Slides supportive final-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 + 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



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.



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?


3. Reduce lenalidomide to 15 mg po daily x 14 days

4. Stop bortezomib


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 +


3rd Time Hold +


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


5. Stop bortezomib


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



Motor

Asymptomatic; clinical or diagnostic

observations only; intervention not

indicated

Moderate symptoms;Limiting instrumental

ADL

Severe symptoms; limiting self care ADL; assistive

device 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.



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



Melphalan

0.25 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

Slides supportive final-1

Sports

Transcript of Slides supportive final-1