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Consensus on Care: New Insights on
Novel Therapies in Multiple Myeloma
Accredited by Medical Education Resources
Supported...
Welcome and Opening Remarks
Beth Faiman: RN, MSN, APRN, BC, AOCN
Cleveland Clinic Taussig Cancer Institute
Cleveland, Ohio
ONS Disclaimer
Meeting space has been assigned to provide a
satellite symposium funded by Celgene Corporation
and Millenni...
Symposium Accreditation
This continuing education activity provides
2.0 contact hours
Medical Education Resources is an ap...
Additional Accreditation
Additional CEU accreditation opportunity –
Clinical Journal of Oncology Nursing (CJON) June
2008 ...
Faculty
Chair:
Beth Faiman: RN, MSN, APRN,
BC, AOCN
Cleveland Clinic Taussig
Cancer Institute
Cleveland, Ohio
Faculty:
Lis...
Agenda
Time Topics Presenter
6:00 – 6:15 Welcome and Introductions Beth Faiman
6:15 – 6:35 IMF Nurse Leadership Board: Tow...
Learning Objectives
• Gain insights on novel therapies in multiple myeloma
- Describe new clinical trial data
- Discuss cr...
Multiple Myeloma Causes,
Symptoms and Treatment
Multiple Myeloma: A Current Perspective
• Etiology of multiple myeloma (MM)
• Epidemiology of multiple myeloma
• Current a...
San Miguel JF, et al. Pathogenesis of Multiple Myeloma: Rationale for New and Novel Therapies. Clinical Care Options:
http...
Myeloma Cells are distinguished from normal
plasma cells by the presence of large nuclei
that are often eccentric
Vescio R...
Multiple Myeloma: Abnormal
Proliferation of Malignant Plasma Cells
Kyle RA and Rajkumar SV. N Engl J Med 2004;351:1860-73
Multiple Myeloma: Epidemiology
• Second most common hematological
malignancy
• Incidence and rates
– 1% of all cancers
– U...
Clinical Manifestations of
Multiple Myeloma
• Overproliferation of plasma cells can cause
– Risk of infection
– Osteolytic...
Major Symptoms at Diagnosis
• Bone pain 58%
• Fatigue 32%
• Weight loss 24%
• Paresthesias 5%
• Asymptomatic 11%
Kyle RA. ...
Common Sites for Bone Involvement
Skull
Spine
• Thoracic
• Lumbar
• Vertebrae
Pelvis
Long bones
Spinal cord
-compression c...
Criteria for Diagnosis of
Multiple Myeloma
Monoclonal plasma cells present in the bone
marrow ≥10%, and/or presence of a d...
Diagnostic Evaluation of
Multiple Myeloma
Test Finding (s) With Myeloma
CBC with differential counts ↓ Hgb, ↓ WBC, ↓ plate...
Durie-Salmon Staging System
for Multiple Myeloma
Durie B, Salmon S. Cancer. 1975;36(9):842-854
Subclassification Criteria
...
β2M=serum β2 microglobulin in mg/dL; ALB=serum albumin in g/dL
International Staging System for
Symptomatic Multiple Myelo...
Challenges in MM Management
• Currently incurable in most patients
• Long-term complete responses are rare
• Median surviv...
MM Treatment Options
Conventional chemotherapy:
• Melphalan
• Doxorubicin
• Cyclophosphamide
Radiation therapy
Stem cell t...
Novel Therapies:
Mechanisms of Action (MOA)
• Thalidomide (THALOMID®
)
– Immunomodulatory, anti-inflammatory, and anti-ang...
IMF Nurse Leadership Board (NLB):
Towards a New Consensus on Managing
the Myeloma Patient
Lisa C. Smith: MSN, FNP, AOCN
Ca...
Novel and Emerging Therapies for
Multiple Myeloma
Benefits and Challenges
Recent FDA Approvals of Novel Agents
VELCADE® 2003 2005
REVLIMID® ___ 2006
THALOMID®
with
dexamethasone
2006 ___
DOXIL®
wi...
Key Benefits of Novel and
Emerging Therapies
IMF-NLB ‘Consensus Statements’ supplement In Press, CJON June 2008;
Rajkumar ...
Key Challenges of Novel and
Emerging Therapies
IMF-NLB ‘Consensus Statements’ supplement In Press, CJON June 2008
• Emerge...
Novel Therapies
Bortezomib (VELCADE®
)
VELCADE®
for injection is indicated for the treatment
of patients with multiple mye...
Updated Side Effects Profile
VELCADE®
Most Commonly Reported Grades 3 & 4
Side Effects > 10%
Percentage
of
Patients
Asthen...
Novel Therapies
Lenalidomide (REVLIMID®
)
REVLIMID®
in combination with dexamethasone
is indicated for use in patients wit...
Updated Side Effects Profile
REVLIMID®
+
dexamethasone
Most Commonly
Reported Side Effects >
20% for all Grades
Percentage...
Novel Therapies
Thalidomide (THALOMID®
)
THALOMID®
in combination with dexamethasone
is indicated for the treatment of pat...
Updated Side Effects Profile
THALOMID®
+
dexamethasone
Most Commonly Reported
Effects > 20% for all grades
Percentage
of
P...
Emerging Therapies
• Low dose dexamethasone with lenalidomide
(REVLIMID®
)
• Pegylated liposomal doxorubicin (DOXIL®
)
wit...
Toxicity (Grade >3)
Arm A
(N=223)
Arm B
(N=222)
Neutropenia 2.7% 3.2%
Thrombocytopenia 1.8% 1.4%
DVT/PE 18.4% 6.3%
Atrial ...
Updated Side Effects Profile
DOXIL®
with
VELCADE®
Most Commonly Reported
Side Effects > 10% for all grades
Percentage
of
P...
Consequences of Inadequately
Managed Side Effects
Therapy associated side
effects lead to a reduction
in patient’s desire ...
IMF Nurse Leadership Board
Nurses from leading MM institutions formed a
Nurse Leadership Board (NLB) in collaboration with
and under sponsorship of t...
Nurse Centric Model of Patient Care*
Nurses are Central to
Patient Management and
Healthcare Resource
Coordination
Patient...
• Nurses play an essential role in managing
patient care
• Nurses are key in efficiently and optimally
managing emergent s...
A Collaborative Assessment was Performed of
Evidence-based and Practice-based Knowledge
and the Nursing Experience of Key ...
Moving Toward Consensus
NLB Determined the Five Most Common
Emergent Side Effects Requiring Clinical
‘Consensus Statement’...
20 Nurse Leaders 5 Teams
Teresa Miceli
Maria Gavino
Kathleen Colson
Kathy Lilleby
Myelosuppression
Sandra Rome
Jeanne West...
‘Consensus Statements’: Review Process
NLB Received One Document With Comment Sheet Per Week 5
Consensus Documents Sent Ov...
‘Consensus Statements’: Team Effort
120 Teleconference Calls
1,300 E-mails exchanged
1,600 work hours
5 Consensus Statemen...
Completion of ‘Consensus Statements’
Five consensus statements on the management of side
effects associated with the novel...
NLB ‘Consensus Statements’
Development and Publication Strategy
NLB
Myelosuppression
DVT/PE
Peripheral neuropathy
GI
Stero...
• The NLB’s ‘Consensus Statements’
development approach is a powerful
model helping to improve patient
management, care an...
•The NLB ‘consensus statements’ will be
periodically reviewed and expanded upon
•The NLB ‘consensus statements’ will be
ad...
Current Nurse Leadership Board Members
Name Affiliation / Address
Deborah Doss, RN, OCN Dana-Farber Cancer Institute
Sandr...
Leadership in Action: Clinical Utility of
the NLB Consensus Statements
Kena C. Miller: RN, MSN, FNP
Roswell Park Cancer In...
Overview of The ‘Consensus Statements’
Issue Statement
•An articulation of the issue or need and its impact on patients,
t...
Myelosuppression:
Definition and Symptoms
http://www.schneiderchildrenshospital.org/peds_html_fixed/peds/transplant/bonetr...
Risk of Grade 3 and 4 Myelosuppression
With Novel Therapies
Anemia Neutropenia Thrombocytopenia
THALOMID®
/
dexamethasone
...
Management of Neutropenia:
REVLIMID®
When ANC Recommended Course
Fall to <1000/mm3
Return to >1000/mm3
and
neutropenia is ...
Management of Thrombocytopenia:
REVLIMID®
When Platelets Recommended Course
Fall to <30,000/mm3
Return to >30,000/mm3
Inte...
Management of Myelosuppression:
VELCADE®
• At the onset of any Grade 4 hematologic
toxicity hold VELCADE®
• Once toxicity ...
Myelosuppression ‘Consensus Statement’
Recommendations For All Novel Therapies
General recommendations
• Monitor signs and...
Overview of Thromboembolic Events (TE)
‘Consensus Statement’
Cancer patients have a higher risk of TE events (blood clots)...
DVT - Signs/Symptoms
• Slight Fever
• Tachycardia
• Unilateral swelling, erythemia warm extremity
• Cyanosis/cool skin if ...
PE - Signs/Symptoms
• Anxiety
• Sudden dyspnea
• Chest discomfort-increase w/ breathing
• Tachycardia, tachypnea
• Low gra...
TE Event - Diagnostics
DVT
• Doppler Ultrasound
• Contrast Venography
• D-Dimer
• Antithrombin Level
PE
• Ventilation Perf...
TE Event - Prophylaxis
Mechanical
• Sequential Compression Devices
• Anti-embolism Stockings
• Exercise Regimen
Pharmaceut...
Thromboembolic Events - Prophylaxis
Pharmaceutical
Agent
Salicylic Acid (aspirin)
Unfractionated Heparin
Low Molecular Wei...
General Strategic Recommendations for
the Management of TE Events
Prophylactic measures which can reduce or
eliminate TE r...
Overview of Peripheral Neuropathy (PN)
‘Consensus Statement’
Adapted from NLB Consensus Recommendations. In Press, CJON Ju...
PN Definition, Signs/Symptoms
Signs/symptoms
• Temporary Numbness
• Tingling
• Parasthesias
• Sensitivity to Touch
• Muscl...
PN and Pain Toxicity Grades
Grade 1
Mild
Grade 2 Moderate Grade 3
Severe
Grade 4
Life-threatening
or disabling
Grade 5
Dea...
PN – Dose/Schedule Modifications
VELCADE®
Therapy
• Grade 1 with pain or Grade 2: Reduce dose to
1 mg/m2
• Grade 3 or Seve...
PN – Dose/Schedule Modifications
(cont’d)
THALOMID®
Therapy
Grade 1 or Mild:
• Continue therapy
Grade 2 or Moderate:
• Int...
General Strategic Recommendations for
the Management of PN
Adapted from NLB Consensus Recommendations. In Press, CJON June...
General Strategic Recommendations for
the Management of PN (cont’d)
For all patients prior to therapy
• B-complex vitamins...
Overview of Gastrointestinal (GI) Side
Effects ‘Consensus Statement’
Novel therapeutics can cause serious GI side
effects ...
GI Conditions Are Common
Side Effects of Novel Therapies
Drug
Incidence of Gastrointestinal Adverse Events Reported
For Al...
Management of Diarrhea
Non pharmacologic
• Increase fluid intake
• Avoid caffeinated, carbonated or heavy sugared drinks
•...
Management of Nausea and Vomiting
Non-pharmacologic
• Dietary intolerance and restrictions
• Avoid exercise and do not lie...
Overview of Steroid Side Effects
‘Consensus Statement’
Steroid Classes:
• Glucocorticosteroids
• Corticosteroids
Steroids ...
Steroid Side Effects Associated with
Multiple Myeloma Therapy
Use of steroids can cause multiple system side
effects, such...
Management of Constitutional Symptoms
• Mood Alterations
- Dose reduction or discontinuation of steroids
- SSRI’s or mood ...
Management of Heme/Immune System
Leukocytosis
• Increase in the number of white blood cells in the
circulating blood
Incre...
Management of Musculoskeletal System:
Muscular
Proximal Myopathy
• Physical therapy
• If severe, hold steroids until impro...
Management of Musculoskeletal System:
Bone
Osteonecrosis
• Evaluation with x-rays (panoramic) or MRI
• Prompt orthopedic r...
Management of Gastrointestinal Effects
Flatulence
- Evaluate medications
- Take Steroids with food in the morning
- Restri...
Management of Endocrine Effects:
Hyperglycemia
Non-pharmacological recommendations (mild blood glucose
elevation, no prior...
Management of Cardiovascular Effects:
Edema
Non-pharmacological recommendations
- Salt restriction
- Elevation of limb
- E...
Overall Recommendations for the
5 Emergent Side Effects of Novel Therapy
Effective management includes:
• Monitoring patie...
New Insights on Novel Therapies in
Multiple Myeloma
Joseph D. Tariman: RN, MN, ARNP-BC, OCN
University of Washington
Seatt...
New Clinical Trial Protocols and Data
(from ASH & ASCO 2007)
– Focus on Phase III trials of patients with Newly
Diagnosed ...
• Offer MM patients personalized
targeted therapy
• Increased therapeutic efficacy
• Improved patient outcomes
Future Dire...
Study Objective
– Assess the survival advantage of MP-T vs MP
in elderly MM patients ≥75 years
– Assess benefit of MP-T vs...
Primary end point
– Overall Survival (OS)
Secondary end points
– Progression Free Survival (PFS)
– Response to Treatment
•...
Cyrille Hulin et al. Blood (ASH Annual Meeting Abstracts)
2007 110: Abstract 75
Results % of Patients who
Stopped Tx
Obser...
• MP-T demonstrates survival advantage in
elderly patients vs MP
• The toxicity was acceptable in this very
elderly popula...
Study Objective
– MP-T treatment of NDMM patients
Study Design
– Placebo-Controlled double blind trial
– Patients received...
Methods
– Patients received either MP (175 pts) or MP-T (182 pts)
– Thalidomide was dose escalated from 200 mg to 400 mg
S...
VISTA Trial: VMP vs MP in NDMM
Study Objective
–Define the differences in efficacy and outcome between VMP vs MP
–VISTA St...
Primary end point
– Time to progression (TTP)
Secondary end points
– Progression-free survival (PFS), overall survival (OS...
Mateos, et al. Haematologica 2008; 93(4) 560-565
VISTA Trial : VMP vs. MP in NDMM
Most Common Adverse Events (in ≥30% pati...
VISTA Trial: VMP vs. MP
in NDMM Results
Efficacy Results VMP (n=344) MP (n=338) P value
CR + PR rate 82% 50% P<.0001
CR ra...
Conclusions
Adverse Events
–46% with VMP
–36% with MP
Patients remained on therapy longer with VMP
–46 weeks with VMP
–39 ...
E4A03: RD vs Rd in NDMM
Study Objective
–Lenalidomide and High Dose Dexamethasone (RD) vs Lenalidomide plus
Low
Dose Dexam...
Survival rate results RD Arm Rd Arm P Value
OS differences (pts <65 ) 90% 98% P=0.015
OS differences (pts 65 & older) 83% ...
E4A03 : RD vs Rd in NDMM Toxicities
Rajkumar et al. Abstract #74 appears in Blood, Volume 110, issue 11, November 16, 2007...
Conclusions E4A03:
Rd vs RD in NDMM
• Rd is associated with superior OS
compared to RD
• Increased mortality in the RD due...
SWOG Trial S0232 : Len+HD vs HD
Study Objective
– To compare Len+HD to HD in NDMM
Study Design
– A randomized, double-blin...
SWOG Trial S0232:
Len+HD vs HD (cont’d)
Primary end point
– Progression-free survival (PFS)
Secondary end points
– Overall...
Results Len+HD HD P Value
1 yr PFS 77% 55% p=0.002
ORR 85.3% 51.3% p=0.001
OS (at 1 yr) 93% 91% p=NS
Grade 3-4 neutropenia...
Conclusions of SWOG Trial S0232:
Len+HD vs HD
Zonder et al. Abstract #77 appears in Blood, Volume 110, issue 11, November ...
Conclusions of SWOG Trial S0232:
Len+HD vs HD (cont’d)
• Len+HD are superior in terms of:
– ORR
– MRR
– PFS
• Both arms of...
VTD vs. TD Prior to SCT
Study Objective
– VTD vs TD in Preparation for Autologous Stem Cell
Transplantation (ASCT) in NDMM...
Results VDT TD P value
CR + near (n)CR 36% 9% P<.001
At least VGPR 60% 27% P<.001
CR + nCR, del(13) 43% 4% P<.001
CR + nCR...
Prophylaxis
– Acyclovir prophylaxis against reactivation of VZV
– TEE prophylaxis with low molecular weight heparin, aspir...
MM-009 and MM-010 Phase III Trials:
Len/Dex vs Dex
Study Objective
–Comparison of Prolonged Overall Survival (OS) with
Len...
Methods for MM-009 and MM-010
Len/Dex vs Dex Studies
Methods
– Pts without prior resistance to Dex evaluated
– Pooled resu...
Results Len/Dex Dex P Value
Overall response, % 60.6 21.9 <0.001
Complete remission rate, % 15.0 2.0 <0.001
Median TTP, mo...
• New combinations of novel therapies may offer
personalized targeted therapy
– Increased therapeutic efficacy
• Important...
Recent NCCN Guidelines
for MM: Induction Therapy
NCCN Practice Guidelines in Oncology-v.1.2008
Multiple Myeloma: Induction...
• Selected, but not inclusive of all regimens
• Order does not imply preference
• Consider herpes zoster prophylaxis for p...
NCCN Guidelines: Primary Induction
Therapy for Transplant Candidates:
• Vincristine/doxorubicin/dexamethasone (VAD)
• Dexa...
NCCN Guidelines: Primary Induction
Therapy for Non-transplant Candidates:
• Melphalan/prednisone (MP)
• Melphalan/predniso...
NCCN Guidelines:
Maintenance Therapy
• Steroids (category 2B)
• Interferon (category 2B)
NCCN Practice Guidelines in Oncol...
NCCN Guidelines:
Salvage Therapy
• Repeat primary induction therapy (if relapse at >6 mo)
• Bortezomib (category 1)1,2
• B...
NCCN Guidelines:
Salvage Therapy (cont’d)
Lenalidomide/dexamethasone1,2,3
1 Lenalidomide/dexamethasone is FDA approved for...
NCCN Guidelines:
Salvage Therapy (cont’d)
• Lenalidomide
• Cyclophosphamide-VAD
• High-dose cyclophosphamide
• Thalidomide...
Closing Remarks
Beth Faiman: RN, MSN, APRN, BC, AOCN
Cleveland Clinic Taussig Cancer Institute
Cleveland, Ohio
NLB Accomplishments
The initial guidelines cover the following:
The development of ‘Consensus Statements’ on the
nursing m...
IMF NLB’s CJON Supplement
Publication Title
Development of Consensus Statements
by the International Myeloma Foundation’s
...
Key Information
• Clinical Journal Oncology Nursing (CJON)
• Number of supplements to be printed - 37,000
• ‘Patient Educa...
Patient Education Tear-Out Tools
General Format and Clinical Utility
• Side effect description
• Novel therapies that may ...
• Publication of the ‘Consensus Statements’
will be immeasurably valuable to the general
nursing community involved in mul...
Communication & Dissemination
• Patient and Nurse Educational Slide Sets
Development
• NLB Speaker’s Bureau
• Oncology Con...
Educational Resources
• American Cancer Society
• National Cancer Institute
• International Myeloma Foundation
- IMF Myelo...
Future Goals of NLB
Frame the Importance of Nursing
Management of Long Term Side Effects
Associated With MM Therapies
Deve...
1. Symposium Accreditation Process
Please complete the CE Certificate Registration and
Program Evaluation Form found in th...
Question & Answer Session
Faculty Panel
Upcoming SlideShare
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  1. 1. Consensus on Care: New Insights on Novel Therapies in Multiple Myeloma Accredited by Medical Education Resources Supported by The International Myeloma Foundation Grant Funding provided by Celgene Corporation and Millennium Pharmaceuticals
  2. 2. Welcome and Opening Remarks Beth Faiman: RN, MSN, APRN, BC, AOCN Cleveland Clinic Taussig Cancer Institute Cleveland, Ohio
  3. 3. ONS Disclaimer Meeting space has been assigned to provide a satellite symposium funded by Celgene Corporation and Millennium Pharmaceuticals via an educational grant during the Oncology Nursing Society’s (ONS) 33nd Annual Congress, May 15-18, 2008 in Philadelphia, Pennsylvania. The Oncology Nursing Society’s assignment of meeting space does not imply product endorsement nor does the Oncology Nursing Society assume any responsibility for the educational content.
  4. 4. Symposium Accreditation This continuing education activity provides 2.0 contact hours Medical Education Resources is an approved provider of continuing nursing education, by the Colorado Nurses Association, an accredited approver by the American Nurses Credentialing Center’s Commission on Accreditation. Please complete the CE Certificate Registration and Program Evaluation Form found in the guidebook and return it to the registration desk
  5. 5. Additional Accreditation Additional CEU accreditation opportunity – Clinical Journal of Oncology Nursing (CJON) June 2008 supplement publication of the International Myeloma Foundation’s (IMF) Nurse Leadership Board (NLB) ‘Consensus Statements’ located at your table
  6. 6. Faculty Chair: Beth Faiman: RN, MSN, APRN, BC, AOCN Cleveland Clinic Taussig Cancer Institute Cleveland, Ohio Faculty: Lisa C. Smith: MSN, FNP, AOCN Cancer Centers of the Carolinas Greenville, South Carolina Kena C. Miller: RN, MSN, FNP Roswell Park Cancer Institute Buffalo, New York Joseph D. Tariman: RN, MN, ARNP-BC, OCN University of Washington Seattle, Washington
  7. 7. Agenda Time Topics Presenter 6:00 – 6:15 Welcome and Introductions Beth Faiman 6:15 – 6:35 IMF Nurse Leadership Board: Towards a New Consensus on Managing the Myeloma Patient Lisa C. Smith 6:35 – 6:55 Leadership in Action: Clinical Utility of the NLB Consensus Statements Kena C. Miller 6:55 – 7:25 New Insights on Novel Therapies in Multiple Myeloma Joseph D. Tariman 7:25 – 7:30 Closing Remarks Beth Faiman 7:30 – 8:00 Question & Answer Session Panel
  8. 8. Learning Objectives • Gain insights on novel therapies in multiple myeloma - Describe new clinical trial data - Discuss critical issues in nursing management and medical implications of major emergent side effects • Discuss the IMF’s NLB ‘Consensus Statements’ for the management of key emergent side effects of novel therapy - Discuss the clinical value of the ‘Consensus Statements’ - Share NLB ‘Consensus Statements’ development strategy - Unify the nursing community behind one standard of care
  9. 9. Multiple Myeloma Causes, Symptoms and Treatment
  10. 10. Multiple Myeloma: A Current Perspective • Etiology of multiple myeloma (MM) • Epidemiology of multiple myeloma • Current and novel therapies in the management of multiple myeloma
  11. 11. San Miguel JF, et al. Pathogenesis of Multiple Myeloma: Rationale for New and Novel Therapies. Clinical Care Options: http://clinicaloptions.com/Oncology/Treatment%20Updates/Myeloma/Modules/Pathophysiology/Pages/Page%203.aspx. What is Multiple Myeloma? • Cancer of plasma cells • Healthy plasma cells produce antibodies or immunoglobulins - Part of our humoral immunity, they are released in response to foreign body invasion • Myeloma cells produce abnormal immunoglobulin - Overproduce monoclonal protein or paraprotein - Ineffective immunoglobulins - Leads to decreased bone marrow function - Destruction of bone tissue
  12. 12. Myeloma Cells are distinguished from normal plasma cells by the presence of large nuclei that are often eccentric Vescio R. Multiple Myeloma & Amyloidosis Program,Jonsson Comprehensive Cancer Center/Cedars–Sinai Medical Center, 2005.
  13. 13. Multiple Myeloma: Abnormal Proliferation of Malignant Plasma Cells Kyle RA and Rajkumar SV. N Engl J Med 2004;351:1860-73
  14. 14. Multiple Myeloma: Epidemiology • Second most common hematological malignancy • Incidence and rates – 1% of all cancers – U.S. incidence: 19,900 new cases per year – U.S. prevalence: 100,000 patients – Deaths: estimated 10,790 per year • More than 80% of affected patients >age 60 • Affects slightly more men than women (1.6:1) Merck Manual Professional. 2005 and George ED, et al. Am Fam Phys. 1999;59(7):1401-1405.
  15. 15. Clinical Manifestations of Multiple Myeloma • Overproliferation of plasma cells can cause – Risk of infection – Osteolytic bone lesions – Hypercalcemia – Bone marrow suppression (pancytopenia) – Renal complication risk • Production of monoclonal M proteins causes – Decreased levels of normal immunoglobulins – Hyperviscosity http://myeloma.org/pdfs/ph07-eng_f2.pdf
  16. 16. Major Symptoms at Diagnosis • Bone pain 58% • Fatigue 32% • Weight loss 24% • Paresthesias 5% • Asymptomatic 11% Kyle RA. Mayo Clin Proc 2003;78:21
  17. 17. Common Sites for Bone Involvement Skull Spine • Thoracic • Lumbar • Vertebrae Pelvis Long bones Spinal cord -compression can occur http://www.emedicine.com/Radio/topic460.htm#section~Introduction
  18. 18. Criteria for Diagnosis of Multiple Myeloma Monoclonal plasma cells present in the bone marrow ≥10%, and/or presence of a documented plasmacytoma + Presence of M component in serum and/or urine* + One or more of the following (CRAB criteria) • Calcium elevation (serum calcium >11.5 mg/dL) • Renal insufficiency (serum creatinine >2 mg/dL) • Anemia (hemoglobin <10 g/dL or 2 g/dL <normal) • Bone disease (lytic lesions or osteopenia) Durie et al for the International Myeloma Working Group. Leukemia. 2006:1-7. *Monoclonal M spike on electrophoresis IgG>3.5g/dL, IgA>2g/dL, light chain >1g/dL in 24-hr urine sample
  19. 19. Diagnostic Evaluation of Multiple Myeloma Test Finding (s) With Myeloma CBC with differential counts ↓ Hgb, ↓ WBC, ↓ platelets Electrolytes ↑ Creat, ↑ Ca+, ↑ Uric acid, ↓ Alb Serum electrophoresis with quantitative immunoglobulins ↑ M protein in serum, may have ↓ levels of normal antibodies Immunofixation Identifies light/heavy chain types M protein β2-microglobulin ↑ Levels (measure of tumor burden) C-reactive protein ↑ Levels (marker for myeloma growth factor) 24-hour urine protein electrophoresis ↑ Monoclonal protein (Bence Jones) Bone marrow biopsy ≥ 10% plasma cells Skeletal imaging Osteolytic lesions, osteoporosis Serum free light chain ↑ Free light chains MRI Evaluation of involvement of disease Alb = albumin; CBC = complete blood count; Creat = creatinine; Hgb = hemoglobin; MRI = magnetic resonance imaging; WBC = white blood cell. Abella. Oncology News International. 2007;16:27; Barlogie et al. In: Williams Hematology. 7th ed. 2006:1501; Durie et al. Hematol J. 2003;4:379; MMRF. Multiple Myeloma: Disease Overview. 2006. www.multiplemyeloma.org; Rajkumar et al. Blood. 2005;106(3):812.
  20. 20. Durie-Salmon Staging System for Multiple Myeloma Durie B, Salmon S. Cancer. 1975;36(9):842-854 Subclassification Criteria A Normal renal function (serum creatinine level <2.0 mg/dL) B Abnormal renal function (serum creatinine level ≥2.0 mg/dL) Stage Criteria Myeloma cell mass (× 1012 cells/m2 ) I All of the following: Hemoglobin >10 g/dL Serum calcium level ≤12 mg/dL (normal) Normal bone or solitary plasmacytoma on x-ray Low M component production rate: IgG <5 g/dL IgA <3 g/dL Bence Jones protein <4 g/24 hr <0.6 (low) II Not fitting stage I or III 0.6–1.2 (intermediate) III One or more of the following: Hemoglobin <8.5 g/dL Serum calcium level >12 mg/dL Multiple lytic bone lesions on x-ray High M-component production rate: IgG >7 g/dL IgA >5 g/dL Bence Jones protein >12 g/24 hr >1.2 (high)
  21. 21. β2M=serum β2 microglobulin in mg/dL; ALB=serum albumin in g/dL International Staging System for Symptomatic Multiple Myeloma Greipp PR, et al. Blood 2005; 102: 190a STAGE VALUES Stage 1 ß2M <3.5 mg/dL ALB ≥3.5 g/dL Stage 2 Not Stage 1 or 3 Stage 3 ß2M >5.5 mg/dL
  22. 22. Challenges in MM Management • Currently incurable in most patients • Long-term complete responses are rare • Median survival with standard therapy is about 3 years • Autologous stem cell transplant may prolong progression free survival, but not curative • Treatment of relapse – No standard therapy – Existing options inadequate • New treatment options needed NCCN Practice Guidelines. Rajkumar SV, et al. Mayo Clin Proc. 2002;77:813-822.
  23. 23. MM Treatment Options Conventional chemotherapy: • Melphalan • Doxorubicin • Cyclophosphamide Radiation therapy Stem cell transplantation: • Autologous • Allogeneic Novel therapeutics: • Thalidomide • Lenalidomide • Bortezomib Thalomid ® Prescribing Information, Revlimid ® Prescribing Information; Velcade® Prescribing Information Steroid therapy: • Dexamethasone • Prednisone
  24. 24. Novel Therapies: Mechanisms of Action (MOA) • Thalidomide (THALOMID® ) – Immunomodulatory, anti-inflammatory, and anti-angiogenic agent – Suppresses production of TNF-α, IL-6, and other cytokines • Lenalidomide (REVLIMID® ) – Immunomodulatory agent with anti-angiogenic and anti-neoplastic properties – Inhibits the secretion of pro-inflammatory cytokines and increases the secretion of anti-inflammatory cytokines • Bortezomib (VELCADE® ) – The first drug in the class of “proteasome inhibitors” • A reversible inhibitor of 26S proteasome complex – Influences apoptotic, cell adhesion, and angiogenic pathways • Liposomal doxorubicin (DOXIL® ) – Used in combination with Velcade® – Reformulated version of the chemotherapeutic agent doxorubicin • Pegylated liposomal delivery » Decreased immunoreactivity » Increased bioavailability Thalomid ® Prescribing Information, Revlimid ® Prescribing Information Velcade® Prescribing Information
  25. 25. IMF Nurse Leadership Board (NLB): Towards a New Consensus on Managing the Myeloma Patient Lisa C. Smith: MSN, FNP, AOCN Cancer Centers of the Carolinas Greenville, South Carolina
  26. 26. Novel and Emerging Therapies for Multiple Myeloma Benefits and Challenges
  27. 27. Recent FDA Approvals of Novel Agents VELCADE® 2003 2005 REVLIMID® ___ 2006 THALOMID® with dexamethasone 2006 ___ DOXIL® with VELCADE® 2006 Accelerated Approval (AA) Regular Approval (RA) Approval based upon: Response Rate Time to Progression (TTP) Thalomid® Prescribing Information, Revlimid® Prescribing Information Velcade® Prescribing Information, Doxil® Prescribing Information
  28. 28. Key Benefits of Novel and Emerging Therapies IMF-NLB ‘Consensus Statements’ supplement In Press, CJON June 2008; Rajkumar et al., 2005; Richardson & Anderson, 2006; Richardson, Hideshima, Mitsiades, & Anderson, 2007 • Targeted therapies with novel mechanisms of action • Provide increased response rate • Provide increased time to progression • Lead to increased survival time
  29. 29. Key Challenges of Novel and Emerging Therapies IMF-NLB ‘Consensus Statements’ supplement In Press, CJON June 2008 • Emergent side effects – Can interfere with adherence to treatment – Adversely affect patients’ quality of life – Can be life threatening • Challenge for nursing management of emergent side effects – Lack of effective practitioner based guidelines • Produces a barrier to providing optimum patient care
  30. 30. Novel Therapies Bortezomib (VELCADE® ) VELCADE® for injection is indicated for the treatment of patients with multiple myeloma who have received at least 1 prior therapy Source: http://www.mlnm.com/products/velcade/full_prescrib_velcade.pdf
  31. 31. Updated Side Effects Profile VELCADE® Most Commonly Reported Grades 3 & 4 Side Effects > 10% Percentage of Patients Asthenic Conditions (fatigue, malaise, weakness) 61% Diarrhea 57% Nausea 57% Constipation 42% Peripheral neuropathy* 36% Vomiting 35% Pyrexia 35% Thrombocytopenia 35% Psychiatric disorders 35% Decreased appetite and anorexia 34% Parasthesia and dysesthesia 27% Anemia 26% Headache 26% Cough 21% Dyspnea 20% Neutropenia 19% Source: http://www.mlnm.com/products/velcade/full_prescrib_velcade.pdf
  32. 32. Novel Therapies Lenalidomide (REVLIMID® ) REVLIMID® in combination with dexamethasone is indicated for use in patients with multiple myeloma who have had at least one prior therapy http://www.revlimid.com/pdf/REVLIMID_PI.pdf
  33. 33. Updated Side Effects Profile REVLIMID® + dexamethasone Most Commonly Reported Side Effects > 20% for all Grades Percentage of patients Constipation 39% Fatigue 38% Insomnia 32% Muscle Cramp 30% Diarrhea 29% Neutropenia 28% Anemia 24% Loss/Lack of Strength 23% Fever 23% Nausea 22% Headache 21% Peripheral edema 21% Dizziness 21% http://www.revlimid.com/pdf/REVLIMID_PI.pdf
  34. 34. Novel Therapies Thalidomide (THALOMID® ) THALOMID® in combination with dexamethasone is indicated for the treatment of patients with newly diagnosed multiple myeloma http://www.thalomid.com/pdf/Thalomid_Pl.pdf
  35. 35. Updated Side Effects Profile THALOMID® + dexamethasone Most Commonly Reported Effects > 20% for all grades Percentage of Patients Hyperglycemia 72.5% Hypocalcemia 72% Edema 57% Constipation 55% Peripheral neuropathy-sensory 54% Dyspnea 42% Rash 30% Confusion 28% Thrombosis/Embolism 23% Peripheral neuropathy-motor 22% http://www.thalomid.com/pdf/Thalomid_Pl.pdf
  36. 36. Emerging Therapies • Low dose dexamethasone with lenalidomide (REVLIMID® ) • Pegylated liposomal doxorubicin (DOXIL® ) with bortezomib (VELCADE® ) Rajkumar V, et al. Blood. 2006;108:[abstract 799]. http://www.doxil.com/
  37. 37. Toxicity (Grade >3) Arm A (N=223) Arm B (N=222) Neutropenia 2.7% 3.2% Thrombocytopenia 1.8% 1.4% DVT/PE 18.4% 6.3% Atrial fibrillation/flutter 3.1% 0.0% Infection/Pneumonia 16.1% 9.0% Fatigue 11.7% 4.1% Hyperglycemia 5.8% 2.3% Neuropathy 0.4% 1.4% A Randomized Phase III Trial of Lenalidomide Plus High-Dose Dexamethasone (Arm A) vs Lenalidomide Plus Low-Dose Dexamethasone (Arm B) in Newly Diagnosed Multiple Myeloma (E4A03) Rajkumar V, et al. Blood. 2006;108:[abstract 799]. Low Dose Dexamethasone/Lenalidomide Updated Side Effects Profile
  38. 38. Updated Side Effects Profile DOXIL® with VELCADE® Most Commonly Reported Side Effects > 10% for all grades Percentage of Patients Nausea 48% Diarrhea 46% Peripheral Neuropathy 42% Fatigue 36% Neutropenia 36% Thrombocytopenia 33% Vomiting 32% Constipation 31% Pyrexia 31% Anemia 25% Asthenia 22% Rash 22% Stomatitis 20% http:http://www.doxil.com/common/prescribing_information/DOXIL/PDF/DOXIL_PI_Booklet.pdf//www.doxil.com/ Hand-foot syndrome (HFS) may occur during therapy with DOXIL®
  39. 39. Consequences of Inadequately Managed Side Effects Therapy associated side effects lead to a reduction in patient’s desire and ability to comply with dosing schedules Reduced Adherence Lower Persistence Patients are less inclined to remain on a therapy for which side effects are not adequately managed Reduced Efficacy Physiological ImpairmentPsychological Impact Social Consequences Lowered self esteem, anxiety and depression which will adversely impact the patient’s overall health Reduced ability to function optimally within relationships, work and other social contexts Adverse side effects that are not properly managed may lead to a variety of physiological impairments Adverse side effects may lead to premature stopping of medication or reduction of dosage to a suboptimal efficacy level Effective management of side effects improves response outcomes and patient’s quality of life
  40. 40. IMF Nurse Leadership Board
  41. 41. Nurses from leading MM institutions formed a Nurse Leadership Board (NLB) in collaboration with and under sponsorship of the International Myeloma Foundation (IMF) with the express purpose of determining the unmet needs of MM patients and to develop action plans to address those needs Statement of Need Catalyzes Creation of a Nurse Centric Initiative IMF-NLB ‘Consensus Statements’ supplement In Press, CJON June 2008
  42. 42. Nurse Centric Model of Patient Care* Nurses are Central to Patient Management and Healthcare Resource Coordination Patient ResearchPatient Counseling Patient Education Patient ManagementPatient Monitoring Patient Advocacy * Developed by ScienceFirst, LLC; All Rights Reserved (www.science-first.com)
  43. 43. • Nurses play an essential role in managing patient care • Nurses are key in efficiently and optimally managing emergent side effects • Managing emergent side effects is an important endeavor for improving MM patient care and treatment outcome • Improving nursing assessment contributes to positive outcomes Effective Nursing Tools Improve Patient Care and Treatment Outcomes IMF-NLB ‘Consensus Statements’ supplement In Press, CJON June 2008
  44. 44. A Collaborative Assessment was Performed of Evidence-based and Practice-based Knowledge and the Nursing Experience of Key Emergent Side Effects with Novel Therapies IMF NLB Process for Developing Consensus Statements
  45. 45. Moving Toward Consensus NLB Determined the Five Most Common Emergent Side Effects Requiring Clinical ‘Consensus Statement’ Development Peripheral Neuropathy DVT and PE Myelosuppression GI Effects Steroid Effects IMF-NLB ‘Consensus Statements’ supplement In Press, CJON June 2008
  46. 46. 20 Nurse Leaders 5 Teams Teresa Miceli Maria Gavino Kathleen Colson Kathy Lilleby Myelosuppression Sandra Rome Jeanne Westphal Deborah Doss Kena Miller DVT/PE Lisa Smith Bonnie Jenkins Kathleen Curran Page Bertolotti GI Beth Faiman Katy Rogers Patricia Mangan Elizabeth Bilotti Steroid Effects Joseph Tariman Stacey Sandifer Ginger Love Emily McCullagh Peripheral Neuropathy
  47. 47. ‘Consensus Statements’: Review Process NLB Received One Document With Comment Sheet Per Week 5 Consensus Documents Sent Over a Five Week Period NLB Compiled New Comments After Review Sub-groups Received Updated Comment Sheet The Updated Comments Sheet Captured All NLB Input Sub-groups Discussed New Comments Via Teleconference Approved Comments Incorporated Into Revised Consensus Statements Revised Consensus Statements Received Medical Accuracy Review Entire NLB Board Conducted Final Approval
  48. 48. ‘Consensus Statements’: Team Effort 120 Teleconference Calls 1,300 E-mails exchanged 1,600 work hours 5 Consensus Statements 10 months 40 weeks of work
  49. 49. Completion of ‘Consensus Statements’ Five consensus statements on the management of side effects associated with the novel therapeutic agents used in treating multiple myeloma patients 1. Myelosuppression 2. Deep Vein Thrombosis/Pulmonary Embolism 3. Peripheral Neuropathy 4. Gastrointestinal Effects 5. Steroids Related Side Effects IMF-NLB ‘Consensus Statements’ supplement In Press, CJON June 2008
  50. 50. NLB ‘Consensus Statements’ Development and Publication Strategy NLB Myelosuppression DVT/PE Peripheral neuropathy GI Steroids Consensus Statements Review Process Finalization Planned meetings and coordination Publication in Clinical Journal of Oncology Nursing June ‘08 NLB IMF-NLB ‘Consensus Statements’ supplement In Press, CJON June 2008 Planned meetings and coordination Editing and Formatting
  51. 51. • The NLB’s ‘Consensus Statements’ development approach is a powerful model helping to improve patient management, care and outcomes • The NLB consensus approach provides a future MODEL for all oncology nursing (i.e. nurses partnering with advocacy groups) Development of The NLB ‘Consensus Statements’ as a Model of Care
  52. 52. •The NLB ‘consensus statements’ will be periodically reviewed and expanded upon •The NLB ‘consensus statements’ will be adopted as “The” Model of Care within the MM nursing community NLB Vision for the Future
  53. 53. Current Nurse Leadership Board Members Name Affiliation / Address Deborah Doss, RN, OCN Dana-Farber Cancer Institute Sandra Rome, RN, MN, AOCN Cedars-Sinai Medical Center Kena C. Miller, RN, MSN, FNP Roswell Park Cancer Institute Jeanne Westphal, RN Meeker County Memorial Hospital Teresa Miceli, RN, BSN Mayo Clinic, Rochester Kathleen Colson, RN, BSN, BS Dana-Farber Cancer Institute Kathy Lilleby, RN Fred Hutchinson Cancer Research Center Stacey Sandifer, RN, BSN Cancer Centers of the Carolinas Ginger Love, RN, OCN University of Cincinnati Hem/Onc Care Joseph Tariman, RN, MN, ARNP-BC, OCN University of Washington School of Nursing Emily McCullagh, RN, NP-C, OCN Memorial Sloan-Kettering Cancer Center Bonnie Jenkins, RN University of Arkansas Medical School Lisa C. Smith, MSN, FNP, AOCN Cancer Centers of the Carolinas Page Bertolotti, RN, BSN, OCN Cedars-Sinai Medical Center Beth Faiman, RN, MSN, APRN, BC, AOCN Cleveland Clinic Taussig Cancer Institute Patricia A Mangan, MSN, CRNP, AOCN Hospital of the University of Pennsylvania Elizabeth Bilotti, RN, MSN, APRN, BC, OCN St. Vincents Comprehensive Cancer Center Jacy Boesiger, RN, BSN, OCN Mayo Clinic, Arizona Tiffany Richards, MS, ANP, AOCNP MD Anderson Cancer Center Kathy Daily RN, TNS H. Lee Moffitt Cancer Center and Research
  54. 54. Leadership in Action: Clinical Utility of the NLB Consensus Statements Kena C. Miller: RN, MSN, FNP Roswell Park Cancer Institute Buffalo, NY
  55. 55. Overview of The ‘Consensus Statements’ Issue Statement •An articulation of the issue or need and its impact on patients, the nursing profession, and society Position Statement •A comprehensive listing of the positions taken in regard to the issue Strategic Recommendations •Identification of recommended strategies and approaches to support the position by addressing the issue or need References •A detail listing of published references that support the position statement and recommended strategies section General Format of Publications IMF-NLB ‘Consensus Statements’ supplement In Press, CJON June 2008
  56. 56. Myelosuppression: Definition and Symptoms http://www.schneiderchildrenshospital.org/peds_html_fixed/peds/transplant/bonetran.htm; Adapted from NLB Consensus Recommendations. In Press, CJON June 2008 Marrow Red Blood Cells White Blood Cells Platelets Anemia – Fatigue, malaise and SOB Neutropenia – Increased risk of bacterial, fungal and viral infections Thrombocytopenia – Bruising and bleeding Neutrophil Eosinophil Lymphocyte Monocyte Basophil
  57. 57. Risk of Grade 3 and 4 Myelosuppression With Novel Therapies Anemia Neutropenia Thrombocytopenia THALOMID® / dexamethasone 16% 13% 4% REVLIMID® / dexamethasone 8% 21% 10% VELCADE® 12% 14% 32% Adapted from NLB Consensus Recommendations. In Press, CJON June 2008 Thalomid® Prescribing Information, Revlimid® Prescribing Information, Velcade® Prescribing Information. http://ctep.cancer.gov/forms/CTCAEv3.pdf Grading based upon: Common Terminology Criteria for Adverse Events (CTCAE) v3.0
  58. 58. Management of Neutropenia: REVLIMID® When ANC Recommended Course Fall to <1000/mm3 Return to >1000/mm3 and neutropenia is the only toxicity Interrupt REVLIMID® treatment, add G-CSF, follow CBC weekly Resume REVLIMID® at 25 mg daily Return to >1000/mm3 and neutropenia if other toxicity Resume REVLIMID® at 15 mg daily For each subsequent drop below <1000/mm3 Return to >1000/mm3 Interrupt REVLIMID® treatment Resume REVLIMID® at 5 mg less than the previous dose* *Do not dose below 5 mg daily Lenalidomide product information. Summit, NJ: Celgene. Adapted from NLB Consensus Recommendations. In Press, CJON June 2008
  59. 59. Management of Thrombocytopenia: REVLIMID® When Platelets Recommended Course Fall to <30,000/mm3 Return to >30,000/mm3 Interrupt REVLIMID® treatment, follow CBC weekly Restart REVLIMID® at 15 mg daily For each subsequent drop <30,000/mm3 Return to >30,000/mm3 Interrupt REVLIMID® treatment Resume REVLIMID® at 5 mg less than the previous dose* . Lenalidomide Product Information. Summit, NJ: Celgene Adapted from NLB Consensus Recommendations. In Press, CJON June 2008 *Do not dose below 5 mg daily
  60. 60. Management of Myelosuppression: VELCADE® • At the onset of any Grade 4 hematologic toxicity hold VELCADE® • Once toxicity has resolved, VELCADE® may be restarted at a 25% reduced dose • Thrombocytopenia - Platelet count decreases and recovers over the cycle - No evidence of cumulative thrombocytopenia - Transfuse if platelet count <25.0 x 109 /L Velcade® Prescribing Information. Adapted from NLB Consensus Recommendations. In Press, CJON June 2008
  61. 61. Myelosuppression ‘Consensus Statement’ Recommendations For All Novel Therapies General recommendations • Monitor signs and symptoms • Monitor CBC • Educate on signs and symptoms Myelosuppression management • Growth factor therapy • Dose reduction as appropriate • Transfusion as indicated Adapted from NLB Consensus Recommendations. In Press, CJON June 2008
  62. 62. Overview of Thromboembolic Events (TE) ‘Consensus Statement’ Cancer patients have a higher risk of TE events (blood clots) which may lead to: • Deep vein thrombosis (DVT) • Pulmonary embolism (PE) MM patients are at an increased risk for blood clots • Patients are at increased risk with high dose dexamethasone treatment • The risk for DVT/PE is further increased in patients treated with novel therapies – THALOMID® – REVLIMID® Measures to prevent novel therapy-associated TE events include: • Mechanical • Myeloma regimen-related • Anticoagulant therapy (clot-preventing) Adapted from NLB Consensus Recommendations. In Press, CJON June 2008. Amir Qaseem et al., 2007, Ann Fam Med; J. B. Segal et al., 2007, Ann Intern Med. http://www.nhlbi.nih.gov/health/dci/Diseases/Dvt/DVT_WhoIsAtRisk.htm TE events are serious and potentially life-altering and life-threatening
  63. 63. DVT - Signs/Symptoms • Slight Fever • Tachycardia • Unilateral swelling, erythemia warm extremity • Cyanosis/cool skin if venous obstruction • Dull ache, pain, tight feeling over area & with palpation • + Homan’s Sign (35% pts) • Distension superficial venous collateral vessels http://www.nhlbi.nih.gov/health/dci/Diseases/Dvt/DVT_SignsAndSymptoms.html Adapted from NLB Consensus Recommendations. In Press, CJON June 2008
  64. 64. PE - Signs/Symptoms • Anxiety • Sudden dyspnea • Chest discomfort-increase w/ breathing • Tachycardia, tachypnea • Low grade fever • Pleural friction rub, crackles followed by diminished breath sounds, wheezing • ECG right axis deviation or new RBBB http://www.nhlbi.nih.gov/health/dci/Diseases/Dvt/DVT_SignsAndSymptoms.html Adapted from NLB Consensus Recommendations. In Press, CJON June 2008 PE is a Medical Emergency
  65. 65. TE Event - Diagnostics DVT • Doppler Ultrasound • Contrast Venography • D-Dimer • Antithrombin Level PE • Ventilation Perfusion Lung (VQ) Scan • Spiral CT Scan • D-Dimer • Antithrombin Level http://www.nhlbi.nih.gov/health/dci/Diseases/Dvt/DVT_Diagnosis.html Adapted from NLB Consensus Recommendations. In Press, CJON June 2008 To maintain therapeutic level INR 2-3
  66. 66. TE Event - Prophylaxis Mechanical • Sequential Compression Devices • Anti-embolism Stockings • Exercise Regimen Pharmaceuticals - Therapy Dose Reductions • THALOMID® : by 50 mg decrements from current dose • Dexamethasone • 20- 40 mg once weekly • 20- 40 mg days 1- 4 on 28d cycle http://www.nhlbi.nih.gov/health/dci/Diseases/Dvt/DVT_Treatments.htm; Adapted from NLB Consensus Recommendations; In Press, CJON June 2008 Thalomid® Prescribing Information; Dexamethasone Prescribing Information
  67. 67. Thromboembolic Events - Prophylaxis Pharmaceutical Agent Salicylic Acid (aspirin) Unfractionated Heparin Low Molecular Weight Heparin - enoxaparin - dalteparin Fondaparinux Warfarin Suggested Dose SD 325 mg or LD 81 mg daily 5000 IU sq bid 40mg sq daily 200IU/kg sc daily 2.5 mg sc daily Weight based • 1 mg < 70 kg • 2 mg ≥ 70 kg Palumbo et al., Leukemia (In press); Adapted from NLB Consensus Recommendations. In Press, CJON June 2008. Amir Qaseem et al., 2007, Ann Fam Med; J. B. Segal et al., 2007, Ann Intern Med. Prophylaxis tailored to individual patient’s risk profile in consideration of the International Myeloma Working Group consensus statement*
  68. 68. General Strategic Recommendations for the Management of TE Events Prophylactic measures which can reduce or eliminate TE risk include: • Aspirin; suggested for patients with no or one risk factor • Low molecular weight heparin or full dose warfarin for patients with two or more risk factors • Low molecular weight heparin or full dose warfarin for all patients with therapy-related risks including: – High dose dexamethasone – Doxorubicin – Multi-agent chemotherapy Adapted from NLB Consensus Recommendations. In Press, CJON June 2008 http://www.nhlbi.nih.gov/health/dci/Diseases/Dvt/DVT_Treatments.html
  69. 69. Overview of Peripheral Neuropathy (PN) ‘Consensus Statement’ Adapted from NLB Consensus Recommendations. In Press, CJON June 2008, Thalomid® Prescribing Information, Velcade® Prescribing Information Colson et al., 2004, Clinical Journal of Oncology Nursing; S. Lonial, 2007, The American Journal of Hematology/Oncology. • THALOMID® /VELCADE® can cause peripheral neuropathy • PN is a challenging adverse event which may: • Affect quality of life • Compromise optimal treatment • Management strategies include: • Ongoing evaluation • Dose and schedule modifications • Pharmacologic interventions • Non-pharmacologic approaches • Patient education
  70. 70. PN Definition, Signs/Symptoms Signs/symptoms • Temporary Numbness • Tingling • Parasthesias • Sensitivity to Touch • Muscle Weakness Severe symptoms • Burning Pain • Muscle Wasting • Paralysis • Organ Dysfunction Adapted from NLB Consensus Recommendations. In Press, CJON June 2008 http://www.ninds.nih.gov/disorders/peripheralneuropathy/detail_peripheralneuropathy.htm Damage to the peripheral nervous system including any injury, inflammation, or degeneration of peripheral nerve fibers
  71. 71. PN and Pain Toxicity Grades Grade 1 Mild Grade 2 Moderate Grade 3 Severe Grade 4 Life-threatening or disabling Grade 5 Death Mild pain not interfering with function Moderate pain interfering with function but not ADL Severe pain severely interfering with ADL Disabling N/A Asymptomatic, weakness on testing only Symptomatic weakness interfering with function but not ADL Weakness interfering with ADL Life-threatening disabling Death Asymptomatic, loss of deep tendon reflexes or paresthesias Sensory alteration or paresthesias interfering with function not with ADL Sensory alteration or paresthesias interfering with ADL Disabling Death http://ctep.cancer.gov/reporting/ctc_v30.html Adapted from NLB Consensus Recommendations. In Press, CJON June 2008 Grading based upon: Common Terminology Criteria for Adverse Events (CTCAE) v3.0
  72. 72. PN – Dose/Schedule Modifications VELCADE® Therapy • Grade 1 with pain or Grade 2: Reduce dose to 1 mg/m2 • Grade 3 or Severe: Hold therapy → PN resolves to baseline • Restart at 0.7 mg/m2 • Consider changing treatment to once weekly • Grade 4: D/C therapy Velcade® Prescribing Information; http://ctep.cancer.gov/reporting/ctc_v30.html; Adapted from NLB Consensus Recommendations. In Press, CJON 2008; ACS, 2005; Armstrong et al, 2005, Oncology Nursing Forum; Colson et al., 2004, Clinical Journal of Oncology Nursing; NCCN 2007; NINDS, 2007; Tariman, 2003, Clinical Journal of Oncology Nursing; Visovsky et al., 2007, http://www.ons.org/outcomes/volume2/peripheral/pdf/PEPCardDet_peripheral.pdf
  73. 73. PN – Dose/Schedule Modifications (cont’d) THALOMID® Therapy Grade 1 or Mild: • Continue therapy Grade 2 or Moderate: • Intermittent → Continue therapy • Continuous → Stop therapy and observe whether symptoms persist • If symptoms resolve → Restart therapy at a reduced dose Grade 3 or Severe: • Hold therapy until PN resolves to baseline • Once symptoms resolve → Restart therapy at a reduced dose Grade 4 or Disabling: • Discontinue therapy permanently Adapted from NLB Consensus Recommendations. In Press, CJON June 2008; Thalomid® Prescribing Information; http://ctep.cancer.gov/reporting/ctc_v30.html; Colson et al., 2004, Clinical Journal of Oncology Nursing; NCCN 2007; NINDS, 2007; Tariman, 2003, Clinical Journal of Oncology Nursing; Visovsky et al., 2007, http://www.ons.org/outcomes/volume2/peripheral/pdf/PEPCardDet_peripheral.pdf.
  74. 74. General Strategic Recommendations for the Management of PN Adapted from NLB Consensus Recommendations. In Press, CJON June 2008; NCCN 2007; NINDS, 2007; Tariman, 2003, Clinical Journal of Oncology Nursing; Visovsky et al., 2007, http://www.ons.org/outcomes/volume2/peripheral/pdf/PEPCardDet_peripheral.pdf. Patient Education •Notify if S/S Worsen •Home safety with decreased sensation in extremities •Is driving appropriate? •Family members to assess hot/cold temperatures if patient is unable to do so Non-Pharmaceutical •Gentle massage of affected areas with cocoa butter, capsaicin cream •Home Health Referral to review safety at home •Assistance with ADL •Referrals: Pain management, neurology, physical/occupational therapy
  75. 75. General Strategic Recommendations for the Management of PN (cont’d) For all patients prior to therapy • B-complex vitamins including B1, B6, B12 (at least 400 mcg) • Folic Acid 1 mg daily For grades 2 or higher • Tricyclic antidepressants • Try Amino Acids (eg, acetyl L-carnitine, L-glutamine and alpha lipoic acid) on an empty stomach • Neurontin® , Lyrica® , Cymbalta® • May apply Lidoderm® Patch 5% to affected area every 12 hours Adapted from NLB Consensus Recommendations. In Press, CJON June 2008, Colson et al., 2004, Clinical Journal of Oncology Nursing; NCCN 2007; NINDS, 2007; Tariman, 2003, Clinical Journal of Oncology Nursing; Visovsky et al., 2007, http://www.ons.org/outcomes/volume2/peripheral/pdf/PEPCardDet_peripheral.pdf; Endo Pharmaceuticals; 2006; Lidoderm® (lidocaine
  76. 76. Overview of Gastrointestinal (GI) Side Effects ‘Consensus Statement’ Novel therapeutics can cause serious GI side effects including: • Constipation • Diarrhea • Nausea • Vomiting Adapted from NLB Consensus Recommendations. In Press, CJON June 2008
  77. 77. GI Conditions Are Common Side Effects of Novel Therapies Drug Incidence of Gastrointestinal Adverse Events Reported For All Grades Constipation Diarrhea Nausea Vomiting REVLIMID® * (Two studies combined, N = 346) 39% 29% 22% 10% THALOMID® * (Open label study, N = 102) 55% 12% 28% 12% VELCADE® (Phase 3 trial, N = 331) 42% 57% 57% 35% *REVLIMID® and THALOMID® administered in combination with dexamethasone Thalomid® Prescribing Information, Revlimid® Prescribing Information, Velcade® Prescribing Information Adapted from NLB Consensus Recommendations. In Press, CJON June 2008
  78. 78. Management of Diarrhea Non pharmacologic • Increase fluid intake • Avoid caffeinated, carbonated or heavy sugared drinks • Dietary changes - avoid fiber Pharmacologic • Caution concerning medications for herbal supplements which can cause diarrhea • Antidiarrheal agents: Imodium® , Lomotil® , tincture of opium, Sandostatin® • Intravenous hydration to correct electrolyte imbalance NLB Consensus Recommendations. In Press, CJON 2008; ASCO’s Curriculum Diarrhea 2005; Bush, 2004, Oncology Nursing Forum; Engelking, 2004, Cancer Symptom Management; Mercadante, 2007, Principles & Practice of Palliative Care & Supportive Oncology.
  79. 79. Management of Nausea and Vomiting Non-pharmacologic • Dietary intolerance and restrictions • Avoid exercise and do not lie flat for 2 hrs after eating • Fresh air and loose clothing • Relaxation, guided imagery, biofeedback, acupuncture Adapted from NLB Consensus Recommendations. In Press, CJON 2008; ASCO’s Curriculum Nausea and vomiting 2005; NCI Nausea and vomiting 2007 Pharmacologic • Select anti-emetics based on how strongly the novel agents stimulate N/V and consider type of N/V - Nausea: Ativan® , Compazine® , Decadron® , Pepcid® , Phenergan® , Reglan® , or Zantac® - Vomiting: Emend® , Zofran® , Kytril® , Anzemet® , or Aloxi® • Intravenous hydration to correct electrolyte imbalance
  80. 80. Overview of Steroid Side Effects ‘Consensus Statement’ Steroid Classes: • Glucocorticosteroids • Corticosteroids Steroids are used as single agents and in combination regimens including: • Dexamethasone • Prednisone • Prednisolone Adapted from NLB Consensus Recommendations. In Press, CJON June 2008; Alexanian, Dimopoulos, Delasalle, & Barlogie, 1992
  81. 81. Steroid Side Effects Associated with Multiple Myeloma Therapy Use of steroids can cause multiple system side effects, such as: – Ophthalmic – Gastrointestinal – Endocrine – Cardiovascular – Dermatologic – Constitutional – Psychiatric – Immune – Musculoskeletal – Bone loss – Body image Adapted from NLB Consensus Recommendations. In Press, CJON June 2008; Tariman & Estrella, 2005
  82. 82. Management of Constitutional Symptoms • Mood Alterations - Dose reduction or discontinuation of steroids - SSRI’s or mood stabilizers (Lexapro™, Celexa™, or Zyprexa® ) • “Let down” Effect - Low-dose steroids - Tapered doses of steroids - Dose reduction - Alter activities/schedule • Insomnia - AM dosing - Evaluate sleep habits - Educate patient regarding sleep preparation - Hypnotic/sedatives (drug class determined by type of insomnia) Adapted from NLB Consensus Recommendations. In Press, CJON June 2008; Mitchell et al. 2006; Page et al 2006; Badger et al 2006; Cerullo, 2007
  83. 83. Management of Heme/Immune System Leukocytosis • Increase in the number of white blood cells in the circulating blood Increased Risk of Infection • Interventions - Educate on signs and symptoms of infection - Notify clinician if temperature >100.5°F - Treat with antibiotics if indicated Adapted from NLB Consensus Recommendations. In Press, CJON June 2008
  84. 84. Management of Musculoskeletal System: Muscular Proximal Myopathy • Physical therapy • If severe, hold steroids until improvement Muscle Cramping • Replete electrolyte imbalances • Correct dehydration • Passive range of motion • L-glutamine 1-3 g/day in divided doses • Baclofen has anecdotally been effective Adapted from NLB Consensus Recommendations. In Press, CJON June 2008; Colson et al., 2004
  85. 85. Management of Musculoskeletal System: Bone Osteonecrosis • Evaluation with x-rays (panoramic) or MRI • Prompt orthopedic referral for evaluation • Pain assessment with appropriate pharmacological interventions • Discontinue steroid use • Low incidence (3%) of Avascular Necrosis but still a concern Osteoporosis • Consider baseline bone density scan • Consider supplementation with calcium 1000 mg/day and vitamin D 400 IU/day • IV bisphosphonates Adapted from NLB Consensus Recommendations. In Press, CJON June 2008; Talamo, et al., 2005; Dawson-Hughes et al, 1997; Guise, 2006; Jackson et al., 2006; Lips et al 1996; Sambrook, 2005
  86. 86. Management of Gastrointestinal Effects Flatulence - Evaluate medications - Take Steroids with food in the morning - Restrict high fiber intake - Simethicone/pepto-bismol Hiccups - Home Remedies • Holding breath while drinking water • Swallowing teaspoon of sugar • Drinking from opposite side of glass - Pharmacological • Baclofen • Chlorpromazine • Metaclopramide Adapted from NLB Consensus Recommendations. In Press, CJON June 2008; Woo-Ming, 2007
  87. 87. Management of Endocrine Effects: Hyperglycemia Non-pharmacological recommendations (mild blood glucose elevation, no prior history of diabetes) • Nutrition counseling to avoid simple carbohydrates and sugar • Weight loss if overweight • Increase physical activity Pharmacological recommendations • If serum glucose >200 mg/dL – Glucose monitoring with possible oral hypoglycemics – Diabetic education (signs/symptoms of hyper/hypoglycemia) – Coordination of care with PCP • If serum glucose >300 mg/dL – All of the above may require insulin therapy Adapted from NLB Consensus Recommendations. In Press, CJON June 2008; Adapted from Pogach, et al., 2004
  88. 88. Management of Cardiovascular Effects: Edema Non-pharmacological recommendations - Salt restriction - Elevation of limb - Elastic compression stockings - Increased physical activity Pharmacological recommendations - Consider diuretic use if moderate to severe (HCTZ, Aldactone® or Lasix® ) Adapted from NLB Consensus Recommendations. In Press, CJON June 2008
  89. 89. Overall Recommendations for the 5 Emergent Side Effects of Novel Therapy Effective management includes: • Monitoring patients carefully • Educating patients and caregivers about what to expect during treatment • Appropriate prophylaxis • Pharmacologic and non-pharmacologic interventions Effective management leads to: • Increased adherence to therapy • Improved quality of life • Prevention of serious adverse events leading to prolonged hospitalization, increased morbidity and mortality Adapted from NLB Consensus Recommendations. In Press, CJON June 2008; Ghobrial, et al. (2007) Oncology, 21, 785-792. Lonial, S. (2007) The American Journal of Hematology/Oncology, 6, 194-196.
  90. 90. New Insights on Novel Therapies in Multiple Myeloma Joseph D. Tariman: RN, MN, ARNP-BC, OCN University of Washington Seattle, WA
  91. 91. New Clinical Trial Protocols and Data (from ASH & ASCO 2007) – Focus on Phase III trials of patients with Newly Diagnosed Multiple Myeloma (NDMM) Recent NCCN Guidelines for MM Therapy New Insights on Novel Therapies in Multiple Myeloma
  92. 92. • Offer MM patients personalized targeted therapy • Increased therapeutic efficacy • Improved patient outcomes Future Direction of New Therapy Combinations and Protocols Adapted from NLB Consensus Recommendations. In Press, CJON June 2008; Ghobrial, et al. (2007) Oncology, 21, 785-792. Lonial, S. (2007) The American Journal of Hematology/Oncology, 6, 194-196.
  93. 93. Study Objective – Assess the survival advantage of MP-T vs MP in elderly MM patients ≥75 years – Assess benefit of MP-T vs MP treatment in NDMM patients ≥75 years Study Design – Randomized, Double-Blind, Placebo-Controlled – Patients receive either MP-T (n=113) or MP (n=116) Hulin, et al. ASH Annual Meeting 2007 110: Abstract 75 IFM 01/01-1 Trial: MP-T vs MP in NDMM elderly patients Melphalan-Prednisone-Thalidomide (MP-T) vs Melphalan-Prednisone (MP) in Elderly Patients and MP-T vs MP in Newly Diagnosed Multiple Myeloma (NDMM) Elderly Patients
  94. 94. Primary end point – Overall Survival (OS) Secondary end points – Progression Free Survival (PFS) – Response to Treatment • Partial Response/Remission (PR) • Very Good Partial Response (VGPR) • Progressive Disease (PD) • Complete Response (CR) – Toxicity Methods – 229 patients treated – Trial stopped after second interim analysis – Results compiled after medium follow-up time of 24 months Hulin, et al. ASH Annual Meeting 2007 110: Abstract 75 IFM 01/01-1 Trial: MP-T vs MP in NDMM elderly patients (cont’d)
  95. 95. Cyrille Hulin et al. Blood (ASH Annual Meeting Abstracts) 2007 110: Abstract 75 Results % of Patients who Stopped Tx Observed Toxicities DVT Somnolence Peripheral Neuropathy Neutropenia Depression MP-T Arm 42% 6% 6% 20% 23% 7% MP Arm 11% 4% 3% 5% 9% 2% Results MP-T (n=116) MP (n=113) P value At least PR (50%) 62% 31% P<.0001 VGPR (90%) 22% 7% P<.0001 CR 7% 1% P<.0001 Survival after PD 9.8 months 9.3 months NS Median OS 45.3 months 27.7 months P=.03 PFS 24.1 months 19.0 months P<.0001 Results from IFM 01/01-1 Trial: MP-T vs MP in NDMM Elderly Patients Hulin et al. ASH Annual Meeting 2007 110: Abstract 75 Hulin et al Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings Part I. Vol 25, No. 18S (June 20 Supplement), 2007: 8001)
  96. 96. • MP-T demonstrates survival advantage in elderly patients vs MP • The toxicity was acceptable in this very elderly population – Shortened thalidomide therapy duration may reduce neurotoxicity – LMWH or aspirin could reduce thrombosis • MP-T has potential to become “reference therapy” for older patients Hulin et al. ASH Annual Meeting 2007 110: Abstract 75 Hulin et al. ASCO Annual Meeting 2007 Presentation: Comparison of melphalan-prednisone-thalidomide (MP-T) to melphalan-prednisone (MP) in patients 75 years of age or older with untreated multiple myeloma (MM). Preliminary results of the randomized, double-blind, placebo controlled IFM 01-01 trial. Conclusions from IFM 01/01 Trial: IFM 01/01-1 Trial: MP-T vs MP in NDMM Elderly Patients
  97. 97. Study Objective – MP-T treatment of NDMM patients Study Design – Placebo-Controlled double blind trial – Patients received either MP-T or MP – No prophylaxis recommended for Venous TE – Patients recruited were not eligible for high dose treatment in Norway, Sweden and Denmark End Points – Overall Survival (OS), Event Free Survival, Response to Treatment, Time to Progression (TTP) and Quality of Life MP-T vs MP in NDMM Patients Melphalan-Prednisone-Thalidomide to Newly Diagnosed Patients with Multiple Myeloma: A Placebo Controlled Randomized Phase 3 Trial Waage et al. ASH 2007 Abstract #78; Also appears in Blood, Volume 110, issue 11, November 16, 2007
  98. 98. Methods – Patients received either MP (175 pts) or MP-T (182 pts) – Thalidomide was dose escalated from 200 mg to 400 mg Study Status – Interim analysis performed in 2004 by an independent committee – 362 patientswith mean age of 75 (49–92) years were included, 55% were male – No significant difference in OS or PFS between the study arms, and only a slightly higher TTP in the MP-T arm – The incidence of venous TE in the unblinded treatmentarm was 7% – Final study results not yet available MP-T vs MP in NDMM Patients (cont’d) Waage et al. ASH 2007 Abstract #78; Also appears in Blood, Volume 110, issue 11, November 16, 2007 “Result surprising in light other studies showing advantage of MP-T over MP”
  99. 99. VISTA Trial: VMP vs MP in NDMM Study Objective –Define the differences in efficacy and outcome between VMP vs MP –VISTA Study • (VELCADE® as Initial Standard Therapy in multiple myeloma: Assessment with melphalan and prednisone) trial of VMP compared with MP in patients aged 65 years who are not eligible for transplantation Study Design and Method – Large International Phase 3 randomized study – Patients of median age of 71 years (30% pts ≥75 years) – VMP arm (IV bortezomib in combination with oral prednisone and oral melphalan) vs MP arm (Oral mephalan and prednisone) – Stratified according to baseline β2-microglobulin, albumin and geographic regions San Miguel et al Blood (ASH Annual Meeting Abstracts) 2007 110: Abstract 76 A Phase 3 Study Comparing Bortezomib–Melphalan–Prednisone (VMP) with Melphalan–Prednisone (MP) in NDMM
  100. 100. Primary end point – Time to progression (TTP) Secondary end points – Progression-free survival (PFS), overall survival (OS), overall response rate (ORR), time to progression (TTP) and duration of response (DOR), andsafety Trial Status – Scheduled interim analysis by Independent Data Monitoring Committee to determine primary end point achievement will be undertaken soon – Efficacy and safety analyses will be reported at a later time San Miguel et al Blood (ASH Annual Meeting Abstracts) 2007 110: Abstract 76 VISTA Trial: VMP vs. MP in NDMM (cont’d)
  101. 101. Mateos, et al. Haematologica 2008; 93(4) 560-565 VISTA Trial : VMP vs. MP in NDMM Most Common Adverse Events (in ≥30% patients) Adverse Event % Toxicities all grades % Toxicities grades 3/4 Anemia 86 10 Thrombocytopenia 93 51 Infection 75 16 Neutropenia 85 43 Asthenia 63 5 Nausea 55 2 Diarrhea 55 16 Peripheral Neuropathy 55 17 Constipation 52 8 Anorexia 38 2 Vomiting 30 2
  102. 102. VISTA Trial: VMP vs. MP in NDMM Results Efficacy Results VMP (n=344) MP (n=338) P value CR + PR rate 82% 50% P<.0001 CR rate 35% 5% P<.0001 Median TTR 1.4 months 4.2 months P<.0001 DOR 19.9 months 16.6 months median not reached DOR for patients with CR 24.0 months 12.8 months N/A Median TTP 24.0 months 16.6 months P<.0001 2-year OS 82.6% 69.5% N/A 2-year OS <75 years 84% 74% N/A 2-year OS ≥75 years 79% 60% N/A San-Miguel ASH 2007 presentation; Lederman, ASH 2007 IMF Multiple Myeloma Highlights for Physicians Mateous et al. Haematologica 2008; 93(4), 560-565
  103. 103. Conclusions Adverse Events –46% with VMP –36% with MP Patients remained on therapy longer with VMP –46 weeks with VMP –39 weeks with MP Patients had a longer time to next therapy Patients also had longer treatment-free survival San Miguel et al Blood (ASH Annual Meeting Abstracts) 2007 110: Abstract 76 VISTA Trial: VMP vs. MP in NDMM These results may establish VMP as a new standard of care for patients not eligible for SCT
  104. 104. E4A03: RD vs Rd in NDMM Study Objective –Lenalidomide and High Dose Dexamethasone (RD) vs Lenalidomide plus Low Dose Dexamethasone (Rd) (RD vs Rd in NDMM) Treatment Regimen –RD patients received lenalidomide 25 mg/day PO days 1-21 every 28 days plus dex 40 mg days 1-4, 9-12, and 17-20 PO every 28 days –Rd patients received lenalidomide at the same dose plus dex 40 mg days 1, 8, 15, and 22 PO every 28 days Study Design –Phase 3 randomized trial –445pts (median age 65 yrs) (Arm A 223 pts Oral RD, Arm B 222 pts Oral Rd) Primary End Point –Response rate at 4 months Rajkumar et al. Abstract #74 appears in Blood, Volume 110, issue 11, November 16, 2007 A Randomized Trial of Lenalidomide Plus High-Dose Dexamethasone (RD) Versus Lenalidomide Plus Low-Dose Dexamethasone (Rd) in NDMM
  105. 105. Survival rate results RD Arm Rd Arm P Value OS differences (pts <65 ) 90% 98% P=0.015 OS differences (pts 65 & older) 83% 95% P=0.004 One year survival 86% 96.5% - 18 month survival rate 80% 91% - Results of E4A03: RD vs Rd in NDMM Rajkumar et al. Abstract #74 appears in Blood, Volume 110, issue 11, November 16, 2007 Lederman, ASH 2007 IMF Multiple Myeloma Highlights for Physicians
  106. 106. E4A03 : RD vs Rd in NDMM Toxicities Rajkumar et al. Abstract #74 appears in Blood, Volume 110, issue 11, November 16, 2007 Major Grade 3 or Higher Adverse Events Toxicity RD% Rd% P value Neutropenia 10 19 0.01 DVT/PE 25 9 <0.001 Infections 16 6 <0.001 Any grade 3 or higher non- hematologic 49 32 <0.001 Any grade 4 or higher non- hematologic 20 9 <0.001 Deaths in first 4 months 5 0.5 0.006
  107. 107. Conclusions E4A03: Rd vs RD in NDMM • Rd is associated with superior OS compared to RD • Increased mortality in the RD due to: - Disease progression - Increased toxicity This study has major implications for the use of Rd over RD in the treatment of NDMM patients Rajkumar et al. Abstract #74 appears in Blood, Volume 110, issue 11, November 16, 2007
  108. 108. SWOG Trial S0232 : Len+HD vs HD Study Objective – To compare Len+HD to HD in NDMM Study Design – A randomized, double-blinded, placebo-controlled trial – Trial closed at 198 pts Zonder et al. Abstract #77 appears in Blood, Volume 110, issue 11, November 16, 2007 Superiority of Lenalidomide (Len) Plus High-Dose Dexamethasone (HD) Compared to HD Alone as Treatment of Newly-Diagnosed Multiple Myeloma (NDMM)
  109. 109. SWOG Trial S0232: Len+HD vs HD (cont’d) Primary end point – Progression-free survival (PFS) Secondary end points – Overall response rate (ORR) – Major response rate (MRR) – Overall survival (OS) – Toxicity Methods – Pts randomized to receive Len+HD (100 pts) or HD (98 pts) – Pts were stratified by ISS stage and SWOG performance status – When unblinded to determine disease progression; pts on HD could crossover to Len+HD – Aspirin (ASA) 325 mg/d was mandated due to initial high rate of thrombosis in Len+HD Zonder et al. Abstract #77 appears in Blood, Volume 110, issue 11, November 16, 2007
  110. 110. Results Len+HD HD P Value 1 yr PFS 77% 55% p=0.002 ORR 85.3% 51.3% p=0.001 OS (at 1 yr) 93% 91% p=NS Grade 3-4 neutropenia 13.5% 2.4% p=0.010 Infections n=38, Gr 3-4=13, Gr 5=1 n=23, Gr 3-4=8, Gr 5=0 p=0.003 TEE 25 7 p=0.089 Results SWOG Trial S0232: Len+HD vs. HD Zonder et al. Abstract #77 appears in Blood, Volume 110, issue 11, November 16, 2007
  111. 111. Conclusions of SWOG Trial S0232: Len+HD vs HD Zonder et al. Abstract #77 appears in Blood, Volume 110, issue 11, November 16, 2007 Observed Toxicities Len+HD HD Neutropenia (%) 13.5 2.4 Infections (n) 14/38 8/23 TEE (n) 25/38 7/38
  112. 112. Conclusions of SWOG Trial S0232: Len+HD vs HD (cont’d) • Len+HD are superior in terms of: – ORR – MRR – PFS • Both arms of this study have the highest 1-yr OS reported • ASA 325/mg dose may not be optimal thromboprophylaxis for pts with NDMM • Study modified to include low dose dex (40 mg q wk) with no change in TEE Zonder et al. Abstract #77 appears in Blood, Volume 110, issue 11, November 16, 2007
  113. 113. VTD vs. TD Prior to SCT Study Objective – VTD vs TD in Preparation for Autologous Stem Cell Transplantation (ASCT) in NDMM Study Design – Randomized trial – Three cycles of induction therapy Methods – Pts. randomized to either VDT (n=129) or TD (n=127) – Stem cells were collected – Consolidation therapy with same treatment to pts – Results drawn from an interim analysis of 256 patients Cavo et al. Blood (ASH Annual Meeting Abstracts) 2007 110: Abstract 73 Bortezomib (VELCADE® )-Thalidomide-Dexamethasone (VTD) vs Thalidomide-Dexamethasone (TD) Prior to Stem Cell Transplantation (SCT))
  114. 114. Results VDT TD P value CR + near (n)CR 36% 9% P<.001 At least VGPR 60% 27% P<.001 CR + nCR, del(13) 43% 4% P<.001 CR + nCR, t(4;14) 47% 8% P=.002 CR + nCR after first ASCT 57% 28% P<.001 CR after first ASCT 45% 19% P<.001 At least VGPR after first ASCT 77% 54% P=.003 Cavo ASH 2007 presentation; Lederman, ASH 2007 IMF Multiple Myeloma Highlights for Physicians Cavo et al. Blood (ASH Annual Meeting Abstracts) 2007 110: Abstract 73 Results VTD vs. TD Prior to SCT Adverse events: • Skin rash > in VTD arm • PN > in VTD arm • DVT 3% in VTD arm 6.5% in TD arm • Reactivation of Varicella Zoster Virus (VZV) 2% in VTD arm 1% in TD arm
  115. 115. Prophylaxis – Acyclovir prophylaxis against reactivation of VZV – TEE prophylaxis with low molecular weight heparin, aspirin, or warfarin; fixed low dose warfarin is effective Conclusions – The response rates after first ASCT were significantly higher in the VTD arm – Longer follow-up is necessary after consolidation therapy – Numbers of TE events were too small to draw firm conclusions VTD vs. TD Prior to SCT Cavo et al. Blood (ASH Annual Meeting Abstracts) 2007 110: Abstract 73 Lederman, ASH 2007 IMF Multiple Myeloma Highlights for Physicians
  116. 116. MM-009 and MM-010 Phase III Trials: Len/Dex vs Dex Study Objective –Comparison of Prolonged Overall Survival (OS) with Len/Dex vs Dex in patients with relapsed or refractory MM Study Design –An update of long-term OS data from the two prospective, randomized, double-blind, placebo-controlled phase III trials (MM-009, MM-010) Study End Point –Long-term overall survival (OS) with Len/Dex vs Dex Weber et al. Blood (ASH Annual Meeting Abstracts) 2007 110: Abstract 412 Long-Term Survival Data for Lenalidomide- Dexamethasone vs. Dexamethasone MM-009 and MM-010 Phase III Trials (Len/Dex vs Dex)
  117. 117. Methods for MM-009 and MM-010 Len/Dex vs Dex Studies Methods – Pts without prior resistance to Dex evaluated – Pooled results of 704 patients from both randomized – Trials (MM-009, MM-010) were evaluated • 353 were treated with Len/Dex • 351 with Dex alone Response rate and TTP are basedon data obtained before un-blinding 47% of patients who received Dexcrossed over to Len/Dex Weber et al. Blood (ASH Annual Meeting Abstracts) 2007 110: Abstract 412
  118. 118. Results Len/Dex Dex P Value Overall response, % 60.6 21.9 <0.001 Complete remission rate, % 15.0 2.0 <0.001 Median TTP, months 11.2 4.7 <0.001 Median OS, months 35.0 31.0 <0.05 Median OS in patients with 1 prior treatment, months Not yet Reached 35.3 0.24 Median OS in patients with >1 prior treatment, months 32.4 27.3 <0.05 Weber et al. Blood (ASH Annual Meeting Abstracts) 2007 110: Abstract 412 MM-009 and MM-010: Long Term Survival Data for Len/Dex vs. Dex Conclusion: Significant improvement in OS achieved with Len/Dex
  119. 119. • New combinations of novel therapies may offer personalized targeted therapy – Increased therapeutic efficacy • Important to monitor these new combinations for emergent adverse side effects • Effective nursing management will help to optimize patient adherence and outcomes Future Direction of New Therapy Combinations and Protocols of Novel Therapies Adapted from NLB Consensus Recommendations. In Press, CJON June 2008; Ghobrial, et al. (2007) Oncology, 21, 785- 792. Lonial, S. (2007) The American Journal of Hematology/Oncology, 6, 194-196.
  120. 120. Recent NCCN Guidelines for MM: Induction Therapy NCCN Practice Guidelines in Oncology-v.1.2008 Multiple Myeloma: Induction Therapy Note: All recommendations are category 2A unless otherwise indicated
  121. 121. • Selected, but not inclusive of all regimens • Order does not imply preference • Consider herpes zoster prophylaxis for patients treated with single agent bortezomib • Prophylactic anticoagulation recommended for patients receiving thalidomide-based therapy or lenalidomide with dexamethasone Recent NCCN Guidelines for MM Induction Therapy: General Notes NCCN Practice Guidelines in Oncology-v.1.2008 Multiple Myeloma
  122. 122. NCCN Guidelines: Primary Induction Therapy for Transplant Candidates: • Vincristine/doxorubicin/dexamethasone (VAD) • Dexamethasone • Thalidomide/dexamethasone • Liposomal doxorubicin/vincristine/dexamethasone (DVD) • Lenalidomide/dexamethasone (category 2B) • Bortezomib/dexamethasone (category 2B) • Bortezomib/doxorubicin/dexamethasone (category 2B) • Bortezomib/thalidomide/dexamethasone (category 2B) NCCN Practice Guidelines in Oncology-v.1.2008 Multiple Myeloma Exposure to myelotoxic agents (including alkylating agents and nirtrosoureas) should be limited to avoid compromising stem-cell reserve prior to stem-cell harvest in patients who may be candidates for transplant
  123. 123. NCCN Guidelines: Primary Induction Therapy for Non-transplant Candidates: • Melphalan/prednisone (MP) • Melphalan/prednisone/thalidomide (MPT) (category 1) • Melphalan/prednisone/bortezomib (MPB) (category 2B) • Vincristine/doxorubicin/dexamethasone (VAD) • Dexamethasone • Thalidomide/dexamethasone • Liposomal doxorubicin/vincristine/dexamethasone (DVD) (category2B) NCCN Practice Guidelines in Oncology-v.1.2008 Multiple Myeloma
  124. 124. NCCN Guidelines: Maintenance Therapy • Steroids (category 2B) • Interferon (category 2B) NCCN Practice Guidelines in Oncology-v.1.2008 Multiple Myeloma
  125. 125. NCCN Guidelines: Salvage Therapy • Repeat primary induction therapy (if relapse at >6 mo) • Bortezomib (category 1)1,2 • Bortezomib/dexamethasone1,2 • Bortezomib/liposomal doxorubicin (category1)1,2 1 Bortezomib/liposomal doxorubicin is preferred to bortezomib single agent 2 Bortezomib single agent is preferred to bortezomib/dexamethasone NCCN Practice Guidelines in Oncology-v.1.2008 Multiple Myeloma
  126. 126. NCCN Guidelines: Salvage Therapy (cont’d) Lenalidomide/dexamethasone1,2,3 1 Lenalidomide/dexamethasone is FDA approved for patients with myeloma who received at least one prior therapy 2 Currently there are two phase lll randomized clinical trials (approximately 700 patients total) demonstrating benefit 3 The panel awaits publication before designating as a category 1 recommendation NCCN Practice Guidelines in Oncology-v.1.2008 Multiple Myeloma
  127. 127. NCCN Guidelines: Salvage Therapy (cont’d) • Lenalidomide • Cyclophosphamide-VAD • High-dose cyclophosphamide • Thalidomide • Thalidomide/dexamethasone • Dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, and etoposide (DT-PACE) • Dexamethasone • Dexamethasone, cyclophosphamide, etoposide, and cisplatin (DCEP) NCCN Practice Guidelines in Oncology-v.1.2008 Multiple Myeloma
  128. 128. Closing Remarks Beth Faiman: RN, MSN, APRN, BC, AOCN Cleveland Clinic Taussig Cancer Institute Cleveland, Ohio
  129. 129. NLB Accomplishments The initial guidelines cover the following: The development of ‘Consensus Statements’ on the nursing management of side effects that patients with multiple myeloma can experience while being treated with novel therapies Peripheral Neuropathy DVT and PE Myelosuppression GI Effects Steroid Effects Adapted from NLB Consensus Recommendations. In Press, CJON June 2008
  130. 130. IMF NLB’s CJON Supplement Publication Title Development of Consensus Statements by the International Myeloma Foundation’s Nurse Leadership Board for the Management of Side Effects of Novel Therapies for Multiple Myeloma Adapted from NLB Consensus Recommendations. In Press, CJON June 2008
  131. 131. Key Information • Clinical Journal Oncology Nursing (CJON) • Number of supplements to be printed - 37,000 • ‘Patient Education Insert Tear Out Tools’ for 5 Side Effects PUBLICATION IN JUNE 2008 CJON ‘Consensus Statements’ supplement publication offers an additional CEU accreditation opportunity
  132. 132. Patient Education Tear-Out Tools General Format and Clinical Utility • Side effect description • Novel therapies that may be associated with the side effect • Signs and symptoms • Risk factors • Healthcare provider recommendations Adapted from NLB Consensus Recommendations. In Press, CJON June 2008
  133. 133. • Publication of the ‘Consensus Statements’ will be immeasurably valuable to the general nursing community involved in multiple myeloma patient care • Communication and dissemination of the ‘Consensus Documents’ are important next steps • Develop new educational materials/tools - Patient related - Nurse related Focus of NLB Commitment
  134. 134. Communication & Dissemination • Patient and Nurse Educational Slide Sets Development • NLB Speaker’s Bureau • Oncology Conference Presentations • ONS Website - www.ons.org • IMF Website - www.myeloma.org
  135. 135. Educational Resources • American Cancer Society • National Cancer Institute • International Myeloma Foundation - IMF Myeloma Today Newsletter - 1 800 425 CURE - IMF Website • www.myeloma.org
  136. 136. Future Goals of NLB Frame the Importance of Nursing Management of Long Term Side Effects Associated With MM Therapies Develop long term care plan information guidelines and booklet Expand initiative to collaborate with nurses worldwide
  137. 137. 1. Symposium Accreditation Process Please complete the CE Certificate Registration and Program Evaluation Form found in the guidebook and return this completed form to the registration desk to receive 2.0 CEU credits 2. CJON Supplement Accreditation Opportunity Please visit www.cjon.org and complete the online tests for a maximum of 3.8 additional CEU credits
  138. 138. Question & Answer Session Faculty Panel

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