4/8/15

1

Welcome and Introductions

Living With MyelomaManaging Side Effects and Quality of Life

April 8, 2015

Sagar Lonial, MD, FACPProfessor and Executive Vice Chair

Department of Hematology and Medical OncologyChief Medical Officer

Winship Cancer InstituteEmory University School of Medicine

Atlanta, GA

Living With MyelomaManaging Side Effects and Quality of Life

4/8/15

2

Disclosures

• Consulting• Bristol‐Myers Squibb

• Celgene Corporation

• Janssen

• Millennium: The Takeda Oncology Company

• Novartis AG

• Onyx Pharmaceuticals

• Sanofi

3

Multiple Myeloma (MM)

Prevalence

20,180 estimated new cases in the U.S. in 2010

Median age at diagnosis: 70 years

Median survival

3 years conventional therapy

4–5 years high-dose therapy

>10,000 patients with MM die each year in the U.S.

Population subgroups

Incidence is twice as high in African Americans

More frequent in men than in women

Long-term disease control is possible in a fraction of patients

American Cancer Society, 2010; Altekruse et al, 2007.4

4/8/15

3

Multiple Myeloma – Description

• Characterized by a plasma cell dyscrasia producing a monoclonal immunoglobulin

• Proliferation often results in extensive skeletal destruction (eg, osteolytic lesions, hypercalcemia, anemia)

• Excess production of M protein can result in renal failure, hyperviscosity syndrome, recurrent bacterial infections, and hematopoietic and immune dysfunction

5

Myeloma Cells

6

4/8/15

4

7

The Immunoglobulin Molecule

• B-cell final product is immunoglobulin (Ig)

• Ig is key piece of immune function

• B cells are stimulated by T cells as well as APCs

APCs, antigen-presenting cells.8

4/8/15

5

M Protein Analysis

9

Criteria for Diagnosis of Myeloma

MGUS• <3 g M spike• <10% plasma cells

AND

SMM• ≥3 g M spike

• ≥10% plasma cells

Active MM• ≥10% plasma cells

• M spike +

AND

No anemia, bone lesions,normal calcium, or

kidney function

MGUS, monoclonal gammopathy of unknown significance; SMM, smoldering multiple myeloma. Kyle et al, 2009.

Anemia, bone lesions,high calcium, or

abnormal kidney function

10

4/8/15

6

Kyle R, et al. N Engl J Med. 2007;356:2582–2590.

Smoldering Multiple Myeloma (SMM)

27% will convert in 15 yearsRoughly 2% per year

40% will convert in 4 yearsRoughly 10% per year

11

Free Light Is Useful for Risk Assessment in SMM

Dispenzeri et al. Blood. 2008.12

4/8/15

7

Updated IMWG Criteria for Diagnosis of Multiple Myeloma

*C: Calcium elevation (>11 mg/dL or >1 mg/dL higher than upper limit of normal)

R: Renal insufficiency (creatinine clearance <40 mL/min or serum creatinine >2 mg/dL)

A: Anemia (hemoglobin <10 g/dL or 2 g/dL < normal)

B: Bone disease (≥1 lytic lesions on skeletal radiography, CT, or PET-CT)BM, bone marrow; CT, computed tomography; IMWG, International Myeloma Working Group; PET, positron emission tomography.Rajkumar SV, et al. Lancet Oncol. 2014;15:e538–e548.

MGUS

• M protein <3 g/dL• Clonal plasma cells in BM

<10%• No myeloma defining events

SMM

• M protein ≥3 g/dL (serum) or ≥500 mg/24 hours (urine)

• Clonal plasma cells in BM ≥10%–60%

• No myeloma defining events

Multiple Myeloma

• Underlying plasma cell proliferative disorder

AND 1 or more myeloma defining events

• ≥1 CRAB* feature• Clonal plasma cells in BM ≥60%

• Serum free light chain ratio ≥100

• >1 MRI focal lesion

13

1960-651965-701970-751975-801980-851985-901990-951995-002000-052005-10

Improving Survival in MM

The use of high-dose therapy (HDT) or melphalan-based novel agent induction therapy has doubled median survival for nearly all patients 14

4/8/15

8

Goals of Induction Therapy

Achieving maximal response ≥ Very good partial response (VGPR) vs complete response (CR) vs minimal residual disease (MRD)

High response rate; rapid response Improve performance status Minimize negative effects on quality of life Not limit PBSC mobilization (for younger

patients)• Do goals depend on cytogenetics and/or

prognostic factors?• Is CR the main endpoint?

PBSC, peripheral blood hematopoietic stem cell.15

Benefit Associated With CR

OS

months

CR

PRVGPR

0

25

50

75

100

0 10 20 30 40 50 60 70 80

CR

0

25

50

75

100

0 10 20 30 40 50 60

VGPR

70

PR

PFS

Gay F, et al. Blood. 2011;117:3025.

PFS

OS

Paiva B, et al. Blood. 2008;112:4017.

IFX- CR in young patients N=635EFS

OS

Lahuerta JJ, et al. J Clin Oncol. 2008;25:5775.

IFX- CR in elderly patients N=1175

MRD- CR in young patients N=147

monthsmonths

EFS, event-free survival; IFX-, immunofixation negative; MRD-, minimal residual disease negative; OS, overall survival; PFS, progression-free survival.

MRD negative

MRD positiveMedians: NR

0 20 40 60 80 100 120 140

0

20

40

60

80

100

P = 0.009

59%

87%

MRD negative

MRD positive

Median : 71 mo

0 25 50 75 100 125

0

20

40

60

80

100

P < 0.001Median : 37 mo

30%

62%

16

4/8/15

9

3 Drugs Are Better Than 2

0

10

20

30

40

50

60

70

80

90

100

TD RD VD VTD VCD RVD

ORR

VGPR

ORR, overall response rate.17

Factors That Influence Improved Outcomes

Better induction

Increasing role of maintenance

Longer duration of therapy

Increased use of HDT

Better Depth of Response

Better Drugs

18

4/8/15

10

Transplant in Era of Novel Agents:Survival Benefit Continues

Palumbo et al. N Engl J Med. 2014.

19

Getting to MRD: New Definitions for CR

S.S. Patient

1×1012

Stringent CR

Molecular/Flow CR

?Cure?

Disease burden

Newly diagnosed

1×108

1×104

0.0

BortezomibLenalidomide

Antibodies

CR

20

4/8/15

11

What Happens When the Best Are Combined?

RVD, lenalidomide, bortezomib, and dexamethasone.Roussel et al. J Clin Oncol. 2014.

RVD Induction

HDT

RVD Consolidation

Lenalidomide Maintenance

21

Current Considerations for Initial Treatment of MM

Induction for younger patients– 3-drug induction followed by autologous

transplant and consolidation in first response1

– Maintenance therapy post-autologous transplant2

– Maximize duration of first response3,4

– Assessing depth of response and understanding implications for patient outcomes5

1. Cavo M, et al. Lancet. 2010;376:2075–2085. 2. McCarthy PL, et al. Expert Rev Hematol. 2014;7:55–66. 3. Palumbo A, et al. N Engl J Med. 2011;364:1046–1060. 4. Lenhers N, et al. ASH 2013. Abstract 3183. 5. Paiva B, et al. Blood. 2012;119:687–691.

22

4/8/15

12

Recommendations for Salvage Therapy in Multiple Myeloma1

NCCN Category 1

Bortezomib

Bortezomib + PLD

Lenalidomide + dexamethasone (RD)

Preferred Regimens

NCCN Category 2A Repeat induction if relapse >6 monthsBortezomib + dexamethasone (VD)Lenalidomide + bortezomib + dexamethasone (RVD) CarfilzomibCyclophosphamide + VD, or RDHD cyclophosphamideDCEPDT-PACE ± bortezomibPomalidomide/dexamethasone Thalidomide + dexamethasone (TD) ±bortezomib

NCCN Category 2A BendamustineBortezomib + vorinostatLenalidomide + bendamustine +dexamethasone

Other Regimens

DCEP, dexamethasone/cyclophosphamide/etoposide/cisplatin; DT-PACE, dexamethasone/thalidomide/cisplatin/doxorubicin/cyclophosphamide/ etoposide; NCCN, National Comprehensive Cancer Network; PLD, pegylated liposomal doxorubicin.1. NCCN Clinical Practice Guidelines in Oncology: Multiple Myeloma. V.2.2014. http://www.nccn.org/professionals/physician_gls/pdf/myeloma.pdf. Accessed March 16, 2014.

23

Questions in the Relapsed Setting

Is 3 better than 2 in early relapse?

Is 2 more than enough in late relapse?

How do we choose among salvage treatments in early relapse (proteasome inhibitor vs immunomodulatory drug based)?

24

4/8/15

13

Selecting Salvage Therapy: General Principles1,2

New additions: carfilzomib, pomalidomideEmerging agents: elotuzumab, ixazomib, panobinostat

Patients with indolent disease, first relapse

Patients with aggressive disease, rapid progression, multi-relapse

Patients who relapse from non-SCT treatment or

Patients with long duration of benefit

from first SCT orPatients in whom

response likely to be short lived

Options include:• Bortezomib or lenalidomide, depending on response to

and composition of initial treatment, presence of renal dysfunction, or underlying peripheral neuropathy

• Watch and wait for low-level M protein (0.2/0.3)

Combination therapy preferred; do not wait for symptomatic relapse• Combinations of novel agents with

chemotherapy/dexamethasone an option

Transplant-based salvage therapy a potential option in eligible patients

SCT, stem cell transplant.1. Lonial S, clinical experience. 2. NCCN Clinical Practice Guidelines in Oncology: Multiple Myeloma. V.2.2014. http://www.nccn.org/professionals/physician_gls/pdf/myeloma.pdf. Accessed March 16, 2014.

25

Drugs in Relapse Proteasome inhibitors

– Bortezomib, carfilzomib, MLN 9708, oprozomib

Immunomodulatory drugs (IMiDs)– Lenalidomide, pomalidomide

Histone deacetylase (HDAC) inhibitors– Panobinostat, Acy-2115

Antibodies– Elotuzumab, daratumumab

Other– KSP, CDK, KPT

CDK, cyclin-dependent kinase; KPT, nuclear transport; KSP, kinase spindle protein.

26

4/8/15

14

Tao of Myeloma Therapy: Mutations Are Not Everything

TamoxifenAndrogen Ablation

HerceptinSteroids

Proteasome InhibitorsIMiDs?

MelphalanDoxil

FGFR3 Inhibitors

IMiDs?Anti‐DKK1?

BRAF inhibitors?

Need to Define Targeting Plasma Cell Biology and Targeting Proliferation 

“Normal” Cell Biology

“Tumor” Cell Biology

27

Targets for Monoclonal Antibodies

28

4/8/15

15

9 2

5

1 20

19 10 12 31 16 29 8 13

4 26 15 3 7 11

17 14

33

27

21 6 30 18 34

23

32

22 28 -100

-50

0

50

100

Rel

ativ

e c

ha

ng

e in

pa

rap

rote

in f

rom

ba

selin

e (

%)

Patient number

A AA A AA A

AA

A

AA AA AA AA AAB

B

B B

C

A

C C C

CC C

2 mg/kg 4 mg/kg 8 mg/kg 16 mg/kg 24 mg/kg< 1 mg/kg

Daratumumab Response

A: serum M-component, B: urine M-component, C: Free Light Chains (FLC)

Lokhorst et al. ASCO. 2013.29

Elotuzumab Background

ADCC, antibody-dependent cellular cytotoxicity; mAb, monoclonal antibody; NK, natural killer.1. Hsi ED, et al. Clin Cancer Res. 2008;14:2775–2784. 2. Tai YT, et al. Blood. 2008;112:1329–1337. 3. Van Rhee F, et al. Mol Cancer Ther. 2009;8:2616–2624. 4. Lonial S, et al. Blood. 2009;114:Abstract 432.

• Elotuzumab is a humanized IgG1 mAb targeting human CS1, a cell surface glycoprotein1,2

• CS1 is highly expressed on >95% of MM cells1-3

– Lower expression on NK cells– Little to no expression on normal tissues

Lenalidomide dosing (50 mg/kg)

Elotuzumab (1 mg/kg) or control IgG1 dosing

Control IgG1

Elotuzumab

Lenalidomide + control IgG1

Elotuzumab + lenalidomide

Tum

or

Vo

lum

e (m

m3 )

Study Day

600

400

300

200

100

0

500

14 28 35 4221

• Elotuzumab is believed to work primarily through NK cell-mediated ADCC against myeloma cells1,2

• In a MM xenograft mouse model, the combination of elotuzumab + lenalidomide significantly reduced tumor volume compared with either agent alone4

Normal plasma cells Plasmacytoma

Lymphoplasmacytic lymphoma

Myeloma cells in bone marrow

30

4/8/15

16

Progression-Free Survival (PFS) From the Phase II Cohort

10 mg/kg (n=36): 33 mos (95% CI:14.883-NA)20 mg/kg (n=37): 18.6 mos (95% CI: 12.912-32.361)Total (n=73): 25.8 mos (95% CI: 15.376-35.713)

In the 10-mg/kg cohort, median PFS was 33 months

In the 20-mg/kg cohort, the median PFS was 18 months

Lonial et al. ASCO. 2013.31

Safety Summary: IMiDs in 2014

• Neuropathy

• DVT

• Myelosuppression

• Rash

Thalidomide

Lenalidomide

• DVT

• Myelosuppression

• Rash

Pomalidomide

• Neutropenia at ↑ doses

• DVT

DVT, deep vein thrombosis.

32

4/8/15

17

• Myelosuppression associated with IMiDs requires early recognition and management to avoid infections and treatment interruption

Managing Myelosuppression With IMiDs

When Neutrophils Recommendation

Fall to <500/mcL or FN (fever ≥38.5° C and ANC <1,000/mcL)

ANC return to ≥500 per mcL

Interrupt treatment, follow CBC weekly

Resume treatment at 3 mg daily

For each subsequent drop to <500/mcL

Return to ≥500/mcL 

Interrupt treatment

Resume treatment at 1 mg < previous dose

Neutropenia Management in Myeloma Patients Receiving Pomalidomide1

ANC, absolute neutrophil count; CBC, complete blood count; FN, febrile neutropenia.1. Pomalyst (pomalidomide) Prescribing Information. http://www.pomalystrems.com/pdf/POM_Full_PI.pdf. Accessed March 25, 2014.

33

Thrombosis in Myeloma: Risk Factors and Prevention1

LMWH, low-molecular-weight heparin; VTE, venous thromboembolism.1. Palumbo A, et al. Leukemia. 2008;22:414–423.

Individual Risk Factors

• Age

• History of VTE

• Central venous catheter

• Diabetes

• Infection

• Cardiac disease

• Immobilization

• Surgery

• Inherited thrombophilia

Myeloma-Related Risk Factors

• Diagnosis

• Hyperviscosity

0 or 1 individual risk factor present: once-daily aspirin

≥2 individual or myeloma-related risk factors: LMWH (once-daily enoxaparin) or full-dose warfarin

34

4/8/15

18

Thrombosis in Myeloma: Risk Factors and Prevention (Cont’d)

• LMWH or full‐dose warfarin regardless of additional risk factors1

• In low‐risk patients receiving lenalidomide, aspirin appears to be effective thromboprophylaxis2

1. Palumbo A, et al. Leukemia. 2008;22:414–423. 2. Larocca A, et al. Blood. 2012;119:933–939.

Therapy‐Related Risk Factors 

• High‐dose dexamethasone

• Doxorubicin

• Chemotherapy with thalidomide or lenalidomide (likely with all IMiDs)

35

Other Important Safety/Adjunctive Issues

When Neutrophils Recommendation

Bone protective therapy1 • Bisphosphonates recommended for all patients with myeloma receiving primary therapy

Hydration • Assess patient for dehydration, counsel on fluid intake, and intervene aggressively to correct

• Caution: overzealous hydration may lead to hyponatremia

GI/Nutritional issues associated with steroids

• Counsel patients on maintaining weight

• Fruit/vegetable-rich diet

• Protein intake, avoid concentrated sweets and carbohydrates

GI, gastrointestinal.

1. NCCN Clinical Practice Guidelines in Oncology: Multiple Myeloma. V.2.2014. http://www.nccn.org/professionals/physician_gls/pdf/myeloma.pdf.

Accessed March 16, 2014.36

4/8/15

19

Discussion: Speaking With the Patient About Adverse Events

In collaboration with nurse professional…

• Discuss the potential for toxicity such as peripheral neuropathy or myelosuppression when combining proteasome inhibitors with IMiDs

• Discuss options for thromboprophylaxis with IMiDs

• Antibiotic prophylaxis with proteasome inhibitors– Possibly for all patients with myeloma

• Recommend/educate the patient on nonpharmacologic strategies for adverse events/symptoms

37

PETHEMA Cure With Old Drugs:What About All the Clones?

Martinez-Lopez et al. Blood. 2011.

Functional cure?

38

4/8/15

20

Conclusions

Defining symptomatic MM is in evolution

Aggressive therapy continues to require aggressive induction (3 drugs) and consolidation with transplant and maintenance

Options in relapse are increasing and, for now, are not used based on a biomarker

Immune therapy is on the way!

39

Thanks to:Jonathan KaufmanAjay NookaCharise Gleason Danni CassabourneMelanie Watson L.T. Heffner Donald HarveyColleen LewisAmelia Langston Claire TorreY. GuS-Y Sun Jing Chen Fadlo Khuri Anand JillellaLeon BernalLarry Boise

Cathy SharpKenisha BaronAnd the Clinical Research Team

IMS

Golfers Against CancerT.J. Martell Foundation

and many others who are part of the B-cell Team

Patients and Families

sloni01@emory.edu

40

4/8/15

21

Question-&-Answer SessionThe speaker’s slides are available for download at

www.LLS.org/programs

Living With MyelomaManaging Side Effects and Quality of Life

Question & Answer SessionThe speaker’s slides are available for download at: www.LLS.org/programs

The Leukemia & Lymphoma Society (LLS) offers:

• Live, weekly Online Chats are moderated by an oncology social worker and provide a friendly forum to share experiences.

WEBSITE: www.LLS.org/chat

• Co-Pay Assistance Program offers financial assistance to qualified cancer patients to help with treatment-related expenses and insurance premiums. Patients may apply online or over the phone with a Co-Pay Specialist.

WEBSITE: www.LLS.org/copay TOLL-FREE PHONE: (877) LLS-COPAY

• For more information about blood cancers and other LLS programs, please contact an LLS Information Specialist. TOLL-FREE PHONE: (800) 955-4572 EMAIL: infocenter@LLS.org

Living With MyelomaManaging Side Effects and Quality of Life