Slides supportive final-1

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Slides supportive final-1

  1. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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
  19. 19. 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)
  20. 20. 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
  21. 21. • 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
  22. 22. 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.
  23. 23. • 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
  24. 24. 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
  25. 25. 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
  26. 26. • 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.
  27. 27. •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
  28. 28. 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
  29. 29. 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
  30. 30. • 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.
  31. 31. 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
  32. 32. 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.
  33. 33. 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

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