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Understanding Multiple Myeloma, Its Treatment, and New Discoveries: Part 1 Presented as a Live Webinar Wednesday, August 12, 2015 12:00 p.m. – 1:00 p.m. EDT On-demand Activity Live webinar recorded and archived to be watched at your convenience Available after October 1, 2015 www.ashpadvantage.com/multmyeloma Planned by ASHP Advantage and supported by an educational grant from Onyx Pharmaceuticals Inc., a subsidiary of Amgen Inc.

Understanding Multiple Myeloma, Its Treatment, and New ......MM = multiple myeloma MGUS = monoclonal gammopathy of undetermined significance BM = bone marrow. Signs and Symptoms of

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Page 1: Understanding Multiple Myeloma, Its Treatment, and New ......MM = multiple myeloma MGUS = monoclonal gammopathy of undetermined significance BM = bone marrow. Signs and Symptoms of

Understanding Multiple

Myeloma, Its Treatment, and

New Discoveries: Part 1

Presented as a Live Webinar Wednesday, August 12, 2015

12:00 p.m. – 1:00 p.m. EDT

On-demand Activity Live webinar recorded and archived to be watched at your convenience

Available after October 1, 2015

www.ashpadvantage.com/multmyeloma

Planned by ASHP Advantage and supported by an educational grant from Onyx Pharmaceuticals Inc., a subsidiary of Amgen Inc.

Page 2: Understanding Multiple Myeloma, Its Treatment, and New ......MM = multiple myeloma MGUS = monoclonal gammopathy of undetermined significance BM = bone marrow. Signs and Symptoms of

Understanding Multiple Myeloma, Its Treatment, and New Discoveries: Part 1

Activity Overview

This educational activity will provide an overview of multiple myeloma, including its pathophysiology, typical presentation, and current therapies. Patient case scenarios will be used to highlight decision points in staging patients and managing therapy.

Learning Objectives

At the conclusion of this application-based educational activity, participants should be able to Review the pathophysiology, epidemiology, clinical features, and disease progression of multiple

myeloma. Explain current therapies for the treatment of multiple myeloma. Assist in the development of a therapeutic plan for patients with multiple myeloma based on state-of-

the-art clinical trial data.

List of Abbreviations

For a list of abbreviations used in the activity, please see pages 23-24.

Continuing Education Accreditation

ASHP is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. This activity provides 1.0 hour (0.1 CEU – no partial credit) of continuing pharmacy education credit (ACPE activity #0204-0000-15-452-L01-P for the live activity and ACPE

activity #0204-0000-15-452-H01-P for the on-demand activity).

Participants will process CPE credit online at http://elearning.ashp.org/my-activities. CPE credit will be reported directly to CPE Monitor. Per ACPE, CPE credit must be claimed no later than 60 days from the date of the live activity or completion of a home-study activity.

Webinar Information

Visit www.ashpadvantage.com/multmyeloma to find Webinar registration link Group viewing information and technical requirements CPE webinar processing information

Additional Educational Activities

Live webinar featuring Part 2 of this series on August 19, 2015 (1 hour CPE) On-demand activities based on Part 1 and Part 2 live webinars (1 hour CPE for each activity, available

after October 1, 2015) – Please note that individuals who claim CPE credit for the live webinar areineligible to claim credit for the on-demand activity

www.ashpadvantage.com/multmyeloma

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Understanding Multiple Myeloma, Its Treatment, and New Discoveries: Part 1

Activity Faculty

Christopher A. Fausel, Pharm.D., M.H.A., BCOP

Clinical Manager, Oncology Pharmacy Indiana University Health Indianapolis, Indiana

Christopher A. Fausel, Pharm.D., M.H.A, BCOP, is Clinical Manager of Oncology Pharmacy at Indiana University Simon Cancer Center (IUSCC) in Indianapolis, Indiana. He oversees the clinical and dispensing pharmacy services at the IUSCC ambulatory infusion center and four satellite infusion clinics. Dr. Fausel also holds academic appointments at the Department of Medicine at Indiana University School of Medicine, Purdue University School of Pharmacy and Pharmaceutical Sciences, and Butler University College of Pharmacy.

Dr. Fausel received his Bachelor of Science degree in pharmacy and Doctor of Pharmacy degree from Albany College of Pharmacy in Albany, New York. He completed an ASHP-accredited pharmacy practice residency at Samuel S. Stratton VA Medical Center in Albany, New York. More recently, he earned a Master of Health Administration degree from Simmons College in Boston, Massachusetts.

Dr. Fausel is the founding Residency Program Director for the postgraduate year two (PGY-2) oncology pharmacy residency at Indiana University Health. He chairs two Institutional Review Boards (IRBs) for Indiana University and serves on the IRB Executive Committee for the university.

Dr. Fausel is a board-certified oncology pharmacist, and he is certified in basic life support by the American Red Cross. He is Chairman of the Board of the Hoosier Cancer Research Network and a long-standing member of ASHP, American Society of Clinical Oncology, and Hematology/Oncology Pharmacy Association.

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Understanding Multiple Myeloma, Its Treatment, and New Discoveries: Part 1

R. Donald Harvey, Pharm.D., FCCP, BCOP

Associate Professor, Hematology/Medical Oncology Emory University School of Medicine Director, Phase 1 Clinical Trials Section Winship Cancer Institute of Emory University Atlanta, Georgia

R. Donald Harvey, Pharm.D., FCCP, BCOP, is Associate Professor in the Department of Hematology and Medical Oncology at the Emory University School of Medicine in Atlanta, Georgia. He also is Director of the Phase 1 Clinical Trials Section at Winship Cancer Institute of Emory University. In addition, Dr. Harvey serves as Co-chair of the Data Safety and Monitoring Committee and as a Pharmacology representative on the Clinical and Translational Research Committee for the cancer center, as well as preceptor for the postgraduate year 2 (PGY-2) oncology residency at Emory University Hospital.

Dr. Harvey received his Bachelor of Science in Pharmacy and Doctor of Pharmacy degrees from the University of North Carolina (UNC) in Chapel Hill. He subsequently completed a pharmacy practice residency at the University of Kentucky Medical Center and College of Pharmacy and a hematology/oncology specialty residency at UNC Hospitals and School of Pharmacy.

Dr. Harvey is a board-certified oncology pharmacist and a fellow of the American College of Clinical Pharmacy. He has authored or co-authored over 60 peer-reviewed publications and is section editor for original research for the Journal of Hematology Oncology Pharmacy. He serves as a reviewer for the British Journal of Cancer,

Journal of Pharmaceutical and Biomedical Analysis, Cancer, Annals of Oncology, Pharmacotherapy, and Journal

of Clinical Pharmacology. Dr. Harvey is a past president of the Hematology/Oncology Pharmacy Association (HOPA), and he now serves as Chair of the HOPA Research Foundation.

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Understanding Multiple Myeloma, Its Treatment, and New Discoveries: Part 1

Disclosure Statement

In accordance with the Accreditation Council for Continuing Medical Education’s Standards for Commercial Support and the Accreditation Council for Pharmacy Education’s Guidelines for Standards for Commercial Support, ASHP Advantage requires that all individuals involved in the development of activity content disclose their relevant financial relationships. A commercial interest is any entity producing, marketing, re-selling, or distributing health care goods or services consumed by, or used on, patients. A person has a relevant financial relationship if the individual or his or her spouse/partner has a financial relationship (e.g., employee, consultant, research grant recipient, speakers bureau, or stockholder) in any amount occurring in the last 12 months with a commercial interest whose products or services may be discussed in the educational activity content over which the individual has control. The existence of these relationships is provided for the information of participants and should not be assumed to have an adverse impact on presentations.

All faculty and planners for ASHP Advantage education activities are qualified and selected by ASHP Advantage and required to disclose any relevant financial relationships with commercial interests. ASHP Advantage identifies and resolves conflicts of interest prior to an individual’s participation in development of content for an educational activity.

R. Donald Harvey, Pharm.D., FCCP, BCOP, declares that he has served as an advisor for Bristol-MyersSquibb, Onyx Pharmaceuticals Inc., and Takeda Pharmaceuticals. He has also participated in researchactivities funded by Acetylon Pharmaceuticals, Inc.; Bristol-Myers Squibb; Calithera Biosciences; CelgeneCorporation; Cleave Biosciences; Novartis Pharmaceuticals; Onyx Pharmaceuticals Inc.; Sanofi; andTakeda Pharmaceuticals.

All other faculty and planners report no financial relationships relevant to this activity.

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Understanding Multiple Myeloma,Its Treatment, and New Discoveries:

Part 1

Christopher A. Fausel, Pharm.D., M.H.A., BCOPIndiana University Simon Cancer Center

Indiana University Health Indianapolis, Indiana

R. Donald Harvey, Pharm.D., FCCP, BCOP Emory University School of Medicine

Winship Cancer Institute of Emory UniversityAtlanta, Georgia

Disclosures

• R. Donald Harvey, Pharm.D., FCCP, BCOP– Research funding (through Emory University):

Acetylon Pharmaceuticals, Inc.; Bristol-Myers Squibb(BMS); Calithera Biosciences; Celgene Corporation;Cleave Biosciences; Novartis Pharmaceuticals; OnyxPharmaceuticals Inc.; Sanofi; and TakedaPharmaceuticals

– Advisory boards: BMS, Onyx Pharmaceuticals Inc.,and Takeda Pharmaceuticals

• All other faculty and planners report no financialrelationships relevant to this activity

Learning Objectives

• Review the pathophysiology, epidemiology,clinical features, and disease progressionof multiple myeloma

• Explain current therapies for the treatmentof multiple myeloma

• Assist in the development of a therapeuticplan for patients with multiple myelomabased on state-of-the-art clinical trial data

Epidemiology

• Multiple myeloma is a clonal plasma celldyscrasia

• 26,850 new cases to be diagnosed inthe U.S. in 2015

• 11,240 estimated deaths in U.S. in 2015• The median age of diagnosis is 69• The disease has a higher incidence in

men and African Americans

National Cancer Institute. http://seer.cancer.gov/statfacts/html/mulmy.html (accessed 2015 Jul 27).

a. Platelets

b. Neutrophils

c. Eosinophils

d. Plasma cells

Multiple myeloma is a disorder that primarily involves which of the following cell types in the marrow?

Plasma Cell Dyscrasias

Kuehl WM et al. Nature Rev Cancer. 2002; 2:175-87.

MGUS Smoldering Myeloma

Intramedullary Myeloma

Extramedullary Myeloma

Myelomacell line

Germinal-centre B cell

BM stromal cell dependence

IL-6 dependence

Angiogenesis

Bone destruction

Increased DNA-labelling index, NF kappa B

Normal long-lived plasma cell

See enlargement p. 15

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What Really Is MM?A Progressive B-cell Disorder

Kuehl WM et al. Nature Rev Cancer. 2002; 2:175-87.

MGUS<10% of cells

(red stain)

BMIncreased

angiogenesis

Lytic bone lesions

Plasma cells in blood

MM = multiple myelomaMGUS = monoclonal gammopathy of undetermined significanceBM = bone marrow

Signs and Symptoms of Myeloma

Bird JM et al. Br J Haematol. 2011; 154:32-75. International Myeloma Working Group (IMWG). Br J Haematol. 2003; 121:749-57.

M – Proteinspillage

Immunedeficiency

Marrowinfiltration /

bonedestruction

Neuropathy (33%)

Renal compromise (30%)

Infection (15%)

Hypercalcemia (15 – 20%)

Bone pain (75%)

Lytic lesions (70%)

Anemia (70%)

Plasma Cells in Blood(Multiple myeloma)

hyperCalcemiaRenal disease

Anemia

Bone disease

Signs and Symptoms

• Extramedullary plasmacytomas (EMPs)– EMPs are plasma cell tumors that arise outside the bone

marrow– Patients with MM may present with extramedullary

plasmacytomas in 7% of cases– The upper respiratory tract is the most common site for

presentation, but may appear in any organ

• Increased susceptibility to infections• Hyperviscosity (rare) presents as headache, blurred

vision, epistaxis, oral bleeding, altered mental status,confusion– Most common with IgA disease because of the dimeric

forms of IgA– Institute plasmapheresis

Myeloma Diagnostic Evaluation

• Medical history and physical examination• Routine testing

– CBC– Serum chemistries, including serum calcium– Serum and urine protein electrophoresis with immunofixation– Quantification of serum and urine monoclonal protein– Measurement of serum free light chains

• Bone marrow analysis– Trephine biopsy and aspirate of bone marrow cells for

morphologic features; cytogenetic analysis and fluorescence in situ hybridization for chromosomal abnormalities

• Imaging– Skeletal survey, MRI if skeletal survey is negative

Kyle RA et al. Leukemia. 2009; 23:3-9.

Myeloma Diagnostic Criteria• Clonal bone marrow plasma cells ≥10% or biopsy-proven

bony or extramedullary plasmacytoma and any one or more of the following myeloma defining events

• Myeloma defining events– Evidence of end-organ damage that can be specifically

attributed to the underlying plasma cell proliferative disorder– Hypercalcemia: serum calcium >0.25 mmol/L (>1 mg/dL)

higher than the upper limit of normal or >2.75 mmol/L (>11 mg/dL)

– Renal insufficiency: creatinine clearance <40mL/min or serumcreatinine >177 µmol/L (>2 mg/dL)

– Anemia: hemoglobin value of >20 g/L below the lower limit ofnormal, or a hemoglobin level <100 g/L

– Bone lesions: one or more osteolytic lesions on skeletal radiography, CT or PET-CT

Rajkumar SV et al. Lancet Oncol. 2014;15:e538-e548.

Myeloma Diagnostic Criteria

• Any one or more of the followingbiomarkers of malignancy– Clonal bone marrow plasma cell percentage≥60%

– Involved:uninvolved serum free light chainratio ≥100

– >1 focal lesion on MRI studies

Rajkumar SV et al. Lancet Oncol. 2014; 15:e538-e548.

See enlargement p. 15

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International Staging System

Greipp PR et al. J Clin Oncol. 2005 ; 23:3412-20.

Stage I Stage II Stage III

-2-Microglobulin(mg/L)

<3.5 3.5-5.4 ≥5.5

Albumin (g/dL)

≥3.5 NA NA

Median survival (months)

62 44 29

Patients (%)

25 35 40

IMWG Uniform Response CriteriaResponse IMWG Criteria

sCR (stringent complete response)

CR as defined below plus normal free light chain (FLC) ratio and absence of clonal cells in the marrow by immunohistochemistry or immunofluorescence

CR (complete response) Negative immunofixation of serum and urine and disappearance of any soft tissue plasmacytomas and <5% plasma cells in bone marrow

VGPR (very good partial response)

Serum and urine M-component detectable or ≥90% reduction in serum M-component + urine <100 mg/24 hour

PR (partial response) ≥50% reduction of serum M protein and reduction in 24-hr urinary M protein by ≥90% or to <200 mg per 24 hour

Durie BG et al. Leukemia. 2006; 20:1467-73.

IMWG Uniform Response Criteria

Response IMWG Criteria

Stable disease Not meeting criteria for CR, VGPR, or progressive disease

Progressive disease of 25% from lowest response value in any of• Serum/urine M-component,• Bone marrow plasma %, or • Hypercalcemia/ new bone lesions

Relapse Requires one or more of• Direct indicators of increasing disease

and/or• End-organ dysfunction (CRAB

features)

Durie BG et al. Leukemia. 2006; 20:1467-73.

Risk Stratification by CytogeneticsRisk Abnormalities Incidence Median OS (yr)

Standard t(11;14)t(6;14)

Trisomies

60% 8 to 10

Intermediate FISH: t(4;14), 1q gainDel13* or

hypodiploidyComplex karyotype

20% 4 to 5

High FISH: Del 17p*, t(14;16)t(14;20)

GEP – High risk signature

20% 3

Munshi NC et al. Blood. 2011; 17:4696-700. Mikhael JR et al. Mayo Clin Proc. 2013; 88:360-76.

OS = overall survivalFISH = fluorescence in situ hybridizationGEP = gene expression profile

Patient Case Scenario

• MR is a 62-year-old woman who presentswith high serum protein and SCr of 2.3mg/dL

• Work up revealed– IgG kappa monoclonal protein 4 g/dL– Skeletal survey normal– No anemia

• Bone marrow biopsy showed 45% clonalplasma cell population

a. Melphalan-prednisone

b. Panobinostat

c. Bortezomib-lenalidomide-dexamethasone

d. Pomalidomide-dexamethasone

Which of the following regimens would be most appropriate for induction treatment in this patient?

8

Page 9: Understanding Multiple Myeloma, Its Treatment, and New ......MM = multiple myeloma MGUS = monoclonal gammopathy of undetermined significance BM = bone marrow. Signs and Symptoms of

Drug Therapy for Myeloma

Bergsagel DE et al. Cancer Chemother Rep. 1962; 21:87-99. McElwain TJ et al. Lancet. 1983; 2:822-4.Barlogie B et al. N Engl J Med. 1984; 310:1353-6. Alexanian R et al. Ann Intern Med. 1986;105:8-11.Berenson JR et al. N Engl J Med. 1996; 334:488-93. Attal M et al. N Engl J Med. 1996; 335:91-7.Singhal S et al. N Engl J Med. 1999; 341:1565-71. Harousseau JL et al. J Clin Oncol. 2010; 28:4621-9. Zonder JA et al. Blood. 2010; 116:5838-41.

Oral melphalan and prednisone

High-dose melphalan

Autologous bone marrow

transplant

High-dose dexamethasone

High-dose therapy with autologousstem cell support

Thalidomide

BortezomibLenalidomide

CarfilzomibPomalidomide

Panobinostat

1962 1983 1984 1986 1996 1999 2005 2012-13

2015

Vincristine-doxorubicin-

dexamethasone(VAD) Bisphosphonates

Immunomodulatory Drugs (IMiDs) - Pharmacology

Richardson PG et al. Blood. 2002; 100:3063-7. Hideshima T et al. Blood. 2000; 96:2943-50.

MM cells

BM stromal cells

PBMC

IL-6TNFIL-1

A. Thalidomide/IMiDs

IL-2IFN

CD8+ T-cells

C. Thalidomide/IMiDs

F. Thalidomide/IMiDs

BM vessels

ICAM-1

VEGFbFGF

E. Thalidomide/IMiDs

B. Thalidomide/IMiDs

NK cells

D. Thalidomide/IMiDs

Proteasome Inhibitors -Pharmacodynamics

Cavo M. Leukemia. 2006; 20:1341-52.

MM Cell Growth

a Bortezomib/Carfilzomib

c Bortezomib/Carfilzomib

b Bortezomib/Carfilzomib

d Bortezomib/Carfilzomib

VEGFbFGF

Bone MarrowVessels

ICAM-1VCAM-1

TNFαVEGF

IL-6

Myeloma Cells

NF-kB

Bone MarrowStromal Cells

Panobinostat - Pharmacology

Kavanaugh SM et al. Am J Health-Syst Pharm. 2010; 67:793-7.

HDAC = histone deacetylase

HDAC Pharmacodynamics

Lemoine M et al. Discov Med. 2010; 54:462-70.

Cell Cycle(p21, cyclins)

HDACi HDACs

Motility(α-tubulin)

Immunity and Inflammation(NFkB, STAT3, TNFα)

Angiogenesis(HIF-1α, VEGF)

Metabolism(GLUT1)

Extrinsic Apoptosis(Death receptors and ligands)

Intrinsic Apoptosis (Bcl-2, Bax)

Monoclonal Antibodies in Myeloma - Pharmacology

Tai YT et al. Blood. 2008; 112:1329-37.

Killer cell

Intact C1

3. ADCC

1. Induction of apoptosis

2. Activation ofcomplement

Fc receptor

Target antigen

Monoclonalantibody

Plasma cell

ADCC = antibody dependent cellular cytotoxicity

See enlargement p. 16 See enlargement p. 16

See enlargement p. 17 See enlargement p. 17

See enlargement p. 18

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Treatment Determination

Rajkumar SV et al. Mayo Clin Proc. 2005; 80:1371-82.

Not a transplant candidatebased on physiologic age, performance status, and

co-morbidity

Potentialtransplant candidate

Conventional chemotherapy orclinical trial

Nonalkylator-based induction witha goal of achieving CR/VGPR

Stem cell harvest

Managing A Multi-Compartmental Treatment Model

Palumbo A et al. N Engl J Med. 2011; 364:1046-60.

Supportive care

Initial therapy

Consolidation Maintenance

Relapsed disease

Transplant-eligiblePatients

Transplant-ineligiblePatients

Consolidation/maintenance/continued

therapy

mSMART

• Multiple myeloma is increasingly recognized as more than one disease, characterized by marked cytogenetic, molecular and proliferative heterogeneity

• The result is widely varied outcome ranging from low to very high risk disease

• Treatment is evolving rapidly as more efficacious agents and combinations become available

• mSMART (Mayo Stratification for Myeloma and Risk-adapted Therapy) is a consensus opinion that takes into account genetically determined risk status and the various treatmentstrategies currently available

• Risk stratification and individualizing treatment options iscomplex and based not just on cytogenetic classification but also on host factors, disease stage and a variety of other prognostic factors

Mikhael JR et al. Mayo Clin Proc. 2013; 88:360-76.

Patient Case Scenario (continued)

• MR finished induction with bortezomib-lenalidomide-dexamethasone x 4 cyclesand achieved a VGPR

• Given the patient’s overall good health, adecision was made to offer herautologous stem cell transplant asconsolidation therapy

a. Cure of the disease

b. Minimal benefit above standard dosechemotherapy

c. Preparation for future allogeneic stem celltransplant

d. Improved chance for CR & potential longerremission duration

Which of the following is a reasonable treatment goal with autologous stem cell transplant for this patient?

Transplant EligibleStandard Risk Intermediate Risk High Risk

Mikhael JR et al. Mayo Clin Proc. 2013; 88:360-76.

Trisomies OnlyT(11;14), t(6;14),

Trisomies +IgHT(4;14)

Del17p, t(14;16), t(14;20)

4 cycles of Rd4 cycles of

CyBorD4 cycles of

CyBorD4 cycles of

RVD

Autologous SCT

Autologous SCT, esp. if not

in CR

Bortezomib based therapy

x 1 year

Bortezomib or CyBorD x 1

year

Collect autologous PBSC

Continue RdAutologous

SCT

2 x Rd then lenalidomide maintenance

Rd = lenalidomide-dexamethasoneCyBorD = cyclophosphamide-bortezomib-dexamethasone

See enlargement p. 18

10

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RVD (Bortezomib, Lenalidomide, Dexamethasone) Induction

• Phase II trial from IFM with 31 patients aged less than 65 yearsall who were transplant eligible

• Median follow-up 39 months

• Treatment– Lenalidomide 25 mg PO daily on days 1 – 14

– Bortezomib 1.3 mg/m2 IV on days 1, 4, 8, 11

– Dexamethasone 40 mg PO on days 1, 8, 15

– Every 21 days x 3 cycles (RVD)

– Followed by autologous SCT (preceded by cyclophosphamide/GCSF stem cell mobilization)

– Followed by RVD consolidation x 2 cycles

– Followed by lenalidomide maintenance for 1 year

Roussel M et al. J Clin Oncol. 2014; 32:2712-7.

Efficacy

Roussel M et al. J Clin Oncol. 2014; 32:2712-7.

ParameterResults at

Completion of All Therapy (n=31)

Results at Completion of

Induction (n=31)

RR (response rate) 97% 93%

CR 58% 23%

VGPR 26% 35%

Minimal residual diseasenegative

58% 16%

3 -year PFS (progression free survival)

77% NR

3-year OS 100% NR

High-risk cytogenetics subgroup 3-year PFS

86% NR

Patients receiving planned therapy

97% 100%

Toxicity – Grade III/IV

Roussel M et al. J Clin Oncol. 2014; 32:2712-7.

ParameterResults at

Completion of All Therapy (n=31)

Results with RVD Induction or

Consolidation (n=31)

Neutropenia 65% 35%

Thrombocytopenia 19% 13%

Anemia 3% 3%

Enterocolitis infection 6% 0%

Fatigue 6% 0%

Rash 3% 3%

Deep venous thrombosis (DVT) 3% 0%

Pulmonary embolism (PE) 3% 0%

Bone pain 3% 3%

Dose reduction (AE) 74% 39%

Discontinuation (AE) 23% 3%

AE = adverse effect

Who Gets Autologous Stem Cell Transplant?

• Age is not a limiting factor• Poor performance status limits patients

from becoming a SCT candidate• Single vs. tandem SCT remain

controversial given mixed clinical trialresults

• Timing of SCT is variable– Immediately post-induction– Delayed– Salvage

Shah N et al. Biol Blood Marrow Transplant. 2015; 21:1155-66.

Autologous Stem Cell Transplant

Palumbo A et al. N Engl J Med. 2014; 371:895-905..

• Primary endpoint: PFS

RANDOMIZEMedian follow-up

51.2 months

Newly diagnosed MM received induction therapy with Rd(N=273)

Melphalan 200 mg/m2 IV with ASCT x 2 as4-month cycles

Melphalan 0.18 mg/kg PO on days 1 – 4 Lenalidomide10 mg PO on days 1 – 21Prednisone2 mg/kg PO on days 1 - 4Every 28 days x 6 cycles

Maintenance within 3 months of completion of consolidation:Lenalidomide10 mg PO daily on days 1 – 21 every 28 days until progression/ toxicity

No Maintenance

RANDOMIZE

EfficacyParameter SCT+M SCT MPR+M MPR

Median PFS 54.7 mo 37.4 mo 34.2 mo 21.8 mo

5-year OS 78.4% 66.6% 70.2% 58.7%

Median PFS – completion of consolidation

43 mo 43 mo 22.4 mo 22.4 mo

Median PFS – from start of maintenance

41.9 mo 21.6 mo 41.9 mo 21.6 mo

CR after maintenance 35.7% 15.7% 33.8% 20%

Palumbo A et al. N Engl J Med. 2014; 371:895-905.

SCT = stem cell transplantMPR = melphalan-lenalidomide-prednisoneM = maintenance

See enlargement p. 19

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Toxicity – Grade III/IV

ParameterSCT

(n=141)MPR

(n=132)Maintenance

(n=116)

No Maintenance

(n=115)

Neutropenia 94% 52% 23% 0

Thrombocytopenia 94% 8% 4% 0

Anemia 23% 2% 2% 0

Gastrointestinal 18% 0 0 0

Infection 16% 1% 6% 2%

Systemic 13% 2% 0 0

Dermatologic 0 0 4% 0

Vascular 1% 2% 2% 0

Second primarycancer

0 0 4% 4%

Palumbo A et al. N Engl J Med. 2014; 371:895-905.

Allogeneic Stem Cell Transplant

• Role is controversial and poorly defined• Potential exists for graft-versus-myeloma

effect• Clinical trial data compared with autologous

SCT is conflicting• Higher CR rates are counterbalanced with

higher treatment-related mortality• Allogeneic SCT is reserved for young, fit

patients with a suitable match or forinvestigation in clinical trials

Shah N et al. Biol Blood Marrow Transplant. 2015; 21:1155‐66.

Transplant - IneligibleStandard Risk Intermediate Risk High Risk

Mikhael JR et al. Mayo Clin Proc. 2013; 88:360-76.

Trisomies OnlyT(11;14), t(6;14),

Trisomies +IgHT(4;14)

Del17p, t(14;16), t(14;20)

RdWeekly

CyBorD for 12 months

Weekly CyBorD for 12

months

RVD for 12 months

Bortezomib based therapy

x 1 year

Bortezomib maintenance x

1 year

Until Progression

Followed by observation

Bortezomib-Melphalan-PrednisoneFirst Line (VISTA Trial)

San Miguel JF et al. J Clin Oncol. 2013; 31:448-55.

• Final analysis of randomized, international phase III clinical trial

– Median follow-up 60.1 months

Patients with previously untreated MM (N=682)

VMPBortezomib1.3 mg/m2 IV on days 1, 4, 8, 11,22, 25, 29, 32 for 4 cycles;Days 1, 8, 22, 29 for 5 cycles +

Melphalan9 mg/m2 PO daily on days 1-4 +

Prednisone60 mg/m2 PO daily on days 1-4(n=344)

MPMelphalan9 mg/m2 PO daily on Days 1-4 +

Prednisone60 mg/m2 PO daily on Days 1-4(n=388)

Nine 6-wk cycles

5-Year Follow-up Data

San Miguel JF et al. J Clin Oncol. 2013; 31:448-55 .

OutcomeVMP

(n=344)MP

(n=338)HR

(95% CI)

5-yr OS (%) 46.0 34.4

Median OS (mo) 56.4 43.10.695*

(0.567-0.852)

Median time to next treatment (mo)

27.0 19.20.557†

(0.462-0.671)

Median treatment-free interval (mo)

16.6 8.30.573†

(0.476-0.69*P = 0.0004†P < 0.0001

Patient Case Scenario (continued)

• After recovery following autologous stemcell transplant, MR and her physiciandiscuss maintenance therapy

• MR is offered a trial of lenalidomidemaintenance

See enlargement p. 19 See enlargement p. 20

12

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a. Hepatotoxicity

b. Mucositis

c. Secondary primary malignancies

d. Hemorrhagic cystitis

Which of the following toxicities of lenalidomide requires long-term follow up?

MPR-R vs. MPR vs. MP

Palumbo A et al. N Engl J Med. 2012; 366:1759-69.

Lenalidomide maintenance reduced the risk of progression by 60%

80

70

100

90

60

50

40

30

20

0

10

5

Pa

tie

nts

(%

)

MPR

MP

MPR-R

0 1510 2520 3530 40

14 Months

13 Months

31 MonthsMedian PFS

Months

HR 0.395 P < .001

HR 0.796P = .135Median follow-up 25 months

HR = hazard ratioMPR-R = melphalan, prednisone, lenalidomide followed by lenalidomideMPR = melphalan, prednisone, lenalidomide followed by placebo MP = melphalan, prednisone, placebo followed by placebo

FIRST Trial

Benboubker L et al. N Engl J Med. 2014; 371:906-17.

Randomized, international Phase III clinical trial

– Primary endpoint: PFS

– Median follow-up 37 months

• Antithrombotic prophylaxis mandated

• Bisphosphonate support allowed

Patients with previously untreated MM, transplant ineligible(N=1623)

Lenalidomide25 mg PO daily on days 1-21 of a 28-day cycle

Dexamethasone40 mg PO days 1, 8, 15, 22 Continuous therapy(n=535)

Lenalidomide25 mg PO daily on days 1-21 of a 28-day cycle

Dexamethasone40 mg PO days 1, 8, 15, 22 For 18 cycles(n=541)

Melphalan 0.25 mg/kg PO daily on days 1-4

Prednisone 2 mg/kg PO daily on days 1-4

Thalidomide200 mg PO daily in 42-day cycles x 72 weeks(n=541)

Efficacy

Benboubker L et al. N Engl J Med. 2014; 371:906-17.

Parameter

Rd Continuous

(n=535)

Rd18 Months

(n=541)MPT

(n=547)

PFS 25.5 mo 20.7 mo 21.2 mo

4-Year OS 59% 56% 51%

Median duration of response

35 mo 22.1 mo 22.3 mo

RR 75% 73% 62%

CR 15% 14% 9%

VGPR 28% 28% 19%

Time to second-line therapy

39.1 mo 28.5 mo 26.7 mo

MPT = melphalan-prednisone-thalidomide

Toxicity

Benboubker L et al. N Engl J Med. 2014; 371:906-17.

ParameterRd

ContinuousRd

18 Months MPT

Infection 29% 22% 17%

Neutropenia 28% 26% 45%

Anemia 18% 16% 19%

Thrombocytopenia 8% 8% 11%

Leukopenia 5% 6% 10%

Lymphopenia 6% 3% 7%

Cardiac disorder 12% 7% 9%

Pneumonia 8% 8% 6%

DVT/PE 8% 6% 5%

Asthenia 8% 6% 6%

Peripheral sensory neuropathy 1% 1% 9%

Secondary Malignancies

• Continuous Rd– 17 patients reported total– 15 patients diagnosed with solid tumors

• Rd for 18 cycles– 30 patients reported total– 29 patients reported with solid tumors

• MPT– 27 patients reported total– Acute myeloid leukemia or myelodysplastic

syndrome reported in 12 of the patients

Benboubker L et al. N Engl J Med. 2014; 371:906-17.

See enlargement p. 20

See enlargement p. 21

13

Page 14: Understanding Multiple Myeloma, Its Treatment, and New ......MM = multiple myeloma MGUS = monoclonal gammopathy of undetermined significance BM = bone marrow. Signs and Symptoms of

CyBorD Induction

• Phase II trial published with 2 cohorts

• Regimen– Cyclophosphamide 300 mg/m2 PO on days 1, 8, 15,

22

– Bortezomib 1.3 mg/m2 IV days 1, 4, 8, 11

– Dexamethasone 40 mg PO on days 1-4, 9-12, 17-20

– Cycle: 28 days x 4 cycles

– Bortezomib changed to 1.5 mg/m2 IV on days 1, 8,15, 22 and dexamethasone to 40 mg PO weekly forcycles 3 and 4 with a second cohort of patients

Reeder CB et al. Blood. 2010; 115:3416-7.

Efficacy

ITTCohort 1

(n=33)Cohort 2

(n=30)All

(n=63)

ORR 88% 93% 90%

CR/nCR 39% 43% 41%

VGPR or better 61% 60% 60%

After 4 cycles (n=28) (n=27) (n=55)

ORR 96% 93% 95%

CR/nCR 46% 48% 47%

VGPR 71% 63% 67%

Reeder CB et al. Blood. 2010; 115:3416-7.

ITT = intention to treatORR = overall response rate

Toxicity – Grade III/IV

ParameterCohort 1

(n=33)Cohort 2

(n=30)

Any AE 48% 37%

Thrombocytopenia 21% 0

Neutropenia 12% 7%

Anemia 9% 0

Peripheral neuropathy 6% 0

Peripheral neuropathy (ALL grades)

64% 57%

Bortezomib dose reduction 21% 13%

Reeder CB et al. Blood. 2010; 115:3416-7.

Next Webinar

• Role of treatment in the salvage setting

• Drug development pipeline

• Supportive care for patients withmyeloma– Modification of agents for end-organ

dysfunction

– Managing renal and bone disease

– Thromboembolism

Conclusion

• Multiple myeloma is a clonal disease ofplasma cells with multiple systemiccomplications

• Therapies, while not curative, haveimproved disease control significantly overthe past decade

• Selection and personalization of treatmentshould be based on a number of clinicaland laboratory-based criteria

Key References

• Rollig C, Knop S, Bornhauser M. Multiplemyeloma. Lancet. 2015; 385:2197-208.

• Rajkumar SV, Landgren O, Mateos MV.Smoldering multiple myeloma. Blood. 2015;125:3069-75.

• Moreau P, Attal M, Facon T. Frontline therapy ofmultiple myeloma. Blood. 2015; 125:3076-84.

• Colson K. Treatment-related symptommanagement in patients with multiple myeloma: areview. Support Care Cancer. 2015; 23:1431-45.

14

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Plasma Cell Dyscrasias

Kuehl WM et al. Nature Rev Cancer. 2002; 2:175-87.

MGUS Smoldering Myeloma

Intramedullary Myeloma

Extramedullary Myeloma

Myelomacell line

Germinal-centre B cell

BM stromal cell dependence

IL-6 dependence

Angiogenesis

Bone destruction

Increased DNA-labelling index, NF kappa B

Normal long-lived plasma cell

Signs and Symptoms of Myeloma

Bird JM et al. Br J Haematol. 2011; 154:32-75. International Myeloma Working Group (IMWG). Br J Haematol. 2003; 121:749-57.

M – Proteinspillage

Immunedeficiency

Marrowinfiltration /

bonedestruction

Neuropathy (33%)

Renal compromise (30%)

Infection (15%)

Hypercalcemia (15 – 20%)

Bone pain (75%)

Lytic lesions (70%)

Anemia (70%)

Plasma Cells in Blood(Multiple myeloma)

hyperCalcemiaRenal disease

Anemia

Bone disease

15

Page 16: Understanding Multiple Myeloma, Its Treatment, and New ......MM = multiple myeloma MGUS = monoclonal gammopathy of undetermined significance BM = bone marrow. Signs and Symptoms of

Drug Therapy for Myeloma

Bergsagel DE et al. Cancer Chemother Rep. 1962; 21:87-99. McElwain TJ et al. Lancet. 1983; 2:822-4.Barlogie B et al. N Engl J Med. 1984; 310:1353-6. Alexanian R et al. Ann Intern Med. 1986;105:8-11.Berenson JR et al. N Engl J Med. 1996; 334:488-93. Attal M et al. N Engl J Med. 1996; 335:91-7.Singhal S et al. N Engl J Med. 1999; 341:1565-71. Harousseau JL et al. J Clin Oncol. 2010; 28:4621-9. Zonder JA et al. Blood. 2010; 116:5838-41.

Oral melphalan and prednisone

High-dose melphalan

Autologous bone marrow

transplant

High-dose dexamethasone

High-dose therapy with autologousstem cell support

Thalidomide

BortezomibLenalidomide

CarfilzomibPomalidomide

Panobinostat

1962 1983 1984 1986 1996 1999 2005 2012-13

2015

Vincristine-doxorubicin-

dexamethasone(VAD) Bisphosphonates

Immunomodulatory Drugs (IMiDs) - Pharmacology

Richardson PG et al. Blood. 2002; 100:3063-7. Hideshima T et al. Blood. 2000; 96:2943-50.

MM cells

BM stromal cells

PBMC

IL-6TNFIL-1

A. Thalidomide/IMiDs

IL-2IFN

CD8+ T-cells

C. Thalidomide/IMiDs

F. Thalidomide/IMiDs

BM vessels

ICAM-1

VEGFbFGF

E. Thalidomide/IMiDs

B. Thalidomide/IMiDs

NK cells

D. Thalidomide/IMiDs

16

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Proteasome Inhibitors -Pharmacodynamics

Cavo M. Leukemia. 2006; 20:1341-52.

MM Cell Growth

a Bortezomib/Carfilzomib

c Bortezomib/Carfilzomib

b Bortezomib/Carfilzomib

d Bortezomib/Carfilzomib

VEGFbFGF

Bone MarrowVessels

ICAM-1VCAM-1

TNFαVEGF

IL-6

Myeloma Cells

NF-kB

Bone MarrowStromal Cells

Panobinostat - Pharmacology

Kavanaugh SM et al. Am J Health-Syst Pharm. 2010; 67:793-7.

HDAC = histone deacetylase

17

Page 18: Understanding Multiple Myeloma, Its Treatment, and New ......MM = multiple myeloma MGUS = monoclonal gammopathy of undetermined significance BM = bone marrow. Signs and Symptoms of

HDAC Pharmacodynamics

Lemoine M et al. Discov Med. 2010; 54:462-70.

Cell Cycle(p21, cyclins)

HDACi HDACs

Motility(α-tubulin)

Immunity and Inflammation(NFkB, STAT3, TNFα)

Angiogenesis(HIF-1α, VEGF)

Metabolism(GLUT1)

Extrinsic Apoptosis(Death receptors and ligands)

Intrinsic Apoptosis (Bcl-2, Bax)

Transplant EligibleStandard Risk Intermediate Risk High Risk

Mikhael JR et al. Mayo Clin Proc. 2013; 88:360-76.

Trisomies OnlyT(11;14), t(6;14),

Trisomies +IgHT(4;14)

Del17p, t(14;16), t(14;20)

4 cycles of Rd4 cycles of

CyBorD4 cycles of

CyBorD4 cycles of

RVD

Autologous SCT

Autologous SCT, esp. if not

in CR

Bortezomib based therapy

x 1 year

Bortezomib or CyBorD x 1

year

Collect autologous PBSC

Continue RdAutologous

SCT

2 x Rd then lenalidomide maintenance

Rd = lenalidomide-dexamethasoneCyBorD = cyclophosphamide-bortezomib-dexamethasone

18

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Autologous Stem Cell Transplant

Palumbo A et al. N Engl J Med. 2014; 371:895-905..

• Primary endpoint: PFS

RANDOMIZEMedian follow-up

51.2 months

Newly diagnosed MM received induction therapy with Rd(N=273)

Melphalan 200 mg/m2 IV with ASCT x 2 as4-month cycles

Melphalan 0.18 mg/kg PO on days 1 – 4 Lenalidomide10 mg PO on days 1 – 21Prednisone2 mg/kg PO on days 1 - 4Every 28 days x 6 cycles

Maintenance within 3 months of completion of consolidation:Lenalidomide10 mg PO daily on days 1 – 21 every 28 days until progression/ toxicity

No Maintenance

RANDOMIZE

Transplant - IneligibleStandard Risk Intermediate Risk High Risk

Mikhael JR et al. Mayo Clin Proc. 2013; 88:360-76.

Trisomies OnlyT(11;14), t(6;14),

Trisomies +IgHT(4;14)

Del17p, t(14;16), t(14;20)

RdWeekly

CyBorD for 12 months

Weekly CyBorD for 12

months

RVD for 12 months

Bortezomib based therapy

x 1 year

Bortezomib maintenance x

1 year

Until Progression

Followed by observation

19

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Bortezomib-Melphalan-PrednisoneFirst Line (VISTA Trial)

San Miguel JF et al. J Clin Oncol. 2013; 31:448-55.

• Final analysis ofrandomized, internationalphase III clinical trial

– Median follow-up60.1 months

Patients with previously untreated MM (N=682)

VMPBortezomib1.3 mg/m2 IV on days 1, 4, 8, 11,22, 25, 29, 32 for 4 cycles;Days 1, 8, 22, 29 for 5 cycles +

Melphalan9 mg/m2 PO daily on days 1-4 +

Prednisone60 mg/m2 PO daily on days 1-4(n=344)

MPMelphalan9 mg/m2 PO daily on Days 1-4 +

Prednisone60 mg/m2 PO daily on Days 1-4(n=388)

Nine 6-wk cycles

MPR-R vs. MPR vs. MP

Palumbo A et al. N Engl J Med. 2012; 366:1759-69.

Lenalidomide maintenance reduced the risk of progression by 60%

80

70

100

90

60

50

40

30

20

0

10

5

Pat

ien

ts (

%)

MPR

MP

MPR-R

0 1510 2520 3530 40

14 Months

13 Months

31 MonthsMedian PFS

Months

HR 0.395 P < .001

HR 0.796P = .135Median follow-up 25 months

HR = hazard ratioMPR-R = melphalan, prednisone, lenalidomide followed by lenalidomideMPR = melphalan, prednisone, lenalidomide followed by placebo MP = melphalan, prednisone, placebo followed by placebo

20

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FIRST Trial

Benboubker L et al. N Engl J Med. 2014; 371:906-17.

Randomized, international Phase III clinical trial

– Primary endpoint: PFS

– Median follow-up 37 months

• Antithromboticprophylaxis mandated

• Bisphosphonatesupport allowed

Patients with previously untreated MM, transplant ineligible(N=1623)

Lenalidomide25 mg PO daily on days 1-21 of a 28-day cycle

Dexamethasone40 mg PO days 1, 8, 15, 22 Continuous therapy(n=535)

Lenalidomide25 mg PO daily on days 1-21 of a 28-day cycle

Dexamethasone40 mg PO days 1, 8, 15, 22 For 18 cycles(n=541)

Melphalan 0.25 mg/kg PO daily on days 1-4

Prednisone 2 mg/kg PO daily on days 1-4

Thalidomide200 mg PO daily in 42-day cycles x 72 weeks(n=541)

21

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Understanding Multiple Myeloma, Its Treatment, and New Discoveries: Part 1

Self-assessment Questions

These questions will be discussed during the activity. Record the answers here for your future reference.

1. Multiple myeloma is a disorder that primarily involves which of the following cell types in the marrow?

a. Plateletsb. Neutrophilsc. Eosinophilsd. Plasma cells

Questions 2-4 refer to the following patient case scenario.

MR is a 62-year-old woman who presents with high serum protein and SCr of 2.3 mg/dL. Work up revealed immunoglobulin G (IgG) kappa monoclonal protein 4 g/dL, skeletal survey normal, and no anemia. Bone marrow biopsy showed 45% clonal plasma cell population.

2. Which of the following regimens would be appropriate for induction treatment in this patient?

a. Melphalan-prednisoneb. Panobinostatc. Bortezomib-lenalidomide-dexamethasoned. Pomalidomide-dexamethasone

3. MR finished induction with bortezomib-lenalidomide-dexamethasone (4 cycles) and achieved a VGPR (verygood partial response). Given the patient’s overall good health, a decision was made to offer her autologousstem cell transplant as consolidation therapy. Which of the following is a reasonable treatment goal withautologous stem cell transplant for this patient?

a. Cure of the diseaseb. Minimal benefit above standard dose chemotherapyc. Preparation for future allogeneic stem cell transplantd. Improved chance for CR & potential longer remission duration

4. After recovery following autologous stem cell transplant, MR and her physician discuss maintenancetherapy. MR is offered a trial of lenalidomide maintenance. Which of the following toxicities of lenalidomiderequires long-term follow up?

a. Hepatotoxicityb. Mucositisc. Secondary primary malignanciesd. Hemorrhagic cystitis

22

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Understanding Multiple Myeloma, Its Treatment, and New Discoveries: Part 1

List of Abbreviations Used in Presentation

ADCC antibody dependent cellular cytotoxicity

AE adverse effect

ASCT autologous stem cell transplant

bFGF basic fibroblast growth factor

BM bone marrow

BP bisphosphonate

CBC complete blood count

CI confidence interval

CR complete response

CRAB hyperCalcemia, Renal disease, Anemia, Bone disease

CT Computed tomography

CyBorD cyclophosphamide-bortezomib-dexamethasone

EMP Extramedullary plasmacytoma

FISH fluorescence in situ hybridization

FLC free light chain

GCSF granulocyte colony stimulating factor

GEP gene expression profile

HDAC histone deacetylase

HDACi histone deacetylase inhibitor

HIF hypoxia-inducible factors

HR hazard ratio

ICAM intercellular adhesion molecule

IFM Intergroupe Francophone du Myélome

IFN interferon-gamma

IgA immunoglobulin A

IgG immunoglobulin G

IL interleukin

IMiD immunomodulatory drug

IMWG International Myeloma Working Group

ITT Intention to treat

IV intravenous

MGUS monoclonal gammopathy of undetermined significance

MM multiple myeloma

MP melphalan-prednisone

23

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Understanding Multiple Myeloma, Its Treatment, and New Discoveries: Part 1

MPR melphalan, prednisone, lenalidomide

MPR-R melphalan, prednisone, lenalidomide followed by lenalidomide

MPT melphalan-prednisone-thalidomide

MRI magnetic resonance imaging

mSMART Mayo Stratification for Myeloma and Risk-adapted Therapy

NF-kB nuclear factor kB

NK Natural killer cells

ORR overall response rate

OS overall survival

PBMC peripheral blood mononuclear cell

PBSC peripheral blood stem cell

PET Positron emission tomography

PFS progression free survival

PO by mouth

PR partial response

Rd lenalidomide-dexamethasone

RR response rate

RVD bortezomib-lenalidomide-dexamethasone

sCR stringent complete response

SCr serum creatinine

SCT stem cell transplant

TNFα tumor necrosis factor alpha

VAD vincristine-doxorubicin-dexamethasone

VCAM vascular cell adhesion molecule

VEGF vascular endothelial growth factor

VGPR very good partial response

VMP bortezomib- melphalan- prednisone

24