download the powerpoint presentation

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:



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

http://www.emedicinehealth.com/

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


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




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%




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



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


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)

http://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


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


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


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


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


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

http://www.schneiderchildrenshospital.org/peds_html_fixed/peds/transplant/bonetran.htm

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

http://www.nhlbi.nih.gov/health/dci/Diseases/Dvt/DVT_SignsAndSymptoms.html

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

http://ctep.cancer.gov/reporting/ctc_v30.html

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


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


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®)


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


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


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


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


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


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


Conclusions of SWOG Trial S0232: Len+HD vs HD


Observed Toxicities

Len+HD HD

Neutropenia (%) 13.5 2.4

Infections (n) 14/38 8/23

TEE (n) 25/38 7/38

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


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


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


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)


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 Guidelines: Maintenance Therapy

• Steroids (category 2B) • Interferon (category 2B)


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 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 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)


Closing Remarks



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


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


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


• 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

http://www.cjon.org/

Question & Answer Session

Faculty Panel

download the powerpoint presentation

Documents

management of multiple

multiple myeloma causes

myeloma patient

new consensus

nursing management

novel therapies

normal plasma cells

nursing community