1. Case 1
• 57 yr old male
• Rib pain – X-ray revealed lytic lesion, biopsy: plasma
cells
• 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
• Hgb 11.6 g/dL, creatinine 0.8 mg/dL, Ca++ 9.0 mg/dL

2. 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

3. What would you do regarding
thromboembolism prophylaxis for
lenalidomide?
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
1. No intervention

4. 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
Palumbo et al, Leukemia 2008, 22: 414-423
Myeloma-Related Risk Factors
Diagnosis
Hyperviscosity
Myeloma Therapy
High-Dose Dexamethasone
Doxorubicin
Multi-Agent Chemotherapy
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)
•LMWH (Enoxaparin 40mg
daily or equivalent)
• Warfarin (Target INR 2-3)

5. Events Aspirin 100 mg/day Warfarin 1.25 mg/day Enoxaparin 40 mg/d
% Events:
thombo-embolic,
cardiovascular
6.4% 8.2% 5%
Randomized Trial of Aspirin, warfarin,
Enoxaparin during thalidomide-
dexamethasone combinations for
myeloma
Palumbo et al. J Clin Oncol. 2011;29(8):986-93:311-319.
P not significant compared with enoxaparin

6. 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, he complains of tingling in fingers and
toes, but denies any pain
• After Cycle 2, the M-protein is 1.3 g/dL

7. What would you do regarding the neuropathy?
2. Change bortezomib to subcutaneous
3. Change bortezomib to weekly
4. Reduce bortezomib to 1.0 mg/m2
5. Stop bortezomib
1. Continue same doses of chemotherapy

8. 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
Motor
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
NCI CTCAE v 4.0 Peripheral Neuropathy
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.

9. Grade 1
Grade 1+Pain or
Grade 2
Grade 2 + Pain or
Grade 3
Grade 4
No Action Reduce to 1.0 mg/m2
Suspend bortezomib
until neuropathy
disappears, then 0.7
mg/m2 and administer
weekly
Discontinue
bortezomib
Guidelines for Bortezomib-Induced
Neuropathy
Mohty et al. Haematolohica. 2012;95:311-319.
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
Guidelines for Thalidomide-Induced
Neuropathy

10. Route of
Bortezomib
Administration
Overall
Response
Rate
Complete
Response
Median
Time to
Response
(months)
Median
Time to
Progression
(months)
Peripheral
Neuropathy
All Grades
Peripheral
Neuropathy
Grade 3/4
IV (n=147) 42% 8% 1.4 9.4 53% 16%
Subcutaneous
(n=47)
42% 6% 1.4 10.4 38% 6%
P-value 0.39 0.04 0.03
Subcutaneous Vs. Intravenous
Bortezomib
1 mg/mL
Add 3.5 mL
0.9% sodium chloride
Add 1.4 mL
0.9% sodium chloride
2 ways to reconstitute a
3.5-mg vial of bortezomib
SC IV
2.5 mg/mL
Bortezomib (Velcade®) Package Insert. 2012.
IV = intravenous; SC = subcutaneous
Moreau P et al. Lancet Oncol. 2011;12:431-440

11. 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

12. What would you do regarding the
thrombocytopenia?
2. Reduce bortezomib to 1.0 mg/m2
3. Reduce lenalidomide to 15 mg po daily x 14 days
4. Stop bortezomib
1. Continue same doses of chemotherapy
4. Stop lenalidomide

13. Guidelines for Bortezomib-Induced Cytopenias
Guidelines for Lenalidomide-Induced Cytopenias
Thrombocytopenia
< 30,000
cells/ μL
On Dosing Day
Hold dose
Several Dosing Days
Held
Lower by 25% or
1 level
(1mg/m2, 0.7mg/m2)
Neutropenia
< 750 cells/μL
On Dosing Day
Hold dose
Several Dosing Days
Held
Lower by 25% or
1 level
(1mg/m2, 0.7mg/m2)
Thrombocytopenia
< 30,000
cells/ μL
1st Time
Hold +
Decrease to 15 mg qD
After counts > 30,000
2nd Time
Hold +
Decrease to 10 mg qD
After counts > 30,000
3rd Time
Hold +
Decrease to 5 mg qD
After counts > 30,000
4thTime
discontinue
Neutropenia
< 1,000 cells/μL
1st Time
Hold + G-CSF
Resume @ 25 mg qD
After > 1,000 cells/ μL
2nd Time
Hold + G-CSF
Resume @ 15 mg qD
After > 1,000 cells/ μL
3rd Time
Hold + G-CSF
Resume @ 10 mg qD
After > 1,000 cells/ μL
4th Time
Hold +
G-CSF
Resume @
5 mg qD
After >
1,000 cells
If several consecutive doses
held and combined with
other myelosuppressive
agent consider dose
adjustment of other agent
(melphalan, lenalidomide,
cyclophosphamide, etc)

14. 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 5, he now complains of pain w/ numbness
in fingers and toes and has difficulty buttoning his shirt
• After Cycle 5, the M-protein is 0.2 g/dL
• After Cycle 4, he still complains of only slight tingling in
fingers and toes and denies any pain

15. What would you do regarding the neuropathy?
2. Change bortezomib to subcutaneous
3. Change bortezomib to weekly
4. Reduce bortezomib to 1.0 mg/m2
5. Stop bortezomib
1. Continue same doses of chemotherapy

16. 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
Motor
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
NCI CTCAE v 4.0 Peripheral Neuropathy
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.
Grade 1
Grade 1+Pain or
Grade 2
Grade 2 + Pain or
Grade 3
Grade 4
No Action Reduce to 1.0 mg/m2
Suspend bortezomib
until neuropathy
disappears, then 0.7
mg/m2 and administer
weekly
Discontinue
bortezomib
Guidelines for Bortezomib-Induced Neuropathy

17. Case 1
• Therapy is held for 2.5 weeks and an attempt to harvest
stem cells with G-CSG (filgastrim) alone is unsuccessful
• The patient decides to proceed to myeloablative
therapy + autologous stem cell transplant (AuSCT)

18. What would you do next?
2. Attempt harvest after cyclophosphamide mobilization
therapy (+/- mobizil)
1. Tell the patient that harvest was unsuccessful and
continue chemotherapy

20. Case 1
• 3 months post- AuSCT the patient is started on
lenalidomide maintenance therapy 10 mg po daily
• Autologous stem cell harvest is successful after
cyclophosphamide chemomobilization and the patient
proceeds with high-dose melphalan + autologous stem
cell transplant (AuSCT)

21. 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

22. • 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.
Case

23. What would you do regarding the extraction?
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.
1. Have the tooth extracted immediately.

24. • The patient has the tooth extracted and after 3 months
zoledronic acid is restarted.
Case
• 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

25. What would you do regarding the creatinine?
2. Stop zoledronic acid and repeat UPEP in 1 month
3. Dose adjust lenalidomide
1. Change therapy the patient’s disease is progressing

26. Lenalidomide
Lenalidomide
Dose (mg)
Creatinine Clearance
(m/min)
10 mg/Day> 30 - 50
5 mg/D
after dialysis
On dialysis
15 mg q48
hours
< 30, NOT on dialysis
Celgene Product Information available at www. Revlimid.com/pdf/revlimid/pl.pdf

27. • 1 month later the total urine protein is 110 mg/d and
zoledronic acid is restarted with no further increase in
proteinuria
Case
• The creatinine improves to 1.3 mg/dL .
• On physical exam the patient has a 4-5 mm fullness on
the left pharyngeal arch.

28. •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
Case

29. You confirm relapse with a second what therapy
do you start?
2. Start lenalidomide 25 mg po x 21 d + dexamethasone
40 mg po weekly
3. Bortezomib 1.0 mg/m2 by subcutaneous injection
weekly
1. Restart lenalidomide 10 mg po daily
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

30. Secondary Primary Malignancies (SPMs):
Lenalidomide CALBG100104 vs. SEER
Author Type Secondary Cancer Incidence
SEER
(1973-2000)
McCarthy
NEJM 2012
Hematologic
n=231 len.
n= 229 plac.
8
1
3.5%
0.4%
6.1%
(95% CI: 5.8%-6.5%)
Based on 23,838
patients observed for
20 years
Solid
n=231 len.
n=229 plac.
10
5
4.3%
2.1%
Attal
NEJM 2012
Hematologic
n=306 len.
n=302 plac.
13
5
4%
2%
6.1%
(95% CI: 5.8%-6.5%)
Based on 23,838
patients observed for
20 years
Solid
n=306 len.
n=302 plac.
10
4
4%
1%
McCarthy PL, et al. NEJM, 2012
Attal M, et al. NEJM, 2012

31. • The patient begins carfilzomib, but on day 1 develops
dyspnea with mild chest pain.
Case
• 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.

32. Toxicity Grade 1 Grade 2 Grade 3 Grade 4
Neutropenia No Adjustment No Adjustment
Hold dose until <
gr. 1
Decrease 1 level
15 mg/m2 then
11 mg/m2
Thrombocytopenia No Adjustment No adjustment No Adjustment
Hold dose
Decrease 1 level
15 mg/m2 then
11 mg/m2
Carfilzomib Hematologic Toxicity Dose Reductions
Jagannath et al. Clinical Lymphoma, Myeloma &Leukemia. 12;310-18, 2012.
Guidelines for Carfilzomib-Induced Renal
Insufficiency
Toxicity Grade 1 Grade 2 > Grade 3
Renal Insufficiency No Adjustment 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

33. Adverse Event Thalidomide Lenalidomide Bortezomib
Pegylated
Liposomal
Doxorubicin/
Bortezomib
Bortezomib/
Melphalan/
Prednisone
Peripheral
neuropathy
   
Deep vein
thrombosis

More with dex

More with dex
Myelosuppression

Neutropenia

Neutropenia,
thrombocytopenia,
anemia

Thrombocytopenia

Neutropenia,
thrombocytopenia,
anemia

Neutropenia,
thrombocytopenia
Hypotension 
Fatigue, weakness     
Sedation 
Rash    
Viral reactivation of
herpes zoster
  
Gastrointestinal
disturbance

Constipation

Constipation, diarrhea

Nausea and vomiting,
diarrhea

Nausea and vomiting,
diarrhea, constipation,
mucositis/stomatitis

Nausea, diarrhea,
constipation, vomiting
Renal Watch for
hyperkalemia

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.

34. Considerations When Treating
Older Individuals
Drug No risk factors 1 or more risk factors
At least one risk factor +
grade 3/4 non-hem AE
Lenalidomide 25 mg/day
Days 1-21/4 weeks
15 mg/day
Days 1-21/4 weeks
10 mg/day
Days 1-21/4 weeks
Bortezomib
1.3 mg/m2 biweekly
Days 1,4,8,11/3 weeks
1.3 mg/m2 weekly
Days 1,8,15,22/5 weeks
1.0 mg/m2 weekly
Days 1,8,15,22/5 weeks
Dexamethasone
40 mg/day
Days 1,8,15,22/4 weeks
20 mg/day
Days 1,8,15,22/4 weeks
10 mg/day
Days 1,8,15,22/4 weeks
Melphalan 0.25 mg/kg
Days 1-4/4-6 weeks
0.18 mg/kg
Days 1-4/4-6 weeks
0.13 mg/kg
Days 1-4/4-6 weeks
Palumbo et al. Blood. 2011;118:4519-4529.
Risk Factors
•Age >75 years
•Mild, moderate, or severe frailty: Patient needs help for household and personal care
•Comorbidities: Cardiac, pulmonary, hepatic, renal dysfunction