Consensus on Care: New Insights on Novel Therapies in Multiple Myeloma
Accredited by Medical Education Resources Supported by The International
Myeloma FoundationGrant Funding provided by
Celgene Corporation and Millennium Pharmaceuticals
Welcome and Opening Remarks
Beth Faiman: RN, MSN, APRN, BC, AOCN
Cleveland Clinic Taussig Cancer InstituteCleveland, 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.
Symposium Accreditation
This continuing education activity provides 2.0 contact hours
Medical Education Resources is an approved provider of continuing nursing education, by the Colorado Nurses Association, an accredited approver by the American Nurses Credentialing Center’s Commission on Accreditation.
Please complete the CE Certificate Registration and Program Evaluation Form found in the guidebook and return it to the registration desk
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, BC, AOCN
Cleveland Clinic Taussig Cancer InstituteCleveland, Ohio
Faculty:
Lisa C. Smith: MSN, FNP, AOCNCancer Centers of the CarolinasGreenville, South Carolina
Kena C. Miller: RN, MSN, FNP Roswell Park Cancer InstituteBuffalo, New York
Joseph D. Tariman: RN, MN, ARNP-BC, OCNUniversity of WashingtonSeattle, Washington
Agenda
Time Topics Presenter6:00 – 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
San Miguel JF, et al. Pathogenesis of Multiple Myeloma: Rationale for New and Novel Therapies. Clinical Care Options: http://clinicaloptions.com/Oncology/Treatment%20Updates/Myeloma/Modules/Pathophysiology/Pages/Page%203.aspx.
What is Multiple Myeloma?
• Cancer of plasma cells
• Healthy plasma cells produce antibodies or immunoglobulins- Part of our humoral immunity, they are released in
response to foreign body invasion
• Myeloma cells produce abnormal immunoglobulin- Overproduce monoclonal protein or paraprotein
- Ineffective immunoglobulins
- Leads to decreased bone marrow function
- Destruction of bone tissue
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 MyelomaMonoclonal plasma cells present in the bone marrow ≥10%, and/or presence of a documented plasmacytoma
+
Presence of M component in serum and/or urine*
+
One or more of the following (CRAB criteria)
• Calcium elevation (serum calcium >11.5 mg/dL)
• Renal insufficiency (serum creatinine >2 mg/dL)
• Anemia (hemoglobin <10 g/dL or 2 g/dL <normal)
• Bone disease (lytic lesions or osteopenia)
Durie et al for the International Myeloma Working Group. Leukemia. 2006:1-7.
*Monoclonal M spike on electrophoresis IgG>3.5g/dL, IgA>2g/dL, light chain >1g/dL in 24-hr urine sample
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
Durie B, Salmon S. Cancer. 1975;36(9):842-854
Subclassification Criteria A Normal renal function (serum creatinine level <2.0 mg/dL) B Abnormal renal function (serum creatinine level 2.0 mg/dL)
Stage CriteriaMyeloma cell mass( 1012 cells/m2)
I All of the following:Hemoglobin >10 g/dLSerum calcium level 12 mg/dL (normal) Normal bone or solitary plasmacytoma on x-rayLow 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/dLSerum calcium level >12 mg/dLMultiple lytic bone lesions on x-rayHigh M-component production rate: IgG >7 g/dL IgA >5 g/dL Bence Jones protein >12 g/24 hr
>1.2 (high)
2M=serum 2 microglobulin in mg/dL; ALB=serum albumin in g/dL
International Staging System for Symptomatic Multiple Myeloma
Greipp PR, et al. Blood 2005; 102: 190a
STAGE VALUES
Stage 1ß2M <3.5 mg/dL
ALB 3.5 g/dL
Stage 2 Not Stage 1 or 3
Stage 3 ß2M >5.5 mg/dL
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
Radiation therapy
Stem cell transplantation:• Autologous• Allogeneic
Novel therapeutics: • Thalidomide • Lenalidomide • Bortezomib
Thalomid ® Prescribing Information, Revlimid ® Prescribing Information; Velcade® Prescribing Information
Steroid therapy: • Dexamethasone • Prednisone
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 InformationVelcade® 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
VELCADE® 2003 2005
REVLIMID® ___ 2006
THALOMID®
with dexamethasone
2006 ___
DOXIL® with VELCADE®
2006
Accelerated Approval
(AA)
Regular Approval
(RA)
Approval based upon: Response Rate
Time to Progression (TTP)
Thalomid® Prescribing Information, Revlimid® Prescribing InformationVelcade® Prescribing Information, Doxil® Prescribing Information
Key Benefits of Novel and Emerging Therapies
IMF-NLB ‘Consensus Statements’ supplement In Press, CJON June 2008;Rajkumar et al., 2005; Richardson & Anderson, 2006; Richardson, Hideshima, Mitsiades, & Anderson, 2007
• Targeted therapies with novel mechanisms of action
• Provide increased response rate• Provide increased time to progression• Lead to increased survival time
Key Challenges of Novel and Emerging Therapies
IMF-NLB ‘Consensus Statements’ supplement In Press, CJON June 2008
• Emergent side effects– Can interfere with adherence to treatment– Adversely affect patients’ quality of life– Can be life threatening
• Challenge for nursing management of emergent side effects – Lack of effective practitioner based
guidelines
• Produces a barrier to providing optimum patient care
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 39%Fatigue 38%Insomnia 32%Muscle Cramp 30%Diarrhea 29%Neutropenia 28%Anemia 24%Loss/Lack of Strength 23%Fever 23%Nausea 22%Headache 21%Peripheral edema 21%Dizziness 21%
http://www.revlimid.com/pdf/REVLIMID_PI.pdf
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
Most Commonly Reported Effects > 20% for all grades
Percentage of
Patients
Hyperglycemia 72.5%
Hypocalcemia 72%
Edema 57%
Constipation 55%
Peripheral neuropathy-sensory 54%
Dyspnea 42%
Rash 30%
Confusion 28%
Thrombosis/Embolism 23%
Peripheral neuropathy-motor 22%
http://www.thalomid.com/pdf/Thalomid_Pl.pdf
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/
Toxicity (Grade >3)Arm A
(N=223)
Arm B
(N=222)
Neutropenia 2.7% 3.2%
Thrombocytopenia 1.8% 1.4%
DVT/PE 18.4% 6.3%
Atrial fibrillation/flutter 3.1% 0.0%
Infection/Pneumonia 16.1% 9.0%
Fatigue 11.7% 4.1%
Hyperglycemia 5.8% 2.3%
Neuropathy 0.4% 1.4%
A Randomized Phase III Trial of Lenalidomide Plus High-Dose Dexamethasone (Arm A) vs Lenalidomide Plus Low-Dose Dexamethasone (Arm B) in Newly Diagnosed Multiple Myeloma (E4A03)
Rajkumar V, et al. Blood. 2006;108:[abstract 799].
Low Dose Dexamethasone/Lenalidomide
Updated Side Effects Profile
Updated Side Effects Profile
DOXIL® with VELCADE®
Most Commonly Reported
Side Effects > 10% for all grades
Percentage of
Patients
Nausea 48%
Diarrhea 46%
Peripheral Neuropathy 42%
Fatigue 36%
Neutropenia 36%
Thrombocytopenia 33%
Vomiting 32%
Constipation 31%
Pyrexia 31%
Anemia 25%
Asthenia 22%
Rash 22%
Stomatitis 20%
http:http://www.doxil.com/common/prescribing_information/DOXIL/PDF/DOXIL_PI_Booklet.pdf//www.doxil.com/
Hand-foot syndrome (HFS) may occur during therapy with DOXIL®
Consequences of Inadequately Managed Side Effects
Therapy associated side effects lead to a reduction
in patient’s desire and ability to comply with
dosing schedules
Reduced Adherence
Lower Persistence
Patients are less inclined to remain on a therapy for which side effects are not
adequately managed
Reduced Efficacy
Physiological ImpairmentPsychological Impact
Social Consequences
Lowered self esteem, anxiety and depression
which will adversely impact the patient’s overall health
Reduced ability to function optimally within
relationships, work and other social contexts
Adverse side effects that are not properly managed
may lead to a variety of physiological impairments
Adverse side effects may lead to premature stopping of medication or reduction of dosage to a suboptimal
efficacy level
Effective management of side effects improves response outcomes and patient’s quality of life
IMF Nurse Leadership Board
Nurses from leading MM institutions formed a Nurse Leadership Board (NLB) in collaboration with
and under sponsorship of the International Myeloma Foundation (IMF) with the express
purpose of determining the unmet needs of MM patients and to develop action plans to address
those needs
Statement of Need Catalyzes Creation of a Nurse Centric Initiative
IMF-NLB ‘Consensus Statements’ supplement In Press, CJON June 2008
Nurse Centric Model of Patient Care*
Nurses are Central toPatient Management and
Healthcare Resource Coordination
Patient ResearchPatient Counseling
Patient Education
Patient ManagementPatient Monitoring
Patient Advocacy
* Developed by ScienceFirst, LLC; All Rights Reserved (www.science-first.com)
• Nurses play an essential role in managing patient care
• Nurses are key in efficiently and optimally managing emergent side effects
• Managing emergent side effects is an important endeavor for improving MM patient care and treatment outcome
• Improving nursing assessment contributes to positive outcomes
Effective Nursing Tools Improve Patient Care and Treatment Outcomes
IMF-NLB ‘Consensus Statements’ supplement In Press, CJON June 2008
A Collaborative Assessment was Performed of Evidence-based and Practice-based Knowledge
and the Nursing Experience of Key Emergent Side Effects with Novel Therapies
IMF NLB Process for Developing Consensus Statements
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
Teresa Miceli
Maria Gavino
Kathleen Colson
Kathy Lilleby
Myelosuppression
Sandra Rome
Jeanne Westphal
Deborah Doss
Kena Miller
DVT/PE
Lisa Smith
Bonnie Jenkins
Kathleen Curran
Page Bertolotti
GI
Beth Faiman
Katy Rogers
Patricia Mangan
Elizabeth Bilotti
Steroid Effects
Joseph Tariman
Stacey Sandifer
Ginger Love
Emily McCullagh
Peripheral
Neuropathy
‘Consensus Statements’: Review Process
NLB Received One Document With Comment Sheet Per Week 5 Consensus Documents Sent Over a Five Week Period
NLB Compiled New Comments After Review
Sub-groups Received Updated Comment Sheet The Updated Comments Sheet Captured All NLB Input
Sub-groups Discussed New Comments Via Teleconference Approved Comments Incorporated Into Revised Consensus Statements
Revised Consensus Statements Received Medical Accuracy Review Entire NLB Board Conducted Final Approval
‘Consensus Statements’: Team Effort
120 Teleconference Calls
1,300 E-mails exchanged
1,600 work hours
5 Consensus Statements
10 months
40 weeks of work
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. Myelosuppression2. Deep Vein Thrombosis/Pulmonary Embolism3. Peripheral Neuropathy4. Gastrointestinal Effects5. Steroids Related Side Effects
IMF-NLB ‘Consensus Statements’ supplement In Press, CJON June 2008
NLB ‘Consensus Statements’ Development and Publication Strategy
NLB
Myelosuppression
DVT/PE
Peripheral neuropathy
GI
Steroids
Consensus Statements Review Process Finalization
Planned meetings and coordination
Publication in Clinical Journal of Oncology NursingJune ‘08
NLB
IMF-NLB ‘Consensus Statements’ supplement In Press, CJON June 2008
Planned meetings
and coordination
Editing and Formatting
• The NLB’s ‘Consensus Statements’ development approach is a powerful model helping to improve patient management, care and outcomes
• The NLB consensus approach provides a future MODEL for all oncology nursing (i.e. nurses partnering with advocacy groups)
Development of The NLB ‘Consensus Statements’ as a Model of Care
•The NLB ‘consensus statements’ will be
periodically reviewed and expanded upon
•The NLB ‘consensus statements’ will be
adopted as “The” Model of Care within the
MM nursing community
NLB Vision for the Future
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’
Issue Statement•An articulation of the issue or need and its impact on patients,
the nursing profession, and society
Position Statement•A comprehensive listing of the positions taken in regard
to the issue
Strategic Recommendations•Identification of recommended strategies and approaches to
support the position by addressing the issue or need
References•A detail listing of published references that support the position
statement and recommended strategies section
General Format of Publications
IMF-NLB ‘Consensus Statements’ supplement In Press, CJON June 2008
Myelosuppression: Definition and Symptoms
http://www.schneiderchildrenshospital.org/peds_html_fixed/peds/transplant/bonetran.htm; Adapted from NLB Consensus Recommendations. In Press, CJON June 2008
Marrow
Red Blood Cells
White Blood Cells
Platelets
Anemia– Fatigue, malaise
and SOB
Neutropenia– Increased risk of
bacterial, fungal and viral infections
Thrombocytopenia– Bruising and
bleeding
Neutrophil
Eosinophil
Lymphocyte
Monocyte
Basophil
Risk of Grade 3 and 4 Myelosuppression With Novel Therapies
Anemia Neutropenia Thrombocytopenia
THALOMID®/ dexamethasone
16% 13% 4%
REVLIMID®/ dexamethasone
8% 21% 10%
VELCADE® 12% 14% 32%
Adapted from NLB Consensus Recommendations. In Press, CJON June 2008Thalomid® Prescribing Information, Revlimid® Prescribing Information, Velcade® Prescribing Information. http://ctep.cancer.gov/forms/CTCAEv3.pdf
Grading based upon: Common Terminology Criteria for Adverse Events (CTCAE) v3.0
Management of Neutropenia: REVLIMID®
When ANC Recommended Course
Fall to <1000/mm3
Return to >1000/mm3 and neutropenia is the only toxicity
Interrupt REVLIMID® treatment, add G-CSF, follow CBC weekly
Resume REVLIMID® at 25 mg daily
Return to >1000/mm3 and neutropenia if other toxicity
Resume REVLIMID® at 15 mg daily
For each subsequent drop below <1000/mm3
Return to >1000/mm3
Interrupt REVLIMID® treatment
Resume REVLIMID® at 5 mg less than the previous dose*
*Do not dose below 5 mg daily
Lenalidomide product information. Summit, NJ: Celgene.Adapted from NLB Consensus Recommendations. In Press, CJON June 2008
Management of Thrombocytopenia: REVLIMID®
When Platelets Recommended Course
Fall to <30,000/mm3
Return to >30,000/mm3
Interrupt REVLIMID® treatment, follow CBC weekly
Restart REVLIMID® at 15 mg daily
For each subsequent drop <30,000/mm3
Return to >30,000/mm3
Interrupt REVLIMID® treatment
Resume REVLIMID® at 5 mg less than the previous dose*
.Lenalidomide Product Information. Summit, NJ: Celgene Adapted from NLB Consensus Recommendations. In Press, CJON June 2008
*Do not dose below 5 mg daily
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)
Adapted from NLB Consensus Recommendations. In Press, CJON June 2008. Amir Qaseem et al., 2007, Ann Fam Med; J. B. Segal et al., 2007, Ann Intern Med. http://www.nhlbi.nih.gov/health/dci/Diseases/Dvt/DVT_WhoIsAtRisk.htm
TE events are serious and potentially life-altering and life-threatening
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.htmlAdapted 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
http://www.nhlbi.nih.gov/health/dci/Diseases/Dvt/DVT_SignsAndSymptoms.htmlAdapted from NLB Consensus Recommendations. In Press, CJON June 2008
PE is a Medical Emergency
TE Event - Diagnostics
DVT
• Doppler Ultrasound
• Contrast Venography
• D-Dimer
• Antithrombin Level
PE
• Ventilation Perfusion Lung (VQ) Scan
• Spiral CT Scan
• D-Dimer
• Antithrombin Level
http://www.nhlbi.nih.gov/health/dci/Diseases/Dvt/DVT_Diagnosis.htmlAdapted from NLB Consensus Recommendations. In Press, CJON June 2008
To maintain therapeutic level INR 2-3
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 2008Thalomid® Prescribing Information; Dexamethasone Prescribing Information
Thromboembolic Events - Prophylaxis Pharmaceutical
Agent
Salicylic Acid (aspirin)
Unfractionated Heparin
Low Molecular Weight Heparin- enoxaparin- dalteparin
Fondaparinux
Warfarin
Suggested Dose
SD 325 mg or LD 81 mg daily
5000 IU sq bid
40mg sq daily
200IU/kg sc daily
2.5 mg sc daily
Weight based• 1 mg < 70 kg
• 2 mg ≥ 70 kg
Palumbo et al., Leukemia (In press); Adapted from NLB Consensus Recommendations. In Press, CJON June 2008. Amir Qaseem et al., 2007, Ann Fam Med; J. B. Segal et al., 2007, Ann Intern Med.
Prophylaxis tailored to individual patient’s risk profile in consideration of the International Myeloma Working Group consensus statement*
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 2008http://www.nhlbi.nih.gov/health/dci/Diseases/Dvt/DVT_Treatments.html
Overview of Peripheral Neuropathy (PN) ‘Consensus Statement’
Adapted from NLB Consensus Recommendations. In Press, CJON June 2008, Thalomid® Prescribing Information, Velcade® Prescribing InformationColson et al., 2004, Clinical Journal of Oncology Nursing; S. Lonial, 2007, The American Journal of Hematology/Oncology.
• THALOMID®/VELCADE® can cause peripheral neuropathy
• PN is a challenging adverse event which may: • Affect quality of life• Compromise optimal treatment
• Management strategies include:• Ongoing evaluation• Dose and schedule modifications• Pharmacologic interventions• Non-pharmacologic approaches• Patient education
PN Definition, Signs/Symptoms
Signs/symptoms
• Temporary Numbness
• Tingling
• Parasthesias
• Sensitivity to Touch
• Muscle Weakness
Severe symptoms
• Burning Pain
• Muscle Wasting
• Paralysis
• Organ Dysfunction
Adapted from NLB Consensus Recommendations. In Press, CJON June 2008http://www.ninds.nih.gov/disorders/peripheralneuropathy/detail_peripheralneuropathy.htm
Damage to the peripheral nervous system including any injury, inflammation, or degeneration of peripheral nerve fibers
PN and Pain Toxicity Grades
Grade 1 Mild
Grade 2 Moderate Grade 3 Severe
Grade 4 Life-threatening or disabling
Grade 5 Death
Mild pain not interfering with function
Moderate pain interfering with function but not ADL
Severe pain severely interfering with ADL
Disabling N/A
Asymptomatic, weakness on testing only
Symptomatic weakness interfering with function but not ADL
Weakness interfering with ADL
Life-threatening disabling
Death
Asymptomatic, loss of deep tendon reflexes or paresthesias
Sensory alteration or paresthesias interfering with function not with ADL
Sensory alteration or paresthesias interfering with ADL
Disabling Death
http://ctep.cancer.gov/reporting/ctc_v30.htmlAdapted from NLB Consensus Recommendations. In Press, CJON June 2008
Grading based upon: Common Terminology Criteria for Adverse Events (CTCAE) v3.0
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
Adapted from NLB Consensus Recommendations. In Press, CJON June 2008; NCCN 2007; NINDS, 2007; Tariman, 2003, Clinical Journal of Oncology Nursing; Visovsky et al., 2007, http://www.ons.org/outcomes/volume2/peripheral/pdf/PEPCardDet_peripheral.pdf.
Patient Education•Notify if S/S Worsen•Home safety with decreased sensation in extremities•Is driving appropriate?•Family members to assess hot/cold temperatures ifpatient 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
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 patch 5%) prescribing information; http://www.mayoclinic.com/health/peripheral-neuropathy/BN00046
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
DrugIncidence of Gastrointestinal Adverse Events Reported For All Grades
Constipation Diarrhea Nausea Vomiting
REVLIMID®*
(Two studies combined, N = 346)
39% 29% 22% 10%
THALOMID®*
(Open label study, N = 102)
55% 12% 28% 12%
VELCADE®
(Phase 3 trial, N = 331)
42% 57% 57% 35%
*REVLIMID® and THALOMID® administered in combination with dexamethasone
Thalomid® Prescribing Information, Revlimid® Prescribing Information, Velcade® Prescribing Information Adapted from NLB Consensus Recommendations. In Press, CJON June 2008
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
Adapted from NLB Consensus Recommendations. In Press, CJON 2008; ASCO’s Curriculum Nausea and vomiting 2005; NCI Nausea and vomiting 2007
Pharmacologic• Select anti-emetics based on how strongly the novel agents
stimulate N/V and consider type of N/V- Nausea: Ativan®, Compazine®, Decadron®, Pepcid®, Phenergan®,
Reglan®, or Zantac®
- Vomiting: Emend®, Zofran®, Kytril®, Anzemet®, or Aloxi®
• Intravenous hydration to correct electrolyte imbalance
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:
– Ophthalmic– Gastrointestinal– Endocrine– Cardiovascular– Dermatologic
– Constitutional– Psychiatric– Immune– Musculoskeletal– Bone loss– Body image
Adapted from NLB Consensus Recommendations. In Press, CJON June 2008; Tariman & Estrella, 2005
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 Clinical Trial Protocols and Data (from ASH & ASCO 2007)
– Focus on Phase III trials of patients with Newly Diagnosed Multiple Myeloma (NDMM)
Recent NCCN Guidelines for MM Therapy
New Insights on Novel Therapies in Multiple Myeloma
• Offer MM patients personalized targeted therapy
• Increased therapeutic efficacy• Improved patient outcomes
Future Direction of New Therapy Combinations and Protocols
Adapted from NLB Consensus Recommendations. In Press, CJON June 2008; Ghobrial, et al. (2007) Oncology, 21, 785-792. Lonial, S. (2007) The American Journal of Hematology/Oncology, 6, 194-196.
Study Objective– Assess the survival advantage of MP-T vs MP in elderly MM
patients ≥75 years– Assess benefit of MP-T vs MP treatment in NDMM
patients ≥75 years
Study Design– Randomized, Double-Blind, Placebo-Controlled– Patients receive either MP-T (n=113) or MP (n=116)
Hulin, et al. ASH Annual Meeting 2007 110: Abstract 75
IFM 01/01-1 Trial: MP-T vs MP in NDMM elderly patients
Melphalan-Prednisone-Thalidomide (MP-T) vs Melphalan-Prednisone (MP) in Elderly Patients and MP-T vs MP in Newly Diagnosed Multiple Myeloma (NDMM) Elderly Patients
Primary end point– Overall Survival (OS)
Secondary end points– Progression Free Survival (PFS)
– Response to Treatment• Partial Response/Remission (PR)• Very Good Partial Response (VGPR)• Progressive Disease (PD)• Complete Response (CR)
– Toxicity
Methods– 229 patients treated
– Trial stopped after second interim analysis
– Results compiled after medium follow-up time of 24 months
Hulin, et al. ASH Annual Meeting 2007 110: Abstract 75
IFM 01/01-1 Trial: MP-T vs MP in NDMM elderly patients (cont’d)
Cyrille Hulin et al. Blood (ASH Annual Meeting Abstracts) 2007 110: Abstract 75
Results % of Patients who Stopped Tx
Observed Toxicities
DVT Somnolence Peripheral Neuropathy
Neutropenia Depression
MP-T Arm 42% 6% 6% 20% 23% 7%
MP Arm11% 4% 3% 5% 9% 2%
Results MP-T (n=116) MP (n=113) P value
At least PR (50%) 62% 31% P<.0001
VGPR (90%) 22% 7% P<.0001
CR 7% 1% P<.0001
Survival after PD 9.8 months 9.3 months NS
Median OS 45.3 months 27.7 months P=.03
PFS 24.1 months 19.0 months P<.0001
Results from IFM 01/01-1 Trial: MP-T vs MP in NDMM Elderly Patients
Hulin et al. ASH Annual Meeting 2007 110: Abstract 75Hulin et al Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings Part I. Vol 25, No. 18S (June 20 Supplement), 2007: 8001)
• 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 75Hulin et al. ASCO Annual Meeting 2007 Presentation: Comparison of melphalan-prednisone-thalidomide (MP-T) to melphalan-prednisone (MP) in patients 75 years of age or older with untreated multiple myeloma (MM). Preliminary results of the randomized, double-blind, placebo controlled IFM 01-01 trial.
Conclusions from IFM 01/01 Trial: IFM 01/01-1 Trial: MP-T vs MP in NDMM Elderly Patients
Study Objective– MP-T treatment of NDMM patients
Study Design– Placebo-Controlled double blind trial– Patients received either MP-T or MP– No prophylaxis recommended for Venous TE– Patients recruited were not eligible for high dose treatment in
Norway, Sweden and Denmark
End Points– Overall Survival (OS), Event Free Survival, Response to Treatment, Time to Progression (TTP) and Quality of Life
MP-T vs MP in NDMM Patients
Melphalan-Prednisone-Thalidomide to Newly Diagnosed Patients with Multiple Myeloma: A Placebo Controlled Randomized Phase 3 Trial
Waage et al. ASH 2007 Abstract #78; Also appears in Blood, Volume 110, issue 11, November 16, 2007
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
MP-T vs MP in NDMM Patients (cont’d)
Waage et al. ASH 2007 Abstract #78; Also appears in Blood, Volume 110, issue 11, November 16, 2007
“Result surprising in light other studies showing advantage of MP-T over MP”
VISTA Trial: VMP vs MP in NDMM
Study Objective–Define the differences in efficacy and outcome between VMP vs MP–VISTA Study
• (VELCADE® as Initial Standard Therapy in multiple myeloma: Assessment with melphalan and prednisone) trial of VMP compared with MP in patients aged 65 years who are not eligible for transplantation
Study Design and Method– Large International Phase 3 randomized study
– Patients of median age of 71 years (30% pts ≥75 years)– VMP arm (IV bortezomib in combination with oral prednisone
and oral melphalan) vs MP arm (Oral mephalan and
prednisone)
– Stratified according to baseline β2-microglobulin, albumin
and geographic regions
San Miguel et al Blood (ASH Annual Meeting Abstracts) 2007 110: Abstract 76
A Phase 3 Study Comparing Bortezomib–Melphalan–Prednisone (VMP) with Melphalan–Prednisone (MP) in NDMM
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 (cont’d)
Mateos, et al. Haematologica 2008; 93(4) 560-565
VISTA Trial : VMP vs. MP in NDMM Most Common Adverse Events (in ≥30% patients)
Adverse Event % Toxicities all grades % Toxicities grades 3/4
Anemia 86 10
Thrombocytopenia 93 51
Infection 75 16
Neutropenia 85 43
Asthenia 63 5
Nausea 55 2
Diarrhea 55 16
Peripheral Neuropathy 55 17
Constipation 52 8
Anorexia 38 2
Vomiting 30 2
VISTA Trial: VMP vs. MP in NDMM Results
Efficacy Results VMP (n=344) MP (n=338) P value
CR + PR rate 82% 50% P<.0001
CR rate 35% 5% P<.0001
Median TTR 1.4 months 4.2 months P<.0001
DOR 19.9 months 16.6 months median not reached
DOR for patients with CR 24.0 months 12.8 months N/A
Median TTP 24.0 months 16.6 months P<.0001
2-year OS 82.6% 69.5% N/A
2-year OS <75 years 84% 74% N/A
2-year OS ≥75 years 79% 60% N/A
San-Miguel ASH 2007 presentation; Lederman, ASH 2007 IMF Multiple Myeloma Highlights for Physicians Mateous et al. Haematologica 2008; 93(4), 560-565
Conclusions Adverse Events
–46% with VMP–36% with MP
Patients remained on therapy longer with VMP–46 weeks with VMP–39 weeks with MP
Patients had a longer time to next therapy
Patients also had longer treatment-free survival
San Miguel et al Blood (ASH Annual Meeting Abstracts) 2007 110: Abstract 76
VISTA Trial: VMP vs. MP in NDMM
These results may establish VMP as a new standard of care for patients not eligible for SCT
E4A03: RD vs Rd in NDMM
Study Objective–Lenalidomide and High Dose Dexamethasone (RD) vs Lenalidomide plus Low Dose Dexamethasone (Rd) (RD vs Rd in NDMM)
Treatment Regimen–RD patients received lenalidomide 25 mg/day PO days 1-21 every 28 days plus dex 40 mg days 1-4, 9-12, and 17-20 PO every 28 days–Rd patients received lenalidomide at the same dose plus dex 40 mg days 1, 8, 15, and 22 PO every 28 days
Study Design–Phase 3 randomized trial–445pts (median age 65 yrs) (Arm A 223 pts Oral RD, Arm B 222 pts Oral Rd)
Primary End Point–Response rate at 4 months
Rajkumar et al. Abstract #74 appears in Blood, Volume 110, issue 11, November 16, 2007
A Randomized Trial of Lenalidomide Plus High-Dose Dexamethasone (RD) Versus Lenalidomide Plus Low-Dose Dexamethasone (Rd) in NDMM
Survival rate results RD Arm Rd Arm P Value
OS differences (pts <65 ) 90% 98% P=0.015
OS differences (pts 65 & older) 83% 95% P=0.004
One year survival 86% 96.5% -
18 month survival rate 80% 91% -
Results of E4A03: RD vs Rd in NDMM
Rajkumar et al. Abstract #74 appears in Blood, Volume 110, issue 11, November 16, 2007Lederman, ASH 2007 IMF Multiple Myeloma Highlights for Physicians
E4A03 : RD vs Rd in NDMM Toxicities
Rajkumar et al. Abstract #74 appears in Blood, Volume 110, issue 11, November 16, 2007
Major Grade 3 or Higher Adverse Events
Toxicity RD% Rd% P value
Neutropenia 10 19 0.01
DVT/PE 25 9 <0.001
Infections 16 6 <0.001
Any grade 3 or higher non-hematologic
49 32 <0.001
Any grade 4 or higher non-hematologic
20 9 <0.001
Deaths in first 4 months
5 0.5 0.006
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
Study Objective– To compare Len+HD to HD in NDMM
Study Design– A randomized, double-blinded, placebo-controlled trial – Trial closed at 198 pts
Zonder et al. Abstract #77 appears in Blood, Volume 110, issue 11, November 16, 2007
Superiority of Lenalidomide (Len) Plus High-Dose Dexamethasone (HD) Compared to HD Alone as Treatment of Newly-Diagnosed Multiple Myeloma (NDMM)
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 Len+HD HD P Value
1 yr PFS 77% 55% p=0.002
ORR 85.3% 51.3% p=0.001
OS (at 1 yr) 93% 91% p=NS
Grade 3-4 neutropenia 13.5% 2.4% p=0.010
Infections n=38, Gr 3-4=13, Gr 5=1 n=23, Gr 3-4=8, Gr 5=0 p=0.003
TEE 25 7 p=0.089
Results SWOG Trial S0232: Len+HD vs. HD
Zonder et al. Abstract #77 appears in Blood, Volume 110, issue 11, November 16, 2007
Conclusions of SWOG Trial S0232: Len+HD vs HD
Zonder et al. Abstract #77 appears in Blood, Volume 110, issue 11, November 16, 2007
Observed Toxicities
Len+HD HD
Neutropenia (%) 13.5 2.4
Infections (n) 14/38 8/23
TEE (n) 25/38 7/38
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
Study Objective– VTD vs TD in Preparation for Autologous Stem Cell
Transplantation (ASCT) in NDMM
Study Design– Randomized trial
– Three cycles of induction therapy
Methods– Pts. randomized to either VDT (n=129) or TD (n=127)
– Stem cells were collected
– Consolidation therapy with same treatment to pts
– Results drawn from an interim analysis of 256 patients
Cavo et al. Blood (ASH Annual Meeting Abstracts) 2007 110: Abstract 73
Bortezomib (VELCADE®)-Thalidomide-Dexamethasone (VTD) vs Thalidomide-Dexamethasone (TD) Prior to Stem Cell Transplantation (SCT))
Results VDT TD P value
CR + near (n)CR 36% 9% P<.001
At least VGPR 60% 27% P<.001
CR + nCR, del(13) 43% 4% P<.001
CR + nCR, t(4;14) 47% 8% P=.002
CR + nCR after first ASCT 57% 28% P<.001
CR after first ASCT 45% 19% P<.001
At least VGPR after first ASCT 77% 54% P=.003
Cavo ASH 2007 presentation; Lederman, ASH 2007 IMF Multiple Myeloma Highlights for PhysiciansCavo et al. Blood (ASH Annual Meeting Abstracts) 2007 110: Abstract 73
Results VTD vs. TD Prior to SCT
Adverse events: • Skin rash > in VTD arm• PN > in VTD arm• DVT
3% in VTD arm6.5% in TD arm
• Reactivation of Varicella Zoster Virus (VZV) 2% in VTD arm1% in TD arm
Prophylaxis– Acyclovir prophylaxis against reactivation of VZV– TEE prophylaxis with low molecular weight heparin, aspirin, or
warfarin; fixed low dose warfarin is effective
Conclusions– The response rates after first ASCT were significantly higher
in the VTD arm – Longer follow-up is necessary after consolidation therapy– Numbers of TE events were too small to draw firm
conclusions
VTD vs. TD Prior to SCT
Cavo et al. Blood (ASH Annual Meeting Abstracts) 2007 110: Abstract 73Lederman, ASH 2007 IMF Multiple Myeloma Highlights for Physicians
MM-009 and MM-010 Phase III Trials: Len/Dex vs Dex
Study Objective–Comparison of Prolonged Overall Survival (OS) withLen/Dex vs Dex in patients with relapsed or refractory MM
Study Design–An update of long-term OS data from the two prospective,randomized, double-blind, placebo-controlled phase III trials (MM-009, MM-010)
Study End Point–Long-term overall survival (OS) with Len/Dex vs Dex
Weber et al. Blood (ASH Annual Meeting Abstracts) 2007 110: Abstract 412
Long-Term Survival Data for Lenalidomide-Dexamethasone vs. Dexamethasone MM-009 and MM-010 Phase III Trials (Len/Dex vs Dex)
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
Results Len/Dex Dex P Value
Overall response, % 60.6 21.9 <0.001
Complete remission rate, % 15.0 2.0 <0.001
Median TTP, months 11.2 4.7 <0.001
Median OS, months 35.0 31.0 <0.05
Median OS in patients with 1 prior treatment, months
Not yet Reached 35.3 0.24
Median OS in patients with >1 prior treatment, months
32.4 27.3 <0.05
Weber et al. Blood (ASH Annual Meeting Abstracts) 2007 110: Abstract 412
MM-009 and MM-010: Long Term Survival Data for Len/Dex vs. Dex
Conclusion: Significant improvement in OS achieved with Len/Dex
• New combinations of novel therapies may offer personalized targeted therapy
– Increased therapeutic efficacy
• Important to monitor these new combinations for emergent adverse side effects
• Effective nursing management will help to optimize patient adherence and outcomes
Future Direction of New Therapy Combinations and Protocols of Novel Therapies
Adapted from NLB Consensus Recommendations. In Press, CJON June 2008; Ghobrial, et al. (2007) Oncology, 21, 785-792. Lonial, S. (2007) The American Journal of Hematology/Oncology, 6, 194-196.
Recent NCCN Guidelines for MM: Induction Therapy
NCCN Practice Guidelines in Oncology-v.1.2008Multiple Myeloma: Induction Therapy
Note: All recommendations are category 2A unless otherwise indicated
• Selected, but not inclusive of all regimens• Order does not imply preference• Consider herpes zoster prophylaxis for patients treated with single agent bortezomib • Prophylactic anticoagulation recommended for patients receiving thalidomide-based therapy or lenalidomide with dexamethasone
Recent NCCN Guidelines for MM Induction Therapy: General Notes
NCCN Practice Guidelines in Oncology-v.1.2008 Multiple Myeloma
NCCN Guidelines: Primary Induction
Therapy for Transplant Candidates:
• Vincristine/doxorubicin/dexamethasone (VAD)• Dexamethasone • Thalidomide/dexamethasone • Liposomal doxorubicin/vincristine/dexamethasone (DVD) • Lenalidomide/dexamethasone (category 2B) • Bortezomib/dexamethasone (category 2B) • Bortezomib/doxorubicin/dexamethasone (category 2B) • Bortezomib/thalidomide/dexamethasone (category 2B)
NCCN Practice Guidelines in Oncology-v.1.2008 Multiple Myeloma
Exposure to myelotoxic agents (including alkylating agents and nirtrosoureas) should be limited to avoid compromising stem-cell reserve prior to stem-cell harvest in patients who
may be candidates for transplant
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 InstituteCleveland, Ohio
NLB Accomplishments
The initial guidelines cover the following:
The development of ‘Consensus Statements’ on the nursing management of side effects that patients with multiple myeloma can experience while being treated
with novel therapies
Peripheral Neuropathy
DVT and PE
Myelosuppression
GI Effects
Steroid Effects
Adapted from NLB Consensus Recommendations. In Press, CJON June 2008
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
• Clinical Journal Oncology Nursing (CJON)
• Number of supplements to be printed - 37,000
• ‘Patient Education Insert Tear Out Tools’ for 5 Side Effects
PUBLICATION IN JUNE 2008
CJON ‘Consensus Statements’ supplement publication offers an additional CEU accreditation opportunity
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
• Publication of the ‘Consensus Statements’ will be immeasurably valuable to the general nursing community involved in multiple myeloma patient care
• Communication and dissemination of the ‘Consensus Documents’ are important next steps
• Develop new educational materials/tools- Patient related- Nurse related
Focus of NLB Commitment
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
Frame the Importance of NursingManagement of Long Term Side Effects
Associated With MM Therapies
Develop long term care plan information guidelines and booklet
Expand initiative to collaborate with nurses worldwide
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
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