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Case 1
• 57 yr old male
• Rib pain – X-ray revealed lytic lesion, biopsy: plasma cells
• Bone marrow 33% +CD38, +CD138, -CD56, λ -, κ + PCT. Protein 7.5 g/dL, Albumin 3.0 g/dL, M-protein 3.2 g/dL: IgG κ, Bence Jones Protein 10 mg/dayFree λ 6.39 mg/L Free κ 24.27 mg/L Free κ: λ 3.798β2M 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
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?
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
Thalidomide & Lenalidomide ThromboprophylaxisIndividual Risk Factors
ObesityPrevious VTECentral Venous Catheter, PacemakerAssociated Disease Cardiac
Chronic Renal DiseaseDiabetesAcute InfectionImmobilization
Surgery Gen. SurgeryAny AnesthesiaTrauma
Medications ESA'sBlood Clotting Disorders
Palumbo et al, Leukemia 2008, 22: 414-423
Myeloma-Related Risk FactorsDiagnosisHyperviscosity
Myeloma TherapyHigh-Dose DexamethasoneDoxorubicinMulti-Agent Chemotherapy
Actions0 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)
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
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
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
Type of PN Grade 1 Grade 2 Grade 3 Grade 4
SensoryAsymptomatic; 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
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
Route of Bortezomib
Administration
Overall Response
RateComplete Response
Median Time to
Response(months)
Median Time to
Progression (months)
Peripheral NeuropathyAll 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 mL0.9% sodium chloride
2 ways to reconstitute a3.5-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
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?
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
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 qDAfter counts > 30,000
2nd Time Hold +
Decrease to 10 mg qDAfter counts > 30,000
3rd Time Hold +
Decrease to 5 mg qDAfter counts > 30,000
4thTime
discontinue
Neutropenia< 1,000 cells/μL
1st TimeHold + G-CSF Resume @ 25 mg qD After > 1,000 cells/ μL
2nd TimeHold + G-CSF Resume @ 15 mg qD After > 1,000 cells/ μL
3rd TimeHold + G-CSF Resume @ 10 mg
qD After > 1,000 cells/ μL
4th TimeHold +
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)
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
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
Type of PN Grade 1 Grade 2 Grade 3 Grade 4
SensoryAsymptomatic; 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
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)
What would you do next?
2. Attempt harvest after cyclophosphamide mobilization therapy (+/- mobizil)
1. Tell the patient that harvest was unsuccessful and continue chemotherapy
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)
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
• 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
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.
• 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
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
Lenalidomide
Lenalidomide Dose (mg)
Creatinine Clearance (m/min)
10 mg/Day> 30 - 50
5 mg/D after dialysisOn dialysis
15 mg q48 hours
< 30, NOT on dialysis
Celgene Product Information available at www. Revlimid.com/pdf/revlimid/pl.pdf
• 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.
• PATHOLOGY REPORT WIDE LOCAL EXCISION LESION LEFT SOFT PALATE:
POLYMORPHOUS ADENOCARCINOMA. Tumor size = 1.7 cmPerineural invasion: PRESENT, MULTIFOCALPeripheral 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
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
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.
81
3.5%0.4% 6.1%
(95% CI: 5.8%-6.5%)Based on 23,838
patients observed for 20 yearsSolid
n=231 len.n=229 plac.
105
4.3%2.1%
Attal NEJM 2012
Hematologic n=306 len.n=302 plac.
135
4%2%
6.1%(95% CI: 5.8%-6.5%)
Based on 23,838 patients observed for
20 yearsSolidn=306 len.n=302 plac.
104
4%1%
McCarthy PL, et al. NEJM, 2012Attal M, et al. NEJM, 2012
• 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.
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 doseDecrease 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/minDecrease 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
Adverse Event Thalidomide Lenalidomide BortezomibPegylated 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.
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/dayDays 1-21/4 weeks
10 mg/dayDays 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/dayDays 1,8,15,22/4 weeks
20 mg/dayDays 1,8,15,22/4 weeks
10 mg/dayDays 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