untitled h1
untitled h2

())*+,-./+0
1-/2+3 456
7*8/8982
:;
'&\#'\#< =+*>-8?
@./+;
\#$%&\#%&\#&' 4A1
4BC)+*;
DE\#'F<&GH\#
A.*I-2J8C-)K
L+?.2-08C-0+K
.?0
@+M.C+/N.>8?+
-?
6-ON
P->Q RC820+*-?O
SB2/-T2+
SU+28C.;  
(
A2-?-9.2
.?0
A8**+2./-,+
7-28/
R/B0U
DV
WXY
VZ[\\3]
[X^_[]`
aba cY^
X[
dX^
ecfdg
\  
X
[X^
eg D\
X
V[\\h\
eDVg dh
'\#`  
GD''F D\
V[\\h\[  
i\^
eDVig d\^[`
b  
&\#H$& W^3  
&G\#j<k\#jk'Hl m3
]a[X^_[]n^aZ  
| 5?,+>/-O./-8?.2 (O+?/>;  bh D3 op   | c        | bq\^[        |        |
|---|--------|--------|--------|
| VDb Dhp3   | ''&FH< | ''&FH< | ''&FH< |
| Y[3   | \  X [X^  eg        |         |         |
| hX\h3   | r` VXa        |         | sX        |
| hYY   | r` VXa        |  [ YZ  XX [hYY DVi  W^X  bY\\        |        |  
et[
\X]
u3  
vjjDVj\#<'$g
untitled h1
()+- ./012345678

9
:  
;<=:
<>
>  
?
>@
<<
;>:  
A;>
B CD\#
%E  
?
F
;:
<:
B
'\#G  
?:<  
::D
9 :H  
;::  
@@
:H  
>
I
:
:
J&AJIG
F>@  
>
> ;::
K&
:D 9 L@
<=>
:>  
<  
:
<:
FA=;
F>@=>
>>>
=>
:;>><  
M;:D  
NFMO
PQR
:>>:
STM>M
<<
>:  
> ?
<:  
;>>:
F>@
@@
:H
:
UD 9 V?
:  
F
;>:
@?>
F>@
;>>
>A
<>:
WXYZ0[\]Z^8 9 L
::::
>@
:;:
>  
;>>:
F>@
@@A:H
O
<=:  
>@ _`Aa  
>
bc\2\X\c\[d8 9
<<
>
>@
P>>  
QH
R=;
>e
DDf  
g =
A;>
Bh
%
%
?
F
;:
<:
Bij
G  
Kk\#G
g l?:<  
f
N?
m'\#
% g l?:<  
=f
:=
<>
K
&D\#
%ED g l?:<  
@;<<f  
K'\#DI
%  
&DkI
%E g l?:<  
><
?
: PMM%=AMM
@>
<@
>
=:>
?
K
'\#\# 9 :=?
::
:  
>@
;>< 9 SN@A:H
U
;  
<O
;:@
TnLNnlO  
>@
oH=O
EO >:
<> 9 l
m'p
: n:>
;>M
q<
R=;
`nqRa
;<
:>>=:
\#A& lr=>
?>
;>:
:  
>@
;><
untitled h1
sz^268

9  
;>
>  
<?>
>@;
`<V?O
O t>@:a  
@@
:H
:
=>;
9 T>>:
F
<M
p
<<:  
=<>
<?>
>@; 9 n<@
<<
<::>:  
&pA: 9 l>
u
<<:  
>@;O
>:;>
?
;>>:  
<@:
>
=
:>
< <<> 9 l>
p
<<:  
O
;>>:
F
<M  
t>
:
`;@:
Pa '&
<<:D
l>
'&
<<:O
;>>:
F
@M
>@
;>
>
<>=
t>
: `;@:
PPa  
>
D
) *++,
./
0+
1
-2
-+.
*3*  
.+
4.,
+.
0
+. 04+
5.,6  
71+
/0+,  
1
,5
0+
+
/
(
+.,
0
+. +4  
-805
5.,,6 ) *8+++9
5,+8+++  
-805
1
15,,
1
1+ 4+  
,,9
,5,  
4+/
,+0, ) *++,
,
0
/0+  
,0
,,
+
0
+/
+
5+,9
0,
0+85+4
4++  
:;<
*3=8= ) =.,
,  
5+
,+0
5  
+  
'&
/01
5++,
+
+4+
><*  
1,6
?
54+
4.+  
'@
/01
5++,
+.
1  
+  
54,  
+.
,5,
+
+
+.  
+.,
550+6 ?440
+.
1
A+
+  
++  
B\#
/01
5++,  
+
,++
+. ;C8D  
+
-+.
,1
54,6
=  
01  
/01
5++,
,4
0,9
+.
440
4
1
,+
+
@(6  
|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|
|---|
untitled h1
abbreviated title crd for smoldering

| Version Date: 09/20/2021                                                                                                                       |                                                                                                                                             |
|------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------|
| 6.1                                                                                                                                            | DATA COLLECTION                                                                                                                             |
| DATA SHARING Plan                                                                                                                              |                                                                                                                                             |
| 6.2                                                                                                                                            |                                                                                                                                             |
| 6.3                                                                                                                                            | Response Criteria                                                                                                                           |
| 6.4                                                                                                                                            | Toxicity Criteria                                                                                                                           |
| 7                                                                                                                                              | NIH REPORTING REQUIREMENTS / DATA AND SAFETY MONITORING PLAN...56                                                                           |
| Definitions                                                                                                                                    |                                                                                                                                             |
| 7.1                                                                                                                                            |                                                                                                                                             |
| 7.2                                                                                                                                            | OHSRP Office of Compliance and Training / IRB Reporting...............................................56                                    |
| 7.3                                                                                                                                            | NCI Clinical Director Reporting                                                                                                             |
| 7.4                                                                                                                                            | NIH Required Data and Safety Monitoring Plan .......................................................................57                      |
| 8                                                                                                                                              | SPONSOR SAFETY REPORTING                                                                                                                    |
| 8.1                                                                                                                                            | Definitions                                                                                                                                 |
| Assessment of Safety Events                                                                                                                    |                                                                                                                                             |
| 8.2                                                                                                                                            |                                                                                                                                             |
| 8.3                                                                                                                                            | Reporting of Serious Adverse Events .....................................................................................................59 |
| 8.4                                                                                                                                            | Waiver of expedited reporting to CCR ....................................................................................................59 |
| 8.5                                                                                                                                            | Safety Reporting Criteria to the Pharmaceutical Collaborators .............................................59                               |
| Reporting Pregnancy                                                                                                                            |                                                                                                                                             |
| 8.6                                                                                                                                            |                                                                                                                                             |
| 8.7                                                                                                                                            | Regulatory Reporting for Studies Conducted Under CCR-Sponsored IND....................63                                                    |
| 9                                                                                                                                              | CLINICAL MONITORING ...................................................................................................................63   |
| 10                                                                                                                                             | STATISTICAL CONSIDERATIONS ..........................................................................................64                     |
| 10.1                                                                                                                                           | Sample Size/Accrual Rate..............................................................................................................64    |
| 10.2                                                                                                                                           | Statistical Analysis of Secondary/Exploratory Endpoints ...................................................65                               |
| 11                                                                                                                                             | COLLABORATIVE AGREEMENTS ........................................................................................................66         |
| Agreement Type - CRADA.............................................................................................................66          |                                                                                                                                             |
| 1.1                                                                                                                                            |                                                                                                                                             |
| 12  HUMAN SUBJECTS PROTECTIONS ................................................................................................66              |                                                                                                                                             |
| 12.1                                                                                                                                           | Rationale For Subject Selection .                                                                                                           |
| 12.2                                                                                                                                           | Participation of Children ...............................................................................................................66 |
| Evaluation of Benefits and Risks/Discomforts ......................................................................6                           |                                                                                                                                             |
| 12.3                                                                                                                                           |                                                                                                                                             |
| 12.4                                                                                                                                           | Risks/Benefits Analysis .................................................................................................................68 |
| 12.5                                                                                                                                           | Consent Process and Documentation .......................................................................................68                 |
| REGULATORY AND OPERATIONAL CONSIDERATIONS ...............................................69                                                    |                                                                                                                                             |
| 13                                                                                                                                             | Study Discontinuation and Closure .............................................................................................69           |
| 13.1                                                                                                                                           |                                                                                                                                             |
| 13.2                                                                                                                                           | Quality Assurance and Quality Control ........................................................................................70            |
| Conflict of Interest Policy ................................................................................................................70 |                                                                                                                                             |
| 13.3                                                                                                                                           |                                                                                                                                             |
untitled h1
version date 09/20/2021

| 13.4    Confidentiality and Privacy ..........................................................................................................70   |                                                                                                                                 |
|----------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------|
| 14   PHARMACEUTICAL AND INVESTIGATIONAL DEVICE INFORMATION .................71                                                                     |                                                                                                                                 |
| 14.1                                                                                                                                               | CARFILZOMIB (IND # 112587)                                                                                                      |
| 14.2                                                                                                                                               | LENALIDOMIDE  (IND # 112587) ................................................................................................73 |
| Dexamethasone (IND # 112587) ...........................................................................................................75         |                                                                                                                                 |
| 14.3                                                                                                                                               |                                                                                                                                 |
| 15                                                                                                                                                 | REFERENCES .                                                                                                                    |
| 16                                                                                                                                                 | APPENDICES                                                                                                                      |
| APPENDIX A:  Performance Status Criteria ............................................................................................82            |                                                                                                                                 |
| APPENDIX B:  Requirements for REMS ................................................................................................83              |                                                                                                                                 |
| APPENDIX C:  Bone Marrow Aspirate Collection, Sorting and Storage ................................87                                               |                                                                                                                                 |
| APPENDIX D:  Peripheral Blood and Urine Collection and Storage..........................................89                                         |                                                                                                                                 |
untitled h1
)+-.

/0
1/-234+.1,  
56
7
8
9
:
;7  
:::
876
<77
:  
=>7
? :
@:7:
A<=
?@B  
76
8C
DE7
77>
AEB  
F
;7>
AFB
GG:9
7
::
>7;>
AHI F
@7
HJK
&'
F
@7
I\#K
&'
F
@7
IJK
&'
F
@7
L'&K
%
&'
F
@7
M'&B
N7
<>77;7>  
=76
AN<=BO;
P>77>  
::
7
>7
>7
86 >G>9  
76
:;:7K
7K  
P>67  
N<=O;
::
7>
6P :G7
=;
;9Q:7>
@7:7  
<=
?@
5R
56
G7:K  
:>7
A>BK
:;77
7>K  
G7:G7
7>
8 9
>;977
7
76
<>77;7
P8
S
A<SB  
P8  
GGPR  
TGGP  
976 76
G7:  
76
:>7  
;>7
9
97
9  
G7:G7
>
R  
T 7
7
76
G7:
8
U;
P8  
GGP
9
76
<S
9
76
:6> G7
7
76
>7;R  
<
7K  
:6>
7
76
:>7  
8
9
<SOGGPV <S
77
8
9  
8676  
8
:>7
>
7
9
97 G7:G7>
86
GP
:>7K
;>  
GP;>
GGP
:>7
R
untitled h1
w 4.x/yz14/. w[w )zy

/]^,1*4_,)  
'R'R' @
`9Q:7P 5
>>>>
76
>G>
7  
G77>
876
66O>a
K
:;>  
76
>;
>>
AbB
7P
:G7
>G>
7  
'R'R& :
`9Q:7P> D 5
7
9:6:  
>G77:
G>>  
>;PP
A@FB
D 5
7
;7  
>G>
Ab`B  
;7  
>;
>>
AbB
7P
:G7
>G>
ABK  
7
>77
76
7  
;9
bAOB
>
A7
76 B
D 5
P;7
7c:7  
:97
76G
A:d9K
K c76>B
D 5
P;7
9:
:7P7  
:d9  
:7
7
::
;7:>
A cG>>
G  
GO  
G>7O:d9
cG>;
9
8
>G>B N`5eC
56>
G7  
GG>
>  
T7
=
AP>
7 \#J%'&%&\#'(BR
D 5
7
P
>;PP
A`B
5
:G
76
b
AOB  
7>
978
G77>  
&\#'&O&\#'H
P>R  
&\#'(  
7
>
'R'RL ecG7
`9Q:7P> D b
7:7
9
c7
7
fbg
>U;:K
c
>U;:K  
@bO '%@bOh'
cG>>  
76
9
8
:G77
) *
+,./0  
+1
2--3  
4
5
6+3 \#7%'8%&\#'(9
4-:
32;;33;::
3<
+3=
>::>3<
2--3 ) *
+,2:;
;:3
6.?@
+-9  
1
4
:-- ;
-1
AB*%*
13  
+- ) *
+,2:;
;:3
63
-3-9  
1
4
:-- ;
33
1
?,3
C:/
6?C>/9
13  
+
-
untitled h1
() +-./01234

,34
0,5613,78  
'9&9' :;<=; <;>  
?@
A  
>A
=B=;C
D
;B
>; ==<<;  
;
>A
=A  
;B
D
E
;B;  
;
;B F><=;  
=
>;A  
;B
A<  
<G
=;  
&\#G\#\#\# >>
<9H'I  
JK  
A<;  
;BA
A
=<A B>==G  
A<==G
G  
;=
D
AA9L  
A =<DG
E;B  
A<FF  
MKN
A  
;B
O;
;;AG
;B<B
E ;B>A
>>
;
D
>F
A<FF9H&KNI  
:>;;G
;E
=;
A;<A
BF >F
;B;  
=AA  
>=
D  
>;
A;;G
= >;B  
<;
A==
?PO@  
A
<;>
?@G
;B<B
;
;BA
;
;B
D=
=BA  
;BA
>AA
A
; <A;9HLG
QI  
<;G
==A  
;
BF
==AA
;  
A;DAB
D= RA
;B;
D
>=;
>AA
;  
>;;A
E;B
PO9  
SBA
A;< A
A
;
D;;
<A;
;BA
>;
AA  
;B
>AA
; 9 PO
A  
>;
>A
=
>;F
A
;B;
A
=B=;C
D F;
=
<D<
?K>;@
T
M
%U  
D
E
>A
=A
T
'\#V  
;B
DA=  
;B
>A
=
A9HWI  
J>=
A;<A BF
A;;
;B
>F=  
PO
A
M9&V  
>;;A  
;B
L\#
AX
;BA >;;A
BF  
'V
<
AR  
>AA
;
9HYG
$I  
ZEFG
AR
=;A  
K >;
[
'9L
%UG
K:P
K>;G  
D
A<
KB;
=B
; RE
;
=  
BB
;  
>AA
?LYV
;
&\#
A@9H'\#I  
;
POG
A  
>=<A
=;
;  
D
;B
==
>;A  
K>;
[ M9\#
%U  
D
E
>A
=A
[
'\#V9  
:;A
AR  
>AA
A
BB
;B
;B;
POG
A;;
;
D  
F  
'\#V
<9H''I  
=
D
AR
A;; ;
=;A
<A  
=
AR
=;H'&I  
>AB
\JSZJ]H'MI
AR =;  
;
;
;B
BBKAR
=;
A;
E
D
^R<G
UG
;A H'NI9  
];
L
AG
AR  
>AA
;  
BB
AR  
>;;AG
<A
;B
DF AR
A
A
W&KWQV9  
;
;
>AA  
BB
AR  
A
AA
;B
& A'9 SB
=<;
A;  
=  
A
=A
EK<>
E;B<;
;;;
<;
A>;;=  
F>A9
OA
>BK>A  
G  
;;;
BA ;
D
<
;  
>AA
;
=;F
AA  
>F
F
A<FF
H'LI9 SB
A;
C
>BA
:::
A;<
<A
F
<A
?%_;BA
FA9 A<F=@  
EA
>A;
D
;B
>AB
A;<
<>  
`=D
&\#\#$
;
;B <
]Z
;
H'QI9
:  
&\#''G  
;;
;
;;
?:SS@G
;
AA ?aLY@
>A;
;
;B
:;;  
bRAB>  
\A
H'WI
ABE
;B Ec
WV
A;;
=>;
AA
?A@G
WV
G
'\#V
F  
>; AA
?dP\@  
LWV
>;
AA
?\@9
];  
W
?
'K&'@ ==A  
;=G
;B
A
=A
;
'MV9
:
;B
;;;
G
'L ?&LV@
>;;A
B
>AAF
AA
?
EK<>
&&
;BA@9
:
;B
A<F= G
&Y
?NQV@
>;;A
>AA
;
=;F
9  
;
;
>AA
?SS\@ =<A
EA
&L
;BA  
;B
A<F=  
FA<A  
;
=B  
;B ;;;  
?>T\#9\#L@9
'(&(& )*++  
,*-.  
/
0
1*++
23
.
4
*
1  
5*5  
1*
*43 *0
*2.
5*
++*
5
45*+  
5
55
5*0
+ *+45*0
11*++0  
+*++
+1++(  
62
&7
1*+
518
5++*+ *2
&\#
.9:
5  
'$
4*
51*(  
62
&\#
1*+
2+
*2
5**5
+
*2*
5*.4*
*
1*
.:;<  
52*1*5=:
5*3* +*0
*1*5=:
5*3*
+*0  
5+1+=:
5*3*
+*
>'?@(  
/2.*
1*++
*
5+  
*
.441  
4.A4*
1*+0
+4*  
3*4
5
*2( 452
2.*
5*+
:
8*
.
B4+*  
+1
3=5544*  
5
;+*( *20
1*+
2.*+
+
8*
5*
5*+  
*2  
53*
.
1+*5
5+
*
C=5*D
5
1*%11**5
+
;2 35
4
++*5
52++(
,*-.
+  
11*
.*
3+.
2.*  
*2
52*1*5  
*2 &7
1*+(
/
5.*
;*2
*2
*+0
.*-.
+**+  
1** *=
5*  
*
***  
*+1*  
=*+1*
5*+0
+ ;
+  
1+%5*
++
+**+
>'$0
&\#@(  
E
5*
12+
/%//
+*4
+2;+ 1+
55  
*2
3
5.*<
.*-.0
0 8*2+  
;
+
4*1  
1**+0
;*2
FGH  
+4.B5*+ 523
3  
1*
+1+
IJK)L  
.**
>&'@(
M+1*
4+14*.
.*+  
3
*+0
.*-.  
*2+
1+
5*
55 52+(  
,*-.
4
*85*
+
5
;*2
+
5*+
54
41*20 K/
+*++
I2L0
+411++
I
1*54
*2.5*1L  
21+ -+*
=5*3*(  
,*-.
++5*
112
41*2
5
.
815 41
*
NNH
IK
'  
&L  
O'?H
IK
N  
GL
;
+
4*1 1**+
>&&@(  
/
*2
*
12+
/%//
+*40
;*2
5.* .*-.0
0  
8*2+0
?\#H  
**
1**+
815 ++
41*2  
+
>&'@(  
/
*0
+
5+
4.+  
1**+ **
;*2
3
*+0
4
++*5  
5*++
++
*
1+*  
+5* (  
1**+
5*  
++**
*
.*-.  
*
+*  
//M I  
*2L
+**  
3
+433  
3* +433  
7
*2+  
'
*20
+15*3
>&N@(
'(&(N /3+**
M4
-.  
-.
+  
**11*
:*18=.+
3+.
2.*
*2*
+ 53*
.
;*2
P=*
*2
+4  
*2
52*1+
(  
1 *
.*-.0
5-.
+**+
A4
1*5
.4*
*
+5*3*  
*2 52*1+
5*3*
+*
3
*2
*1*5  
5+1+
+(  
E+0
5-.
+
++ 5*3
*
=1*+
1*++
51
*
.*-.0
:
5*.4*
* ;
3+  
41*2  
+411++
>&G=&7@(  
/
3*
+
+4+* 5-.
2+
5*3*
+*
.*-.
++**  
5
+
>&Q@( -.
5
+
;:
++*5
;*2
8*2+
*
25
*4
5 *2
>&Q@(  
E
4.  
12+
/  
12+
//
+*4+  
54*
3+** 5-.
*85*  
55  
4*1
(  
R
+452
12+
/.%//
*
+ 8
5.*
*21
;*2
5-.0
0  
;
+ 8*2+  
5*%1+
4*1  
1**+(  
,+  
*2+ +*40  
6M  
5-.
;+
*  
*2
+
+5*
1*  
*2
+*4 their highest dose cohort received. Based on data from an interim analysis including 12 evaluable newly diagnosed MM patients (who received up to 8 cycles of carfilzomib, lenalidomide and dexamethasone), 83% achieved VGPR.  Among 19 patients evaluable for toxicity, less than 1% patients experienced grade 1 peripheral neuropathy.  
As of April 2020, carfilzomib has been examined in approximately 6,582 people in a research setting. It has been found that carfilzomib can cause a reactivation of hepatitis B
virus. Additionally, there have been 4 cases of Progressive Multifocal Leukoencephalopathy (PML) possibly linked to Carfilzomib.  
1.2.4
untitled h1
proposed study investigation with correlative

Given carfilzomib's potent anti-myeloma activity and lack of peripheral neuropathy, we propose a pilot investigation study of combination therapy (Cycles 1-8 carfilzomib, lenalidomide and dexamethasone) in high-risk SMM patients followed by extended dosing with lenalidomide (for 12 cycles). Proposed correlative studies include gene expression profiling on CD 138 + pre- and post- carfilzomib plasma cells, identification of potential biomarkers (blood, urine, bone marrow aspirates), proteasome activity and ubiquination assays, and effects on downstream signaling targets.  
Patients will also undergo evaluation for minimal residual disease at regular interval time points, using multi-parametric flow cytometry, FDG PET-CT, Diffusion weighted MRI
(DW-MRI) and detection of clonality using heavy and/or light chain immunoglobulin rearrangement. Current response criteria in MM are often limited in predicting clinical response and duration of response, and minimal residual disease (MRD) use in MM is still under current investigation.  Immunophenotyping of abnormal plasma cells using multi-parametric flow cytometry has prognostic value in the post-autologous stem cell transplantation setting, and patients achieving negative MRD flow status compared to those with residual positive MRD flow status had longer OS (median not reached vs. 89 months, p = 0.002). 22   Other techniques, such as, polymerase chain reaction (PCR) of Ig heavy chain (IGH) rearrangements and light chain genes have also been employed in evaluating for MRD and found to have prognostic significance in showing prolonged PFS
after intensive therapy. 23 More recently, two important published meta-analysis data have suggested that MRD negative status ( < 10 -5 sensitivity) is an important endpoint that is associated with improved direct clinical benefit, both in terms of PFS and OS [27, 28].  
Furthermore, in the updated 2015 IMWG response criteria for multiple myeloma, both MRD negative CR and sustained MRD negative CR at 10 -6 to 10 -5 sensitivity are formal response categories signifying "deep" responses. There is limited published data on MRD
status as surrogate marker in the smoldering myeloma setting.  
FDG-PET CT has been valuable at localizing intramedullary and extramedullary disease in MM.  FDG uptake is able to distinguish between active lesions and chronic disease, scar tissue, necrotic tissue, radiation changes, and other benign disease.  The sensitivity of FDG-PET in detecting myelomatous involvement is approximately 85%, and its specificity is approximately 90%. 25 Along the lines of more advanced imaging techniques, DW-MRI has recently been found as a potential complementary imaging modality that focusses on the actual myeloma plasmacytoma disease rather than subsequent bone destruction. The MY-RADS group state that because skeletal survey and CT predominantly help to detect the destructive effects of myeloma on trabecular and cortical bone rather than disease within the bone marrow space, sensitivity and capability
(  
()
)  
*)
)+
,&$  
))(
.)*
/
. 0
/
/(1  
2  
)*  
.)*
)*
.
(30(
40)
)
))
/ .+
5.16  
)/07
/
(30(
8
1)/
/(96  
))( 07)
)
17)
1
0)(
07
)*
)/076
)1
0*(6
/ ((6  
()3((+
:
0)()6
:
.(
0)  
)*
/
. 1
)(
(73/
(()1)6
();)((7
0)()6  
)0)  
0
((+
<)*7*
=>2%2
0
(
)0)  
((6
:
(  
(()1 (30
.)*
.
)0*?7(6
++
@A;:6
.*0*
*1
(*.  
(()1)  
BBC 03
)
DBC  
=>2%2+
,E\#7)
.*;/
:
3)0(
0
03) @A;:
(?70(
)*)  
(()1
)
07
()  
1/)  
3))
((
)0)  
)+
<)*
/)  
@A;:
(?70(  
)*) )*  
?70F
)
3
8GE\#;DH
7)(9  
)3)+
I6
)*
)(*3 33)
7(
00)
17(
.)*
0
()
*(
)*
3))
)
((((
(3( )
)))  
(3(
*))
3
)
0*(  
(
(J+
,E'6
E&2* 0)
K;<@
0)(
.
37/(*  
))3)
)
3) ()J)  
0(
1)(  
)*
0?7()6
)3))6  
3) .*;/
:  
.
/))
(3(
(((()(
0((
00
0)(+
K; <@
0)(  
?7
1)
.)*
00
)(6
07 (((()(  
370/)  
)*
.
.
/
7
/
)*
73L( 0)(
(30  
)
:
)
0?7()  
((
3)0(+ ,&$-
:03)
(70*
)0*?7(
)
3(30)1
00
)(  
*1 17)
(3(
)
)*3+
>0)1
.)*
<)
M
81(
)
\#B%&\#%&\#'H96
/
.
(3) /3(
.
/
/)  
(0*
()7(
)
)*
(0)  
)*
=:+
'+&+H )7)  
N 0
)*
))  
)*
3)0
.
)
*(
/
37/(*  
)*
00
()  
O)
(
.)*  
7)3  
3))(+  
2* 7/
/
J
0)
)(
.
37/(*  
)*
(  
&\#'&
((7 P>Q
(*.
)*)
3))(
01
O)
(
.)*  
8'\#;'H
9 )
70)
)3
(
*1  
(0)
3((  
(711
/)  
)*
)*3
(,EE;EH-+  
2.
()7(
80)*
)
+  
<))
)
+9
. 070)
)
7)7(
52  
()7
8=7/
)
+9
((((
)(3) /
3))(
)
70)
)*3
.)*
3*6  
3(+ :3))6
0)*  
07(
(*.  
1
(711
/)  
3))( 01  
03
)
30/
8'HC
1(+
&EC6
3
R
\#+\#E9,ED-+  
<
( 0(
(F  
(0
3
0(
8=9
.(
)  
)* 73(
03
)
)*
30/
73(  
)*
)(
.)*  
077)1
00 =(
B;SC  
)*  
(  
)*
)*
()7(
,ET-+  
5.16
)
(*7
/ )
)*)
(70*  
(F
*(
/
.
F.  
()/(*  
7)3  
3))( 01
F)
)*36
(70*
(
3*,EB-+  
<
)*  
)*
) J
)(
7(  
)
3*
O3(76  
(0)  
)/ 0
/).
7
)
8'&;;\#'\#B9  
)*(+  
@(3)
)*(
0(
(F (0
06
3()  
*0
((  
)*
)(
.)*
(0
0( /
(0
(
U1)(V
()
(*.  
(0)
1)  
(711
/)
lenalidomide arms compared to placebo[33-35]
In a recent meta-analysis presented by Palumbo et al. at ASCO 2013[36] including over 3000 patients reporting SPM cumulative incidence from randomized phase III trials comparing Len vs. No Len treatments, the cumulative incidence rates of hematologic SPMs at 36 months was 1.4% Len vs. 0.4% No Len (HR 3.8, 95% CI 1.15-12.62, p =
0.029) and solid SPMs at 36 months was 2.6% Len vs. 2.9 % No Len (HR 1.1, 95% CI 0.62-2.00, p = 0.72).  In a subset analysis, investigators reviewed specific treatment regimens.  Cumulative incidence of hematologic SPMs at 36 months were consistently higher in regimens following lenalidomide + melphalan 1.8% vs. lenalidomide +
cyclophosphamide 0.3% vs. lenalidomide alone 0.3% vs. melphalan alone 0.4% (HR
3.8, 2.11-6.86, p<0.001).  Unfortunately, the meta-analysis did not account for duration of lenalidomide therapy.  However, it does seem to imply there is an increased risk of SPM in patients exposed to both melphalan and lenalidomide agents.  Our study does not have melphalan exposure. Therefore, extrapolating cumulative SPM incidence (78% in lenalidomide arm) from the published randomized lenalidomide maintenance trials[33-35] would likely be overestimating incidence in our population given the lack of melphalan exposure in our trial. Recently, colleagues from the Mayo Clinic published long-term results of their experience with lenalidomide and dexamethasone.  
They report a SPM incidence of 6.6% in a regimen that does not include melphalan.  
Furthermore, recent data show that the risk of SPM is inherently associated with plasma cell disorders independent of therapy. For example, MGUS patients have an increased risk of AML/MDS, which is the most common SPM reported in multiple myeloma patients[37].  
Currently no direct study allows us to accurately estimate anticipated SPM incidence, however, based on prior studies, recent meta-analysis, and lack of melphalan exposure with lenalidomide, we would anticipate an incidence range of 5.2-8% with a median follow-up period of 3 years.  
In accord with these recent publications, lack of alkylator exposure and a similar study design to the phase III Spanish PETHEMA Quiredex trial, we increased lenalidomide 10 mg extended dosing from the initially proposed 1 year to 2 years in patients that maintain their current clinical response and do not show signs of progression as outlined in Section 6.3 or reasons for removal from protocol therapy listed in Section 3.5.  
1.2.6
untitled h1
patient reported outcome/quality of life

Patient-Reported Outcomes Measurement Information System (PROMIS) is a healthrelated patient reported outcome (PRO) quality of life measurement instrument that was developed by NIH/NCI to standardize patient-reported outcomes for national use by research clinicians. Two versions of PROMIS are available to researchers: computeradaptive tests (CATs) and short forms.[38-43] The short forms are brief, static instruments that have demonstrated similar reliability to the longer, dynamic CATs, which provide precise measures for studying populations with widely varied responses and longitudinal self-report data. Each short form includes 4 to 8 items, measures reported health outcomes in the past 7 days on a Likert type scale and takes less than 5 minutes each to complete; collectively we anticipate the questionnaires chosen for this study to take approximately 20 minutes in total.  
)*+
,-.-,/
,.  
0  
1-1
,/
12
0
2-
.-,
34'56
7-1  
2
1-1
8-,9
,.-,  
)*  
:--,
7-1
-7-1
-1
8;0/
/
<-1,  
12
0 :.0,1
0=
172/
7
0
<:  
-1,
,-.9>((?
@1
,- :-8  
-1
:
,-.
7,
-1
:-::.7,
:,%8-9 +
-1
8.,-./
7
1:  
,1)*,  
-2
1-1
::.- 71
-17,
7.
0
-
,  
.-,  
88
-9 A2
-1-1
,
8  
,  
,
0,2-/
,
:-2
- 2.-1
8
--
)*,9 BCDEF
G,  
H0.
'/
&\#&'
)*+
,.2,  
8:-9
untitled h1
) +-.+/0

122*223*4/
145
*467++3*4/ )89 *+,-,.,+,/0
:6,/*6,1  
&;';' <=>?
@
&;';';'A@@?
>?@
BC
B?@=  
=@=
=  
>@D
=
E
@B
A=D
<C?@@  
?=>??
F@B
@B
GE@ A@BH
I<  
@B
JD@@  
GE@
=H
H
?
H  
E?
@B
<@@  
KL
M>D
@NO(PQ R >
SD@
TU
%
%
E
F
D?
=?
TVW
X  
YZ\#X R [E?=  
Q
\E
]'\#
% R [E?=  
>Q
?>
=@
Y
&;\#
%G R [E?=  
BD==Q  
Y'\#;(
% R [E?=  
@=
E
?  
^SH
_H  
A`_%_  
@  
@B
'
?
?D
<
aIb_`Q
[@
@B
?=@  
@B
C?@@H
A`_%_  
D= <  
D@@?
FB
BC  
=@=@
@
<;c R <CC%>SCC
B@
=B
@
>?@
E
Y
'\#\#
&;';';&?>E
??
F@B
@B
D?@
O
FL?  
E  
@B
FQ R >
=
D@
T
';\#
% R d
=
D@
]&\#\#
%&O
B> R >
>E>  
B@
=B
]'\#
%G
[IJ
E
LDD%E @
a=
\#;&ZS';Z(c 47/*e  
[?  
[@
G
aC?
@
\#(%'f%&\#'gcH
@B
D
D@
? JaSc  
@h
@BH
D
@B
?=@  
@B
A=D
<C?@@H
D@@? F@B>@
?>E
??
a;;H
S?DL
Y'c  
?
E
;
_B?
?  
F@B @B
?@
=@
<KM  
?D?
=@;  
&;';';i[
]'g
?;  
j=>?  
?  
C?
C@
@  
=>@
CE  
@B >?  
=kE  
=E@
F@B  
D@@?
Y'g
?  
H =B  
l=>  
@B?
?@>H
E>@  
E
E  
>@>
D@=
@?;
&;';';O`bM
D=
?@@>?
Y&
am?L
]Z\#XH
?
1nn*45,o
1c
&;';';(A@@?
>?@
BC  
F
>=@
?  
EFQ R E?>@
>@DB
=>@
a[Ic
]';\#
m%>G 47/*e  
[@
@B
?=@  
@B
C?@@H
D@@?
F@B  
[I  
\#;(
m%>G
p Y';\#
m%>G  
?
E  
==
DDD@
a;;H
D@@?
F@B E?
>@D
@B@
?
=B=  
@B@
?
@
=>?
=D=@?c; R D@@?
]f(
m%>G R BE
]
g
%G
a@?>??  
D??Ec R @@
E>E
Y';(
^
?@@>@
>DD @ R [_aMb_c%[G_aMA_c
Yi;\#
^
?@@>@
>DD
@  
adGIc R >
=@
qVrs
^
?@@>@
dGI;
<
?>
=@
?
EC
';(
^ dGIH
@
=
ac  
Mt
a?@@
>
@@
@c  
)*+
,
.\#
%/ 0
1
,
22)+
,
232+45)+
+6/  
722)+8
9 7':\#
;
<8
=
**
7
3*8
=
>\#/?.  
@A
B&
=
) +
7
%C8/ 0 5@
1
,
22)+
,
+6  
+6
1
1
*+,*6 )*D
2+  
+  
**
7EE8  
+6
262 3
**
7FE84G
2,+
7HIJ8
7*++)+ *+8
K)+*/ L  
*
,
+
,
*)  
&:
6)
)
22+
M6 *)  
)*+
,
.\#
%/
&/'/'/(J
+
+
6N
O
G++*
)*+
*
,
2**
*
P664*3
Q
G
2>'&A  
G*6
IHMRH<>'SA  
2+/  
TUMHD  
+
*+
1
, V3)O
CO
+*
>':A  
*
,
)*
+  
66
*3
**O 2
,
1
G*
2*
-WXY  
+6
1D L )  
G+
-ZX[\] L J< )G**
1+6
)2+  
&
)NN
),)
*+G* L )
NN%)NN
@C
+
-^
7,)+
_'\#\#8 L I**N
2*  
G+
N
7NN
+G  
`
2*  
*)
G+
,
-abY  
&
*)22**N
N)+*
1+6  
(4+6
G8 L
cI*
.\#d4(\#d L <,
I
)G6+G
e-fbY  
cI*  
28  
)2+ -W
)NN
),)
*+G* L +7:`':8  
7'BG8  
'K L J2*
22)+
I* L J
1+6
)*
,+*  
'
2
* L IHM4M
1+6
2
*
1+6
2*
)G+3
1+6)+
)
*++2 ,
*+)2+  
&/'/'/B<
*+)
G+2G+*
)*+
,
*+
+
+6
+
Hg
GO  
, 1  
,
+
2G
1+6
+6
K)+*  
Hg/
&/'/'/?M6
2+*  
2h,  
+6
NG
6)
+)*  
)31/  
M6 ))+
+*
)*  
+6*
+
7//O
8  
31
+
, ++2/  
i  
264,
G++  
)*+  
+
)*
K)+ 2+2G+/  
@*  
26,
G++
7@cI8j
)*+
6N  
+N
*)
or urine pregnancy test within 10-14 days and again within 24 hours prior to prescribing lenalidomide for Cycle 1 (prescriptions must be filled within 7 days) and must either commit to continued abstinence from heterosexual intercourse or begin TWO acceptable methods of birth control, one highly effective method and one additional effective method AT THE SAME TIME, at least 28 days before she starts taking lenalidomide.  FCBP must also agree to ongoing pregnancy testing.  Men must agree to use a latex condom during sexual contact with a FCBP even if they have had a successful vasectomy. All patients must be counseled at a minimum of every 28 days about pregnancy precautions and risks of fetal exposure; see APPENDIX B:
Requirements for REMS. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. In regard to carfilzomib, FCBP and their male partners must agree to use at least one method of effective contraception for at least 30 days after the last dose of carfilzomib and males must agree to use contraception and not to donate sperm for at least 90 days after the last dose of carfilzomib.  
2.1.1.9 Ability of subject to understand and the willingness to sign a written informed consent document.  
2.1.2  Exclusion Criteria 2.1.2.1 Patients who are receiving any other investigational agents.  
2.1.2.2  Concurrent systemic treatment or prior therapy within 4 weeks for SMM.  NOTE:
Treatment with corticosteroids for other indications is permitted 2.1.2.3 Patients with a diagnosis of MM as defined by the 2014 IMWG diagnostic criteria[45]
2.1.2.4 Contraindication to any concomitant medication, including antivirals, anticoagulation prophylaxis, tumor lysis prophylaxis, or hydration given prior to therapy 2.1.2.5 History of allergic reactions attributed to compounds of similar chemical or biologic composition to carfilzomib or lenalidomide agents used in study, such as bortezomib or thalidomide, in addition to patients with known allergy to sulfobutyl ether βcyclodextrin (Captisol®).  
2.1.2.6  Uncontrolled hypertension or diabetes 2.1.2.7 Pregnant or lactating females. Pregnant women are excluded from this study. The effects of carfilzomib on a developing human fetus are unknown.  Lenalidomide is teratogenic with unknown potential for abortifacient effects.  Breastfeeding women and women planning on breastfeeding may not participate. No studies of carfilzomib have been conducted on breast feeding women and it is not known if it is excreted in milk.  
Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with Carfilzomib/Lenalidomide, breastfeeding should be discontinued if the mother is treated with Carfilzomib/Lenalidomide.  
2.1.2.8  Significant cardiovascular disease with NYHA Class II, III or IV symptoms, or hypertrophic cardiomegaly, or restrictive cardiomegaly, or myocardial infarction within 3 months prior to enrollment, or unstable angina, or unstable arrhythmia.  
2.1.2.9  Active hepatitis B or C infection.  
&)')&)'\#*+
,./
++
0-1
,2+%3-4
50 ++4  
50
+,-102
635+6-) &)')&)'',26-1
7.
&
-1  
++  
0-1
'8
+ -)
&)')&)'&9,-,2++
,24
52-4  
,-3 ,-4
+6--,
,+-3
124
2+-5  
6,-+4
,, 1-14  
6+,1-,
++%+,
+-2-+
0-1
&
0:+
-102
- ,6,
0-1
+-2
;2-+) &)')&)'<*+
-1
,
=6
5+
,
,,  
-1
+:4  
+-2 ,3>
,,?
>,6
-1
6-1+
5  
+6-+  
0-12,-3 -16
2
+&
+  
4
-1
,,
+,
-1
3+--4
-1 +:+  
-1+
+-2  
2-01
-1
6-5-+  
,+
,+
5++)
&)')&)'8@
+2
0-1
'
-1
6
-)
&)')< ,2---
A-,6+2,+
0
,2
B/*
6-662-+  
2-+
61+,
+)  
C -4
2
2-+
61+,  
-0:
1+  
11
6+-
-+) D1+
6-,  
+
5
5+-,
6
2
2,
6+
B/* 05+-+)
/
-4
0
0
0:
0-1
+6,+-+  
-1
B/*
,
C,  
A-- ,2-36
+-2E+6,,
625,
+3,
2,-+
=))4
D0--4
F,5:4 -,)?  
+
5
2+  
,2-,-3-+)  
G
5
6+-
+-52625,
0
5
+25--1
/H  
30  
663  
3,  
2+)
/3+--+  
+
-:
6  
E6+
6-+26626+  
+, 2+
01
6--+
-1  
-0:4  
+266
52-1 ++)
D1+
26+  
2+  
+
+3
+
,,2-
+2,+
=))4 3+--+  
63
-%:+
625,
35
+2,+  
-
,,
-+
01,1  
6-
+E?)
untitled h1
iji klmnnopoq

Nrstusvpwo  
&)&)' ,
,-3-+
6
6
5
,+-  
+:
,-3-+
-1
5
6
5
-1
+25@,1+
+  
,+,2
-1 0X  
Y Z4
0--4  
6+  
-61
,2,-+
0-1
6+6,-3
+25@,-+
Y 30  
>+,
,+
,2
*[A4
5+-2+4
-,) Y 30  
>+/4
>E4  
D
+ Y 30  
>+61-61+  
3+ 30  
>+6-1
+6,+%6-+  
+6,
5
+-, 626++
G
03  
,+
-1+
,-3-+
1+
5
;2+
+,\IJ]J\)
untitled h1
2.2.2

Screening activities performed after a consent for screening has been signed The following activities will be performed only after the patient has signed the screening consent for this study or the consent for study 01C0129 (provided the procedure is permitted on that study) on which screening activities may also be performed. Assessments performed at outside facilities or on another NIH protocol within the timeframes below may also be used to determine eligibility once a patient has signed the consent.  
A complete history and physical examination with documentation of measurable disease and assessment of performance status using the ECOG scale must be performed prior to study entry.  
The following studies and laboratory tests will be completed 4 weeks prior to study entry, unless otherwise noted:
untitled h1
.

CBC with differential and reticulocyte count  
.  
Acute Care (sodium, potassium, chloride, CO2, glucose, BUN, creatinine), Mineral
(serum calcium, phosphate, magnesium and albumin) and Hepatic (alkaline phosphatase, ALT, AST, total and direct bilirubin) Panels, and CrCl calculation
.  
Uric acid, LDH, and Beta-2 Microglobulin
.  
Serum protein electrophoresis (SPEP) and immunofixation to assess for presence and quantity of monoclonal protein (M-protein)
.  
Random urine sample for protein electrophoresis (UPEP) and immunofixation to assess for monoclonal protein in the urine (Bence-Jones proteinuria). Collect a 24 hour urine sample if necessary for confirmation of Smoldering Multiple Myeloma diagnosis [i.e. if patient's serum monoclonal protein is not measurable (< 1.0 g/dl)].  
. . .  
Serum free light-chain studies Quantitative immunoglobulins Viral serologies:  Hepatitis B surface antigen and Anti Hepatitis C (HCV) antibody. If Anti HCV is positive, will follow with HCV RNA PCR
.  
If the patient does not meet Mayo Clinic criteria or the criteria set forth by Rajkumar, Landgren, Mateos for high-risk SMM, but he/she has evidence of immunoparesis, the patient will have to undergo a bone marrow core biopsy and/or aspirate with flow cytometry to determine high-risk disease as defined by the PETHEMA criteria. If a bone marrow aspirate is done at screening, then the sample can be processed for baseline assays (see APPENDIX C:  Bone Marrow Aspirate Collection, Sorting and Storage) to minimize the number of bone marrow biopsies
.  
Serum or urine pregnancy test in women of child-bearing potential.  
.  
12-lead EKG
.  
A skeletal survey of the axial and appendicular skeleton will be performed.  (NOTE:  A skeletal survey does not have to be repeated if performed at the NIH within 3 months of screening.)
•
A spinal MRI (cervical/thoracic/lumbar) is required prior to study entry to exclude ≥ 2 lytic lesions; if patient has had an MRI performed at an outside facility, one performed at
()*
+
,
-.
/.,  
/
0  
+12
0.0++3
4(5678  
9,
,2 +1,  
,2
:10
);+,,<
:76%6  
01
)  
0,,+
=2
2; 1,1,
,
)3>  
4?@ABC  
9
)
+
,
2;
,
/
0,  
0
, ,2
()*
=,2
D
,2+  
+13>
untitled h1
efg hijaklkhi?a

Jbmknajiak@?
I?O
Naiapn
Phoiab
Hj@Lbopjbn  
+,,  
+,,.+
.0,+
433<
=2  
0,10,
+
,Q  
0,1
,20  
=2 0,10,
+
,Q
R+,.>
=
,Q
01
0  
5:
9SR&<  
:,10,
T
,,.+
U0,+
.
23
untitled h1
&3d3' 1

V.+  
1
.+  
+
0,10,+
=2
1+,
,
0,10,  
,2
11
,
/., ,
+./+-.,
++
,
,2
+,.
,;,  
,  
,2
+,.3
9  
+, +1
.
,
+
-.
,
+.
,+0,
0,  
+1
. 0,10,+<
,
,
,2
+,
,+  
0,
6+
45(56>
0./+2 -.,+  
,
+0
,
-.+  
.,
.,2,+3  
,
1.+
02<
+1
.
,+<
/,
1,<  
+.+
;+
;, 497>3 );.+
=2  
,
,
,2
1,  
0,10,  
,2+
,
4+1
.>
=
,
/ +13 EFW AJBIAXB?A
INNKM?XB?A
I?O
JI?O@XKYIAK@?ZNAJIAK[KLIAK@?
HJ@LBOPJBN  
&3\3' 2,+  
| ?]^_`a      | ?b^`   | O`cdaefgehi   |
|-------------|--------|---------------|
| '           | .,0          |  .,0  0,,+ =,2 22R+Q ++               |
| O`cejibgehi | ?b^`   | O`cdaefgehi   |
| 9           | 7k0,8  6,,  4l/<  ;   Sk,2+>        | l/ 4)m< S+ '< &< n< $< 'o<  'p  ,2 &nR 11>q  ; 4:5< S+ 'R&'  ,2 &nR 11q k10,8 , ;   11 '  '>q < Sk,2+ 4:5  )m< S+ '< &< n< $<  'o< 'p< &&<  &D  ,2 &nR 11q k10,8 , ;  11 '  '>  4(5678 + .0 1,;,  9, * ;+ ,  #p%'&%&#'r3>               |
| s           | 7k0,8  6,,  4l/<  ;   Sk,2+>        | l/ 4)m< S+ '< &< n< $< 'o<  'p  ,2 &nR 11>q  ; 4:5< S+ 'R&'  ,2 &nR 11>q <  Sk,2+ 4:5  )m< S+ '< &< n< $< 'o< 'p< &&<  &D   ,2 &nR 11> 4(5678 50 1,; =,2 9, *3 ;+ ,  #p%'&%&#'r>               |  
&3\3& 9+  
%.0
++,q
0R/  
Rl3
untitled h1
() +-./01.

.2,/3,4051  
678  
77
9:
:6:6
:
9
;
;
:
6::
:8;<  
:
7: *  
:6  
96;7
77:  
7:=
6:>6<
&<?<' @787A
B
CD:;
:>:7
;;:
ECFBG
BHA
BHHA  
H;  
&<?<& C
I J K6:;:87
=>:  
9
I
6;:  
9;6 J L>;8:;  
9:
7
;6
76
9
>:;:7
I
7::< J L:;86
MLK%7::76
EL
;=>6
A
;:
:
766G J N
'OPQ
7:6  
N
'OPD
7:6
7
6:
I:8
6>96R>:
7:=6 9:8
7:6
:
9  
:8
S>
T9< J B:6
7:=:  
R>:7:
E;;8
9  
9
IG< J L>9>
8=
%
8:
78
:<
&<?<O B;8
CA
UA  
L J B ;8
9  
>
6;6  
6:  
6:968  
99V<  
E
,WW.1X0Y
XZBB@FNL[
N\  
B;8
C  
U
7:  
:G J >9>:
;  
7:=:  
77>:
;:66
9
]DV
>69: 66
E;:G< J Z;;:66
666
:
:
7:7  
:
6:
;;::7
76< J L>7]:
6:>6< J B;8
9
I
7::
6666  
77>:
;6
76
>
:8
7:
KD^
^A
N J B;8
9
I
9
6666  
>
7
;;>:6
7>A
9>:
:
: :
H
76
EN_  
NPGA
T`TA  
Fa
76
>6
I
7::< J MN`
B@H%H
67
I:8
_
IV6  
6:>
:  
;
:
6::
:8;<  
FbH@\
:
:  
7:
*)c)d J N>6
^8:
^8
C
EN^DLG
Ee7;:\
;::6
I:8  
7:D 7:  
9:
:
;
>
:
6::=  
6:7
66
&<?<_ f>6:6%B::D;:
b>:76
EBb6G
154.g  
7:
*
untitled h1
d -43xh

0Iw/.I.14,4051 D)C -43Xh
X.-0J1  
B::6
I:8
88
6V  
I
9  
:8
;:
6:>  
::
I:8
OD> 79:
E76
'DP
7]9
&\#%Ok
%&A  
&?
A
e:86
&\#
776
'D_  
'\#  
776
?DPG
I
9
e:  
6<
Z  
:6:  
;7>6
I
:V
;7
;
:8
:>
A
7:
d)l<  
154.g H::
6
;
:
9
6:  
>:;::
966<  
Z:
:8
=6::m6
67: E<<A  
:
:A
;::
67
66A
:7<GA
;::6  
9
::
inpatient basis.  Any cases of planned hospitalization are not considered reportable serious adverse events per Section 8.4. 3.1.1 Cycles 1-4 and 5-8
.  
.  
.  
. .  
Cycle 1 ONLY: Carfilzomib 20 mg/m² per dose, days 1 and 2; Carfilzomib 36 mg/m² per dose, days 8, 9, 15, and 16 Cycles 2-8: Carfilzomib 36 mg/m² per dose, days 1, 2, 8, 9, 15, and 16 Cycles 1-8: Lenalidomide 25 mg/day, days 1–21 every 28 days  
Cycles 1-4: Dexamethasone 20 mg/dose, days 1, 2, 8, 9, 15, 16, 22, and 23 For patients who choose to undergo stem cell harvest, the next cycle may be delayed for up to 5 weeks.  
.  
Cycles 5-8: Dexamethasone 10 mg/dose, days 1, 2, 8, 9, 15, 16, 22 and 23 followed by extended lenalidomide
After receiving first 4 cycles, patients who are considered to be eligible for subsequent high dose therapy/autologous stem cell transplant (ASCT) will be encouraged to undergo autologous stem cell harvesting for potential use in the future. In accord with current clinical standards, the decision whether a given patient is eligible for subsequent high dose therapy/ASCT, or not, will be based on a clinical assessment conducted by the transplant cnter that evaluates the patient.
untitled h1
3.1.2 maintenance and ongoing treatment

After 8 cycles, patients will proceed to extended dosing phase I of lenalidomide (Days 1-21 of 28 dy cycle) for 12 cycles. After 12 cycles of extended dosing of lenalidomide, patients who maintain their current clinical response and do not meet criteria of PD as defined in Section 6.3 will have the option to continue lenalidomide as clinically indicated for an additional year on extended dosing phase II. After 2 years of maintenance, patients will be followed by clinical and laboratory examination every 3-6 months until disease progression requiring treatment. If patients progress, they may be contacted by phone or email to gather survival information. (Note: patients who have not progressed after 2 years of maintenance therapy, but decide to continue lenalidomide maintenance at an outside facility, may also be followed on this protocol as above for long term follow-up at the discretion of the investigator. This follow up will consist of clinic and laboratory examination, however, if the patient is undergoing these investigations at an outside facility, follow-up can be limited to NIH investigator-patient or NIH investigator-outside physician communication of test results.)
Of note: On October 19, 2015, the study was closed to accrual for administrative reasons.  
Eighteen patients had enrolled at that time. Effective with Amendment H (version date 0/12/17), the study status will change to "Open-Recruiting" to allow for enrollment of the remaining 10-12 patients as per the statistical analysis plan of this protocol.
untitled h1
(7&7& c>

(7&7&7'DE
F :
'?  
&\#
%&
8G
9>
H
(\#
9;>  
>
'  
&I
;=
(J
%&
8G
>
AI
$I
'KI  
'J F :
&@A?  
(J
%
&
8G
9>
H
(\#
9;>  
>
'I
&I
AI
$I
'KI  
'J F
:;
LM*L*)  
9
9;  
NN;
>;9:;>  
(7&7&7&O F :
'@A?  
&K  
>
'@&'  
&A@
:: O
:N>9>
>=9
E
>BB
B=I  
>=9
;
E
EPI :=B  
N7 F 8  
>  
>
>>I
;
>=9
E
;P
>
>
>
N>>E  
;=
>
7  
8
;
>
>>  
;=
;
I
;
>=9
;
E  
9N7 F <;;>
B=
;P  
;=
;=
N>:E
>  
>=9
E
>;9:; ;
>P
:
:
:  
:;:;
>;9
>;
;7 F O
QHRS
B
E
NH
;
>:=
>9ET:;>  
;=
9; ;=
N;:N;  
;=>
;
;  
:=
;
;=  
;=
>9:
NH>
Q9>> ;=
:;9  
;:
;  
9;>
:;S7  
O
B
E NH  
:::
B;=
;=
UR
N  
N;7  
< >;
UR
V9;>  
N=>:>
B=
N>:E >:=
>9ET:;>  
;
;=>
;I  
>:=
>9ET:;>  
;
;=>
trial, must be registered in and must comply with all requirements of the REMS®
program.  Prescriptions must be filled within 7 days.  Only enough lenalidomide for one cycle of therapy will be supplied to the patient each cycle.  
3.2.2.3 Dexamethasone
.  
Cycles 1-4:  20 mg oral or IV on days 1, 2, 8, 9, 15, 16, 22, and 23
.  
Cycles 5-8:  10 mg oral or IV on days 1, 2, 8, 9, 15, 16, 22, and 23
In Cycle 1, the following supportive care measures will be implemented:
•
Hydration will be administered prior and subsequent to carfilzomib dosing.  
Oral hydration:  All subjects must be well hydrated (i.e., volume replete).  Begin o oral hydration equal to approximately 30 mL/kg/day (~6–8 cups of liquid per dy), starting 48 hours prior to the planned first dose of carfilzomib.  
IV hydration:  500 mL (250 mL before & 250 mL after carfilzomib) OR 1000 mL
o
(500 mL before & after carfilzomib) of normal saline or other appropriate IV fluid formulation must be given before and after each carfilzomib dose during Cycle 1.  
Total volume will be determined at the discretion of clinician and volume status of patient.  
In subjects considered to be still at risk for TLS at completion of Cycle 1, hydration should be continued into subsequent cycles if clinically indicated.  
Harvesting Stem Cells After receiving first 4 cycles, patients who are considered to be eligible for subsequent high dose therapy/autologous stem cell transplant (ASCT) will be given the option to undergo autologous stem cell harvesting (not as part of this protocol) for potential use in the future.  
Collection and delivery can be conducted at outside institutions.  In accord with current clinical standards, the decision whether a given patient is eligible for subsequent high dose therapy/ASCT, or not, will be based on a clinical assessment conducted by the transplant center that evaluates the patient.  
If harvesting and delivery of high dose therapy/autologous stem cell transplant is conducted at NIH Clinical Center, it will be conducted under a separate protocol.  
Transplant eligible patients will be defined as age <75 years with no significant disease co-morbidities and ECOG ≤ 2. For patients who choose to undergo stem cell harvest, next cycle may be delayed for up to 5 weeks.
Extended Dosing Phase I:  Cycles 9-20
.  
Patients will go on to receive extended dosing with oral lenalidomide 10 mg/dose,  
given daily for 21 days of a 28 day cycle, for 12 cycles.  
.  
Lenalidomide ordered in the extended dosing phase of the study will be prescribed by NIH Clinical Center physicians in one month increments for all patients. Upon completion of phone counseling per the REMS® program, the NIH Clinical Center
.
3.2.3
.  
.
.  
.  
.
3.2.4
)*+,
)+,.  
&/  
+0))  
1
.
+1
1
1*
)11
. 2)++
34 5 6
678
)11+  
1*
21
+
)*+  
1*
+109  
. )+,.
.
:;<
,
1
)*+,+  
1*
,1+4
678 )11+
+1
.
=0
1
*3
,
+0)3+
),
1+1
+ 01  
>??@ABCD
EF88G:H;I
7J  
=01+  
GK  
*3 1*
),
1+1
)
.
,
11
)*+,4
;
1*+
,++9
1*
, )*+,
+0.1
1*
+01+
1
:;<
,
1  
3-4
L)
,)1 13
),
1+1
+01  
,)1  
)*
,0+
)
1*
GM )9
:;<
,
)*+,
)+,.  
&/N
+0))  
1
. +1
1
1*
)11
.
2)++
34 O4&4( G21
H+
8*+
;;
P)1QJ
,+
&'1*0*
O&
P,13
-1*
F1 3+
1
\#R%''%&\#'OQJ 5 F1
'&
,,+  
21
+  
+
P)*+
;Q9
)11+
-*
1 1*
,01
,,
+)+  
1
1
,1  
8H
+  
,1
STU
*3
1*
)1
1
,10  
'\#
%+
+
,,
,1
1
4
6
1*+
)11+
-*  
1
.
21
+
)*+ ;;9
111  
.  
01
1  
P3+
1
\#R%''%&\#'OQ
+
))3
.
1*
;74 5 V
.  
21
+
)*+
;;
.
)+,.
.
:;< ,
1
)*+,+  
1*
,1+  
)11+4
L)
,)1
)*
,0+
)
1*
GM
)9
1*
:;<
,
1
)*+,
- )+,.  
&/  
+0))  
1
.
+1
1
1*
)11
.
2)++
34 5 6
678
)11+  
1*
21
+
)*+  
1*
+109  
. )+,.
.
:;<
,
1
)*+,+  
1*
,1+4
678 )11+
+1
.
=0
1
*3
,
+0)3+
),
1+1
+ 01  
>??@ABCD
EK  
*3
1*
),
1+1
)
.
, 11
)*+,4
;
1*+
,++9
1*
,
)*+,
+0.1
1*
+01+
1
:;< ,
1  
3-4
L)
,)1  
13
),
1+1
+01 ,)1  
)*
,0+
)
1*
GM
)9
:;<
,
)*+, )+,.  
&/  
+0))  
1
.
+1
1
1*
)11
.
2)++ 34 5 W*
01  
21
+
-+
1
.+  
1*
+10
+  
1* 8*+
;;;
1
X02
1  
%21*+
.
1,
3+4
.+31  
**N+Y  
)11+
,0,1
. 1*
)+*
8GW<GF
+10
0)4  
;
1*+
+109
1*
111  
,3
$ ,,+  
0,1
1*)
-1*  
21*+
.
1,4  
;
F00+1  
&\#''9
1*
X02
)1,
-+ 1
+1)  
1,
111
1
&
+4  
;
19
1*
1* +1
Z
)*+
;;;
1+
3+11  
1,
- )0.+*  
&\#'&
-1*  
-N0)
)+  
O\#
1*+
1
[( 1*+4  
W01  
1*  
1*+
+10+
,10  
1,
01 )++
-1*  
)  
1  
1,&$9O\#4
untitled h1
)) +-.

/,+0102340,5-  
6789:  
;
<==>
?@  
>
@A=>  
B<A
>  
@ >==
CDDE
@
=
<FA
=
FG
=F
AA=
>  
%
=
?@
=
=
=F
AA=%H@>=
>
>@<<
=
=F
<==IE
=F>
>==G
> J
=
K
A>  
<=K
<=A
G=D  
L@=FE
<<==> ===>
>>
K
<==>
@
=
>=A
>>
A@
J=F =><==
<K>
J
=
K
A>  
<=K
<=A
G=D
M==>
>>
@<
=
'NO  
>>D
P
=>
J
K  
=
== G
A=>
=
=F
<==
B<=@>D  
| QDQD' R> @A=>: ;@A= MF>              | +STUVSWXUYZ[S   |            |            |
|--------------|-----------------|------------|------------|
| \S[U]^_ZV^_S | 2U`a^]bZV^c     | 2de]SY fgh | 2de]SY igj |  
k>
> &N  
R> 'l&'  
&m  
AA Q(
%& &# '# 7
G
> @A= &#  
R> 'l&'  
&m  
AA &n
%& '# o 8J
G >
@A= 'N  
R> 'l&'  
&m  
AA &#
%& o # 8F
G >
@A= '#  
R> 'l&'  
&m  
AA # L@
G >
@A= N  
R> 'l&'  
&m  
AA QDQD'D'p  
qK
>>  
=  
AA=r
DDE
AqK
>
@A=>  
<=
><=D  
;  
=F
&
> @A=>  
?@
J=F
qKE
>=@
===
J
K
>A=@  
=F <==
J  
=F<D QDQD'D&;
=F
>  
>@=  
=BA=
=
&
Js>  
J=FF
===  
@<
=
Q Js>  
A=
=
===E
=F
>@KHA=
J  
=F<  
QDQD& t=A
8BA=:  
;@A=
MF> QDQD&D'R@
=
=F
=@  
=F
>>
=  
=F
K
JE
G=>
AA@
J=F =F
>=
=J
AA>  
===  
=
K
@
=
>>
K@
J
K B<=  
>
@A=>
=
=F
>A=  
=F
G>==D QDQD&D&7  
'  
AF
J
AA
C  
'  
G
=F
AA
@
B=>
<F>IE <==>
@>=
=
=F
J
A=  
>  
K>  
>
@A=> =K
QDQD': u P6
v
'D\#
B
'\#$
%p u M==
A@=
v
nN
B
'\#$
%p
@
AA>
'lmr
M==
A@=
wN\#
B
'\#$%p
@ AA>
$  
K
;
=F>
A=>  
=
=  
R
'  
J
AAE  
J
AA  
===
J =
K
==
@=
=F
=BA=
F>
>GD  
;
=F
>  
>@=
=
&
Js> J=FF
===  
@<
=
Q
Js>  
A=
=
===E
=F
>@KHA=
J  
=F<D
)
*+
,-**
.+-*
/.
..
*
*0
1212'3
*+
,-**
4 *
4+.+
/
4
0  
0
.*
5  
.. 6/*2  
1212&21)  
5**
,5*+0.*5  
/*5
/
*+
..3
*+
*+ 4
.*4/
*7
5.
89+0.*5%:/*5
*0
04;2  
| <=>?@A?BCD?EFGHI   | JFGIKHL?@HLF   | MI>NHKO?@HA   |
|--------------------|----------------|---------------|
| P * Q &R S '#$%T                    | U 0*+ T  V03 4 W 472  U 55+.*. *X./*2                |               |
| */ * Y &R S '#$%T                    | -/  * S*  - /.*                | -/ .V0 * / -Z               |
| /0-[/*  *  Q &R S '#$%T                    | U 0*+ T  V03 4 W 472  U 55+.*. *X./*2                |               |
| */ * Y &R S '#$%T                    | -/  * S*  - , /.*                | -/ .V0 * / -Z               |
| ZV0  0 - /. * *+ .. -.*  ,-** \F]D>?EFGHI  ^_A`?K]DF \F]D>?E=HK M?]GDa JFGIKHL?@HLF MI>NHKO?@HA P- * Q #2R S '#$%T  *  Q '2# S '#$%T 4*+ , U T  V02 b -*  c 1  4*+ , 8- *5*/  1d21e  -/-* *5*/   1de  f ' +/;  c g2 P4 W 47 */- * Y '2# S '#$%T -/ T *  S* - /.*2  -/ V0 * / -Z  /0-[/* 5 * Q #2R S  '#$%T  * Q '2# S '#$%T 4*+  , U T  V02 b -*  c 1  4*+ ,  c g2 P4 W 47 */- * Y '2# S '#$%T -/ T *  S* - /.*2  -/ V0 * / -Z  ZV0  0 - /. * *+ .. -.*  ,-**2                    |                |               |  
12121 :XU*.
9S.*h
)/.*
i+-  
121212'9S.*
Y  
1
4
[/
555*
-*/
/
*
0
+
/*
-,
*
j c
'
/--5.
042  
),-**
4
*
4+.+
/
4
0
+ 0
.*
5  
..
6/*2 121212&k.
*S.*
+-,
j  
'3
-/0-[/*
-4
0
/.
*
S*
- ,
8..
*
*0  
-.*
1212';  
*+
,,*
4
*
0 ***
*
0
*+
i)2  
)
*+
,,*
4
*
0
/*
* ***3
*+
5**  
.*/
*+
/
-2 1212121
,-0
.**  
*0.
0*-3
.*
+ .*
0
555*
*+5  
S5*2 121212gi**4*+
c
1  
++
55+
/5*+3
c
1  
++
X0-* -+  
0-*
-+  
3  
1  
++
+5--*,*
.*4
0 ,  
5*.
*+52  
| )*+,-./01./* 203.4.5.*6   | 706.+8 90/.:.4,5.0+6   |
|---------------------------|------------------------|
| ;<= <>  ?@ AB                           | C<D=E   F G==  =>G                        |
| HE< =>I<<% I<                           | J   <== =>GE=D =DE=K <==   = F<==L< <D= = DE= < FK                        |
|  C<ED=   I<  DMD=NAE=K  ?@==FO CC  PCN G E<  I E< =  <== AQ <  DDE=  D=<   <ED= =>    <DG= D<<B R S'NT# % U C< ED  = '#     C< 'N&' R VWX Y% ?= ZE <<B U C< ED  Y = 'T  F [( >E<  R VWX Y% ?ZE <<B U CD<  Y = T     << < F   < = <<K                           |                        |  
| \,]:.-^01._ 203.4.5.*6   | 706.+8 90/.:.4,5.0+6   |
|--------------------------|------------------------|
| @D D=%JG<<=F=                          | A &` J DaI E= V A '  <E =  E DaI <                        |
| bE Y<<  cd S  =>  e` dfXg D<  D=O  ED DO  G><G>=h dWXg D<   G=<<Eh diXg D<   DDEh  &N D<  YCJ J DaI E=  I=<  <E  D><=< >F <FK <E = E < JG< a<=  <Gj    J DaI E= <<  K <E = E < kEG=> A & === = EG=> e=> G` J  DaI E= <F = V A ' e=>E= GK b>  <== = j= < F ED=K @ <EIlD= e=> <G=<  D<=F >= EO  e>=>  = E =O E<= >F => < > E=  <E=  =E = I<K @= e>D>O ===   D=E = ED <  G==  I e=>e   =>GK <=F J= QE  bjD=` E D= d & m I<O   = DD << => 'T  Y%O  D= DD  D<< = << =>  ZE = T#n   I<O    ><< o=>> <  D=E =  ED=  ?<E D=  D= DDBK pq rsstuvwsrvxy sz {rtqux|z}uv~ <E e>  ED=  >< DF = e=> &Tn  I<h <== = ' <  F ED=K pq zs rsstuvwsrvxy sz {rtqux|z}uv~ <   I <E = => <D=  => G><DK Q  G==<  ><< DF DaIO => < <  = I <= = => ><< GDEK  € ' < <E<GD=O > DaIK <  FE= e=> ED O <GDD  €O  <=  F<E  ED <G=< <E<=F  'K € ' < DO G=  <D=E DaIK € => <<  ' <  jDEO DaI <==  <E =  < <O  DD GGG=K€ <= F<I 'DG>G=>   ?'B < <E<GD=                          |                        |  
| ()*+,-./0,1 2/3,4,5,67   | 8/7,9: ;/<,+,4)5,/97 F AK@   B I>  A AJ BI LA? I AA BBB>M  NO PQR ST UVWOSXYZ[ \W[ XZ]\^Z[ ^V U\XOS]_VYS`a  B> IA>J AK@b NO ^cZ [S\dWVTST ST  ZeU]f[Z[a AK@ A @ I>> > >? BgJI IM  = >? A> AJIh B> IA>J  AK@M   |
|--------------------------|---|
| FB>A =B>i  = >?@>A AB>?  CDDE%FGH I IJIBA>  > > g IJA>i   I & AIAJ>g gJIh > I>  &j I B>h i  C'H >> @J@ Ck llm A>H k 'L  Gno > p lL Gno q  C&H  g>  rD % rnD  s>?  @J@ t l g>   rnD % rD Ck uL GnoH  &um I JA>M vI  @ wIA>  g  JA> >I>I >J >   JwJA  ?B>>LA> I LAJM  F AK@ J> IJ> > @IM  >  @> sxM IJ AK@ s>?   &um I JA>  JwJA ?B>>LA> I  LAJM  F AK@ J> IJ> > @IM > >>  @J@  A> @J@ sxM  GB IJ>  >> @J@ > h IJ  AK@ I s>?  &um I JA>  Jw JA ?B>>LA> I LAJM  t l g>  >> @J@  vJwJA ?B>>LA>  C>>@J>@ > AK@H 8,74/95,9y6 4)*+,-./0,1 D?@>A AB>? CDrH = >? II I IJIBA>h ? AK@    B I>  A AJ BI LA? I AA BBB>M = Dr I Ah B>  IA>J AK@M = >? II I LAJh  AK@ A @ I>>M                          |   |
untitled h1
lmlmz vi

Ja>Ii
{L>
Vi
E?Ii
=  
==  
| |69)-,</0,<6   |    |
|----------------|----|
| }I I                | '#    vI 'w&'  &j  AA    |
| q g I JA>                | u    vI 'w&'  &j  AA    |  
lMlMu F>A
DLA>i
{L>
vI
E?II
=  
==
lMlMuM'q  
'
C
s>?
~
I
B
>  
'H  
g
>?
AA
J
L>I
B?Ih B>>I
JI>
>
>?
s
A>  
I  
@I  
I
JA>I >@
lMlMzi ro  
'M\#
L
'\#$
%n
) *++
,-+
./\#
0
'\#$%1
,,2
$  
3 4
+52
,+2  
+
+  
6
'  
7
+5
,,8
+++
9
+
3 ++
-+
+5
+0,+
52
27  
++
32:
4
+5
2  
2-+ +
&
9;2  
9+55
+++  
-<
+
(
9;2  
,+
+
+++8
+5
2-3=,+
9  
+5<:  
(:(:/:&4  
<++
7<2
+53,+<  
-+<
+5
,,8
+5
+5 9
,+2
9+;
<,
>2
?53,+<%@-+<
+3
39A:  
| BCDEFGEHIJEKLMNO                         | PLMOQNREFNRL   |
|------------------------------------------|----------------|
| S + T &/ 0 '#$%1                                          | U 18 9 V 9;: U <<5,+, +W ,-+:                |
| +- + X &/ 0 '#$%1                                          | 2-  + 0+ 2 -,+   -  +                |
| -32Y-+  + T &/ 0 '#$%1                                          | U 1: U <<5,+, +W,-+                |
| +- + X &/ 0 '#$%1                                          | *++ 9   +5<   - +                |
| ZL[JDEKLMNO  \]G^EQ[JL ZL[JDEKCNQ _E[MJ` | PLMOQNREFNRL   |
| S2 + T #:/ 0 '#$%1  +  T ':# 0 '#$%1 9+5 7                                          | U 1: a 2+  b ( 9+5 7  >2 +<+-  (c:(  2-2+ +<+-  (c   . ' 5-A  b d: S9 V 9;                |
| +-2 + X ':# 0 '#$%1                                          | 2- 1 + 0+ 2 -,+:                |
| -32Y-+ < + T #:/ 0 '#$%1   + T ':# 0 '#$%1 9+5 7                                          | U 1: a 2+  b ( 9+5 7   b d: S9 V 9;                |
| +-2 + X ':# 0 '#$%1                                          | *++ 9   +5<   - +                |  
(:(:e @WU+,
?0,+W
f0+
62
*52  
(:(:e:'?0,+
X  
(
9
Y2++
3
5
-+
27
+
g
b
' 32
-22
2<,
39:
(:(:e:&h,
+0,+
52
27
g  
'  
328
2-32Y-+
22
9
3
-,
+ 0+
2
7
>,,
+
+3  
,+
ijijkA  
+5
72
7+
92  
+ 3
+++
+
3
+5
*4:  
4
+5
72
7+
92  
+
3
-+
+ +++8
+5
<++  
,++5
2:  
4
+5
,2  
=-2+
228 2
,+2  
,,
+
+3
39:
(:(:e:(
723
,++  
+3,
3+2  
,+2
,+
3 <<<+
+5<  
0<+:  
| )*++*, -.,/012*+12.  3*415161.7   | 8*71,9 :*21;15/61*,7 BC D (E A  ?  ?@@ @ F@ ?  GH@ H ?A IJ? @ K D ' BC D LE ?H@G   J I@@   @AI   |
|-----------------------------------|---|
| <=>?@ ?A >?@ ?A MN DO                                   | P?H@G   J I@@  @AI   |
| QG? @AR??%R?                                   | S   ?@@ @AIG@H @HG@T ?@@   @ J?@@U? ?H@ @ HG@ ? JT  B ('=]# % ^ P? GH  @ '#     P? '=&' B K_` a% M@ bG ??O ^ P? GH  a @ ']  J Lc AG?  ? HdR  ? ReT B K_` a% MbG ??O ^ PH? a  @ ]     ?? ? ?  @  ??T   |
|  P?GH@V   R?  HWH@=DG@T  M<XYZV N@@JE PP   [P=I G?  R  G? @ ?@@ D\ ?   HHG@ H@?    ?GH@ @A    ?HI@ H??TO                                   |   |  
(T(Tf @ (T(TfT'g@@?  
R
R?J  
@A
A?I@  
?@@  
HH
'
P?
'  
& @AI
M@
@A
?H@  
@A
J?@@OT (T(TfT&G@
R?
MHRH
e%@E
HG@
HE
E
AI@H
I?E
GH
H  
aPSO e
R
I  
P
'E
&E
cE
']E  
&&  
HH
'  
P
'  
HA
HH
G HH?
&=c  
P
'
M
e@A
f
?
I
@  
'O  
J
@A
HH
G F@?
IA??
C  
CCT (T(TfT(
@?@?
HG
?G
I@
H@IA??E
?G
GF@E
?G
A@
HA?E
bG@@@J
GRG?E
R@=&
HRG  
e
R I
@
R?  
P
'  
HA
HH  
P
'
M
e@A
f
?
I
@
'O  
J
@A
HH
G
F@?
IA?
C  
CCT  
GR?bG@
?G
GF@
e  
R
I  
@A?
I@@?
HH
H@T (T(TfTL
G
?I  
I@
H@IA??
MhgZgO  
GF@
@
????
H
I@  
@A
G
M>H=i?
I@GO
@
R
I
@ R?E  
'  
HA
HH
'=cE  
'M
e@A
f
?
I
@  
'O  
J @A
HH
G
F@?
IA?
C  
CCT  
C
I@@?
eA?
?GR
??
? R?@
@
R
?G
>H=
i?
I@
bG@H@E  
&L=AG
hgZg e
R
I
@
R?E  
'  
HA
HH
'=cE  
'
M
e@A
f
? I
@  
'O  
J
@A
HH
G
F@?
IA?
C  
CCT
X@Ae?E
&L=A hgZg
>H=i?
bG@H@
e
R
?@@  
hgZg
?IH? I
@
R?E  
'  
HA
HH
'=cE  
'
M
e@A
f
?
I
@ 'O  
J
@A
HH
G
F@?
IA?
jLklT (T(TfT]g@@?
e
AJ
HH
J?@?
e@A
Smg  
?@
I??
@?
???? @FH@%?
H@?  
P
'E
&E
cE
']E  
&&  
HH
'  
P
'
M
e@A
f
? I
@  
'O  
HA
HH
G
HH?
&=c  
P
'
M
e@A
f
?
I
@
'O  
J
@A
HH
G
F@?
IA??
C  
CCT  
R  
GI
@
f ?
I
gC
?H@  
HH  
?@H
??T
()()*)+,./-0/  
11
2/-/
3
.
4  
11
1-) ()()*)*56789:;
/1
%
6<8=
3
.
4  
4--/
./>
0 11/
'8?  
4-.-/  
-@  
11
?  
/
1@2>
0 11/
$8&\#  
4-.-/  
-@  
11
&\#  
/
1@2> 0
11
&'  
.  
4-.-/  
----)  
60 A-/
4@/
>
56789:;
/1/
%
6<8=/  
4
-@/ 4--/
-@
6
-2
-@  
11
?
//  
/4/)
,9= /1->
4-
.
/B
@2  
9:;8;
%
6<8=
- 4//) ()()*)?60  
A-/
4@//
=  
==>
5C9
4--/
3
/.
D0
- @2
41
-//
0
EFFGHIJK
L)  
M1
-4@/1/
3
. D0
/0./0-/
N=O
11
1
23)  
?9C9O
J\B
;I @ MND
?N:D @ '&  
?]X @ \W;?^  
M
DDDD:D  
I=D  
:C  
9:O
8DD
:CGD
D9P
PG_  
M:
::  
:::O
N:D  
`%=
(='a
D D9C8
ND:D  
I::O
D
:
AD
D
::
<E_  
F
I::D
GC
9CD
:
8
D:
9
CND:O
@:
99  
P  
8I
:
L GSD_  
:
9:
b*c  
DI99
:D  
D9C
DID  
9:D
:
P
99:_
Z
9:
bO
:N
:8D  
D9CO :
:  
:C
D9C
PO
8O  
P
G
DI_
\:O
:C:  
DD
D9C
P%8
:D:D  
D8ND
G
:
P 9D
I:9
N:D_  
)*+ ,-./0
12345/26 789:
;::
< 9
' 9
&=> ?@:
;:: ABCDD
7  
77E< ? ;::  FG=HI ;D:%B989 JD K
' > 'L && '  M9CN% ? 9 O >O K
' N
:C 99 99
$ P
I BCD
7=
M9CN
A9
$=&#E% ?  
9
&#  
BCD
77= 9CN
A9
&'=(&E% ;::
::
O
O
O
I ?N
(=Q :CDRO
O
< KDD BDD :  
; BS: 9
9
NG @  
|    |
|----|
| @@ @ @ @ @ @ @    |
| @ @ @ @ @ @  @ @ O  @ @ @ TUB%9 VD: @ @@@@@ @ ?WX @ @@ 7 D: @ 8: YPD @ @@@@@ @  @@D9C J%H Z @ @ @ @ @H  HB?B  7F?  @ @ @ @ @ V :8DP @ D:  NMDDD: @ B9 ;D:9 9@ @    9 @9O O  @ @  @ S: 8N @ FKX B?;=; @ 7  DI @D K8D [C: 7@J G%MDI: @  :D:D @    |  
((  
* +,
,-,.+
/
0,1
,2
,.+.,
.+,2
3.+,  
4-+2
5,--+2
.12
6&2
+.-2
/782
.,92
4-+
..+2
51-51,2
-+  
:+9  
;5,.
4<
51-51,-2
3=>2
3>2
,,  
.,
:+:9 ?-2
+.
.2
@A
,,2  
=B;*  
86>CD  
?>  
?>>
0  
:
5
,
:-* :* E
-,+.+
;5
/
-+.
,  
;5  
,:*  
F
;5  
,:
5-,G2
;5  
83
?
0
:
5 .* ?.
,-,4+  
-+9  
.1:
5,,*  
3  
.1:
5,,
4A/?9  
-H+
,+
01D
'9
1,
+  
1-,.,  
:,
51.,I  
&9
1,
:
,+
5-,5+
,
-,
&) .-.+,G
,14**2
11
-,  
,  
,1
5.
&)
.-.+,G
,1-9*
B+
H,51-2
A/?
5,,0 1G
5.
,-,5
,,
JK*
=.
,,
51-.0
:
L+
,
-+:,
-+,,
8F;
.
,  
G0* * ?.
,-,4+  
-+9
+-,
..+
0,1
'\#
M
')  
0,1
&)
1+5
,
5-.:  
.
' 45-.5,+-,
:  
0,1
N
-9* * A/?
0,1
+  
-,+,
+-,
1G  
5.
,-,
4-+  
+9
0<  
,1
-,
&O  
,1
G
&O
01
,15
4.+
:<
,159I
,
-.,+,  
,
B
&O
5-,
,1
-,  
*  
A0,1 +
-,+,
+-,
1G  
5.
,-,
4-+  
+9
0<  
,1
-,
&O  
,1
G
')
01  
,15 4.+
:<
,1592
,
-.,+,  
,
B
')  
B
&O
5-,
,1
-,  
4- PQQRSTUV
W9* *
,-,.+
-+
5,
.,51--2
-+
+H,2
+
.,51--2
+
+H,2
-+  
1, .1-2
L+,,,G
+:+-2
:,X&
.:+  
0
:
5
,
:
B
'  
.1
..*  
+:-L+,
-+ +H,2
+
+H,2  
+
.,51-0  
:
5  
,15,,..
.,* * /:
0
-5,  
:50
:
-,
,
B5,*  
?,12
0
.,,2
AF;%.,,.-2
B
'(O -,%@C?%-,
4Y+
=:9  
1G%1,
.1
+:+
,
45,9
%
83%Z3
+,,- .+
?,1
45,9*
A
-.
:,
5+5--2  
+,:
0  
:
+
01.1
.
:,
,1
8F; 0
:
5* 1* A66>86>C
86
=68@C
3??=FC%BC=C>CB
F8
3C8BC8>  
4G,
\#N%&\#%&\#'O9*  
?CEF67
>C[>D  
65,
.
' B
&
:
0
-5,  
-,  
B'(O
-,
4@C?
-,+
.G,
-,+-9*  
86>CD  
>1  
., 0,1
3 ,
;
4G,
\#\%(\#%&\#'N9* * /
0
-5,  
:5.
:
5
]%X
&'  
,
..
*  
/
0
-5,  
:50
:
-,
, ;,
.,2
B5,,  
=:
.
4B=92
0
.,,
4:
0
+51,5  
5.-92
B
'(O -,%@C?%-,2  
]%X
1G%1,
.1
+:+
,
%
83%Z3
+,,
.+
?,1 45,9*
F
0
+5
52
?C>%>0
:  
55H,
+* ^* 3,
+2
0X+5
0
:
G
(X\
,1+,
5-
--2  
,1*  
?,,
:
0
,  
L+,
, ,G
..
.,2
**
0
5-,X,15
,H.,*  
?,,01
1G
5--G
-01  
-,+
0
:
0 0,1
-,
-.
:,
,-,..
.,*
?,,01  
,<  
,,,
0
.,+
,
:
0  
-+GG :
51  
..
G-,*
?,,01
-1  
(&
..
,,,
0
:
0
,
-,
G
\
,1:
..
G-,
0,1
:, G+,  
:
:
0
:5
,
,1
-.,  
,1
G-,,*
6
,2
5,,01  
,
5--2
:+,
.
, .,+  
-+
,15
,  
+,.,2  
:
0
:
..  
:,
H,
G
(X\
,1-*
3,,G2  
()
previated Title:  CRd for Smoldering Myeloma
sion Date:  09/20/2021 data may be captured by investigator-patient or investigator-physician phone or email communication if the required examinations have
performed at the outside facility.  
disease progression, marrow and FDG-PET/CT are optional Creamed the performed at baseline discovers between development day I of every think cent decided with at the day in at the collection at the collection at the
day I of each e DO '
one marrow biopsy and aspirate will be performed on patient at baseline, during cycles I-8 if patient achieves CR or at the end of cycle 20 if no CR is achieved, a
tring cycl han 2 missed doses of lenalidomide. For cycles 2.8, the preferred adjustment is -1/+3-day wi
han 2 missed doses of lenalidomide. For cycles 9-forvard, the preferred adjustmen epeat myeloma tests at treatment termination Vithin 7 days prior to D1 of each cycle al Center for this visit, a regust will be made to collect required clinical labs (specify as needed) from a local physician or laboration.
If not possible, patients may be a the discretion of the Principal Investigator, PET/CT may replace MRI in patients who have a contraindication to MRI
untitled h1
+ -./0

123
-.4562/107.2 (898' :;:  
<=>
:
;
?
@;@
:AB
BC:  
C;BC;:  
:B@  
;
BB B
;@;
C;BC;:
BD
;
;@
<=>
B
;8  
=
:
;:;:  
CBA:
C A;:
;@
<=>
B
;E
C;BC;:  
@D
;
C  
;@:
B:;:  
;@  
; BD
?
:AB
BC8  
B:
;@;  
;
C;  
;@
:;A
;;;
F
;
? CD  
C  
?
;@
<=>
B
;8
untitled h1
(898( ?a

I@
<=
F
BD
;@
B:;:  
:
JC::
::B;
F;@
C;B
C;BC;8 ;@:
B:;:  
?
C
B;
?
;@
<=>  
:  
?
?A:
;
;@ C;BC;%A
:
CCC;8  
I@
A;  
;@:
C;:  
;
? ;@
<=
ID  
K
?A:;
GB8
untitled h1
+l -m706m71

N.M
M64.O1P
Nm.4
5M.0.-.P
0Q6M15R
123
.Nn
/0S3R
-M706M71  
G
;
D  
:;AE
;
A:;
?  
;
@D  
:A?TB;:
BC;  
:;
D:; CCJ;
(\#
:
UV%W
X
:Y
F
;@
:;
:  
:;A
;@C8  
(8)8' ;  
D  
C;B
;@C Z G;;:
F;@
B
BB  
(  
[
D:
D;:
;
;
A ;@C  
?
;\  
;@C
;
;@
:B;  
;@
CBC
D:;;8 Z G;;:
]A  
;@
&
:
AB;:  
B^?8 Z IJB;
@:
;
:D
;
&
F\:  
F;@@
;;;  
AC
;
(
F\: B;
;
;;; Z _
(
W?:;
:@  
?:;
:@ _
(
AC;@ _
(
@C::;D;
B; `::  
C:;
D:?
BC@C;@
UGaY  
;@?;B BC;@
UIbY
Z G;;
BC;:
;@
C;B
U:
A;  
B;
*+cY
Z G::  
:: G;;
B@::
;  
;@C I@
CBC
D:;;  
D
C;;  
C;B
;@C B::
A
;
B
B;:E
BCBE
;B8 Z G;;
?B:
C;8
(8)8& dW;A
; Z G;;
]A:;:
;
?
F;@F  
:;A
* +,- * .-/01/
,,
,-,
2,-2
/  
,3,,1/
4/,
,/,5 ,,/
206
73,0
,-3  
3//
,
/3,,0  
/,8  
68,
94
3-:
:  
00
6/,;  
/866
3 /,8
/0-8
,
,/0,  
,6/,,5 * .,,/
2-6
,
3//
48,
0-/
,
0,8  
,0 4
(&
00/
,  
8,/
0,  
/,  
/,8
,
,/0,  
,- 6/,,5 * .,
//  
030,
,
6
0/, 0
8
untitled h1
< =>?=>@abc?b

@Dea=Cba>?Fg@Dcfhidf
C?E
=>?Faedicba>?F <Jk Bh@>I
Lmfaf
Fm?Ei>@D  
N5'5' O,  
P8
,
Q8/  
5R
-,S  
T
/84U0,/
8/,
4
2
-,
955:
68
3,;5  
V -,
W8
,
33X,
(\#
Y%Z%
9[\]^
083/  
W8
3
;:
/,, N^
-8/
3
,
,3
/,
/  
0_45 45`a
-,S  
TW8,
-,
/
W8
3
,
/  
0
':
/30 3,,/
,
-/Z  
,8
//
/  
,X0,5
b0
-,
08/
4,
8/
9(\#  
3
Z
,
/,
N^
-8/
4
0
':
+
';
,68/
8/
9&c\#  
,
c\#\#  
333,
,68/
8
3
,
0- /  
0
';5
`
:
6  
,
&c\#
,
c\#\#
2
0_4 /,,5
,8  
%
,68/
-,:
/
:  
/84/W8, 00/5
,
3,,/  
60  
68
6  
U8/,
-,
,
68
3,,
/:
/30  
3,,/
2,
,
/Z  
00
85  
b, 68
2
4
,
,
,/0,  
00  
68
/,,8/  
3,,5 05`
/84U0,/
0/
,
4
/,
,
/Z  
bY
,
03,  
0
':
-, /-8
4
0,8
,
/84/W8,
00/  
00
0,5 N5'5& Y4,
,
5T333,
0-/,/:
08
0,:  
03,
4
08,/
9V;
2,- 3,,
08,
/-8
4
4,  
62
3
,
0_4
/5  
/8,/ 4,
/,8/
8/,
4
62  
003,4
3
,
/,
,- 0_4
/5 4584U0,/
2,4,
4,/
0//,,
2,//  
,8
0/
955:
/8 0,
d
c\#e
0/:
Y+O
d
&7
0/:
80
0
d
c\#e
0/:
3-/3-,
d c\#e
0/:
3,//8
d
(\#e
0/:
008
d
&\#e
0/;
3
,
/
/-8 ,
06
,/0-8
/
N5'5( 0
,
5/  
/3,/
0,6  
bY:
/80/
6/:
0-/%/:
/3:
8/: 6,:
8/0
,,:
2Z//:  
03:
/_8/:  
0/
8
8,38,5
*+,--.
/
*
--0
1-0.1
*.2
/0
32
3
' 4.
'  
&  
-01+
5+'+5 -
+6
78
339.:
33
0-0:
9:  
.
*.09
* .--9-+  
33-*-.:  
93
9
*3:
.-019-3  
.911-2
3:
39
..:
.
33
3-+
*+;
3..  
78
9.*
1;
.  
9.
;2.
<2=;<>
-090 -0  
13..
/-0
&5
09.  
-0
33
.*3
/  
-0
2-+
5+'+? @13
00
.A
78
1--.B
+;19
.
1
/
*
1.3*
-0
62.--C.
.3-+  
70. .9*D3-.  
32
19
(\#\#  
,@
E64
=3
'
4
F&:
4
F'>:
3-9
&
.
3
'
4
'
=-
5
.>:
-0
93
.
(\#\#  
,@
G4: 3-9
-090
4
'H  
3
'+  
;19
.
.09
*
D9.33
- -0
13A
.-+  
9*D3-.
/0  
-19
.09
*
.39..
/-0
-0 8
,31
62.--+
untitled h1
ijk lmnopqrpstopuvmtwlx

Qnyltmp  
9*D3-.  
32
E  
1--.9..  
33
3-+
F.-93-.  
*
9.  
9-1
339.
*9.09
*
2 1103-3+
untitled h1
ijz nols[ytnvrnlsto

@
;.1
)'  
(&?  
.9-*
--2
-F39
-0*-3
110]. 2  
-0
9
-0
1-31
-0
.-9+
;-F^
2.
/  
* /  
-0.
1--.
/-0
_`a(\#
%  
32
]1+
6
: -1
0  
1103-3  
--..
=
29.
-0*F*.>
-F 39/-0
-0
.1  
]1
1F139
=++:  
*
/
*1..> .
b9+
c/2:  
3..:
-0
33  
0
/0
33
3-+
untitled h1
iji xpd

Noe
Dpd
Fmtfxg\Nhsp  
@
i332  
?\#\#  
;332  
)\#\#  
E64
-0909
33. /030
3j*
.
2+
untitled h1
ijk nolslstlsy

Fmtfxg\Nhsp  
,--.
.A  
21
3-.
/
*  
-*-3
110].+  
.A
....- /
*
1
*
33
2.--+  
`
.-3:
*-3
1--.  
1--.
-A 303
.-.
/
*  
E3110].
=
.
-.>
2
.A  
,, 3-+
untitled h1
ijm fmtvmnppsdn

Or\Lsqtyn\
\Nrptnoynfxn\Tfnlxg
Qfo\R  
,--.  
-0.
.-9
/
*  
/  
/.
93:
3-2 *02
..  
.1-.
-0
*
.9.-2  
,8
.
1
-0
- ..  
329.
....+
6
,8
.
.9.13-:
/-00
.--
)*+,
-.+/)0-1.
+
220  
0  
-2)-0  
2220
-0) 0-0
-1.
+
003
*+
-1.
+
-)0.  
45
-)3
untitled h1
678 9<=>=>?

@
A>Bc?
D9@Ae
B:<F=>A<=>Gh  
I)0J
KLM  
N).)0  
01-0.3
KOJP
200O1  
)- KLM
O
+
O  
-0.3
Q
-.+/)0O1  
)
KLMP
221NO01
0J- -1.
+
)-3  
KLM
O1
R.
000
O01
)*+
-1.
+
)- 0  
-
-20
)0J
KLM
)0
01.1.0  
O
01 000
O01
)*+3
Q
-.+/)0O01
)0J
KLM
)0J0P
)*+
-1.
+ O011
.0
)0
R.0
)03
untitled h1
) +-./01230451-3

6+,
,-3-/,*7  
  
)89 :1+3;-*1<-=
*+..-*01+= :>?@ABC@ 5DEBCF
*GHA@
IJK
LE -CM
LN
*GHA@
KO 5DEBCF
-PQ@CM@M
5L?BCF
;R>?@?
LN *GHA@?
SJITU
-CM
LN
*GHA@
IT
+, *GHA@?
I9JVIU-CM
LN
*GHA@
VIU -CM
LN
0E@>QW@CQX 6LAALYJ4Z
;@EBLM
>NQ@E
VI
HGHA@?
LN W>BCQ@C>CH@
@[@EG
VJ\
WLCQR?] 5B?@>?@
;ELFE@??BLC  
^_`%ab cc c c c  
| ^_`%ab   | c   | c   | c   | c   | c   |
|---|-----|-----|-----|-----|-----|
| d_e_f gh __   | c   | c   | c   | c   | c   |
| gab%__fi   | c   | c   |     |     |     |
| fd e_`  `_  `j f`  dkd _ % li   mi d__ ii n=+0-o =LQ QL  p@ Z@ENLEW@M >? LN /W@CMW@CQ 7 n[@E?BLC  M>Q@ T\UVTUIT9qrr   | c   | c   |     |     |     |
| se_t   | c   |     |     |     |     |
| se_t   | c   |     |     |     |     |
| u'vwx i_%y zeii e%  fj_   | c   | c   | c   | c   | c   |
| {_` if` k i kh| fd mz_  y_ }df _ ~ud f &w   f`j  €  f w    i f`j Xud €z_ ui ^`ii s^`i a  aat   f`j d ffi $&#% €  ff &#     f`j d ffi &'v&%€  f v& s   ___t ' ud _` ghƒe ^|  ii if` k%d _i_i  idji h _ k fi  e_f j_i   |     |     |     |     |     |
untitled h1
''

H  
Ee`
K  
e  
^_i  
h
f_j
i_di
_`d`
ief
_ei  
_dki  
i_
kh|
ki  
jk_  
ji__
if_|
_dk _ei  
k
idki__d_  
_`
iii
_
k
e f_j
h_`
_
y
sji
_
\#%&\#%&\#'t|
k
h
ie_  
kei
h
k k_  
if`
i_di
_
_`
if_  
_`
^a  
ud
z_i
e`i
|
k
h
kei  
ie_i  
e_ _`i
e__i
_`_  
u
_j
_
_`  
ff
w
ii  
iei
)*+,,
)
-.
,
/
)
0
12/
0,3
-1,  
2 )1,
1-
-,
,3
-2,  
,3
+4* 2*2,  
)
05
-,  
)
0  
-,  
)
0
-1- /,  
67789:;<
=  
2,
>?@?A*
*,B
-,/--2,
0,3
)
0
-12
0
)
1  
, ,
22
/,2  
,3
-/,
,3
-,/
2,  
22  
,-,
,
C
,3
-1-*  
/23
-,/
2/
)/,  
,
,
,
,3
0D
* +,3%4/3-,23-,D  
E
0
)1
-1,
0
)
-,
, 2
,
F1,,  
G),
25
H,
2, 132
B/,
)
4
25
F  
2
,
H,
,* 4/3-,232
-,
0
)
1
/
,3
2,  
4
25 F*  
+2
)/
0
)
---//3-,23-,
.-/23 F
'IJ5
3,
23-5
FKL
,2*  
+2
2B,
,2,- 0
)
---/B//3-,23-,
.
-,)-,-5 -,2-,-5
-,
2
1,--*  
*
-/
F--D
M N0
2,,D
4/13,1  
),
12)
0 2,,
2/,
BB-5
)/,
,
,
,5
,3
/
,3
0 ,-D
F'IJ5
F'$5
F(K5
FIJ5  
FKL*
32,-,2
23- /13,12
)
12OF'IJ
1-,BP
2/
)/,
,
,
,
)-,
F'$  
F(K5
2FIJ5  
2- FKL*  
Q3-,/0
)
1
/
,3
2,  
HRS
S
,3
0
2,,
/,  
,3
T4
G),  
+,3*
* N4H  
2,,2-D  
4,13N4H%2,,23
)
1 1,,  
,31,2  
,3
T4
G),  
+,3
2 ,,2U,*
V
,
H
OB,
\#L%I\#%&\#'WP5 N4H%2,,2
,  
)
B  
,3
1,,X/,2-
1  
))
0
-1,  
,3R1,
,-,
), 1
,3  
FG
22
),
1,2%12/
0323
2/,  
, ,3  
),-5
Q-,
4FD
++FN5
+
+,B
F- O++FPY
B*
,5
Z[+
15
03
\
-]/25
2TV
-- 2B,
,2,R
0
-1,
0
)
-,
,
,3
)  
,3
F*
^/
OE/
'\#%(T'\#LP  
,3
F1,,  
G),
2 -,
,
F
'IJ
_  
F
'IJ
`
2,-*
F*
^/  
-,
0
- 1
,3
)0
--
/-,
)
0
-1,  
aFb
-]/2
----,  
F
,B,*
M Z[+
1
,,
\
-]/25  
aFb
-]/2  
F ----,D
E
0
-1,0
)
22,  
-,
,
,3
^/ G)
,
J
22
/2,  
5
,
&\#  
I&
22
,,,
,
/
0R/1
-,03
E
-1,
22,
O
,3 -10
22,  
,3
1,,-*P  
V,
)-D
F'IJ_
120
)
1/  
)
0
-1,3B-,*
E- )'*+,
-.
/
0
.1  
2)3
.45
1
67.1 8)9
:
;<  
11%/=
>
.45
-5 >?..
..
8?  
.5-.<  
-@
A
9  
B1 .50.451
1
?1.@
?11
.  
@
?.
-.
/
1
0 ?5  
.?1.
/
0
70
C9  
?.
/
0
.1
51 01-=.9
:
1@
.
.?.  
0
.1
1
D)B%:E:F  
>1 1
.45-@
.
0/9 G H
/@
0  
5
.?.@  
..-1
-0
1
/ 0
.1
1
B?17
H1-=.
?9  
?
.45
1=
2)3 .45-9
?.  
1
/
0
.5011
1
B?17
H1-=. ?9
/1=51  
?.
1.9 G )
'*+I
-1.  
0.
.?.
/
0
C -71
1-1.
.5-=
.
-1A
?@
JB.@
1-9 1=
K5
;09
B
-1  
)'*+I
-.
/
.
0
-515
1
.1 0
/
.1
-.  
51=
..9
B1
1=
.
1
?1.@ L  
M)NB
150  
??=
0
/
0
--1  
?
..9 G H1=
-1.
/
0
--1@
01-=@  
1
1  
00A9 -1
OPQ  
.1  
0
/
00A9
B.  
B1
E 87.
1
\#L%*\#%&\#'R<@
B.  
B1
7.
1
\#'%'&%&'@
.?1 .?.
/
0
.1  
);
5
)9
K59 G B.?1
.?.  
.
5
1-1  
/.1
. 11.@
?1.
-171@  
504511
?1=/.  
.1 /
.?19 79 B1
-5
?
-5
)JBI@
JBI  
?1I0.
...
0
/@
0@  
5
.?.
/
0
?9
N=
?5?. 1=.
...
/
0
1
51=
-=-1C
5
0  
-1
/1= -51-.  
>?1
9
N=.  
1
1
1@
051
-5 1=
/9 G J>1
S1
458JS<
-01
/1=
:- E1  
:F5-1.
8:E:F<
D)B
*+,
,-.
/
0
11  
-+
.-23-4  
40-,
/-+ 5657%89:  
-,  
-+
-,
4-1
,34-,
.-;
5657<, =/0>
3
?@
,,,  
1.,
+.
,3,  
1-  
44
-,A
*+
-,  
,3,
/
0
3
. =.0>
*:A
*+
,3,
/
0
4
00B  
-+
C7
D8
E0F
0-4+
-+
?G6
.
,+3-H
/+4+
-H
-+
,3,
/
0 ,-I
:**?I
J,H
7+A9A 9C
GGG%5C7%57K%9J 8  
9.
:,-- '\#$\#)
?/
63,+
:1H CA
L&%M&H  
&&(NH 1
3H
9
&\#$$) *I
&(\#2(\#&2M)L) JI
J-A,OA++,A1
*+
4-1
?@
,,,
0
3
/
0
3  
-
1,-.-.
3-P.,-,  
-,/-+
.
40-,A *+,
4.
0.  
,  
-+
/
0.- 3-I
'A *24
433D.,PFI  
4,4+  
-+
--.
+,
,+/
-+3--,
,B
0
.-+3,
-+,
/+  
.
+1
-2-.
*
4
4-A
E
,
..
-+
,
3-;
-+,  
/-+ .
,.0,-,
0/  
A
?@
9?:,P
/
0
.,
;
-+ Q9R
,P.4  
*24,
4-A
G3.,.4  
0
7C  
/+
0  
33S&
.  
3.9?:
/
0  
/+4+ /
.
/+
0
44
-/
'\#  
J9*:
-.0,A
4- 3-,
4.
-+
/
,-,H
0,H
N  
H
'  
& ,A
&A @
,
.433+,,
D?7F  
43
.0
1-, D?QF
9?:,PI
T+
S  
,P.4
/
0
3 33+
0
0,  
?7,  
?Q,A
T+ 0
D
'\#
E
J9*:
-.0F
,3
/
0
440,
9?:
S-4-A
*+,
9?:
/
0
.,
;  
43
1,A
,-4%-.
-4
--,
0,  
,P.4
-A 8.-+H  
33+4
1/
0
;
, 2/
,,4,-.
D@T:F
/+-+
4- 1-,
3,3,
3--,
/-+
-
3,,
04+4 1,3--4
,,A
:-H
-+,  
1-,  
0 ;  
,,4/-+
--1,
1-,A
)A 4-9?:I
*9?:,P
/
0
3  
4-9?:  
,,,,-
,.
,,
D9FA
G
-+
Q9R
-44 ,,
3,4  
-+
4H
-+
0
/
, 4.
-+
B/
4.-4
0-,A
:33S(LU  
)**+
,,))  
*,  
./ 0,++1
*,
*,
(23
,+)00
*+0*+%*+1
4 0,0*51
0.
*+0*+  
67'(1
''7'(1
(7'(1
'(7'61
'67'81
'9) 1  
0:;  
<,1
*,
++
4
0.+  
/*,
=>?
+
4*,
*, ,*0
0+  
0.*
*0
**+
+
*
*, ))0,
.+  
+
0+;
@
00*
4
-*4
'\#
A
B><C
*./+1
**-1
*0D
*./+  
/
.+  
)0++  
*, +)
4
/  
/  
*,
&
,.+;  
(; E
F)++
)G
HC+I
4
/
)  
>'J8K
0+  
0*
4*,
>HC+I
+.*+;
C*1
)), /%L@
4
5  
.
*
+*.+;
M
'\#
A
B><C *./
4
/
.+  
*,+
).)+;
-;
N.
+./+*
++
@
4  
L@+
4
/
)0++1
+*1  
++++
/
*,
<) A/
.+
.*)*
4
0**  
.
+./+*+
0.
/.*
* 0++
*
*
<+1
>
+./+*+1
0*
+./+*+1
>8K
<O0+ >(KPF)JO
<O0+;
C++++*
4
0.
.0*
D+1
;;
L>O'1
<O J1
<ACO(
%
>(\#;  
Q L@
00*  
+)0R+SG
<4
8O'\#  
B><C
R).)
*)S  
@> =0.*  
L)*
<./+
RL@7
/.  
/0D
*
*)S
4
/ 00*  
0,
)**;
N*
*
00*1
F
*,
/ +)
/
*
-+
+*+;
<,
*  
F0*
*  
0, /
4
+,.
/
0  
*,
*./; Q @
4
00*  
+)0+G
'  
/
4
4
/
00*
0,
)**
0*
<
)*+
Q @G
@+1
J>')1
)+*
8  
1
)+*
'  
)+*
&
+
4G
@+1
)+*
8  
1
)+*
'  
)+*
&
+
H*0*  
TG
C+
+
+
)++/
*
*,
)**
+
+0,.
)+
+  
*0*
* *,
<)
/
R*)UV;,;-7
.
A
*
+.V;,;-7
O ?.
A
*
V;,;-S  
0
*,
<)
/
*
&(\#O96\#O6JJ\#
4, *,
+)
+
4  
/
/
4
0  
*
)0D
.);
2;';& +0,
@%.  
W  
2;';&;'C*  
*1
.)
*
'\#\#00  
)),
/
4
/
00*;  
<,
.* /
00*
4
/
0**
/
*,
./  
F)*+
*
/
)1  
/ *,
)**X+
)),
/
0.*;  
<)0
*
)*+
0.G Q @+ Q >+
8  
'2  
0
'
'  
00
.
00+
&O87  
)**
0,-+  
*
*,  
00
8  
+
0,-
* +
',
-./
0
1
2
.  
'3  
4
./
55
6
551
$ 7
6
8.
1
2/11
,9  
993:  
2..
5/41  
. ./  
55
&\#  
1
5/4:
6
551
&';<&  
1 5/4  
.
...
..= * >4
<;?
./1
6
./
21.;.5
-;62
2 * +11
@11A
.  
.
2.  
./
2..
/1
211  
11
)='=&=&B/
1.
67  
22/
7
15/
.671  
55. 1.
.
5/  
./
74
.
2.1  
56
76.  
.
.
.
./
-A  
C
D
16
12.
.67
,B3:  
'\#
D
16
/2
.67 ,EBB3:  
'\#
D
>+BF
4
.2
.67  
1.  
./
G
@511
,G@3  
'\#%)F\#$
,H
D73  
77I=
F.:
62
.
18
'\#
>+BF
.671  
7
55.  
461
82.1
.
7
2
-./
H+F 57.1:
1
7
?
D
>+BF
4
.2
.67  
11 1.  
./
J6
D7=
)='=&=<F.  
4
.:
228.
()
D  
6
7
55.
.  
1.
6 55.
562  
1.  
11  
1.
.
5/  
./
74
.
2.1= B25
.
2.1
56A * G1 * +
C  
')  
5
'
'  
4
55
6
551
&;C
'
,
-./
0
1
2
.  
'3  
4
./
55
6
551
$
7
6
8.
1
2/11
,9  
993  
2..
5/41 .
./  
55
&\#  
1
5/4:
6
551
&';<&  
1 5/4  
.
...
..= * +11
@11A
.  
.
2.  
./
2..
/1
211 11= KLMNO  
B/
6.  
6
55.
7
5..
7
./
67 82.1
.
7
2=
)='=&=(5.  
1.  
22/
7  
6
6.  
PQQNKRST
R= 2
U6.1  
VA  
B/
.  
85.
.  
5/
7
- 1/6
7
5  
./
12
.67=
6
121
1/6
7
I2.
.  
.2.6  
<\#;?\#
2
.
7
.=
)='=&=)@2/
7
%
6
121  
2..1
7
W  
2.. 16  
6
7I1
1
1
6
55..1:  
5.
.
55 6.51  
./
16.1  
./
1.6
5.  
55  
.1.
. W
./
121=  
65/
7I1  
56
76.  
.
.
.A
* @2/
7
5..
1111  
556.
21
51
6 ./
5.  
V;X
X:
+= * 676.
2  
5.4.  
556.
2.11
7
W;I 617.
11
* +,,-..
...
,/  
,.-/012
0-0  
.- ,,--0
0.  
* 3401.-4. * 5.  
2
-46  
..
0-6-
* 7,8
2
9
2
....  
4
0
,,4-.
04:
24- ;
0.
<=(  
=>?:
@A@:  
BC
0.
4.
9 0--D
* E  
4
.,.  
..000
2
9
2
.- +,-6
E-08.
,  
,
.F40  
-8
G=H
.F40D
ID'DJ 3
K
L=A/7M;%;
untitled h1
id'djd'084

L=A/7M;
.0
9
2
,  
,--.
2.:
4
00.
'/>  
,-2-.
-8  
00
>  
2-:
4
00.
$/&\#  
,-2-.  
-8
00
&\#  
2-:
4
00.
&'/J&  
,-2-.  
--- --D  
=4
N-.
,8.
:
L=A/7M;
.0.  
,
-8. ,--.
-8
=
-6
-8  
00
>
..  
.,.D
+73
.0-: ,-
2
.5
86  
7M;/;
,..D
untitled h1
id'djd&704.

7
'>L/L=A
7M;%;
:
-8
.42O09
86
.
06  
.4 0.42.-0
<DD:
40.:
.40.:
N-.?  
(/)
84.D  
42O0-.
9
2
04 5
94
-8.
,
40
.
-8
5.  
9
2
.5
6 ,
'>L/L=A
O0-D
P  
082
,-9
86  
04,
-6
,0
-.- -8  
-8
002
,  
-8  
-8
.0  
-8  
2
-8
.0D '>L/L=A:
Q'>LR/4N40.
.  
L=+
,,6
,804-0D  
3- ,
O0-:
-8
.42O0-S.
2
40.
6
9
2
646  
.-05D  
B/ 2-0
.42O0-.
9-8
.2
40.
6.
26
'I\#
%  
2
.084
-8 .0
-8
73D  
42O0-.
9
2
.5  
N0..6
,8.0
N
-8
&( 84.
,
O0-D
7--.
9
,-8
B3
00  
-8  
-8
L/'>
7M;%;
.0  
,,8
64. 00..
9
2
2<.0
6
3G  
-8
-042..?D  
;8
'>L/L=A
O0- ,04
9
2
O0
2
9
2  
T&\#  
.
<.4
08
3G
4.
\#D$U 9%6?
4.8
6  
,  
T&\#
.0.D
;8
O0.9
2
64,/  
,.-/ .-  
0<DD:
2:
8-:
..:  
0-?D
P8
2
<6-N
-.?
.--0
7M;%;  
9
2
,
2
- ,,N'/84
,.O0,
7M;%;
.,,04.D  
;8
,-9 2
.-40
8  
40
-8
.D
ID'DJDJ@0
0.
2
4.  
*+'+(
,--.  
/  
-0  
-0
12
3
,
43,5  
621 1
7
8/
.1029
70:
;../<
-0
.
.1
2.
- /.
.02
/
2.  
7=2;+  
3
>
?@=3
*+'+(+'102
A
7  
;--.<
70
/
?@=3
.1.
7
/
;  
;--.
- /.<
11
(  
70
;-10.  
,<
<
%
,?<  
-0
---+
?2
7=2;
;<
.1.  
/  
;-0
.1
-0 :.--+  
@
;
/?@=3
.1.  
12;--.<  
70
7  
0:
/.
?@=3
.1<
-0
.
-;-.<
.
;;1/+
untitled h1
+'+(+&12.

?@=3
8;-.
1.  
-0
2.  
7
:2.
-..2.
;0.+ B0  
1-.
1-.
-0
1  
2.
/-7
-..2.+
C
--;-. 7
/  
;
-0
?@=3
.1.  
-0
.  
.
,DB%B.<
/2.
-+ A
?@=3<  
81-.7
/
2.  
..
E2+
11 ;;12.
7
/
2.  
11-+
?@=3
:2-.
7
/
1. ;2
8;-+
untitled h1
+'+ -i2-1.

B0
,I3
JK
.-27
/
.
1.;--.
70
.;H
D.0
;.0+
B0.
.-2-.
7
/
./.9
-0
.-
:
11
411. &=L
59
-0
.-
:
F
11
411.
$=F&
59
:
F=M
-0.
-02
-0 7=2;
;0.9
<
-0  
;-.
-H  
---+
1
-0
.2.
0:
- /
:
-0
2.<
;-1;
-0.
;
-0
.-2
7
/
- .2/N1-.
70
.;H
-0
D.0  
;.0+  
A2-0<
-020
;--.
7
/
:
-0 ;O;2-P  
1;,I.<
7
/
1.  
;-/
:70 ,I.  
1;  
..  
.
.
-0.
.  
8;;-+
,I3<
-0
,-;I2-1
.23.4,I3Q5<
. 2
/
-0
63.--2-.  
R-0  
;:.
11.  
.10.
11..
- 1-<
;1.<
:<  
.;.:
.2.  
0-0  
7>/  
11
- ;--.+
B0
.0.
-07
/
;
-0.
.-2
::
E2.-.  
-0
.
;0.1
21-<
8-<
;..<
-2<
.;
.-2/1<
/;-1;- .1
.  
1-:-.<
;
-1<
;
-.-<  
1-:
21-+
C
1;2- -/-=/.
;;1.
8.-.
7010
1
2-S
1;2;-:
-.-.
4CB5
7010
1 7
;-/29
-0.<
;-0
-;F)
E2.-.
;.
-0
;;
.0- .
/.  
;-.;.+
B0
E2.-.  
8;1-H  
-0
&\# 2-.
1;-+
C.
./<
-0
,I3  
/
1;-2
/.  
-0.
CB
,I3
-/;;1-9 --:<
-0
;;
.0.
;.
-0
;;8
7
/
2.+
?7
/
.12
-0
-//.  
&
;..7.+
@0
.2-.  
..<
-0
7
/
8;- 81  
.2/-
.
F?  
K/-8<
.
;;;-+  
2/N1-.  
enrolled onto the study may begin completion of PROs at the next scheduled visit after amendment activation at the discretion of the investigator (i.e., PROs are not limited to newly enrolled subjects and/or those who complete one at baseline/prior to treatment).  
NOTE: As of February 1, 2021 PROMIS surveys are no longer completed.
untitled h1
5.2 samples for genetic/genomic analysis

5.2.1 Description of the scope of genetic/genomic analysis Genomic testing will be done as described in Section 5.1.1.  
5.2.2  
Description of how privacy and confidentiality of medical information/biological specimens will be maximized
Confidentiality for genetic samples will be maintained as described in Sections 5.3.1 and 5.3.2.  
In addition, a Certificate of Confidentiality has been obtained for this study. 5.2.3 Management of Results Subjects will be contacted if a clinically actionable gene variant is discovered. Clinically actionable findings for the purpose of this study are defined as disorders appearing in the American College of Medical Genetics and Genomics recommendations for the return of incidental findings that is current at the time of primary analysis. (A list of current guidelines is maintained on the CCR intranet:
https://ccrod.cancer.gov/confluence/display/CCRCRO/Incidental+Findings+Lists ).  
Subjects will be contacted at this time with a request to provide a blood sample to be sent to a CLIA certified laboratory within the NIH or as a send-out test to another CLIA certified lab.  
This is the only time during the course of the study that incidental findings will be returned. No interrogations regarding clinically actionable findings will be made after the primary analysis.
untitled h1
5.2.4

Genetic counseling If the research findings are verified in the CLIA certified lab, the subject will be referred to a genetic healthcare provider within the NIH for the disclosure of the results. These activities will be funded by the Center for Cancer Research.
untitled h1
5.3 sample storage tracking and

5.3.1 Procedures for Collecting, Processing, and Storage of Bone Marrow biopsies
.
untitled h1
see appendix c

.  
Orders for bone marrow biopsies should be placed in the Clinical Research Information System (Clinical Research Center, NIH, Bethesda, MD).
.  
Materials for research studies will be documented on form NIH 2803-1.  Samples will not be sent outside NIH without appropriate approvals and/or agreements, if required.
.  
Bone marrow biopsies will be submitted in native condition to the NIH Clinical Center Department of Laboratory Medicine and handled according to routine procedures for diagnosis.  Bone marrow core biopsies will be fixed and paraffin embedded for histological and immunohistochemical analysis and long-term storage.  Bone marrow aspirates will be prepared according to routine procedures.  Five to ten air-dried aspirate smears will be stored long-term.  
) *+
,-..  
/
0
.,+.  
.-1
0
,  
+1
.2  
+1 .,+3  
4'56
,.+7
,.
-.
0
/
.+  
.8/.+  
+1.
.,. .+  
98
:/;3 ) <
+1
,8,..  
.+=
0
.,+
0
/
..  
8>8
8/ -+3  
?
+
@+
A
B7.
+
\#C%'&%&\#'D;=
+1.
.-1
.,. 0
.+  
+1
/+  
+1
:,1
-.
E-1  
+,+8 -+=  
.-8
+
+F  
+1
G*
4,++  
A+,+13
@.
@+
A
B7.
+
\#C%'&%&\#'D;=
+1.
.,.
0
/
.+ +,+8
-+=  
.-8
+
+F%,
2  
+1
G*A
4,++
:/+
-3
<
+  
+1.
.,.=
,.
-+-+
F .-10.F=
343
+
&(\#HDC\#HC'65  
98  
+&(\#H6I6H5I'53 ) <2
.,-.
0
/
0,,  
88  
/
0+1
+1
,++J. --..
8/=
,8+
+  
./
,+1
2
/=  
.+  
>8 +
23  
K1
>8
+
2.  
+  
+,+8 7+.3  
@
<F
?
+/.
A?
?++
*+  
,- *7+
.
8.  
+-F
+1
.,.3 ) K1
?*
0  
..  
8+-,+
.+8-+  
.,.
.  
7+3 ,+
0
/
,
+1
>8+.  
.-+
LMN3 I353& ?-8.  
.+
.8=
,,1
/=  
8
.,-.  
+1
E
?-..
O  
PQQRSTUV
T  
,-..  
.,. ?.
H
WXYYZ
Q[Y\]^^_`a
bY[]
cWQbd
B43
<J.
:/;
+  
G*E-e3137 +
.+
&(
18.
/
+.,+
.,.
B+1
<
/
.
,;3 <
.,
,-F8,=
,
'\#&H''$C(3  
,.  
+
/
7
+
+1
<
:/
B(E'';3
<
+
1,=
&(\#HDC\#HC'6\#
B
/
,-..
8/;
=  
.0= &(\#HDC\#HC'$\#
B
-,1/
8/;3 <
>8.+.  
.,
,-..=
-+-+
E?
/
H
+ G*E-e31373  
) @
.,.
.+
+
+1
E
?-..  
BE?;
0
/
/-=
0+1
+
+
.+  
+1
:/+f
8+2
/
+1
E?3
K1.
.  
.-8
,=
0+1
--..
+ :/+f
+
+  
E?
,.=
01  
..8
78
8.
--8+.3 *.++  
:/+f  
.
+
+
-,8+.
.,/
43
<3
K1. -,8+.  
17  
,..0
.+-+  
.-3 ) :/+f
-+.  
8>8
/*4  
7
.,  
.,
/f=
01-1
-+ /
+/-F
+
,++.
0+18+
:/+f
--..3
K1
+  
-1
., -8.
+1
,++
*4=
=
+
%,+8/=
+
0=
-+
,+= .=
+
+,=
.
0
.
/f  
2
-+3
?++
,1-.
..-+ 0+1
+1
--+
,++
8/  
,7  
+1
..+3
<
-1
.,=
+1
+.
..-+
0+1
+1
,-..
+1
B  
.,
,-..=
.+ -+.  
+1
0=
+-3;3 ) E.,.  
.+  
//f.  
-F
2
+
+1
H&\#  
H6\#g -+
.+/+
>8+.3  
K1.
2.  
-+
.+  
+1
E?  
)*
*
+,
-./
*
0)*
1.)  
-./2
34
5)*)
*
*6 7*  
89
*
7
..0
7
7*
)*
*  
*)4 : ;..))
*
)*
..
)0)
)
)*.*4
0)
<
7
)*
9*
89)*
7 ).6  
*6
0*.4
;
89)*)  
*  
*./  
=7*>
4 ;
).6)  
89
*
)  
)**
*6*
*6
)0)  
*
7
9) ).6
090))
)).*
<*6
*6)
*
?)
0
*6
,@
001
0*.A  
*6*
99)
)0)
9)*
7
*9
*
*6
@B4
,*
)
*6
)0)7*  
*6
+, B.0
,1)**
*
)9
*6*
*6
)0)
89)*  
7
9) .))**
<*6
,@
0014 : -<
.0*  
*6)
)*92
)0)
<  
)*
)
*
714 ;..))
*
*6)
)0)
<  
7
*
<
,@
001  
* 0*.2
*
*6
6*)
*
9)
*6
*4 : ,2
*  
*2  
0**
<*6<)  
*6
)*9  
)
*
<)6  
*6
>)* )0)
*
7
9*C2
*6
19
9)*
01  
<**
89)*4
-<
.0* *6)
89)*2
*6
)0)
<
7
)*
?
*9
*
*6
0**2  
)
89)*A4 D6
B,
<
.  
))  
9*.0*
)*9.*  
)0)
)  
1*4 0*
<
7
0
*6
89*)  
).*
EFG4
: 0
7.)  
/
*
0**
06.)  
*
..
*4 D6)
*
<  
7
01
*
1)**)
)*  
*6)
0*.2
1 )*
9)  
=7*>4
,*
)
.*.
*6*
*6
)0
)
/
*
0** *
)9.6
)
.2
2
*)  
))  
*62  
6)*.
* 79*
*6
*92  
*
.*
*0
<*6
*6)
17)4
(4H4H 0)
0.))  
*6
30**  
=7*
.  
+,
=7* B*6 : @0)2
7
<  
006
7
)0)
<
7
7*  
*6 I*0*6
.*  
*6
+,
=7*  
B*6
?=BA  
*6
I* .*
?IA  
*6
3=2
4 : 0)  
.
7
*6
=B
I2
3=
I  
J9
=74  
D))9
).*)2  
006 7
)0)
<
7
7*  
)*  
*6
J9
7  
=B
B*.)  
7 <*69*  
0)
*)  
<
7
7
<*6
*6
9)
=B
I  
3= I
)0
..))
,3
974 : D6
*)60
7*<
*6
..))
,3
97  
*6
0**
..
* <
7
)*  
).9
*7)
*6*
)
*  
9
7./
90
7
3)4
J92
K
L2  
34
31
=1)4 : D6
J9
7*  
=B
B*.)  
=7
<
00
*))9
)*)2
+; 3+;  
.6
)04  
0)2
)*)  
1
7.
.9)
<
7
)*
K00
*97)
/
<*6
*6
)0
..))
,3
97  
./
MN\#O C)  
*6
J9
7*  
=B
B*.)  
=74
(4H4P B*.
0*
Q
0
3)*9.*
;
)0.)
*6*  
*
*6
.0*  
*6
0*.
<
7
)*  
*6 .*)
).7
714 D6
0.0
1)**
<
.
*6
<R  
) *+,
+-+
./0/
10
2+31
102+  
3,
0,+
456 17
8  
07  
0  
+/-0,9  
-,,
.,/.+ 0+,6 ) -+
+,  
,+,
1,.
0,+  
+-0
1  
+0/6 ) :
,/
-1+
++0,
.,/
+-+6
untitled h1
<=>=

?@Aab?>C@D
=D<
Be=Af=>C@D ;Gh <=>=
?@Aab?>C@D  
I/
JK
.
1
+-+1  
3+
,  
,
,  
L/2+
-++.
-,0, 0,0
++,
4M*9  
+2
,
0020N
0++,0  
,++6
I/
-0- 3+,,N
++0,
3+,,+%+0/
2++
%  
0,0,
,  
.
+++, .,/
,/
,
,
,+6
J  
8
,
.
/3
,+
+
,/, +0/
,
0
1
,,12,
,  
32
/2
+21O0,
-,0-,6
:
3+
3,+
4:P+9N
02
00
+0,
1
+  
1, 32,+N
++  
+3,N
.
1
.
2,
,2
,
1+  
+,18,  
,/ 3,6
*02,
:P+  
,/
+,
+,2
,3,  
,2
*
'
,/2/
M\#
+
,
,/
+, +  
+,2
26
Q
M\#
+
,
,/
+,
,3,N  
3+
3,+
./0/ +2+  
,
,
,/
+,2
,3,  
,
1
06
:
1
1,
32
.
1
0  
,/
,1+
+  
:P  
,/
1, 1,
+
0/0,8
1  
,/
.R  
) +2,+  
+0,2,  
,/
+,2 K+
++0,
.,/
00
++  
+-,+
) S2+
,,,  
,/
,/-2,0
,3, K+
++0,
.,/
,/  
,/
+2+
3+
3,N
02
/+-,8,6 K+
O2
1
,/
K3+,,
,
1  
+0,
00
-0, K  
1
1,
+2,
+
0+
00
+0,N
,/
3+,,
. -3
,+
12,
,/
0,
,7
.,/
+-0,
,
,/
,+,
2  
12,
,/
-,,T+ 2,06
BUV
WX
YZ[V\
]^W_`V[^`Ya
*,
.
1
+,
00
,
bbN
c*:
2,+  
dKb K,2
0+
,,
0/2
+
--016 AWYY
W^
V`YZ^[_ZeWU
WX
VfZfa
/2
.
10
.
,/,  
O
10/  
2
,
-,0, +21O0,
0,,  
,
,
/+
002N
,/+
.
1
-,
5-,2+
- S2,+  
+0,
gGhGH6 i6'6' jL,
.L2,
00, k/
-,,+
,
,/
L,
.L2-N
,/
.
,
.
1
00,R  
) 3+
3,+
,
,
81
) +233
+,,2+
./0/
.
1
00,
1
-/  
00
3+, ) ,
00
,/03
untitled h1
)'& +

,-  
-.
+/
0/.
1
.  
+2
-..3
.2/
+/
4
+//.  
.2
2/-. +2.
/
4
/  
.2
0./
.
1.  
0./
1./5 -./5  
-2/+6/
+/*
72
/0+
+0..
4
+0
-..
1. .5
-..
2/.5
4
/2./
8+0
/-+.
/  
-.25
5  
/095
:/.0
/0
/2.5  
////.
1
.2
..
-2/+*
untitled h1
)' <4

=..
>.  
?.2
@/..0./  
A.2
0
.
B.0.
+
++0/.+/  
+C+5
/
-../  
+.
. 2C
+.
0.
1.
/.0/  
-.
D
//
.  
0./ /..0.
1.4
/+20
.C
C/./
.
.2  
.2/
-.+*
72/
/0./
4
1 4
.
.2  
/+2
E0/3
.2
.
4
1
.
.
.2
/.0
.1/  
.2
+
+*
F.
1  
.//0
/-/
4  
-../  
.2/ -.+
1.4
/+20
C/./  
1
4  
.
.
.2
.1/
/
+.*
untitled h1
ghx oymszqmy

[Oplyopk  
/-/
////./
4
1
>
'  
C
++
0
+/
':\  
C
.2 ++
0
+/
$:&\#]
+/
$5
'&5
'(5
'\  
C
.2
++
0
+/
&':;&] +/
&'5
&^5
&_5
;\#  
;&*  
>0
.2
4:0-5
/-/
////./
4
1
C
;:)
.2/5
0//
1
4
.
0./
+.
.
42+2
. .
4
1  
.
+C
/-/
.
.
/.
*  
)*;*' >//
=./ ` /01
/  
/  
.2
4]
/0
:-.
/
a
'
%b c/01c
0
:/-D
/
a
&\#\#
%&^
20/  
/0
D-
1
<AA
2. +2  
'\#
%b  
4.2  
1
D-.
1  
2.
+2
.*
` 72
/0  
2.
+2
8<b9
//
/  
-.+0
0/  
.
/-/
. .2
-../
42
2C
:/+.
//*
d2
0/
.2/
//5
.
/
-..
.
.
.2.
.2
<b
C/
C
+/1
4.2
+2/  
0+.  
.
/
-/.
+
C./*
720/5
1.2
.2
C  
.2
CC
.2
0CC
<b
/.8**5
.2
CC%0CC
.  
CC: 0CC
+9
/20
1
+/  
////
/-/*
72
/0
<b
// /20
1
0/  
////
/-/  
.2
1/
/0
%
0  
-./
.
e/01f
1
..
+.
8/0  
-.
a
'%b
%
0 -.
a
&\#\#
%&^95  
.2
1/
C  
.2
CC
<b
/
a
'\#%b +
81
.9*
=../
+0  
.2
/.0  
.2
1//  
<b  
8**5 /01
/0%09
/20
1
.2  
/
42  
C0.
0/
<b
/-/ +.*
72
.2/
/20
4
0/0
+.  
<b
/0./* ` @  
.
1
+//
/  
2.+
/-/5
+.  
/0
+ -.5
/0
010  
2.
+2
842
..  
/-/9  
*
+
,./0
,
-
1,12
1*-1
*13
3
4+
-/
+1+*-4
--15 6 **13
7+1
4
,11  
,1  
-0
311  
4-
+
-+08*
5
,11
+-*
1
7+*
+-* 1,1  
+,115
90
,11
1
31  
1:11 ;
10*
3
1+*11
/-0
-0
<=
3
4
-0
,-
-0
1-*5 6 >,,+  
+  
+
31
-0  
1-,
3  
1
?,1  
@5
A--1;
1*+0
31  
+-
*+-*-1  
*+
,-1
-0
+-4  
115
= -01
1-*-1;
*7
+-,011
/
3
-,3
-0
++ 3
3
3
1
?,1@BCD;
CEF5 6
*
1,+1
/
3
,  
'  
+0
++
.++1
'GE2  
' .
/-0
D
1
,  
'2  
4
-0
++
.++1
$G)&25  
&CG0
H<I<1
/
3 ,
+  
+*?@
1,1
.+
1*  
04 3+
-4  
+
,
*7-25  
=
,--1
/01 1*3
11
1
313
1*
J+
K1
,8*-+-; &C
0
H<I<
/
3
,
31;  
'  
+0
++
'GE;  
'
.
/-0
D 1
,  
'2  
4
-0
++
*
7-1
,01
=  
==5  
A-0/1;
&CG 0
H<I<
J+GK1
8*-+/
3
1-  
H<I<
1,+1 ,
31;  
'  
+0
++
'GE;  
'
.
/-0
D
1
,  
'2
4
-0
++
*
7-1
,01BCLF5 6 >1  
M
.41
\#(%'D%&\#'E2;
,
,/
3
N
.G2 -;
-0
,
-0
1+
-0
41--;
,--1
/-0*1*3
11
1
3
5 L5)5& 1,1
,
=-
9:
O*,
- *-,
BC$F  
+-B&';
(\#F
L5)5&5'
I4*
1,1
-
6 PQRSTU
VQ ,1,1
1  
3/
,*1W
>31+  
,0-,+
3+
,1
+1
3
/
+-
3 /
1,-1
*1
-0
0-G+
-/G-*3
,,+0
4,  
43 M<
X/
+-3  
N
-+
*-,  
/-0  
* 11-4
'  
'\#Y
*++1  
005
untitled h1
6 z[]^'^[

Vabcd`[`
Q`Eca^E`
Sevqu ,1,1
1  
3/
,*1W  
f
XM  
31+  
+
+1  
3
/
3 *01-+01
**1++
.,1+%
31+  
+
+1
1 31  
-0
:,,%
3
-5 6 Vabcd`[`
Q`eca^e`
SVQU f-4
*7
-0
1*  
*  
1,,+  
1-11* ,1+-1  
ghi
,1
+1  
3
/
untitled h1
6 j'k

Vabcd`[`
Q`Eca^E`
S^Vqu  
*
+
,+  
./  
-/.0++1
./ 23/
+//2+4(\#5 6 789:
;<<=
>?9@A?B
C8DE<FD8
G7;>CH 2  
2
I./
/-/,
,
23/
,2/
/  
-/.0++
$\#J  
/
2-/  
+2
I./
.2+
2
I./
K
L'\#\#
.
&)0M  
N
/0
+2  
2
I./  
2+2,1  
OPQR
-+  
/0 ,/S
KK  
2KK
TU
K+
+
V2  
.
/0
I ./
-/M
6 >?9@A?B
C8DE<FD8
G>CH OWQR
2-/  
+2
I./  
2-/  
&)I0
2
I./
, OPQR  
/
L&\#\#
.
&)0M  
N
/0
+2  
2
I./  
2+2,1 OWQR
-+  
/0
,/S
KK  
2KK
TU
K+
+ V2  
.
/0
I./
-/ 6 X@?YB8
ZAD8?D8
GXZH [/
/
-/  
1
\]^1
^  
.++K
++M  
_
-/+
+ V2  
`S
K
.++K  
S
,
++  
.0+/2+ S
.M
.0+/2+  
/
V2
/
+/+
/0+
+.+ V2/+M
6 >9<a98DDAb8
=AD8?D8
G>ZH V2+  
/0
Sc N-+  
OdWR  
S+/
+.+
K2  
/0
S  
&
-+-2/K +2/+c  
e 2
I-./
%
f/0
,+2/
-+
2+/
,
OQgWhijklg
m0 +2
I-./
-++  
On
%  
+2-/
/  
.+ +//
I-./
+
OWhijkg e o
I-./
%
f/0
,+2/
-+
2+/
,
OdQQphidqr e s  
.//+
S/02/
+2,
+2  
2
I./
K+c
/0 ,/S
KK  
2KK
TU
K+M
m0
,+2/ -+
2+/
,
t'\#%M e u
S
.+
.-/c
/0
,+2/
J
2+/
,
OnQR e */
K./  
S
,
++  
+/
/++2
.+-/+ /
-+  
+v  
3+/
,
++  
+/
/++2
.+-/+ e *K./  
0.-/0/
,
//,2/
+
/
/0
.+
- ./K
+M
untitled h1
6 c8b?ed8

W9<X
Yc _  
/0
Sz  
e ..
+2  
2
I./
,
23/ -/.0++M  
_..  
,+
/0/ /  
+/.  
/
,  
+
{.+  
|M s//+1
+2-0
,+  
-/
2-/2/+  
2- ./+
/0/  
/
-/K  
++M
N
/0+
+/2/+1 23/  
-/.0++
S
,
/./
,
/0
-, ,
,
+
{.+|M  
) *+,
.
(/
,0
10  
-2
3
4
) 5,,1  
-2
0  
,00
6778
4
,01-8
-1 3
08
2,117
97:7: ;00<=
>++ ;=
0  
0  
0-
--
,00  
-28
4212+
11>0 0-7 97:7? *>
@00,0 A2
>
+
0,0
0
0>  
-2
0>1  
30- 0,0
>-2
0-21>
,00+
00
0
3B1-+
1>-7
untitled h1
cde fghijifk

Jlifmlin  
A2
4
+0
+>0  
0>
-2
0
12 ,-42  
-2
0->7  
A2
01,-0  
010
>  
-2
+0
OP
A  
5+0
Q+-0
6A5QR
+0
?7\#
4
3
>-S  
5Q ,-7  
5
,,,--0
02>
2+
1100  
1,  
-2
A5Q
+0 ?7\#7  
5
1,  
-2
A5Q
+0
?7\#
1
3
4  
-2
AQ;
43
0- 62--,T%%1-,7117+%,-1*+,-%1-1U,,1-0%1-172-V1-1U?\#R7
untitled h1
wdf gylz

Gbbijm
Gb
Jg^Zcinxjm
Nxa
Flnixix[
`
Ilg
Lmzglfix[ H7&7' Qi,,-  
;0  
-2
,j>-0  
;1
e\#'T
,012
Q+-0  
;1 e\#&
O<,1
k>
>3B1-0
012
>
27
O-T
l
PO*
,-0
-2- -2  
>-1,,3
4  
3
,,
-20
,107 h7&7& P@
j>-0  
;P
,->
+4 ;0  
-2
,j>-0  
;1
e\#'T
,012
Q+-0
>
27
untitled h1
wdm xji

Jcixijnc
Ailmjfgl
Lmzglfix[  
;30
i,->0
,-2
lk;  
P
4
0
3
,-2
OP
1 *1-7  
5
0,0>300
0
100
0
,-0  
P
4
3
+3
-2 1
*1-7 P
-20
,-08  
-20
-211>
4-2
:\#
0
1+  
012 -+02>
3
,+  
-2
1
*1>00
-2  
>
- ,00+
007 A
,-20
-208
,0
0  
013
-2
11>0-10  
-2
-2
*7 *2>OPn5o727+
4-2  
3>000  
-2
-27
untitled h1
+ -./

0123.014
4565
5-4
758169
:;-.6;0.-<
=>5- ?@A@' Bcd
Efghh%Gci
J  
JI
CC
GCI
H
K
H
DDLH
KM
KI
DHHG  
N
CHF HH  
HI
H
H
GCOGG
CI
DHH@
PCGG
NOH
G
F
H  
G GCH  
DDCN
K
N  
NG  
HI
HLCH
H  
D
DHHG@
Q
H
K
N
CCH  
H  
FK
N
HI
DCD
FGHH GGCH
FGHH@
RFHG
H
SOHG  
LDH
DH
G
GCN GCH
*+T+U
K
N
GONHH
KHI
HI
DDDH
HG@
JI
DCD
FGHH
K
FK
FG
FH  
GDG
H  
CI
DHH
H
GO GH  
H
CCOC@
JI
DCD
FGHH
K
DG
COCH  
GODFG
HI FGHH  
DF
DDDH
H  
GDGNHG
H
HI
NG  
HI GCI
GH@
untitled h1
v 7=-70

758169
01=;06.-< V+U 418.-.6.;-7 W@'@' Qfg
Rfh  
Q
OHK
C
CCOC  
DHH  
CC
FGHH
GONXCH
GH DICOHC
DOCH  
KICI
G
H
CGG
IF  
COG
HGID
KHI
HIG HHH@
Q
FG
FH
YQRZ
C
HI
N  
OFN  
OH
G
YCO  
N
NH
Z[
GDH[  
GG
HD
GGCH
KHI
HI OG  
C
YFGHHZ
DOCH[
KIHI  
H
H
H
HI
C YFGHHZ
DOCH
YE\
R)
Y&ZZ@
untitled h1
w@'@& og

Qfg
Rfh
Yqrz  
Q
FG
FH  
GOGDCH
FG
CH
G
CG
GOG  
HI
FK  
HI FGHH  
HI
GDG[
H
GOHG  
HI
K]
^ PHI[  
Q
_HIH
FG
FH
YG
GCH
V+U+`Z
EDHH
IGDHaH  
DH  
LGH
IGDHaH
b Q
IGDHaH%GG
HIH
G
D_D
Y@@[
CHF  
GCIO
GO
D
H
HI
GHH  
HI
GHOZ[  
D
IGDHaH  
D_LGH CH[  
DCO
SO
N
HI
DHC[
KHIOH  
GOG
HH IHI[
G
H
CG  
GOG
FG
FH@
b Q
IGDHaH%GG
HIH
G
G
F
N
_C
GG
Y@@[ IGDHaH  
DHH  
GONXCH
CFCZ
G
H
CG  
GOG
FG FH@ b RC  
FGHG  
GHG  
NGFH
OHG
HIH  
H
GOH  
GG
H HI
IGDH
KO
H
N
CG  
GOG
FG
FH@
JI
G  
GM C
C
GIO
N
FOH  
H  
HI
HI
GOG
CH@
* +,,-
,../.
,01,-,0/
-2
1.0.-  
0.-,3
* 4
.%1-2
.-
5/-.
6-,
-2
,0
-27
1
8-2-7  
90 2,/-:
1
.,  
,0,
6,
0
;/.
<27
1,
0/ ///.
=0-7
-2  
=/:
-2
/-
,01=.  
90 .  
,0.
-6/6  
-2
0-.,
,
-2,
-3
>3'3? @8-2-
4
6,
6
,0,/.6,
.,
.,
A8-2-A
7  
-2
6< -2
-2
6,-
,/,7
-,
..0.
/.,
-2
/-
,01=.,B -23
5,
.0  
6,
6
,0,/.6,
.-2-7
2
..0
,6
7
226
.0,
-23
C&'D?'&3?&E
untitled h1
>3'3f 6-

G2
,6
.2
46,
H6<
1
,,,,
0-:
-2
G4H
6,
F3\#3  
>3'3( -,2/
-0
+0.- 4
4H,
<
26
-2
-,2/
,-0
/0.,,,,
0,
-2
-,I  
- -3 * J
G2
,  
,1
/,,1-2-2
,-0
/0..0,
-2
6, 6-3
,1
/,,1,
-2-2
,
6.
,0,
.0,
-,2/ 1-<
-2
,-0
/0.
-2
6,
6-3
* KJ
G2
,  
,1
/,,1-2-2
,-
-2
,-0 /0..0,
-2
6-3
untitled h1
lmn oppqpprqst

Uv
Povqtw
Qxqstp  
4H
..<
.0
6,./-7  
,-7
,,,,
,6-
-,2/
,-0
/0.
-C
,-0
/0.-E7
- ,0
-2
6-7
,0,,,  
0-.3
G2
,,,,
,6
-,2/
- -2
,-0
/0.<
1  
1
-2,
<-2
-2  
0-2B  
,,
,
-2
D
DY4
'()&
,
-2
,/./
6,-
,0186,--3  
4H, ..0
0
-2
..
//
<
1
.0///,,
-,2/3  
4H,
<
1
<
-202
,0-3
untitled h1
4h

<
1I  
* 4,,,,  
,6
-,2/
,-0
/0.
-C
- ,-0
/0.-E
1  
.,
,-0
/2,.
,
-2
D
DY4
'()&
, -2
,/./
6,-
,0186,--3
* .  
-2
///4H
/7
-2
.
.  
./-0  
-2 ..
-1,3  
* +,
-./.
0/1  
20
0-/
3.02
0
-.
+
+45
'(6& 0
-.
0323
70-
0/1870--9
+  
2
70
7-0:
30  
02;<=9
5
0/0
70
7-0 2  
-.  
070-3/20-/01
3-. 030
,-.
-.
>23  
0
02?<@9
untitled h1
?<a bcdebfghi

Ej
Kcbgelk
Mnocbkc
Cochfk  
5
5P
-.-0
3-28
0/0
2
-0
-.  
570
P7- 32
Q-0-.R/
>33/01
0/1-S,-.
&T
./0
,00U
VV
/0
-.  
5P
39  
5
>23-0
-. >33R/-0  
/  
02?<@9 5
5P
3/02/
-.
-0
021  
02?<W9 5P
3-0
,
1
0/1--.  
2
02.
SU
-X VV-Y9.97  
-.  
ZQ  
0-/
2-9  
5P
3-
0-/2-0
2
1
/
-X .--30X%%2292297%2/2%03%V%+0[[Q0-/2-0
+,
-.
0000
-.
5P
1
VV:
-.
0/332/-
-.
7-
1
R/01
-.
VV  
0./
1
37
0
0
0
30019
untitled h1
?<@ mgocb

Ej
C]Dcngfcn
Bcdebfghi
Fe
^^B  
50
-.  
.03-_/
00
300  
3
-.
0-/
1`2-70: 23-/
0  
3
-.0
0-/:
-.
,
1
3
>3
-. 0309
a,7:  
-.
0
72
0/0
2/0
-0.3
1-,
-.
0-/
/
-.
7-:
3-.
7  
>3
22
02?<A9
untitled h1
?<b kmjcfc

Bcdebfghi
^Bgfcbgm
Fe
Fdc
Ddmbem^Clfg^Mf
^Effmgebmfebk  
5
7-0
01,
/01
3
-.  
-0
VV-Y9.979 h.  
V2  
/50
,
0  
3-0
-.
/2-/0
0
021 1,9
)9(9' 5P
35 5
5P0:
>23
hi:
22/
-.
0/1`2.0
0
-.  
20- SQ+U
/j\#
0
-.
00  
0-/
--/01
/
2/- 35
k1
0
0
0
3001
1/
-.
6
2
0  
- 23
-.
-9  
Mll
mnopo
qr
FfK
stou
vp
wpxqwupy
uq
Mszp{
no
n
Kpw|qto
My}pwop C}p{u
~KMC
uwqtz
up
{qwsnl
xwqmpoo
|u|{
W@
qtwo
qr
up
ml|{|mnl
o|up
vpmqs|{z nnwp
qr
up
p}p{u h.
5P
30  
-.
5P
/33+  
-2.
+
j(\#\#
0./
1 >%
--.
5
k1
-X
h8
99
+>
/1X
)))8)'T8)(j +
2/-0
,.
-.
99  
21
/0X
[TT&\#6'j'\#T P
SV  
0300
,-.  
02/  
22,-.
5UX 0728088/0Y92
untitled h1
)(& +

-.
,
/  
)*(*&*',.+,%0 01  
.23
+,,
124
3
51
,
5
3.
+,
62
3 ,,
6,2
.73*
85
,2,
.73
61
.1,.  
,2  
5,
.21 3,
,1,  
++2
3
+2.,19
1  
+.4,9
1  
.23
+,,
%
,2  
+,1
124
41
.,5
.,.+,
,21  
31, 1:4
.,5,
4  
;\#
1
,
,,,
6,2
.73*
<
+.
..41 4
,21
,9
+,,1
124
3
++1  
,2
+,,
27
,
,2
,41*
=1  
,1 .21  
.,  
1  
19
.73
.
.41
,
2 62
1,
,  
+,
6*
73
.41
3>,
,:.,  
+, 33,1
,
11
,2,
6
6
,2  
143?.,1
.5
,2
.
1*
.73 1,
,
+,
,1  
33,1
4
,2
+  
11
61
,
,,. ,
11
4+
,
&
%@%  
,1  
4+
,
\#*)
%@%  
33,1*
<
.73
1
41
4
+.9  
,2
143?.,
3.1
+,
62
,@
,21 49
12
124  
,2
51,,  
1,4
1,
,*
A2
51,,
124 ,
/  
,2
+.  
1.411
6>4+
6,2
,2
143?.,*
<,
1
,
@6 .73
6
4.
,2
..  
.,.+,51*
B4
,  
.1
1@  
541 ,2311
11.,
6,2
.739
143?.,1
.4,
41  
.,.+,51 2
,2  
.,.+,
11.,
6,2  
1@  
,2311
124
.1 ,,5
,2  
.,5
.,.+,*
A2
,2  
,
.,.+,
124
3
41  
..+,3
.,.+,5
,21
6
3 1.411
6,2  
143?.,1
,
,2
,  
,  
4
+,.+,*
)*(*&*&,.+,%C 1  
+4.,5
+,,
124
3
51
,
5
,2  
.2
62
3
,, 6,2
.73*
A2
+,,  
.73
,
3
,1
5
1  
,1
., 1+  
4@6*  
143?.,1
,,
6,2
.73
%  
,2  
+,1
D .23
+,,E
124
41
.,5
.,.+,5
,21  
31,  
1:4 .,5,
62
,,
6,2
.73  
$\#
1
,
,,,*
<
+.
..41
4 ,21
,9
+,,1
124
3
++1  
,2
+,,
27
,
,2
,41* 143?.,1
124
3
51
,  
,2
51,,  
1,4
1,
,  
,2 5,
,2,
,2  
+,
3.1
+,
4
,2
1,4*
F+
.+,  
,21 ,9
,2
51,,
124
,
/  
,2
+.  
1.411
6>4+
,2
+.
4,.
6,2
,2
143?.,*
A2
,2  
,
.,.+,
124
3
41  
..+,3
.,.+,5
,21
6
3 1.411
6,2  
143?.,1
,
,2
,  
,  
4
+,.+,*
untitled h1
)(&=1

0  
G
1,41  
.73
25
3
.4.,  
31,
6*
73
124
, 3
41
4
31,
*
=1,
6  
6
+  
31, ,
+,.+,  
..
,1
6,2
.73*
<,
1
,
@6
62,2
.73
1
+1,
24
31,
@*
B4
,
,2
+,,  
51
.,1  
41
,1 .739  
.1
124
3  
62,2
,
1.,4
41  
,
1.,4 39
,@
,
..4,
,2
+,,
3,  
.73
,
,2
,2*  
<  
6 31,1
4
,2
1,49
12
41,  
,2
51,,  
1,4
1,
,*
A2
)*++
*,+
.
+,+
+,
*-/01+
,*
/*+
+,
+  
*1-**
2
-3 2+,
+,
*-/01+4 5464&47.8
3+
+ .
)*
931
3+*
-*+
1+,
3++
-/:
:
*9:
2,+:
*)+ 1+
;44
:
+:
*)<:
+*,3
+
;44
3//
+:
-=2 +*,3:
+
+
+<:
+  
+  
*++  
+*+
1+* 11++
1+*:  
1
+++
3)4  
>,
)*++
*
*3*/ )-+  
)*
)+*
+
+
2,+,
1+  
?*-*@  
*  
/) 3*+4  
>,
)*++
*
*3*/  
3+
)*
)+*
+  
*
*1/ /24
-*
)*
)+*
;.8<  
/)4  
>,
)*++
-*+ 2+
-*  
A+1,
B6\#\#.  
.8
*
*
*
3**/  
+
*+
2+,
&7 ,-*  
/
2  
+,
)+4  
>,
+  
2**
*,/
+  
+,
3+4  
>, 2++
3+
-*+
/
13+  
*-33
+  
/
1*
2+,
&7
,-*%' /-***  
+
+,
+*+  
+,
2
2=
4  
>,
+
3+
-*+
/
*
13+ *
3**/:
1
****+  
+,
1-*
+*,3
/+2
+,
)+  
+,
)*++
3-1+;*<:  
)/4  
C+
+
)/
+
+,
+  
+,
+
3+ ;44:  
+  
+,
)*
)+  
/+
)-*
1)
+
+,
3+<
-*+
/ 1-+  
2D-3
3+4  
.  
3+
+
1-+
*-+  
+,
.8
*
E-4 >,  
+1=
-/
;FDDGCD\#H'$<  
+,
*++-+
3+1
-/
*,- /
1
.8
3+*
;  
+,
9
1)
++<
*+
+
4  
.
13  
+,
9 +***
1+  
+,
.8
3+
+  
*,/
++1,
+
+,
.8 +
2+,
+,
3++
1*4  
|  3+ I- + 5( * .)- -+: G4J4 #H$#' > KL  MNOOPQRSOQTNUS V,L  MWONP RTXQWRRT K9L MWONP RTXQWYYU 8DL  +L-*+Z141   |
|---|  
5464&463+
V1
+ V1*  
*-*31+
31*
;1
3*+)
31
+*+
** **
*++<  
*-/01+
112,
+,
*-/01+
*  
:  
2+,
&5 *  
+,
*-/01+[*
*+
*  
:  
1*
+
3+/
)+*4 \
*
+
/
*1++4
>,
31:
*-*31+
31: 3*+)
31
+*+
-*+
/
3+
+  
I+
+
/
1*: +,
333+
+,:
-*
+,
V1
C+
3+
K:  
33)
E-)+
4
>,  
*-/01+
*,/  
+  
/*++1D1*+:
3/ 931  
3-1+)
+91+  
-+,
)-+  
1-*4
>,
C)*++
2
2
+,  
*-/01+
-+
13+  
+,
31:  
-*+ +  
I+
+
/-+
+,
-+1  
+,
31
;+, /
-+1<
-*
+,
V1
K2D-3
3+
K:  
33)
E-)+
4 C
+,
-+1  
+,
31
2*
/
;44:
*3+-*  
+,3-+1
/+<:
+,  
)*+,,
+-.
/,
,0
.,1
+  
234
)
,0
.,1
,+
,+.+
1,5
,
.+,
0
/,
+  
23
,  
6.
,
,
0 1+5  
,///,
,-5
7,&8
-.+  
,)*+,,9+
:7  
,- *,
.+
,23
/,
;5  
//*
<.*,
4 2
,
,-+
,-,
11.
7,&=
+  
0,+-.
0
/,5
7,-.,  
, 1.+,5
+
23+4
)
,5  
,
,,
&=
+
,-,
,)*+,,
+.+/1,+
+ ,
,
,
.,
>/+.
,  
+-.
+
0
/,
,  
6.
, ,
0
1+5  
,///,
,-5
7,&8
-.+  
,)*+,,9+ :7  
,*,
.+
,23
/,
;5  
//*
<.*,
4
untitled h1
?@ab

Cdefbghi  
)  
/,  
+.0J1,
,:  
01+
/,5
,
+.0J1, ,:  
+-.
,
,)*+,,5  
,/,  
/,
+-.
0 *+
,
1
-,-1
/*
,4 6.
,
,1,
),K  
/, 6.
, =(
+
2*. .,5
L4M4
\#N$\#' O
;K  
PQRRSTUVRTWQXV Y-K
PZRQS
UW[TZUUW ;>K PZRQS
UW[TZ\\X 3]K .+,^141
/,
7
0
/
,10,*
,4
untitled h1
qu 'abc'defg

B`Agfhfij  
=4(4'
2
<.
/1
/,+%7]./
,
kk
7
0
+.0,,
,K kk,^4-4*  
,
,
Y)  
+,.
1,4  
;+  
+,.1,+ 1
0
.
-K -,,/+K%%114114*%1.1%+/%k%;+ll)+,.1,+
,
>/+.  
)  
/,,
01+
/,
.
,1.+  
,+,.5
,+,.
,,,
+-.
0 +1,.
,5  
,/1
/,
,
,/+  
,
,&8
-.+ 7,)*+,,
01+
7  
,4
O)*+,,
+-.
,
,/+  
, ,&8
-.+  
7,.,1  
,Y1
01+
:75 Y1
,+
+
,  
+  
234
m7*5
1,
0,+  
0,1,+
+/,.+
+1+
,-,
,
+.+
1,
n+1,
Q_\_op
+-.
0
/,
+ 23+4 O.,1  
/1+
n+/,.+
+15
1,*
,,5
1,/1 /15  
0,-5  
1,
0,p
+-.
0
7
./  
1.,4
untitled h1
)(& +

-./0  
.,,/
/10  
,1  
21  
,
/.
0
,1
/,0
,,,  
,
/,
&)
/
,
/,
/  
$\#
/
,
,1
/,
/ 234*
+2  
,1
.,,5/
.,
/
,
2/
,
4  
67*
89:;
,1
0,2 .2/
</.,0/
/2;
2,:
,,;
2,.2
.2;  
4,1; 2,
4,=
220  
,1
,  
,1
/,
/
0,
&)
/
,
/,
/  
$\#
/
,
,1
/,
/  
234
/10;  
.//4;
4
9
0.
20,*
untitled h1
>?@ abcdefghai

Abjhagklc
Mha
Ngdokbn
Phlodpgbo
Dloba
Ppaqnjhlnhabo
Klo  
R9
,2,  
,1
:/,,;
;
,1
STU
/./;
9
.,  
/0/.2, :/
2,
,1,
/
4,1
/0/  
0-.2,*  
9
.,  
67
/  
/0/.2, 2,  
,1
/
:2
,
/0/,  
20/
,/1.
4,9
,1
/,0 .02,  
,1
:/
:,*  
9
,
RU6  
.,2.,
:/,,/
<**; :/,,/
,
91
,1
/./
/
.:
0
0
,/
STU/  
0  
:/,,5/ STU=  
STU
/,
.,  
.,,
/0/
/V/  
22
,/  
,1
/02;
/ /
/
.//4;  
222
,
&'
R
+,
W'&*W&*
6
/0/
:,/
9
4
.,
,
,1
RU6
,
/,
0  
/0
,*
untitled h1
x peklkpfe

Yhlkghaklc  
6/  
/./  
22
,/;
RU6
0,/
Z0
,1  
,
,  
, .*
[1
5/
.
9/  
2,
\
/,0
,;
/.22
,
,1,
20 2,
,1
,.,,  
.  
/2
/,0
.,/]
12
,
,1
.,2; 0,/;
S8
7(;  
^+/]  
10
/04_2,/
.,2,*
[1/
/  
,101 .,
:2,  
/,0
,
9,1
/02
20,,
20/
\
` S
2/,
.2//  
` 74,
2, ` U0
/,,  
220,4, ` 6:/
:,/
, ` /./
////,*
[1
,
.
/
-,/
,
0,a/,
/21
91
,1  
/
,1
2, 2,*
[1/
,
9
4
,
4
./
.
4  
2,2,*
,/  
Z0 4
,  
-.2
,
,
,1
.//  
22
,/*
+/
,
,1/ /,0
9
,
4
,  
9
9,1
,1
,
202,*
untitled h1
+ -.-/-/0.1

023,/456.-/23, *+7*,.8915
,/:5;.006<.1
6.-5  
=>
?
@ABCD  
C>E
C
E
C
C
F>C>
GE  
E
EEBC
FC> EG@ECC
BC  
?CCE
FC>
>>HEI  
F>
J>@C
C
EC  
KLM  
@E GC
C>  
N
BBE  
CCCO
=>
ECG
F
C  
'&
DG@
?CCE  
C
HE?I
DE  
B>
?CC ?HCCC
E
F
E
C
B>
BB  
CCCO
=>
?BC
B  
@E
F
@ C  
B>
?CCO
P
'&
DG@
?CCE  
Q  
?CCE
J>@C
KLMR
C>
C>
?@@C  
C>E
BBG
E
SO)T  
C>
CG
?@@C  
KLM
B E
&\#TO
=>
?@@C  
Q  
FC>  
Q\#T
B
E
N\#O(T  
C>
CG
?@@C KLM
B
E
Q\#TO
=>GER
@C
Q  
?CCE
GC  
'&
FC>  
KLM
FG
?D EC
DB
C>C
C>
CG
?@@C  
KLM
FE
BEECC
FC>
Q\#T  
E
??E C
&\#TO
P  
C
F  
E
G@  
DG@
?CCER
C>
C
BBG
B
F
@
EC C
'UO
P
'H&
?CCE
?
C>
B
@  
C>E
CR
C
J?BC
C>C
BBG
BG
@
B?C
(
C
'&
C>EO VC  
WDE
C
\#S%''%&\#')X
F
?C
C
C  
?BC
B>C  
C
?BE  
C>
E?E
C
C
C>  
C>E
??GCO  
YE
?
EGCE  
C>
EC
N
DG@
?CCE  
C>
C
?C
B>CR
S
?CCE
>D J?B  
KLM  
@CC
E?E
WNSOQTXO  
VC  
WDE
C
\#S%''%&\#')X
F F
C  
?BC
B>C  
'(
DG@
?CCE  
C
ECC
C>
E?E C  
C>E
B>C
?C  
C>
C
B>C  
'&
DG@
?CCEO
ZC>
'( DG@
?CCER  
CFHE
$\#T
BB
CD  
C>
??C  
?CCE
FC> KLM  
C
F
JC
[%H
'UT  
C>
@ED
??C  
C>
J?BC
??C
E NSTO
=>GER
'(
F  
?CCE
F
@
DGC  
E?E
E?C  
C>
C
'& ?CCEO
P
C>
??CE
FC>  
KLM  
EGBC
E
W??JC
?\\#O)Q
@ ]E>^E
JBC
CECXR
C>  
C
C
?C
C>
EGCE
E?CR  
C
EGC
F @
C>
B@
??C  
KLM  
C  
FC>  
CFHE
$\#T
BB
CD @GC
C>E
@ED
??CO
P
C>  
&N
CC
?CCE
F>B>
B
@
B@ DGCR  
E?
CFHE
$\#T
BB
CD  
C>
??C  
?CCE
FC>
KLM
C
F
JC
??JC
[%H
''T  
C>
@ED
??C  
C>
J?BC ??C
E
N(T
W&U  
&N
E?EER  
J?XO
_
C
?CCE
C
C>E
?BC
B>C
F
F
C>
EB
?CE GC  
E?E  
M]
C
@
C
FC>
C
?BE`
C
F
E
F
GE
C BGBC
ECC
EE
@
BG
EG@C?E
W>??
DEO
H>??X`  
C
F ?D
C
EC
C
C>
C>C
D@  
C>
?C
B>C  
'&
?CCEO V
'N
?CCE  
C>
C
G
&\#'&H&\#'U
J>@C
KLM  
@CC
E?EER BG
'S
FC>
E
DC  
'(
F>
F
aWHXO
Y
FC> VC
b
WDE
C
\#Q%'S%&\#'NXR
C>
?
@ABCD  
C>
C
E
DE
C
BE C>
?BE  
C>
ECC  
C>
a
WHX  
CO
=>
C
F
@
JC
C  
CC  
*\#
+,.//0
/  
01
2/3  
//  
*\#
+,.//04
/3
$*5
/670 88
/+
6/3
-,/  
80+/+
0//  
/3
9
:7;  
/  
<\#5
6, =%7
'&1<51
>
/3
9
:7;  
/
6
?*54
*\#
.//0
6,
./
/3
0//
/
- /
6/3  
$*5
/670
88
/+  
=%7
$1$51
@0  
A,
&\#'?4  
//  
&'
.//0
3+  
/3
/  
/
0
/8./
/3/ '7&
.//0
.
/3
6
8/,
/
88,1
B3,04
/
0
C.8/
/3/
/3  
&$ .//0
8  
..C/
&
01
B
6  
,
+,.//0
08
,04
/3
88,
8
6
0/
/
(D1
untitled h1
efghijkjlijlmkn

Koknpili
Qr
Ismqotkupvswxnqukjqup
Sotxqloji  
8
./0  
,/  
0.0  
.00  
0,++
:-/3
-838 .00  
.00
/
+/
0.//8
,/.
;1  
9,/  
0.0
0
0
/  
0.0
/
00
.00  
/31  
Y00  
0,++
0
0
/  
0/,
/
/
.00  
/31  
9,/  
0.0  
.00 0,++
6
0//
,0
/3
Z.7  
7[
/301
8
./0 6
0
8,
/  
,/  
97/+  
\1
@
,
8/+
0/,0
6
.  
/
0000
8]
+/
-8
8/+/  
+0//  
0,
00  
1  
0,
00 6
,/3
C.
,0
,/7./8
6
8//4
Y7-0
/83^,04 +8
1
_
6/3
@/
`
:+0
/
\#*%'<%&\#'?;4
/3
08
-a8/+0
6
0 8,b  
'1B
0//
/3
,9
:7;  
/4
0//
/3
8/  
.//0
63
3+ 9
:7;  
'  
0  
,1
B30
8/
6
0//  
6/3  
$*5 /670
88
/+1
&1B
8.
/3
,/80  
/3
'?
.//0  
&\#')  
/
/3
D&  
&\#'<  
/
-8,0
/3
0/8
8/  
+01  
6
+0 &\#')
/
/3
'?/3
.//
60
1
B3
9
:7;  
/0
6
8.
-/6 /30
/6
83/0  
.//0
,0  
/67/
c03d0
C8/
/0/1
@
/3
8.00
,/80
-/6
/3
/6
83/0
6
/./
0
C./  
6
- ,0
.../
7./8
0//0/8
/0/0
6/3,/
a,0//  
,/.  
8.001 D1B
-/  
./
0/
/  
+,.//0
/
,
838/]
/3 0/  
/3  
0/  
,
0,-a8/0
//  
./81
@
C./
-a8/+
0
0  
/
+,/
c>e
/  
+.//0 6
/
`
:+0
/
\#*%'<%&\#'?;
6/3
0.8/
/
8008/
/
33
0[
+01 73370[
.//01
Z6
33
0[
c>e
[0  
,/.  
//,
6
- +,/4
4
)f')4
')f'(4
')f&\#4  
'<.4  
?f')1
23
+,/0
0,/0
6 8
/3
0,/0  
/3
g>
`-/  
Y/3  
/3  
`-/ 0,/0
:B0/
>9b
YY9c4
Y0  
Y/+
90
:YY9;;  
,/,
0,/0
6
- ,0  
/3
001  
*+  
,-%./+
0+  
1*
./2
+131
4
0
531
15
1
+6+  
+3
+11+17+
4
0
+70
5
18
9+
1*+
531+  
0 6  
6+1
*7  
0+  
1*
+6+
+31+
01:
1*
+
4  
1 0
73
6+1  
1*
71;1  
1*
;61
13  
1*
++
31<=
+31+ 4
1
0
531  
>?18@
untitled h1
aa bcddefcgehijk

Elgkkmknho Aapaelgkkmknh
Hqrk
S
Bgete  
U*
4
9V9+  
++71
41*
1*+
617W  
9:
278
X
71
41* /;
.*7317+Y:
278  
Z0
X[\#&($)Y=  
61  
- X[\#&($(Y8
untitled h1
a ]^men

O^F_Kbho
Rgchkbhicno A\Pagehicnedk
`Cg
O^F_Kbh
Okdkbhicn  
+  
+1
4+
730
6+
7
6+
1*1
76++
66;1
'\#a  
*17
7+:
71
&\#:\#\#\#
611+
3b)'c8  
71
+13+
*5 +*4
1*1  
+
67
0
de  
8b)c  
1  
6++
1
)
+  
** +<  
1  
+
f&?f(a
1
)
+
41*  
UU.  
g
&
+
b'&:
'hc8  
71+ +  
7+8  
277
1+  
+
**  
i7<+
76
1
37++: 71
'j8h
07<
+
6
'\#\#:
\#\#\#
+  
'\#8\#
07<
+
6
'\#\#:\#\#\#
+ 76
1
(8f
4*1
+
6
'\#\#:
\#\#\#
+  
j8'
4*1
+
6
'\#\#:
\#\#\#
48 U*  
1
1*  
+
f)
+  
b)'c8  
9+
+37*:
4
;671
1*1
1* k1  
611+  
1*+
1
4
0  
31+  
1*  
78 611+  
1*+
+13
4
7++1  
611+  
1  
+7
1
1*
l2m 7
18
U*
4
0  
+30k71
+71
0+
41*  
1
:
1*71:  
78 U*+
617
;73+
711  
61
4  
75
1*+
5+11
3
1 5  
6++0
+<+
1
1*
13+  
408
untitled h1
apreghibirehicn

C`
B]Idtgkn  
.17
611+
41*  
;1
8
.11+
3
1*  
'n  
;73 1*+
+13
073+
73+  
3
611
4
1
65
o31
Z0 1
1
k3+1
1*
73+  
1*+
+138
untitled h1
appkjed^ehicn

C`
Fknk`Iho
Ent
Gioqortiobcm`Cgho  
31:  
+  
730
7
41*
o31
7671+  
+<1
713+: :  
3  
*6778  
51
6*+
5
1*1
f$a  
611+ 4
*5
0+5
+<1
01+
1
1  
++b)&c8  
U11  
**
+< 611+  
37
+<1
1
51+  
773  
651
01 5+0
0  
+
41*
8  
2
1:
11  
41*
611
1? 1*6317+
0
++
0
07+
++5  
1
++
+11+  
+
7+ 1*
611  
73  
6
6++  
+355  
5
+3558  
U* 01  
+7*  
+3
++
<+
3+
sVd?.tU
U:
4
711:
.
17*o3+
4
4
3+
1
60
61*  
+6+
0
+1
+371 77
<+8  
)*)  
+,
)+./0)
)0++.
0++)
1+,-+
..  
+ .,+,0-+.
+)2  
3145
+
-)+
6
+
+,+
.765  
18+ 0+)
,6+5
,)
6
+)+  
0,)
'
+)  
.6+
1+, /+,)
1+,  
+/.+  
46
)
.+
0)2  
9,
)+
.+
0,)
' +  
1
)  
0++)
,)
),1
:;<=
>?@
+)
+  
;
..) '&
0++)
1+,
A'=
-0+,2BC<D
E.-)
F
6+
)0)%+ /0+
0-0))
G40-.+-5
..+5
@H9%9
).5
IJ8K  
6 1
60)L  
+
)*
+
+,
0++2  
M+,-,
0++)
1
))
+ 0  
).+  
+,
@H9%9
).)  
6
1
60))5
..
/0. ,)
),1
+,+
+,
.
)*
)
+2 9,
+.
+)+
0  
+,
)+.)
1+,
+  
0++
))  
04.  
.) +6)
.0)5
)
1
)
0).,.
)+))
+
0+.0+  
0))6 6)  
+,
4+
+,+
.+
)  
).)2
'&2<2'N1
@++
)*)
untitled h1
'&2<2'2'+

H/0)-  
O
+,)
)+-5
0++)
1
.4
00/+
+,
PI?
@H9%9
).)
G)
.+ ).+
QRSRTRSL2
9,
0.-)  
0
PI?
@H9%9
).)
1
1
..
0.)5
)0.
0.-)
00
+
+,)
))))+)  
).,
0-0))2 9,
++
+
)  
).,
0-0))
1
6
00/+
<2(
2
untitled h1
'&2<2'2&u

1)  
@  
6-)  
+,  
1,
+,
6
1)
15
,+,))5
+
+ +)+
1  
6
0))-5  
.+
+
+,
681
)+2
'&2<2'2<V-)+)
H+
).+
)).+
1+,
)1
0++
-.+6
F-)+)2
'&2<2'2WK+4-)
+,+
@5
65
.+5  
.0)
-2
9,
8+
)*)  
+,
.+,+
.-
.+  
.++  
4)2
'&2<2'2CU
1
)0+  
60)
X.
65
0
+
+,
)+5
.+5  
+
+,
.
)+,+.5  
)))
+
)+2
'&2<2'2(@H9%9  
IJ8K
).)
@H9%9  
.-)
0,).
).+
+,
0.+  
+4-)  
+, .))+
+  
)+  
6.*  
<\#
-+)2
9,
IJ8K  
.-)
0,).
).+ +
.))+
+  
)+  
6.*  
6-+
'Y
,-)2
'&2<2'2Z@).,.  
.
)*)
M)).+
1+,
+
K.+  
. P)
X  
+.
)*)  
+,
))  
)6+  
.-)
+
)+))2
untitled h1
+-./010234546/70

8589:0/0  
;<
=>
>>
=?  
@??
?@AA
=
=>
>>
?B  
@@C=?  
D
=EA= @  
AF=
=>@G
?B  
E@?C
?
=
?
=
C=D>
=>
AA
F= =>=
@==?  
<  
=>@H  
@==G
CA>  
@==
F=  
? ??A=
D=>
@  
<?F
?B=
=
<=?H  
CA>  
=
DC  
=
== AC
=>
??
F
<?F
F  
AAC?  
F
??<
AA AAC?H  
I?A=  
<@CA=CG
F
D
F@?G
JKL%L
?A  
IMNO
?  
=
?B
A@
=
=>
BD  
F
@=>  
?@? ??
=H
untitled h1
+pqr50457

S.Rq400
85T
Trquv45787/R5  
L>  
A?=
AC=
D
F
@<
?  
@>?A  
A=A
AC=
=
=> @=A@=  
A?=
?W?X
?
@@AF  
<D
@
=
A?=H  
Y
?= ?=C
<?==
W?
5R74
=
=>
F==  
=>?
?A=X
D
AC
E@
=>
@AC?
=?=?
<<  
=>?
?=CG  
=>
??A=
?B?G
?A=?  
F=?H
O  
= Z
@==
AAG
?
CA>
=
?
?  
=
<D
=>
AC=
D
F
<G AC  
@@=C=
=
?AC??
=
D=>
?G  
F?
%
=>
<??G  
= ?B
[C?=?  
?=
?=C
<?==H
Y
?  
A?=
AC=
D
F F=
@
=
=
=
=>
?=CH
L>
=
A?=
@A??
?
D
?
NA?=G
D>
[CG  
=B
@A  
@? =
WHHG
<
=@>  
=>
\O]
@@<
=
@=?
C?  
A@A
D=> @AG
AC
]JJ
JA
^\#^X
@
?A=  
=>
?=
?=C
<?==  
D=> =>
=  
=>
@=A@=%A?=
?W?XH  
M>=>  
@?  
=G
=>
@<A
=>
?CF_A=
D
F
=H
?=
<?==?
W
@=A@=%A?=
?G D>  
@?X
D
F
A=  
@<=  
WHHG
AA
A?C=
XH
M>
A?=
? ACA=
=G
=>
@=A@=%A?=
?
D
F  
=>
@<=
=C =>
?AC??  
D
F
AC
=
A=
=  
@<=
?==  
H
?=
D
F
AC=
D=>
[C
?=C?  
=>
@>?A
AC=
WD>A>
AC? =>
@=C=  
A=A
AC=
?=
=
@=A@=X  
?
?AF
FDG
D=>  
C WNA=AX
?=C  
=>
A=A
AC=H  
M>
[CG
D=??
?=C
D
F F=
?
?
?AF  
=>
<?==  
@=A@=H 5R74`
J?
=
=>=
A?=  
===
WA?=
F
YA=
J==X
C?=
F F=
F  
?=
@@@=
A?
?=C
<?==
WHHG
IG
\JG
JYG
IaXH ]D<G
?=C
<?==?
=  
=
=>?
A=
WHH
\?X
D>  
?=
?
F =
F=
A?=G  
?  
N===
@AC?
?CA>
?
?AH
?=  
=>
@=
F@??
@  
=>?
?=C
D
F
F=
=
=>
=  
=> @ACH
O
=>
@==
C??
=>
@=
F@?
=
=>=
=G
=>
C?
D
F
AC=
=>
A
A  
=>
?A>
AH
C
WNA=AX
?=C  
A=A
AC=`
M>  
C
?=C  
A=A
AC=
?
C?  
=>
AC==  
A?=
= =>
\O]
A
=G
=>?
?=C
D
C?
=>
D
=
F=
=>
[C
?=C?H  
b YF
@=
WD>A>
?
=
&'
c
J=
''
A@=Xd
G b ?=
@=
WD>A>
?
&'
c
J=
''
A@=X
*+
,./,
0.//1
0,.0,/  
2/,,/
3
23
2+
.0/  
,- 002
./,
.+,  
/./
,
,/0.,2
.,/
4
,
./,56
,- /
/.  
7
+/
3
,/
.,1
7+,
/
,
8+9
:,,2/,,  
,0,.0,
3
/
,.+,
+/  
1
/,+/ +/9
;<=>?  
,
,
@A
AB&1
@7,  
*.+,
,C
/, A.//  
,
,
4991
2.,  
0,.0,
,,
37, ./,
,5
+
-9
'&9D9'8+/,  
E2  
/,  
/,  
.
F.,2,/
A
,
,/+7G.,
/
,./,  
,-/
/,+
0B/.
.,2,/
/,  
/., HIHIJ  
7
09 E
8+/,  
32  
./,  
,-/
.,2,/
/
,22  
/K
,
,- /+7G.,/9  
F
32
3
,
2/
.,
,-,/  
3  
,/+7G.,/
2
,-,
,- .,2,/  
,
,
,
/+,7,  
/.  
0,.0,  
/.- 0,./9  
L-/
.,2,/
.+
,
0.,.7
7
.
+,
3,-+,
,32
/
., .+,
/2./1
+,M  
,NCO
.
,1
0
0B/.
.,2,/ +,0
/,+/  
7,
./,  
.
/
7
,/+./9  
L/+7G.,/
3 7
02
3,,
0,,
,
,
0,.0,
/
,3
7 3-,
,
,
7
,
/  
./,  
,
/.9
untitled h1
jp q>rstu=<qv

U;W
<X>Qu=Y<;Ut
Z<;[Yw>Qu=Y<;[ Jpij[=Swv
Wy[Z<;=Y;Su=Y<;
U;W
Zt<[Sq>  
L-/
/,+  
7
,0
/+/0  
0,+
,,  
,/
/+., /7
.+/9  
E,,
,.,1
.+,
,/  
/,+
/+/0/
,,1
3
7
02
7
,/+/0  
,,
0,
,
/,+
0,.0,/1
CN* /0/  
+,
+,-,/9
C
,/,+
/
0,+
,,  
/+/01
,- A.0
C2/,,
4AC5
3
00,  
/,+
0,.0,/1
,C/,,+,
23 :
4C:51  
/0/  
3
02
,/4/5  
,,,  
/+/0/9 ,+
0,.0,/
3
7
.,.,1
/
00.71  
7  
.-/
,
/,+
2/, /.-+9
.+/,./
,-,  
3,
,,  
/+/0/
.+1
7+,  
,
,
,?  
\ *,,  
+]0.,1
/.,1  
+..0,7
/K
,
0,.0,/ /,,  
..
,-,
3+
3,
/,00 \ C/+.,
.0.
,
0,.
8+,/ \ *,
,-,  
,
/+.,
.0,
%
2+7 ,,
,-,
,0
0,
-/
7
,
\ *,,  
+,,
,+  
/+
.
../
7+,
/,1
0,.
.0.1  
,
8+, //1  
/,/
,/0/1
C:  
/
00.71
^  
*+
F/,,
4^*F59
untitled h1
)+-./0123

/44.5/678
/69
-./0123
7:625:0  
;<
==
>?
@
A
?
BC?
?  
>?C
=C=?D
?  
E= >A=
==?D
=C??  
=A?F  
G
HCI
BC?
? A
@
E
HA
?
>=E  
>?J>
BC?
?F KC?
=?
LKM
A=C>
@
E
A?
E
@?<
?<
?
?
>>? ?
K
=<=N>
?<?
@
E
C  
?<
?E>
@
E
?F
G
>>
?  
? >
@
E
=C=?
?
?<
>?  
==?%>C?F
O@
@??
?
PA?
Q=C>
LPQ>MD
?<
?>
@
H
?<?
?< ==
?
>
=C=?  
?  
?  
E=
>A=>  
==?D
=C?
L=MD  
A?  
=A=
@?<
?<
A?=D
R??
=
S>?
T
=
Q=?=
LRS
TQMD  
AA=E
C?
BC?> LFFD
T
UE?
Q=?=>
LTUQMD
T
C=?C
Q=?=>
LTQMMF
;<
H>??
>?
@
AH
=?
==>>
?  
?
?
>?>D
>C=
?%=C?>D
A?>  
?<
ACA>  
?  
C?
E
?<
>A>D  
>A=?
E
=
C?
C?<?>F
untitled h1
)+76v0172

:V
16285842
W:0173  
;<
A=  
?<>
>?C  
=?C  
A=H
C=D
>C=<
>
E
?< A<=C?=
C>?D
>
=?=F  
;<D  
=?C
==?  
?>?  
A>>
@< <H  
?<
>D
=C=?D
>>D
ACE=?D  
>A=?  
?<>
?
@
E >=>  
F
OC?<D
A>>
@<
<H  
A=H
==?  
?>?
@
E BC
?
<H
>C=<
==?>  
@
?<?
>
AAA?
?
?<
A?=A?  
?< >  
=C=?  
?<>
?F  
;<
>?C
><A  
=XC=?
@?<
?<
Y?
= R>??C?
<>
>?E><
A=>  
A=C>  
>?C
CA
E>
?
>=> ==?>  
?>?  
@
>?E><  
=<>  
?<
?  
A?
C?>
?>?F
untitled h1
)+z76v198621/0123

/69
W51[/73  
Q?=A?
=??  
AH=
>
>?=?
<  
?C>?
E
?<
A?=A?
H>??>D ?<
>?D  
?<
>A>F
;<>
=??
>
\?
?
=H
?>?  
E=
>A>
?=
?>?>  
?
?
?<
==
?
?
?
A?=A?>F
;<D
?< >?C
A?=D
=C??D
?D  
?<
?
?
@
E
<  
>?=? ==F
Y
?
==
?<
>?C  
?<
?
@
E
>
?  
CC?<I ?<
A?
@?<C?
A
@??
AAH  
?<
>A>F
G
>=<
=?H?>
@
E
=C=?  
>
AH?  
>??
>
A>>EF
;<
>?C
?D
?<
C?<I
A>??H>  
?<
>A>D
A>??H>  
?< R>??C?
H@
]
LR]MD
%
C?
=>  
>A=?  
=C?> =>
BC
?
E
?
E
?<
H>??D
=C
EC?
?
?
?D
= =>
L=D
==D  
<>A?M  
A<=
=>  
?<
A?=A?>  
?<>
>?CF
;< ==
>?C
>?
@
A?
==>>
?
>C=<
=>F
;<
>?C
A?=A?J>
=?=?
?
@
E
>=C
>?
?
=<
==
>? ?
C>
C
?<
>?CF
G?
?<  
?<
>?CD  
=>
@
=?C
?
E
NA?  
Abbreviated Title:  CRd for Smoldering Myeloma Version Date: 09/20/2021 secure location for as long a period as dictated by the reviewing IRB, Institutional policies, or sponsor requirements.  
Study participant research data which is for purposes of statistical analysis will not include the participant's contact or identifying information. Rather, individual participants and their research data will be identified by a unique study identification number. The study data entry and study management systems used by the clinical sites will be secured and password protected. At the end of the study, all study databases will be archived at the NIH Clinical Center.  
To further protect the privacy of study participants, a Certificate of Confidentiality has been issued by the National Institutes of Health (NIH).  This certificate protects identifiable research information from forced disclosure. It allows the investigator and others who have access to research records to refuse to disclose identifying information on research participation in any civil, criminal, administrative, legislative, or other proceeding, whether at the federal, state, or local level. By protecting researchers and institutions from being compelled to disclose information that would identify research participants, Certificates of Confidentiality help achieve the research objectives and promote participation in studies by helping assure confidentiality and privacy to participants.
untitled h1
14 pharmaceutical and investigational device

14.1.1 Source Carfilzomib is provided to investigator by Amgen, Inc.  
14.1.2 Toxicity A comprehensive listing of all toxicities (i.e., very common, common, etc.) are listed in the informed consent document.  The approved USPI may also be referenced for current information related to this agent. See below information regarding most significant toxicities:
untitled h1
fetal risk

Do not use Carfilzomib during pregnancy. If Carfilzomib is used during pregnancy, it may cause birth defects or death to a developing baby. Women of childbearing potential must use 2 forms of contraception or continuously abstain from heterosexual sex during and for 4 weeks after Carflizomib treatment.  
Tumor Lysis Syndrome:
Fatal instances of tumor lysis syndrome have been reported during treatment with lenalidomide.  
The patients at risk of tumor lysis syndrome are those with high tumor burden prior to treatment.  
These patients should be monitored closely and appropriate precautions taken.  
Most common adverse reactions:
Fatigue, vomiting/nausea, fever, respiratory infection, hypertension, diarrhea, loss or decrease of appetite, insomnia, neutropenia, peripheral edema Very rare and serious adverse reactions:
Abbreviated Title:  CRd for Smoldering Myeloma Version Date: 09/20/2021 Cytomegalovirus, progressive multifocal leukoencephalopathy (PLM), pericarditis, pancreatitis, posterior reversible encephalopathy syndrome (PRES), cholestasis, hepatitis B virus reactivation, thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS)
14.1.3 Formulation and preparation
untitled h1
14.1.3.1 formulation

Carfilzomib for injection is a sterile, white to off-white lyophilized powder and is available as a single-use 60 mg vial. Each 60 mg vial contains 60 mg of carfilzomib, 3000 mg sulfobutylether beta-cyclodextrin, 57.7 mg citric acid, and sodium hydroxide for pH adjustment (target pH 3.5).
untitled h1
14.1.3.2 preparation

Vials will be reconstituted with Sterile Water for Injection to a concentration of 2 mg/mL by adding 29 mL to the 60 mg vial. The calculated dose will be withdrawn from the vial and further diluted into a 100 mL intravenous bag of 5% Dextrose Injection, USP. Refer to the FDA- approved labeling for detailed reconstitution and dilution instructions.
untitled h1
14.1.3.3 inspection

The reconstituted drug solution in the vial should be a clear liquid. Inspect all vials for the presence of any suspended particles, particulate matter, discoloration or hazy solution prior to administration.  
If the solution is not clear or particles exist in inspected vials, record the observation in the appropriate Drug Accountability Log and notify Amgen immediately.  
.  
DO NOT USE THE DRUG.  
Place the vial(s) into a plastic bag labeled as "Quarantined" with the date.  
. .  
Store labeled quarantined drug in a temperature-monitored refrigerator and ensure they are physically segregated from the drug that is available for use.  
Amgen will instruct the clinical site on how to proceed with quarantined vial(s).  
.
14.1.3.4 Calculation of Dose Each dose will consist of Carfilzomib for Injection administered on a mg/m² basis and should be based on the patient's actual calculated body surface area (BSA).  
The BSA should be calculated based upon the institution's practice and method of calculation should remain consistent throughout a subject's participation in the trial.  
Subjects with a BSA > 2.2 m² will receive a dose based upon a 2.2 m² BSA.  
14.1.4 Stability and Storage 14.1.4.1  Lyophilized Drug Product Lyophilized Carfilzomib for Injection must be kept in the labeled drug cartons and stored at 2°C - 8°C (36°F - 46°F) in a refrigerator. If procedures permit, the refrigerator should be continuously monitored, and temperature records retained for review.  
The refrigerator should also be on a backup generator and alarmed for temperature deviations if available.  Lyophilized Carfilzomib for Injection exposed at any time to temperatures exceeding 3°C / 86°F must be discarded
')*'*)*&+,--./.
0.+-
1+  
.
2
,
+,--.
,3+-4
-5
+
,.+
6
,  
- 7+8
+
&9
:
;9
7<=9>
:
)=9>8  
-3-.  
'?9
: <\#9
7?$9>
:
;=9>8
..,*
1+
+,--.-4
@6  
AB+,
,-6  
-- &)
5.,*
/1
C1D
>EEFE
GH10IAGAFE/
1
E1CDADJDE/
/JK*
')*'*)*</./.
0.+- L.M-5
?N
/O-,
AB+
++
.,4
@6
,5.
36
6 ,.
.,,
3  
,-M
33-* /.@6
,
,-6  
&)
5.,  
-5  
)
5.,  
-3-.
-5  
2
+,--.-*  
A
-4
-5
.,
,.,5.
6
P.6-
-3-.
3
,--*
')*'*?L,-3+.,
@6
M
6
,6
-2.,
.,
2
<\#
.-,
-5.5  
335
+2.,
++,,
2+
,  
,+
.,  
3  
+?N /O-,
AB+-*
A.,,
+
6
,-33  
,M
M  
3-,
O3+
., +-,*
/
O
+@6
M-5  
,,  
.,
,.-.,
M-5
-5
.,*
>.,5  
L>DE
.
,-M-5  
.  
?\#
G  
\#*$N
C  
?N /O-,
AB+73-+.  
.,,
-5.5  
335  
@
356-, ,Q8*
')*'*=A+3-6-, A  
2,-.
.,
5.
2
+,,4
+@6
,5M
,+
-:
356+
5.
+-+5
H0<L)%?*
K2
-5-5
++ +@6
Q
++.,
O-53-+
2
-5
+-2
3O
5,  
33-, +-2-,4
-5
++
2+  
-5,  
2,.-,
,
+*
C
++
,+. -+-,
52
6  
3--,
+2  
2
-,
-6@
6 H0<L)*
24  
,
B.,--,
52
6
P.  
++-+- 3--,
+2
+@6*
IM24
+.,5.
6
O+,  
,-- ++-+-,
M5+5  
,.6,--,  
5.
H0<L)*
untitled h1
rstuvwxyvz[]z[w

^Zx[
_
Rru`Abc ')*&*'.+  
EdGAA/e
78
,
32
2,-6  
A+*
.
3-2 ,+5  
/23L7L/L8f
')*&*&DO+-
L
+35,2
,  
-O+-,
7**4
2
+4
+4
-+*8  
,
-5
+,+.-*  
D5
332
J0A  
,
6
+  
+.- -5,
-*  
6M  
,,+-O+-,g
>,Q /
.,
EdGAA/
.
3+*
G4  
-5
.4
+., 6
6-,  
23Q
,-.*
D5
,  
QM
5.  
**
*+*
,-..
./
0*+*
+1*+
,*.2  
3  
.
-. 4,5
*  
,-.
1*+
,*.  
*+
*  
/4
112
3
6 ,+1
4**5
1*
&
*/
4,
*.*.
1
.**
78933:; ***2
<  
,+1
4**
-.*
-.
&
.  
,*,4* ,*--.
1.*  
+*.=.=  
>
6?.
*
78933:
***2
@*,
A=,* 78933:
,
,-.
.,*
-*4  
*+1,*42
3
*+
4 .*-.
B
)  
>
+*,
*=,*.
6  
C-*  
4**.
**
6*+
*+ ,1*  
78933:  
=*+.
*+  
4**.
**
6*+
=*+. 2 :4
8
A+1..  
D71. 8-.
*+11,
/*.
E4*
4
/-.
*+1..  
4- 1.F
+/
,,
4**.
6*+  
**
6*+  
,1* *+42  
G
.,*
,.
.?  
:8A  
D7
6.
1./  
4**.
6*+ 6+
6
**
6*+
78933:  
=*+.
*+4  
,,
*2 G,
,*. G  
.-.
*,
,*.
,*/.0H+.
.  
EHF  
*=,
4
,..
EA7IF
+/
1
4*2
A+.
/*.
,
1
*2 D**.
6*+  
4
+.*  
B
>
.+
..,*
6*+
*+
***
.+* ,/
78933:2
78933:
*-4*  
.,*-*
.+1
,. B
&0)
.?
.+2
78933:
-.*
1
.,*
5
B
>
.+5 =*/  
1--.
.+5  
H  
A7I
.
.-.4,*  
.+*
1
.-
6
.,*-*  
*+.
,*.2 A9.. J*
.*,.  
*..
.
+/
1
4*
***
6*+ 2
A+
4**.
*
.?  
*..
.  
*+.
6*+
++
*1- 4
*
***2
A+.
4**.
.+1
*
,.  
444*
4,-*. *?2
.*
,
/.
,*.
KLMNOP
J*-5
-*45
,.*4*5
+5
-.,
,45
5
4=5
44+ 5
-.5
1,?
45
-44
.4*
*,*
,*5
.45
QQ..5 *+1,*45
*  
.+2
untitled h1
-.

/.
,*.  
,
,*5
,
.,+5
,,
-5
.**.*
++5 *.*
1.*-,*R
*.5
,*.  
*+
.?5
S*.5  
?R
1
/.
1
.-.  
,**.2
')*&*+,-.  
//.  
0
1
2
3-//
3
4/3-3  
3..*  
54*
1
/6
78
'\#8
'7  
&7  
4/3-3  
.9
5-4.
:93  
.9
/.4  
.9 ;.
3
/93<3=*
')*&*)
.2.  
.  
0
392
3.
.  
./.1  
4.
3-9.  
/.4.
;4336
9.  
4*
')*&*7>3..
/4-3  
/.
1
3-//
6?
<=
.
.9
4
.
:94
. 2
3/3
.
3./.4/.3
.  
49
.9-9
.9
@?
/*  
0
1 2
39//
4.
.
/..3  
/4A
-/
4.  
.9
4
.
/94*  
B..3 1
4.  
3-4.
-2  
4/3-3  
44  
3C  
.9  
D.9 3-//  
2
3/3
.  
.*
''*&*E
54/.2.3 3-.3  
9
6.
.23
3.-3  
44
3.-3
391
.9.
@F055G
3 .9
.2H
2  
92.3  
-43
.9
4.49
:)7\#
/.91
3-3.
.9.
3
.
A
.
4-3  
2
3-2I4.
.
:)7\#D
23
.24
.4.3 *
G;
J9
;
13
4D3.
1.9
8
.9
;
>K
13
. 34.  
.C
9168
.9
;
;
13
43
2
')L*
:4
.  
; /3
638  
444
1.9
44
I-.  
23  
3.
44
/4.4 /..3
46
.93
4.8
3
4
3..  
*
J D3..  
-./
33  
'\#  
9  
4.  
.9
3 3
/94A.43  
D  
D1*
D3..  
3
&7D
3 1
9  
4.  
.9
/94A.43  
..
*  
@;/4.
493 2.
3333.3  
:M  
5N
1
236
.
1
3..8
2-.
.93 493
1
.
4.
2
44..  
3..*
4..
M9/3
M9.  
543
.9
3A  
M9233 @.9/.4
.38  
.9
.3
.9.  
43
.9
3A  
.92338
3-49
3 3.
4.
.9/38
392
-3
1.9
4-.  
/..3
46 1.9
;.93*
untitled h1
'++&-./0

12/34
5602 70/4
8069/
/0  
2:;
<  
2:
9;
=6 >/
0?/4
329@2
2;
7/2
?
A09 B200204
722  
20020
0/0 =3/4
80
2:  
/0 32/32:04
C20622 C6909/4
0/0
D)EF;
2
0/3
6223
D&)EF
G2/90/4
7622;
>369 2604
G3
03?/322 32 >/
0?/4
56/;
G
/0/
23// C6909/4
H3/01
99
D&&EF;
B3/;
I032
0/90
D&EF
'*+,+,<30  
6604 C
-?0
D/F4
* =H/0;
230;
2
23
6926904  
*
%J
D'
J;
)
J;
,\#
JF
'*+,+*8200
6/32 C4
820
A09
2
0
/2
B=
3620+ =+I+4
820
0132
1
'\#
302+
'*+,+)=/60?02 0/04  
GKL30
D090/F;
0132
I//;
J1
D20?29F
H4  
823:
D090/F;
M366
D090/F;
731
D090/F;
720? D090/F;
>01
D090/F;
<261
D090/F;
=0?
D090/F; =.?6
D090/F;
J60?
D090/F;
N0?
D090/F;
O306
D6??F; 62
D090/F;
30?
D090/F;
-232
D090/F;
-9 D6??F
untitled h1
+ -.--/0-1

'2 3456
0789:;
<79=>
?
<@AB;:>
CDDE2
FG
3HHI
J36
3K
K
KHL &\#\#M2  
&2 5
N3JI
OH
PI
QRKS
I
HKSKO
PJI
TU
VI
T
WI
HH 3I  
X3I
Y4
ZWI
3H[45
Y
\]
^_6
1--,
0789:;
1=7=@>=@9>
,:`@:ab
*cd+e CDD+b
f7>:g
h8
/h`:if:;
CDDd
1--,
g7=7
>Bfi@>>@h82
FG
XHS5I
P6
VH K
F5HH4HL
&\#\#M2 j2 Q5H55
kI
N
lI
PK[
mnI
P
3I
Xo[S
6
p7==:;8>
h< >B;`@`7q
@8
iBq=@rq:
is:qhi7t
7
rhrBq7=@h8ef7>:g
>=Bgs
h<
r7=@:8=>
g@7A8h>:g
@8 1a:g:8
<;hi
*cdu
=h
CDDu2
v
w_xy
zy{|_
&\#\#(I
C+}'~6'$$j'$$$2 2 Q4
QI
o[4
I
P5R
3I
NK
I
T
I
X4
YQI
45H I
P
PI
455
WI
N45H
W3
\]
^_6
ir;h`:g
>B;`@`7q
@8
iBq=@rq:
is:qhi7
78g =:
@ir79=
h<
8h`:q
=:;7r@:>2
_||
&\#\#MI
***}~6&~')&~&\#2
~2 N
lI
Q
3I
m
I
QH
W3I
R5
VZI
T5
XI
P5R 3I
Q4
I
[
WI
X5
P
\]
^_6
h8h9qh87q
A7iihr7=s
h<
B8g:=:;i@8:g >@A8@<@9789:
1
9h8>@>=:8=qs
r;:9:g:>
iBq=@rq:
is:qhi7t
7
r;h>r:9=@`:
>=Bgs2 _||
&\#\#$I
**u}&&6~'&~'(2
)2 n55
XI
3O
WI  
mI
TU
I
Q4S
n6  
ih8h9qh87q
A7iihr7=s r;:9:g:>
iBq=@rq:
is:qhi7
@8
ih>=
r7=@:8=>2
_||
&\#\#$I
**u}&&6~'M~&&2
(2 0;@=:;@7
<h;
=:
9q7>>@<@97=@h8
h<
ih8h9qh87q
A7iihr7=@:>b
iBq=@rq:
is:qhi7
78g ;:q7=:g
g@>h;g:;>t
7
;:rh;=
h<
=:
8=:;87=@h87q
s:qhi7
h;@8A
;hBr2  
v ^\^]|_
&\#\#jI
*C*}~6($(~(2 M2 Q
3I
S4
I
o[4
I
N5
PI
m[
YI
l
WI
P5R 3I
QH
W3I
H
NWI
j6
p;:`7q:89:
h<
ih8h9qh87q
A7iihr7=s
h< B8g:=:;i@8:g
>@A8@<@9789:2  
y_
v
\
&\#\#)I
u+}'j6'j)&'j)$2 $2 Q
3I
S4
I
o[4
I
l
WI
N5
PI
m[
YI
H
NWI j6  
qh8Ae=:;i
>=Bgs
h<
r;hA8h>@>
@8
ih8h9qh87q
A7iihr7=s
h<
B8g:=:;i@8:g >@A8@<@9789:2  
y_
v
\
&\#\#&I
u}M6~)~)$2
'\#2 N
lI
n55
X6
p7==:;8>
h<
ih8h9qh87q
A7iihr7=s
h<
B8g:=:;i@8:g >@A8@<@9789:
78g
iBq=@rq:
is:qhi7
@8
`7;@hB>
:=8@9;79@7q
A;hBr>t
>Brrh;=
<h; A:8:=@9
<79=h;>
@8
r7=hA:8:>@>2
\ \x^
&\#\#$2
''2 Q
3I
5H
ZPI
S4
I
P5R
3I
Q4H
mWI
T
WI
N5 PI
m[
YI
W[
PYI
Y5K  
\]
^_6
0q@8@97q
9hB;>:
78g
r;hA8h>@>
h<
>ihqg:;@8A
7>sir=hi7=@9
iBq=@rq:
is:qhi72  
y_
v
\
&\#\#(I
u+}&~6&~M& &~$\#2
'&2 P5R
3I
Q
3I
QH
W3I
S4
I
N5
PI
X5
WI
[
WI H
NWI
jI
JH
3I
Q4
Q
\]
^_6
iiB8hAqhfBq@8
<;::
q@A=
97@8
;7=@h
@> 78
@8g:r:8g:8=
;@>
<79=h;
<h;
r;hA;:>>@h8
h<
>ihqg:;@8A
7>sir=hi7=@9
iBq=@rq: is:qhi72
_||
&\#\#MI
***}&6(M~(M$2
'j2 mm5
ZI
5
XI
H
JI
JK
I
H5
I  
K
3JI J
WI
HV4
JI
35
WI  
N5
T5
V
\]
^_6
/:a
9;@=:;@7
=h
@g:8=@<s
)*+,
-.
/)-0)1++*-2
*2
3-2-45-265
0633-/6789
-.
:241)76*2
+*02*.*46241
62; +3-5;1)*20
3:57*/51
3915-36
<6+1;
-2
3:57*/6)63171)
.5-=
497-317)9
62659+*+
-. <-21
36))-=
/56+36
4155+>
?@AAB
&\#\#(C
DDEF(GH&IJKL&I$&>  
'M> NOP
QC
R
SC
TU
QH
V3-5;1)*20
3:57*/51
3915-36>
?@AAB
&\#'IC DWXF&\#GHY\#K$LY\#(I>
'I> ZNT[
C
Z\PUT
RC
Z]
^C
PUU
_C
N
C
`UT
aH
b2*7*65
c1)+:+ ;1.1))1;
315/86562d/)1;2*+-21
781)6/9
.-)
6+93/7-367*4
3:57*/51
3915-36
+7601 bdd6
)62;-3*e1;
+7:;9f
g915-36
h)-:/
-.
i1+71)2
V=1;12>
jkl
m
nopqorA@
'$$YC XEF&GH$IL'\#&> 'K> TU
QC
RstL
RC
Zt
uC  
R
P]
aC
R[PT
aaC
v
wC _
aC
U
RC
S
xC
vyzLR{
a
pr
o@H
g:57*41271)|
}62;-3*e1;|
~/12d 6<15|
86+1
bbb
)*65
-.
1265*;-3*;1d1631786+-21
12;1
+
81)6/1:7*4 <+7127*-2
*2
V3-5;1)*20
g:57*/51
g915-36
67
*08
}*+,
-.
)-0)1++*-2
7-
V93/7-367*4
gg
}1+:57+
-.
781
*)+7
b271)*3
2659+*+
H
n
rlor
A
p
l@po>
'(> TU
QC
RstL
RC
Zt
uC  
R
P]
aC
R[PT
aaC
v
wC _
aC
U
RC
S
xC
vyzLR{
a
pr
o@H
V3-5;1)*20
g:57*/51
g915-36 Vgg
67
*08
}*+,
-.
)-0)1++*-2
7V93/7-367*4
*+16+1  
86+1
bbb| }62;-3*e1;|
g:57*41271)
)*65
6+1;
-2
1265*;-3*;1d1631786+-21
12d;1 6+
b2;:47*-2
-55-=1;
<9
g6*27126241
81)6/9
=*78
12
5-21
+
¡)1673127> H
¢£¤
rlor
A
¥¦  
§ol¨>
ZTy>
'J> v
C
©Tt
RC
Rª
aC
TyO
©C
_y[T
C
_TPO
Z©C
ZP]
H
V7):47:)1
-. WEV
/)-716+-31
.)-3
916+7
67
Wf«  
)1+-5:7*-2>
orklp
'$$(C
¨FKK&MGHMKYLM('>
'$> y[U
wvC
¯
wC
y[PUT
`C
ª
©C
TTP
^xC
°y
uC ZPUUP
aRC
_L±[P
©C
R
C
vUy[T
Z
pr
o@H
-)71e-3*<
-)
8*08d ;-+1
;1631786+-21
.-)
)156/+1;
3:57*/51
3915-36>  
j²@
m
£pB
&\#\#IC ¬XWF&MGH&MJ(L&M$J>
&\#>
P
a°C
y[
C
³[P¯
´³C
©sPU
xC
[s]
SC
³s
C
syO
C
wTPyy
uC
wP]
xC
¯
S
pr
o@H
-)71e-3*<
/5:+
315/86562 62;
/)1;2*+-21
.-)
*2*7*65
7)1673127
-.
3:57*/51
3915-36>  
j²@
m
£pB
&\#\#JC ¬XµF$GH$\#KL$'(>
&'> y[U
wvC
`
^C
R
C
aOP]ªO
xaC
aT[
C
N
´C
x¯
©^C ¶
`C
v[]
C
y[UU
R
pr
o@H
1265*;-3*;1|
<-)71e-3*<|
62; ;1631786+-21
4-3<*267*-2
781)6/9
*2
/67*127+
=*78
21=59
;*602-+1;
3:57*/51 3915-36>
?@AAB
&\#'\#>
&&> TU
QH
g626013127
-.
7)1673127d)15671;
6;c1)+1
1c127+
*2
/67*127+
=*78 3:57*/51
3915-36>
·opl
¸lpor
¹pº
&\#'\#C
¨
V://5
WH&MLY&>
&Y> vTt
xC
RP
´C
Ry
»C
©Ust
xC
¼PUT
C
Z
C
_P
°³C ©
©C
vss
wC
³P
³
pr
o@H
½5*2*465
-:74-31
-.
*33:2-05-<:5*2
5*087
486*2 6395-*;-+*+
6..147*20
781
,*;219>
p¾¿lA@
ˬo@
¸lo¾@or
&\#\#$>
&*+ ,
,./
0123
1425667
80,3
9
:0
0;
<0- ;=>
?@A
B
CD
EFG
HIJKJLMNO
PQJKRKJS
NT
UVWXYXZ
P
INR[\
KOO[R[O]K^\[
KI_K^KJNO NT
J_[
`ONJ[P]NM[+
aEbcCd
eCf
&\#\#(gYh'ijGki)ilki$'+
&m+ .26
,06
no6>
@A
06/
.,2
,
,4AA .p
;2=
Bq6l.6
11
CD
EFG
UNJ[IJ
PQJKRKJS
NT
QPOTK\rNMK^Z
P
INR[\Z KOO[R[O]K^\[
KI_K^KJNO
NT
J_[
L^KsLKJKIW`ONJ[P]NM[
`PJ_tPSZ
PuPKI]J
`O[Q\KIKQP\ MNv[\]
NT
ML\JK`\[
MS[\NMP+
wFxxy
&\#\#(XXzh$jGi&)'li&$\#+
&k+ @A
B;
0123
272/
?;pA>/
.;>
045/
,22>
@- p
;2
{
CD
EFG
|POTK\rNMK^
QPI
KIvLQ[
JLMNO
Q[\\
v[PJ_
J_ONLu_
][\[QJKR[ KI_K^KJKNI
NT
J_[
Q_SMNJOS`]KIW\K}[
PQJKRKJS
NT
J_[
`ONJ[P]NM[+
wFxxy
&\#\#$- XX~h'kjGi*i$li**(+
&(+ ;
<A
G
VWvOKR[I
JO[PJM[IJ
`POPvKuM
TNO
I[t\S
vKPuIN][v JOPI]`\PIJ
[\KuK^\[
ML\JK`\[
MS[\NMP
`PJK[IJ]+
wxbC
Eddx
dEbfFEbD
&\#'k- Xh(jG$'il$'*+
&)+ 2>6
:1pAl;>2
9=>A
1=
<6
0186/2A
1- 6A
@2
.<p
11>
.
CD
EFG
H]]NQKPJKNI
NT
KIKMP\ V[]KvLP\
K][P][
KJ_
L`[OKNO
LORKRP\
LJQNM[]
KI
UPJK[IJ]
KJ_
L\JK`\[ S[\NMP
H
[JPWPIP\S]K]+  
bcxF
&\#'(h'jG&)lim+
&$+ >>2
9>>
0,
;52pA
B?22>
;1>
,0- 45/
,1
:>A
456
9l@
CD
EFG
LKv[\KI[]
TNO HQsLK]KJKNIZ
IJ[O`O[JPJKNIZ
PIv
V[`NOJKIu
NT
_N\[WNvS
V
KI
S[\NMP S[\NMP
V[]`NI][
H]][]]M[IJ
PIv
KPuIN]K]
S]J[M
WVH+
&\#'$Xh'jGml 'i+ i\#+ 56/>
>56
0BA
8q6
8
?.<>56A
9- 9/
56
9l@,
,A/22lA2>>
1G
H``\KQPJKNI
NT XW
U
PIv
vKTTL]KNI
t[Ku_J[v
KMPuKIu  
KI
ML\JK`\[
MS[\NMP QNM`POK]NI
NT
TLIQJKNIP\
KMPuKIu
MNvP\KJK[]+
Cd cEb
¡x¢dbEF
x£
b¢cFCEd
Cy c bC Eby
xFCc¢FEd
E¤ b¤
&\#'mhmjG*($l*$&+
i'+ <>
;>>2
>
,0
o1/
0q>A
,p>
B?- <027
:G
_N\[WNvS
KTTL]KNIWt[Ku_J[v
V
MPuKIu
TNO
H]][]]M[IJ
NT O[PJM[IJ
V[]`NI][
KI
S[\NMP+
&\#'*YXhijG()ml($*+
i&+ 9>>
04¥2
84A
12>
56
B;2
B4¦56
-
66
ql<2
4
,
CD
EFG
KTTL]KNIWt[Ku_J[v
KMPuKIu
TNO
INIWKIRP]KR[ PIv
sLPIJKJPJKR[
MNIKJNOKIu
NT
^NI[
MPOONt
KITK\JOPJKNI
KI
`PJK[IJ]
tKJ_ MNINQ\NIP\
`\P]MP
Q[\\
vK][P][
P
QNM`POPJKR[
]JLvS
tKJ_
_K]JN\NuS+
&\#''- XhkjG(&'l(&)+
ii+ 1AA
;2=>l5>
oA
<A
,2
@B5
8A
192 42/
;<A
;
CD
EFG
§[IP\KvNMKv[
MPKIJ[IPIQ[
PTJ[O
]J[MWQ[\\
JOPI]`\PIJPJKNI
TNO
ML\JK`\[
MS[\NMP+
¨
©b¤F  
Cy
&\#'&ggh'$jG'()&l'($'+
i*+ 5A6
@;=7
.9>A
92
,,9>>2
956>
@<<A
- AA2
?1q>
,0o3  
CD
EFG
§[IP\KvNMKv[
PTJ[O
]J[MWQ[\\ JOPI]`\PIJPJKNI
TNO
ML\JK`\[
MS[\NMP+
¨
©b¤F  
Cy
&\#'&ggh'$jG'((\#l'()'+
)*+ ,-.
/0
123
0
4
0
56
0
,7-88
90
7
:0
;<<
10 =37>:?28?3
=0
@A
0
=<
5
BC
DEF
GHIJKILHLM
NOIPNKQHRKQO JSOPJROIJ
THS
IOUNV
QKPWIHMOQ
RLNJKXNO
RVONHRP+
Y
Z[\E
]
^B_
&\#'&0
`aab'$cF'(*$> '(d$+
)d+ eOfHIQ
gSKRPSV
hPNKQIPIfKOM
KI
ijhh
kSOPJOQ
UKJl
mOIPNKQHRKQOn  
hOJPo pIPNVMKM
HT
a`q`
gPJKOIJM rs776F%%+%/78,+87t7.uv\#w-uv\#w78uvx'&(w9.v>xy
)(+ 3
0
,
0
5<7<<
z0
5
{0
|23s
0
;
}0 9-<<
u0
}
~F
KM
HT
PfLJO
RVONHKQ
NOLORKP
PIQ
RVONHQVMXNPMJKf MVIQSHROM
PTJOS
RLNJKXNO
RVONHRP
PIQ
KJM
XSOfLSMHS
QKMOPMO
he+
E_
&\#''0 qb'*cFx\#d>x\#$&+
)+
40
;<s
0
}
:0
s
F
klO
TLJLSO
HT
HLJfHROM
ROPMLSOROIJn
KJOR PIKIW
JPKNHSOQ
MlHSJoTHSRM
PIQ
fHRXLJOSKOQ
PQPXJKO
PMMOMMROIJ+
DEC  
EB BBD  
D[
[CB[DC[DE
[DE  
DEC  
EB
DBC  
CBDCB[C
DB
D[_ BDECDC[
&\#\#(0
a
eLXXN
F'))>'x'+
)$+
40  
=0
7
/0
7s83
{0
A
|0
z-7
0
/7
40
|
0
|-<< 40
s  
BC
DEF
klO
gPJKOIJoOXHSJOQ
LJfHROM
hOPMLSOROIJ
ITHSRPJKHI
eVMJOR ghe
QOONHXOQ
PIQ
JOMJOQ
KJM
TKSMJ
UPO
HT
PQLNJ
MONToSOXHSJOQ
lOPNJl
HLJfHRO
KJOR
PIMn
¡o  q+
][DE  
E[DE
B_BE\
&\#'\#0
a`b''cF''($>''$x+
x\#+ A
50
}.7
40
~¢
0
|77
|0
5
90
78s
/:0
7
;F ghe
QOXSOMMKHI
ROPMLSOM
XOSTHSR
MKRKNPSNV
JH
NOWPfV
ROPMLSOM
SONPJKO
JH
P MJSLfJLSOQ
QKPWIHMJKf
KIJOSKOU
THS
QOXSOMMKHI
KI
fPIfOS
XPJKOIJM+
DEC  
EB BBD  
D[
[CB[DC[DE
[DE  
DEC  
EB
DBC  
CBDCB[C
DB
D[_ BDECDC[
&\#'0
£b*cF')*(>')d(+
x'+ }
:0
|-7
:}0
{¢<3
:0  
40
17<
=¤0
1>ss
s
:0 ,¥0
;
F
GHRXLJOSKOQ
pQPXJKO
kOMJKIW
KI
gOQKPJSKf
¦SPKI
kLRHS
GNKIKfM+ ][DE  
D[
D[_
C
D[D\BB[C
&\#'(0
¡§b)cF&$>&$(+
x&+ }z=0
|¢
0
<
/,0
4.
/0
3
{0
,7
¨0
u¢
0
9<
,0
}- ;0
1¢
4F
©OPMKKNKJV
PIQ
QKPWIHMJKf
PffLSPfV
HT
JlO
gPJKOIJoOXHSJOQ
LJfHROM hOPMLSOROIJ
ITHSRPJKHI
eVMJOR
ghe
KJOR
PIM
THS
SHLJKIO
MLSOKNNPIfO
HT MNOOX
PIQ
TPJKWLO
XSHNORM
KI
PRLNPJHSV
fPIfOS
fPSO+
ªD[B
&\#'d0
b'cF&$\#d> &$'(+
x)+ =
}u0
8s3
:0
|<<
0
,7
0
4?
¨0
7s83
{0
,
90
;<s
0 ,
¤:0
<  
BC
DEF
¦SKIWKIW
ghe
JH
XSPfJKfOn
SKOT
PIQ
XSOfKMO
MVRXJHR MfSOOIKIW
KI
PRLNPJHSV
fPIfOS
fPSO+
ªD[B
&\#'*0
bdcF$&(>$)x+
xx+ 7¢7
/50
46-<
/0
<<?
90
«¬®¯°
u0
~
/0
1±23
0
<²
}0 40
{<A?3
0
:3-.¢3
/:
BC
DEF
³OPNJloONPJOQ
´LPNKJV
HT
mKTO
OMLNJM
©SHR JlO
XOIomPON
PIQHRKOQ
glPMO  
pegµ
kSKPN
µPNLPJKIW
GPSTKNHRK mOIPNKQHRKQO
PIQ
jO¶PROJlPMHIO
·OSMLM
mOIPNKQHRKQO
PIQ
jO¶PROJlPMHIO
KI gPJKOIJM
¸KJl
ONPXMOQ
hLNJKXNO
hVONHRP+
][DE  
ªE[DE
¹[E\
&\#'d+
x*+ 23¨0
46-<
/0
,-.
/0
|
:0  
;0
7<
¨0
50 1<<
:0
5<77<
¥0
8s<
,
BC
DEF
IJOSIPJKHIPN
hVONHRP
¸HSKIW
SHLX
)*+,-.+
/01-.01,
230
-4.
+1,563717
32
8)9-1*9.
8:.938,;
<=>?@A
B>?CD
&\#'EF GHI'&JKLM(NLE(;  
EO; P
F
QR
F
STUT
VF
W
XF
U
YK
Z,6
7*3)016.
*03-.16[/0.,-1616. 0,-13
0.*9,/.
\]
4
)016.
*03-.16
16
)7),9
/9161/,9
6.*403935:^
_@`abCDCcd
ef=bDAC>g &\#\#OF
GGIMJK&ELN&E$;
Eh; i
jF
Xk
SF  
F
lU
mF
V
nPF
Po
F
pUoU
lXF
P
XVF
qR
nlF
oopR  
@A
=DK
r-:*1/,9
7.0)8
188)6321s,-136
*,--.067
20.t).6-9: .8.05.
16
188)6383+)9,-30:
-4.0,*:
,6+
,0.
,773/1,-.+
u1-4
,
4154
+.50..
32 0.7*367.
16
8)9-1*9.
8:.938,;
vb
w
x=@y=ACD
&\#\#(F
G]zILJKOLENOO\#;  
E(; YTU
F
Qo
F
p
F
To
mF
YTU
XjF
j
{K
|035637-1/ },9).
32
)60.9,-.+
,-:*1/,9
7.0)8
188)6321s,-136
*,--.067
+)0165
8)9-1*9.  
8:.938,
-4.0,*:;
w
x@y=ACD
B>?CD
&\#'&F
HKMM;
E$; ST
QYF
~TUUT
XPF
T
XF
Q
XF
Q
QF
qU
WF
Yo
F STU
F
VUo
XF  
l
@A
=DK
6-.06,-136,9
)612308
0.7*367.
/01-.01, 230
8)9-1*9.
8:.938,;
<@@y=
&\#\#OF
\I$JK'EOhN'EhM;
L\#; pU
lYF
Q
QF
QU
XF
p
F
Xop
F
R
SF
iT
F i
YF
qU
F
q  
@A
=DK
r
*4,7.
\
7-)+:
32
30-.381
16
0.9,*7.+ 0.20,/-30:
8:.938,;
_
>cD
w
@
&\#\#MF
z]I&OJK&O\#$N&O'h; L';
Z,6/.0
-,-17-1/7
.}1.u
GH\
pooK%%U;;%  
L&; W
qF
Yo
qF
Vo
jF
PTUo
XqF
P
F
SU
qF
{U
F iT
F  
XF
PU
S
@A
=DK
.}1.u
32
G\
*,-1.6-7
u1-4
6.u9:
+1,5637.+
8)9-1*9.
8:.938,;
=dC
fD>?
`bC?@@>c
&\#\#MF
I'JK&'NMM;
LM; XiTkRi
qXF
So
SF
Xop
F
U
S~F
qU
jQF
m
QWF Pk
SF
oiNYUo
WF
Yop
WqF
~
q
@A
=DK
Z,0219381 .6,91+381+.
,6+
.s,8.-4,736.
6
¡.u9:
1,5637.+
¢)9-1*9.
¢:.938,£
61-1,9 .7)9-7
32
|4,7.
[
¢¢Z
¤01,9;
¥¦x
¥>>=D
@@A>c
¥§Ab=?A
&\#'\#F
GG¨I&'JK(O&N;
untitled h1
) +-./01-2 +-./03

+4  
,-56758+.129+9:2
1509-50+  
| -17; ,<=>?=@ABC< 2DADEF 2CAG<   | HA=B?>FIJ ,<=>?=@ABC< 2CAG<   |    |    |
|---------------------------------|-------------------------------|----|----|
| K                                 | LMNOPM                               | QNP    | LMNOP    |
| '##                             | RS  NOPMS   TN  MMU                               |    |    |
| #                               | R NPTPU VW NPTS  X P N   OYMM  ON ZP[WP MPNPU                               | $# | \X P N   NPTP]   MM  MOPM   MMU    |
| (#                              | R NPTP ZP[ P]  M MM  MOPM   MMU                               |    |    |
| '                               | OPMS XWP XWPU  MPNP  O[MN MPWWM  NPTPS XWP XWP  X  P N WP Z^   [P   MP PW _UUS [P  [WMZ^S N Z^`U                               | a# | M  MS WX P N    NPTP  P  NPT  Z^U    |
| b#                              | cWM NNM MMMPNS  XWP M X P N  MP   [M%[ MU                               |    |    |
| &                               | d X ef#g  P[ PU  \XWP  NOX    MYNS XWP WX P N WP   Z^ NPTPMU hO   XWP  P[ f#g  Z^  [WMU                               | f# | cWM NMX MMMPN   cWP N NU    |
| i#                              | LMXS cWM MON N   MMMPNU                               |    |    |
| j                               | d X kf#g  P[ PU  OX   P MYNS  N P X  N[   P[ f#g  Z^ [WMU                               | j# | T MXS  [MOPlP NPU LP[  P PU    |
| &#                              | m MN^S [MOPlP                               |    |    |
| '##g XU OP  MXU P N    MYNU nP N P X   N[U                                 | '#                            | XWS P ONMMM NPU LP[ P PU    |    |
| i                               | OMM OU                               |    |    |
| f                               | LU                               | #  | LU    |
untitled h1
)+-./

01  
2+34.2+5+,67
892
2+57 2:;<;
=>
8?@Ab
+Cd=;Ef?G
*F?Hiaijk
6?;@:Ih
Le:M?B:I?;
Aim
)Jj?D@Anb?
0:F@O
P=I@F=B 5?@O=M;  
QRST  
U V WSST
TXR
Y
TSRZS
[
S
[  
S
SX
\T] ST
^
Y
T_
S
S_
\S  
S
ZS
TR[
\
S
SS ]  
`
S_
SX
TR[a
SX
^
Y
TSRZS
S
Z
SX  
RTS
S
S
'b(((bc&dbecdf]  
\SST
^
Y
T_
S
S_
SX
TR[
SX] g
\SST
^
Y
T_
S
S_
TR[
\Z
hSX  
T ZXY
\SS  
[
f
SXT  
T  
S
ZXY
\SSi] V g
\SST
TXR
S
S
Y
R
SX\  
S
TS
&(
T
^ TZSRS  
] V
\SST
TXR
S
S
Ya
T  
T\
R
SX\  
S
TS
&( T
^
TZSRS  
] V j
RX  
ZZ  
SX\  
Y
\TZY
^SX
ZX
ZZ SX\] V k
\SST
^
Y
QR
S
T
SX
Ulmnnoa
WSSbWXTZ
kS
g] V T
RTS
\ZSZ
Z\S
YTSZ  
RT  
Z
R
TpR
ZSZS
^SX \S
T  
T  
ZXY
\SS
SXRXRS
SX
S
RS
SSSa
R
T
SR\ST  
S
TS
&(
T
^
TZSRSa
[  
X
XT
R  
TRZZTTR
[TZS] Y^  
RSX
ST V gT  
ZXY
\SS
RTS  
S
RT
S^
Y
T  
ZSZ\S TRSRT  
S
\ZSZ
Z\S
YTSZ  
XSTpR
SZRT
R SX
^
S
\T
S
S
SXT
TSRq
'i  
S
TS
&(
T
Y
TSS r
&i
SXRXRS
SX
S
RS  
SSSr
di
R
T SR\STr  
ci  
S
TS
&(
T
S  
TZSRS]  
Y^
RSX
ST] gT
S  
ZXY
\SS
RTS
T
SX
Ulmnnoa
WSSbWXTZ
kS g
SXS
TT
R  
\TS
S
\S  
S
X[
SX
YS
S
X[
ZX]
untitled h1
tt

Kttzs
^Sx
Wz  
`X
RT  
\S
T  
RT
SXT
XT
S
Y
TSR  
XT SX
ZS  
SX  
XR
T  
T\]  
m
T
TSRZSR
S
S SX]  
`X
T  
_^
XR
SSZ
ZS[
TRYTSZ
SXS
ZRTT
T[
b SXS
YSX
ZST]  
k
YS
[\S
TSR  
T
ZST
SXS
\RZ
ST  
SX
T\  
_T
^X
Z[
SX
R R
\Z]  
`X
SSZ
ZS  
XRT
ZS
Y
R
RS] `Xa  
T_
sS
\
S
\[S
\Z
RTS
Y
YT[]
k
TSR
\SZ\ST
RTS
Y
TS
S
SX
S
Ut
\a  
Y
^
Y
S
Z\
^SX
SX
QRST  
Ut]
untitled h1
criteria for females of childbearing

This protocol defines a female of childbearing potential as a sexually mature female who: 1) has not undergone a hysterectomy or bilateral oophorectomy or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months).
untitled h1
the investigator must ensure that

.  
Females of childbearing potential comply with the conditions for pregnancy risk
.  
.  
minimization, including confirmation that she has an adequate level of understanding Females NOT of childbearing potential acknowledge that she understands the hazards and necessary precautions associated with the use of lenalidomide Male patients taking lenalidomide acknowledge that he understands that traces of lenalidomide have been found in semen, that he understands the potential teratogenic risk if engaged in sexual activity with a female of childbearing potential, and that he understands the need for the use of a condom even if he has had a vasectomy, if engaged in sexual activity with a female of childbearing potential.
untitled h1
contraception

Females of childbearing potential (FCBP) enrolled in this protocol must agree to use two reliable forms of contraception simultaneously or to practice complete abstinence from heterosexual intercourse during the following time periods related to this study: 1) for at least 28 days before starting lenalidomide; 2) throughout the entire duration of lenalidomide treatment; 3) during dose interruptions; and 4) for at least 28 days after lenalidomide discontinuation.  
The two methods of reliable contraception must include one highly effective method and one additional effective (barrier) method. FCBP must be referred to a qualified provider of contraceptive methods if needed. The following are examples of highly effective and additional effective methods of contraception:
o o Highly effective methods:
Intrauterine device (IUD)
.  
Hormonal (birth control pills, injections, implants)
. .  
Tubal ligation
.  
Partner's vasectomy Additional effective methods:
Male condom
.  
.  
Diaphragm Cervical Cap
.  
Because of the increased risk of venous thromboembolism in patients with multiple myeloma taking lenalidomide and dexamethasone, combined oral contraceptive pills are not recommended. If a patient is currently using combined oral contraception the patient should switch to one of the effective method listed above. The risk of venous thromboembolism continues for 4–6 weeks after discontinuing combined oral contraception. The efficacy of contraceptive steroids may be reduced during co-treatment with dexamethasone.  
*+,
.-,/,0,
--,
--1,
2,3  
1-4
1,
,
,3
,  
-,  
0
.
56
7+31,1
,5,1- -30
5
1+,10  
+,,2,3
0,+6
untitled h1
71

,-,  
1
-0+.+1
,-,2,3  
0
--,.,  
8\#
*9%:
0-,
5 +  
135
+,,;
10  
135
+,,
23 1,
,
1+,
5-,1;
0,
526
untitled h1
<

-,,  
=>?@A>
B@CD>ECFG  
H<7
0-,
3.
,2
,.
+1
,-,I--,.,  
,
-,
8\# *9%:J
+
,
+-15
6  
K3
-,
+1
,-,
0-,
5
+
2,3 '\#/')
+
,
+-15  
,3
-1
+1
,-,
0-,
5
+ 2,3
&)
30+
,
+-15
6  
K3
+,,  
,
1. 0,
,3
*.-,,
3.
,3,
,3
-0,
,3+1
,-,
,.6 L@A>
B@CD>ECFM  
0-,  
,
+1,1
1+,
5-,1  
,
0
1
0 -N0
1,1,
2,3
+,  
135
+,,
,3030,
,3
, 0,  
,,,;
0
,0+,  
,
-,
&(
2
-1,0,;
.  
3
30  
-011--0
.-1,6 O0
-,0
+,1+,  
&(
2  
-1,0,
=>?@A>
B@CD>ECFG P H<7
2,3
0  
-,0
110-,  
,
3.
+1
,-,24 ,3
-,
&(  
,,,;
10
,0+,
,3
. &(
,3030,
,3  
0,  
,,,;
10
- ,0+,-;
,  
-1,0,;  
,
O
&(
2 -1,0,6  
*
-,0
11
0;
,3
+1
,-,
0-,
110 24  
,3
-,
&(  
,,,;
10
,0+,-; ,3
.
')
,3030,
,3  
0,  
,,,; 10
,0+,-;
,  
-1,0,;  
,
O
')  
O
&( 2  
-1,0,6 P Q,
13
.-,;
,3
*.-,,
0-,
1
2,3
,3
H<7
,3,
-3
1,0
,
0- ,2
5
,3
5,3
1,
,
13
.-,
0
,3
,
,3,
5,3
1,
- R06 P *
+1  
+-,.
+1
,-,
110  
-,0
+,,;  
0-, 5
,
-1,06 P 71
,-,  
100-,
5
+  
+,,
--3
+ 3
+1
,-,  
3
-,0
5
56  
:
,,,
0-, 5
,+
-1,0
0
,3.0,6 P H0-,  
,
5-,  
5-,
0
-,0
+,1+,  
, -,
&(
,  
-1,0,6 L@A>
B@CD>ECFG P 0-,
+1,1
1+,
5-,1  
0
1
0
-N0
1,1,
2,3
+,  
135
+,,
,3030,
,3
,
0,
,,,;
0
,0+,  
,
-,
&(
2
-1,0,;
.  
3
30  
-011--0
.-1,6 Abbreviated Title:  CRd for Smoldering Myeloma Version Date: 09/20/2021  
If pregnancy or a positive pregnancy test does occur in the partner of a male study patient
.  
during study participation, the investigator must be notified immediately.
untitled h1
++-./0

12  
34-,
5*6647
*8+/6*9,
14::,19/4-;
8469/-<
*-.
8946*<, =>  
?
@  
ABCDE  
>
=>
FGH  
=>I
J>K
L
@
>
M>J  
>K N=>
OGPQR S BJ  
L
@
LMJJ
JTK
L
M=  
>T
=
J=T
U> J>
N=
J=T
>V
AUWV
?>TJV
XQR S A>
>T  
W>
L
>T>
@
KMT>M
J
L
M NY\#'Z[$)Z[[\YQR  
CT
T>
?
==>
>=T
@
L  
'\#
]
>KL
JK TM
^=K>
>KL
>
>T
JM=
==>
J>  
MM  
_>
J  
>T `@
>>
]L>R S a>
J>
TM
JK>L  
b=>  
>T
KJcJ
J>>R  
J
J
@>T
J>
TMV
I  
JJ
>T
\#Rd
]  
JR S ?
@
JMJ
@
L
==>
J
L
@
=
LMJJ  
JM>J JJR
eJM>
J>
&
==  
@  
MT
J>  
I
JM=
> W>
L
>=T=
>
L
I
>
W>
=>V
XM>>  
]L =
N'
]
@  
>
W>M>T  
'
]
NM>Q
@
L
I
> U
=V
X  
J=T
JJJJ
M>JJQR  
MJ>  
V  
=K JM=JV
JM>
dZ(
]  
L
@  
@
=>>  
=
J> TM
=>
JR S ?
@
=
LMJJ  
=>  
@
JM>J
@
L
_ MZL  
TJ>=%KTJ>=T=
JJ  
>
J>R B
=>  
@
JM>J
@
L
J>
J
Z
JM>
JJ  
>T
J> @
L
fR S e>
M=JJ  
>T
M>T
M>>V
=>
J=>J
@
L
J>
>
>T
=K XJ>=J  
]L>V
]gV
AU
K
>T
=>  
h
V
X >>
KLK
TI
%
T>
=T
>V ie%Ae
K>>J
NA  
L
V
J  
e>
W
NIJ
> \#)%'&%&\#'\QR S `
JM>
JM=  
@
=>>
K
>T
=>  
WZj
jV
>
J=T
'
]  
JM>
@
J
>  
'\#]
JK
TM ^=K>V
=M
>KL
>T>  
_
L
>
IJ
dZ)
>JR
]L
>KL
@>T M>>
V
KkK
>
KL  
>R  
XI
>
>
>T
`@ >>
]L>
Y&[\#
NJM=J
=>
T>M>=
MJJ
TI >=
>
=>  
KJ>
L
M=JJ
>QR  
CeC
DJ=>
M=hKM I  
K
=>
I
>T
JM=
KJ
NY\#'Z[$)Z$&$dQR  
eJM> @J
>
LJV  
==
(%  
=T
L>@
==J
'Z(V  
==
&\#%
=T
L>@
==J
$Z&\#  
K
>>>
>>%  
=T L>@
==J
&'  
L
@
L
J>  
MJ
=
@
=>> KMT>M
>
WZj
jcJ
LR S `
JM>
J>  
X'Y(
J>V
^Xl
JkK=V
_
JkK=V =I>
J>KJV
J  
JM>
JM
>
>T
mK
]L> N?K
'\#%[A'\#)Q
g=
JM>
JM  
DXCe
J
>  
=R CJ
@>T
Y\#
K>J  
JM
>
>T
L  
M=JJR
`
LJ
JMJV =J
@
L
J>  
X'Y(n  
o
=>JR  
X'Y(n
MJ
=J
@
L
IL f  
L>=T
>
L
J>
>
eM>I
C=TJ  
^Xl
JkK=  
>
*  
+
,-./0  
1'2(3
/4,
5
6
,4.
6
107,
8 9.0  
:4
,.6,-.4
4
;4,<
1'2(=
,4
5
4
6  
4>
;44
, ,,0 ? @
,;4
,;/  
/44/,%@AB<
,;4<
,  
4
B
CD,
4 \#E%'&%&\#')F<
@AB%/44/
4  
6
D  
4>
;447,
.4, /,  
;  
6,
6
5
,;,
4  
4>3;4
4,4
64 ;
4>  
1G
//
64
;4/%;/.
5>/>
/.4
,
4> G64
H,4
A1I
JJ1@<
J,  
J4D
1,
CJJ1F0 ? @
,;4
,;/
,,,,
;4,,I  
'
G
5
6
D
4
A
/<
1  
,/>
,,,,
;4,,0
:4
:4
B
CD,
4
\#E%'&%&\#')F<
4>, ,
;40
untitled h1
)+-./

-0  
*+1.*2+1)3
4355),61.,+
7533+78.5,
),9851):+ 4;<<=
*><?@Aabcd
7<>@  
E
FEG
HIJ
KEL
M  
NIO  
GFP
Q  
L
FFE
E
REGS
TRLFEL  
U VR
E
'\#\#
W  
RRP
Q
X
Q
FFE
E
GL
GRE
ELQG
KYMZ GL
PR
ELQG
K[YYM  
\]Y^
ELQGS  
YP
LE  
Q
FFE
X
Q FEE
Q
EP
LQ  
_REG
E
Q
RZ  
Q
EP
REE`G
RRPabcd ed
FLES
U L f FE
gh'\#
W
Q  
GL
GRE
ELQ
KYMS f ^X
EP
Q
E
FE
Q
GE
E  
EREL  
i\#
LEGS f RE
GL  
FG
Q
FEL
E
j
G  
k
LEG
E
'&\#\#_S f lREE
&
mLEG  
'SkWG
FP
E
EX
&W
FnGS f op
E
E
h&\#  
X f E  
h(\#
p  
GE
LE
GPRE
U lG
f FE
g
W
Q  
GL
PR
ELQ
K
ERMS f lF
E  
XE
F  
E
LE
E  
RFGGS f RE
RG  
FG
Q
FEL
E
j
G  
k
LEG
E
'&\#\#_S f lREE
&
mLEG  
'SkWG
FP
E
EX
&W
FnGS f op  
GE  
h(\#
pS
U RE
Q
FLE f ^
nLG
Q
GR  
q
X
Q
FFE  
'\#
\]Y^
n
ER
Kq] \]Y^
irrrjiM
ELQS  
sR
E  
EREL
LE
RFGG
QGS
V
R
FE U ^RR_E
jk
W  
L
X
Q
FFE
E  
GE
L
FFE
FLR LEP
GGS  
YP
LE  
L
FFE
X
Q
FEE
Q
EP
LQ _REG
E
Q
RS U YG
E  
GFXhFR
FF
ELQ U op
E
E
h&\#  
X U E  
h(\#
p  
GE
LE
GPRE
WQ  
RG ^
GRFG  
E
Q
Q
R
EP
F
GE`G
GE
RFLGS
YP
X EZ  
E
Rn  
EP
GRF
QZ
LGE
Q
t
E
EP
GRF
Q Rn  
EP
nE
GPEu h REE
GEL
v]
w
-
sample type
-
date/time of draw (DD/MMM/YY 24:00)
-
- - -
-
time point (ex. C1D1 pre, C1D1 24hr post)
any collection issues (short draw, delayed processing, etc.) protocol title/number institute name contact information
.  
Do not include the patient name, medical record number, or initials.