The Prevention and Management of
Drug- Id
Induced Perih
ipheral Neuropath
thy
in Multiple My
pyeloma
PG Richardson, J Laubach, R Schlossman,
IC Ghobrial, D Doss,
Doss, M McKenney,
McKenney K Noonan,
Noonan,
K Colson, S Chuma, M Gannon, K McCormick
CS Mitsiades, N Munshi, KC Anderson
Jerome Lipper Multiple Myeloma Center
Dana-Farber Cancer Institute,
Harvard Medical
Medical School
Boston, MA
IMW XII February 2008
Incidence of PN in Pts With Multiple
Myeloma
ˇ Incidence:
11-20% in newly diagnosed pts, with up to 60% of pts
with abnormal NCS at diagnosis 1,2
83% in relapsed and refractory pts as assessed by
clinical neurologic examination 3
39% - 50% in advanced, rel/refy pts
pts as detected by
abnormal NCS studies 3,4
Therapies associated with PN;
p; Vincristine, Platinum,
Thalidomide, Bortezomib.
1. Chaudhry V, et al. J Peripheral
Peripheral Nervous
Nervous System. 2008;13(4)275-282
2. Richardson PG, et al. J Clin Oncol. Epub ahead of print. 2009.
3. Richardson PG, et al. J Clin Oncol. 2006;19:31133120.
4. Mileshkin L, et al. J Clin Oncol. 2006;20;24(27):45074514.
Symptoms and Characteristics
of PN in MM
ˇ Usually length-dependent axonal, mixed sensorimotor13
yg
p,
ˇ Some forms of PN involve damage to only 1 nerve and are
called mononeuropathies4
ˇ Symptoms are symmetric, distal, and progressive,1 and
include the following
Prickling sensation and/or tinglin
gg
g
Temporary numbness
Sensitivity to touch
Muscle weakness
weakness
ˇ In rare cases, can be disabling/life threatening1
1. Tariman JD, et al. and the IMF Nurse Leadership Board. Clin J Oncol Nurs. 2008;12(suppl 3):2936.
2. Mileshkin L, Prince HM. Leuk Lymphoma. 2006;47(11):22762279.
3. Mileshkin L, et al. J Clin Oncol. 2006;20;24(27):45074514.
4. National Cancer Institute: PDQ Pain. Accessed February 20, 2009.
Incidence of Thal- PN in Pts With Multiple
Myeloma
ˇ Incidence after Thal treatment
Clinically apparent: 39%75%1
Electrophysiologic testing and/or clinically apparent: 25%
85%13
85%
ˇ Neuropathy is commonly mild -moderate
Review of phase 2 trials found 6% incidence of grade 3/4 PN
in 1674 pts with Rel/Refy MM2
in 1674 pts with Rel/Refy MM
PN generally occurs following chronic use over a period of
mos and is cumulative 14
ˇ Reports following relatively short-term use also exist
ˇ Symptoms may resolve slowly or not at all
1. Mileshkin L, et al. J Clin Oncol. 2006;20;24(27):4507 4514.
2. Mileshkin L, Prince HM. Leuk Lymphoma. 2006;47(11):2276 2279.
3. Ghobrial IM, Rajkumar SV. J Support Oncol. 2003;1(3):194 205.
4. Richardson PG, et al. Mayo Clin Proceedings. 2004
Patient Assessment During Thalidomide
Treatment
ˇ Baseline physical exam and clinical assessment1
ˇ Neurotoxicity assessment1
Monthly for first 3 mos
When symptoms appear
appear or increase
At each examination or consultation while on therapy
Clinical monitoring may be supplemented with validated
patient-completed tools2
ˇ Consideration should be given to electrophysiologic
testing, measure
measure SNAP* at baseline and
and every
6 mos3
*SNAP, sensory nerve action potential.
1. Tariman JD, et al. and the IMP Nurse Leadership Board. Clin J Oncol Nurs. 2008;12(suppl 3):2936.
2. Mileshkin L, Prince HM. Leuk Lymphoma. 2006;47(11):22762279.
Increased Duration of Thalidomide
Increases Risk of PN
ˇ Increased risk after 6 mos of
73
80
treatment1,2
70
ˇ In a study of 75 pts with RR
MM, incidence of PN increased
60
ients
from 38% at 6 mos to 73% at 12
50
mos1
38
pat
40
Median Thal dose, 58 g (range,
tof
30
n
0.6432 g)
20
Median duration of treatment, 22
wks (range, 0.4120.4 weeks)
Perce
10
Medi
dian dose i t
n ensity, 373
/d
mg
0
(range, 82770 mg/d)
PN at 6
PN at 12
months
months
1. Mileshkin L, et al. J Clin Oncol. 2006;20;24(27):45074514.
2. Ghobrial IM, Rajkumar SV. J Support Oncol. 2003;1(3):194205.
Predictive Value of Electrophysiologic
Studies (EPS)
ˇ Trial of 75 pts with RR MM: pts
pp
underwent EPS at
baseline and every 3 mos
ˇ Overall, abnormalities on baseline NES did not
predict development of PN
Positive predictive value of abnormal baseline EPS for
subsequent development of
of PN
PN was
was 46%
73% of pts who developed severe PN had abnormal
baseline findings
ˇ Negative predictive value of normal baseline EPS
was 53%
EPS: electrophysiologic studies
Mileshkin L, et al. J Clin Oncol. 2006;20;24(27):45074514.
Vitamin B12
B12 Deficiency
ˇ Serum vitamin B12 measurement should be part
p
of
the initial evaluation of patients with MM
Identifying vitamin B12 deficiency is important in pts
recei ing
v
active therapy for MM
MM that
that has
has potential
neurotoxic side effects
ˇ Vitamin B12
B12 deficiency has been
been reported in
in 17% of
pts with MM
Correction of B12 deficiency may improve anemia and
increase ability to tolerate potentially neurotoxic drugs
Baz R, et al. Cancer. 2004;101(4):790795.
Management Recommendations and
Summary for PN
PN and
and Thal
ˇ PN usually occurs following chronic use of Thal for 6
mos
can develop even with short-term use
ˇ Pts treated
treated with Thal should
should be
be examined monthly for
for first
3 mos and then periodically for detection of early signs of
PN
Numbness
Tingling or pain in hands/feet
ˇ Consider EPS, consisting of measurement of SNAP
amplitudes at
at baseline
baseline and
and every 6 mos to
to detect
detect
asymptomatic PN
ˇ If symptoms of Thal -induced PN develop, discontinue
Thal if
if clinically
clinically appropriate
Normal Anatomy of the dorsal root ganglion (DRG)
Ski
Dorsal (up)
Ventral (down)
Key Message: The sensory nervous system is more vulnerable than
the motor nervous system to circulating blood toxins due to free
access of the blood to the DRG.
Key Messages about Time Course of Lesion
Progression
g
from In Vivo studies with Bz, other PI's
1.
Morphologic lesions can be seen within the DRG neuronal
cell bodies within 24 hrs following a single IV dose
administration of boronate proteasome inhibitor (Bz)
(Bz) at
at
MTD.
2.
DRG lesions in the absence of degenerative nerve lesions
support DRG as the primary target following IV
administration of Bz.
Silverman et al ASH 2008
Conclusions
ˇ Proteasome inhibitor (PI)
(PI) induced
induced PN is
mechanism based
ˇ Cellular effects are observed across
proteasome inhibitors with different chemical
chemical
scaffolds and are related to blood PI with an
apparent threshold
ˇ Tt
Target for PI
PI i d
n uced PN
PN is th
the neuronal cellll
body
ˇ Protein perturbation,
p, as evidenced by
neuronal cell body cytoplasmic aggregates, is
an early cellular change
Clinical Characteristics of PN in Phase II
Tr
T ials
r
of Bortezomib (n=256
(n=
)
256
ˇ Primarily sensory; no pts with motor alone
ˇ S m
y ptoms
mptoms: paresthesia
p
, burning dysesthesia,
numbness
Lower > Upper extremities
ˇ Exam findings
Diminished sensation distally, no significant
weakness
Sensory polyneuropathy
ˇ EPS testing on a subset of pts (n= 12):
No change (10/12 pts: 5 abnormal @ baseline)
P
i
rogress on on sensory NCS (1/12 t
p )
s
Progression on QST (1/12 pts)
Length-dependant axonal small fiber polyneuropathy
1. Richardson et al. JCO 2006. 24(19): 3113-20
Treatment-emergent PN Summary
ˇ 35% of pts reported treatment-emergent PN of any grade by NCI CTC
Onset plateaued at cycle 5 (~30 mg/m2 cummulative dose)
ˇ Pts with and without PN by FACT/GOG-Ntx at baseline had similar
ff
frequency of treat
t
men
t
-emergen PN
PN (36%
(36% in each group)
Grade 3 PN tended to be more frequent in pts with baseline
neuropathy (14% with vs 4% without; p = 0.08)
ˇ Increase in FACT/GOG-Ntx and TNS from baseline to end-of-study in
pts with and without treatment-emergent PN
Consistent for all subscales of TNS except
p motor examination
scores in pts without treatment-emergent PN
Increased PN scores in pts not experiencing painful PN suggests
subclinical evolving PN
Positive correlation between cumulative Bz dose
d
an FACT/GOG
FACT/GOG-
Ntx summary score and TNS
1. Richardson et al. JCO 2006. 24(19): 3113-20
Outcomes and Reversibility
ˇ 35 (14%)
() pts
p
had G 3 PN or PN leading to
discontinuation
14 (16%) pts discontinued
8 (50%)
(50%) had
had onset during first
first 3 cycles
31 (34%) pts had dose reduced
19 (21%) pts had at least one dose held
ˇ 25/35 (71%) t
p s h d
a
t
symp oms resol /i
ve mprove
13 (37%) during treatment
11 (31%)
() after treatment
1 (3%) unclear time of resolution
ˇ Median duration from last dose to
resolution/improvement 47d (range 1-
1 529)
-
1. Richardson et al. JCO 2006. 24(19): 3113-20
Recommended Dose Modifications for PN
Severity of PN
Modification of
of Dose
Dose and
and Regimen
(Signs and symptoms)
Grade 1 without pain
or
No action
loss of function
Grade 1 with pain
Reduce bortezomib from
from 1 3
. to
to 1 0
.
or
mg/m2
Grade 2
Grade 2 with pain
pain
Wi
W thhold
i
until toxicity resolves.
or
Reinitiate with bortezomib at 0.7 mg/m2
Grade 3
administer once per week
Grade 4
Discontinue bortezomib
1. Richardson et al. JCO 2006. 24(19): 3113-20
Onset of PN in pts with no PN at Baseline
(n=60)
any
G3/4
ˇ 37% of pts have a probability of developing first onset of PN (any
Grade) at a cumulative dose of 30 mg/m2 compared to a 50% probability
of overall population
PN in APEX - Conclusions
ˇ
Incidence of PN in APEX (overall: 37%; G 2 in 27%) is comparable
with that in phase 2 trials
Incidence of G 3 PN in APEX (9%) is lower than in phase 2 trials,
possibly owing to use of dose modification protocol
Incidence and severity of PN appear to be unaffected by age or prior
therapy
ˇ
G 2 PN associated with bortezomib treatment in APEX was
reversible in approximately two-thirds of pts; the majority
experienced complete resolution to baseline
Use of dose modification for PN appears to increase the proportion of
patients experiencing resolution or improvement of PN
PN or dose modification did not appear to affect TTP
Richardson et al, BJH 2009; 144: 895-903
Incidence of PN and prior Diabetes
Pts with peripheral neuropathy, %
Any grade
grade
Grade 3
Requiring discontinuation
HgbA1C > ULN (n = 41)
39
710
HgbA1C ULN (n = 278)
38
99
History of diabetes (n = 42)
31
55
No history of diabetes
39
10
10
(n = 290)
HgbA1C > ULN or history of
33
5
7
diabetes (n = 60)
HbgA1C ULN and no history of
diabetes
39
10
10
(n = 272)
HgbA1C: glycosylated hemoglobin
Richardson et al, BJH 2009; 144: 895-903
Onset of PN generally occurs by cycle 5
100
90
80
)
55cycles
cycles
8
8 cy
cy cles
cles
70
s(%
60
All
patient 50
of
on 40
30
Proporti
Grade 3/4
20
10
0
0
10
20
30
40
50
60
Cumulative calculated dose (mg/m2)
Richardson et al, BJH 2009; 144: 895-903
Bz in upfront MM: Conclusions (n=65)
(n=65)
ˇ Treatment-emergent PN by NCI CTCAE (64%) manageable
Only 1 (3%) Gr 3 PN; no Gr 4
ˇ PN was responsive to bortezomib dose modification and
pharmacologic treatment in most pts
Resolution of PN: 85%
Resolution of neuropathic pain: 88%
ˇ Underlying small-fiber PN appears more common in MM than
previously appreciated
6 of 19 (32%) of pts with PN at baseline had pure small-fiber PN
7 of 15 (47%) pts with new, treatment-emergent PN had pure small-
fiber neuropathy
ˇ No clinically significant autonomic
autonomic or motor PN
PN
ˇ No correlation between severity of painful PN by NCI CTCAE, clinical
examination, neurophysiologic testing, or neurite count
Severity of NP by
yy CTCAE did not correlate well with these
parameters
Richardson et al, JCO epub ahead of print 2009
Supplements/ Pharmacologic Interventions
for PN
PN
ˇ
Vitamins:
Multi-
Multi B complex
complex vitamin (B6,
(B6, B12,
B12, B1 ~ RDA)
Folic acid (folate) 1-2 mg/d
Magnesium, Calcium (myalgia)
Potassium
Vitamin E
ˇ
Amino acids, others:
L-carnitine 500 mg BID with food; up to 2000 mg/day
Alpha lipoic acid 400-600 mg/day with food
L-glutamine 10 g/day for 1 week followed by 1 g TID
Emollient creams cocoa butter, spearmint, menthol
ˇ
Interventions for G 1 PN, neuropathic pain:
Step 1: daily vitamins and/or nutritional supplements
Step 2: add gabapentin 300mg TID; titrate as tolerated up to 1,200mg
TID
Step 3: add nortryptiline 25mg qhs, increase up to 50mg after 2 wks,
then increase by 25mg monthly as tolerated up to 100mg qhs; add
duloxetine 2060mg QD
Mechanism of action:
Alpha-lipoic acid (ALA) is a metabolic cofactor of the pyruvate dehydrogenase
complex and a strong antioxidant
Glucose
Glucose
Increased Oxidative Stress
Pyruvate
E2
PDH
E1
E3
Metabolic
function
ALA
Metabolic
(DEXLIPOTAM)
function
Mitochondrial impairment leading to degeneration of
dorsal root ganglion (DRG) neurons in peripheral
nerves
Conclusions/Future Directions
ˇ Prompt Dose Reduction, Schedule Change, Discontinuation
hP
when N
PN emerges, Use f
o S
l
upp ements, Symptom R l
e ili f
e
ˇ Combination Therapy
ˇ Risk-adapted Approach
ˇ Optimal Sequence of Treatments
ˇ Further Evaluation of PN,
Characterization, Effect of Interventions
ˇ New Agents with less neurotoxicity
gy eg 2nd generation
g
PI's,
Lenalidomide
Rationally Based Combination Therapies
ˇ
Bortezomib and Hsp 90
ˇ
Lenalidomide and mTOR
inhibitor
inhibitor
ˇ
Bortezomib and doxil
ˇ
Lenalidomide and Anti-CD40
ˇ
Bortezomib and NPI-0052
antibody
ˇ
Bortezomib and perifosine
ˇ
Lenalidomide and doxil
Bortezomib and perifosine
ˇ
Bortezomib and LBH 589
ˇ
Lenalidomide and HuLuc63
ˇ
Bortezomib and Smac
ˇ
Lenalidomide and LBH 589
peptides
ˇ
Lenalidomide and perifosine
ˇ
Bortezomib and Bcl 2
ˇ
Lenalidomdide and
inhibitor
Bevacizumab
ˇ
Bortezomib and p38 MAPK
ˇ
Lenalidomide and Vaccine
inhibitor
ˇ
Bortezomib and HuLuc63
Lenalidomide and Bortezomib low rate of PN
Tanespimycin
py
+ BZ and PNY
ˇ 57 pts received
received bortezomib (1.3
(1.3 mg/m2
mg/m ) + tanespimycin
(150-340 mg/m2)
ˇ Median Relative Dose Intensity
ˇ Bortezomib
95% (range 59-105%)
ˇ 28 pts received >3 cycles of the combination
ˇ No pt with G3 or greater PNY ~ role of HSP 70?
ˇ In the 228 pts treated with 1.3 mg/m2 bortezomib in the
SUMMIT and CREST phase 2 trials, 13% developed G3
treatment-emergent PNY
Richardson et al, ASH 2007
Rodent Model of Neuropathy
Bo
Bort
r e
t zomib
mib 0 2
. mg
mg/k
/ g IV Bo
Bolu
lus an
and KOS
KO
0
- 953
0953 20
20 0
. mg
mg/k
/kg 60
60 min
min IV Infu
f sio
i n
(q2wkx3) in Male Sprague Dawley Rats
Average Group Sensory Threshold Readings Over Time (g) 0706-001#3
)
study ongoing
66.0
(g
62.0
58.0
Threshold 54.0
n=6
Control
ory 50.0
s
n=6
n=
Bo
B r
o tez
t
omi
om b
i
46.0
n=6
Combination
Sen
42.0
roupG 38.0
gea 34.0
30.0
Aver
7 8 9 10 1112 131415 1617 1819 202122 2324 252627 28 29 3031 323334 3536 37 38 3940
St
S udy Da
Day
ˇ
Rats were treated with saline (control), bortezomib (0.2 mg/kg), or bortezomib (0.2
mg/kg) plus tanespimycin (20 mg/kg). Sensory thresholds were measured using a
von Frey
Frey Anesthesiom
Anesthesiometer
ˇ
Combination of tanespimycin with bortezomib demonstrated a lack of neurotoxicity
compared to bortezomib alone, indicating a neuroprotective effect of tanespimycin
Richardson et al, ASH 2007
Clinical Investigators in MM - A Global Network: Leadership, including Anderson KC.,
Dalton W., Harousseau JL., San Miguel J., Kyle R.
APEX/ SUMMIT/CREST/ Upfront Bz Investigators: Millenium; Celgene; J & J; BMS
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