14th	  Interna+onal	  Myeloma	  Workshop	  in	  Kyoto	

Higher	  incidence	  of	  injec.on	  site	  reac.ons	  a2er	  subcutaneous	  bortezomib	  administra.on	  on	  the	  thigh	  compared	  with	  the	  abdomen
Tomohiko	  Kamimura1,	  Toshihiro	  Miyamoto2
Noriko	  Yokota3,	  Yong	  Chong1,2,	  Yoshikiyo	  Ito1,	  	  Koichi	  Akashi2	

1Department	  of	  Hematology	  and	  3Department	  of	  Nursing,	  	Harasanshin	  Hospital,	  Fukuoka,	  Japan	
2Department	  of	  Medicine	  and	  Biosystemic	  Science,	  	Graduate	  School	  of	  Medical	  Science,	  Kyushu	  University,	  Fukuoka,	  Japan		Background-1	
Subcutaneous (sc) rather thanintravenous administration of bortezomib(Bor) is becoming more common fortreating multiple myeloma (MM) because
scBor results in lower incidence andseverity of peripheral neuropathy and has
equivalent efficacy. 	

Moreau. Haematologica 2008; Moreau. Lancet Oncol 2011
Lonial. Curr Hematol Malig Rep. 2011; Arnulf. Haematologica 2012	

Background-2	
Bor is an irritant cytotoxic agent when it
leaks out; therefore, it is recommended
that injections of scBor should berotated among 8 different sites on theabdomen and thigh. However, detailed
information about injection site
reactions (ISR) have not been
sufficiently documented. 	
Moreau. Haematologica 2008; Moreau. Lancet Oncol 2011
Lonial. Curr Hematol Malig Rep. 2011; Arnulf. Haematologica 2012	Design and Methods	
We	  retrospecKvely	  analyzed	  the	  incidence	  and	  severity	  of	  ISR	  following	  scBor	  administraKon	  in	  15	  Japanese	  paKents	  with	  MM.	  The	  frequencies	  of	  grade	  0,	  grade	  1	  and	  grade	  2	  ISR	  in	  the	  thigh	  were	  compared	  with	  those	  in	  the	  abdomen	  using	  the	  χ2-­‐
test.	  The	  body	  mass	  index	  (BMI)	  of	  paKents	  with	  grade	  0–1	  or	  2	  ISRs	  in	  the	  thigh	  was	  compared	  using	  the	  Mann–Whitney	  U-­‐test.	  	Design and Methods	
Procedure	  of	  scBor	  Administra.on	
scBor concentration: 2.5 mg/ml
3.0 mg Bor reconstituted with
1.2 ml normal saline.		
5	1	6	
2	
7	
3	
8	
4

scBor injection sites: 8 different sites
The injection site is rotatedamong 8 different sites—
upper and lower quadrants of
the right and left abdomen
and proximal and distal sites
on both thighs. 	

Moreau. Lancet Oncol 2011

Design and Methods	
Evalua.on	  of	  ISR	The	  tolerability	  of	  scBor	  at	  the	  injecKon	  site	  was	  evaluated	  systemaKcally	  2–hrs	  a_er	  injecKon	  and	  every	  day	  during	  the	  ﬁrst	  treatment	  cycle	  during	  hospitalizaKon.	  A_er	  the	  second	  cycle,	  ISRs	  were	  evaluated	  at	  every	  visit,	  and	  between	  visits	  paKents	  documented	  their	  own	  ISRs	  in	  a	  detailed	  diary.	  	
Table	  1.	  Grading	  of	  ISR	  according	  to	  NCI	  CTC	  ver.	  4.0	Grade	  1	Grade	  2	tenderness	  with	  or	  without	  associated	  symptoms	

pain,	  lipodystrophy,	  edema,	  or	  phlebiKs	  Grade	  3	Grade	  4	ulceraKon,	  necrosis,	   ISRs	  with	  life-­‐threatening	  severe	  Kssue	  damage,	   consequences,	  requiring	  or	  any	  indicaKon	  for	  urgent	  intervenKon	
operaKve	  intervenKon	

Grade	  5	death	

Treatment Regimen with scBor 	
scBD	
scBor	  (1.3mg/m2)	  day	  1,	  8,	  15,	  and	  22	  	  dexamethasone	  (40	  mg/body)	  day	  1,	  8,	  15,	  and	  22	  	  	  	  	  scVCD	  (once-­‐weekly)		  scBor	  	  (1.3	  mg/m)	  	  cyclophosphamide	  (	  300	  mg/m2)	  dexamethasone	  (40	  mg/body)	  day	  1,	  8,	  15,	  and	  22	  	Patient Characteristics (n=15)	
Age		

70	  (range	  54−85)

Disease	  status
Newly	  diagnosed

7

Relapsed	  /	  refractory

8ivBor	  prior	  to	  scBor	  	  Median	  dosage	  (range)	  (mg/m2)

5	  	  17.6	  (5.2−70.6)	  Regimens	  including	  scBor
BD	  (once-­‐weekly)

4VCD	  (once-­‐weekly)

9

BD→VCD

2Median	  dosage	  of	  scBor	  (range)	  (mg/m2)

10.4	  	  (5.2−30.6)

Patients’ and ISRs’ Flow (n=15)	
Figure	  2	15	  pa.ents	  	  	  158	  scBor	  injecKons	5	  pa.ents	  	  	  Without	  	  any	  grade	  of	  ISR	  10	  pa.ents	  	  	  With	  grade	  1	  and/or	  grade	  2	  ISR	  5	  pa.ents	  	  	  With	  grade	  1	  ISR	  5	  pa.ents	  	  	  With	  	  grade	  1	  and	  2	  ISR	  Without	  	  any	  grade	  of	  ISR	  	  111	  scBor	  InjecKons	  (70.3%)	

With	  grade	  1	  ISR	  	  40	  scBor	  injecKons	  (25.3%)	

With	  grade	  2	  ISR	  	  7	  scBor	  injecKons	  (4.4%)	

3	  pa.ents	  	  	  With	  	  once	  grade	  2	  ISR	  (no.5,	  8	  and	  15)	  2	  pa.ents	  	  	  With	  	  twice	  grade	  2	  ISR	  (no.9	  and	  12)	  Representa.ve	  case	  (pa.ent	  no.	  9)	  with	  skin	  erythema	a	b	c	d	e	A	  65-­‐year	  old	  female	  (paKent	  9)	  with	  skin	  erythema,	  (a)	  classiﬁed	  as	  grade	  1	  ISR,	  2	  days	  a_er	  the	  1st	  scBor	  injecKon	  on	  the	  le_	  upper	  abdomen	  	(b)	  Skin	  erythema	  quickly	  resolved	  without	  treatment	  3	  days	  a_er	  the	  injecKon	  	(c)	  Two	  days	  a_er	  the	  3rd	  scBor	  injecKon	  on	  the	  proximal	  le_	  thigh,	  skin	  erythema	  recurred	  and	  progressively	  increased	  in	  size	  with	  phlebiKs	  and	  ﬁnally	  progressed	  to	  grade	  2	  ISR	  3	  days	  a_er	  the	  3rd	  injecKon.	  This	  ISR	  lesion	  did	  not	  expand	  further;	  therefore,	  no	  treatment	  was	  required	  and	  ISR	  resolved	  a_er	  24	  days.	  	
(d)	  PigmentaKon	  persisted	  43	  days	  a_er	  the	  3rd	  scBor	  injecKon	  	Kamimura . Eur J Haematol 2013	

Incidence	  of	  ISR	  (thigh	  vs.	  abdomen)	
100	  n=93	

Grade	  1	  I	  SR	80	  100	  n=93	

80	  n=65	

60	  n=65	

Other	  grade	

60	  40	  40	  20	  20	  0	  Grade	  2	  ISR	n=18	   Grade	  1	   n=22	  (27.3%)	 P=0.87	 (23.7%)	

Thigh	  Abdomen	  0	  Other	  grade	

n=6	   Grade	  2	  (9.2%)	 P=0.014	 n=1	  (1.1%)	

Thigh	  Abdomen	  Kamimura . Eur J Haematol 2013	

Major	  toxici.es	  (NCI	  CTC	  ver.	  4.0)				
Thrombocytopenia (grade 3)
New grade 3 thrombocytopenia
Grade 3 baseline thrombocytopenia
Neutropenia (grade 3)
New grade 3 neutropenia
Grade 3 baseline neutropenia
Anemia (grade 3)
New grade 3 anemia
Grade 3 baseline anemia
Peripheral neuropathy (new/worse)
Grade 1/2 peripheral neuropathy
Grade 3/4 peripheral neuropathy
Infection (grade 3)
Liver dysfunction (>grade 3)

n (%)
000
3 (20%)
2 (13%)
1 (7%)
3 (20%)
03 (20%)0/4
3 (20%)
1 (7%)
2 (13%)
0 (0%)

Kamimura . Eur J Haematol 2013	

Conclusion	
We	  conclude	  that	  4	  diﬀerent	  sites	  at	  the	  abdomen,	  avoiding	  the	  thigh,	  would	  be	  feasible	  and	  more	  suitable	  for	  scBor	  injecKon	  because	  ISR	  may	  be	  less	  common	  and	  severe	  and	  rapidly	  disappear	  within	  the	  interval	  before	  the	  next	  injecKon.	  Further	  large,	  prospecKve	  studies	  are	  required	  to	  assess	  the	  safety	  and	  eﬃcacy	  of	  scBor.