Copyright © 2010, Research To Practice, All rights reserved. Part III: Multiple Myeloma Monday,...

Copyright © 2010, Research To Practice, All rights reserved.

Part III: Multiple MyelomaMonday, October 4, 20107:30 PM - 8:30 PM ET

Monday Night with Research To Practice: An 8-Part Live CME Webcast Series

Kenneth C Anderson, MDKraft Family Professor of Medicine, Harvard Medical SchoolChief, Division of Hematologic NeoplasiaDirector, Jerome Lipper Multiple Myeloma CenterDirector, LeBow Institute for Myeloma TherapeuticsDana-Farber Cancer InstituteBoston, Massachusetts

Morie A Gertz, MDProfessor and ChairDepartment of MedicineMayo Clinic Rochester, Minnesota

Neil Love, MDModeratorResearch To PracticeMiami, Florida

Disclosures for Moderator Neil Love, MD

Dr Love is president and CEO of Research To Practice, which receives funds in the form of educational grants to develop CME activities from the following commercial interests: Abraxis BioScience, Allos Therapeutics, Amgen Inc, AstraZeneca Pharmaceuticals LP, Aureon Laboratories Inc, Bayer HealthCare Pharmaceuticals/Onyx Pharmaceuticals Inc, Biogen Idec, Boehringer Ingelheim Pharmaceuticals Inc, Bristol-Myers Squibb Company, Celgene Corporation, Cephalon Inc, Eisai Inc, EMD Serono Inc, Genentech BioOncology, Genomic Health Inc, Lilly USA LLC, Millennium Pharmaceuticals Inc, Myriad Genetics, Inc, Novartis Pharmaceuticals Corporation, OSI Oncology, Sanofi-Aventis and Spectrum Pharmaceuticals Inc.

Disclosures for Kenneth C Anderson, MD

N/A = Not Applicable

Advisory Committee and Consulting Agreements

Celgene Corporation, Millennium Pharmaceuticals Inc, Novartis Pharmaceuticals Corporation, Onyx Pharmaceuticals Inc.

Paid Research N/A

Speakers Bureau N/A

Disclosures for Morie A Gertz, MD

Advisory CommitteeCelgene Corporation, Eisai Inc, Millennium Pharmaceuticals Inc.

Paid Research N/A

Speakers Bureau N/A

N/A = Not Applicable


Lenalidomide, Bortezomib, and Dexamethasone Combination Therapy in Patients With Newly Diagnosed Multiple Myeloma.Richardson PG et al. Blood 2010;116(5):679. Proc ASCO 2010;Ab 8016.

Lenalidomide Plus High-dose Dexamethasone Versus Lenalidomide Plus Low-dose Dexamethasone As Initial Therapy for Newly Diagnosed Multiple Myeloma: An Open-label Randomised Controlled Trial. Rajkumar SV et al. Lancet Oncol 2010;11(1):29.

Bortezomib, Melphalan, and Prednisone Versus Bortezomib, Thalidomide, and Prednisone As Induction Therapy Followed by Maintenance Treatment With Bortezomib and Thalidomide Versus Bortezomib and Prednisone in Elderly Patients With Untreated Multiple Myeloma: A Randomised Trial. Mateos MV et al. Lancet Oncol 2010 Aug 24. [Epub ahead of print]. Optimising Bortezomib in Newly Diagnosed Multiple Myeloma.Rajkumar SV. Lancet Oncol 2010 Aug 24. [Epub ahead of print].


Lenalidomide Maintenance After Transplantation for MyelomaAttal M et al. Proc ASCO 2010;Ab 8018.

Phase III Intergroup Study of Lenalidomide Versus Placebo Maintenance Therapy Following Single Autologous Stem Cell Transplant (ASCT) for Multiple Myeloma (MM): CALGB 100104McCarthy PL et al. Proc ASCO 2010;Ab 8017.

Evaluating the Effects of Zoledronic Acid (ZOL) on Overall Survival (OS) in Patients (Pts) With Multiple Myeloma (MM): Results of the Medical Research Council (MRC) Myeloma IX StudyMorgan G et al. Proc ASCO 2010;Ab 8021.

Case History: Dr Anderson

• A 43-year-old woman is diagnosed with symptomatic IgA multiple myeloma

• Hb 8.0 g/dL• Albumin 3.5 g/dL• beta 2 microglobulin 3.0 mg/L

1) What is the stage of her disease?

34%

43%

23%

0% 10% 20% 30% 40% 50%

ISS Stage I

ISS Stage II

ISS Stage III


International Staging System for Multiple Myeloma

Greipp PR et alJ Clin Oncol 2005;23(15):3412-20.

International Staging System

ISS Stage CriterionMedian Survival

ISerum β2-microglobulin < 3.5mg/L

Serum albumin ≥ 3.5 g/dL62 months

II Neither Stage I nor Stage III 44 months

III Serum β2-microglobulin ≥ 5.5mg/L 29 months

Greipp PR et al. J Clin Oncol 2005 23(15):3412-20

2) What treatment, if any, would you recommend?

16%

5%

24%

16%

18%

13%

8%

0%

0% 5% 10% 15% 20% 25% 30%

None

TD (thalidomide-dexamethasone)

RD/Rd (lenalidomide-dexamethasone)

VD (bortezomib-dexamethasone)

VTD (bortezomib-thalidomide-dexamethasone)

RVD (lenalidomide-bortezomib-dexamethasone)

RVD melphalan and auto-transplant

RVD melphalan and auto-transplant lenalidomide maintenance

Has your approach to initial induction therapy for patients with MM who are eligible for transplant changed substantially in the past year?

47%

0% 10% 20% 30% 40% 50%

Percent responding

“Yes”

How has it changed?

I am using more triple-drug regimens 71%

I am using more bortezomib-based regimens 62%

I am using low-dose dexamethasone instead of high-dose dexamethasone as part of initial induction therapy

57%

I am using more lenalidomide-based regimens 38%

Other 6%

29%

26%

23%

7%

5%

2%

8%

0%

5%

10%

15%

20%

25%

30%

35%

Rd/RD RVD VD VdoxD TD VTD Other

Multiple Myeloma: First systemic treatment for patients deemed eligible for transplant by the treating oncologist (N = 128 patients)

National Patterns of Care Study, 2010, N = 43 medical oncologists


Lenalidomide, Bortezomib, and Dexamethasone Combination Therapy in Patients with Newly Diagnosed Multiple Myeloma

Richardson PG et alBlood 2010;116(5):679-86.

≥ PR ≥ VGPR CR + nCR CR

All Patients ( N = 66) 100% 67% 39% 29%

Phase 2 Population ( N = 35) 100% 74% 57% 37%

Efficacy and Safety of RVD in Newly Diagnosed Myeloma

Richardson PG et al. Blood 2010;116(5):679-86.

Select Grade 3-4 Events with RVD

Sensory Neuropathy

Neuropathic Pain

Motor Neuropathy Neutropenia

Thrombo-cytopenia

Thrombo-embolism

2% 3% 2% 9% 6% 5%


Phase III Intergroup Study of Lenalidomide versus Placebo Maintenance Therapy Following Single Autologous Stem Cell Transplant (ASCT) for Multiple Myeloma (MM): CALGB 100104McCarthy PL et al Proc ASCO 2010;Abstract 8017.

Lenalidomide Maintenance After Transplantation for MyelomaAttal M et alProc ASCO 2010;Abstract 8018.

Lenalidomide (n = 210)

Placebo(n = 208) Hazard Ratio p-value

Time to Progression

Not Reached 25.5 months 0.42 <0.0001

McCarthy PL et al. Proc ASCO 2010;Abstract 8017.

Efficacy of Lenalidomide-Maintenance in Post-Transplant Setting

Lenalidomide (n = 307)

Placebo(n = 307) Hazard Ratio p-value

3-Year PFS 68% 34% 0.46 <0.0000001

Attal M et al. Proc ASCO 2010;Abstract 8018.

Erik Rupard, MDFort Gordon, GA

How would you manage a young patient with

MM, who achieves a good response with the

initial cycle of Rd, but tolerates Rd poorly

with profound nausea and fatigue. I have

seen a number of patients on Rd with

significant GI adverse events?


What about the effects of R on stem cell collections?

Richard Polkinghorn, MDBrunswick, ME

A 45-year old woman presents with

symptomatic myeloma and altered mental

status, and found to have increased

ammonia level without deranged liver

function. What is known about the

association between myeloma and

increased ammonia levels?

Case History: Dr Gertz

• A 79-year old woman is diagnosed with symptomatic IgA multiple myeloma

• Hb 10.6 g/dL

• Albumin 3.7 g/dL

• beta 2 microglobulin 3.2 mg/L

• Cytogenetics – Normal

• FISH t(11;14)

• Plasma Cell Labeling Index 0%

3) Would you consider this patient eligible for a transplant?

76%

24%

0% 10% 20% 30% 40% 50% 60% 70% 80%

Yes

No

Number of Patients Considered Eligible for Transplant In a Cross-Sectional Study from US Community Oncologists (N = 264 Patients)

National Patterns of Care Study, Research to Practice, 2010, N = 43 medical oncologists

≤45 50 55 60 65 70 75 80 85 ≥90

Yes (n = 128)No (n = 136)

6%

4%

13%

2%

47%

9%

19%

0%

0% 10% 20% 30% 40% 50%

Other

4) What treatment, if any, would you recommend?

CYBOR-D (cyclophosphamide-bortezomib-dex)

VD (bortezomib-dex)

V-PLD (bortezomib-PLD)

RD/Rd (lenalidomide-dex)

TD (thalidomide-dex)

VAD (vincristine-doxorubicin-dex)

MP (melphalan-prednisone)

22%21%

17% 17%

10%

2%

11%

0%

5%

10%

15%

20%

25%

VD Rd/RD MPT MPV MP RVD Other

Multiple Myeloma: First systemic treatment for patients deemed not eligible for transplant by the treating oncologist (N = 129 patients)

National Patterns of Care Study, 2010, N = 43 medical oncologists

Case History: Dr Gertz (continued)

• The patient is treated with lenalidomide plus dexamethasone


Lenalidomide plus High-Dose Dexamethasone versus Lenalidomide plus Low-Dose Dexamethasone as Initial Therapy for Newly Diagnosed Multiple Myeloma: An Open-Label Randomized Controlled Trial

Rajkumar SV et alLancet Oncology 2010;11(1):29-37.

RD (N = 223) Lenalidomide-

High Dose Dexamethasone

Rd (N = 222)Lenalidomide-

Low Dose Dexamethasone p-value

≥ PR ( by Cycle 4) 79% 68% 0.008

1-Year OS 87% 96% 0.0002

Grade 3-4 Adverse Events (by 4 Months)

52% 35% 0.0001

Deep Venous Thrombosis

26% 12% 0.0003

Grade 3-4 Infections

16% 9% 0.04

Safety and Efficacy Comparison of RD versus Rd

Rajkumar SV et al. Lancet Oncology 2010;11(1):29-37.


Bortezomib, Melphalan, and Prednisone Versus Bortezomib, Thalidomide, and Prednisone As Induction Therapy Followed by Maintenance Treatment With Bortezomib and Thalidomide Versus Bortezomib and Prednisone in Elderly Patients With Untreated Multiple Myeloma: A Randomised TrialMateos MV et alLancet Oncol 2010 Aug 24. [Epub ahead of print].

Mateos MV et al. Lancet Oncol Aug 24. [Epub ahead of print].

Induction with VMP versus VTP Followed by Maintenance with VT versus VP for Untreated MM in Patients > 65 Years

Bortezomib (V): Induction phase, 1.3 mg/m2 twice weekly during a 6-weekfirst cycle, then weekly during subsequent cycles; maintenance phase, 1.3 mg/m2 twice weekly days 1, 4, 8 and 11 every 3 months

VMP(n = 130)

Maintenance

Induction VTP(n = 130)R1

R2R2

VT VP VT VP

VMP (N = 130)

VTP (N = 130) p-value

≥ PR 80% 81% 0.9

CR (immunofixation-negative) 20% 28% 0.2

Near CR (immunofixation-positive) 12% 8% 0.2

Partial response 48% 45% 0.7

Progression-free survival 34 mos 25 mos 0.1

Overall survival (3-year) 74% 65% 0.3

>Grade 3 Peripheral neuropathy 7% 9% 0.6

> Grade 3 Neutropenia 39% 22% 0.008

> Grade 3 Thrombocytopenia 27% 12% 0.0001

> Grade 3 Cardiac events 0 8% 0.001

Patients discontinuing due to SAEs 12% 17% 0.03

Safety and Efficacy of Induction VMP vs VTP

Mateos MV et al. Lancet Oncol Aug 24. [Epub ahead of print].


Bortezomib, Melphalan, Prednisone and Thalidomide (VMPT) Followed by Maintenance with Bortezomib and Thalidomide for Initial Treatment of Elderly Multiple Myeloma Patients

Palumbo A et alProc ASCO 2010;Abstract 8013.

VMP versus VMPT VT in Elderly Myeloma

VMP(n = 253)

VMPT VT(n = 250) p-value

≥ PR 81% 89% 0.01

CR 24% 38% 0.0008

3-Year PFS 40% 54% 0.006

3-Year OS 84% 86% 0.60

Palumbo A et al. Proc ASCO 2010;Abstract 8013.

*Three patients in twice weekly and one patient in once weekly group are not evaluable because they never began therapy.

NeuropathyVMP (Twice-weekly-

Bortezomib Schedule)VMP (Weekly-

Bortezomib Schedule)

All Grade (n = 63, 190*) 43% 21%

Grade 3 / 4 14% 2%

Should cytogenetics be obtained in all patients to stratify risk?


Evaluating the Effects of Zoledronic Acid (ZOL) on Overall Survival (OS) in Patients (Pts) With Multiple Myeloma (MM): Results of the Medical Research Council (MRC) Myeloma IX Study

Morgan G et al.

Proc ASCO 2010;Abstract 8021.

• Randomized to zoledronic acid versus clodronate, with treatment continued at least until disease progression

• ZOL significantly prolonged OS vs CLO (HR=0.84, p=0.0118)

— After adjustment for SREs (HR=0.85, p=0.0178)

• ZOL significantly reduced proportion of patients with SREs vs CLO (p=0.0004)

Morgan GJ et al. Proc ASCO 2010;Abstract 8021.

Improvement in Overall Survival with Zoledronic Acid (ZOL) in Patients with Newly Diagnosed Stage I-III Multiple Myeloma (N = 1,960)

Neil Fishbach, MDFairfield, CT

In view of the risk for osteonecrosis of

the jaw in patients receiving IV

bisphosphonates, is there a time or

role for spacing the administrations?


Is the depth of response as important in the non-transplant eligible patients as it is in the transplant eligible patients…or gentler, sequential approaches just as good or even preferred?

Margaret Deutsch, MDRaleigh, NC

For an elderly patient with myeloma, who

attains CR in a few cycles of VMP, is there a

role for maintenance bortezomib?

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