Life e x pecta nc y  of greater  t ha n 1 2 wee ks.  
 
3. 1. 4  E C O G perf or ma nce stat us < 2. 
 
3. 1. 5  All st u d y  partici pa nts  m ust be re gistere d i nt o t he ma n dat or y Re v Assist ® 
pr o gra m,  a n d be willi n g a n d a ble t o c o m pl y wit h t he  re q uire me nts of 
Re v Assist ® . 
 
3. 1. 6  Patie nts  m ust ha ve n or mal  or ga n  a n d marr o w  f u ncti o n as defi ne d  bel o w: 
 
o  A N C  
> 1, 0 0 0/ µ L 
o  platelets  
> 5 0, 0 0 0/ µ L 
o  t otal bilir u bi n  
≤ 1. 5 X u p per  li mit of n or mal  
o  A S T( S G O T)/ A L T( S G P T)     ≤ 2. 5 X u p per  li mit of n or mal  
o  Car diac Ejecti o n Fracti o n        ≥ 4 5 % 
o  Creati ni ne  cleara nce  
> 6 0 cc/ mi n 
( Creati ni ne cleara nce ca n be calc ulate d eit her b y  2 4  h o ur uri ne  c ollecti o n, or if 
uri ne is n ot a vaila ble, b y  C oc kcr oft -Ga ult  f or m ula∗). 
 
 
 
 
∗ T he  C oc kcr oft -Ga ult  f or m ula t o esti mate t he creati ni ne cleara nce 1 9: 

7  
 
a d mi nistere d m ore  t ha n 2 wee ks  earlier. Patie nts  ma y  ha ve recei ve d bis p h os p h o nate  
t hera p y as part of  r o uti ne m yel o ma  care at a n y  ti me pri or  t o st u d y e ntr y. 
 
3. 2. 2  Patie nts  ma y  n ot be recei vi n g a n y  ot her i n vesti gati o nal a ge nts. 
 
3. 2. 3  Hist or y  of  aller gic reacti o ns attri b ute d t o 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 le nali d o mi de (i ncl u di n g t hali d o mi de) or mel p hala n. 
 
3. 2. 4  K n o w n  p ositi ve f or HI V  or i nfecti o us he patitis,  t y pe B or C.  
 
3. 2. 5  U nc o ntr olle d  ill ness i ncl u di n g, b ut n ot li mite d t o, o n g oi n g  or acti ve i nfecti o n, 
s y m pt o matic c o n gesti ve heart  fail ure, u nsta ble  a n gi na pect oris,  car diac arr h yt h mia, or 
ps yc hiatric  ill ness/s ocial sit uati o ns t hat w o ul d li mit c o m plia nce wit h st u d y 
re q uire me nts. 
 
3. 2. 6  Pre g na nt  a n d lactati n g w o me n are e xcl u de d fr o m t he st u d y beca use t he ris ks 
t o a n u n b or n  fet us or p ote ntial ris ks i n n ursi n g i nfa nts are u n k n o w n. 
 
3. 2. 7  Hist or y  of t hr o m b osis or t hr o m b oe m b olic e ve nt wit hi n last 6 0 da ys  pri or t o 
st u d y e ntr y. 
 
 
4.  R E GI S T R A TI O N  P R O C E D U R E S  
Ce ntr al  P atie nt  Re gistr ati o n  
Patie nts  will be  ce ntrall y re gistere d wit h t he  Weill C or nell  Me dical C olle ge  ( W C M C), Di visi o n  
of He mat ol o g y  a n d Me dical  O nc ol o g y Cli nical  Researc h  Office.   T o re gister a patie nt,  fa x t he 
f oll o wi n g d oc u me nts  t o t he Cli nical  Researc h  Office at  6 4 6-9 6 2 - 1 6 1 0: 
 
•  W C M C  Patie nt  re gistrati o n f or m 
•  First  a n d last pa ge of  t he f ull e xec ute d i nf or me d c o nse nt f or m, pl us a d diti o nal 
pa ges  i n c hec k b o xes f or c orrelati ve st u dies  are re q uire d. 
•  F ull y  e xec ute d HI P A A researc h  a ut h orizati o n f or m 
•  Eli gi bilit y  c hec klist si g ne d a n d date d  b y  i n vesti gat or a n d researc h n urse  
•  D oc u me ntati o n  of a n y  eli gi bilit y wai vers  gra nte d  
•  C o nfir mati o n  of s p o ns or re gistrati o n, w he n  a p plica ble 
•  F or  i n patie nts, si g ne d c o nse nt d oc u me ntati o n  te m plate 
 
Ce ntral  re gistrati o n i nf or mati o n is re vie we d a n d e ntere d i nt o t he He m O nc ce ntralize d researc h 
data base.   D oc u me ntati o n of patie nt  re gistrati o n will be  fa xe d t o t he I n vesti gati o nal P har mac y  t o 
all o w f or release of  st u d y a ge nt. 

8  
 
5.  T R E A T M E N T P L A N  
 
5. 1  
St u d y Desi g n  / A ge nt  A d mi nistr ati o n  
 
T his is a  p hase 1/ 2 st u d y of t he i nc or p orati o n of hi g h- d ose le nali d o mi de i nt o hi g h -d ose  
mel p hala n  c o n diti o ni n g pri or t o a ut ol o g o us ste m cell tra ns pla ntati o n ( A S C T) f or 
rela pse d/refract or y m ulti ple m yel o ma  ( R R M M). A b o ut 2 1 s u bjects will partici pate i n p hase 1 of 
t he st u d y at Weill C or nell  Me dical  C olle ge.  P hase  1 of t he st u d y will d ose  escalate le nali d o mi de 
i n a series of s u bjects i n a 3 + 3  desi g n  t hr o u g h 6 d ose le vels of le nali d o mi de (as per m o difie d  
Fi b o nacci  escalati o n) t o deter mi ne  t he ma xi mal t olerate d d ose ( M T D) of le nali d o mi de pri or t o 
A S C T. T he  le nali d o mi de d osi n g i n t he p hase 1 p orti o n of t he  st u d y is s h o w n i n T a ble 1 bel o w:  
 
T a ble 1: Pla n ne d  d ose le vels of le nali d o mi de i n P hase 1 p orti o n  of st u d y 
 
 
 
 
 
Fi n di n g  t he d ose -li miti n g t o xicit y ( D L T) will  deter mi ne  t he M T D.  T he  p ote ntial D L Ts  are 
defi ne d  b y  t he criteria i n T a ble 2 . 
 
T a ble 2: D ose  li miti n g t o xicities ( D L T). [ N ote t hat Da y  0 is defi ne d  as t he da y of 
ste m cell i nf usi o n]. T o xicit y  is gra de d  as per 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) versi o n  
-1  
1  
2  
3  
4  
5  
6  
2 5 m g  dail y  x 5 da ys  
2 5 m g  t wice dail y  x 5 da ys  
2 5 m g  q A M,  5 0 m q  q P M x 5 da ys  
5 0 m g  q A M,  7 5 m g  q P M x 5 da ys  
7 5 m g  q A M,  1 0 0 m g  q P M x 5 da ys  
1 0 0 m g  q A M, 1 5 0 m g q P M x  5 da ys  
1 5 0 m g  q A M, 2 0 0 m g  q P M x  5 da ys  
D ose  Le vel  
Le n ali d o mi de  D ose  / Sc he d ule  

9  
 
3 
 
 
 
 
 
 
 
T he  p hase 1 trial starts at d ose le vel 1 ( 5 0 m g dail y  d ose)  as per t he treat me nt sc he ma ( pa ge i). 
Escalati o n  c o m me nces t o t he ne xt d ose le vel after t hree patie nts are treate d wit h n o D L T.  If 1 
patie nt  at a d ose le vel e x perie nces D L T,  a n a d diti o nal t hree patie nts are treate d at t hat d ose le vel. 
If 2 patie nts  e x perie nce a D L T  at d ose le vel 1, t he n t he trial will rec o m me nce at d ose le vel -1.  
M T D  of le nali d o mi de is defi ne d  b y  t he d ose le vel t hat has  less t ha n 2/ 6 D L Ts ( See T a ble 3 ). 
 
T a ble 3: 3 + 3  d ose escalati o n sc he ma t o deter mi ne ma xi m u m t olerate d d ose ( M T D) 
base d  o n d ose -li miti n g t o xicit y ( D L T). 
 
# D L T / # S u bjects  
Decisi o n  
0/ 3  
Escalate  t o t he ne xt  hi g her  d ose  
1/ 3  
A d d  3 patie nts  t o t he sa me d ose c o h ort 
1/ 6  
Escalate  t o t he ne xt  hi g her  d ose  / trial e n ds if alrea d y 
at D ose  le vel 4  
≥ 2/ 3  or  ≥ 2/ 6  
Decrease  d ose  f or o n g oi n g  st u d y 
 
T he  M T D is  defi ne d  as t he ma xi m u m  d ose wit h  < 2/ 6  D L T’s.  If t here are 2 or  m ore  D L T’s  at 
d ose  le vel -1,  all test d oses  will  be declare d  t o ha ve  e xcee de d t he M T D.  
 
I n m ore  detail,  i n t he tra ns pla nt p hase of t he st u d y, all partici pa nts  will recei ve oral  le nali d o mi de 
(at t he pre -deter mi ne d  d ose  le vel i n t he p hase 1 p orti o n, a n d at t he M T D f or le nali d o mi de i n t he 
p hase 2 p orti o n) f or 5 da ys  ( desi g nate d as da ys - 5 t o - 1 i n t he Treat me nt  Sc he ma a b o ve). O n  
da ys - 2 a n d -1,  all patie nts  will recei ve 1 0 0 m g/ m2 of i ntra ve n o us mel p hala n  o nce dail y  f or a t otal 
of 2 d oses  ( 2 0 0 m g/ m2t otal).  After  a peri o d of 2 4- 7 2 h o urs  has  ela pse d fr o m t he last mel p hala n  
d ose ( desi g nate d as Da y  0) eac h patie nt will recei ve i nf usi o n of at least 2. 0  x 1 06/ k g of  
a ut ol o g o us C D 3 4 +  ste m cells. As per  c o n ve nti o nal Ne w  Y or k  Pres b yteria n  H os pital  ( N Y P H) 

1 0  
 
a ut ol o g o us tra ns pla ntati o n pr ot oc ol,  all patie nts  will  recei ve dail y  fil grasti m ( G-C S F) starti n g o n 
da y + 1  p ost i nf usi o n of ste m cells u ntil ste m cell e n graft me nt.  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 of 5 0 0  / c u. m m a n d platelet  c o u nt of 2 0, 0 0 0/ m m3 u ntra nsf use d.  
C o nc o mita nt  me dicati o ns  a n d ot her s u p p orti ve care f or t he tra ns pla nt p hase of t he st u d y are 
descri be d  bel o w i n secti o n 5. 2. B o ne marr o w  bi o ps y will be  perf or me d  f or all patie nts o n Da y  -2,  
j ust pri or t o mel p hala n  i nf usi o n. T o xicit y will be  assesse d o n a  c o nti n ui n g basis d uri n g t he 
c o urse of t he A S C T a n d t hereafter o n  a bi wee kl y basis f or  t he first t w o m o nt hs a n d  t hereafter o n 
a m o nt hl y basis.  B o ne marr o w bi o ps y as well  as ot her la b orat or y st u dies t o deter mi ne t he e xte nt 
of m yel o ma  will be  perf or me d  o n Da y  1 0 0 t o defi ne t he res p o nse rate t o t he le nali d o mi de + 
mel p hala n  A S C T.  
 
I n t he mai nte na nce p hase of t he st u d y, all patie nts  will be gi n  le nali d o mi de at a d ose of 2 5 m g 
dail y  f or da ys  1-2 1  of  a 2 8 da y c ycle o n Da y  + 1 0 0.  T his t hera p y will c o nti n ue u ntil t here is 
eit her pr o gressi o n  of disease  (as defi ne d  b y  I U R C, A p pe n di x  C) or i nt olera bilit y t o le nali d o mi de 
de vel o ps,  e ve n after d ose re d ucti o n ( d ose re d ucti o n sc he d ule o utli ne d bel o w i n secti o n 
6.) Res p o nse  rate a n d d urati o n of res p o nse will  be meas ure d  e ver y 2 8 da ys as defi ne d  b y  t he 
I U R C (see A p pe n di x C)  u ntil disease rela pse/ pr o gressi o n  or 3 6 m o nt hs ha ve ela pse d fr o m da y  
0, w hic h  e ver occ urs first. 1 8  
 
P hase 2 of  t he st u d y will e x pa n d t he n u m ber  of partici pa nts i n t he M T D  ar m of t he trial a n d 
f oll o w t he treat me nt pla n  o utli ne d a b o ve. U p t o 2 9  patie nts  will be  e nr olle d at Weill C or nell  
Me dical  C olle ge a n d  Ce dars -Si nai  Me dical  Ce nter  i n p hase 2 of t he st u d y. 
 
T he  a utol o g o us  tra ns pla nt will be  perf or me d  o n a n i n patie nt basis. Re p orte d  a d verse e ve nts a n d 
p ote ntial ris ks are descri be d i n Secti o n  7.  A p pr o priate  d ose m o dificati o ns  f or le nali d o mi de are 
descri be d  i n Secti o n  6.  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 m a y  be  a dmi nistere d  wit h t he  i nte nt t o treat t he patie nt’s  mali g na nc y.  
 
5. 2  
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  
 
Tra ns pla nt  P hase:  Patie nts will recei ve s u p p orti ve care acc or di n g t o i nstit uti o nal g ui deli nes  f or 
a ut ol o g o us tra ns pla nt reci pie nts. All patie nts  will  be treate d i n pri vate r o o ms wit h he pafilters.  
Patie nts  will recei ve a nti bacterial, a nti viral a n d a ntif u n gal pr o p h yla xis. All  patie nts  will recei ve 
t hr o m b o pr o p h yla xis wit h l o w-m olec ular  wei g ht  he pari n  ( L M W H) at a d ose of 4 0 m g 
s u bc uta ne o usl y o nce dail y,  starti n g fr o m da y  - 5 u ntil da y  + 1 4  or u ntil platelet c o u nt has  dr o p pe d  
t o < 5 0 K,  w hic he ver  c o mes first. All patie nts will als o recei ve pr o p h ylactic  a nti bi otics, a nti virals, 
a n d a ntif u n gals as per us ual N Y P H tra ns pla nt pr ot oc ol w hic h  us uall y,  b ut n ot i n all cases, 
c o nsists of le v ofl o xaci n 5 0 0 m g dail y  a n d fl uc o naz ole 1 0 0 m g dail y,  u ntil e n graft me nt, as well as 
eit her valac ycl o vir  5 0 0 m g t wice dail y  or ac ycl o vir 4 0 0 m g t wice dail y  fr o m Da y  + 1  t o 6 m o nt hs 
p ost -tra ns pla nt. Le v ofl o xaci n bacterial  i nfecti o n pr o p h yla xis  will start at 5 0 0 m g o nce a da y  o n 
Da y  - 1. Difl uca n  4 0 0 m g  dail y  a n d valac ycl o vir 5 0 0 m g t w o ti mes per  da y  will be  starte d u p o n 
a d missi o n.  Br oa d -s pectr u m a nti bi otics a n d a ntif u n gals will be i nstit ute d f or fe ver a n d si g ns of 
i nfecti o n.  All bl o o d pr o d ucts  will be irra diate d a n d le u k o de plete d.  Patie nts will be  scree ne d f or 
C M V vire mia b y  pcr wee kl y a n d t h ose w h o test p ositi ve will  recei ve ga ncicl o vir.    Patie nts will  
ha ve dail y  bl o o d c o u nts a n d electr ol ytes w hile i n h os pital. T his ca n be decrease d  t o C B C  3 x per  
wee k  u ntil e n graft me nt a n d t he n r o uti nel y wit h f oll o w u p a p p oi nt me nts. T he  electr ol ytes are 
d o ne dail y  w hile i n h os pital b ut ca n be decrease d  t o be decrease d  t o r o uti ne m o nit ori n g at f oll o w 

1 1  
 
u p a p p oi nt me nt o nce disc har ge d  a n d t he li ver f u ncti o n tests s h o ul d be d o ne 2 x per  wee k  i n 
h os pital b ut decrease d  t o r o uti ne m o nit ori n g  at f oll o w u p a p p oi nt me nts o nce t he patie nt  is 
disc har ge d.   Li ver  f u ncti o n tests will be d o ne at least t wice a wee k.  A ntie metics will  be use d  
pr o p h ylacticall y  a n d o n a n  as nee de d  basis. Patie nts  will recei ve f ull tra nsf usi o n s u p p ort. 
 
5. 3  
D ur ati o n  of T her a p y  a n d  Criteri a  f or Re m o v al  Fr o m St u d y  
 
I n t he a bse nce of treat me nt dela ys  d ue  t o a d verse e ve nt(s), treat me nt  ma y  c o nti n ue u ntil o ne of 
t he f oll o wi n g criteria a p plies:  
 
o  Disease pr o gressi o n,  
 
o  I nterc urre nt ill ness t hat pre ve nts  f urt her a d mi nistrati o n of treat me nt, 
 
o  U nacce pta ble  a d verse e ve nt(s), 
 
o  Pre g na nc y  or a p ositi ve pre g na nc y  test, 
 
o  Patie nt  deci des  t o wit h dra w fr o m t he st u d y, or 
 
o  Ge neral  or s pecific  cha n ges  i n t he patie nt’s c o n diti o n re n der t he patie nt  
u nacce pta ble f or f urt her treat me nt i n t he j u d g me nt of t he  i n vesti gat or. 
 
 
5. 4  
E arl y  Ter mi n ati o n  of St u d y  
 
We  pla n t o recr uit 3 patie nts i nitiall y  a n d o bser ve treat me nt si de effects a n d a d verse e ve nts f or 
t w o f ull c ycles of t hera p y.  If t here are seri o us or life-t hreate ni n g si de effects, t he st u d y will be  
ter mi nate d a n d n o f urt her patie nts  will be  accr ue d. St u d y -ter mi nati n g e ve nts are liste d bel o w:  
 
•  A br u pt  or u ne x pecte d  patie nt deat h  
•  Gra de 4 ras h or ne ur o pat hic dr u g  t o xicit y 
•  I nt olera bilit y of st u d y dr u g  re gi me n 
 
 
5. 5  D ur ati o n  of F oll o w  U p  
 
Patie nts  will be  f oll o we d f or 3 years  after re m o val fr o m st u d y or u ntil  deat h, w hic he ver  occ urs 
first. Patie nts  re m o ve d fr o m st u d y f or u nacce pta ble  a d verse e ve nts will be  f oll o we d u ntil 
res ol uti o n or sta bilizati o n  of t he a d verse  e ve nt. 
 
6.  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  
 
T he  d ose le vels a n d escalati o n strate g y f or le nali d o mi de i n t he p hase 1 p orti o n of t he st u d y are 
o utli ne d i n detail  a b o ve. 

1 2  
 
I n t he mai nte na nce p hase (starti n g Da y  + 1 0 0), le nali d o mi de will be  gi ve n  dail y  f or da ys  1- 2 1 of  
a 2 8 da y  c ycle. T he  d ose of le nali d o mi de will be  m o difie d  f or t o xicit y as liste d bel o w.  D oses  
m ust be a dj uste d f or a d verse  e ve nts dee me d  relate d t o le nali d o mi de b y  t he i n vesti gat or. D oses  
ma y  be  a dj uste d f or a d verse e ve nts relate d t o st u d y me dicati o ns n ot liste d bel o w  at t he discreti o n  
of t he i n vesti gat or. 
 
Le nali d o mi de d oses  d uri n g t he mai nte na nce p hase will be  m o difie d  d ue t o t o xicit y as f oll o ws: 
 
D ose 
Le vel  
A ge nt   D ose  
-4  
Le nali d o mi de 5 m g/ da y  P O o n da ys  1 -2 1 of  2 8 da y  c ycle. 
-3  
Le nali d o mi de 1 0 m g/ da y  P O o n da ys  1 -2 1 of  2 8 da y  c ycle. 
-2  
Le nali d o mi de 1 5 m g/ da y  P O o n da ys  1 -2 1 of  a 2 8  da y  c ycle 
- 1 
Le nali d o mi de 2 5 m g/ da y  P O  o n da ys  1 -2 1  +  G -C S F  5 μ g/ k g/ da y  ( or e q ui vale nt 
pe g ylate d  G -C S F  d osa ge).  
0  
Le nali d o mi de 2 5 m g/ da y  P O  o n da ys  1 -2 1  of  a 2 8  da y  c ycle. 
 
If ne utr o pe nia is t he o nl y  t o xicit y f or w hic h d ose re d ucti o n is necessar y, t he first d ose  re d ucti o n 
ste p is D ose  Le vel  – 1.  F or all ot her  t o xicities re q uiri n g d ose re d ucti o n, t he first d ose re d ucti o n 
ste p is D ose le vel – 2. T o xicities a n d d ose re d ucti o n g ui deli nes  are liste d i n t he f oll o wi n g ta ble: 
 
D ose  M o dific ati o n  Sc he d ule  f or Le n ali d o mi de  
N CI  C T C v 3. 0  
T o xicit y  Gr a de  
Da y  2 -1 4  of C ycle  
≥Da y  1 5 of C ycle  
Gr a de  3 ne utr o pe ni a  
( A N C < 1 0 0 0  
cells/ m m 3) 
ass oci ate d  wit h  fe ver 
(te m per at ure ≥ 
3 8. 5 °C)  or  Gr a de  4 
ne utr o pe ni a  ( A N C < 
5 0 0  cells/ m m 3) 
•  
H ol d  (i nterr u pt d ose).  
•  
F oll o w  c bc wee kl y.  
•  
If ne utr o pe nia  has  res ol ve d t o ≤ 
gra de  2,  restart at ne xt  l o wer 
d ose  le vel a n d c o nti n ue t he 
c ycle u ntil  Da y  2 1.  
•  
O mit  le nali d o mi de f or re mai ne d f or 
c ycle. 
•  
If ne utr o pe nia  is t he o nl y  t o xicit y f or 
w hic h  a d ose  re d ucti o n is re q uire d, G- 
C S F  ma y  be  use d  a n d t he d ose  
mai ntai ne d  f or t he ne xt  c ycle at t he 
treati n g p h ysicia n’s  discreti o n.  
T hr o m b oc yt o pe ni a  ≥ 
Gr a de  3 ( pl atelet 
c o u nt < 5 0, 0 0 0  / 
m m
3) 
•  
H ol d  (i nterr u pt d ose).  
•  
F oll o w  c bc wee kl y.  
•  
If t hr o m b oc yt o pe nia res ol ves t o 
≤ gra de  2,  restart at ne xt  l o wer 
d ose  le vel a n d c o nti n ue t he 
c ycle u ntil  d a y  2 1.  
•  
H ol d  a ntic oa g ulati o n  f or platelet  
c o u nt <  5 0, 0 0 0/ m m 3  
•  
O mit  le nali d o mi de f or re mai n der of  
c ycle. 
•  
Restart  at ne xt  l o wer d ose  le vel f or ne xt  
c ycle 
•  
H ol d  a ntic oa g ulati o n  f or platelet  c o u nt 
< 5 0, 0 0 0/ m m 3  
A ne mi a  ≥ Gr a de  3  
( H g b < 8 g/ d L)  
•  
H ol d  (i nterr u pt d ose).  
•  
F oll o w  c bc wee kl y.  
•  
If a ne mia res ol ves t o ≤ gra de  2,  
restart at ne xt  l o wer d ose  le vel 
a n d c o nti n ue t he c ycle u ntil  d a y  
2 1.  
•  
O mit  le nali d o mi de f or re mai n der of  
c ycle 
•  
Restart  at ne xt  l o wer d ose  le vel f or ne xt  
c ycle 
N o n -blisteri n g  r as h 
Gr a de  3 
•  
If Gra de  3  h ol d  (i nterr u pt) d ose.  
F oll o w  wee kl y.  
•  
If t he t o xicit y res ol ves t o ≤ 
•  
O mit  le nali d o mi de f or re mai n der of  
c ycle. 
•  
Restart  at ne xt  l o wer d ose  le vel f or ne xt  

1 3  
 
 
 
gra de  1  pri or  t o Da y  2 1  restart at 
ne xt  l o wer d ose  le vel a n d 
c o nti n ue t he c ycle u ntil  Da y  2 1.  
•  
Disc o nti n ue  le nali d o mi de st u d y 
dr u g.  
c ycle 
Des q u a m ati n g  
( blisteri n g) r as h of  
a n y gr a de  
•  
Disc o nti n ue  le nali d o mi de 
•  
Disc o nti n ue  le nali d o mi de 
Er yt he m a  
m ultif or me  ≥ Gr a de  
3  
•  
Disc o nti n ue  le nali d o mi de 
•  
Disc o nti n ue  le nali d o mi de 
Si n us br a d yc ar di a  / 
ot her  arr h yt h mi a  = 
Gr a de  2 
•  
H ol d  (i nterr u pt) d ose.  F oll o w  at 
least wee kl y.  
•  
If t he t o xicit y res ol ves t o ≤ 
gra de  1 pri or  t o Da y  2 1  restart at 
ne xt  l o wer d ose  le vel a n d 
c o nti n ue t he c ycle u ntil  Da y  2 1.  
•  
O mit  le nali d o mi de f or t he re mai n der of  
t he c ycle a n d restart at ne xt  l o wer d ose  
f or ne xt  c ycle 
Gr a de  ≥ 3  
•  
Disc o nti n ue  le nali d o mi de 
•  
Disc o nti n ue  le nali d o mi de 
H y per  or 
H y p ot h yr oi dis m  
Gr a de  ≥ 2 
•  
O mit  le nali d o mi de f or t he 
re mai n der of  t he c ycle 
•  
E val uate  eti ol o g y a n d i nitiate 
a p pr o priate  t hera p y 
•  
Restart  Le nali d o mi de  at ne xt  
l o wer d ose  le vel f or ne xt  c ycle 
•  
O mit  le nali d o mi de f or t he re mai n der of  
t he c ycle 
•  
E val uate  eti ol o g y a n d i nitiate 
a p pr o priate  t hera p y 
Restart  Le nali d o mi de  at ne xt  l o wer 
d ose  le vel f or ne xt  c ycle 
 
 
7.  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  
 
A d verse  e ve nt ( A E) m o nit ori n g a n d re p orti n g is a r o uti ne part  of e ver y cli nical trial.  T he  
i n vesti gat or will  be re q uire d t o pr o vi de a p pr o priate i nf or mati o n c o ncer ni n g a n y fi n di n gs t hat 
s u g gest si g nifica nt hazar ds, c o ntrai n dicati o ns, si de effects, or preca uti o ns perti ne nt  t o t he safe 
use of t he dr u g u n der i n vesti gati o n.  Safet y  will be  m o nit ore d  b y  e val uati o n of a d verse e ve nts 
re p orte d b y  patie nts or o bser ve d  b y  i n vesti gat ors or researc h staff, as well  as b y  ot her 
i n vesti gati o ns s uc h as cli nical la b orat or y tests, x-ra ys, electr ocar di o gra p hs,  etc. 
 
7. 1  
St u d y A ge nt  / Met h o d  Ris ks:  
 
A.  Mel p hala n  
 
1.  M yel os u p pressi o n  is t he maj or  d ose -li miti n g t o xicit y, occ urri n g re g ularl y at d oses 
> 2 0 m g/ m 2. 
 
2.  Na usea,  v o miti n g,  diarr hea - occasi o nal,  rarel y se vere. 
 
3.  Tra nsie nt  he patic tra nsa mi nase ele vati o ns are occasi o nall y see n, b ut rarel y se vere. 
 
4.  M uc ositis  is occasi o nall y  see n a n d ca n p ote ntiall y be as se vere as W H O gra de 4 ( u na ble t o 
t olerate oral  i nta ke of s oli ds or li q ui ds).  Care  is ge nerall y s u p p orti ve wit h  m o ut h was hes,  
oral  visc o us  li d ocai ne, a n d, i n s o me cases, i ntra ve n o us narc otics  are use d  u ntil heali n g  

1 4  
 
occ urs.  
 
5.  Miscella ne o us - t here is t he rare p ossi bilit y t hat cataract f or mati o n, sec o n dar y 
mali g na ncies,  sterilit y, c or o nar y arter y disease  a n d h y p ot h yr oi dis m  ma y  occ ur. 
 
B.  A ut ol o g o us  Peri p heral  Bl o o d  Ste m Cell  I nf usi o n 
 
T he  v ol u me of t he peri p heral  bl o o d ste m cell ( P B S C) i nf usate is a p pr o xi matel y 8 0 0- 
1 0 0 0cc f or t he a vera ge a d ult.  I nf usi o ns of marr o w ma y  pr o d uce v ol u me o verl oa d  a n d 
s u bse q ue nt p ul m o nar y e de ma w hic h  ca n be pre ve nte d a n d treate d b y  di uretic  
a d mi nistrati o n.  Ste m cell i nf usi o n is rarel y ass ociate d wit h  aller gic reacti o ns. S mall, 
s u bcli nical p ul m o nar y e m b oli ma y occ ur, b ut t hese  rarel y if e ver re q uire a n y  i nter ve nti o n. 
Rarel y,  re nal fail ure d ue t o he m o gl o bi n uria  ca n be see n. Sta n dar d  pre-me dicati o ns f or  
bl o o d pr o d ucts  ma y  be use d bef ore a d mi nistrati o n  of t he marr o w  graft,  ge nerall y  
c o nsisti n g of di p he n h y dra mi ne or aceta mi n o p he n;  i n s o me cases, c ortic oster oi ds are 
gi ve n,  es peciall y  if t he patie nt has ha d  aller gic reacti o ns t o bl o o d pr o d ucts  i n t he past. 
 
I n ver y  rare circ u msta nces, a n a ut ol o g o us ste m cell graft ma y  fail t o e n graft either  as a 
pri mar y  fail ure t o rec o ver marr o w  f u ncti o n, ma nifeste d b y  fail ure of  earl y rec o ver y of 
m yel oi d  a n d er yt hr oi d ele me nts i n t he marr o w,  or as a n a br u pt o nset of marr o w  
h y p o plasia  d uri n g t he p ost -tra ns pla nt peri o d.   a) If A N C < 0. 2  x 1 09 o n da y 2 8  of t he 
sec o n d tra ns pla nt t he patie nts will recei ve G M -C S F  (i nstea d of  t he us uall y recei ve d G- 
C S F  t hat is gi ve n  fr o m Da y  0 u ntil e n graft me nt) at a d ose of 5 0 0  u g/ m2/ da y S C.  If A N C  
< 0. 5  x 1 09 o n da y 3 5, t he patie nt  will recei ve re-i nf usi o n of bac k u p.  I n a d diti o n, t he G M - 
C S F  will c o nti n ue. 
 
C.  Bl o o d  Pr o d uct  I nf usi o ns 
 
I nf usi o ns of fracti o nate d bl o o d pr o d ucts  ma y  pr o d uce  v ol u me o verl oa d,  w hic h ca n be 
ma na ge d  wit h di uretics.   T he y  ma y  als o i n d uce aller gic reacti o ns of varia ble se verit y, 
ma n y of w hic h  ca n be pre ve nte d  or miti gate d  b y  pre me dicati o n  wit h a nti p yretics, 
a nti hista mi nes, a n d c ortic oster oi ds. T hese pr o d ucts ma y als o ser ve as vect ors of seri o us 
i nfecti o n [e. g., C M V, he patitis,  HI V].   T o circ u m ve nt t his, pr os pecti ve  bl o o d d o n ors will  
be scree ne d f or e vi de nce of he patitis  B,  HI V,  H T L V -I/II a n d C M V i nfecti o n. C M V will  
be pre ve nte d  b y  W B C  de pleti o n. HI V[ -] a n d he patitis B sA g[ -] a n d C A b [ -] bl o o d 
pr o d ucts  deter mi ne d  b y  c urre ntl y a vaila ble ser ol o gic testi n g will be  use d  at all ti mes. 
All bl o o d pr o d ucts  are irra diate d [ 3 0 0 0r,1 3 7Cs]  t o circ u m ve nt t he ris k of G v H D ca use d 
b y  c o nta mi nati n g l y m p h oc ytes i n t he tra nsf use d fracti o ns. 
 
D.  P ne u m oc ystis  Cari nii  Pr o p h yla xis  – Tri met h o pri m/ S ulfa met h o xas ole  
 
T he  ris k of tri met h o pri m a n d s ulfa met h o xaz ole i n t he d oses  gi ve n  are pri maril y  
h y perse nsiti vit y  reacti o ns a n d si g ns of f olate deficie nc y.   A n y  patie nt wit h k n o w n  
h y perse nsiti vit y  t o t hese c o m p o u n ds will n ot recei ve t hese dr u gs  a n d will recei ve a n 
alter nati ve a ge nt, eit her da ps o ne or pe nta mi di ne  u p t o t he discreti o n  of t he i n vesti gat or. 
E.  Her pes  Z oster  Pr o p h yla xis  – Ac ycl o vir  / Valac ycl o vir  

1 5  
 
Eit her  ac ycl o vir or valac ycl o vir  will  be use d f or t his i n dicati o n.  T he  seri o us ris ks 
i n v ol ve d wit h t he  use of ac ycl o vir  i ncl u de seiz ure a n d re nal fail ure, h o we ver  t hese are 
rarel y see n.  M ore c o m m o nl y, ac ycl o vir has  bee n  ass ociate d wit h  na usea  / v o miti n g,  
diarr hea,  hea dac he,  a n d ras h.  Valac ycl o vir  has  bee n rarel y  ass ociate d wit h re nal fail ure, 
a plastic a ne mia, a na p h yla xis, t hr o m b otic  t hr o m b oc yt o pe nia p ur p ura / he m ol ytic -ure mic  
s y n dr o me, ps yc h osis, a n d seiz ure.  M ore c o m m o n si de effects of valac ycl o vir  t hat are 
see n i ncl u de na usea  / v o miti n g,  a b d o mi nal pai n, ele vate d li ver f u ncti o n tests, a n d ras h. 
A n y  s ubject se nsiti ve t o o ne  of t hese a ge nts ma y  recei ve t he ot her,  or n o  a ge nt at all, at 
t he discreti o n  of t he i n vesti gat or. 
 
H.   G-C S F (fil gastri m)  
 
T he  o nl y si de-effect o bser ve d fre q ue ntl y is b o ne pai n. Mil d hair t hi n ni n g has bee n  
re p orte d b ut t he  c o m bi nati o n of c he m ot hera p y a n d ra di ot hera p y of  t he prese nt pr o gra m  
will ca use u ni versal  al o pecia. S ple n o me gal y has bee n  rarel y re p orte d. Flare - u p of pre - 
e xisti n g a ut o-i m m u ne diseases  a n d ps oriasis ha ve  als o bee n  re p orte d. 
 
I n vesti g ati o n al A ge nt  Ris ks  
 
Le nali d o mi de  
Le nali d o mi de has  bee n st u die d i n healt h y  v ol u nteers a n d i n patie nts wit h ca ncer of t he bl o o d a n d 
ot her or ga ns  of t he b o d y  as well  as i n patie nts  wit h ot her  diseases.  As  wit h a n y ot her 
e x peri me ntal treat me nt t here m a y  be si de effects or ris ks ass ociate d wit h  le nali d o mi de, s o me of 
w hic h  are n ot yet  k n o w n. 
T he  f oll o wi n g is a list of t he m ost me dicall y si g nifica nt or m ost c o m m o n si de effects re p orte d i n 
c o m plete d a n d o n g oi n g st u dies c o nsi dere d t o be relate d t o le nali d o mi de. I n s o me cases, si de 
effects ca n be seri o us, l o n g-lasti n g, m a y  ne ver  g o  a wa y, or ca n ca use deat h.  T his list is n ot  
c o m plete b ut  y o ur  St u d y D oct or  will  a ns wer a n y  q uesti o ns y o u  mi g ht  ha ve a n d pr o vi de  y o u  wit h  
m ore  i nf or mati o n. 
Ver y  C o m m o n ( Greater t ha n 1 0 % c ha nce t his will ha p pe n)  
L o w  n u m ber of w hite bl o o d cells ( wit h or wit h o ut fe ver) [ Le u k o pe nia, Ne utr o pe nia,  Fe brile  
ne utr o pe nia,  Gra n ul oc yt o pe nia,  L y m p h o pe nia];  A ne mia;  Decrease i n cells t hat hel p  y o ur  bl o o d  
cl ot [ T hr o m b oc yt o pe nia]; Visi o n Bl urre d;  Diarr hea;  Pai n [ U p per a b d o mi nal pai n, A b d o mi nal 
pai n,  T o ot hac he],  C o nsti pati o n; I n di gesti o n [ D ys pe psia]; Na usea;  V o miti n g; Feeli n g  wea k  a n d 
u n well  [ Ast he nia]; Tire d  [ Fati g ue]; S welli n g  [ E de ma, Peri p heral  e de ma]; Fe ver  [ P yre xia]; 
C hills;  P ne u m o nia or ot her  i nfecti o ns [ P ne u m o nia, Br o nc hitis,  U p per res pirat or y tract i nfecti o n, 
Uri nar y  tract i nfecti o n, Er ysi pelas,  Gastr oe nteritis,  Her pes  si m ple x, Her pes  z oster, I nfl ue nza, 
L o wer  res pirat or y tract i nfecti o n, Si n usitis, Se psis,  Bactere mi a]; S ore  t hr oat [ Nas o p har y n gitis, 
P har y n gitis];  St uff y  n ose [ R hi nitis]; Wei g ht  l oss ; Decrease d  a p petite; Hi g h  bl o o d s u gar 
[ H y per gl yce mia]; C he mical  i m bala nce i n bl o o d [ H y p o kale mia, H y p ocalce mia,  
H y p o p h os p hate mia,  H y p o ma g nese mia,  H y p o natre mia]; Pai n i ncl u di n g m uscles,  j oi nts, a n d n o n - 
car diac c hest  pai n [ Pai n i n e xtre mit y, Pai n  i n li m b, Art hral gia,  Bac k  pai n,  B o ne pai n,  M uscle  
s pas ms, M usc ul os keletal  pai n, M uscle cra m p, C hest pai n a n d M yal gia];  Dizzi ness; Altere d  se nse 
of taste [ Dys ge usia],  Hea dac he;  E ye le ns cl o u d y [ Cataract]; A b n or mal  se nse of t o uc h 
[ H y p oaest hesia]; Pai n a n d decrease d  se nsati o n i n ner ves  [ Ne ur o pat h y, Peri p heral  ne ur o pat h y,  

1 6  
 
Peri p heral  se ns or y ne ur o pat h y];  S ha ki n g [ Tre m or]; C o u g h;  S h ort ness  of breat h  [ D ys p nea]; 
N ose blee d  [ E pista xis]; Bl o o d  cl ot i n l o wer e xtre mities, l u n gs, heart,  brai n,  a n d ot her or ga ns 
[ P ul m o nar y e m b olis m, Dee p  vei n  t hr o m b osis]; Dr y s ki n; Itc hi n g [ Pr urit us]; Aller gic reacti o n  
[ Ras h, H y perse nsiti vit y  (i n u nc o m m o n cate g or y)]; Feeli n g  sa d [ De pressi o n], N ot slee pi n g well  
[I ns o m nia]. 
C o m m o n ( bet wee n a 1- 1 0 % c ha nce t hat t his will ha p pe n):  
A b n or mall y l o w n u m ber of bl o o d cells [ Pa nc yt o pe nia]; Destr ucti o n  of re d bl o o d cells 
[ He m ol ytic a ne mia]; Heart attac k [ Ac ute m y ocar dial i nfarcti o n]; A b n or mal  heart  beats  [ Atrial 
fi brillati o n, Pal pitati o ns,  Tac h ycar dia];  Heart st o ps w or ki n g  [ Car diac fail ure, C o n gesti ve  car diac 
fail ure]; L o w  o x y ge n t o heart  tiss ue [ M y ocar dial isc he mia]; Dr y  m o ut h; Decrease d  acti o n of 
i ntesti ne [ Gastr oi ntesti nal m otilit y  dis or der];  Bile  fl o w fr o m li ver sl o we d or  bl oc ke d  
[ C h olestasis]; G o ut; Fall;  Br uise [ C o nt usi o n]; L o were d  le vel of c o nsci o us ness  wit h dr o wsi ness,  
listless ness, a n d a pat h y [ Let har g y]; A b n or mal li ver  la b tests [ A b n or mal li ver f u ncti o n tests, 
Ala ni ne  a mi n otra nsferase i ncrease d,  Ga m ma -gl uta m yltra nsferase i ncrease d]; I ncrease i n li ver 
pr otei n  t hat i n dicates i nfla m mati o n i n b o d y [ C-Reacti ve pr otei n  i ncrease d]; L oss  of fl ui d 
[ De h y drati o n]; Dia betes  [ Dia betes mellit us]; Hi g h  uric  aci d i n bl o o d [ H y per urice mia]; Ir o n b uil d  
u p i n b o d y [Ir o n o verl oa d]; M uscle  wea k ness;  Ca ncer  [ Ac ute m yel oi d  le u ke mia, B-cell 
l y m p h o ma, Basal  Cell  Carci n o ma,  S q ua m o us  cell carci n o ma]; Str o ke [ Cere br o vasc ular 
acci de nt]; Ti n gli n g  of s ki n [ Parest hesia]; Fai nti n g  [ S y nc o pe]; Verti g o  ( pr o ble m wit h i n ner ear 
w hic h  lea ds t o feeli n g t hat e ver yt hi n g is s pi n ni n g) M o o d y [ M o o d altere d]; Ki d ne y fail ure [ Re nal 
fail ure]; Breat hi n g  dis or der [ Res pirat or y  distress]; E xcessi ve  s weati n g [ h y per hi dr osis]; Ni g h t 
s weats; S ki n re d ness [ Er yt he ma]; S welli n g  of s ki n fille d wit h bl o o d [ He mat o ma]; S welli n g  of 
bl o o d vessels  [ Vasc ulitis]; Hi g h  or l o w  bl o o d press ure [ H y perte nsi o n, H y p ote nsi o n]; Bl o o d  n ot 
getti n g  t o e xtre mities [ Peri p heral isc he mia]; Cl ot i n vei n [ T hr o m b osis],  S u d de n  i ncrease i n t u m or 
size [ T u m or flare], Ra pi d  deat h  of ca ncer cells w here  t he acc u m ulati n g c o nte nts of d yi n g  ca ncer  
cells ca use a n i m bala nce i n t he c he mistr y of t he b o d y  w hic h  ca n lea d t o ki d ne y da ma ge  [ T u m or 
l ysis s y n dr o me ( T L S)]; Bl o o d  ca ncer t hat ca uses decrease d  n u m ber of re d blo o d cells, w hite  
bl o o d cells, a n d platelets  beca use t he y d o n ot de vel o p n or mall y [ M yel o d ys plastic s y n dr o me]. 
F urt her m ore,  t he f oll o wi n g ris ks ha ve bee n re p orte d after mar keti n g  of le nali d o mi de a n d are 
c o nsi dere d b y  Cel ge ne t o be relate d: 
•  S welli n g  of l u n gs [ P ne u m o nitis] 
•  O ver  a n d u n deracti ve t h yr oi d [ H y pert h yr oi dis m a n d H y p ot h yr oi dis m],  
•  Se vere  aller gic c o n diti o ns i ncl u di n g 
o  s welli n g u n der s ki n [a n gi oe de ma] 
o  Se vere  s ki n reacti o ns i n v ol vi n g li ni n g of t he n ose, m o ut h, st o mac h a n d i ntesti nes 
or ras h lea di n g t o t he se parati o n of t he t o p la yer of s ki n [ Ste ve ns-J o h ns o n 
S y n dr o me  a n d T o xic E pi der mal  Necr ol ysis],  
 
•  T L S.  
•  Ac ute  Graft  vers us  H ost Disease - after a b o ne marr o w  tra ns pla nt, ne w cells attac k t he 
b o d y w hic h  ca n res ult i n a b d o mi nal pai n  or cra m ps, na usea,  v o miti n g,  diarr hea,  ja u n dice 
( yell o wi n g of  s ki n), or s ki n ras h. 

1 7  
 
Sec o n d  ne w  c a ncers 
•  I n cli nical trials of ne wl y dia g n ose d  m ulti ple m yel o ma,  a n i ncrease d rate of sec o n d ne w  
ca ncers ha ve bee n  see n i n patie nts  recei vi n g le nali d o mi de c o m pare d wit h  patie nts  i n t he 
ot her ar m ( n ot recei vi n g le nali d o mi de). T hese ne w ca ncers i ncl u di n g ac ute le u ke mia 
( bl o o d ca ncers), l y m p h n o de ca ncers, a n d s oli d t u m ors were  see n i n patie nts recei vi n g 
le nali d o mi de ta ke n t o get her wit h  mel p hala n  or i m me diatel y after hi g h  d ose mel p hala n  
a n d ste m cell tra ns pla ntati o n.  A n i ncrease of bl o o d a n d l y m p h n o de ca ncers was  als o 
see n i n t he cli nical trials w here  patie nts recei ve d le nali d o mi de after ste m cell tra ns pla nt. 
W he n le nali d o mi de is gi ve n  wit h  de xa met has o ne  a hi g her  n u m ber  of s ki n ca ncers a n d 
s oli d t u m ors ha ve bee n  re p orte d. Patie nts  s h o ul d ma ke t heir d oct ors  a ware of t heir 
me dical  hist or y a n d a n y  c o ncer ns t he y ma y  ha ve re gar di n g t heir o w n i ncrease d ris k of 
ot her ca ncers. Y o ur d oct or will  be c hec ki n g y o u  f or a n y p ossi ble ne w  ca ncers t hat ma y  
de vel o p  d uri n g y o ur  treat me nt. 
•  Ot her  Ris ks  
•  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;  please tell y o ur  d oct or  if y o u  are ta ki n g di g o xi n. 
•  Y o ur c o n diti o n ma y  n ot get  better or  ma y  bec o me  w orse w hile  y o u  are i n t his st u d y.  F or  
m ore  i nf or mati o n a b o ut ris ks a n d si de effects, as k y o ur  St u d y D oct or.  
 
7. 2  A d verse E ve nt  C h ar acteristics  
•  
C T C A E  ter m ( A E descri pti o n) a n d gr a de:   T he  descri pti o ns  a n d gra di n g  scales 
f o u n d i n t he re vise d 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) versi o n  3. 0 will be utilize d f or A E  re p orti n g.  A c o p y of  t he C T C A E  
versi o n  3. 0 ca n be  d o w nl oa de d fr o m t he C T E P we b site (htt p://cte p.ca ncer. g o v ). 
 
•  
Attri b uti o n  of t he A E:  
- 
Defi nite  – T he  A E  is cle arly rel ate d t o t he st u d y treat me nt. 
- 
Pr o ba ble  – T he  A E  is likely rel ate d t o t he st u d y treat me nt. 
- 
P ossi ble – T he  A E  m ay  be  rel ate 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 ully rel ate d t o t he st u d y treat me nt. 
- 
U nrelate d  – T he  A E  is cle arly N O T rel ate d t o t he st u d y treat me nt. 
 
7. 3  Rec or di n g  of A d verse E ve nts  
 
All a d verse e ve nts will be  rec or de d o n a patie nt  s pecific a d verse e ve nt l o g.  T he  A E  l o g will be  
mai ntai ne d b y  t he researc h staff a n d ke pt i n t he patie nt’s  researc h c hart. 
 
 
 
 
7. 4  Seri o us  A d verse E ve nt  ( S A E) Re p orti n g  
 
7. 4. 1.  Defi niti o n of  S A E  

1 8  
 
S E RI O U S  A D V E R S E E V E N T S  i ncl u de deat h,  life t hreate ni n g a d verse 
e x perie nces, h os pitalizati o n or pr ol o n gati o n  of h os pitalizati o n, disa bilit y  or 
i nca pacitati o n, o ver d ose,  c o n ge nital a n o malies, pre g na nc y,  a n d a n y  ot her  
seri o us e ve nts t hat ma y  je o par dize t he s u bject or 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 i n t his defi niti o n.  
 
7. 4. 1. 1 Pre g na ncies:  
 
Pre g na nc y  of a fe male s u bject or t he  fe male part ner of  a male  s u bject 
occ urri n g  w hile t he  s u bject is o n st u d y dr u g or wit hi n 4 wee ks  after t he 
s u bject’s last d ose of st u d y dr u g are c o nsi dere d e x pe dite d re p orta ble 
e ve nts.  If t he s u bject 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 s u bject 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  m ust be 
re p orte d t o Cel ge ne Dr u g Safet y  wit hi n 2 4 h o urs  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 facsi mile usi n g t he S A E F or m. 
 
T he I n vesti gat or will  f oll o w t he pre g na nt  fe male u ntil c o m pleti o n of t he  
pre g na nc y  a n d m ust n otif y Cel ge ne Dr u g  Safet y  of t he o utc o me  as 
s pecifie d bel o w.   T he  I n vesti gat or will pr o vi de  t his i nf or mati o n as a 
f oll o w-u p  t o t he i nitial S A E.  
 
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), t he I n vesti gat or s h o ul d f oll o w t he 
pr oce d ures  f or E x pe dite d  Re p orti n g  S A Es  t o Cel ge ne (i.e., re p ort t he 
e ve nt t o Cel ge ne  Dr u g  Safet y  b y  facsi mile wit hi n 2 4 h o urs  of t he 
I n vesti gat or’s k n o wle d ge of t he e ve nt). 
 
A n y  s us pecte d fetal e x p os ure t o le nali d o mi de m ust be  re p orte d t o Cel ge ne  
wit hi n 2 4 h o urs  of bei n g  ma de a ware of  t he e ve nt.  T he  pre g na nt  fe male 
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. 
 
All ne o natal  deat hs  t hat occ ur wit hi n  3 0 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 3 0 
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. 
 
I n t he case of a  li ve “ n or mal” birt h, Cel ge ne  Dr u g Safet y  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. 
 
7. 4. 2.  Re p orti n g  of  S A E t o I R B  
 
All S A Es occ urri n g  o n t his st u d y will be  re p orte d t o t he I R B acc or di n g t o t he I R B 
p olic y.   T he f oll o wi n g pr oce d ure will be f oll o we d f or re p orti n g S A E  t o t he I R B: 

1 9  
 
 
•  
C o m plete  t he S A E  C o ver  S heet  ( See A p pe n di x B)  
•  
C o m plete  t he I R B U ne x pecte d,  St u d y -relate d A d verse E ve nts,  
I nci de nts, a n d I nf or mati o n Re p orti n g  F or m.  T his f or m s h o ul d be 
s u b mitte d wit hi n  7 cale n dar da ys  of i n vesti gat or n otificati o n  of t he 
e ve nt. 
•  
If t he e ve nt is n ot i m me diatel y re p orta ble as per  t he I R B p olic y,  
o nl y t he S A E C o ver S heet m ust be c o m plete d. T hese  e ve nts will  
be re p orte d t o t he I R B at t he ti me of c o nti n ui n g re ne wal o n t he 
A d verse  E ve nt & I N D Safet y  Re p orti n g C u m ulati ve Ta ble.  
 
F or ms  m a y  als o be d o w nl oa de d fr o m t he I R B we bsite  at: 
htt p:// weill.c or nell.e d u/rese arc h/f or ms _ a n d _ p olicies/ir b _f or ms/i n de x. ht ml  
 
7. 4. 3.  Re p orti n g  of  S A E t o F D A  
 
If a n S A E  occ urs o n t his st u d y, t he e ve nt will be file d o n a  Me d Watc h  f or m wit h  
t he F D A  ( F or m 3 5 0 0 A). 
 
A d verse  dr u g reacti o ns t hat are seri o us, u nliste d/ u ne x pecte d, a n d at least p ossi bl y 
ass ociate d t o t he dr u g,  a n d t hat ha ve n ot pre vi o usl y bee n re p orte d i n t he 
I n vesti gat ors br oc h ure,  or  refere nce safet y i nf or mati o n d oc u me nt  s h o ul d be 
re p orte d pr o m ptl y  t o t he F o o d  a n d Dr u g  A d mi nistrati o n  ( F D A) i n writi n g b y  Dr.  
T o mer  Mar k (t he pri nci pal  s p o ns or-i n vesti gat or).  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. 
 
T he  pri nci pal  s p o ns or-i n vesti gat or s hall n otif y t he F D A b y  tele p h o ne or b y fa x of 
a n y u ne x pecte d fatal or life  t hreate ni n g e x perie nce ass ociate d wit h  t he use of  t he 
dr u g as s o o n as p ossi ble b ut n o later t ha n 7 cale n dar da ys  after t he s p o ns ors i nitial 
recei pt of t he  i nf or mati o n.  Eac h  p h o ne call or fa x  s hall be tra ns mitte d t o t he F D A 
ne w  dr u g re vie w di visi o n i n t he Ce nter  f or Dr u g  E val uati o n a n d Researc h  or  t he 
pr o d uct  re vie w di visi o n i n t he Ce nter  f or Bi ol o gics  E val uati o n  a n d Researc h  t hat 
has  res p o nsi bilit y f or re vie w of t he I N D. 
 
T he  pri nci pal  s p o ns or-i n vesti gat or m ust als o call t he F D A  as s o o n as a n a d verse 
reacti o n occ urs.  T he p h o ne n u m ber is ( 3 0 1) 5 9 4- 5 7 7 8. A rec or der is a vaila ble 
after h o urs.   Re p ort t hese reacti o ns t o t he F D A wit hi n te n ( 1 0) w or ki n g  da ys b ot h 
ver bal  a n d writte n. 
 
T he  a d dress of t he F D A is: 
F D A  
Di visi o n of O nc ol o g y 
H F D -1 5 0  
1 4 5 1 R oc k ville  Pi ke  
R oc k ville,  M D  2 0 8 5 2 -1 4 4 8  
 
T he p h o ne n u m ber of  t he F D A is:  ( 3 0 1) 5 9 4- 5 7 7 8 

2 0  
 
Please as k  t o s pea k wit h t he  Di visi o n of O nc ol o g y.  
 
7. 4. 4.  Re p orti n g  of  S A E t o  Cel ge ne  
 
Seri o us  a d verse e ve nts ( S A E) are defi ne d  a b o ve.  T he  i n vesti gat or m ust i nf or m 
Cel ge ne i n writi n g usi n g  a Cel ge ne  S A E  f or m or M E D W A T C H  3 5 0 0 A f or m of 
a n y S A E  wit hi n 2 4 h o urs  of bei n g  a ware of t he e ve nt. T he writte n  re p ort m ust be 
c o m plete d a n d s u p plie d t o Cel ge ne  wit hi n 2 4 h o urs / 1 b usi ness da y .  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 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), if a vaila ble. 
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 
o n a f oll o w-u p  re p ort. A fi nal re p ort t o d oc u me nt  res ol uti o n of t he S A E  is 
re q uire d. T he  Cel ge ne trac ki n g n u m ber ( R V-M M -PI - 0 4 5 8) a n d t he i nstit uti o nal 
pr ot oc ol  n u m ber  s h o ul d be i ncl u de d o n S A E re p orts ( or o n t h e fa x c o ver letter) 
se nt t o Cel ge ne.   A c o p y of t he fa x tra ns missi o n c o nfir mati o n of t he S A E  re p ort t o 
Cel ge ne s h o ul d be attac he d t o t he  S A E  a n d retai ne d wit h  t he patie nt  rec or ds. 
 
T he  c o ntact i nf or mati o n f or Cel ge ne  is: Cel ge ne C or p orati o n  
Dr u g  Safet y  
8 6 M orris  A ve n ue  
S u m mit, NJ  0 7 9 0 1 
 
T oll Free:  
8 0 0 -6 4 0 -7 8 5 4  
P h o ne:  
9 0 8 -6 7 3 -9 6 6 7  
Fa x:  
9 0 8 -6 7 3 -9 1 1 5  
E mail:  dr u gsafet y @cel ge ne.c o m  
 
 
7. 4. 5 
Pr o visi o ns  f or A d verse E ve nts  
 
Necessar y  pr o p h yla xis  will be a d mi nistere d.  A nti -e metics a n d will be  
prescri be d  if necessar y.   Bl o o d  a n d platelet  tra nsf usi o ns will be gi ve n  as 
cli nicall y i n dicate d.  Pa mi dr o nate  or Z ole dr o nic  aci d ma y be gi ve n  m o nt hl y  
as part  of sta n dar d care. 
 
7. 4. 6  A d verse e ve nt u p dates/I N D safet y re p orts 
 
Cel ge ne  s h all n otify t he I nvesti g at or vi a a n I N D S afety Re p ort  of t he 
f oll o wi n g i nf or m ati o n: 
•  
A ny  A E ass oci ate d  wit h t he use of st u dy dr u g i n t his st u dy or i n ot her  
st u dies t h at is b ot h seri o us a n d u nex pecte d.  
•  
A ny  fi n di n g fr o m tests i n l a b or at ory a ni m als t h at s u g gests a 
si g nific a nt risk f or h u m a n  s u bjects i ncl u di n g re p orts of m ut a ge nicity,  
ter at o ge nicity, or c arci n o ge nicity. 

2 1  
 
T he  I nvesti g at or s h all n otify his/ her  I R B pr o m ptly of t hese ne w seri o us a n d 
u nex pecte d  A E(s)  or si g nific a nt risks t o s u bjects. 
T he  I nvesti g at or m ust kee p c o pies of all A E i nf or m ati o n, i ncl u di n g 
c orres p o n de nce wit h Cel ge ne  a n d t he I R B, o n file. 
 
 
7. 4. 7 
A n n u al Re p orts  
 
If t his st u d y meets  t he F D A  re q uire me nts f or I N D e xe m pti o n, t he A n n u al Re p ort  
s h o ul d be  file d i n t he st u d y’s Re g ul at or y  Bi n der,  a n d a c o p y pr o vi de d t o Cel ge ne  
C or p or ati o n  as a s u p p orter of t his st u d y as f oll o w: 
 
Cel ge ne C or p orati o n  
Att n: Cli nical  Scie nce Researc h  
8 6 M orris  A ve n ue  
S u m mit, NJ   0 7 9 0 1 
Tel:  ( 9 0 8) 6 7 3 -9 0 0 0  
 
All a dverse  ex perie nce re p orts m ust i ncl u de t he p atie nt  n u m ber,  a ge,  sex, wei g ht, severity of 
re acti o n ( mil d, m o der ate,  severe), rel ati o ns hi p t o dr u g ( pr o b a bly rel ate d, u nk n o w n rel ati o ns hi p, 
defi nitely  n ot rel ate d), d ate a n d ti me of a d mi nistr ati o n of test me dic ati o ns  a n d all c o nc o mit a nt 
me dic ati o ns,  a n d me dic al  tre at me nt pr ovi de d.    T he i nvesti g at or is res p o nsi ble f or ev al u ati n g all 
a dverse  eve nts t o deter mi ne w het her  criteri a f or “seri o us ” a n d as defi ne d  a b ove are p rese nt. 
T he  i nvesti g at or is res p o nsi ble f or re p orti n g a dverse  eve nts t o Cel ge ne as descri be d  i n secti o n 
7. 4. 4.  
 
8.  P H A R M A C E U TI C A L  I N F O R M A TI O N 
 
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 st u d y a ge nts ca n be f o u n d 
i n Secti o n  7. 1. T he pr o perties  of t he  i n vesti gati o nal a ge nt i n t his st u d y, le nali d o mi de, are 
liste d bel o w.  
 
R E V LI MI D ® (le nali d o mi de), 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 nti-a 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: 
 
C he mic al  Str uct ure of Le n ali d o mi de  
 
O 
O 
H 
N 
N 
O 
 
N H 2  
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  

2 2  
 
T he  e m pirical f or m ula f or le nali d o mi de is C 1 3 H 1 3 N 3 O 3, a n d t he gra m  m olec ular  wei g ht  is 
2 5 9. 3. 
 
Le nali d o mi de is a n off-w hite  t o pale -yell o w  s oli d p o w der.  It 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. Le nali d o mi de 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 d e 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. 
 
R E V LI MI D ® (le nali d o mi de) is a vaila ble i n 5 m g, 1 0 m g,  1 5 m g,  a n d 2 5 m g  ca ps ules f or oral  
a d mi nistrati o n. Eac h  ca ps ule c o ntai ns le nali d o mi de as t he acti ve i n gre die nt  a n d t he f oll o wi n g 
i nacti ve i n gre die nts: lact ose a n h y dr o us, micr ocr ystalli ne cell ul ose,  cr oscar mell ose  s o di u m, 
a n d ma g nesi u m  stearate. 
 
8. 1. 1  Cli nic al P h ar m ac ol o g y  
 
T he  mec ha nis m  of acti o n of le nali d o mi de re mai ns t o be f ull y c haracterize d. 
Le nali d o mi de p ossesses  i m m u n o m o d ulat or y a n d a ntia n gi o ge nic pr o perties.  
Le nali d o mi de i n hi bite d  t he secreti o n of pr o-i nfla m mat or y c yt o ki nes a n d i ncrease d t he 
secreti o n of a nti-i nfla m mat or y c yt o ki nes fr o m peri p heral  bl o o d m o n o n uclear cells. 
Le nali d o mi de i n hi bite d  cell pr oliferati o n  wit h var yi n g  effecti ve ness (I C 5 0s) i n s o me 
b ut n ot all cell li nes.  Of  cell li nes teste d, le nali d o mi de was  effecti ve i n i n hi biti n g 
gr o wt h  of Na mal wa cells (a h u ma n B cell l y m p h o ma cell li ne wit h a deleti o n of o ne 
c hr o m os o me 5) b ut was  m uc h less effecti ve i n i n hi biti n g gr o wt h  of K G - 1 cells 
( h u ma n m yel o blastic cell  li ne, als o wit h a deleti o n  of o ne c hr o m os o me 5) a n d ot her  
cell li nes wit h o ut c hr o m os o me 5 deleti o ns.   Le nali d o mi de i n hi bite d  t he e x pressi o n of 
c ycl o o x y ge nase - 2 ( C O X- 2) b ut  n ot C O X - 1 i n vitr o. 
 
8. 1. 2  P h ar m ac o ki netics  a n d Dr u g  Met a b olis m  
 
Le nali d o mi de,  i n healt h y v ol u nteers,  is ra pi dl y a bs or be d f oll o wi n g oral  
a d mi nistrati o n wit h ma xi m u m  plas ma  c o nce ntrati o ns occ ur ri n g bet wee n  0. 6 2 5 a n d 
1. 5 h o urs  p ost -d ose.  C o a d mi nistrati o n wit h f o o d d oes  n ot alter t he e xte nt of 
a bs or pti o n ( A U C) b ut d oes re d uce t he ma xi mal plas ma  c o nce ntrati o n ( C ma x) b y 
3 6 %.  T he  p har mac o ki netic dis p ositi o n of le nali d o mi de is li near. C ma x  a n d A U C  
i ncrease pr o p orti o natel y  wit h i ncreases i n d ose.  M ulti ple  d osi n g at t he rec o m me n de d 
d ose -re gi me n d oes n ot res ult i n dr u g acc u m ulati o n. 
 
P har mac o ki netic  sa m pli n g i n m yel o d ys plastic s y n dr o me ( M D S) patie nts  was n ot 
perf or me d.  I n m ulti ple m yel o ma  patie nts ma xi m u m  plas ma  c o nce ntrati o ns occ urre d  
bet wee n  0. 5 a n d 4. 0 h o urs p ost- d ose b ot h o n Da ys  1 a n d 2 8. A U C  a n d C ma x  val ues  
i ncrease pr o p orti o nall y  wit h d ose f oll o wi n g si n gle a n d m ulti ple d oses.  E x p os ure  
( A U C) i n m ulti ple m yel o ma  patie nts  is 5 7 % hi g her t ha n i n healt h y male  v ol u nteers. 
 
8. 1. 3  P h ar m ac o ki netic  P ar a meters  

2 3  
 
I n vitr o ( 1 4 C) -le nali d o mi de bi n di n g  t o plas ma  pr otei ns is a p pr o xi matel y  3 0 %. 
T he  meta b olic pr ofile of le nali d o mi de i n h u ma ns  has  n ot bee n  st u die d. I n healt h y 
v ol u nteers,  a p pr o xi matel y t w o-t hir ds of le nali d o mi de is eli mi nate d u nc ha n ge d  
t hr o u g h uri nar y  e xcreti o n. T he pr ocess  e xcee ds t he gl o mer ular  filtrati o n rate a n d 
t heref ore is partiall y or e ntirel y acti ve.  Half -life of  eli mi nati o n is a p pr o xi matel y 3 
h o urs 
 
8. 2  
Dr u g  S u p pl y  a n d D os a ge  
 
T he  pla n ne d  d ose le vels of le nali d o mi de f or p hase 1 tra ns pla nt p orti o n of t he 
i n vesti gati o n is as o utli ne d  i n o n pa ge i. T he M T D  deter mi ne i n t he p hase 1 p orti o n of 
t his st u d y will be  use d i n t he  tra ns pla nt p hase of  t he p hase 2 p orti o n.  T he  mai nte na nce  
d ose of le nali d o mi de is t he sa me re gar dless of  st u d y p hase.  Mai nte na nce  
le nali d o mi de will be gi n  at Da y + 1 0 0  at a d ose of 2 5  m g/ da y,  orall y  f or 1- 2 1 da ys  
f oll o we d b y  a 7- da y rest peri o d  ( 2 8 da y  c ycles). S u bjects e x perie nci n g a d verse  
e ve nts m a y  nee d  st u d y treat me nt m o dificati o ns  as o utli ne d a b o ve i n Secti o n  6. 
 
Cel ge ne C or p orati o n  will  s u p pl y Re vli mi d ® (le nali d o mi de) t o st u d y partici pa nts  at n o 
c har ge t hr o u g h t he Re v Assist ® pr o gra m.  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 a n d all 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 Cel ge ne’s 
Re v Assist ® pr o gra m.  
 
If a d ose of  le nali d o mi de is misse d,  it s h o ul d be ta ke n as s o o n as p ossi ble o n t he sa me 
da y.   If it is misse d  f or t he e ntire da y,  it s h o ul d n ot be ma de  u p. 
Patie 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. 
 
8. 3  
Or deri n g  a n d P ac k a gi n g  
 
Le nali d o mi de will be  s hi p pe d directl y  t o patie nts.   B ottles  will  c o ntai n a s ufficie nt 
n u m ber of ca ps ules t o last f or o ne c ycle of d osi n g.  
 
8. 3. 1  St or a ge a n d S peci al  H a n dli n g  I nstr ucti o ns 
 
St u d y dr u g s h o ul d be st ore d at r o o m te m perat ure a wa y fr o m direct  s u nli g ht a n d 
pr otecte d  fr o m e xcessi ve heat  a n d c ol d.  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 t he cli nical d osa ge f or ms u nless t he y are weari n g  gl o ves.  
 
8. 3. 2  Prescri bi n g  I nf or m ati o n 
 
Le nali d o mi de ( Re vli mi d ® ) will  be pr o vi de d  t o researc h s u bjects f or t he d urati o n of 
t heir partici pati o n  i n t his trial at n o c har ge t o t he m or t heir  i ns ura nce pr o vi ders.  
Le nali d o mi de will be  pr o vi de d i n acc or da nce wit h t he  Re v Assist ® pr o gra m  of Cel ge ne  
C or p orati o n.   Per  sta n dar d Re v Assist ® 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, a n d all 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 

2 4  
 
t he Re v Assist ® 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. 
 
 
8. 4 Le n ali d o mi de  Acc o u nt a bilit y  
 
Le nali d o mi de  I n ve nt or y Rec or ds  – T he i n vesti gat or, or a res p o nsi ble part y desi g nate d  
b y  t he i n vesti gat or, will  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 
all a ge nts recei ve d fr o m S p o ns or o n a Dr u g  Acc o u nta bilit y Rec or d  F or m  ( D A R F). 
 
9.  S T U D Y  E V A L U A TI O N S  
 
Patie nts  will be  f oll o we d dail y  d uri n g t heir i n patie nt sta y d uri n g  t he tra ns pla nt p orti o n of  t he 
st u d y ( Da y - 5 u ntil e n graft me nt). T hereafter,  t he y will be  f oll o we d i n cli nic o n da ys  + 2 8,  + 5 6,  
+ 1 0 0,  a n d t hereafter e ver y 2 8 da ys  ( +/- 2 da ys ). Wit hi n t w o wee ks  of a d missi o n t o t he h os pital  
f or tra ns pla nt, fe males of  c hil d beari n g p ote ntial m ust ha ve  a pre g na nc y test wit h a se nsiti vit y of 
at least 5 0 mI U/ d L.  T hereafter,  fe males of c hil d beari n g p ote ntial will t he n ha ve a pre g na nc y test 
e ver y 2 8 da ys  if t he y ha ve re g ular or n o me nstr ual  c ycles or e ver y 1 4 da ys if t he y are irre g ular 
( See A p pe n di x  D f or c o m plete  pre g na nc y testi n g, birt h c o ntr ol a n d c o u nseli n g).  Fe males  of 
c hil d beari n g p ote ntial ma y  als o nee d t o ha ve a pre g na nc y test if a peri o d is misse d  or if  t here is 
u n us ual  me nstr ual  blee di n g.   F C B P  will ha ve a d diti o nal pre g na nc y  tests at disc o nti n uati o n  of 
st u d y dr u gs  a n d at Da y  2 8 after disc o nti n uati o n  of st u d y dr u gs  ( F C B P wit h  irre g ular me nstr ual  
c ycles will  als o ha ve  a pre g na nc y test at Da y  1 4 after disc o nti n uati o n  of st u d y dr u gs). D uri n g  
sc he d ule d st u d y visits patie nts  will u n der g o  t he f oll o wi n g e val uati o ns f or  assess me nt of  res p o nse 
a n d t o xicit y ( de picte d i n T a ble 4 bel o w). Baseli ne  e val uati o ns are t o be c o n d ucte d wit hi n  6 wee ks  
pri or t o tra ns pla nt date,  u nless ot her wise n ote d. A St u d y Cale n dar  of Assess me nts  is s h o w n o n 
t he ne xt pa ge i n T a ble 4 . 
 
T a ble  4: St u d y C ale n d ar  
 
Scr e e ni n g  
Tr a ns pl a nt  P h as e  
M ai nt e n a nc e P h as e  
 
( < 6 wee ks  
pri or t o 
tra ns pla nt 
date: Da y  0)  
Da y  + 2 8  
Da y  + 5 6  
Da y  + 1 0 0  
( C ycle 1, Da y  
1)  
C ycle  
1, Da ys  
8, 1 5, 2 2  
All  Ot her  
C ycles  
Da y  1 
Off 
St u d y 
I nf or me d C o nse nt  
X  
 
 
 
 
 
 
C o m plete  me dic al  hist or y 1  
X 1  
X  
X  
X  
X  
X  
X  
P h ysic al  e x a m, K P S,  vit al  
si g ns, wei g ht 1  
X 1 
X  
X  
X  
X  
X  
X  
C B C 1  
X 1 
X  
X  
X  
X  
X  
X  
C o m plete  met a b olic  
pr ofile 1, 2  
X 1 
X  
X  
X  
X  
X  
X  
S P E P,  I F, q u a nt  
i m m u n o gl o b uli ns1  
X 1 
X  
X  
X  
 
X  
X  
Ser u m  free li g ht c h ai ns 1  
X 1 
X  
X  
X  
 
X  
X  
2 4 -h o ur  uri ne  f or U T P,  
U P E P,  UI F 1  
X 1 
X  
X  
X  
 
X  
 
Ser u m  pre g n a nc y  test1, 3  
X 1  
X  
X  
X  
X  
X 3  
X 3  
2 4 -h o ur  uri ne  f or 
cre ati ni ne cle ar a nce 
X  
 
 
 
 
 
 
C hest  x -r a y 
X  
 
 
 
 
 
 

2 5  
 
 
P ar a n as al  Si n us  X -r a y 
X  
 
 
 
 
 
 
De nt al  Cle ar a nce  
X  
 
 
 
 
 
 
β 2M
1  
X 1 
 
 
 
 
 
 
C R P,  L D H,  uric  aci d 1  
X 1  
 
 
 
 
 
 
L D H 1, T S H 1  
X 1  
 
 
 
 
 
 
Ec h oc ar di o gr a m  or  
M U G A  
X  
 
 
 
 
 
 
P ul m o n ar y  F u ncti o n  
Testi n g  
X  
 
 
 
 
 
 
Re gister  p atie nt  i nt o 
Re v As sist® pr o gr a m 5  
X  
 
 
 
 
 
 
S kelet al  s ur ve y or  w h ole  
b o d y  P E T/ C T  sc a n 
X  
 
 
X  
 
X 4 
 
B o ne  m arr o w  bi o ps y  a n d  
as pir ate 4  
X  
X 7 
 
X  
 
X 4 
 
F A C T -B M T  s ur ve y f or 
q u alit y  of  life 
X  
 
 
X  
 
X 6 
 
C o nc urre nt  me dic ati o n  use  
s ur ve y1  
X  
X  
X  
X  
X  
X  
X  
Dr u g  dis pe ns ati o n  5  
C o nti n u o us  
A d verse  e ve nt m o nit ori n g  
C o nti n u o us  (as defi ne d  i n detail  i n Secti o n  5. 1)  
1.  Wit hi n  4  wee ks  pri or  t o st arti n g tre at me nt. U T P  =  uri ne  t ot al pr otei n;  U P E P  =  uri ne  pr otei n  
electr o p h oresis;  UI F = uri ne  i m m u n ofi x ati o n; S P E P  = ser u m pr otei n  electr o p h oresis;  I F = ser u m 
i m m u n ofi x ati o n; β 2M = bet a - 2 micr o gl o b uli n.  
2.  I ncl u des s o di u m, p ot assi u m,  c hl ori de,  C O 2, c alci u m, bl o o d  ure a  nitr o ge n  ( B U N), cre ati ni ne, gl uc ose,  
al b u mi n,  t ot al pr otei n,  al k ali ne  p h os p at ase,  t ot al bilr u bi ne,  S G O T/ A S T,  S G P T/ A L T.  
3.  Pre g n a nc y  tests f or fe m ales of  c hil d be ari n g  p ote nti al.   A fe m ale of  c hil d be ari n g  p ote nti al  ( F C B P) is a 
se x u all y m at ure  fe m ale w h o:  1)  h as  n ot  u n der g o ne  a h ysterect o m y  or  bil ater al  o o p h orect o m y;  or  2)  
h as  n ot  bee n  n at ur all y  p ost me n o p a us al  f or at  le ast 2 4  c o nsec uti ve m o nt hs  (i.e., h as  h a d  me nses  at  a n y  
ti me i n t he prece di n g  2 4  c o nsec uti ve m o nt hs). Pre g n a nc y  tests m ust  occ ur  wit hi n  1 0  – 1 4  d a ys  a n d  
a g ai n  wit hi n  2 4  h o urs  pri or  t o prescri bi n g  le n ali d o mi de ( prescri pti o ns m ust  be  fille d wit hi n  7 d a ys).  
F C B P  wit h  re g ul ar or  n o  me nstr u ati o n  m ust  h a ve  a pre g n a nc y  test wee kl y  f or t he first 2 8  d a ys  a n d  
t he n e ver y 2 8  d a ys  w hile  o n  t her a p y (i ncl u di n g bre a ks  i n t her a p y); at  disc o nti n u ati o n  of  le n ali d o mi de 
a n d  at  D a y  2 8  p ost  t he l ast d ose  of  le n ali d o mi de. Fe m ales  wit h  irre g ul ar me nstr u ati o n  m ust  h a ve  a 
pre g n a nc y  test wee kl y  f or t he first 2 8  d a ys  a n d  t he n e ver y 1 4  d a ys  w hile  o n  t her a p y (i ncl u di n g bre a ks  
i n t her a p y), at  disc o nti n u ati o n  of  le n ali d o mi de a n d  at  D a y  1 4  a n d  D a y  2 8  p ost  t he l ast d ose  of  
le n ali d o mi de(see A p pe n di x  III: Ris ks  of  Fet al  E x p os ure,  Pre g n a nc y  Testi n g  G ui deli nes  a n d  
Acce pt a ble  Birt h  C o ntr ol  Met h o ds).  
4.  T o  c o nfir m C R  or  w he n  cli nic all y i n dic ate d. 
5.  Le n ali d o mi de  m ust  be  prescri be d  t hr o u g h a n d  i n c o m pli a nce  wit h  Cel ge ne’s  Re v Assist ®  pr o gr a m.  
Prescri pti o ns  of  le n ali d o mi de m ust  be  fille d wit hi n  7 d a ys.  
6.  T o  be  d o ne  C ycle  6,  d a y  1 o nl y.  See  a p pe n di x  E f or q uesti o n airre  
7.  T o  be  d o ne  o n  D a y  - 2 (t w o d a ys  pri or  t o ste m cell i nf usi o n) 
 
L a bs  re q uire d as  per  t he st u d y c ale n d ar o n  d a ys  + 2 8, + 5 6  a n d  + 1 0 0  c a n be  d o ne  ( +/-) 2  d a ys  
 
 
 
 
 
 
 
 
9. 1  
B aseli ne E v al u ati o n  

2 6  
 
All baseli ne e val uati o ns  are t o be d o ne wit hi n  6 wee ks  of start of  t hera p y, u nless ot her wise  
s pecifie d: 
 
•  C o m plete  bl o o d c o u nt ( C B C) wit h  differe ntial a n d  platelets  ( WI T HI N 4 W E E K S  O F  
T R E A T M E N T)  
•  C o m plete  meta b olic  pr ofile (i ncl u di n g  s o di u m, p otassi u m, c hl ori de, C O 2, calci u m, 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, S G O T/ A S T,  S G P T/ A L T.   ( WI T HI N 4 W E E K S  O F  T R E A T M E N T)  
•  T S H  ( WI T HI N 4 W E E K S  O F  T R E A T M E N T)  
•  C R P, L D H,  uric  aci d ( WI T HI N 4 W E E K S  O F  T R E A T M E N T)  
•  Beta - 2 micr o gl o b uli n ( WI T HI N 4 W E E K S  O F  T R E A T M E N T)  
•  2 4 -h o ur uri ne c ollecti o n f or t otal pr otei n, pr otei n  electr o p h oresis, a n d i m m u n ofi xati o n. 
•  Ser u m  pr otei n  electr o p h oresis,  ser u m i m m u n ofi xati o n, ser u m q ua ntitati ve  
i m m u n o gl o b uli ms, a n d ser u m free li g ht c hai ns st u dies.( WI T HI N 4 W E E K S O F  
T R E A T M E N T)  
•  P h ysical  e xa mi nati o n wit h hist or y,  vital  si g ns, a n d perf or ma nce stat us ( WI T HI N 4 
W E E K S  O F  T R E A T M E N T)  
•  C o nc urre nt  me dicati o n  use s ur ve y( WI T HI N 4 W E E K S O F T R E A T M E N T)  
•  F A C T -B M T  q ualit y of  life s ur ve y 
•  W h ole b o d y P E T -C T  sca n or s keletal s ur ve y 
•  Ser u m  pre g na nc y test (f or fe males of  c hil d beari n g p ote ntial)  ( WI T HI N 1 0 -1 4  D A Y S  
P RI O R  T O A N D  A G AI N WI T HI N 2 4 H R S  O F  P R E S C RI BI N G  L E N A LI D O MI D E  
wit h se nsiti vit y descri be d  a b o ve) 
•  
B o ne marr o w  as pirate a n d c ore bi o ps y 
•  Re gistrati o n  of patie nt i nt o Re v Assist  pr o gra m  
•  Sta n dar d  pre -n o ne marr o w tra ns pla nt e val uati o n, i ncl u di n g: 
•  C hest  x-ra y 
•  Para nasal  si n us x-ra y 
•  P ul m o nar y f u ncti o n testi n g, i ncl u di n g s pir o metr y a n d diff usi o n  ca pacit y 
•  2 4 h o ur uri ne  f or creati ni ne cleara nce 
•  Ec h ocar di o gra m  or M U G A  sca n 
•  De ntal  cleara nce ( writte n  d oc u me ntati o n  of de ntal  i ns pecti o n b y  de ntist  i n dicati n g 
n o acti ve i nfecti o ns or nee d  f or t o ot h e xtracti o n) 
 
9. 1. 1  Da y  - 2 ( T w o da ys  pri or t o Mel p hala n  I nf usi o n) 
•  B o ne marr o w  as pirati o n a n d bi o ps y 
 
9. 2  
D a y + 2 8( +/ - 2 d a ys) a n d D a y + 5 6 ( +/- 2 d a ys) visits ( Tr a ns pl a nt p h ase)  
 
•  C o m plete  bl o o d c o u nt ( C B C) wit h  differe ntial  a n d platelets  
•  C o m plete  meta b olic  pr ofile (i ncl u di n g s o di u m, p otassi u m, c hl ori de, C O 2,  
calci u m, 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, S G O T/ A S T,  S G P T/ A L T.  

2 7  
 
•  2 4 -h o ur uri ne c ollecti o n f or t otal pr otei n, pr otei n  electr o p h oresis, a n d 
i m m u n ofi xati o n. 
•  Ser u m  pr otei n  electr o p h oresis, ser u m i m m u n ofi xati o n, ser u m q ua ntitati ve  
i m m u n o gl o b uli ms, a n d ser u m free li g ht c hai ns st u dies. 
•  P h ysical  e xa mi nati o n wit h hist or y,  vital  si g ns, a n d perf or ma nce stat us 
•  C o nc urre nt  me dicati o n  use s ur ve y 
•  Ser u m  pre g na nc y test (f or fe males of  c hil d beari n g p ote ntial)  
 
9. 3  
D a y + 1 0 0 ( +/- 2 d a ys) visit ( C ycle 1, D a y  1 of M ai nte n a nce p h ase)  
 
•  C o m plete  bl o o d c o u nt ( C B C) wit h  differe ntial  a n d platelets  
•  C o m plete  meta b olic  pr ofile (i ncl u di n g  s o di u m, p otassi u m, c hl ori de, C O 2,  
calci u m, 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, S G O T/ A S T,  S G P T/ A L T)  
•  2 4 -h o ur uri ne c ollecti o n f or t otal pr otei n, pr otei n  electr o p h oresis, a n d 
i m m u n ofi xati o n. 
•  Ser u m  pr otei n  electr o p h oresis, ser u m i m m u n ofi xati o n, ser u m q ua ntitati ve  
i m m u n o gl o b uli ms, a n d ser u m free li g ht c hai ns st u dies. 
•  P h ysical  e xa mi nati o n wit h hist or y,  vital  si g ns, a n d perf or ma nce stat us 
•  C o nc urre nt  me dicati o n  use s ur ve y 
•  Ser u m  pre g na nc y test (f or fe males of  c hil d beari n g p ote ntial: 1 0 - 1 4 da ys  pri or t o 
a n d a gai n wit hi n 2 4 hrs of prescri bi n g  le nali d o mi de) 
•  F A C T -B M T  q ualit y of  life s ur ve y 
•  B o ne marr o w  as pirate a n d c ore bi o ps y 
•  W h ole b o d y P E T -C T  sca n or s keletal s ur ve y as cli nicall y i n dicate d t o c o nfir m 
c o m plete re missi o n or disease  pr o gressi o n.  
 
9. 4  
D a y + 1 0 8, 1 1 5, 1 2 2 visits ( C ycle 1, D a y  8, 1 5, 2 2  of C ycle  1 i n M ai nte n a nce p h ase)  
 
•  C o m plete  bl o o d c o u nt ( C B C) wit h  differe ntial  a n d platelets  
•  C o m plete  me ta b olic pr ofile (i ncl u di n g  s o di u m, p otassi u m, c hl ori de, C O 2,  
calci u m, 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, S G O T/ A S T,  S G P T/ A L T)  
 
9. 5  
All ot her c ycles  o n m ai nte n a nce p h ase,  D a y 1 a n d E n d - of-st u d y visit  
 
•  C o m plete  bl o o d c o u nt ( C B C) wit h  differe ntial  a n d platelets  
•  C o m plete  meta b olic  pr ofile (i ncl u di n g  s o di u m, p otassi u m, c hl ori de, C O 2,  
calci u m, 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, S G O T/ A S T,  S G P T/ A L T,  L D H,  uric  aci d, 
P h os p h or o us, Ma g nesi u m)  
•  2 4 -h o ur uri ne c ollecti o n f or t otal pr otei n, pr otei n  electr o p h oresis, a n d 
i m m u n ofi xati o n. T his test is n ot re q uire d at t he e n d- of-st u d y visit.  
•  Ser u m  pr otei n  electr o p h oresis, ser u m i m m u n ofi xati o n, ser u m q ua ntitati ve  
i m m u n o gl o b uli ms, a n d ser u m free li g ht c hai ns st u dies. 
•  P h ysical  e xa mi nati o n wit h hist or y,  vital  si g ns, a n d perf or ma nce stat us 

2 8  
 
•  C o nc urre nt  me dicati o n  use s ur ve y 
•  Ser u m  pre g na nc y test (f or fe males of  c hil d beari n g p ote ntial)  
•  B o ne marr o w  as pirate a n d c ore bi o ps y, t o c o nfir m c o m plete re missi o n or 
pr o gressi o n  of disease,  as cli nicall y i n dicate d.  T his test is n ot re q uire d at t he e n d- 
of-st u d y visit u nless  cli nicall y i n dicate d. 
•  W h ole b o d y P E T -C T  sca n or s keletal s ur ve y, t o c o nfir m c o m plete  re missi o n or 
pr o gressi o n  of disease,  as cli nicall y i n dicate d. T hese tests are n ot re q uire d at t he 
e n d-of -st u d y. 
•  F A C T -B M T  q ualit y of  life s ur ve y ( C Y C L E 6 D a y 1, o nl y) 
 
 
9. 6  
P ost  st u d y f oll o w-u p  
 
All atte m pts will be  ma de  t o f oll o w patie nts  u ntil pr o gressi o n  or deat h. S u bjects  w h o ha ve bee n  
disc o nti n ue d  fr o m st u d y will still be  f oll o we d i n a cli nic setti n g t o t he f ullest e xte nt p ossi ble  o n a 
m o nt hl y t o bi-m o nt hl y  basis.  T h ose w h o c h o ose n ot t o res u me re g ular cli nic f oll o w-u p will be  
c o ntacte d e ver y 6 m o nt hs b y  tele p h o ne or electr o nicall y  t o c ollect p ost st u d y i nf or mati o n. T he  
p ost-st u d y c ollecti o n i nf or mati o n will c o nsist of tele p h o ne i nter vie w bet wee n t he cli nical 
i n vesti gat or a n d t he disc o nti n ue d patie nt.  T he  i nf or mati o n re q ueste d will  be c urre nt disease  
stat us, c urre nt treat me nt use,  a n d p h ysical  stat us of t he patie nt.  
 
9. 7  
Criteri a  f or re m o v al fr o m st u d y 
 
Treat me nt  wit h st u d y dr u gs is t o be disc o nti n ue d  w he n  a n y  of t he f oll o wi n g occ urs:  
 
•  Pr o gressi ve disease  (see A p pe n di x  C)  
•  A d verse  e ve nt(s) t hat, i n t he j u d g me nt of a n I n vesti gat or, ma y  ca use se vere or per ma ne nt  
har m or w hic h  r ule o ut c o nti n uati o n of  st u d y dr u g  
•  Maj or  vi olati o n  of t he st u d y pr ot oc ol 
•  N o n -c o m plia nce or  refusal  of t he pate nt  t o c o nti n ue treat me nt a n d/ or e val uati o n 
•  Wit h dra wal  of c o nse nt 
•  Patie nt  is l ost t o f oll o w-u p  
•  Deat h  
•  Pre g na nc y  or a p ositi ve pre g na nc y  test 
•  T he  patie nt  ac hie ves a sta ble platea u  a n d is eli gi ble t o pr ocee d  t o hi g h  d ose c he m ot hera p y 
a n d ste m cell tra ns pla ntati o n 
•  T he  de vel o p me nt  of a n y  c o-m or bi d  c o n diti o n or e xcessi ve  t o xicit y t hat w o ul d ma ke  
f urt her partici pati o n i n t he pr ot oc ol  u nsafe 
•  At t he  discreti o n  of t he pri nci pal  i n vesti gat or a n d/ or Cel ge ne  C or p orati o n  f or a n y reas o n 
 
A n y  p ossi ble pre mat ure  disc o nti n uati o n  w o ul d be d oc u me nte d  a de q uatel y wit h reas o ns bei n g 
state d, a n d i nf or mati o n w o ul d ha ve t o be iss ue d acc or di n g t o l ocal re q uire me nts (e. g., I R B/ E C, 
re g ulat or y a ut h orities, etc.). 
T he  res p o nsi ble Cli nical  I n vesti gat or as well as t he S u p p orters ( Cel ge ne C or p orati o n) ha ve t he 
ri g ht t o disc o nti n ue t his st u d y at a n y  ti me f or reas o na ble me dical  or a d mi nistrati ve reas o ns  i n a n y  
si n gle ce nter.  P ossi ble reas o ns f or ter mi nati o n of t he st u d y c o ul d be b ut are n ot li mite d t o: 

2 9  
 
•  U nsatisfact or y  e nr oll me nt wit h res pect t o q ua ntit y or q ualit y.  
•  I nacc urate or i nc o m plete data  c ollecti o n. 
•  Falsificati o n  of rec or ds. 
•  Fail ure  t o a d here t o t he st u d y pr ot oc ol.  
 
1 0  M E A S U R E M E N T  O F  E F F E C T  
 
1 0. 1  Dise ase Res p o nse  
 
Disease res p o nse cate g or y (e. g. partial  res p o nse, ver y g o o d  partial  res p o nse, c o m plete res p o nse, 
stri n ge nt c o m plete  res p o nse) will  be as defi ne d  b y  t he I nter nati o nal U nif or m Res p o nse Criteria  
f or M ulti ple  M yel o ma  ( A p pe n di x C).  
 
1 0. 2  D ur ati o n  of Res p o nse  
 
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  fr o m t he ti me 
meas ure me nt  criteria are met f or C R or P R ( w hic he ver is first rec or de d) u ntil t he first date t hat 
rec urre nt or pr o gressi ve  disease is o bjecti vel y d oc u me nte d (ta ki n g as refere nce f or pr o gressi ve  
disease t he s mallest meas ure me nts  rec or de d si nce t he treat me nt starte d). 
 
1 0. 3  O ver all  S ur vi v al  
 
O verall  s ur vi val: T he  i nter val bet wee n  t he da y  of  tra ns pla ntati o n ( Da y 0)  a n d date  of deat h.  If t he 
date  of deat h is u ncertai n,  t he date  of  last c o ntact wit h t he  s u bject will be use d.  
 
1 0. 4  Q u alit y  of  Life  
 
Q ualit y  of life  will be  e val uate d a n d sc ore d usi n g t he q uesti o n naire  fr o m t he b o ne marr o w  
tra ns pla nt s u bscale of t he F u ncti o nal  Assess me nt  of Ca ncer  T hera p y a vaila ble fr o m  
w w w.facit. or g . See A p pe n di x E f or a n e xa m ple q uesti o n naire.  
 
1 1  
D A T A  R E P O R TI N G  / R E G U L A T O R Y C O N SI D E R A TI O N S  
 
1 1. 1  
D at a  C ollecti o n  
 
T he  data  c ollecti o n pla n f or t his st u d y  is t o utilize  t he Re d Ca p data base wit h  s u p p ort fr o m t he 
i nstit uti o nal C T S A  ( Cli nical Tra nslati o n  Scie nce  A war d)  ce nter t o ca pt ure all treat me nt, t o xicit y, 
a n d efficac y data f or all e nr olle d patie nts.  
 
1 1. 2 
Re g ul at or y  C o nsi der ati o ns  
 
All pr ot oc ol  a me n d me nts a n d c o nse nt f or m m o dificati o ns  will be ma de b y  t he Pri nci pal  
I n vesti gat or. Cel ge ne will  ha ve t he o p p ort u nit y t o re vie w a n d a p pr o ve t he c ha n ges pri or t o 
s u b missi o n of t hese c ha n ges t o t he l ocal I R B a n d distri b uti o n t o partici pati n g  sites. 
 
1 2.  S T A TI S TI C A L  C O N SI D E R A TI O N S  

3 0  
 
1 2. 1  
St u d y Desi g n/ E n d p oi nts  
 
T his st u d y is desi g ne d  t o occ ur  i n t w o secti o ns: A p hase 1 st u d y, i n w hic h t he pri mar y o bjecti ve 
is t o deter mi ne t he ma xi m u m  t olerate d d ose ( M T D) of le nali d o mi de t o be use d  wit h sta n dar d 
mel p hala n - base d a ut ol o g o us ste m cell tra ns pla ntati o n; a n d 2) A p hase 2 st u d y, i n w hic h t he 
pri mar y  e n d p oi nt is t o deter mi ne t he d urati o n of res p o nse t o le nali d o mi de + mel p hala n  
c o n diti o ni n g f or a ut ol o g o us ste m cell tra ns pla ntati o n. 
 
F or  t he p hase 1 st u d y: 
 
Deter mi nati o n  of t he d ose -li miti n g t o xicit y ( D L T) a n d st u d y met h o ds are  defi ne d  a b o ve i n 
Secti o n  5. T he desi g n  is c o nstr ucte d t o re d uce t he c ha nce of escalati n g  t he d ose w he n  t he 
pr o ba bilit y of D L T  is hi g h, a n d i ncrease t he c ha nce of escalati n g  t he d ose w he n  t he pr o ba bilit y 
of D L T  is l o w.  T he ma xi m u m t olerate d d ose is defi ne d  as t he hi g hest d ose le vel wit h a n 
o bser ve d  i nci de nce of D L T  i n n o m ore t ha n o ne o ut of si x patie nts  treate d at a partic ular  d ose 
le vel.  T he  d ose escalati o n sc he me is as f oll o ws: 
 
T he  d ose escalati o n sc he me pr o vi des  t he f oll o wi n g pr o ba bilities of  escalati o n base d  o n t he tr ue 
c ha nces of D L T  at a s pecific d ose le vel. O ne  ca n see t hat t he pr o ba bilit y of escalati o n is hi g h  if 
t he t o xicit y ris ks are l o w. 
 
Tr ue Pr o ba bilit y  of  T o xicit y:  . 0 5 
. 1 0 
. 2 0 
. 3 0 
. 4 0 
. 5 0 
. 6 0 
Pr o ba bilit y  of  Escalati o n:  
. 9 7 
. 9 1 
. 7 1 
. 4 9 
. 3 1 
. 1 7 
. 0 8 
 
 
After  t he deter mi nati o n  of t he M T D, a  p hase 2 trial will be i nitiate d wit h t he d ose selecte d o n t he 
basis  of t he p hase 1 st u d y. 
 
F or  t he p hase 2 st u d y: 
 
T he  pri mar y  e n d p oi nt is meas ure me nt  of d urati o n of res p o nse, as defi ne d  i n Secti o n  1 1. T he  
d urati o n  of res p o nse t o t he st u d y me dicati o ns will be c o m pare d t o hist orical  data  f or sta n dar d 
A S C T usi n g  mel p hala n  c o n diti o ni n g al o ne. Hist oricall y,  5 0 % of  patie nts  wit h rela pse d M M will  
mai ntai n res p o nse at 1 2 m o nt hs f oll o wi n g  A S C T. E nr oll me nt  of a t otal of 2 9 patie nts  i n t he 
e x pa n de d M T D c o h ort ( p hase 2 p orti o n  of st u d y) will gi ve  a n 8 0 % p o wer t o detect  a 2 5 % 
differe nce i n t he pr o p orti o n of patie nts  i n c o nti n ue d res p o nse at 1 2 m o nt hs wit h a n t w o -taile d 
al p ha = 0. 0 5. D urati o n  of res p o nse, o verall  s ur vi val a n d ot her  s uc h ti me-relate d e n d p oi nts will be  
a nal yze d via t he Ka pla n -Meier  met h o d a n d l o g-ra n k test will be use d  t o deter mi ne statistical  
si g nifica nce. 
 
 
 
 
 
1 2. 2  
S a m ple  Size/ Accr u al  R ate  

3 1  
 
F or  t he p hase 1 p orti o n of t he st u d y: A mi ni m u m of si x  a n d a ma xi m u m  of 3 6 patie nts  w o ul d be 
treate d o n t his trial.  It is e x pecte d t hat t he st u d y will accr ue 1 0 patie nts per year  a n d will  ta ke 
a p pr o xi matel y 3 0 m o nt hs. 
 
F or  t he p hase 2 p orti o n  of  t he st u d y: A n  e nr oll me nt of 2 9 patie nts  i n t he e x pa n de d M T D c o h ort 
will be  re q uire d.  It is e x pecte d t hat t he st u d y will accr ue 1 5 patie nts  per year  a n d will  ta ke 
a p pr o xi matel y 3 6 m o nt hs. 
 
1 2. 3  
A n al ysis of Sec o n d ar y  E n d p oi nts  
 
T he  sec o n dar y e n d p oi nt of o verall  res p o nse rate will be  meas ure d  as defi ne d  i n Secti o n  1 1. 
Fis her e xact  test a n d St u de nt t test ( or Wilc oc o n  ra n k-s u m test) will be  use d t o ass ociate cate g or y 
of res p o nse wit h  p ote ntial ris k fact ors s uc h as se x, disease sta ge,  C-reacti ve pr otei n  ( C R P), β - 2 
micr o gl o b uli n,  lactate de h y dr o ge nase,  a n d al b u mi n. All  P val ues  will  be 2 si de d wit h statistical 
si g nifica nce e val uate d at t he 0. 0 5 α le vel. T he  precisi o n of t he o btai ne d  esti mates will  be 
assesse d b y  calc ulati n g  9 5 % c o nfi de nce i nter vals.  
 
T he  sec o n dar y e n d p oi nt of q ualit y of life  ( Q O L) will be  meas ure d  via F A C T -B M T q uesti o n naire  
( A p pe n di x E).   Fis her  e xact test a n d St u de nt  t test ( or Wilc o x o n ra n k-s u m test) will be  use d  t o 
ass ociate Q O L  sc ore wit h cate g or y of  res p o nse, d urati o n of res p o nse, as well as t he ot her  
p ote ntial ris k fact ors liste d a b o ve s uc h as se x, disease sta ge,  C-reacti ve pr otei n ( C R P),  β - 2 
micr o gl o b uli n,  lactate de h y dr o ge nase,  a n d al b u mi n. All  P val ues  will  be 2 si de d wit h statistical 
si g nifica nce e val uate d at t he 0. 0 5 α le vel. T he  precisi o n of t he o btai ne d  esti mates will  be 
assesse d b y  calc ulati n g  9 5 % c o nfi de nce i nter vals.  
 
1 2. 4  Re p orti n g  a n d E xcl usi o ns  
 
1 2. 4. 1 
E v al u ati o n of  t o xicit y. All patie nts 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 wit h  le nali d o mi de. 
 
1 2. 4. 2 
Ev al u ati o n of res p o nse. All p atie nts  i ncl u de d i n t he st u dy will be assesse d  f or 
res p o nse t o tre at me nt if t hey h ave receive d at le ast a ut ol o g o us ste m cell tr a ns pl a nt ati o n 
( u n der we nt D ay  0 ste m cell i nf usi o n). 
 
 
1 3.  
P R O T O C O L  A M E N D M E N T S  A N D D E VI A TI O N S  
 
A n y  a me n d me nt t o t his pr ot oc ol  m ust be a gree d t o b y  t he Pri nci pal I n vesti gat or a n d re vie we d b y  
Cel ge ne.  A me n d me nts  s h o ul d o nl y be s u b mitte d t o I R B/ E C after c o nsi derati o n of Cel ge ne  
re vie w. Writte n verificati o n  of I R B/ E C a p pr o val will be o btai ne d bef ore a n y  a me n d me nt, w hic h  
affects s u bject safet y or efficac y, is i m ple me nte d.  A me n d me nts  t hat are a d mi nistrati ve i n nat ur e 
d o n ot re q uire I R B/ E C a p pr o val b ut will be  s u b mitte d t o t he I R B/ E C f or i nf or mati o n p ur p oses.  
 
All pr ot oc ol  a me n d me nts a n d c o nse nt f or m m o dificati o ns  will be ma de b y  t he Pri nci pal  
I n vesti gat or. Cel ge ne  will ha ve t he o p p ort u nit y t o re vie w a n d a p pr o ve t he c ha n ges pri or t o 
s u b missi o n of t hese c ha n ges t o t he l ocal I R B a n d distri b uti o n t o partici pati n g  sites. 

3 2  
 
1 4  
R E G U L A T O R Y C O N SI D E R A TI O N S  
 
1 4. 1  
I nstit uti o n al Re vie w  B o ar d/ Et hics  C o m mittee a p pr o v al  
 
T he  pr ot oc ol  f or t his st u d y has  bee n desi g ne d  i n acc or da nce wit h t he  ge neral  et hical pri nci ples  
o utli ne d i n t he Declarati o n  of Helsi n ki.  T he  re vie w of t his pr ot oc ol  b y  t he I R B/ E C a n d t he 
perf or ma nce of  all as pects of t he st u d y, i ncl u di n g t he met h o ds use d f or o btai ni n g i nf or me d 
c o nse nt, m ust als o be i n acc or da nce wit h pri nci ples e n u nciate d i n t he declarati o n,  as well as I C H 
G ui deli nes,  Title 2 1 of  t he C o de of Fe deral  Re g ulati o ns  ( C F R), Part  5 0 Pr otecti o n  of H u ma n  
S u bjects  a n d Part  5 6 I nstit uti o nal Re vie w B oar ds.  
 
T he I n vesti gat or will  be res p o nsi ble f or pre pari n g d oc u me nts  f or s u b missi o n t o t he rele va nt 
I R B/ E C a n d o btai ni n g writte n a p pr o val f or t his st u d y.  T he a p pr o val will be o btai ne d  pri or  t o t he 
i nitiati o n of t he st u d y. 
 
T he  a p pr o val f or b ot h t he  pr ot oc ol  a n d i nf or me d c o nse nt m ust s pecif y t he date of a p pr o val, 
pr ot oc ol  n u m ber  a n d versi o n, or a me n d me nt n u m ber.  
 
All pr ot oc ol  a me n d me nts will be  re vie we d b y  Cel ge ne C or p orati o n  pri or  t o s u b missi o n a n d 
a p pr o val b y  t he I nstit uti o nal Re vie w B oar d  (I R B) bef ore t he y ca n be  i m ple me nte d. T he 
i n vesti gat or is als o res p o nsi ble f or n otif yi n g  t he I R B/ E C of a n y seri o us de viati o ns fr o m t he 
pr ot oc ol,  or a n yt hi n g else t hat ma y i n v ol ve a d de d ris k t o s u bjects. 
 
A n y  a d vertise me nts  use d  t o recr uit s u bjects f or t he st u d y m ust be re vie we d a n d a p pr o ve d b y  t he 
I R B/ E C pri or t o use.  
 
1 4. 2  
I nf or me d C o nse nt  Pr oce d ures  
 
T he I n vesti gat or m ust o btai n i nf or me d c o nse nt of a s u bject or his/ her  desi g nee  pri or t o a n y  st u d y 
relate d pr oce d ure as per G C P’s as set f ort h i n t he C F R  a n d I C H g ui deli nes.  
 
D oc u m e ntati o n t hat i nf or me d c o nse nt occ urre d  pri or t o t he s u bject’s e ntr y i nt o t he st u d y a n d t he 
i nf or me d c o nse nt pr ocess  s h o ul d be rec or de d i n t he s u bject’s s o urce d oc u me nts. T he ori gi nal  
c o nse nt f or m, si g ne d a n d date d  b y  t he s u bject a n d b y  t he pers o n c o nse nti n g t he s u bject pri or t o  
t he s u bject’s e ntr y i nt o t he st u d y, m ust be mai ntai ne d  i n t he I n vesti gat or’s st u d y files.  At t he  
pre -a d missi o n c o ns ultati o n, patie nts will be f ull y  i nf or me d as t o t he p ur p oses a n d p ote ntial ris ks  
a n d be nefits  i n v ol ve d i n t his st u d y. Patie nts  will ha ve  a m ple o p p ort u nit y t o as k q uesti o ns  bef ore  
c o nse nti n g. Le gal  g uar dia ns  will si g n i nf or me d c o nse nt f or  le gall y i nc o m pete nt patie nts  i n 
acc or da nce wit h h os pital  p olic y.  
 
 
 
1 4. 3  
Pr otecti n g  Pri v ac y  a n d  C o nfi de nti alit y  
 
C o nfi de ntialit y  will be  mai ntai ne d  wit hi n t he li mits of t he la w. Patie nt  na mes or a n y  ot her  
i de ntif yi n g i nf or mati o n will n ot be use d  i n re p orts or p u blicati o ns  res ulti n g fr o m t his st u d y. O nl y  
q ualifie d  staff fr o m Ne w  Y or k  Pres b yteria n  H os pital,  Weill Me dical  C olle ge of C or nell  

3 3  
 
U ni versit y,  t he F o o d  a n d Dr u g  A d mi nistrati o n,  t he Cel ge ne C or p orati o n  or ot her s u p p orters s uc h 
as t he Nati o nal  Ca ncer  I nstit ute will be  a ble t o re vie w patie nt me dical  rec or ds. 
Cel ge ne a ffir ms t he s u bject’s ri g ht t o pr otecti o n  a gai nst i n vasi o n of pri vac y.   I n c o m plia nce wit h  
U nite d States  fe deral re g ulati o ns, Cel ge ne  re q uires t he I n vesti gat or t o per mit Cel ge ne’s  
re prese ntati ves a n d, w he n necessar y,  re prese ntati ves of t he F D A  or ot her re g ulat or y a ut h orities 
t o re vie w a n d/ or c o p y a n y me dical rec or ds rele va nt t o t he st u d y i n acc or da nce wit h l ocal la ws. 
S h o ul d direct  access t o me dical  rec or ds re q uire a wai ver  or a ut h orizati o n se parate fr o m t he 
s u bject’s state me nt of i nf or me d c o nse nt, it is t he res p o nsi bilit y of t he I n vesti gat or t o o btai n  s uc h 
per missi o n  i n writi n g fr o m t he a p pr o priate i n di vi d ual. 
 
1 4. 4  
St u d y rec or ds re q uire me nts  
 
T he I n vesti gat or m ust e ns ure  t hat t he rec or ds a n d d oc u me nts  pertai ni n g  t o t he c o n d uct of t he 
st u d y a n d t he distri b uti o n of t he st u d y dr u g, t hat is c o pies of C R Fs  a n d s o urce d oc u me nts  
( ori gi nal d oc u me nts,  data, a n d rec or ds [e. g., h os pital rec or ds; cli nical a n d office c harts; 
la b orat or y n otes; me m ora n da;  s u bject’s diaries  or  e val uati o n c hec klists; p har mac y dis pe nsi n g 
rec or ds; rec or de d data  fr o m a ut o mate d i nstr u me nts; c o pies or tra nscri pti o ns certifie d after 
verificati o n  as bei n g acc urate c o pies; micr ofic hes;  p h ot o gra p hic  ne gati ves,  micr ofil m,  or 
ma g netic me dia;  x-ra ys; s u bject files; a n d rec or ds ke pt  at t he p har mac y,  at t he la b orat ories, a n d 
at me dic o -tec h nical de part me nts i n v ol ve d i n t he cli nical st u d y; d oc u me nts  re gar di n g s u bject 
treat me nt a n d st u d y dr u g acc o u nta bilit y; ori gi nal si g ne d i nf or me d c o nse nts, etc.]) be retai ne d b y  
t he I n vesti gat or f or as l o n g as nee de d  t o c o m pl y wit h nati o nal a n d i nter nati o nal re g ulati o ns 
( ge nerall y 2 years  after disc o nti n ui n g cli nical de vel o p me nt  or after t he last mar keti n g a p pr o val).  
T he I n vesti gat or a grees t o a d here t o t he d oc u me nt/rec or ds rete nti o n pr oce d ures  b y  si g ni n g t he 
pr ot oc ol.  
 
1 4. 5  
Pr otecti o n  of H u m a n  Ri g hts  
 
Partici pati o n  i n t his trial is v ol u ntar y.  All patie nts  will be  re q uire d t o si g n a state me nt of  
i nf or me d c o nse nt, w hic h  m ust c o nf or m t o Weill C or nell  Me dical  C olle ge  I R B g ui deli nes.  
 
Patie nts  will be  eli gi ble f or t his trial re gar dless of ge n der  or racial/et h nic bac k gr o u n d.  All  
patie nts  m ust f oll o w t he  g ui deli nes  f or pre g na nc y testi n g, birt h c o ntr ol a n d c o u nseli n g relate d  t o 
t he ris k of fetal e x p os ure t o le nali d o mi de as o utli ne d  i n A p pe n di x  D.  
 
 
1 4. 6  
Pre m at ure Disc o nti n u ati o n  of St u d y  
 
T he  res p o nsi ble l ocal cli nical I n vesti gat or as well  as Cel ge ne  ha ve t he ri g ht t o disc o nti n ue t his 
st u d y at a n y  ti me f or reas o na ble me dical  or a d mi nistrati ve reas o ns  i n a n y  si n gle ce nter.  P ossi ble 
reas o ns f or ter mi nati o n of t he st u d y c o ul d be b ut are n ot li mite d t o: 
 
•  U nsatisfact or y  e nr oll me nt wit h res pect t o q ua ntit y or q ualit y.  
•  I nacc urate or i nc o m plete data  c ollecti o n. 
•  Falsificati o n  of rec or ds. 
•  Fail ure  t o a d here t o t he st u d y pr ot oc ol.  

3 4  
 
•  Seri o us  a d verse e ve nts, i nt olera bilit y of dr u g re gi me n, or s u d de n/ u ne x pecte d deat h  i n a n y  
of t he earl y trial ( u p t o t hree patie nts) partici pa nts,  as o utli ne i n secti o n 9. 2. 
 
1 4. 6. 1 St u d y as a  w h ol e  
 
Cel ge ne reser ves  t he ri g ht t o ter mi nate t his cli nical st u d y at a n y ti me f or reas o na ble me dical  or 
a d mi nistrati ve reas o ns.  
 
A n y  p ossi ble pre mat ure  disc o nti n uati o n  w o ul d be d oc u me nte d  a de q uatel y wit h reas o ns bei n g 
state d, a n d i nf or mati o n w o ul d ha ve t o be iss ue d acc or di n g t o l ocal re q uire me nts (e. g. I R B/ E C, 
re g ulat or y a ut h orities, etc.). 
 
1 4. 7  
Be nefits  of t he Pr ot oc ol  
 
T he  p ote ntial  be nefit of t his st u d y is t he de vel o p me nt of a safe a n d effecti ve treat me nt  pr o gra m  
f or M M patie nts w h o ha ve disease rela pse.   K n o wle d ge will be  ac q uire d a b o ut t his treat me nt 
pr o gra m,  its t olera bilit y, a n d t he effecti ve ness of le nali d o mi de  ( Re vli mi d ®) i n c o m bi nati o n wit h  
mel p hala n  pri or  t o a ut ol o g o us ste m cell tra ns pla nt t he treat me nt of rela pse d or refract or y M M.  If 
effecti ve, t his treat me nt pla n ma y  i m pr o ve disease -free a n d o verall  s ur vi val M M patie nts.  
 
1 4. 8  
Ris ks i n  Rel ati o n  t o A ntici p ate d  Be nefit  
 
T he  ris ks ass ociate d wit h partici pati o n  i n t his trial are c o m me ns urate wit h  t he e x pecte d ris ks of 
ot her p ote ntial t hera pies a n d are reas o na ble gi ve n  t he p ote ntial  be nefit  t o patie nts wit h ne wl y 
dia g n ose d  M M.  If t he c o m bi nati o n of le nali d o mi de wit h mel p hala n -base d  a ut ol o g o us  ste m cell 
tra ns pla ntati o n de m o nstrate d  is as effecti ve a gai nst rela pse d M M as  a ntici pate d, t his re gi me n 
c o ul d bec o me  sta n dar d of care lea di n g t o i m pr o ve d s ur vi val. 
 
1 4. 9  
Alter n ati ve  Tre at me nts  
 
Patie nts  w h o ref use t o partici pate i n t he st u d y or deci de d  t o wit h dra wal  fr o m t he st u d y will be  
gi ve n  t he o pti o n t o c h o ose  sta n dar d c he m ot hera p y, ot her i n vesti gati o n st u dies, s u p p ortive care,  
or n o a nti-ca ncer treat me nt at all.  S o me patie nts  treate d wit h  sta n dar d c he m ot hera p y d o be nefit. 
Treat me nt  wit h eit her t hali d o mi de or le nali d o mi de al o ne or i n c o m bi nati o n wit h c ortic oster oi ds 
has  pri or pr o ve n  efficac y. F urt her m ore,  t hera p y wit h a n a ut ol o g o us ste m cell tra ns pla nt usi n g 
sta n dar d mel p hala n  c o n diti o ni n g al o ne ma y  als o be of be nefit.  W hile  t he res ults of t hese 
t hera pies ha ve bee n e nc o ura gi n g, l o n g-ter m re missi o ns are rare, n o patie nts are c ure d a n d n o ne 
of t he dr u gs  use d i n t hese sta n dar d treat me nts are free of si de effects. We  belie ve  t hat t his n o vel  
re gi me n will i m pr o ve  res p o nse rates a n d d urati o n  of re missi o n. 
 
 
 
1 4. 1 0  I nce nti ves 
 
N o i nce nti ves will be  offere d  t o patie nts/s u bjects  f or partici pati o n  i n t he st u d y.  Partici pati o n  is 
v ol u ntar y.  

3 5  
 
1 4. 1 1  C osts  
 
Patie nts  a n d/ or t heir me dical  i ns ura nce c o vera ge will be  res p o nsi ble f or pa yi n g  f or t heir 
h os pitalizati o n,  d oct or  visits,  dia g n ostic  tests, c he m ot hera p y dr u gs,  a n d ot her me dici nes  use d i n 
t heir care directl y. T hese  c osts are e x pecte d t o be  e q ui vale nt t o t h ose  of sta n dar d treat me nt. 
 
Le nali d o mi de ( Re vli mi d ® ) will  be pr o vi de d  t o researc h s u bjects f or t he d urati o n of t heir 
partici pati o n  i n t his trial at n o c har ge t o t he m or t heir i ns ura nce pr o vi ders i n acc or da nce wit h t he  
Re v Assist ® pr o gra m.   Le nali d o mi de  will be  will be  s hi p pe d directl y  t o patie nts. 

3 6  
 
 
R E F E R E N C E S  
 
1.  
Je mal A, Sie gel  R, War d E, M urra y T, X u  J, T h u n MJ. Ca ncer  statistics, 2 0 0 7.  C A Ca ncer  
J Cli n.  2 0 0 7; 5 7: 4 3 -6 6.  
2.  
M u ns hi N, Tric ot  G, Barl o gie  B:  Plas ma  cell ne o plas ms.  I n: De Vita J, V T.,  Hell ma n  S,  
R ose n ber g  S A, e ds. Pri nci ples  a n d Practice of O nc ol o g y.  P hila del p hia,  P A:  Li p pi nc ott  
Willia ms &  Wil k o ns;  2 0 0 1: 2 4 6 5 -2 4 9 9.  
3.  
K yle  R A, Raj k u mar S V.  M ulti ple  m yel o ma.  N E n gl  J Me d.  2 0 0 4; 3 5 1: 1 8 6 0- 1 8 7 3. 
4.  
Sel b y  PJ, Mc El wai n  TJ,  Na n di  A C et al. M ulti ple  m yel o ma treate d  wit h  hi g h  d ose 
i ntra ve n o us mel p hala n.  Br  J Hae mat ol.  1 9 8 7; 6 6: 5 5- 6 2. 
5.  
Attal  M, Har o ussea u  J L, St o p pa A M  et al. A pr os pecti ve,  ra n d o mize d trial of a ut ol o g o us 
b o ne marr o w  tra ns pla ntati o n a n d c he m ot hera p y i n m ulti ple m yel o ma.  I nter gr o u pe Fra ncais 
d u M yel o me.  N E n gl  J Me d.  1 9 9 6; 3 3 5: 9 1- 9 7. 
6.  
C hil d  J A, M or ga n  GJ, Da vies  F E  et al. Hi g h -d ose  c he m ot hera p y wit h he mat o p oietic ste m- 
cell resc ue f or m ulti ple  m yel o ma.  N E n gl  J Me d.  2 0 0 3; 3 4 8: 1 8 7 5- 1 8 8 3. 
7.  
Si n g hal  S, Me hta  J, Desi ka n  R et al. A ntit u m or acti vit y  of t hali d o mi de  i n refract or y 
m ulti ple m yel o ma.  N E n gl  J Me d.  1 9 9 9; 3 4 1: 1 5 6 5- 1 5 7 1. 
8.  
Bartlett  J B, Dre d ge K, Dal gleis h  A G. T he e v ol uti o n of t hali d o mi de a n d its I Mi D 
deri vati ves  as a ntica ncer a ge nts. Nat  Re v  Ca ncer.  2 0 0 4; 4: 3 1 4- 3 2 2. 
9.  
K ni g ht  R.  I Mi Ds: a n o vel class of i m m u n o m o d ulat ors. Se mi n  O nc ol.  2 0 0 5; 3 2: S 2 4-3 0.  
1 0.  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 3- 2 1 3 2. 
1 1.  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 3 3 -2 1 4 2.  
1 2.  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 mise d c o ntr olle d trial. La ncet.  2 0 0 6; 3 6 7: 8 2 5 -8 3 1.  
1 3.  Pal u m b o  A, Falc o  P, C orra di ni  P et al. Mel p hala n,  pre d nis o ne,  a n d le nali d o mi de treat me nt 
f or ne wl y  dia g n ose d  m yel o ma:  a re p ort fr o m t he GI M E M A --Italia n M ulti ple M yel o ma  
Net w or k.  J Cli n O nc ol.  2 0 0 7; 2 5: 4 4 5 9- 4 4 6 5. 
1 4.  Ric har ds o n  P G, Sc hl oss ma n  R L,  Weller  E et al. I m m u n o m o d ulat or y dr u g C C - 5 0 1 3 
o verc o mes  dr u g resista nce a n d is well  t olerate d i n patie nts wit h rela pse d m ulti ple  m yel o ma.  
Bl o o d.  2 0 0 2; 1 0 0: 3 0 6 3- 3 0 6 7. 
1 5.  Mitsia des  N, Mitsia des  C S, P o ula ki V et al. A p o pt otic si g nali n g i n d uce d b y  
i m m u n o m o d ulat or y t hali d o mi de a nal o gs i n h u ma n m ulti ple m yel o ma cells: t hera pe utic 
i m plicati o ns. Bl o o d.  2 0 0 2; 9 9: 4 5 2 5- 4 5 3 0. 
1 6.  C he n  N,  La u  H, K o n g L et al. P har mac o ki netics  of le nali d o mi de i n s u bjects wit h vari o us  
de grees  of  re nal i m pair me nt a n d i n s u bjects o n he m o dial ysis.  J Cli n  P har mac ol.  
2 0 0 7; 4 7: 1 4 6 6 -1 4 7 5.  
1 7.  Ric har ds o n  P G, Bl o o d  E,  Mitsia des  C S et al. A ra n d o mize d p hase 2 st u d y of le nali d o mi de 
t hera p y f or patie nts wit h rela pse d or rela pse d a n d refract or y m ulti ple m yel o ma.  Bl o o d.  
2 0 0 6; 1 0 8: 3 4 5 8 -3 4 6 4.  
1 8.  D urie  B G, Har o ussea u  J L, Mi g uel  J S 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- 1 4 7 3. 
1 9.  C oc kcr oft  D W, Ga ult  M H. Pre dicti o n  of creati ni ne cleara nce fr o m  ser u m creati ni ne. 
Ne p hr o n.  1 9 7 6; 1 6( 1): 3 1- 4 1. 

3 7  
 
2 0.  Pal u m b o  A, Raj k u mar  S V, Di m o p o ul os  M A et al. Pre ve nti o n  of t hali d o mi de- an d  
le nali d o mi de-ass ociate d t hr o m b osis i n m yel o ma.  Le u ke mia.  2 0 0 8; 2 2: 4 1 4- 4 2 3. 
2 1.  K ni g ht  R, De La p  R, Zel dis J. Le nali d o mi de a n d  ve n o us t hr o m b osis i n m ulti ple m yel o ma.  
Ne w  E n gla n d  J o ur n of Me d, V ol 3 5 4, 2 0 0 6: 2 0 7 9. 

3 8  
 
 
 
 
A P P E N DI X  A 
 
 
Perf or m a nce St at us Criteri a  
 
 
E C O G Perf or m a nce St at us Sc ale  
 
K ar n ofs k y  Perf or m a nce Sc ale  
Gra de  
Descri pti o ns  
Perce nt  
Descri pti o n  
 
0 
N or mal  acti vit y.  F ull y  acti ve, a ble 
t o carr y o n all pre-disease  
perf or ma nce wit h o ut restricti o n.  
1 0 0 
N or mal,  n o c o m plai nts, n o e vi de nce 
of disease.  
9 0 
A ble  t o carr y o n n or mal  acti vit y; 
mi n or si g ns or s y m pt o ms of disease.  
 
 
1 
S y m pt o ms,  b ut a m b ulat or y. 
Restricte d  i n p h ysicall y stre n u o us 
acti vit y, b ut a m b ulat or y  a n d a ble 
t o carr y o ut w or k of a li g ht or 
se de ntar y nat ure (e. g., li g ht 
h o use w or k,  office w or k).  
 
8 0 
N or mal  acti vit y wit h eff ort; s o me 
si g ns or s y m pt o ms of disease.  
 
7 0 
Cares  f or self, u na ble  t o carr y o n 
n or mal  acti vit y or t o d o acti ve w or k. 
 
 
2 
I n be d < 5 0 % of  t he ti me. 
A m b ulat or y  a n d ca pa ble of all 
self-care, b ut u na ble t o carr y o ut  
a n y w or k  acti vities.  U p  a n d a b o ut 
m ore  t ha n 5 0 % of  wa ki n g  h o urs.  
 
6 0 
Re q uires  occasi o nal  assista nce, b ut  
is a ble t o care f or m ost of  his/ her  
nee ds.  
5 0 
Re q uires  c o nsi dera ble assista nce a n d 
fre q ue nt me dical  care. 
 
3 
I n be d > 5 0 % of  t he ti me.  Ca pa ble  
of o nl y li mite d self-care, c o nfi ne d 
t o be d or c hair m ore  t ha n 5 0 % of 
wa ki n g  h o urs.  
4 0 
Disa ble d,  re q uires s pecial care a n d 
assista nce. 
3 0 
Se verel y  disa ble d,  h os pitalizati o n  
i n dicate d.  Deat h  n ot i m mi ne nt.  
 
4 
1 0 0 %  be dri d de n.  C o m pletel y  
disa ble d.   Ca n n ot  carr y o n  a n y 
self-care.  T otall y  c o nfi ne d t o be d 
or c hair. 
2 0 
Ver y  sic k, h os pitalizati o n  i n dicate d. 
Deat h  n ot i m mi ne nt. 
1 0 
M ori b u n d, fatal pr ocesses  
pr o gressi n g  ra pi dl y. 
5  
Dea d.  
0  
Dea d.  

3 9  
 
 
A P P E N DI X  B 
 
W C M C  I R B S A E  R e p o rti n g  F or ms  
 
htt p: / / w ei ll. c o r n ell. ed u / re s e a rc h /f   o r ms_ a n d_ p oli ci e s / i rb_f    o r m 
s /i n de x. html  

4 0  
 
A p pe n di x C  
 
I nter n ati o n al U nif or m  M ulti ple  M yel o m a  Res p o nse  Criteri a  (I U R C) 
 
Stri n ge nt  C o m plete Res p o nse  (s C R) re q uires all of  t he f oll o wi n g: 
 
All of t he criteria of  c o m plete res p o nse 
 
N or mal ser u m  free li g ht c hai n rati o 
 
A bse nce  of m o n ocl o nal cells o n  b o ne  marr o w  as pirate b y  i m m u n o hist oc he mistr y or i m m u n ofl u oresce nce 
C o m plete Res p o nse  ( C R) re q uires all of  t he f oll o wi n g: 
 
A bse nce  of  t he ori gi nal  m o n ocl o nal  pr otei n  i n ser u m a n d uri ne  b y  i n m m u n ofi xati o n. T he  prese nce  of  oli g ocl o n o nal  ba n ds  c o nsiste nt wit h  
oli g ocl o nal i m m u ne  rec o nstit uti o n d oes  n ot  e xcl u de C R.  
 
≤5 %  plas ma  i n a b o ne  marr o w  as pirate a n d als o o n tre p hi ne b o ne  bi o ps y,  if bi o ps y  is perf or me d.  If a bse nce of m o n ocl o nal pr otei n is s ustai ne d 
f or 6 wee ks  it is n ot necessar y  t o re peat t he b o ne  marr o w,  e xce pt i n patie nts  wit h  n o n -secret or y m yel o ma  w here  t h e marr o w  e xa mi nati o n m ust  
be  re peate d after a n i nter val of at least 6 wee ks  t o c o nfir m C R.  
 
N o i ncrease  i n size or n u m ber of l ytic  b o ne  lesi o ns ( de vel o p me nt of a c o m pressi o n fract ure d oes  n ot  e xcl u de res p o nse) 
 
Disa p peara nce  of s oft tiss ue  plas mac yt o ma.  
Ver y  G o o d  P arti al  Res p o nse  ( V G P R) re q uires all of  t he f oll o wi n g: 
 
Ne gati ve  ser u m a n d uri ne  pr otei n  electr o p h oeresis  wit h persiste nce  of m o n ocl o nal pr otei n detecta ble  o n  i m m u n ofi xati o n O R 
 
≤9 0 %  re d ucti o n i n ser u m m o n ocl o nal  pr otei n  le vel wit h uri ne  m o n ocl o nal  pr otei n  le vel <  1 0 0 m g  i n 2 4  h o ur  c ollecti o n. 
P arti al  Res p o nse ( P R)  re q uires all of  t he f oll o wi n g: 
 
≥5 0 %  re d ucti o n i n t he le vel of t he ser u m m o n ocl o nal para pr otei n.  
 
Re d ucti o n i n 2 4 h  uri nar y  li g ht c hai n e xcreti o n eit her b y ≥9 0 %  or t o < 2 0 0 m g.  
 
F or  pate nts  wit h   li g ht c hai n o nl y  disease,  t he n a 5 0 %  re d ucti o n i n t he differe nce  bet wee n  t he i n v ol ve d a n d u ni n v ol ve d  free li g ht c hai n le vel 
ma y  be  s u bstit ute d f or t he M-pr otei n  meas ure me nt.  
 
F or  patie nts  wit h  n o n -secret or y m yel o ma  o nl y,  ≥5 0 %  re d ucti o n i n plas ma  cells  i n  a b o ne  marr o w  as pirate a n d o n  tre p hi ne b o ne  bi o ps y,   if 
bi o ps y  is perf or me d.  
 
≥5 0 %  re d ucti o n i n t he size of s oft  tiss ue plas mac yt o mas  ( b y ra di o gra p h y or cli nical e xa mi nati o n).  
 
N o i ncrease  if size or n u m ber of l ytic  b o ne  lesi o n ( de vel o p me nt of a c o m pressi o n fract ure d oes  n ot  e xcl u de res p o nse) 
St a ble  Dise ase ( S D) re q uires t he f oll o wi n g: 
 
N ot  meeti n g  t he criteria stri n ge nt c o m plete res p o nse (s C R), c o m plete res p o nse ( C R), ver y  g o o d  partial  res p o nse ( V G P R), or  partial  res p o nse 
( P R) 
Pl ate a u:  
 
Sta ble  val ues  ( wit hi n 2 5 % a b o ve or bel o w val ue  at  t he ti me res p o nse is a d dresse d)  
Patie nts  i n w hic h  n o  si g nifica nt c ha n ge ( < 5 0 % decrease  or < 2 5 %  i ncrease fr o m baseli ne) i n t h e pr o d ucti o n rate  of  t he m o n ocl o nal ser u m  pr otei n  or  
Be nce -J o nes pr otei n  e xcreti o n a n d n o  ne w  l ytic lesi o ns a n d/ or plas mac yt o mas  are detecte d.  
Rel a pse fr o m C R  re q uires at le ast o ne of t he f oll o wi n g: 
 
Rea p peara nce  of  ser u m or  uri nar y  para pr otei n  o n  i m m u n ofi xati o n or  r o uti ne electr o p h oresis,  c o mfir me d b y  at  least o ne  f urt her i n vesti gati o n 
a n d e xcl u di n g oli g ocl o nal  i m m u ne rec o nstit uti o n. 
 
≥5 %  plas ma  i n a b o ne  marr o w  as pirate or tre p hi ne  b o ne  bi o ps y.  
 
De vel o p me nt  of  ne w  l ytic lesi o ns of  s oft tiss ue plas mac yt o mas  or  defi nite  i ncrease i n t he size of  resi d ual b o ne  lesi o ns ( de vel o p me nt of  a 
c o m pressi o n fract ure d oes  n ot e xcl u de c o nti n ue d res p o nse a n d ma y  n ot  i n dicate pr o gressi o n).  
 
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/ dl or 2. 8 m m ol/l) n ot  attri b uta ble t o a n y ot her  ca use. 
Pr o gressi ve dise ase  ( P D) f or p atie nts  n ot i n C R  re q uires o ne  or  m ore of  t he f oll o wi n g: 
 
> 2 5 %  i ncrease i n t he le vel of  t he ser u m m o n ocl o nal  para pr otei n,  w hic h  m ust  als o be  a n a bs ol ute i ncrease of  at least 5 g/ L  a n d c o nfir me d b y  at  
least o ne  re peate d i n vesti gati o n. 
 
> 2 5 %  i ncrease i n t he 2 4 h  uri nar y  li g ht c hai n  e xcreti o n, w hic h  m ust  als o be  a n a bs ol ute i ncrease of  at least 2 0 0 m g/ 2 4 h  a n d c o nfir me d  b y  at 
least o ne  re peate d i n vesti gati o n. 
 
> 2 5 %  i ncrease i n plas ma  cells i n a b o ne  marr o w  as pirate a n d o n  tre p hi ne b o ne  bi o ps y,  w hic h  m ust  als o be  a n a bs ol ute i ncrease of  at least 
1 0 %.  
 
Defi nite  i ncrease i n t he size of e xcisti 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  ne w b o ne  lesi o ns or  s oft tiss ue plas mac yt o mas  ( de vel o p me nt of  a c o m pressi o n  fract ure d oes  n ot  e xcl u de c o nti n ue d res p o nse 
a n d ma y  n ot  i n dicate pr o gressi o n).  
 
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/ dl or 2. 8 m m ol/l) n ot  attri b uta ble t o a n y ot her  ca use. 

4 1  
 
A P P E N D I X D: Ri s k s of F etal E x p o s u r e, P r e g n a n c y Te s ti n g 
G u i deli n es a n d A c c e pta b le Bi rth C o n tr ol M et h o ds 
Ris ks Ass oci ate d  wit h Pre g n a nc y  
T he  use of le nali d o mi de i n pre g na nt  fe males a n d n ursi n g m ot hers  has n ot bee n  st u die d n or has  
t he effect of t he  le nali d o mi de o n h u ma n e g gs a n d s per m.  Le nali d o mi de is str uct urall y relate d t o 
t hali d o mi de. T hali d o mi de is a k n o w n  h u ma n terat o ge nic acti ve s u bsta nce t hat ca uses se vere life- 
t hreate ni n g birt h defects.   A n e m br y ofetal de vel o p me nt st u d y i n a ni mals i n dicates t hat 
le nali d o mi de pr o d uce d  malf or mati o ns i n t he offs pri n g  of fe male m o n ke ys w h o recei ve d t he dr u g 
d uri n g pre g na nc y.   T he  terat o ge nic effect of le nali d o mi de i n h u ma ns ca n n ot be r ule d o ut. 
T heref ore,  a ris k mi ni mizati o n  pla n t o pre ve nt  pre g na nc y m ust be o bser ve d. 
All  st u d y partici pa nts  m ust  be re gistere d i nt o t he ma n dat or y Re v Assist ® pr o gra m,  a n d be willi n g  
a n d a ble t o c o m pl y wit h t he  re q uire me nts of Re v Assist ® . 
Criteria  f or fe males of c hil d beari n g p ote ntial ( F C B P) 
T his pr ot oc ol  defi nes  a fe male  of c hil d beari n g  p ote ntial as a se x uall y mat ure  fe male w h o: 1) has  
n ot u n der g o ne a h ysterect o m y  or bilateral  o o p h orect o m y or 2) has  n ot bee n  nat urall y  
p ost me n o pa usal  f or at least 2 4 c o nsec uti ve m o nt hs (i.e., has  ha d  me nses at a n y ti me i n t he 
prece di n g  2 4 c o nsec uti ve m o nt hs). 
T he  i n vesti gat or m ust e ns ure  t hat: 
•  Fe males   of c hil d beari n g  p ote ntial  c o m pl y wit h  t he c o n diti o ns  f or  pre g na nc y ris k 
mi ni mizati o n,  i ncl u di n g c o nfir mati o n t hat s he has  a n a de q uate le vel of u n dersta n di n g 
•  Fe males  N O T  of  c hil d beari n g   p ote ntial ac k n o wle d ge  t hat  s he  u n dersta n ds t he hazar ds  
a n d necessar y  preca uti o ns ass ociate d wit h  t he use of le nali d o mi de 
•  Male  patie nts  ta ki n g le nali d o mi de ac k n o wle d ge  t hat  he u n dersta n ds  t hat traces  of 
le nali d o mi de ha ve  bee n  f o u n d i n se me n, t hat he u n dersta n ds  t he p ote ntial terat o ge nic ris k 
if e n ga ge d i n  se x ual acti vit y wit h   a fe male  of c hil d beari n g  p ote ntial, a n d t hat  he 
u n dersta n ds  t he nee d  f or t he use of a c o n d o m e ve n if he has  ha d  a vasect o m y,  if e n ga ge d 
i n se x ual acti vit y wit h a  fe male of c hil d beari n g p ote ntial. 
C o ntrace pti o n  
Fe males  of c hil d beari n g p ote ntial ( F C B P) e nr olle d i n t his pr ot oc ol  m ust  a gree t o use  t w o relia ble 
f or ms  of c o ntrace pti o n si m ulta ne o usl y  or t o practice  c o m plete a bsti ne nce fr o m heter ose x ual  
i nterc o urse d uri n g t he f oll o wi n g ti me peri o ds  relate d t o t his st u d y: 1) f or at least 2 8  da ys  bef ore  
starti n g le nali d o mi de; 2) t hr o u g h o ut t he e ntire d urati o n of  le nali d o mi de treat me nt; 3) d uri n g d ose 
i nterr u pti o ns; a n d 4) f or at least 2 8 da ys after le nali d o mi de disc o nti n uati o n.  
T he  t w o  met h o ds  of relia ble c o ntrace pti o n m ust   i ncl u de o ne   hi g hl y effecti ve  met h o d  a n d  o ne 
a d diti o nal effecti ve ( barrier)  met h o d. F C B P   m ust  be referre d t o  a q ualifie d  pr o vi der   of 
c o ntrace pti ve met h o ds if nee de d.  T he  f oll o wi n g are e xa m ples of hi g hl y effecti ve a n d a d diti o nal 
effecti ve met h o ds of c o ntrace pti o n: 

4 2  
 
o  Hi g hl y effecti ve met h o ds: 
 I ntra uteri ne de vice (I U D) 
 H or m o nal  ( birt h c o ntr ol pills, i njecti o ns, i m pla nts) 
 T u bal  li gati o n 
 Part ner’s  vasect o m y  
o  A d diti o nal  effecti ve met h o ds: 
 Male  c o n d o m 
 Dia p hra g m  
 Cer vical  Ca p  
Beca use   of  t he i ncrease d ris k  of ve n o us   t hr o m b oe m b olis m i n patie nts  wit h  m ulti ple  m yel o ma  
ta ki n g le nali d o mi de a n d de xa met has o ne,   c o m bi ne d oral  c o ntrace pti ve pills  are  n ot 
rec o m me n de d. If  a  patie nt is c urre ntl y  usi n g  c o m bi ne d oral  c o ntrace pti o n t he patie nt   s h o ul d 
s witc h t o o ne   of  t he effecti ve  met h o d liste d a b o ve. T he  ris k  of  ve n o us t hr o m b oe m b olis m 
c o nti n ues  f or  4 −6 wee ks  after  disc o nti n ui n g  c o m bi ne d oral  c o ntrace pti o n. T he  efficac y  of 
c o ntrace pti ve ster oi ds  ma y  be re d uce d d uri n g c o-treat me nt wit h de xa met has o ne.  
I m pla nts a n d le v o n or gestrel-releasi n g i ntra uteri ne s yste ms are ass ociate d wit h  a n i ncrease d ris k 
of i nfecti o n at  t he ti me  of i nserti o n a n d irre g ular va gi nal  blee di n g.  Pr o p h ylactic  a nti bi otics 
s h o ul d be c o nsi dere d partic ularl y  i n patie nts wit h ne utr o pe nia.  
Pre g na nc y  testi n g 
Me dicall y   s u per vise d  pre g na nc y tests wit h   a mi ni m u m  se nsiti vit y  of  5 0 mI U/ m L   m ust  be 
perf or me d  f or fe males of  c hil d beari n g p ote ntial,  i ncl u di n g fe males of c hil d beari n g p ote ntial w h o  
c o m mit t o c o m plete a bsti ne nce, as o utli ne d  bel o w.  
Bef ore st arti n g  le n ali d o mi de 
Fe m ale P atie nts:  
F C B P   m ust  ha ve t w o  ne gati ve  pre g na nc y tests (se nsiti vit y  of at least 5 0  mI U/ m L)   pri or t o 
prescri bi n g  le nali d o mi de. T he  first pre g na nc y test m ust be  perf or me d  wit hi n  1 0 -1 4  da ys  pri or t o 
prescri bi n g  le nali d o mi de a n d t he sec o n d pre g na nc y test m ust  be perf or me d  wit hi n  2 4 h o urs pri or  
t o prescri bi n g  le nali d o mi de. T he  patie nt  ma y  n ot recei ve le nali d o mi de u ntil  t he I n vesti gat or has  
verifie d  t hat t he res ults of t hese pre g na nc y tests are ne gati ve.  
M ale  P atie nts : 
M ust  a gree t o practice  c o m plete a bsti ne nce or a gree t o use  a c o n d o m d uri n g se x ual c o ntact wit h  
pre g na nt   fe males   or  fe males  of   c hil d beari n g  p ote ntial  t hr o u g h o ut   t he  e ntire  d urati o n    of 

4 3  
 
le nali d o mi de treat me nt, d uri n g d ose i nterr u pti o ns a n d f or at least 2 8 da ys  f oll o wi n g le nali d o mi de 
disc o nti n uati o n,  e ve n if he has  u n der g o ne a s uccessf ul vasect o m y.  
D u ri n g st u d y p artici p ati o n  a n d  f or 2 8 d a ys f oll o wi n g le n ali d o mi de disc o nti n u ati o n 
Fe m ale P atie nts:  
•  F C B P  wit h  re g ular or n o me nstr ual c ycles m ust a gree t o ha ve  pre g na nc y tests wee kl y  f or 
t he first  2 8 da ys   of  le nali d o mi de treat me nt, i ncl u di n g  d ose i nterr u pti o ns a n d  t he n e ver y  
2 8 da ys  t hr o u g h o ut  t he re mai ni n g  d urati o n  of le nali d o mi de treat me nt,  i ncl u di n g  d ose 
i nterr u pti o ns, at le nali d o mi de disc o nti n uati o n,  a n d at Da y   2 8  f oll o wi n g le nali d o mi de 
disc o nti n uati o n.  If me nstr ual  c ycles are irre g ular,  t he pre g na nc y  testi n g  m ust occ ur  
wee kl y  f or t he first 2 8 da ys  of le nali d o mi de treat me nt, i ncl u di n g d ose i nterr u pti o ns, a n d 
t he n e ver y  1 4 da ys  t hr o u g h o ut  t he re mai ni n g d urati o n   of le nali d o mi de treat me nt, 
i ncl u di n g d ose i nterr u pti o ns, at le nali d o mi de disc o nti n uati o n, a n d at Da y  1 4 a n d Da y  2 8 
f oll o wi n g le nali d o mi de disc o nti n uati o n. 
•  At  eac h visit,  t he I n vesti gat or m ust c o nfir m wit h  t he F C B P  t hat s he is c o nti n ui n g t o use 
t w o relia ble  met h o ds of  birt h  c o ntr ol at eac h visit   d uri n g t he ti me t hat birt h  c o ntr ol is 
re q uire d. 
•  If pre g na nc y or a p ositi ve pre g na nc y test d oes  occ ur i n a st u d y patie nt,  le nali d o mi de m ust 
be i m me diatel y disc o nti n ue d. 
•  Pre g na nc y  testi n g a n d c o u nseli n g m ust  be perf or me d  if a patie nt  misses  her  peri o d  or  if 
her  pre g na nc y test  or her  me nstr ual  blee di n g  is a b n or mal. Le nali d o mi de  treat me nt m ust 
be te m p oraril y disc o nti n ue d d uri n g t his e val uati o n. 
•  Fe males   m ust a gree t o a bstai n fr o m breastfee di n g   d uri n g  st u d y partici pati o n  a n d  f or at 
least 2 8 da ys  after le nali d o mi de disc o nti n uati o n. 
M ale  P atie nts:  
•  M ust  practice  c o m plete a bsti ne nce or use a c o n d o m d uri n g se x ual c o ntact wit h  pre g na nt  
fe males  or fe males of  c hil d beari n g  p ote ntial  t hr o u g h o ut t he e ntire d urati o n   of 
le nali d o mi de treat me nt,  d uri n g  d ose  i nterr u pti o ns a n d  f or at least  2 8 da ys  f oll o wi n g 
le nali d o mi de disc o nti n uati o n, e ve n if he has  u n der g o ne  a s uccessf ul vasect o m y.  
•  If pre g na nc y or a p ositi ve pre g na nc y test d oes  occ ur  i n t he part ner of a male  st u d y patie nt 
d uri n g st u d y partici pati o n, t he  i n vesti gat or m ust be n otifie d  i m me diatel y. 
A d diti o nal  preca uti o ns  
•  Patie nts  s h o ul d be i nstr ucte d ne ver  t o gi ve le nali d o mi de t o a n ot her pers o n.  
•  Fe male  patie nts  s h o ul d n ot d o nate  bl o o d d uri n g t hera p y a n d f or at least 2 8 da ys  f oll o wi n g 
disc o nti n uati o n  of le nali d o mi de. 

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•  Male  patie nts  s h o ul d n ot  d o nate  bl o o d, se me n or  s per m d uri n g t hera p y or  f or at least 2 8 
da ys  f oll o wi n g disc o nti n uati o n of le nali d o mi de. 
•  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 m a y  be prescri be d  wit h  eac h c ycle of 
t hera p y. 

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A p pe n di x E: F u ncti o n al  Assess me nt  of C a ncer  T her a p y  – B o ne  M arr o w  
Tr a ns pl a nt  
 

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