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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.