Management of Novel Therapeutics' Side
Effects : A Nurse Centric Model
Sponsored by Medical Education Resources
Supported by The International Myeloma Foundation
Grant Funding is provided by
Celgene Corporation and Millennium Pharmaceuticals
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)
32nd Annual Congress, April 24-27, 2007 in Las
Vegas, Nevada. 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.
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.
Faculty
Chair:
Patricia Mangan: MSN, CRNP
Sandra Rome: RN, MN, AOCN
Abramson Cancer Center
Cedars-Sinai Medical Center
University of Pennsylvania
Los Angeles, California
Philadelphia, Pennsylvania
Teresa S. Miceli: RN, BSN
Joseph D. Tariman: RN/APN,
Mayo Medical Center
MN, APRN, BC, OCN
Rochester, Minnesota
University of Washington
Seattle, Washington
Welcome and Opening Remarks
Patricia A. Mangan, MSN, CRNP
Abramson Cancer Center
University of Pennsylvania
Philadelphia, Pennsylvania
Learning Objectives
· Describe the currently available novel
multiple myeloma therapies
· Discuss critical issues in nursing
management and medical implications of side
effects associated with multiple myeloma
therapeutic agents
· Identify strategies for improving the quality of
care and outcomes for patients by effective
management of side effects
Agenda
Time
Topics
Presenter
6:15 - 6:20
Welcome and Agenda Review
Patricia Mangan,
MSN, CRNP
6:20 - 6:50
Current Management of Multiple Myeloma
Patricia Mangan,
MSN, CRNP
6:50 - 7:15
Management of Myelosuppression Associated
Teresa S. Miceli,
with Novel Therapeutic Agents
RN, BSN
7:15 - 7:40
Management of Peripheral Neuropathy
Joseph D. Tariman,
Associated with Novel Therapeutic Agents
RN/APN, MN,
APRN, BC, OCN
7:40 - 8:05
Management of DVT/PE Associated with Novel
Sandra Rome, RN,
Therapeutic Agents
MN, AOCN
8:05 - 8:15
Improving Patient Support and Education
Patricia Mangan,
MSN, CRNP
Current Management of
Multiple Myeloma
Patricia A. Mangan, MSN, CRNP
Abramson Cancer Center
University of Pennsylvania
Nurse Centric Model of Patient Management
Patient Monitoring
Patient Management
Patient Counseling
Patient Research
Nurses are Central to
Patient Management and
Healthcare Resource
Coordination
Patient Advocacy
Patient Education
Nurses' Roles in Managing Patients
With Multiple Myeloma
Patient Monitoring
Patient Management
Patient Counseling
Patient Research
Nurses are Central to
Patient Management and
Healthcare Resource
Coordination
Patient Advocacy
Patient Education
Multiple Myeloma: A Current Perspective
· Etiology of multiple myeloma
· Epidemiology of multiple myeloma
· Current and novel therapies in the management
of multiple myeloma
Relevant Nurse Centric Areas of Activity
Patient Research
Patient Education
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 and
destruction of bone tissue
San Miguel JF, et al. Pathogenesis of Multiple Myeloma: Rationale for New and Novel Therapies. Clinical Care Options: Accessed 22 February, 2007.
http://clinicaloptions.com/Oncology/Treatment%20Updates/Myeloma/Modules/Pathophysiology/Pages/Page%203.aspx.
Myeloma Cells 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/Cedars­Sinai 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
­ Osteolytic bone lesions
­ Hypercalcemia
­ Bone marrow suppression (pancytopenia)
· Production of monoclonal M proteins causes
­ Decreased levels of normal immunoglobulins
­ Hyperviscosity
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
Myeloma Bone Pathology
Lytic Lesions
· 67% incidence at
diagnosis
· Conventional x-rays
show "punched out"
lesions where
bone has eroded
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 >1 g/dL in 24-hr urine sample
Durie et al for the International Myeloma Working Group. Leukemia. 2006:1-7.
Durie-Salmon Staging System for Myeloma
Myeloma cell mass
Stage
Criteria
(× 1012 cells/m2)
I
All of the following:
<0.6 (low)
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
II
Not fitting stage I or III
0.6­1.2 (intermediate)
III
One or more of the following:
>1.2 (high)
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
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 Myeloma
STAGE
VALUES
ß M <3.5 mg/dL
Stage 1
2
ALB 3.5 g/dL
Stage 2
Not Stage 1 or 3
Stage 3
ß M >5.5 mg/dL
2
2M=serum 2 microglobulin in mg/dL; ALB=serum albumin in g/dL
Greipp PR, et al. Blood 2005; 102: 190a
Challenges in Management
· Currently incurable in most patients
· Chemotherapy response rates = 50% to 70%
­ Long-term complete responses are rare
­ Median survival with standard therapy is about 3 years
· Autologous stem cell transplant prolongs 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.
Treatment Options
Conventional Chemotherapy:
· Dexamethasone
· Melphalan
· Prednisolone
Novel therapeutics:
· Thalidomide
· Lenalidomide
· Bortezomib
Stem cell transplantation:
· Autologous
· Allogeneic
Radiation therapy
Novel Therapeutics ­
What is Targeted Therapy
Normal
Cells
Cancer
Cells
Drugs targeted at pathways, processes and physiology
which are uniquely disrupted in cancer cells:
· Receptors
· Genes
· Angiogenesis
· Tumor pH
New agents may enhance efficacy either alone or
combined with chemotherapy and or radiation
Novel Therapy: Advancement in Care
Conventional Chemotherapy Novel Targeted Agents
Target metabolites incorp.
Target aberrant molecules
into DNA/RNA
or pathways unique to
Mechanism Target microtubules:
cancer cells
impaired meiosis
Activity
Cytotoxic
Static or toxic
Specificity/ Low specificity, targets
Higher specificity for
Efficacy
proliferating cells
tumor cells
Toxicity
Broad toxicity
Lower toxicity
Adapted and modified from Amato Giaccia, MD; Stanford University.
Thalidomide/Lenalidomide Target MM Cells
in the BM Microenvironment
Thal/IMiDs
Inhibition of proliferation
Thal/IMiDs
Induction of Cell Cycle
Arrest/Apoptosis
Inhibition of
MM Cells
Adhesion:
VCAM
Bone Marrow
Thal/IMiDs
Selections
Stromal Cells
Cellular
X
Interaction
X
Inhibition of
T Cell activation
Bone Marrow
expression
and proliferation
Blood Vessels
Stimulation of
Thal/IMiDs
production
VEGF
X
IL-6
Inhibition of
IL-2
TNF-cx
Angiogenesis
IFNY
Activation
Th-1 Cells
Thal/IMiDs
Release of
NK Cells
cytotoxic
mediators
Adapted from www.aapsj.org
MM Cells Lysis
1.Hideshima et al. Blood 96: 2943, 2000 Davies et al. Blood 98: 210, 2001Gupta et al. Leukemia 15: 1950, 2001. 2. Mitsiades et al. Blood 99: 4525, 2002
Lentzsch et al Cancer Res 62: 2300, 2002
Thalidomide: Mechanism of Action and
Indication
Description:
· Immunomodulatory, anti-inflammatory, and anti-
angiogenic agent
Mechanism of action:
· Suppresses production of TNF-, IL-6, and other
cytokines
Indication
· Thalidomide is indicated in combination with
dexamethasone for treatment of newly diagnosed MM
Thalomid ® Prescribing Information.
Thalidomide: Dosage and Administration
Thalidomide dosage: 200 mg PO once daily in 28-day
treatment cycle
· Dosing may range between 50-200 mg daily
· With water, preferably at bedtime and >1hr after
evening meal
· With dexamethasone given 40 mg PO
days 1-4, 9-12, 17-20 of cycle
Cycle Day
0
5
10
15
20
25
28
Repeat
Thalidomide
Dexamethasone
Thalomid ® Prescribing Information.
Thalidomide: Potential Side Effects
· Thromboembolic complications, particularly
in combination with steroids or chemotherapy
· Peripheral neuropathy
· Sedation, fatigue
· Constipation
· Rash, usually on trunk, back, arms, legs
· Cumulative exposure contributes to toxicity
· Teratogenic-- severe, life-threatening birth
defects if taken during pregnancy
Manufacturer's warning:
Thalidomide results in an increased risk of venous thromboembolic events
(VTE, PE), particularly when used in combination with standard chemotherapy
Thalomid ® Prescribing Information.
Lenalidomide: Mechanism of Action and
Indication
Description:
· Immunomodulatory agent with anti-angiogenic and
anti-neoplastic properties
Mechanism of action:
· Inhibits the secretion of pro-inflammatory cytokines
and increases the secretion of anti-inflammatory
cytokines
Indication:
· Lenalidomide is indicated in combination with
dexamethasone for the treatment of patients with
multiple myeloma who have received at least one
prior therapy
Revlimid ® Prescribing Information.
Lenalidomide: Dosage and Administration
Lenalidomide dosage: 25 mg PO once daily on
days 1-21 of a 28-day treatment cycle
· With water, as a single 25-mg capsule
· Dexamethasone given 40 mg PO
days 1-4, 9-12, 17-20 of cycle
Cycle Day
0
5
10
15
20
25
28
Repeat
Lenalidomide
Dexamethasone
Revlimid ® Prescribing Information.
Lenalidomide: Potential Side Effects
· Neutropenia, thrombocytopenia and anemia
· Diarrhea, constipation, nausea and vomiting
· Itching
· Rash
· Fatigue, tiredness
· Back pain
· Cough, dizziness, headache
· Difficulty sleeping
· May cause severe, life-threatening birth defects
if taken during pregnancy
Manufacturer's warnings:
Associated with significant neutropenia and thrombocytopenia
Results in an increased risk of venous thromboembolic events (VTE) and
pulmonary embolism (PE) when used in combination chemotherapy
Revlimid ® Prescribing Information.
S.T.E.P.S.®/RevAssist® : Education and
Distribution Programs for Thalidomide and
Lenalidomide
· S.T.E.P.S.-- System for Thalidomide Education and
Prescribing Safety. Only prescribers and pharmacists
registered in S.T.E.P.S. are allowed to prescribe and
dispense thalidomide
· Lenalidomide is only available under a special
restricted distribution program. This program is called
"RevAssit"
· Designed with feedback from the FDA, healthcare
providers, and patients
· Originated to address toxicity associated with fetal
exposure to thalidomide/lenalidomide
Thalomid PI, Celgene Corporation, Summit, NJ, 2006; Revlimid PI, Celgene Corporation, Summit, NJ, 2006.
Bortezomib: Mechanism of Action, Indication
Description:
· The first drug in the class of "proteasome inhibitors"
Mechanism of action:
· A reversible inhibitor of 26S proteasome complex
· Influences apoptotic, cell adhesion, and angiogenic
pathways
Indication:
· Bortezomib is indicated for the treatment of patients
with multiple myeloma who have received at least one
prior therapy as a single agent or in combination
Velcade® Prescribing Information.
Cellular Impact of Proteasome Inhibition
Cancer cells depend upon
proteins regulated by the
3 Inhibition of the
proteasome for
proteasome by
proliferation,
bortezomib
metastasis,
increases the
and survival
concentration of
intracellular proteins,
affecting multiple
1
2
signaling cascades
Proteasomes
within cells
are enzyme
complexes that
degrade intracellular
proteins in a
regulated manner
in all cells, both
4
5
healthy and cancerous
Degraded
The disruption of signaling
Proteasome
proteins
cascades in cancer cells can lead to cancer
Intracellular proteins
cell death and inhibit tumor growth
(signals) tagged
Bortezomib
for degradation
1. Invest New Drugs. 2000; 18: 109-121. 2. Physiol Rev. 2002; 82: 373-428. 3. Sci Am. 2001; 284: 63-73. 4. Cell. 1998; 92: 367-384.
Bortezomib: Dosing and Administration
· Administer bortezomib at 1.3 mg/m2 as a 3- to 5-
second IV push
· Dose twice weekly for two weeks (Days 1, 4, 8, and 11)
followed by a 10-day rest period (Days 12-21)
· At least a 72-hour rest period between doses is
required
Day 1
Day 4
Day 8
Day 11
10-Day
REPEAT
bortezomib
bortezomib
bortezomib
bortezomib
REST
CYCLE
PERIOD
1.3 mg/m2
1.3 mg/m2
1.3 mg/m2
1.3 mg/m2
Millennium Pharmaceuticals, Inc., 2003.
Bortezomib: Potential Side Effects
· Aesthenic conditions (fatigue, weakness)
· GI side effects: loss of appetite, nausea, vomiting,
diarrhea, and constipation
· Thrombocytopenia
· Peripheral neuropathy
· Fever
· Joint pains, arthralgia, myalgias, muscle cramps
· Edema of face, hands, feet, or legs
· Shortness of breath, dizziness, blurred vision,
hypotension
· Women should avoid becoming pregnant during
therapy
Velcade® Prescribing Information.
Recovery of platelet counts prior to each
successive cycle of therapy
Platelet counts drop during the dosing periods (Days 1­11),
returning to baseline during the rest period (Days 12­21)
220
200
t
180
n
Cou
160
140
Platelet
10,000/µLX 120
Mean
100
80
60
Cycle 1
Cycle 2 Cycle 3 Cycle 4 Cycle 5 Cycle 6 Cycle 7 Cycle 8
Lonial S et al. ASH 2003. Abstract 1632.
Side Effects of Novel Therapies That
Need Medical Attention
· Deep vein thrombosis
· Pulmonary embolism
· Peripheral neuropathy
· Myelosuppression
· GI: Severe nausea, vomiting, diarrhea, and
constipation
· Steroid effects
Consequences of Inadequately Managed
Side Effects
Psychological Impact
Physiological Impairment
Reduced Adherence
Adverse side effects may
Adverse side effects that
Therapy associated side
lead to lowered self esteem,
are not properly managed
effects lead to a reduction
anxiety, and depression
may lead to a variety of
in patient's desire and
which will adversely impact
physiological impairments
ability to comply with
the patient's overall health
dosing schedules
Social Consequences
Lower Persistence
Reduced Efficacy
Adverse events may lead to
Patients are less inclined
Adverse side effects may
reduced ability to function
to remain on a therapy for
lead to premature stopping
optimally within
which side effects are not
of medication or reduction
relationships, work, and
adequately managed
of dosage to a suboptimal
other social contexts
efficacy level
Effective management of side effects improves
response outcomes and patient quality of life
Management of Myelosuppression Associated
With Novel Therapeutic Agents
Teresa S. Miceli, RN, BSN
Mayo Medical Center
Rochester, Minnesota
Nurses' Roles in Managing Myelosuppression
Patient Monitoring
Patient Management
Patient Counseling
Patient Research
Nurses are Central to
Patient Management and
Healthcare Resource
Coordination
Patient Advocacy
Patient Education
Management of Myelosuppression
· Defining the challenge
· General monitoring and management
­ Anemia
­ Thombocytopenia
­ Neutropenia
· Management specific to novel therapeutic agents
· Patient education
Relevant Nurse Centric Areas of Activity
Patient Monitoring
Patient Management
Patient Education
Myelosuppression: Definition and Symptoms
Anemia
Red Blood Cells
­ Fatigue, malaise
and SOB
Lymphocyte
Marrow
Monocyte
White Blood Cells
Eosinophil
Neutropenia
­Increased risk of
Basophil
bacterial, fungal
and viral infections
Neutrophl
Thrombocytopenia
Platelets
­Bruising and
bleeding
http://www.schneiderchildrenshospital.org/peds_html_fixed/peds/transplant/bonetran.htmMF NLB Guidelines for Management of Myelosuppression
Related to Novel Therapies for MM.
NCI Toxicity Grading
Laboratory values ­ NCI CTCAE v3.0
Hematologic toxicity grades:
Value/unit
Grade 1
Grade 2
Grade 3
Grade 4
Hgb (g/dL)
<LLN-10.0
<10.0-8.0
<8.0-6.5
<6.5
ANC X109/L
<LLN ­ 1.5
<1.5-1.0
<1.0-0.5
<0.5
Platelets X109
<LLN ­ 75
<75-50
<50-25
<25
The NCI Common Terminology Criteria for Adverse Events
(CTCAE) v3 is used for identifying treatment-related adverse
events to facilitate the evaluation of new cancer therapies,
treatment modalities, and supportive measures
Monitoring Myelosuppression ­ Anemia
· Defined as lower than normal number of
red blood cells
· Anemia may be mild, moderate or, severe
Severity
Hb range
Symptoms
Mild
9.5-11.5g/dL
asymptomatic
Moderate
8-9.5g/dL
symptomatic
Severe
<8g/dL
life threatening
NCCN Guidelines. Available at: http://www.nccn.org/patients/patient_gls/_english/_fatigue/1_introduction.asp, Abshire, 2001;
Lesperance, Wu, & Bernstein, 2002; Segel et al., 2002a; Tender & Cheng, 2002.
Monitoring Myelosuppression ­ Neutropenia
· Defined as a decrease in circulating neutrophils
in the peripheral blood
· Neutropenia may be classified as mild, moderate,
or severe
ANC counts
Risk for infection
1000-1500/mm3
mild
500-1000/mm3
moderate
<500/mm3
severe
Santolaya ME, et. al, J Clin Oncol. 2001; 19(14): 3415 - 342 ; Pizzo PA, N Engl J Med. 1993; 328(18): 1323 - 1332 .
Monitoring Myelosuppression ­
Thrombocytopenia
Defined as a platelet count less than 100,000 cells per
mm3 (normal range of 150,000 to 400,000 cells per mm3)
Platelet counts
Symptoms
<50,000/mm3
life-threatening
hemorrhagic bleeding
10,000-15,000/mm3
spontaneous bleeding
Mansen, T.J., McCance, K.L., & Field, R.B. (1998). Alterations of leukocyte, lymphoid, and hemostatic function. In K.L. McCance & S.E. Huether (Eds.),
Pathophysiology: The biological basis for disease in adults and children (3rd ed., pp. 845-874).
Myelosuppression ­
The Nursing Management Challenge
· Myelosuppression is commonly associated with
novel therapies
· It can lead to life threatening complications and
treatment interruption
· Patients can experience a sense of social
isolation and limited ability to work
Management of Myelosuppression - Anemia
Standardized precautions and interventions vary from
one facility to another.
Recommendations for patients with anemia are:
· Recognizing that some patients tolerate a greater
degree of anemia
· Transfusion of red cells if a patient is symptomatic or
hemoglobin is <8.0 g/dL.
· Institute use of erythropoiesis-stimulating agents
(ESA) if not contraindicated
Note: Erythropoietin can enhance DVT Risk
Leukemia and Lymphoma Society. Understanding Drug Therapy and Managing Side Effects.
Management of Myelosuppression - Anemia
Erythropoiesis-stimulating agent (ESA) is
recommended1
· For patients with hemoglobin concentration that has
declined to a level <10 g/dL
· For hemoglobin 10-12 g/dL
Determined by clinical
circumstances
Surveillance until levels
ESA
fall closer to 10 g/dL
FDA WARNING/REGULATORY ALERT
November 17, 2006: FDA notified healthcare professionals of clinical study2 showing ESA dosed
to target hemoglobin of 13.5 g/dL is associated with significantly increased risk for serious and
life-threatening CV complications ­ death, myocardial infarction, hospitalization for congestive
heart failure, or stroke ­ as compared to target hemoglobin of 11.3 g/dL.
1. Rizzo JD, et al. Blood 2002 Oct 1;100(7):2303-20: 2. Drueke TD, et al. N Engl J Med. 2006;355:2071-2084.
Management of Myelosuppression -
Neutropenia
Generally accepted practices to manage neutropenia:
· Proper hand washing to reduce contact exposures
· Wearing of high filtration mask to reduce airborne infections
· Avoidance of crowds and potential contagion
· Administering IV antibiotic therapy for a febrile event
· Use of growth factors
Management of Myelosuppression ­
Neutropenia
Colony-Stimulating Factors (CSFs) should be
considered in patients who have prognostic factors
predictive of poor clinical outcomes,
such as:
· Prolonged neutropenia (>10 days)
· Profound neutropenia (<0.1 x 109/L)
· Age greater than 65 years
· Uncontrolled primary disease
CSFs should not be routinely used for patients with
mild neutropenia who are afebrile
Smith TJ, et al.. J Clin Oncol 2006 Jul 1;24(19):3187-205.
Management of Myelosuppression -
Thrombocytopenia
To reduce bleeding for the patient with
thrombocytopenia these practices are recommended:
· Minimizing invasive procedures
· Transfusing platelets prior to necessary invasive
procedures
· Transfusing platelets at any sign of bruising or
bleeding
· Interleukin-11 aids in preventing and managing
thrombocytopenia
Risk of Grade 3 or 4 Myelosuppression
With Novel Therapies
Drug
Anem
Neutro
Thrombo
Thalomide/dex
16%
13 %
4 %
Lenalidomide/dex
8 %
21 %
10 %
Bortezomib
12 %
14 %
32 %
Anem=anemia; Neutro=neutropenia; Thrombo=thrombocytopenia
IMF NLB Guidelines for Management of Myelosuppression Related to Novel Therapies for MM
Monitoring Myelosuppression ­
Novel Therapy Specific
Thalidomide
· Ongoing especially if prone to neutropenia
Lenalidomide
· Weekly for the first 8 weeks of therapy and at least
monthly thereafter
Bortezomib
· Prior to each dose
Management of Myelosuppression ­
Thalidomide
Treatment
should NOT
be initiated
ANC<0.75x109L
Pre-therapy
Re-evaluate
ANC
medication
Assessment
regimen
ANC decreases
ANC0.75x109L
to <0.75x109L
Initiate
Regular
thalidomide
ANC
treatment
monitoring
ANC remains
stable
Maintain
therapy
Management of Myelosuppression ­
Lenalidomide
When ANC
Recommended Course
Fall to <1000/mm3
Interrupt lenalidomide treatment,
add G-CSF, follow CBC weekly
Return to >1000/mm3 and
neutropenia is the only toxicity Resume lenalidomide at 25 mg
daily
Return to >1000/mm3 and
Resume lenalidomide at 15mg
neutropenia if other toxicity
daily
For each subsequent drop
Interrupt lenalidomide treatment
below < 1000/mm3
Return to >1000/mm3
Resume lenalidomide at 5 mg
less than the previous dose
Do not dose below 5 mg daily
Lenalidomide product information. Summit, NJ: Celgene.
Management of Myelosuppression ­
Lenalidomide
When Platelets
Recommended Course
Fall to <30,000/mm3
Interrupt lenalidomide treatment,
follow CBC weekly
Restart lenalidomide at 15 mg
Return to >30,000/mm3
daily
For each subsequent drop
Interrupt lenalidomide treatment
< 30,000/mm3
Resume lenalidomide at 5 mg less
Return to >30,000/mm3
than the previous dose
Do not dose below 5 mg daily
Lenalidomide product information. Summit, NJ: Celgene.
Management of Myelosuppression ­
Bortezomib
At the onset of any Grade 4 hematologic toxicity,
bortezomib should be held
Once toxicity has resolved, bortezomib may be
restarted at a 25% reduced dose
Thrombocytopenia
· Platelet count decreases and recovers over the cycles
· No evidence of cumulative thrombocytopenia.
· Transfuse if platelet count <25.0 x 109/L
Velcade® Prescribing Information.
Recovery of Platelet Counts Prior to Each
Successive Cycle of Therapy
Platelet counts drop during the dosing periods (Days 1­11),
returning to baseline during the rest period (Days 12­21)
220
200
t
180
n
Cou
160
140
Platelet
10,000/µLX 120
Mean
100
80
60
Cycle 1
Cycle 2 Cycle 3 Cycle 4 Cycle 5 Cycle 6 Cycle 7 Cycle 8
Lonial S et al. ASH 2003. Abstract 1632.
Patient and Caregiver Education
It is important to educate the patient and caregiver on
the following:
· The importance of blood count monitoring while
receiving treatment
· The normal and critical values of blood counts
· Neutropenia and bleeding precautions
· Indications for contacting medical personnel based on
institution policy
· Emergency contact numbers
Management of Myelosuppression ­
Conclusion and Summary
· Myelosuppression is a frequent side effect of novel
therapies
· It can lead to life-threatening complications and
therapy interruption
· Monitoring is key to identifying myelosuppression,
selecting therapy, and preventing complications
· Treatment ranges from instituting pancytopenic
precautions to transfusions, growth factor
administration, and treatment adjustments
Proper management and education
will enhance patient outcome
Management of Peripheral Neuropathy
Associated With Novel Therapeutic Agents
Joseph D. Tariman, RN/APN, MN, APRN, BC, OCN®
Predoctoral Research Fellow
Biobehavioral Nursing and Health Systems
Achievement Rewards for College Scientists
School of Nursing
University of Washington
Seattle, Washington
Nurses' Roles in Managing
Peripheral Neuropathy
Patient Monitoring
Patient Management
Patient Counseling
Patient Research
Nurses are Central to
Patient Management and
Healthcare Resource
Coordination
Patient Advocacy
Patient Education
Management of Peripheral Neuropathy
· Defining the challenge
· General monitoring and management
· Novel therapeutic agent specific management
­ Thalidomide
­ Bortezomib
· Patient education
Relevant Nurse Centric Areas of Activity
Patient Monitoring
Patient Management
Patient Education
Peripheral Neuropathy: Definition
· Sensory damage or
parethesia
· Marked by
­ Tingling, numbness,
prickling sensation
­ Muscle weakness
­ Burning pain
­ Loss of reflexes
· Can lead to permanent
nerve damage and
persistent, unrelieved
neuropathic pain
Kirchmair R. et al. Circulation. 2005. 111(20):2662-2670; Mileshkin L, Prince H.M.. Leuk Lymphoma. 2006; 47(11): 2276-9.
Peripheral Neuropathy Associated
With Multiple Myeloma
· Peripheral neuropathy may be a complication of
multiple myeloma itself
· 5% incidence rate in multiple myeloma
· Fractures or tumor compressing nerve roots cause
radiculopathy
· Functional impairment and symptoms depend on
nerves affected
· Generally a late complication
http://www.millennium.com/clinicians/oncology/velcade/duration.asp; accessed 3/20/07;
http://www.oncolink.com/types/article.cfm?c=13&s=42&ss=836&id=9552, accessed 3/24/07
Severity of Peripheral Neuropathy:
NCI Common Terminology Criteria for
Adverse Events (CTCAE) 3.0
NCI CTCAE grades of peripheral sensory neuropathy
· Grade 1: Asymptomatic; loss of deep tendon reflexes or
paresthesia (including tingling) but not interfering
with function
· Grade 2: Sensory alteration or paresthesia (including
tingling), interfering with function, but not
interfering with ADL
· Grade 3: Sensory alteration or paresthesia interfering with
ADL
· Grade 4: Disabling
· Grade 5: Death
Calhoun EA, et al. Presented at 36th Annual Meeting of American Society of Clinical Oncology, 2000. Proc Am Soc Clin Oncol .19: 2000 (abstr 1751); 2000;
Cella et al., 1993 National Cancer Institute Cancer Therapy Evaluation Program, 1999. 1999. NCI Cancer Program, 1999.
Severity of Neuropathic Pain:
NCI Common Terminology Criteria for
Adverse Events (CTCAE) 3.0
NCI CTCAE grades of neuropathic pain
· Grade 0: None
· Grade 1: Mild pain not interfering with function
· Grade 2: Moderate pain: pain or interfering
with function but not ADLs
· Grade 3: Severe pain: pain or analgesics severely
interfering with ADLs
· Grade 4: Disabling­referral to neurology or pain
management
Colson K, et al. (2004). Clin J Oncol Nursing. 2004; 8(5); 473-480.
Monitoring Peripheral Neuropathy -
Early Signs and Symptoms
· New symptoms
· Numbness or tingling in extremities
· Burning sensation
· Increased sensitivity to touch
· Neuropathic pain
· Changes in pre-existing symptoms
· If patients recognize worsening of symptoms
between visits, they should be instructed to contact
healthcare provider immediately
Colson K, et al. Clin j Oncology Nursing. 2004; 8(5)): 473-480.
Monitoring Peripheral Neuropathy -
Assessment
· Baseline sensory nerve examination of
extremities
· Periodic updates on nerve sensory examination
· NCI neuropathy questionnaire*
· Evaluate ability to perform activities of daily living
and instrumental activities of daily living at visits
· Utilize verbal or non-verbal pain scales to identify
neuropathic pain
*Cella et al.. 1993 National Cancer Institute Cancer Therapy Evaluation Program, 1999. NCI Cancer Program, 1999.
Risk Factors for Occurrence of
Peripheral Neuropathy
Patients previously treated with other drugs that cause
neuropathy
· Vinca alkaloids like vincristine
· Chemotherapies such as cisplatin, paclitaxel,
methotrexate, cytarabine, ifosfamide, suramin
· HIV medications (NRTIs or PIs)
· Post-transplant immunosuppressives (eg, tacrolimus)
Careful risk/benefit assessment required in these
patients before prescribing novel chemotherapies for
multiple myeloma
Colson K, et al. Clin j Oncology Nursing. 2004; 8(5): 473-480.
Peripheral Neuropathy ­
The Nursing Management Challenge
· One of the most challenging and dose-limiting side
effects of novel therapies
· Can negatively impact QOL, mobility, activities of daily
living, and independence
· Must be addressed in a timely manner
­ Prevent progression and irreversible nerve damage
­ Ensure appropriate pain management
­ Patient education can reinforce importance of side
effect vigilance, increase awareness of symptoms,
and establish a method for tracking symptom
changes
Colson K, et al. Clin j Oncology Nursing. 2004; 8(5)): 473-480.
Management of Peripheral Neuropathy ­
Supplemental and Prescribed Treatments
Dietary supplementation
· Vitamins
· Magnesium
· Amino acids
Consider medications
· Gabapentin: start at 100 mg tid, titrate up to
maximun of 600 mg tid as needed
· Lidocaine patch 5%: 1.5 patch to each pain
area for max. 12 hr/d
Colson K, et al. (2004). Clin J Oncol Nursing. 2004; 8(5); 473-480.
Peripheral Neuropathy Is a Common
Side Effect of Novel Chemotherapies
Incidence of Drug-Induced
Drug
Peripheral Neuropathy Reported
Thalidomide/dex
25% - 75%
Bortezomib
34%
Lenalidomide/dex
2%
Based on Thalomid PI, Celgene Corp, Summit, NJ, 2006; Velcade PI, Millennium Pharmaceuticals Inc., Cambridge, MA, 2003; Revlimid PI, Celgene Corp, Summit, NJ, 2006; Mileshkin L, et
al. Clin Oncol. 2006;4507-4514; Tariman JD. Clin J Oncol Nursing.2003;7(2):143-147; Colson K, et al. Clin J Oncol Nursing. 2004;8(5):473-480; Doss DS. Clin J Oncol Nursing.
2006;10(4)514-520.
Protocol for Following Neuropathy in Patients
Receiving Novel Chemotherapies
Before treatment
· Establish baseline patient profile
During treatment
· Evaluate toxicities and monitor neuropathies
· Institute nursing interventions to minimize toxicity
while maximizing treatment benefit
· Provide patient education
· Address Grade 3 and 4 toxicities
After treatment
· Continue patient counseling and support
Colson K, et al. Clin j Oncology Nursing. 2004; 8(5)): 473-480.
Management of Peripheral Neuropathy:
Grade 1 or 2
In the event of peripheral neuropathy, early
interventions recommended include:
· Massage affected area with cocoa butter regularly
· Vitamin supplement
· Diet: Increase potassium intake
If symptoms worsen:
· Reduce dose of thalidomide, or bortezomib
· Temporarily discontinue treatment
· Initiate pharmacologic interventions such as pain
medication or lidocaine patch
· Physical therapy
IMF NLB Guidelines for Management of Peripheral Neuropathy Related to Novel Therapies for MM.
Management of Peripheral Neuropathy:
Grade 3 or 4
Grade 3 & 4 symptoms:
· Further reduce dose or discontinue therapy
· Assessment of safety issues (falls, cuts, burns)
· Pain management and referral to neurology
· Physical therapy
IMF NLB Guidelines for Management of Peripheral Neuropathy Related to Novel Therapies for MM.
Management of Peripheral Neuropathy ­
Bortezomib
Severity of Peripheral Neuropathy
Modification of Dose and Regimen
Signs and Symptoms
Grade 1 (paresthesias, weakness and/or No action
loss of reflexes) without pain or loss of
function
Grade 1 with pain or Grade 2
Reduce bortezomib to 1.0mg/m2
(interfering with function but not with
activities of daily living)
Grade 2 with pain or Grade 3 (interferes
Withhold bortezomib until toxicity
with activities of daily living)
resolves. When toxicity resolves
reinitiate with a reduced dose of
bortezomib at 0.7 mg/m2 and change
treatment schedule to once per week
Grade 4 (sensory neuropathy that is
Discontinue bortezomib
disabling or motor neuropathy that is
life threatening or leads to paralysis
Lenalidomide product information. Summit, NJ: Celgene.
Patient and Caregiver Education
It is important to educate the patient and caregiver on
the following:
· Early signs or symptoms of peripheral neuropathy
· Prior to therapy, patients may receive a combination of
supplements
· Reassure patients that early management leads to
optimizing and maintaining treatment
· All interventions should take into account patient
history and current medical status
· Instructions to call healthcare provider at earliest
symptoms
· Emergency contact numbers
Management of Peripheral Neuropathy:
Conclusion
· Dose reductions or drug holiday should be considered
If symptoms of neuropathy develop
· If neuropathy returns to baseline, treatment may be
resumed in lower dose
· Drug should be discontinued, if clinically appropriate
· Pain management is important to quality of life (QOL)
Proper management and education
will enhance patient outcome
Management of DVT/PE Associated with Novel
Therapeutic Agents
Sandra Rome, RN, MN, AOCN
Heme-Onc CNS
Cedars-Sinai Medical Center
Assistant Clinical Professor
UCLA School of Nursing
Nurses' Roles in Managing Patients With
VTE and DVT
Patient Monitoring
Patient Management
Patient Counseling
Patient Research
Nurses are Central to
Patient Management and
Healthcare Resource
Coordination
Patient Advocacy
Patient Education
Management of Venous Thromboembolism and
Deep Vein Thrombosis
· Defining the challenge
· General monitoring and management
· Novel therapeutic agent specific management
­ Thalidomide
­ Lenalidomide
· Patient education
Relevant Nurse Centric Areas of Activity
Patient Monitoring
Patient Management
Patient Education
Venous Thromboembolism and Deep Vein
Thrombosis: Definition
· VTE occurs when a thrombus (blood clot) develops in a vein
· DVT is the occurrence of a clot in a deep vein
· Significant danger results if part of blood clot breaks off,
travels through the bloodstream, and lodges in the lung,
brain, or heart
Deep Vein Thrombosis (DVT)
Normal
Deep Vein
Embolus
Blood Flow
Thrombosis
Deep veins of the leg
http://www.nlm.nih.gov/medlineplus/ency/article/000156.htm. http://www.sirmeeting.org/images/DVT_normal_and_embolus.jpg
Nursing Assessment Contributes to
Positive Outcomes
· Identify risks and recommend prevention
· Early recognition of symptoms of VTE
· Implementation of prophylaxis
· Dependent on institutional practices
· Sensitive to patient factors
Features Predictive of DVT
Clinical features predicting probability of DVT
· Active cancer (ongoing treatment)
· Paralysis, paresis, or recent plaster immoblization of
lower extremities
· Recently bedridden >3 days
· Major surgery requiring anesthesia within 12 weeks
Amir Q, et al. Ann Fam Med. 2007;5(1):57-62.
Features Predictive of PE
Clinical features predicting probability of PE
· Previous pulmonary embolism or DVT
· Heart rate >100 bpm
· Recent surgery or immobilization
· Clinical signs of DVT
· Alternative diagnosis less likely than PE
· Hemoptysis
· Cancer
Amir Q, et al. Ann Fam Med. 2007;5(1):57-62.
Monitoring VTE ­ Signs and Symptoms
Deep Vein Thrombosis
· Swollen area of the leg
· Pain or tenderness in the leg. The pain is usually in one
leg and may be felt only when standing or walking
· Increased warmth in the area of the leg that is swollen
or in pain
· Red or discolored skin
Pulmonary Embolism
· Shortness of breath
· Chest pain with deep breath
Adadpted from NHLBI website: http://www.nhlbi.nih.gov/health/dci/Diseases/Dvt/DVT_SignsAndSymptoms.html. Accessed 25 March 2007; Tariman
JD. Clin J Oncol Nursing.2003;7(2):143-147.
VTE ­ The Nursing Management Challenge
· Patients with multiple myeloma are at increased risk
for thromboembolic events.
· Patients are at increased risk with high dose
dexamethasone treatment
· The risk for DVT/PE is further increased in patients
treated with novel therapies
· May have life-altering consequences
· Can interfere with continuation of therapy, treatment
options, and/or patient adherence
General Prevention and Treatment of DVT
Prevention and early interventions
may include:
· Anti-embolism stockings
· Sequential compression devices
· Exercise regimen
· Low-dose aspirin
· Reduced drug doses
· Different dosing schedule
· Drug therapy
Drug Therapy for DVT or PE
Anticoagulants are the principal prevention and
treatment for DVT and PE
· Fractionated heparin
· Warfarin
· Low-molecular-weight heparins (LMWHs)
· Aspirin
Amir Qaseem et al. Ann Fam Med. 2007;5(1):5762. ©2007 Annals of Family Medicine. J.B. Segal et al. Ann Intern Med. 2007;146(3):I43.
Risk for VTE With Thalidomide or
Lenalidomide Administration
DVT or PE has been shown in several studies
to occur during thalidomide therapy
· 1%-3% on monotherapy (1-3)
· 10%-12% with concomitant dexamethasone (3,4)
· >25% with concomitant doxorubicin (1,5)
1. Osman K, et al. N Engl J Med. 2001;344:1951-952; 2. Zangari M, et al. Blood. 2001;98:1614-1615; 3. Rajkumar SV, et al. J Clin Oncol.
2002;20:4319-4323; 4. Cavenagh JD. Br J Haematol. 2003;120:18-26; 5. Zangari M, et al. Blood. 2002;100:1168-1171.
Black Box Warnings: Risk of DVT and PE With
Thalidomide and Lenalidomide
Thalidomide
· Manufacturer's warning: thalidomide results in an
increased risk of venous thromboembolic events,
particularly when used in combination with standard
chemotherapy
Lenalidomide
· Manufacturer's warning: lenalidomide results in an
increased risk of DVT and PE when used in
combination chemotherapy
Thalomid PI, Celgene Corporation, Summit, NJ, 2006; Revlimid PI, Celgene Corporation, Summit, NJ, 2006.
Possible Adjustments When Given With Other
Chemotherapeutic Agents
· Escalate dose gradually
· 50 mg/d for 2 weeks
100 mg/d for 2 weeks 200 mg/d
· Reduce drug doses
· Alter dosing schedule
· Concomitant blood thinning with warfarin or
heparin therapy
Ghobrial IM, Rajkumar SV. J Support Oncol. 2003;1(3):194-205.
Risk for DVT Necessitates Specialized Care
Treatment regimen adjustments when administered in
combination
Prophylactic maintenance therapy with anticoagulant
drugs under consideration (particularly for patients
with prior DVT)
· Warfarin
· Low molecular weight heparin (LMWH)
· Aspirin
Regular blood monitoring during therapy
· Partial thromboplastin time (PTT)
· International normalized ratio (INR)
­ Maintain at 1.2 to 1.5
Tariman JD. Clin J Oncol Nursing. 20037(2):143-147. Knight R, et al. NEJM 354:19 2006
Proposed Protocol for Anticoagulant
Prophylaxis Against DVT
High Risk
Prior Hx
Low Risk
Moderate Risk
(+ doxorubicin,
of DVT
(monoRx)
(+ other chemo)
paclitaxel,
gemcitabine)
Warfarin
Yes
Low-dose
Warfarin
to maintain
LMWH
INR 2-2.5
Low-dose Warfarin
LMWH
No
None
or
or
Low-dose Aspirin
Warfarin
LMWH=low molecular-weight heparins
Adapted from Ghobrial IM, Rajkumar SV. J Support Oncol. 2003;1(3):194-205.
Patient and Caregiver Education
It is important to educate the patient and caregiver on
the following:
· Signs and symptoms of a DVT and PE:
­ Arm or leg warmth or swelling
­ A new pain in the leg when standing or walking
­ Shortness of breath
­ Chest pain
· DVT and PE are medical emergency
· Emergency contact numbers
Management of DVT and PE: Conclusion and
Summary
· DVT and PE are serious and potentially life-altering
events
· Occur with increasing frequency in setting of
combination chemotherapy
· Requires ongoing monitoring and intense vigilance
· Patients should call healthcare provider at first sign of
DVT or PE symptom
· Requires immediate intervention
· Consider prophylactic anticoagulation
Proper management and education
will enhance patient outcome
Improving Patient Support and Education
Patricia Mangan, MSN, CRNP
Abramson Cancer Center
University of Pennsylvania
Philadelphia, Pennsylvania
Support Groups and Counseling
· Friends and family can provide support
· Social worker or counselor
· Clergy
· Support groups for people with multiple myeloma
­ International Myeloma Foundation
­ American Cancer Society
­ National Cancer Institute
http://www.emedicinehealth.com. Accessed 22 March 2007.
Patient Education Materials
www.myeloma.org
Easy Access to Information on Multiple
Myeloma: Web Links
International Myeloma Foundation
· http://www.myeloma.org/
American Cancer Society
· http://www.cancer.org/docroot/home/index.asp
National Cancer Institute
· http://www.cancer.gov
Medline Plus: Cancer
· http://www.nlm.nih.gov/medlineplus/multiplemyeloma.html
Healthfinder
· http://www.healthfinder.gov/hg/files/?id=11660
Nurse Centric Model of Patient Management
Patient Monitoring
Patient Management
Patient Counseling
Patient Research
Nurses are Central to
Patient Management and
Healthcare Resource
Coordination
Patient Advocacy
Patient Education
Nurse Centric Initiatives ­
IMF Nurse Leadership Board
A partnership with multiple myeloma nurses to gain
insights into their unmet needs and to address them
and those of their patients by accomplishing the
following objectives:
· Provide insights into the needs of myeloma nurses and
their patients
· Identify and implement key nursing education
programs
· Facilitate information flow between the IMF and
oncology nursing organizations
Current IMF - Nurse Leadership Board
Activities
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 will cover the following
­ Myelosuppression
­ Peripheral Neuropathy
­ DVT/PE
­ Steroid Effects
­ GI Side Effects
Question & Answer Session

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