Management of Multiple Myeloma: The Changing Paradigm

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1 Management of Multiple Myeloma: The Changing Paradigm Diane G. Cope PhD, ARNP, BC, AOCN Nurse Practitioner Florida Cancer Specialists Fort Myers, Florida Steve Charley Frances Ivan Jeanne Slide Not Available Slide Not Available 60 of 67 Counties of Florida directly affected by Hurricane Frances. Estimated % of Citrus Industry destroyed after two hurricanes in three weeks Slide Not Available 1

2 Now Florida faces another Chapter of 2004 Hurricane Season Charley, Frances, Ivan, Jeanne?? Multiple Myeloma Disease Overview Physiology/Pathophysiology Treatment Options Advances in Therapy Multiple Myeloma 2 nd most common cancer of the blood Estimated 15,270 new cases in ,090 for males 7,180 for females Estimated 11,070 deaths in ,430 for males 5,640 for females Peak age: years Incidence is greater in African Americans than in whites (2:1 ratio) Native Pacific Islanders Risk Factors: Multiple Myeloma Genetic factors Chronic exposure to low-dose ionizing radiation Occupational exposure (eg. Chemical) Chronic antigenic stimulation (eg. Recurrent infections and drug allergies) Durie, 2001; Sheridan & Serrano, 2000 ACS, 2004, MMRF, 2004 Multiple Myeloma Cancer of plasma cells predominate in the bone marrow Causes bone lesions Populate bone marrow lowering blood count Affects immune, renal, circulatory system Munshi, Tricot, & Barlogie, 2001 Immunoglobulins Five major classes: IgG IgM IgA IgE IgD Two heavy chains Two light chains 2

3 Immunoglobulins: Function Multiple Myeloma Immunoglobulin IgG IgA IgM IgE IgD Based on information from: Devenney & Erickson, 2004 Function Coats micro-organisms Protects body orifices Degrades bacteria Hypersensitivity and allergic response B lymphocyte regulation and production Myeloma cells produce abnormal immunoglobulins IgG: 60-7 IgA: 2 IgD, IgE, IgM: Rare-2% Light chain myeloma Bence Jones protein: 14% M protein found primarily in urine Multiple Myeloma: Bone Marrow Adhesion molecules on surface that target bone marrow Secrete cytokines that increase osteoclast activity and suppress osteoblast activity Produce growth factors that promote angiogenesis (VEGF) Invade hard, outer bone (bone lesions) Suppression of normal immunoglobulins causes infection Anemia, neutropenia, abnormal platelet function Munshi, Tricot, & Barlogie, 2001; Sheridan & Serrano, 2000 Multiple Myeloma: Blood Elevated serum M protein causes increased plasma volume and viscosity Circulatory problems Central nervous system Kidneys Pulmonary function Bleeding Multiple Myeloma: Kidney M proteins, light chain casts, Bence Jones proteins collect in organs Impair kidney function Tubular degeneration Renal failure Multiple Myeloma: Hypercalcemia Bone destruction causes hypercalcemia Symptoms: Vomiting Constipation Changes in mental status Lethargy Contributes to renal failure 3

4 Initial Evaluation Initial Evaluation Bone pain in which lytic bone lesions are discovered 85% of patients develop bone disease Solitary or multiple osteolytic lesions 3 pathologic fractures; 10-15% SCC Bone disease results in bone marrow suppression: Anemia: fatigue, weakness, dyspnea Neutropenia: infections Thrombocytopenia: bleeding Hyperviscosity: Increased total serum protein concentration Vascular sludging, oral bleeding, epistaxis, blurred vision, parasthesias, CHF Hypercalcemia (present in 25% of patients at diagnosis) Nausea, fatigue, confusion, polyuria, constipation Renal insufficiency (20-25% of patients at diagnosis) Initial Evaluation History and Physical Blood and urine Complete blood count (CBC) Complete chemistry profile (BUN, calcium, creatinine) LDH profile Beta-2 microglobulin Quantitative immunoglobulin levels Urinary protein excretion in 24 hours Serum and urine protein electrophoresis with immunofixation Bone x-ray and marrow Complete skeletal radiographic survey (MRI and/or CAT as needed) Bone marrow aspiration and biopsy with cytogenetics and plasma cell labeling index Multiple Myeloma Durie-Salmon Staging System Slide Not Available Stage I Hgb > 10 g/dl Serum calcium normal or < 12 mg/dl Absence of anemia, renal failure, hypercalcemia, and lytic bone lesions IgG < 5 g/dl IgA < 3 g/dl Bence Jones protein < 4 g/24 hr Low myeloma cell mass (<0.6 cells x /m 2 ) Bone x-ray normal or solitary bone plasmacytoma Stage II MMRF, 2004 Neither Stage I or III Intermediate myeloma cell mass ( cells x /m 2 ) 4

5 Durie-Salmon Staging System Disease Manifestation Stage III Hgb < 8.5 g/dl Serum calcium > 12 mg/dl Advanced lytic bone lesions IgG > 7 g/dl IgA > 5 g/dl Bence Jones protein > 12 g/24 hr High myeloma cell mass (>1.2 cells x /m 2 ) MGUS Smoldering Myeloma Stage I Stage III Subclassifications: A: Cr < 2 mg/dl (normal) B: Cr > 2 mg/dl (abnormal) MMRF, 2004 Disease Manifestation: Asymptomatic Multiple Myeloma Monoclonal gammopathy of undetermined significance: MGUS Characteristics Precancerous, asymptomatic condition Plasma cells: < 1 Presence of serum/urine M protein (stable) No or limited bone involvement 3 develop plasma cell disease within 15yrs Management Observation, with treatment beginning at disease progression NCCN, 2004 Disease Manifestations Asymptomatic Multiple Myeloma Smoldering Myeloma Characteristics Bone marrow infiltration with plasma cells >1 but <2 Presence of serum/urine M protein IgG: g/l; IgA: g/l Bence Jones protein <1.0g/24h No anemia, renal failure, or hypercalcemia Absence of symptoms No bone involvement on skeletal survey NCCN, 2004 Management Observation, with treatment beginning at disease progression Disease Manifestations Asymptomatic Multiple Myeloma Disease Manifestation: Asymptomatic Multiple Myeloma Stage I Similar to Smoldering Myeloma Low tumor burden Low M protein No anemia, renal failure, or hypercalcemia Bone lesions NCCN, 2004 Management Observation, with treatment beginning at disease progression MGUS, Smoldering, Indolent, Stage I No survival advantage in treating smoldering or indolent myeloma Treatment of smoldering or indolent myeloma should only be done in a research setting MGUS patients are likely to die of other medical causes 5

6 Disease Manifestations Symptomatic Multiple Myeloma Plasmacytoma Stage II/III Disease Manifestations Symptomatic Multiple Myeloma Plasmacytoma Solitary lesion Immediate treatment RT Bisphosphonates NCCN, 2004 Disease Manifestation: Symptomatic Multiple Myeloma Standard Treatment Melphalan/Prednisone VCR/BCNU/Melphalan/cyclophosphamide/pred(VBMCP) Vincristine/doxorubicin/dexamethasone (VAD) Dexamethasone Thalidomide/dexamethasone Response Stem cell transplant Continue standard therapy until plateau Primary refractory disease Stem cell transplant Salvage chemotherapy NCCN, 2004 Treatment Advances: Thalidomide for Multiple Myeloma Thalidomide indication: Acute treatment for erythema nodosum leprosum Standard therapy: systemic chemotherapy Positive results in patients with relapsed/refractory disease Used in clinical practice off label Alexanian & Weber, 2000; Barlogie, Cool & Herrington, 2002; Zangari, et al., 2001 Thalidomide: Mechanisms of Action Thalidomide Activity Single-Agent Activity Refractory Multiple Myeloma Phase II Study in 84 Patients, mg/d M Protein Response Complete remission 9 decrease 75% decrease 5 decrease 25% decrease Patients, No. (%) 2 (2) 6 (7) 6 (7) 7 (8) 6 (7) Patients With Bone Marrow Response, No. (%)* 2 (100) 5 (83) 3 (60) 4 (100) 3 (75) bfgf = basic fibroblast growth factor; ICAM = intercellular adhesion molecule; IFN = interferon; IL = interleukin; MM = multiple myeloma; NK = natural killer; TNF = tumor necrosis factor; VEGF = vascular endothelial growth factor. Reprinted from Biomedicine & Pharmacotherapy, 2002;56: Richardson P, Hideshima T, Anderson K. Thalidomide in multiple myeloma. 2002, with permission from Editions scientifiques et medicales Elsevier. Total 27 (32) 17 (81) *Bone marrow response could not be evaluated in 6 patients with an M protein response (1 with 75%, 3 with 5, 2 with 25%) and in 30 patients with no M protein response. Adapted with permission from Singhal S, Mehta J, Desikan R, et al. Antitumor activity of thalidomide in refractory multiple myeloma. N Engl J Med. 1999;341: Massachusetts Medical Society. All rights reserved. 6

7 Thalidomide Activity Additional Studies in Relapsed/Refractory Myeloma Thalidomide Activity Lead Investigator Thalidomide Dose, mg/d Duration of Therapy No. of Evaluable Patients Response, No. (%) Combination Therapy for Relapsed/Refractory Myeloma 77 patients received thalidomide 100 mg/d and dexamethasone 40 mg, d 1-4 each mo Alexanian Until relapse (26)* M Protein Reduction No. of Patients (%) Rajkumar NR 16 PR: 4 (25) (18) 50-75% 18 (23) Hideshima Median 6 mos (range mos) 44 CR: 1 (2) PR: 11 (25) SD: 5 (11) *Clinical response was defined as >5 reduction in M protein and/or >75% reduction of Bence Jones protein. NR = not reported; PR = partial response; CR = complete response; SD = stable disease. Alexanian R, et al. Semin Hematol. 2000;37: Hideshima T, et al. Blood. 2000;96: Rajkumar SV, et al. Mayo Clin Proc. 2000;75: <25% (or disease progression) Palumbo A, et al. Haematologica. 2001;86: (25) 26 (34) Thalidomide Activity Combination Therapy for Refractory Myeloma 44 patients enrolled Thalidomide 200 mg/d; 400 mg after d 14 Dexamethasone 20 mg/m 2, d 1-4, 9-12, 17-20; monthly for 4 d thereafter PR in 24 (55%) patients 75% reduction of serum M protein: 13 (3) patients MTR of 1.3 mos (range, mos) PR = partial response; MTR = median time to response. Dimopoulos MA, et al. Ann Oncol.2001;12: Thalidomide Activity Previously Untreated Myeloma - Combination Therapy Treatment plan Thalidomide 200 mg/d* Dexamethasone 40 mg/d repeated monthly! Odd cycles (d 1-4, 9-12, 17-20)! Even cycles (d 1-4) 32 responses (64%) confirmed 3 patient deaths (pancreatitis, pulmonary embolism, infection) *The first 7 patients were dose escalated, but dose escalation was discontinued due to grade 3/4 skin toxicity in the remaining patients. Rajkumar SV, et al. J Clin Oncol. 2002;21: Thalidomide Activity Single-Agent Thalidomide 28 patients Response rate: 36% CR: 0 MTTR: 4.2 mos Previously Untreated Myeloma Combination Thalidomide/Dexamethasone 40 patients Response rate: 72% CR: 5 patients (16%) MTTR: 0.7 mos Thalidomide Activity Smoldering or Indolent Multiple Myeloma 16 patients given thalidomide mg/d Responses 5 reduction in M protein: 6/16 (38%) 25 reduction in M protein: 11/16 (69%) Median response duration not yet reached CR = complete response; MTTR = median time to remission for responding patients. Weber D, et al. J Clin Oncol. 2003;21: Rajkumar SV, et al. Leukemia. 2001;15:

8 Summary of Thalidomide Activity Thalidomide has activity and is currently under further investigation in multiple myeloma In relapsed/refractory patients In newly diagnosed/previously untreated patients As a single agent In combination with dexamethasone or multiagent chemotherapy Alexanian R. et al. Semin Hematol. 2000;37: Barlogie B, et al. Blood. 2001;98: Barlogie B, et al. Proc Am Soc Clin Oncol. 2002; 21:269a. Abstract Barlogie B, et al. Blood. 2002;100:210a. Abstract 789. Dimopoulos MA, et al. Ann Oncol. 2001;12: Abstract Hideshima T, et al. Blood. 2000;96: Palumbo A, et al. Haematologica. 2001;86: Rajkumar SV, et al. Mayo Clin Proc. 2000;75: Rajkumar SV, et al. Leukemia. 2001;15: Rajkumar SV, et al. J Clin Oncol. 2002;21: Singhal S, et al. N Engl J Med. 1999;341: Weber D, et al. J Clin Oncol. 2003;21: Zangari M, et al. Blood. 2001;98: Toxicity Thalidomide Toxicities GradeI/II Peripheral 85% neuropathy Sedation 75% Constipation 80-9 Skin rash 45% Weakness 6 Grade III/IV 3-5% 5-1 5% 3-5% Generally well-tolerated Dose reduce or hold therapy Ghobrial & Rajkumar, 2003 Nursing Management: Thalidomide Toxicities Peripheral neuropathy: hands and feet Discontinue therapy Sedation: fatigue, confusion, memory loss Bedtime dosing Avoid concomitant sedative medications Constipation Preventative bowel regimen Skin rash: pruritic, erythematous, macular eruptions Symptomatic treatment Weakness Monitor blood pressure, hydration Concomitant use of diuretics, antihypertensives, cardiovascular medications Nursing Interventions and Patient Management Education Discussion of potential side effects critical Written information important How to recognize effects How to manage effects Contact person for questions Doss D, Gholz R, Goldman D, et al. Nursing roundtable. April 17, Patient Management Older Patient Needs Appropriate dosing 50 mg/d initially Increase by 50 mg to mg/d target To reduce somnolence, split dose and/or add methylphenidate Cardiovascular risk may be higher Summary of Patient Management Nurses play key management role for patients on thalidomide Educate patients about thalidomide Facilitate adherence to S.T.E.P.S program Manage side effects Manage needs of older patients Doss D, Gholz R, Goldman D, et al. Nursing roundtable. April 17, S.T.E.P.S = System for Thalidomide Education and Prescribing Safety. Doss D, Gholz R, Goldman D, et al. Nursing roundtable. April 17,

9 Patient Management: DVT Side Effect Management DVT higher with thalidomide in patients receiving combination chemotherapy 14 of 50 patients (28%) receiving thalidomide/chemotherapy 2 of 50 patients (4%) receiving chemotherapy alone LMWH anticoagulation therapy Results: no significant DVT difference at 12 mos 13% of patients on thalidomide/lmwh! Versus 35% or patients on thalidomide but not LMWH (historical controls) 19% of patients not on thalidomide (historical controls) DVT = deep vein thrombosis; TT II = total therapy II; LMWH = low-molecular-weight heparin. Zangari M, et al. Blood. 2001;98: Zangari M, et al. Blood. 2002;100:398a. Abstract Patient Management Control of vascular complication Prophylactic anticoagulants! Enoxaparin sodium! Low-molecular-weight heparin! Warfarin! Baby aspirin Doss D, Gholz R, Goldman D, et al. Nursing roundtable. April 17, Treatment: Symptomatic Multiple Myeloma Standard Treatment Melphalan/Prednisone VCR/BCNU/Melphalan/cyclophosphamide/pred(VBMCP) Vincristine/doxorubicin/dexamethasone (VAD) Dexamethasone Thalidomide/dexamethasone Response Stem cell transplant Continue standard therapy until plateau Primary refractory disease Stem cell transplant Salvage chemotherapy NCCN, 2004 Stem Cell Transplant Higher CR rates Superior survival Compared to standard dose Rx Widely applicable Older patients Renal failure Not curative Types of Transplants Single vs Double Autografts Autologous Allogeneic Tandem autologous Autologous followed by mini-allogeneic French Intergroup study 399 previously untreated patients < 60 years PR: 42% (single); 5 (double) EFS: 1 (single); 2 (double) OS: 21% (single); 42% (double) Attal et al., studies: HOVON, Bologna 96, MAG: no statististical difference 9

10 Treatment: Multiple Myeloma Symptomatic Multiple Myeloma Standard Treatment Melphalan/Prednisone VCR/BCNU/Melphalan/cyclophosphamide/pred(VBMCP) Vincristine/doxorubicin/dexamethasone (VAD) Dexamethasone Thalidomide/dexamethasone Response Stem cell transplant Continue standard therapy until plateau Primary refractory disease Stem cell transplant Salvage chemotherapy Salvage chemotherapy Repeat primary conventional therapy (if relapse > 6mo) Cyclophosphamide-VAD Etoposide/dexa/cytarabine, cisplatin (EDAP) High-dose cyclophosphamide Thalidomide Bortezomib NCCN, 2004 Mechanism of Action of Bortezomib1 Velcade (bortezomib) 1 Indicated for treatment of MM patients that have received at least two prior therapies and have progressive disease on last therapy Proteasome inhibitor The 26S proteasome is a large protein complex that degrades tagged proteins 2 Bortezomib is a reversible inhibitor of the chymotrypsin-like activity of the 26S proteasome 3 4 Outline: Velcade Phase II Clinical Trials SUMMIT (025) Phase II Clinical Trials CREST (024) Phase III Clinical Trial APEX (039) Nonclinical studies showed bortezomib to be cytotoxic to a variety of cancer cell types Inhibition of the 26S proteasome prevents proteolysis of tagged proteins which can affect multiple signaling cascades with the cell 1. Millennium Pharmaceuticals, Inc., SUMMIT: Treatment Plan1 Bortezomib 1.3 mg/m2 IV push over 3-5 seconds 21-day cycle Administered on days 1, 4, 8, and 11 with a 10-day rest period (days 12-21) 72 hours between doses 8-cycle study period For CR patients, 2 cycles beyond confirmed CR Extension protocol available for patients experiencing benefit 1. Millennium Pharmaceuticals, Inc.,

11 25% 2 15% 1 5% SUMMIT: Response Rates with Bortezomib (N=193)* 4% 6% 35% 18% 7% 24% 35% overall response (CR+PR+MR) 27% CR+PR 24% stable disease (SD) 59% of patients SD or better CR Near CR PR MR SD *Of 202 patients, 193 were evaluable for response and duration of response Near CR met all the criteria for a CR, with the exception of detectable M protein by immunofixation Numbers rounded to nearest integer. Richardson et al. N Engl J Med. 2003;348: SUMMIT: Most Common Adverse Events 1 N=202 Nausea Diarrhea Fatigue Thrombocytopenia Constipation Vomiting Anorexia Peripheral Neuropathy Pyrexia Anemia Edema Grades 1-2* 58% 41% 37% 13% 41% 27% 32% 22% 3 23% 25% Grade 3* 6% 7% 12% 28% 2% 8% 2% 12% 4% 8% 1% Grade 4* 1% 3% 1% *National Cancer Institute Common Toxicity Criteria (NCI CTC, Version 2.0) 1. Millennium Pharmaceuticals, Inc., SUMMIT: Conclusions CREST: Study Summary 1 Bortezomib demonstrated encouraging activity in a heavily pretreated multiple myeloma patient population who had received at least 2 prior therapies and had progressed on their most recent therapy Overall response rates New England Journal of Medicine, 193 patients evaluable 1! 1 CR and near CR! 35% CR+PR+MR! 59% Stable disease or better Updated median duration of response: 12.7 months (8.2, NE) 2 Updated median overall survival: 17.0 months (434, 643 d) Manageable toxicities NE = not estimable 1. Richardson et al. N Engl J Med. 2003;348: Berenson et al. EHA 2004 Open-label, multicenter, randomized phase II dose-response study in 54 patients Bortezomib 1.0 mg/m 2 or 1.3 mg/m 2 /dose A median of 3 prior therapies 48% received prior stem cell transplants Bortezomib administered as an IV push over 3-5 seconds 21-day cycle Administered on days 1, 4, 8, and 11 for up to 8 cycles 72 hours between doses Extension protocol available for patients experiencing benefit 1. Jagannath et al., ASH 2002 CREST: Summary of Response, Duration, and Survival Responses, CR + PR 1.0 dose, 3 (1 CR) 1.3 dose, 38% (1 CR) Median duration of response for both groups has not yet been reached Overall survival 1.0 dose, 17 months 1.3 dose, not yet reached CREST Study: Conclusions 1 Responses observed with 1.0 mg/m 2 and 1.3 mg/m 2 doses CR observed at both 1.3 and 1.0 mg/m 2 Overall response (CR + PR) of 38% with 1.3 mg/m 2 and 3 with 1.0 mg/m 2 Manageable toxicities 1. Jagannath et al. ASH Berenson et al. March Millennium Pharmaceuticals, Inc.,

12 Velcade: Dosing Guidelines 1.3mg/m 2 as a 3-5 second IVP Dose twice weekly for two weeks (Days 1,4,8 and 11) Followed by 10 day rest period (Days12-21) 72 hour rest period between doses Bortezomib: Side Effects Peripheral Neuropathy: Treatment with bortezomib may be associated with a peripheral neuropathy that is predominately sensory, although rare cases of mixed sensorimotor neuropathy have been reported. Patients with pre-existing symptoms and/or signs of peripheral neuropathy may experience worsening during treatment with bortezomib. Patients should be monitored for symptoms of neuropathy, such as numbness, a burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, or neuropathic pain. Hypotension: Treatment with bortezomib may be associated with orthostatic/postural hypotension throughout therapy. Caution should be used when treating patients with a history of syncope, patients receiving medications known to be associated with hypotension, and patients who are dehydrated. Gastrointestinal Adverse Events: Nausea, diarrhea, constipation, and vomiting may occur during treatment with bortezomib. Bortezomib: Side Effects Thrombocytopenia: Complete blood counts including platelet counts should be frequently monitored throughout treatment with bortezomib. Thrombocytopenia was maximal at Day 11 and usually recovered by the next cycle. Onset is most common in Cycles 1 and 2 but can continue throughout therapy. There have been reports of gastrointestinal and intracerebal hemorrhage in association with thrombocytopenia induced by bortezomib. Patients with Hepatic or Renal Impairment: Patients with renal and hepatic impairment should be closely monitored for toxicities. Bortezomib: Asthenic Conditions 1 Incidence of Asthenic Conditions (fatigue, malaise, weakness) Overall incidence 65% Grade 3* 18% Grade 4* <1% Discontinued due to fatigue 2% First onset of fatigue most often reported during 1st and 2nd cycles of therapy Most patients in clinical trials were able to continue therapy despite fatigue *NCI CTC, Version 2.0 Peripheral Neuropathy with Bortezomib: Phase II Studies Incidence of Treatment Emergent Peripheral Neuropathy Overall 37% Grade 3* 14% Grade 4* Discontinuation due to events 6% Bortezomib: Management Peripheral Neuropathy Recommendations Monitor patients for symptoms of neuropathy and/or pain at each treatment visit Patients should contact their physician if they experience new or worsening symptoms of peripheral neuropathy Early detection and appropriate dose/schedule modification may result in the resolution or improvement of neuropathy Peripheral neuropathy is predominantly sensory, although cases of mixed sensorimotor neuropathy have been reported Symptoms include: numbness, burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort or neuropathic pain *NCI CTC, Version mg/m 2 dose population 12

13 Recommended Dose Modifications for the Management of PN Bortezomib: Hypotension Severity of Peripheral Neuropathy Signs/Symptoms Grade 1 (paresthesia and/or loss of reflexes without pain or loss of function) Grade 1 with pain or Grade 2 (interfering with function but not with activities of daily living) Grade 2 with pain or Grade 3 (interfering with activities of daily living) No action Modification of Dose and Regimen Reduce bortezomib to 1.0 mg/m 2 Withhold bortezomib therapy until toxicity resolves. When toxicity resolves reinitiate with a reduced dose of bortezomib at 0.7 mg/m 2 and change treatment schedule to once per week. Characteristic 12% of patients experience hypotension Orthostatic/postural hypotension, usually mild to moderate (Grade 1 or 2 in severity) may occur throughout therapy Precautions Caution should be used when treating patients with a history of syncope, who are receiving medications known to be associated with hypotension, or who are dehydrated Grade 4 (permanent sensory loss that interferes with function) Discontinue bortezomib 1. Millennium Pharmaceuticals, Inc., 2004 Bortezomib: Management Hypotension Recommendations for patients Seek medical advice if they experience symptoms of dizziness, light-headedness, or fainting spells Maintain hydration Exercise caution when operating machinery including automobiles Management may include Adjustment of antihypertensive medications Rehydration Administration of mineralocorticoids Bortezomib: Gastrointestinal Toxicities N=228 Nausea Diarrhea Appetite decreased & anorexia Constipation Vomiting Grades 1-2* Grade 3* Grade 4* 58% 6% 43% 7% <1% 41% 3% 4 2% 29% 7% <1% Patients should be advised regarding appropriate measures to avoid dehydration Administer fluids and electrolytes if patient becomes dehydrated Patients should be instructed to seek medical advice if they experience symptoms of dizziness, light-headedness, or fainting spells Administration of antiemetics and antidiarrheals as needed *NCI CTC, Version 2.0 Bortezomib: Thrombocytopenia 1 Incidence of thrombocytopenia Overall incidence 43% Grade 3* (10-50 x 10 9 /L) 27% Grade 4* (<10 x 10 9 /L) 3% Discontinuation 4% Bortezomib: Managing Thrombocytopenia 1 Characteristics Dose related decrease in platelet count during treatment period (days 1-11) with return to baseline during the rest period (days 12-21) Nadir ~4 of baseline Gastrointestinal and intracerebral hemorrhages have been reported Recommendations Frequently monitor platelet count throughout treatment Observe patients for signs of thrombocytopenia, such as bleeding or bruising Mechanisms of platelet reduction are probably unique Treatment may need to be held with serious Grade 4 thrombocytopenia Treatment may be reinitiated at a reduced dose after resolution of toxicities *NCI CTC, Version

14 Bortezomib: Other Hematologic Toxicities 1 Hematologic toxicities Anemia Neutropenia Overall incidence 32% 24% Grade 3* 9% 13% Grade 4* 0 3% Discontinuation <1% <1% Although pyrexia occurred in 36% of patients, the incidence of febrile neutropenia was <1% Frequently monitor complete blood count (CBC) throughout treatment Management may include the use of growth factors or red blood cell transfusions at physician s discretion *NCI CTC, Version 2.0 APEX: Treatment Plan Eligibility: Progression after 1-3 previous treatments Bortezomib 1.3mg/m2 IV Days 1,4,8,11 every 3 weeks for 8 cycles Maintenance Bortezomib 1.3mg/m2 IV/week for 4 of 5 weeks for 3 cycles Dexamethasone 40 mg for 4 days on days 1,9, 17 every 5 weeks for 3 cycles Maintenance Dexamethasone 40 mg for 4 days on day 1 every 4 weeks for 5 cycles Interim Results Bortezomib (n=327) Dexamethasone (n= 330) Median Time to 5.7 months 3.6 months Progression Richardson, 2004 Treatment Advances Thalidomide derivatives CC-5013 (Revlimid) CC-4047 (Actimid) Drug combinations Thalidomide/Dex vs Dex Thalidomide/Melphalan/Prednisone Bortezomib +/- Dex: First line Bortezomib/Melphalan/Thalidomide Bortezomib/Doxirubicin Bortezomib/Doxil Doxil/Vincristine/Decadron (DVd) Arsenic Trioxide Supportive Treatments Radiation therapy Pain management Erythropoietin/Darbepoetin therapy Colony Stimulating Factors IV Gammaglobulin Antifungal therapy Prophylactic antibiotics: controversial Bisphosphonates Hypercalcemia: hydration Renal insufficiency: hydration Nursing Interventions Case Study Knowledge of disease process Patient education Knowledge of older patient needs: comorbidities, polypharmacy, financial, social support Monitoring side effects Monitoring complications Patient/family support Mr. S: 72 yr old male, retired lawyer, downhill skier athlete/metal winner Diagnosed 1997, no bone involvement Treatment: Melphalan/Prednisone; Thalidomide for 8 months Velcade for 18 months Revlimid for 3 months 14

15 Conclusion Questions? Comments? 15