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Case 1
• 57 yr old male
• Rib pain – X-ray revealed lytic lesion, biopsy: plasma
cells
• Hgb 11.6 g/dL, creatinine 0.8 mg/dL, Ca++ 9.0 mg/dL
• Bone marrow 33% +CD38, +CD138, -CD56, λ -, κ + PC
T. Protein 7.5 g/dL, Albumin 3.0 g/dL, M-protein
3.2 g/dL: IgG κ, Bence Jones Protein 10 mg/day
Free λ 6.39 mg/L Free κ 24.27 mg/L Free κ: λ 3.798
β2M 1.8 mg/L Alb 3.5g/dL: ISS stage I
• Bone survey: multiple small lytic lesions in ribs, skull
and right femur
Case 1
• Patient started on induction with
bortezomib 1.3 mg/m2 IV on days 1, 4, 8, 11
lenalidomide 25 mg po daily x 14 days
dexamethasone 20 mg day 1,2,4,5,6,7,8,9,11,12
What would you do regarding
thromboembolism prophylaxis for
lenalidomide?
1. No intervention
2. Aspirin 81 mg po daily
3. Enoxaparin or equivalent 40 mg subcutaneous daily
4. Warfarin adjusted to keep INR 2-3
5. Warfarin 1.25 mg po daily
Thalidomide & Lenalidomide Thromboprophylaxis
Individual Risk Factors
Obesity
Previous VTE
Central Venous Catheter, Pacemaker
Associated Disease
Cardiac
Chronic Renal Disease
Diabetes
Acute Infection
Immobilization
Surgery
Gen. Surgery
Any Anesthesia
Trauma
Medications
ESA's
Blood Clotting Disorders
Actions
0 or 1 Risk Factor:
ASA 81-325 mg po daily
> 2 Risk Factors:
• LMWH (Enoxaparin 40mg
daily or equivalent)
• Warfarin (Target INR 2-3)
Myeloma-Related Risk Factors
Diagnosis
Hyperviscosity
Myeloma Therapy
High-Dose Dexamethasone
Doxorubicin
Multi-Agent Chemotherapy
•LMWH (Enoxaparin 40mg
daily or equivalent)
• Warfarin (Target INR 2-3)
Palumbo et al, Leukemia 2008, 22: 414-423
Randomized Trial of Aspirin, warfarin,
Enoxaparin during thalidomidedexamethasone combinations for
myeloma
Events
% Events:
thombo-embolic,
cardiovascular
Aspirin 100 mg/day
Warfarin 1.25 mg/day
Enoxaparin 40 mg/d
6.4%
8.2%
5%
P not significant compared with enoxaparin
Palumbo et al. J Clin Oncol. 2011;29(8):986-93:311-319.
Case 1
• Patient started on induction with
bortezomib 1.3 mg/m2 IV on days 1, 4, 8, 11
lenalidomide 25 mg po daily x 14 days
dexamethasone 20 mg day 1,2,4,5,6,7,8,9,11,12
• After Cycle 2, the M-protein is 1.3 g/dL
• After Cycle 2, he complains of tingling in fingers and
toes, but denies any pain
What would you do regarding the neuropathy?
1. Continue same doses of chemotherapy
2. Change bortezomib to subcutaneous
3. Change bortezomib to weekly
4. Reduce bortezomib to 1.0 mg/m2
5. Stop bortezomib
NCI CTCAE v 4.0 Peripheral Neuropathy
Type of
PN
Grade 1
Grade 2
Grade 3
Grade 4
Sensory
Asymptomatic; loss of
deep tendon reflexes or
paresthesia
Moderate symptoms;
limiting instrumental
ADL
Severe symptoms,
limiting self care
ADL
Life-threatening
consequences;
urgent intervention
indicated
Asymptomatic; clinical
or diagnostic
observations only;
intervention not
indicated
Moderate symptoms;
Limiting instrumental
ADL
Severe symptoms;
limiting self care
ADL; assistive
device indicated
Life-threatening
consequences;
urgent intervention
indicated
Motor
CTCAE = common terminology criteria for adverse events; NCI = National Cancer Institute;
aThese definitions are not specific to MM and the classification of a PN event as grades 1–4 may be subject to investigator bias.
Richardson et al. Leukemia. 2012;26:595-608.
Guidelines for Bortezomib-Induced
Neuropathy
Grade 1
No Action
Grade 1+Pain or
Grade 2
Grade 2 + Pain or
Grade 3
Grade 4
Reduce to 1.0 mg/m2
Suspend bortezomib
until neuropathy
disappears, then 0.7
mg/m2 and administer
weekly
Discontinue
bortezomib
Guidelines for Thalidomide-Induced
Neuropathy
Grade 1
Grade 1+Pain or
Grade 2
Grade 2 + Pain or
Grade 3
Grade 4
No Action
Reduce dose by 50% or
hold until neuropathy
disappears and re-initiate
at 50% dose
Suspend thalidomide
until neuropathy
disappears, re-initiate
at low- dose if PN < 1
Discontinue
thalidomide
Mohty et al. Haematolohica. 2012;95:311-319.
Subcutaneous Vs. Intravenous
Bortezomib
Median
Median
Peripheral
Time to
Time to
Neuropathy
Response Progression
All Grades
(months)
(months)
Route of
Bortezomib
Administration
Overall
Response
Rate
Complete
Response
IV (n=147)
42%
8%
1.4
9.4
53%
16%
Subcutaneous
(n=47)
42%
6%
1.4
10.4
38%
6%
0.39
0.04
0.03
P-value
IV
SC
Add 1.4 mL
0.9% sodium chloride
2.5 mg/mL
Peripheral
Neuropathy
Grade 3/4
Add 3.5 mL
0.9% sodium chloride
2 ways to reconstitute a
3.5-mg vial of bortezomib
IV = intravenous; SC = subcutaneous
1 mg/mL
Moreau P et al. Lancet Oncol. 2011;12:431-440
Bortezomib (Velcade®) Package Insert. 2012.
Case 1
• Patient continues on induction with
bortezomib 1.3 mg/m2 SC on days 1, 4, 8, 11
lenalidomide 25 mg po daily x 14 days
dexamethasone 20 mg day 1,2,4,5,6,7,8,9,11,12
• During cycle 4, Day 8 of therapy the patient’s platelet
count is 33,000
What would you do regarding the
thrombocytopenia?
1. Continue same doses of chemotherapy
2. Reduce bortezomib to 1.0 mg/m2
3. Reduce lenalidomide to 15 mg po daily x 14 days
4. Stop bortezomib
4. Stop lenalidomide
Guidelines for Bortezomib-Induced Cytopenias
Thrombocytopenia
< 30,000
cells/ μL
Neutropenia
< 750 cells/μL
On Dosing Day
Hold dose
On Dosing Day
Hold dose
Several Dosing Days
Held
Lower by 25% or
1 level
(1mg/m2, 0.7mg/m2)
Several Dosing Days
Held
Lower by 25% or
1 level
(1mg/m2, 0.7mg/m2)
If several consecutive doses
held and combined with
other myelosuppressive
agent consider dose
adjustment of other agent
(melphalan, lenalidomide,
cyclophosphamide, etc)
Guidelines for Lenalidomide-Induced Cytopenias
Thrombocytopenia
< 30,000
cells/ μL
Neutropenia
< 1,000 cells/μL
1st Time
Hold +
Decrease to 15 mg qD
After counts > 30,000
1st Time
Hold + G-CSF
Resume @ 25 mg qD
After > 1,000 cells/ μL
2nd Time
Hold +
Decrease to 10 mg qD
After counts > 30,000
2nd Time
Hold + G-CSF
Resume @ 15 mg qD
After > 1,000 cells/ μL
3rd Time
Hold +
Decrease to 5 mg qD
After counts > 30,000
3rd Time
Hold + G-CSF
Resume @ 10 mg qD
After > 1,000 cells/ μL
4thTime
discontinue
4th Time
Hold +
G-CSF
Resume @
5 mg qD
After >
1,000 cells
Case 1
• Patient continues on induction with
bortezomib 1.3 mg/m2 SC on days 1, 4, 8, 11
lenalidomide 25 mg po daily x 14 days
dexamethasone 20 mg day 1,2,4,5,6,7,8,9,11,12
• After Cycle 4, he still complains of only slight tingling in
fingers and toes and denies any pain
• After Cycle 5, the M-protein is 0.2 g/dL
• After Cycle 5, he now complains of pain w/ numbness
in fingers and toes and has difficulty buttoning his shirt
What would you do regarding the neuropathy?
1. Continue same doses of chemotherapy
2. Change bortezomib to subcutaneous
3. Change bortezomib to weekly
4. Reduce bortezomib to 1.0 mg/m2
5. Stop bortezomib
NCI CTCAE v 4.0 Peripheral Neuropathy
Type of
PN
Grade 1
Grade 2
Grade 3
Grade 4
Sensory
Asymptomatic; loss of
deep tendon reflexes or
paresthesia
Moderate symptoms;
limiting instrumental
ADL
Severe symptoms,
limiting self care
ADL
Life-threatening
consequences;
urgent intervention
indicated
Asymptomatic; clinical
or diagnostic
observations only;
intervention not
indicated
Moderate symptoms;
Limiting instrumental
ADL
Severe symptoms;
limiting self care
ADL; assistive
device indicated
Life-threatening
consequences;
urgent intervention
indicated
Motor
Guidelines for Bortezomib-Induced Neuropathy
Grade 1
No Action
Grade 1+Pain or
Grade 2
Grade 2 + Pain or
Grade 3
Grade 4
Reduce to 1.0 mg/m2
Suspend bortezomib
until neuropathy
disappears, then 0.7
mg/m2 and administer
weekly
Discontinue
bortezomib
CTCAE = common terminology criteria for adverse events; NCI = National Cancer Institute;
aThese definitions are not specific to MM and the classification of a PN event as grades 1–4 may be subject to investigator bias.
Richardson et al. Leukemia. 2012;26:595-608.
Case 1
• The patient decides to proceed to myeloablative
therapy + autologous stem cell transplant (AuSCT)
• Therapy is held for 2.5 weeks and an attempt to harvest
stem cells with G-CSG (filgastrim) alone is unsuccessful
What would you do next?
1. Tell the patient that harvest was unsuccessful and
continue chemotherapy
2. Attempt harvest after cyclophosphamide mobilization
therapy (+/- mobizil)
Case 1
• Autologous stem cell harvest is successful after
cyclophosphamide chemomobilization and the patient
proceeds with high-dose melphalan + autologous stem
cell transplant (AuSCT)
• 3 months post- AuSCT the patient is started on
lenalidomide maintenance therapy 10 mg po daily
Case
• 3 months post- AuSCT the patient restarts zoledronic
acid monthly after previously being cleared by the
dentist
• M-protein reduces to 0, but immunofixation remains
positive at 6 months post-AuSCT
Case
• The patient develops right lower jaw pain and is
evaluated by the dentist and has an abscess, which
responds to antibiotic therapy, but the tooth needs
extraction.
What would you do regarding the extraction?
1. Have the tooth extracted immediately.
2. Stop zoledronic acid and have the tooth extracted
immediately.
3. Hold zoledronic acid, treat the tooth, wait at least 1
month, if possible, and extract the tooth.
Case
• The patient has the tooth extracted and after 3 months
zoledronic acid is restarted.
• The patient continues on lenalidomide 10mg/d in near
CR by SPEP
• 1 year post-AuSCT the patient’s creatinine begins to
rise and is 1.97mg/dL (creatinine clearance 33 ml/min)
• 24 hr UPEP reveals a rise in total protein to 453 mg/d
(Bence Jones protein 7 mg/d) : previous total
proteinuria 87 mg/d with 5 mg Bence Jones protein
What would you do regarding the creatinine?
1. Change therapy the patient’s disease is progressing
2. Stop zoledronic acid and repeat UPEP in 1 month
3. Dose adjust lenalidomide
Lenalidomide
Creatinine Clearance
(m/min)
Lenalidomide
Dose (mg)
> 30 - 50
10 mg/Day
< 30, NOT on dialysis
15 mg q48
hours
On dialysis
5 mg/D
after dialysis
Celgene Product Information available at www. Revlimid.com/pdf/revlimid/pl.pdf
Case
• 1 month later the total urine protein is 110 mg/d and
zoledronic acid is restarted with no further increase in
proteinuria
• The creatinine improves to 1.3 mg/dL .
• On physical exam the patient has a 4-5 mm fullness on
the left pharyngeal arch.
Case
•PATHOLOGY REPORT
WIDE LOCAL EXCISION LESION LEFT SOFT PALATE:
POLYMORPHOUS ADENOCARCINOMA.
Tumor size = 1.7 cm
Perineural invasion: PRESENT, MULTIFOCAL
Peripheral margin: FOCALLY CLOSE < 2 MM
•The patient begins a 6 week cycle of radiotherapy with
curative intent of the head and neck tumor – lenalidomide
placed on hold
•2 months later the SPEP reveals an M-protein of 0.4
mg/dL
You confirm relapse with a second what therapy
do you start?
1. Restart lenalidomide 10 mg po daily
2. Start lenalidomide 25 mg po x 21 d + dexamethasone
40 mg po weekly
3. Bortezomib 1.0 mg/m2 by subcutaneous injection
weekly
4. Carfilzomib 20 mg/m2 d 1,2,8,9,15,16
Dexamethasone 4 mg IV d1
250 cc NS before carfilzomib
5. Pomalidomide 4 mg po daily x 28 day cycles +
Dexamethasone 40 mg po weekly
Secondary Primary Malignancies (SPMs):
Lenalidomide CALBG100104 vs. SEER
Author
Type
McCarthy
NEJM 2012
Hematologic
n=231 len.
n= 229 plac.
Solid
n=231 len.
n=229 plac.
Attal
NEJM 2012
Hematologic
n=306 len.
n=302 plac.
Solid
n=306 len.
n=302 plac.
Secondary Cancer
Incidence
8
1
3.5%
0.4%
10
5
4.3%
2.1%
13
5
4%
2%
10
4
4%
1%
SEER
(1973-2000)
6.1%
(95% CI: 5.8%-6.5%)
Based on 23,838
patients observed for
20 years
6.1%
(95% CI: 5.8%-6.5%)
Based on 23,838
patients observed for
20 years
McCarthy PL, et al. NEJM, 2012
Attal M, et al. NEJM, 2012
Case
• The patient begins carfilzomib, but on day 1 develops
dyspnea with mild chest pain.
• Furosemide 20 mg IV improves the dyspnea
• During the next cycle pre-hydration is decreased to 125
cc’s prior to carfilzomib, which is well tolerated.
Carfilzomib Hematologic Toxicity Dose Reductions
Toxicity
Grade 1
Neutropenia
Thrombocytopenia
No Adjustment
No Adjustment
Grade 2
Grade 3
No Adjustment
Hold dose until <
gr. 1
Decrease 1 level
15 mg/m2 then
11 mg/m2
No adjustment
No Adjustment
Grade 4
Hold dose
Decrease 1 level
15 mg/m2 then
11 mg/m2
Guidelines for Carfilzomib-Induced Renal
Insufficiency
Toxicity
Renal Insufficiency
Grade 1
No Adjustment
Grade 2
> Grade 3
No Adjustment
Hold dose until > 30 Ml/min
Decrease 1 level :15 mg/m2 then
11 mg/m2 then d/c; if Cr Cl did not
improve in 7 days or if creatinine >
2 mg/dL
Jagannath et al. Clinical Lymphoma, Myeloma &Leukemia. 12;310-18, 2012.
Adverse Event
Thalidomide
Lenalidomide
Peripheral
neuropathy

Deep vein
thrombosis

More with dex

More with dex

Neutropenia

Neutropenia,
thrombocytopenia,
anemia
Myelosuppression
Bortezomib
Pegylated
Liposomal
Doxorubicin/
Bortezomib
Bortezomib/
Melphalan/
Prednisone




Thrombocytopenia

Neutropenia,
thrombocytopenia,
anemia

Neutropenia,
thrombocytopenia








Nausea and vomiting,
diarrhea

Nausea and vomiting,
diarrhea, constipation,
mucositis/stomatitis

Nausea, diarrhea,
constipation, vomiting

Hypotension
Fatigue, weakness

Sedation

Rash



Viral reactivation of
herpes zoster
Gastrointestinal
disturbance

Constipation
Renal
Watch for
hyperkalemia


Constipation, diarrhea

Reduce dose for
decreased CrCL
Doxil® (doxorubicin) [prescribing information]. Raritan, NJ: Centocor Ortho Biotech Products, LP; 2010; Revlimid® (lenalidomide) [prescribing information].
Summit, NJ: Celgene; 2010; Thalomid® (thalidomide) [prescribing information]. Summit, NJ: Celgene; 2010; Velcade® (bortezomib) [prescribing information].
Cambridge, MA: Millennium Pharmaceuticals, Inc; December 2010.
Considerations When Treating
Older Individuals
Risk Factors
• Age >75 years
• Mild, moderate, or severe frailty: Patient needs help for household and personal care
• Comorbidities: Cardiac, pulmonary, hepatic, renal dysfunction
Drug
No risk factors
25 mg/day
Days 1-21/4 weeks
1.3 mg/m2 biweekly
Bortezomib
Days 1,4,8,11/3 weeks
40 mg/day
Dexamethasone Days 1,8,15,22/4 weeks
Melphalan
0.25 mg/kg
Days 1-4/4-6 weeks
Lenalidomide
1 or more risk factors
15 mg/day
Days 1-21/4 weeks
1.3 mg/m2 weekly
Days 1,8,15,22/5 weeks
20 mg/day
Days 1,8,15,22/4 weeks
0.18 mg/kg
Days 1-4/4-6 weeks
At least one risk factor +
grade 3/4 non-hem AE
10 mg/day
Days 1-21/4 weeks
1.0 mg/m2 weekly
Days 1,8,15,22/5 weeks
10 mg/day
Days 1,8,15,22/4 weeks
0.13 mg/kg
Days 1-4/4-6 weeks
Palumbo et al. Blood. 2011;118:4519-4529.