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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
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 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.
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approver by the American Nurses Credentialing
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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
Faculty
Chair:
Beth Faiman: RN, MSN, APRN,
Kena C. Miller: RN, MSN, FNP
BC, AOCN
Cleveland Clinic Taussig
Cancer Institute
Cleveland, Ohio
Roswell Park Cancer Institute
Buffalo, New York
Faculty:
Lisa C. Smith: MSN, FNP, AOCN Joseph D. Tariman: RN, MN,
Cancer Centers of the Carolinas
Greenville, South Carolina
ARNP-BC, OCN
University of Washington
Seattle, Washington
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
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
Multiple Myeloma Causes,
Symptoms and Treatment
Multiple Myeloma: A Current Perspective
• Etiology of multiple myeloma (MM)
• Epidemiology of multiple myeloma
• Current and novel therapies in the
management of multiple myeloma
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
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.
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.
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.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.
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
Major Symptoms at Diagnosis
• Bone pain 58%
• Fatigue 32%
• Weight loss 24%
• Paresthesias 5%
• Asymptomatic 11%
Kyle RA. Mayo Clin Proc 2003;78:21
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
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)
*Monoclonal M spike on electrophoresis IgG>3.5g/dL, IgA>2g/dL, light chain >1g/dL in 24-hr urine sample
Durie et al for the International Myeloma Working Group. Leukemia. 2006:1-7.
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.
Durie-Salmon Staging System
for Multiple Myeloma
Myeloma cell mass
( 1012 cells/m2)
Stage
Criteria
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)
Subclassification Criteria
A Normal renal function (serum creatinine level <2.0 mg/dL)
B Abnormal renal function (serum creatinine level 2.0 mg/dL)
Durie B, Salmon S. Cancer. 1975;36(9):842-854
International Staging System for
Symptomatic Multiple Myeloma
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
2M=serum 2 microglobulin in mg/dL; ALB=serum albumin in g/dL
Greipp PR, et al. Blood 2005; 102: 190a
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.
MM Treatment Options
Conventional chemotherapy:
•
•
•
Melphalan
Doxorubicin
Cyclophosphamide
Steroid therapy:
•
•
Dexamethasone
Prednisone
Novel therapeutics:
•
•
•
Thalidomide
Lenalidomide
Bortezomib
Stem cell transplantation:
•
•
Autologous
Allogeneic
Radiation therapy
Thalomid ® Prescribing Information, Revlimid ® Prescribing
Information; Velcade® Prescribing Information
Novel Therapies:
Mechanisms of Action (MOA)
• Thalidomide (THALOMID®)
– Immunomodulatory, anti-inflammatory, and anti-angiogenic agent
– Suppresses production of TNF-, 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
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
Novel and Emerging Therapies for
Multiple Myeloma
Benefits and Challenges
Recent FDA Approvals of Novel Agents
Accelerated
Approval
(AA)
Regular
Approval
(RA)
Approval based upon:
Response
Rate
Time to Progression
(TTP)
VELCADE®
2003
2005
REVLIMID®
___
2006
THALOMID®
with
dexamethasone
2006
___
DOXIL® with
VELCADE®
Thalomid® Prescribing Information, Revlimid® Prescribing Information
Velcade® Prescribing Information, Doxil® Prescribing Information
2006
Key Benefits of Novel and
Emerging Therapies
•
•
•
•
Targeted therapies with novel
mechanisms of action
Provide increased response rate
Provide increased time to progression
Lead to increased survival time
IMF-NLB ‘Consensus Statements’ supplement In Press, CJON June 2008;
Rajkumar et al., 2005; Richardson & Anderson, 2006; Richardson, Hideshima, Mitsiades, & Anderson, 2007
Key Challenges of Novel and
Emerging Therapies
•
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
IMF-NLB ‘Consensus Statements’ supplement In Press, CJON June 2008
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
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
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
Updated Side Effects Profile
REVLIMID® +
dexamethasone
Most Commonly
Reported Side Effects
> 20% for all Grades
Percentage
of patients
Constipation
Fatigue
Insomnia
Muscle Cramp
Diarrhea
Neutropenia
Anemia
Loss/Lack of Strength
Fever
Nausea
Headache
Peripheral edema
Dizziness
39%
38%
32%
30%
29%
28%
24%
23%
23%
22%
21%
21%
21%
http://www.revlimid.com/pdf/REVLIMID_PI.pdf
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
Updated Side Effects Profile
THALOMID® +
dexamethasone
http://www.thalomid.com/pdf/Thalomid_Pl.pdf
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%
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/
Updated Side Effects Profile
Low Dose Dexamethasone/Lenalidomide
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)
Toxicity (Grade >3)
Arm A
(N=223)
Arm B
(N=222)
Neutropenia
2.7%
3.2%
Thrombocytopenia
1.8%
1.4%
18.4%
6.3%
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%
DVT/PE
Atrial fibrillation/flutter
Rajkumar V, et al. Blood. 2006;108:[abstract 799].
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%
Hand-foot syndrome (HFS) may occur during therapy with DOXIL®
http:http://www.doxil.com/common/prescribing_information/DOXIL/PDF/DOXIL_PI_Booklet.pdf//www.doxil.com/
Consequences of Inadequately
Managed Side Effects
Psychological Impact
Physiological Impairment
Reduced Adherence
Lowered self esteem,
anxiety and depression
which will adversely impact
the patient’s overall health
Adverse side effects that
are not properly managed
may lead to a variety of
physiological impairments
Therapy associated side
effects lead to a reduction
in patient’s desire and
ability to comply with
dosing schedules
Social Consequences
Lower Persistence
Reduced Efficacy
Reduced ability to function
optimally within
relationships, work and
other social contexts
Patients are less inclined
to remain on a therapy for
which side effects are not
adequately managed
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
IMF Nurse Leadership Board
Statement of Need Catalyzes Creation
of a Nurse Centric Initiative
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
IMF-NLB ‘Consensus Statements’ supplement In Press, CJON June 2008
Nurse Centric Model of Patient Care*
Patient Monitoring
Patient Management
Patient Counseling
Patient Research
Nurses are Central to
Patient Management and
Healthcare Resource
Coordination
Patient Advocacy
* Developed by ScienceFirst, LLC; All Rights Reserved (www.science-first.com)
Patient Education
Effective Nursing Tools Improve Patient
Care and Treatment Outcomes
•
•
•
•
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
IMF-NLB ‘Consensus Statements’ supplement In Press, CJON June 2008
IMF NLB Process for Developing
Consensus Statements
A Collaborative Assessment was Performed of
Evidence-based and Practice-based Knowledge
and the Nursing Experience of Key Emergent
Side Effects with Novel Therapies
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
20 Nurse Leaders
5 Teams
DVT/PE
Peripheral
Neuropathy
Joseph Tariman
Sandra Rome
Jeanne Westphal
Stacey Sandifer
Deborah Doss
Ginger Love
Kena Miller
Emily McCullagh
Myelosuppression
GI
Steroid Effects
Teresa Miceli
Lisa Smith
Beth Faiman
Maria Gavino
Bonnie Jenkins
Katy Rogers
Kathleen Colson
Kathleen Curran
Patricia Mangan
Kathy Lilleby
Page Bertolotti
Elizabeth Bilotti
‘Consensus Statements’: Review Process
NLB Received One Document With Comment Sheet Per Week
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
5
‘Consensus Statements’: Team Effort
10 months
120 Teleconference Calls
1,300 E-mails exchanged
1,600 work hours
40 weeks of work
5 Consensus Statements
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.
2.
3.
4.
5.
IMF-NLB
Myelosuppression
Deep Vein Thrombosis/Pulmonary Embolism
Peripheral Neuropathy
Gastrointestinal Effects
Steroids Related Side Effects
‘Consensus Statements’ supplement In Press, CJON June 2008
NLB ‘Consensus Statements’
Development and Publication Strategy
Consensus Statements
Review Process
Editing and
Formatting
Myelosuppression
NLB
DVT/PE
NLB
Peripheral neuropathy
Planned
meetings
and
coordination
GI
Steroids
IMF-NLB ‘Consensus Statements’ supplement In Press, CJON June 2008
Finalization
Planned meetings and
coordination
Publication
in Clinical
Journal of
Oncology
Nursing
June ‘08
Development of The NLB ‘Consensus
Statements’ as a Model of Care
•
•
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)
NLB Vision for the Future
•
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
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
Leadership in Action: Clinical Utility of
the NLB Consensus Statements
Kena C. Miller: RN, MSN, FNP
Roswell Park Cancer Institute
Buffalo, NY
Overview of The ‘Consensus Statements’
General Format of Publications
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
IMF-NLB ‘Consensus Statements’ supplement In Press, CJON June 2008
Myelosuppression:
Definition and Symptoms
Anemia
Red Blood Cells
– Fatigue, malaise
and SOB
Lymphocyte
Monocyte
Marrow
White Blood Cells
Eosinophil
Neutropenia
Basophil
– Increased risk of
bacterial, fungal
and viral infections
Neutrophil
Thrombocytopenia
Platelets
– Bruising and
bleeding
http://www.schneiderchildrenshospital.org/peds_html_fixed/peds/transplant/bonetran.htm; Adapted from NLB Consensus
Recommendations. In Press, CJON June 2008
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%
Grading based upon:
Common Terminology Criteria for Adverse Events (CTCAE) v3.0
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
Management of Neutropenia:
REVLIMID®
When ANC
Recommended Course
Fall to <1000/mm3
Interrupt REVLIMID® treatment, add
G-CSF, follow CBC weekly
Return to >1000/mm3 and
Resume REVLIMID® at 25 mg daily
neutropenia is the only toxicity
Return to >1000/mm3 and
neutropenia if other toxicity
Resume REVLIMID® at 15 mg daily
For each subsequent drop
below <1000/mm3
Interrupt REVLIMID® treatment
Return to >1000/mm3
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
Management of Thrombocytopenia:
REVLIMID®
When Platelets
Recommended Course
Fall to <30,000/mm3
Interrupt REVLIMID® treatment,
follow CBC weekly
Return to >30,000/mm3
Restart REVLIMID® at 15 mg daily
For each subsequent drop
<30,000/mm3
Interrupt REVLIMID® treatment
Return to >30,000/mm3
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
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
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
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)
TE events are serious and potentially life-altering and life-threatening
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
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
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
PE is a Medical Emergency
http://www.nhlbi.nih.gov/health/dci/Diseases/Dvt/DVT_SignsAndSymptoms.html
Adapted from NLB Consensus Recommendations. In Press, CJON June 2008
TE Event - Diagnostics
DVT
PE
• Doppler Ultrasound
• Ventilation Perfusion Lung
(VQ) Scan
• Contrast Venography
• D-Dimer
• Antithrombin Level
• Spiral CT Scan
• D-Dimer
• Antithrombin Level
To maintain therapeutic level INR 2-3
http://www.nhlbi.nih.gov/health/dci/Diseases/Dvt/DVT_Diagnosis.html
Adapted from NLB Consensus Recommendations. In Press, CJON June 2008
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
Thromboembolic Events - Prophylaxis
Pharmaceutical
Agent
Suggested Dose
Salicylic Acid (aspirin)
SD 325 mg or LD 81 mg daily
Unfractionated Heparin
5000 IU sq bid
Low Molecular Weight Heparin
- enoxaparin
- dalteparin
40mg sq daily
Fondaparinux
2.5 mg sc daily
Warfarin
Weight based
200IU/kg sc daily
• 1 mg < 70 kg
• 2 mg ≥ 70 kg
Prophylaxis tailored to individual patient’s risk profile in consideration of
the International Myeloma Working Group consensus statement*
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.
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
Overview of Peripheral Neuropathy (PN)
‘Consensus Statement’
• 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
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.
PN Definition, Signs/Symptoms
Damage to the peripheral nervous system including any injury,
inflammation, or degeneration of peripheral nerve fibers
Signs/symptoms
Severe symptoms
• Temporary Numbness
• Burning Pain
• Tingling
• Muscle Wasting
• Parasthesias
• Paralysis
• Sensitivity to Touch
• Organ Dysfunction
• Muscle Weakness
Adapted from NLB Consensus Recommendations. In Press, CJON June 2008
http://www.ninds.nih.gov/disorders/peripheralneuropathy/detail_peripheralneuropathy.htm
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
Grading based upon:
Common Terminology Criteria for Adverse Events (CTCAE) v3.0
http://ctep.cancer.gov/reporting/ctc_v30.html
Adapted from NLB Consensus Recommendations. In Press, CJON June 2008
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
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.
General Strategic Recommendations for
the Management of PN
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
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.
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
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
GI Conditions Are Common
Side Effects of Novel Therapies
Drug
Incidence of Gastrointestinal Adverse Events Reported
For All Grades
Constipation
Diarrhea
Nausea
Vomiting
39%
29%
22%
10%
55%
12%
28%
12%
42%
57%
57%
35%
REVLIMID®*
(Two studies combined,
N = 346)
THALOMID®*
(Open label study,
N = 102)
VELCADE®
(Phase 3 trial,
N = 331)
*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
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.
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
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
Adapted from NLB Consensus Recommendations. In Press, CJON 2008; ASCO’s Curriculum Nausea and vomiting 2005;
NCI Nausea and vomiting 2007
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
Steroid Side Effects Associated with
Multiple Myeloma Therapy
Use of steroids can cause multiple system side
effects, such as:
–
–
–
–
–
–
Constitutional
Psychiatric
Immune
Musculoskeletal
Bone loss
Body image
–
–
–
–
–
Ophthalmic
Gastrointestinal
Endocrine
Cardiovascular
Dermatologic
Adapted from NLB Consensus Recommendations. In Press, CJON June 2008; Tariman & Estrella, 2005
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
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
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
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
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
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
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
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.
New Insights on Novel Therapies in
Multiple Myeloma
Joseph D. Tariman: RN, MN, ARNP-BC, OCN
University of Washington
Seattle, WA
New Insights on Novel Therapies
in Multiple Myeloma
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
Future Direction of New Therapy
Combinations and Protocols
• Offer MM patients personalized
targeted therapy
• Increased therapeutic efficacy
• Improved patient outcomes
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.
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
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 (cont’d)
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
Results from IFM 01/01-1 Trial: MP-T vs MP
in NDMM Elderly Patients
Results
% of Patients who
Stopped Tx
Observed Toxicities
DVT
MP-T Arm
MP Arm
Somnolence
Peripheral
Neuropathy
Neutropenia
Depression
42%
Cyrille Hulin et al. Blood (ASH Annual Meeting
6%
6% 2007 110: Abstract
20% 75
Abstracts)
23%
7%
11%
4%
9%
2%
3%
5%
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
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)
Conclusions from IFM 01/01 Trial: IFM 01/01-1
Trial: MP-T vs MP in NDMM Elderly Patients
• 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.
MP-T vs MP in NDMM Patients
Melphalan-Prednisone-Thalidomide to Newly Diagnosed
Patients with Multiple Myeloma: A Placebo Controlled
Randomized Phase 3 Trial
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
Waage et al. ASH 2007 Abstract #78; Also appears in Blood, Volume 110, issue 11, November 16, 2007
MP-T vs MP in NDMM Patients (cont’d)
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 patients with 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 treatment arm was 7%
– Final study results not yet available
“Result surprising in light other studies showing
advantage of MP-T over MP”
Waage et al. ASH 2007 Abstract #78; Also appears in Blood, Volume 110, issue 11, November 16, 2007
VISTA Trial: VMP vs MP in NDMM
A Phase 3 Study Comparing Bortezomib–Melphalan–Prednisone
(VMP) with Melphalan–Prednisone (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
VISTA Trial: VMP vs. MP in NDMM
(cont’d)
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), and safety
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
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
Mateos, et al. Haematologica 2008; 93(4) 560-565
VISTA Trial: VMP vs. MP
in NDMM 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
82.6%
69.5%
N/A
2-year OS <75 years
84%
74%
N/A
2-year OS ≥75 years
79%
60%
N/A
Efficacy Results
2-year OS
San-Miguel ASH 2007 presentation; Lederman, ASH 2007 IMF Multiple Myeloma Highlights for Physicians
Mateous et al. Haematologica 2008; 93(4), 560-565
VISTA Trial: VMP vs. MP in NDMM
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
These results may establish VMP as a new
standard of care for patients not eligible for SCT
San Miguel et al Blood (ASH Annual Meeting Abstracts) 2007 110: Abstract 76
E4A03: RD vs Rd in NDMM
A Randomized Trial of Lenalidomide Plus High-Dose Dexamethasone (RD) Versus
Lenalidomide Plus Low-Dose Dexamethasone (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
Results of E4A03: RD vs Rd in NDMM
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%
-
Rajkumar et al. Abstract #74 appears in Blood, Volume 110, issue 11, November 16, 2007
Lederman, ASH 2007 IMF Multiple Myeloma Highlights for Physicians
E4A03 : RD vs Rd in NDMM Toxicities
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 nonhematologic
49
32
<0.001
Any grade 4 or
higher nonhematologic
20
9
<0.001
Deaths in first
4 months
5
0.5
0.006
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 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
SWOG Trial S0232 : Len+HD vs HD
Superiority of Lenalidomide (Len) Plus High-Dose
Dexamethasone (HD) Compared to HD Alone as Treatment
of Newly-Diagnosed Multiple Myeloma (NDMM)
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
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
Results SWOG Trial S0232:
Len+HD vs. HD
Results
Len+HD
HD
P Value
1 yr PFS
77%
55%
p=0.002
85.3%
51.3%
p=0.001
93%
91%
p=NS
13.5%
2.4%
p=0.010
n=38, Gr 3-4=13, Gr 5=1
n=23, Gr 3-4=8, Gr 5=0
p=0.003
25
7
p=0.089
ORR
OS (at 1 yr)
Grade 3-4 neutropenia
Infections
TEE
Zonder et al. Abstract #77 appears in Blood, Volume 110, issue 11, November 16, 2007
Conclusions of SWOG Trial S0232:
Len+HD vs HD
Observed Toxicities
Len+HD
HD
Neutropenia (%)
13.5
2.4
Infections (n)
14/38
8/23
TEE (n)
25/38
7/38
Zonder et al. Abstract #77 appears in Blood, Volume 110, issue 11, November 16, 2007
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
VTD vs. TD Prior to SCT
Bortezomib (VELCADE®)-Thalidomide-Dexamethasone
(VTD) vs Thalidomide-Dexamethasone (TD) Prior to Stem
Cell Transplantation (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
Results VTD vs. TD Prior to SCT
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
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
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
VTD vs. TD Prior to SCT
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
Cavo et al. Blood (ASH Annual Meeting Abstracts) 2007 110: Abstract 73
Lederman, ASH 2007 IMF Multiple Myeloma Highlights for Physicians
MM-009 and MM-010 Phase III Trials:
Len/Dex vs Dex
Long-Term Survival Data for LenalidomideDexamethasone vs. Dexamethasone 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
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 based on data obtained
before un-blinding
47% of patients who received Dex crossed over to
Len/Dex
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
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
Not yet
Reached
35.3
0.24
32.4
27.3
<0.05
Median OS in patients with 1 prior
treatment, months
Median OS in patients with >1 prior
treatment, months
Conclusion: Significant improvement in OS
achieved with Len/Dex
Weber et al. Blood (ASH Annual Meeting Abstracts) 2007 110: Abstract 412
Future Direction of New Therapy
Combinations and Protocols of Novel Therapies
• 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
Adapted from NLB Consensus Recommendations. In Press, CJON June 2008; Ghobrial, et al. (2007) Oncology, 21, 785792. Lonial, S. (2007) The American Journal of Hematology/Oncology, 6, 194-196.
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
Recent NCCN Guidelines for MM
Induction Therapy: General Notes
• 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
NCCN Practice Guidelines in Oncology-v.1.2008 Multiple Myeloma
NCCN Guidelines: Primary Induction
Therapy for Transplant Candidates:
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
•
•
•
•
•
•
•
•
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
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
NCCN Guidelines:
Maintenance Therapy
• Steroids (category 2B)
• Interferon (category 2B)
NCCN Practice Guidelines in Oncology-v.1.2008 Multiple Myeloma
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
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
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
Closing Remarks
Beth Faiman: RN, MSN, APRN, BC, AOCN
Cleveland Clinic Taussig Cancer Institute
Cleveland, Ohio
NLB Accomplishments
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
The initial guidelines cover the following:
Peripheral Neuropathy
DVT and PE
Myelosuppression
GI Effects
Steroid Effects
Adapted from NLB Consensus Recommendations. In Press, CJON June 2008
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
Key Information
PUBLICATION IN JUNE 2008
•
Clinical Journal Oncology Nursing (CJON)
•
Number of supplements to be printed - 37,000
•
‘Patient Education Insert Tear Out Tools’ for
5 Side Effects
CJON ‘Consensus Statements’ supplement
publication offers an additional CEU accreditation
opportunity
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
Focus of NLB Commitment
•
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
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
Educational Resources
•
American Cancer Society
•
National Cancer Institute
•
International Myeloma Foundation
- IMF Myeloma Today Newsletter
- 1 800 425 CURE
- IMF Website
•
www.myeloma.org
Future Goals of NLB
Expand initiative to collaborate with
nurses worldwide
Frame the Importance of Nursing
Management of Long Term Side Effects
Associated With MM Therapies
Develop long term care plan information
guidelines and booklet
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
Question & Answer Session
Faculty Panel