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Changing Patient Care in Multiple Myeloma: The IMF Nurse Leadership Board’s Long-Term Survivorship Care Plan

Accredited by Medical Education Resources

Supported by The International Myeloma Foundation

Grant Funding Provided by Celgene Corporation and Millennium – The Takeda Oncology

Company

May 13, 2010San Diego

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Time Discussion Topic Presenter

12:00 - 12:10 PMWelcome/Introductions and Multiple Myeloma Overview

Elizabeth Bilotti

12:10 - 12:30 PMUpdate on Current Therapies for the Treatment of Multiple Myeloma

Beth Faiman

12:30 - 12:45 PM The NLB’s Long-Term Survivorship Care Plan Joseph Tariman

Impact of Myeloma Disease, Treatments, Long-Term Effects and Patient-Specific Characteristics on:

12:45 - 1:00 PM ○ Bone Disease and Bone Health○ Functional Mobility

Teresa Miceli

1:00 - 1:15 PM ○ Renal Complications○ Sexuality and Sexual Dysfunctions

Tiffany Richards

1:15 - 1:30 PM ○ Health Maintenance Elizabeth Bilotti

1:30 PM Closing Remarks Elizabeth Bilotti

Agenda

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Update on Current Therapies for the Treatment of

Multiple Myeloma

Beth Faiman, MSN, APRN-BC, AOCN®

Cleveland Clinic Taussig Cancer InstituteCleveland, OH

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NCCN Review CategoriesTransplant

NCCN Category Non Transplant

NCCN Category

Bortezomib/Dexamethasone* 1 Bortezomib/Melphalan/Prednisone (VMP) 1

Bortezomib/Thalidomide/Dexamethasone (VTD)*

1 Melphalan/Prednisone/Thalidomide (MPT) 1

Lenalidomide/Dexamethasone*

1 Lenalidomide/low Dexamethasone* 1

Bortezomib/Doxorubicin/Dexamethasone*

1 Melphalan/Prednisone (MP) 2A

Dexamethasone* 2B Vincristine/Doxorubicin/Dexamethasone (VAD)* 2B

L-Doxorubicin/Vincristine/Dexamethasone (DVD)*

2B Thalidomide/Dexamethasone* 2B

Thalidomide/Dexamethasone* 2B Dexamethasone* 2B

Bortezomib/Lenalidomide/Dexamethasone (VRD)

2B L-Doxorubicin/Vincristine/Dexamethasone (DVD)

2B

NCCN Clinical Practice Guidelines in Oncology, v.3.2010

Generic Name Trade NameBortezomib VelcadeLenalidomide RevlimidThalidomide Thalomid

*Combinations recently reviewed by NCCN

NCCN Categories of Evidence and Consensus:1 High-level evidence, uniform consensus2A Lower-level evidence, uniform consensus2B Lower-level evidence, non-uniform

consensus

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Revised Categories of Evidence and Consensus – NCCN Guidelines, 2010

Multiple Myeloma Therapy Previous Category

New Category

Bortezomib/Dexamethasone 2B 1

Bortezomib/Thalidomide/Dexamethasone (VTD) 2B 1

Lenalidomide/Dexamethasone 2B 1Bortezomib/Doxorubicin/Dexamethasone 2B 1Lenalidomide/low Dexamethasone 2B 1

Thalidomide/Dexamethasone 2A 2B

Dexamethasone 2A 2B

Vincristine/Doxorubicin/Dexamethasone (VAD) 2A 2B

L-Doxorubicin/Vincristine/Dexamethasone (DVD) 2A 2B

NCCN Clinical Practice Guidelines in Oncology, v.3.2010

NCCN Categories of Evidence and Consensus:1 High-level evidence, uniform consensus2A Lower-level evidence, uniform consensus2B Lower-level evidence, non-uniform

consensus

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NCCN: Changing Categories of Consensus

• Change is a natural process secondary to constant stream of data from recent clinical studies

• Categories 2A and 2B are not indicative of inferiority of the treatment:

…non-uniform consensus does not represent a major disagreement, rather it recognizes that given imperfect information, institutions may adopt different approaches. A Category 2B designation should signal to the user that more than one approach can be inferred from the existing data…

NCCN, “Categories of Evidence and Consensus”, 2010

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Future of MM Therapy: Recent and Ongoing Clinical Studies

Patient Treatment Largely Determined by Transplant Status

• Transplant-ineligible patients– Bortezomib/Melphalan/Prednisone – Bortezomib/Thalidomide

vs. Bortezomib/Thalidomide/Prednisone – Bortezomib/Prednisone

– Bortezomib/Melphalan/Prednisone/Thalidomide – Bortezomib/Thalidomide vs. Bortezomib/Melphalan/Prednisone

– Melphalan/Prednisone vs. Melphalan/Prednisone/Thalidomide– Melphalan/Prednisone vs.

Melphalan/Prednisone/Lenalidomide vs. Melphalan/Prednisone/Lenalidomide (continued Lenalidomide)

• Transplant-eligible patients– Lenalidomide after ASCT– Melphalan/Prednisone/Lenalidomide (MPR) vs. high dose

Melphalan• Lenalidomide/Dexamethasone in Smoldering Myeloma

– QUIREDEX Study• New combinations and early studies

– EVOLUTION Study– Pomalidomide/low Dexamethasone– Carfilzomib– Carfilzomib/Lenalidomide/Dexamethasone– Elotuzumab/Lenalidomide/Dexamethasone

Point about transplant-ineligible studies

Point about transplant eligible studies

Point about early studies

Beth – Could you add

short comments

for each cat or should we

reomove

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VMP vs. VTP Followed by VT vs. VP(ASH 2009 - PLENARY SESSION)

Mateos et al, Blood 114, Abstract 3, 2009

• Study Objective:– Testing an alkylating agent (Melphalan) and an

immunomodulatory drug (Thalidomide) as a partner for Bortezomib

• Study Design:– Prospective, multicenter, randomized– Induction: patients randomized to 6 cycles of VMP vs. VTP– Maintenance: patients randomized to VT vs. VP for up to 3

years

A Phase III Study of Bortezomib/Melphalan/Prednisone (VMP) vs. Bortezomib/Thalidomide/Prednisone (VTP) Followed by Bortezomib/Thalidomide (VT) vs. Bortezomib/Prednisone (VP) in Elderly NDMM Patients

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Conclusions from VMP – VT vs. VTP – VP

• Both induction schedules are highly effective with similar ORR and CR– More neutropenia but less cardiac toxicity and peripheral neuropathy

with VMP• Both maintenance therapies markedly improve responses• Combination of these induction and maintenance regimens tend to

overcome the poor prognosis of high-risk cytogenic abnormalities (CA) in elderly MM patients

Induction ≥PR, % CR, % CR/nCR, % TTP, % PFS, % OS, %

VMP 81 22 36 75 71 81

VTP 79 27 36 70 61 84

Maintenance CR, % 1Y TTP, % 1Y OS, %

VT 46 84 92

VP 38 71 89

p-Value NS 0.05 NS

Mateos et al, Blood 114, Abstract 3, 2009

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Bortezomib/Melphalan/Prednisone/Thalidomide – Bortezomib/Thalidomide

Palumbo et al, Blood 114, Abstract 128, 2009

• Study Objective:– Compare VMPT with a maintenance regimen including Bortezomib and

Thalidomide with VMP without a maintenance regimen

• Study Design:– Prospective, randomized

– Both regimens amended to 9 5-week cycles

– Bortezomib modified to weekly administration (days 1,8,15,22)

A Phase III Study of VMPT Followed by Maintenance with Bortezomib and Thalidomide for Initial Treatment of Elderly Multiple Myeloma Patients

Bortezomib 1.3 mg/m2 Melphalan 9 mg/m2 Days 1-4 Prednisone 60 mg/m2 Days 1-4 Thalidomide 50 mg Days 1-42

Bortezomib 1.3 mg/m2 Melphalan 9 mg/m2 Days 1-4 Prednisone 60 mg/m2 Days 1-4

No Maintenance

Bortezomib 1.3 mg/m2 Days 1, 15Thalidomide 50 mg/day continuously

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Conclusions from VMPT – VT vs. VMP

• VMPT followed by VT was superior to VMP for response rates and PFS

• The weekly infusion of Bortezomib significantly reduced the incidence of grade 3-4 peripheral neuropathy– From 18% to 4% (p=0.0002) in VMPT arm– From 13% to 2% (p=0.0003) in VMP arm

• This is the first report showing the superiority of a 4-drug regimen followed by maintenance compared to standard therapy (VMP)

Study Arm PR, % VGPR, % CR, % 2Y PFS, % 2Y OS, %

VMPT-VT 86 55 34 70 89.6

VMP 79 47 21 58.2 89.0

p-Value 0.02 0.07 0.0008 0.0008 0.84

Palumboet al, Blood 114, Abstract 128, 2009

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Melphalan/Prednisone vs. Melphalan/Prednisone/Thalidomide

Kapoor et al, Blood 114, Abstract 615, 2009

MP vs. MPT as Initial Therapy for Previously Untreated Elderly and/or Transplant Ineligible Patients with Multiple Myeloma: A Meta-Analysis of Randomized Controlled Trials

• Study Objective:– Systemic review of randomized controlled trials to

compare efficacy of MP with MP+T– Clinical endpoints are Response Rate (RR),

Progression-Free Survival (PFS) and Overall Survival (OS)

• Study Design– Comprehensive search of database to identify

randomized controlled trials– Meta-analysis by pooling results on clinical endpoints

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Conclusions from MP vs. MPT

• Five prospective randomized controlled trials were identified– 1571 patients were evaluable in the studies

• The pooled odds ratio of responding to treatment indicated that MPT was better than MP in achieving at least a partial response

• The pooled hazards ratios for PFS and OS were in favor of MPT

• Analyses suggest that MPT is superior to MP in terms of response and survival

Kapoor et al, Blood 114, Abstract 615, 2009

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MP vs. MPR vs. MPR – R

Palumbo et al, Blood 114, Abstract 613, 2009

• Study Objective:– In previous studies Lenalidomide was efficacious in

relapsed/refractory MM– Compare safety and efficacy of MPR in NDMM patients

• Study Design:

A Phase III Study to Determine the Efficacy and Safety of Lenalidomide in Combination with Melphalan and Prednisone (MPR) in Elderly Patients with Newly Diagnosed Multiple Myeloma

Melphalan 0.18 mg/kg Days 1-4 Prednisone 2 mg/kg Days 1-4 Lenalidomide 10 mg QD PO Days 1-21

Melphalan 0.18 mg/kg Days 1-4 Prednisone 2 mg/kg Days 1-4 Lenalidomide 10 mg QD PO Days 1-21

Melphalan 0.18 mg/kg Days 1-4 Prednisone 2 mg/kg Days 1-4 Placebo Days 1-21

LenalidomidePlacebo

Lenalidomide

Pro

gre

ssio

n

Placebo

9 28-day cycles

Cycles 10+

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Conclusions from MP vs. MPR vs. MPR – R

• MPR – R regimen reduced risk of progression by 50% vs. MP alone

• MPR followed by Lenalidomide maintenance is a new therapeutic option and can be considered a new standard for elderly patients

Study Arm (patients) ORR, % CR, % ≥ VGPR, % PR, %

MPR-R (152) 77 18 32 45

MPR (153) 67 13 33 34

MP (154) 49 5 11 37

Palumbo et al, Blood 114, Abstract 613, 2009

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Lenalidomide after ASCT

Attal et al, Blood 114, Abstract 529, 2009

First Analysis of a Phase III Study of the Intergroupe Francophone Du Myelome (IFM 2005 02)

• Study objective– Controlling the residual disease after high-dose therapy

• Neuropathy a major limiting factor in previous study– Lenalidomide evaluated as a newer agent without neurological

toxicity• Study design

– Prospective, randomized, placebo controlled– 1st line ASCT less than 6 months before enrollment – Consolidation with Lenalidomide, 25 mg/day, po, 21 days/month, 2

months– Maintenance till relapse:

• Lenalidomide, 10-15 mg/day

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2 month consolidation with Lenalidomide:– 80% of patients were able to receive the planned 2 cycles

of consolidation– Significantly improved the sCR/CR rate

Conclusions from Lenalidomide after ASCT

Attal et al, Blood 114, Abstract 529, 2009

Post-consolidation category improvement

CR to

sCR

VGPR to

CR/sCR

PR to

VGPR/CR/sCR

n, patients 5 29 25

Patient Status sCR/CR Rate p-Value

Pre-consolidation 0.10.0005

Post-consolidation 0.144

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Melphalan/Prednisone/Lenalidomide vs. High Dose MelphalanMPR vs. Melphalan (200 mg/m2) and Autologous Transplantation in Newly Diagnosed Myeloma Patients: An Interim Analysis

Palumbo et al, Blood 114, Abstract 350, 2009

• Study objective:– To compare Melphalan/Prednisone/Lenalidomide (MPR) with tandem

Melphalan (200 mg/m2) in patients younger than 65 years

• Study design:– Induction, 4 28-day cycles

• Lenalidomide 25 mg days 1-21 • Low-dose Dexamethasone 40 mg days 1,8,15,22

– Consolidation:• MPR arm: 6 28-days cycles

– Melphalan 0.18 mg/kg days 1-4– Prednisone 2 mg/kg days 1-4– Lenalidomide 10 mg days 1-21

• Melphalan arm: tandem melphalan 200 mg/m2 with stem cell support

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Conclusions from MPR vs. MEL200

Rd Induction PR VGPR CR

Response, at least, % 84 27 5

Consolidation Arm

1 Year PFS, %

1 Year OS, %

Neutro-penia, %

Thrombo-cytopenia,

%

Infections %

GI

%

MPR 96 98 34 16 3 1

MEL200 94 99 97 97 21 17

p-Value n/a n/a <0.001 <0.001 <0.001 <0.001

• Rd is an effective and safe induction regimen• Both MPR and MEL200 improved the quality of response

– At 1 year follow-up, PFS and OS are similar in both groups– Longer follow-up is needed

Palumbo et al, Blood 114, Abstract 350, 2009

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Lenalidomide/Dexamethasone in Smoldering Myeloma

• Study objective– To investigate whether early treatment prolongs the time to

progression (TTP) in sMM patients at high risk• Study design

– Multicenter, randomized, open-label– High risk population defined by Plasma Cells ≥10% and M-component ≥3g/dL– Len/Dex arm, 9 4-week cycles:

• Lenalidomide: 25 mg/daily, days 1-21• Dexamethasone: 20 mg/daily, days 1-4 and 12-15 (total dose 160 mg)• Maintenance with Lenalidomide, 10 mg on days 1-21 evert 2 months

until progression

Phase III trial of Lenalidomide/Dexamethasone vs. therapeutic abstention in Smoldering Multiple Myeloma (sMM) at high risk of progression to symptomatic MM

Mateos et al, Blood 114, Abstract 614, 2009

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• In sMM patients, lack of treatment is associated with early progression (17.5 months) with bone disease

• Lenalidomide/Dexamethasone treatment prolonged TTP and induced CRs with a manageable and acceptable toxicity profile

Conclusions From Lenalidomide/Dexamethasone in Smoldering Myeloma

Interim Analyses Patients PR%

VGPR%

CR%

sCR%

ORR%

Evaluable patients 40 53 21 11 5 90

Completed 9 cycles 16 53 27 13 7 100

Mateos et al, Blood 114, Abstract 614, 2009

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Emerging New Treatments in Early Development

ASCO 2009; Kumar et al, Blood 114, Abstract 127, 2009; Lonial et al, Blood 114, Abstract 432, 2009; Richardson et al, Blood 114, Abstract 301, 2009; Siegel et al, Blood 114, Abstract 303, 2009; Wang et al, Blood 114, Abstract 302, 2009; Niesvizky et al, Blood 114, Abstract 304, 2009

• EVOLUTION Ph II Study– Novel 3- and 4-drug combinations: VDR, VDC, VDCR– Exploring the combination of Bortezomib and Dexamethasone with

Lenalidomide and Cyclophosphamide in NDMM patients• Development of a novel proteosome inhibitor, Carfilzomib

– Appears to work in patients that are resistant to Bortezomib– Prior therapy with Bortezomib doesn’t preclude a good response– Minimal neuropathy and myelosuppression

• Development of Pomalidomide, an immunomodulatory drug– Evidence of efficacy in heavily pretreated patients with

relapsed disease– Acceptable safety profile

• Development of Elotuzumab, a monoclonal antibody against a glycoprotein that is highly and uniformly expressed in MM– Manageable toxicity profile in combinations with other agents– Promising preliminary efficacy data

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• 2 new clinical paradigms are shaping out:– Control Option

• Careful use of drugs, using agents sequentially

– Cure Option• Aggressive treatment in hope for cure for some patients

Future Direction of New Therapy Combinations & Protocols of Novel Therapies

ASCO 2009; ASH 2009

Treatment of Smoldering MM patients provided first evidence of efficacy in preventing progression

• Evolving role of the new drug combinations for transplant eligible and ineligible patients– New 4-drug aggressive regimen (VMPT)

– New strategy for Bortezomib: weekly dose with much better tolerability

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Conclusions

• Novel combination therapies exhibit great potentials in improving response rate, time to progression, progression-free survival, and overall survival outcomes

• Randomized clinical trials are underway to compare which of these novel combinations will offer patients better OS balanced with a good quality of life