a live training program for the multidisciplinary myeloma care team ---------- x, 2010

A Live Training Program for the Multidisciplinary Myeloma Care Team

---------- X, 2010


---------- X, 2010

Welcome and Introduction

Sagar Lonial, MD – ChairDirector, Translational Research, B-Cell Malignancy ProgramVice Chair of Clinical AffairsAssociate Professor of Hematology and Medical OncologyEmory University School of MedicineWinship Cancer InstituteAtlanta, Georgia

Welcome and Introduction


Learning ObjectivesLearning Objectives

• At the conclusion of this educational activity, participants will be able to:– Select appropriate treatment sequencing approaches for

individual multiple myeloma patients based on pre-existing comorbidities

– Design a comprehensive management plan tailored for myeloma-related complications such as renal impairment, bone complications, asthenia, and anemia

– Identify myeloma treatment-associated side effects– Choose appropriate interventions to manage side effects of

myeloma treatments such as gastrointestinal side effects, peripheral neuropathy, and VTE

FacultyFaculty


Sandra E. Kurtin, RN, MS, AOCN®, ANP-C Clinical Assistant Professor of Medicine and NursingUniversity of ArizonaHematology/Oncology Nurse PractitionerArizona Cancer CenterTucson, Arizona

FacultyFaculty

Ann F. Mohrbacher, MD Associate Professor of Clinical MedicineKeck School of MedicineUniversity of Southern California Los Angeles, California

David Siegel, MD, PhDDivision Chief, Myeloma The John Theurer Cancer CenterHackensack University Medical CenterHackensack, New Jersey Clinical Professor of MedicineNew York University Medical CenterNew York, New York

Faculty DisclosuresFaculty Disclosures

• Dr. Sagar Lonial has received consultant fees and grant support related to research activities from Millennium Pharmaceuticals, Inc., Celgene Corporation, Bristol-Myers Squibb, and Novartis AG.

• Sandra Kurtin has received honoraria related to speakers’ bureau activities from Celgene Corporation.

• Dr. Ann Mohrbacher has received honoraria related to speakers’ bureau activities from Millennium Pharmaceuticals, Inc. and Celgene Corporation.

• Dr. David Siegel has received honoraria related to speakers’ bureau activities from Celgene Corporation and Millennium Pharmaceuticals, Inc.

AgendaAgenda

• 8:00-10:30 am: Practice Considerations Update, Real-World Patient Challenges, Faculty Critical Assessment and Ask the Experts Part I – Considerations in Practice Update: Newly Diagnosed

Patient (30 minutes)– Faculty present newly diagnosed cases (3-5 minutes)– Attendees deliberate (15 minutes)– Faculty review attendees’ strategies for newly

diagnosed patients and critically discuss appropriate management plans (15 minutes)

– Q&A (10 minutes)

AgendaAgenda

– Considerations in Practice Update: Renal Impairment and Bone Disease (30 minutes)

– Faculty present renal impairment and bone disease case (5 minutes)

– Attendees deliberate (15 minutes)– Faculty review attendees’ strategies for newly


– Q&A (10 minutes)

• 10:30-10:40 am: Break

AgendaAgenda

• 10:40 am-1:00 pm: Real-World Patient Challenges Part II– Considerations in Practice Update:

Relapsed/Refractory Disease and Salvage Therapy (20 minutes)

– Faculty present relapsed/refractory case (5 minutes)– Attendees deliberate (10 minutes)– Faculty review attendees’ strategies for newly


AgendaAgenda

• Considerations in Practice Update (Side Effect Management): Peripheral Neuropathy (15 minutes)

• Considerations in Practice Update (Side Effect Management): VTE, Anemia, Asthenia, Infection and GI Side Effects Management (15 minutes)

• Faculty present peripheral neuropathy case (5 minutes)• Attendees deliberate (10 minutes)• Faculty review attendees’ strategies for peripheral neuropathy and

critically discuss appropriate management plans (10 minutes)• Faculty present VTE, anemia, asthenia, infection and GI side effects

case (5 minutes)• Attendees deliberate (10 minutes)• Faculty review attendees’ strategies for VTE, anemia, asthenia,

infection and GI side effects case and critically discuss appropriate management plans (10 minutes)

AgendaAgenda

– Q&A and introduction to additional resources (5 minutes)

• 1:00 pm: Chair Conclusions and Closing RemarksLunch and Adjournment

The Mastery of Myeloma CourseThe Mastery of Myeloma Course

A First Word…A First Word…

• It is essential to remain current with evidence-based practice guidelines: – Several are frequently updated, eg:

National Comprehensive Cancer Center Network (NCCN) Practice Guidelines in Oncology

International Myeloma Working Group (IMWG) American Society of Clinical Oncology (ASCO) Managing the Side Effects of Novel Agents for Multiple

Myeloma: Guidelines and Patient Education Sheets; IMF Nurse Leadership Board, published in the Clinical Journal of Oncology Nursing, 2008

The NCCN Practice Guidelines for Multiple Myeloma Serve as Only One Example:

The NCCN Practice Guidelines for Multiple Myeloma Serve as Only One Example:

NCCN Clinical Practice Guidelines in Oncology. Multiple Myeloma (v.1.2011) [7-27-2010].

The NCCN Version 1.2011 Multiple Myeloma Updates Include:

The NCCN Version 1.2011 Multiple Myeloma Updates Include:

• A recommendation to move serum-free light chain assay from useful under some circumstances to standard practice in the initial diagnostic work-up

• Changed “progression to stage II or higher disease” to “progression to symptomatic disease”

• Regarding time point for assessing response, a bullet has been added to remind practitioners that “some responses can occur late post-transplant”

NCCN Clinical Practice Guidelines in Oncology. Multiple Myeloma (v.1.2011) [7-27-2010].

The NCCN Version 1.2011 Multiple Myeloma Updates also Include:


• New combinations of agents have been included in the list of recommended therapies: – Bortezomib/cyclophosphamide/dexamethasone combination has

been added to primary induction therapy for transplant candidates [aka CyBorD] <category 2A>

– Bortezomib/dexamethasone combination was added to primary induction therapy for non-transplant candidates [BD aka VD] <category 2A>

– Melphalan/prednisone/lenalidomide combination was added to primary induction therapy for non-transplant candidates [LMP aka RMP] <category 2A>

– Cyclophosphamide/bortezomib/dexamethasone combination was added to salvage therapy [CBD aka CVD] <category 2A>

– Cyclophosphamide/lenalidomide/dexamethasone combination was added to salvage therapy [LCD aka RCD] <category 2A>

NCCN Clinical Practice Guidelines in Oncology. Multiple Myeloma (v.1.2011) [7-27-2010].Lenalidomide is not currently approved by the FDA for use as first-line therapy in multiple myeloma.



• Systemic light chain amyloidosis:– Added bortezomib dexamethasone to primary treatment

– Added cyclophosphamide/thalidomide/dexamethasone combination to primary treatment

NCCN Clinical Practice Guidelines in Oncology. Multiple Myeloma (v.1.2011) [7-27-2010].Lenalidomide is not currently approved by the FDA for use as first-line therapy in multiple myeloma.

Newly Diagnosed Multiple Myeloma:Considerations in Practice Update

Newly Diagnosed Multiple Myeloma:Considerations in Practice Update



Goals of Induction Therapy: The Potential Transplant Patient

Goals of Induction Therapy: The Potential Transplant Patient

• Rapid responses• Depth of responses (high response rates)• Durable responses!• Improve performance status• Not limit PBSC mobilization• Common questions:

– Does induction therapy really matter?– Does the choice depend upon cytogenetics or

prognostic factors?– What if you achieve a complete response, what next?

No Single Primary Induction Therapy Fits All Patients

No Single Primary Induction Therapy Fits All Patients

• Regarding induction therapy– No single induction therapy regimen has emerged as

a clear winner for all multiple myeloma patients

• Studies of the associated cytogenetic abnormalities indicate that multiple myeloma is a heterogeneous disease– It is expected that in the future, risk-adapted

approaches will further refine patient management

Diagnosis• Survival 3–5 years• Survival <6 months without Rx• ~12,000 deaths per year

Initial therapy • Melphalan, prednisone

+ Thal + Bz + Len•BD•Ld

Initial therapy• Bz combinations

Bz + Dex Bz + Cyc + Dex Bz + Dox + Dex• Len combinations Len + Dex Bz + Len + Dex•Thal + Dex

Relapsed disease• Transient response • Survival 1–3 years

Salvage therapy•Repeat primary therapy (if relapse >6 months)• Cyclophosphamide + VAD + BzD + LD• Etoposide, Dex, cytarabine, cisplatin• Thal +/− Dex • Len +/− Dex• Bz +/− Dex • Bz combos (eg, PLD)• Bz + Len + Dex• Other novel therapies (clinical trials)

• Stem cell harvest, subsequent autostem cell transplant (single vs. double)

+/− maintenance (Thal, Bz, Len)• Investigational therapy (eg, allo-SCT) • Novel Auto-SCT (eg, Mel, Bz)

Transplantcandidate

Non-transplantcandidate

Relapsed/refractory disease• Shorter TTP• Survival 6–9 months

Multiple Myeloma: Current Treatment (USA) Adapted From NCCN Practice Guidelines (v1.2011)

Multiple Myeloma: Current Treatment (USA) Adapted From NCCN Practice Guidelines (v1.2011)

Lenalidomide is not currently approved by the FDA for use as first-line therapy in multiple myeloma.

Examples of New Induction Therapies Prior to Autologous Transplant

Examples of New Induction Therapies Prior to Autologous Transplant

• Thalidomide, dexamethasone ± doxorubicin (TAD)

• Bortezomib, dexamethasone (VD)

• Bortezomib, thalidomide, dexamethasone (VTD)

• Lenalidomide, dexamethasone (RD)

• Cyclophosphamide, bortezomib, dexamethasone (CyBorD)

• Clarithromycin, lenalidomide, dexamethasone (BiRD)

• Bortezomib, peg-doxorubicin, dexamethasone (PAD)

• Bortezomib, lenalidomide, dexamethasone (VRD)

• And others

NCCN Clinical Practice Guidelines in Oncology. Multiple Myeloma (v.1.2011) [7-27-2010].Myeloma Treatment Resources: Managing Myeloma Compendium of Drug Regimens (MMCDR)Available at www.ManagingMyeloma.com


What We Know and Don’t KnowWhat We Know and Don’t Know

• New drugs improve induction CRs, higher CR rates after ASCT– Which drug combinations are optimal for patients

proceeding to transplant?

• Do higher response rates observed after novel drugcombinations + ASCT improve survival?

• Some new drugs effect stem cell yields

• If your patient achieves CR after novel induction therapies, is a transplant optional?

Palumbo A, et al. Leukemia. 2008;22:414-423.; Bensinger W, et al. 2008;26:480-492.

Most Common Two-Drug RegimensMost Common Two-Drug Regimens

NCCN-listed myeloma therapies (v.1.2011, released 7/2010)Transplant candidates

Bortezomib/dexamethasone (category 1)

Lenalidomide/dexamethasone (category 1)

Thalidomide/dexamethasone (category 2B)

Thalidomide Two-Drug RegimenThalidomide Two-Drug Regimen

• Thalidomide/dexamethasone (category 2B)

ParameterThal/Dex(n = 100)

VAD(n = 104)

P Value

VGPR before PBSC collection (%) 25 7 .0027

VGPR before Mel 200 (%) 35 13 .002

VGPR 6-month post-ASCT (%) 44 42 .87 (NS)

Mean duration of hospitalization before PBST (all causes) 8.3 days 20 days .0001

VTE 23 8 .004

VTE = venous thromboembolismMacro, et al. 2006.

Thal/Dex Provides Higher Response Rates Prior to ASCT But Is No More Effective Than VAD Assessed 6-months

Post-ASCTThal/Dex vs. VAD (Phase III)

Thal/Dex Provides Higher Response Rates Prior to ASCT But Is No More Effective Than VAD Assessed 6-months

Post-ASCTThal/Dex vs. VAD (Phase III)

N = 204

Untreated MM Age <66 years

n = 100Thal/Dex

n = 104VAD regimen

RANDOMIZE

RANDOMIZE

PBSC mobilization (Cy + G-CSF)

91%

91%

4 months Mel 200; ASCT

83%

Lenalidomide Two-Drug RegimensLenalidomide Two-Drug Regimens

• Lenalidomide/dexamethasone (LD)– Dexamethasone 40 mg PO QAM on days 1–4, 9–12,

and 17–20 of each 28-day cycle

• Lenalidomide/(low-dose) dexamethasone (Ld)– Dexamethasone 40 mg PO QAM on days 1, 8, 15

and 22 of each 28-day cycle

Rajkumar SV, et al. Lancet Oncol. 2010;11:29-37.NCCN Practice Guidelines in Oncology-Multiple Myeloma (v.1.2011).

(category 1)

Analysis of Phase III E4A03 TrialLD vs. Ld

Analysis of Phase III E4A03 TrialLD vs. Ld

LD = high-dose dexamethasone; Ld = low-dose dexamethasone; SD = stable disease; PO = orallyRajkumar SV, et al. Lancet Oncol. 2010;11:29-37.

RANDOMIZE

LDLenalidomide

dexamethasone× 4 cycles

LdlenalidomideLow-dose


TDthalidomide


< PR

Off study to SCT; or, continue len/dex at

physician’s discretion

CR/PR/SD

• Lenalidomide: 25 mg PO on Days 1–21 of a 28-day cycle• Dexamethasone: 480 mg total per cycle (regular dose)

160 mg total per cycle (low dose)

PR/CR


E4A03 Updated Analysis: Median F/U 36 Months

E4A03 Updated Analysis: Median F/U 36 Months

• 404 patients (91%) are off study– 197 were off study by 4 months– 253 were off study by 6 months

• Median duration of therapy– Arm A: 4 months

– Arm B: 6 months

PFSP

FS

Pro

ba

bili

ty

0

20

40

60

80

100

Time in Months

0 6 12 18 24 30 36

222 182 139 115 78 42 19

217 180 149 121 83 37 19

Numbers at Risk

RD

Rd

p = .08 log-rank;

p = .04 Pepe-Fleming

Ld

LD

TTP

TT

P P

rob

ab

ility

0

20

40

60

80

100

Time in Months

0 6 12 18 24 30 36

217 181 138 115 77 42 19

215 179 148 121 84 38 18

Numbers at Risk

RD

Rd

p = NS

Ld

LD

OS

Sur

viva

l Pro

babi

lity

0

20

40

60

80

100

Time in Months

0 6 12 18 24 30 36

223 208 195 184 173 123 78

222 217 212 201 192 146 83

Numbers at Risk

RD

Rd

Ld

LD

75%

3-year OS rate

Best

Response

CR (%)

> VGPR (%)

> PR (%)

ED (%)

LD 17 51 81 5

Ld 14 40 70 0.5

Rajkumar SV, et al. 2008; Rajkumar SV, et al. Lancet Oncol. 2010;11:29-37.


E4A03: Landmark Analysis at 4 Cycles Median F/U: 36 MonthsE4A03: Landmark Analysis at

4 Cycles Median F/U: 36 Months

431 patients alive at 4 cycles

Off therapy at 4 cycles

N = 183

Primary therapy beyond 4 cycles

N = 248

No transplantN = 93

(median age: 68)

Transplant N = 90

(median age: 57)

LdN = 140

(median age: 66)

LDN = 108

(median age: 65)

3-year OS 56%

3-year OS 92%

3-year OS 79%

3-year OS 79%

Rajkumar SV, et al. 2008; Rajkumar SV, et al. Lancet Oncol. 2010;11:29-37. Lenalidomide is not currently approved by the FDA for use as first-line therapy in multiple myeloma.

E4A03: OS Landmark Analysis Transplant or Primary Therapy After 4 Cycles

E4A03: OS Landmark Analysis Transplant or Primary Therapy After 4 Cycles

Transplant following 4 cycles of LD vs. Ld

Primary therapy beyond 4 cycles of LD vs. Ld

Transplant, N = 90

(median age: 57 years)

LD, N = 108 (median age: 65 years)

Ld, N = 140 (median age: 66 years)

P=NS

Su

rviv

al P

rob

ab

ility

0

20

40

60

80

100

Time in Months

0 6 12 18 24 30 36

50 50 49 48 47 35 20

40 40 40 38 37 32 21

Numbers at Risk

RD

Rd

Ld

LD

92%

3-year OS rate

Median F/U: 36 months

Su

rviv

al P

rob

ab

ility

0

20

40

60

80

100

Time in Months

0 6 12 18 24 30 36

108 108 103 97 90 67 44

140 140 139 133 128 95 51

Numbers at Risk

RD

Rd

79%

3-year OS rate

LD

Median F/U: 36 months

Ld

Rajkumar SV, et al. 2008; Rajkumar SV, et al. Lancet Oncol. 2010;11:29-37.Lenalidomide is not currently approved by the FDA for use as first-line therapy in multiple myeloma.

Bortezomib Two-Drug RegimenBortezomib Two-Drug Regimen

• Bortezomib/dexamethasone (category 1)

NCCN Practice Guidelines in Oncology-Multiple Myeloma (v.1.2011).

First-Line Therapy in MM Bortezomib + Dexamethasone (Phase III)

First-Line Therapy in MM Bortezomib + Dexamethasone (Phase III)

A1VAD x 4 VAD x 4 Bort/Dex x 4 Bort/Dex x 4

DCEP x 2 DCEP x 2

Melphalan 200 mg/m2

+ ASCT

Melphalan 200 mg/m2

+ ASCT

Melphalan 200 mg/m2

+ ASCT

Melphalan 200 mg/m2

+ ASCT

Induction

Consolidation

Transplant 1

A2 B1 B2

Randomization age ≤ 65 years

stratified by β2m (> 3 mg/L vs. ≤ 3 mg/L) and

presence of chromosome 13 abnormalities (FISH analysis)

Second ASCT or RIC allo if < VGPR within 3 months

FISH = fluorescence in situ hybridization; Bort = bortezomib; DCEP = dexamethasone, cyclophosphamide, etoposide, cisplatin; RIC = reduced-intensity conditioning Harousseau, Mathiot, et al. 2008.

Bort/Dex vs. VAD InductionBort/Dex vs. VAD Induction

*Modified EBMT criteria.ITT = intent to treat; nCR = near complete response; EBMT = European Group for Blood and Marrow Transplantation Harousseau, Marit, et al. 2008; Harousseau, Mathiot, et al. 2008.

Response* to Induction

ITT Analysis VAD(n = 242; %)

Bort/Dex(n = 240; %) P Value

CR 1.4 6.1 .0109CR + nCR 6.7 15 .0035> VGPR 16 39 < .0001> PR 65 82 < .0001

CR + nCR 19 37 .0016

> VGPR 38 57 < .0001

> PR 79 84 NS

Post-First ASCT Response

CR + nCR 32 39 < .0001

> VGPR 47 68 < .0001

Post-Second ASCT Response

PFS: Two-Year Median F/UPFS: Two-Year Median F/U

VAD: 101 eventsMedian: 28 months 2-year PFS: 60%

Bort/Dex (B1 + B2) VAD (A1 + A2)

100

80

60

40

20

00 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40

Time (Months)

Kap

lan

-Mei

er E

stim

ate

(%) Bort/Dex: 71 events

Median: NR 2-year PFS: 69%

P Value (log-rank) = .0115

NR = no responseHarousseau, Marit, et al. 2008.

OS: Two-Year Median F/UOS: Two-Year Median F/U

100

80

60

40

20

0

Kap

lan

-Mei

er E

stim

ate

(%)

P Value (log-rank) = .4689

Bort/Dex (B1 + B2)

VAD (A1 + A2)

VAD: 33 deaths2-year OS: 88%

Bort/Dex: 29 deaths2-year OS: 90%

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40Time (Months)

Harousseau, Marit, et al. 2008.

IFM 2005-01 Trial: Toxicities During InductionIFM 2005-01 Trial: Toxicities During Induction

6.3%1.3%Grade 3/4 Peripheral Neuropathy

35.3%22.6%Peripheral Neuropathy (all grades)

10.1%5.4%Rash (all grades)

21.4%16.7%Fatigue (all grades)

38.2%40.6%Grade ≥ 3 Adverse Events

14.2%

VADN=239

10.5%Grade ≥ 4 Adverse Events

Bortezomib/Dexamethasone

N=238Adverse Events

Harousseau JL, et al. Blood (ASH Annual Meeting Abstracts) 2007;110:450.

VAD (A1+A2), N=242

Bortezomib+dexamethasone (B1+B2), N=240

Hematologic Toxicity

0

2

4

6

8

10

Anemia Neutropenia Platelets

%

No issues with stem cell collection were found

Triple Drug RegimensTriple Drug Regimens

NCCN-listed myeloma therapies (v.1.2011, released 7/2010)• Transplant candidates

– Bortezomib/cyclophosphamide/dexamethasone (category 2A) CyBorD

– Bortezomib/doxorubicin/dexamethasone (category 1) PAD

– Bortezomib/lenalidomide/dexamethasone (category 2B) BLD aka RVD

– Bortezomib/thalidomide/dexamethasone (category 1) BTD aka VTD

• Examples of other common three drug combinations– Lenalidomide, cyclophosphamide, dexamethasone

LCD aka RCD– Clarithromycin, lenalidomide, dexamethasone

BiRD

NCCN Practice Guidelines in Oncology-Multiple Myeloma (v.1.2011); Myeloma Treatment Resource (MTR): Managing Myeloma Compendium of Drug Regimens (MMCDR v.1.2010). Available at www.ManagingMyeloma.com


BTD vs. TD for SCT InductionBTD vs. TD for SCT Induction

Phase III study: Updated results1

• Endpoints: Primary – CR/nCR post-induction; Secondary – CR/nCR post-SCT and consolidation, TTP, EFS, PFS, OS, stem cell yield, safety

• Patients: 450 planned patients – 474 enrolled (Arm A, n = 236; Arm B, n = 238)• Dose: Three 21-day cycles

• DVT prophylaxis: Patients randomized to LMWH, enoxaparin (40 mg/day), aspirin (100 mg/day), or warfarin (1.25 mg/day)2

BTD = bortezomib, thalidomide, dexamethasone; DVT= deep-vein thrombosis1Cavo M, et al. Blood (ASH Annual Meeting Abstracts). 2008;112;158. 2Cavo M et al. Blood (ASH Annual Meeting Abstracts) 2008;112:3017.; Lovenox® prescribing information, 2008.

Arm A– BTD: Bort 1.3 mg/m2 Days 1, 4, 8,

11; Dex 40 mg day of and day after Bort; Thal 200 mg/day

MaintenanceDex

Arm B– TD: Thal 200 mg/day; Dex 40 mg

Days 1–4, 9–12

SC collection +

Mel 200 Mel 200

Consolidation TD

Consolidation BTD

RANDOMIZE

BTD vs. TD for SCT InductionBTD vs. TD for SCT Induction

Response* Induction

BTD (n = 226; %)

TD(n = 234; %)

P Value

CR/nCR 32 12 < .001

≥ VGPR 62 29 < .001

≥ PR 94 79 < .001

*Modified EBMT criteria.Cavo, et al. 2008.

Response First SCT Second SCT Consolidation

BTD (n = 226; %)

TD (n = 234; %)

P Value BTD > TD P Value BTD > TD P Value

CR 43 23 < .001 CR .004 CR .001

CR/nCR 55 32 < .001 nCR .03 nCR .005

≥ VGPR 76 58 < .001 ≥ VGPR .001 ≥ VGPR .001

PFS and OS by Study Randomization BTD vs. TD

PFS and OS by Study Randomization BTD vs. TD

Months Months

PFS OS

2-year rates

BTD (n=226) 90%TD (n=234) 80%

P=.009

2-year rates

BTD (n=226) 96%TD (n=234) 91%

P=.2

Median follow-up for BTD and TD: 15 months

Fre

qu

ency

Cavo M. 2008.

Reducing ToxicityReducing Toxicity

• Can we reduce the dose of bortezomib in therapy and maintain efficacy while reducing toxicity?– Two approaches

Reduce the amount of drug given during a twice-weekly schedule (ie, 1.0 mg/m2 on days 1, 4, 8, 11) or

Reduce the number of doses to a once-weekly schedule (ie, 1.3 mg/m2/d or 1.5 mg/m2/d on days 1, 8, …)

Reduced-dose Bortezomib plus Thalidomide plus Dexamethasone (vTD) to Bortezomib plus Dexamethasone

(VD) as Induction Treatment prior to ASCT in de novo Multiple Myeloma (MM):IFM2007-02

Reduced-dose Bortezomib plus Thalidomide plus Dexamethasone (vTD) to Bortezomib plus Dexamethasone

(VD) as Induction Treatment prior to ASCT in de novo Multiple Myeloma (MM):IFM2007-02

• Phase III randomized trial• Primary endpoint: CR rate after induction treatment• Secondary endpoints: ≥ VGPR and ≥ PR, and toxicity including

incidence of PN

Arm A– vTD: Bort 1.0 mg/m2/d days 1, 4, 8, 11;

Thalidomide 100 mg/d days 1-21; Dex 40 mg daily days 1-4 and 8-11

Arm B– VD: Bort 1.3 mg/m2/d on days 1, 4, 8, 11;

Dex 40 mg/d on days 1-4 and 8-11

RANDOMIZE

Moreau P, et al. J Clin Oncol. 2010, 28:15s (abstr 8014).

NCT00910897

http://clinicaltrials.gov/ct2/show/NCT00910897

vTD vs. VD as Induction Treatment Prior to ASCT in de novo MM:IFM2007-02

vTD vs. VD as Induction Treatment Prior to ASCT in de novo MM:IFM2007-02

0.0446654≥VGPR

0.339284≥PR

0.056047CR +nCR

Post ASCT

.0969081≥PR

.0475036≥VGPR

0.153122CR + nCR

0.681412CR

PvTDVDResponse Rate %

There was no difference regarding toxicity between the 2 arms of the study, except for peripheral neuropathy (PN). Grade > 2 PN occurred in 28% of the cases in the VD arm vs. 16% in vTD (P = .04), and treatment was interrupted due to PN in 4 cases of the VD arm vs. 0 in the VTD arm (P = .12)

Moreau P, et al. J Clin Oncol. 2010, 28:15s (abstr 8014).

Examples of Emerging Triple TherapiesExamples of Emerging Triple Therapies

• Clarithromycin/lenalidomide/dexamethasone (BiRD)

• Cyclophosphamide/lenalidomide/dexamethasone (CRD)

• Cyclophosphamide/bortezomib/dexamethasone (CyBorD) (category 2A)

• LBD (RVD) (category 2B)– Already in significant use even as trials are ongoing

Clarithromycin plus Lenalidomide plus Dexamethasone (BiRD)

Clarithromycin plus Lenalidomide plus Dexamethasone (BiRD)

• All patients received clarithromycin, lenalidomide, and dexamethasone in 28-day cycles

– Dose adjustments were permitted according to the toxicity criteria

– Prophylactic treatments included aspirin 81 mg QD; omeprazole 20 mg QD; one double-strength tablet of trimethoprim/sulfamethoxazole BID, 3 times a week

• N=72• ORR: 90.3%

– sCR, 30.6%– CR, 8.3%– VGPR, 34.7%– PR, 16.7%– MR, 5.6%– SD, 0%– Non-evaluable, 4.2%

• DoR: 333 days (range, 15-920)• Est 2-year EFS: 85.2%, with SCT

75.2%, without SCT

Niesvizky R, et al. Blood. 2008;111(3):1101-1109.

DoR = duration of response; EFS = event-free survival; ORR = overall response rate (≥PR)

9.7Thrombosis

4.2Tremor

4.2Hypocalcemia

5.6Diverticular abscess

5.6Rash

11.1Myopathy

Grade 3/4 toxicities nonhematologic

22.2Thrombocytopenia

13.8Anemia

19.4Neutropenia

% Grade 3/4 toxicities Hematologic

More than half of these events due to interruption or poor compliance with aspirin therapy!!


Clarithromycin plus Lenalidomide plus Low-dose Dexamethasone (BiRd) vs. Lenalidomide plus Low-

dose Dexamethasone (Ld)

Clarithromycin plus Lenalidomide plus Low-dose Dexamethasone (BiRd) vs. Lenalidomide plus Low-

dose Dexamethasone (Ld)

• Case-matched study, blinded and performed according to age, gender and transplant status

P = .2194.212.5Dermatological

P = .2189.716.7Infections

P = .01223.6%8.3%Thrombocytopenia

Grade 3/4 toxicities

P = .17089.7%73.0%3-year OS:

P = .04448.3 mo27.5 moPFS (median)

P = .07148.3 mo27.5 moTTP (median)

P < .00173.6%33.3%≥VGPR

P < .00145.8%13.9%CR

P valueBiRd (n=72)Ld (n=72)ITT analysis

Gay F, et al. Am J Hematol. 2010 Jun 4. [Epub ahead of print].

• Promising results justify the need for large, randomized control trialLenalidomide is not currently approved by the FDA for use as first-line therapy in multiple myeloma.

One Comparison Study of Two Triple Therapies

One Comparison Study of Two Triple Therapies

• Three consecutive trials among new therapies– Lenalidomide/dexamethasone vs. – Cyclophosphamide/lenalidomide/dexamethasone

(CRD) vs.– Cyclophosphamide/bortezomib/dexamethasone

(CyBorD)

Lenalidomide is not currently approved by the FDA for use as first-line therapy in multiple myeloma.Khan ML, et al. J Clin Oncol. 2010;28:15s (abstr 8131).

LD vs. CRD vs. CyBorD in Newly DiagnosedLD vs. CRD vs. CyBorD in Newly Diagnosed

21%27%12%ISS Stage III

NR41%11%35%CR/nCRAfter all cycles

95%

2.6

67%

47%

CyBorD(n=63)

P=.5287%91%OS 2-year

P=.352.33.2PFSMedian years

P=.000430%38%VGPR4 x cycles

P<.00012%13%CR/nCR4 x cycles

P-valueCRD(n=53)

Len/Dex(n=34)

•Median age was 62 •74 of the patients underwent stem cell transplantation•Risk profile by mSMART classification: high risk (N=40) or standard risk (N=89)

Median number of cycles delivered was higher for RD (8 vs. 5 vs. 4).Khan ML, et al. J Clin Oncol. 2010;28:15s (abstr 8131).


58%13%20%Neuropathy

3%11%3%Thrombosis

8%,

41%,

CyBorD

(n=63)

P=.0325%9%Grade 4

toxicities

P=.00274%59%Grade 3

toxicities

P-valueCRD

(n=53)

Len/Dex

(n=34)

Lenalidomide is not currently approved by the FDA for use as first-line therapy in multiple myeloma.Khan ML, et al. J Clin Oncol. 2010;28:15s (abstr 8131) .


• OS (2-year) no significant difference between regimens

• Median PFS (all 150) patients regardless of regimen was 2.6 years

• Transplantation status did not impact PFS (median: 3 vs. 2.3 years, P=.74) – OS was superior in transplanted patients (3-year: 95% vs. 75%, P=.001)

• High risk mSMART patients had earlier relapse (2-year PFS: 50% vs. 70%, P=.03) than standard risk despite use of either lenalidomide or bortezomib

• Conclusions: – CyBorD demonstrates superior response rates and similar or less toxicity when

compared to RD and CRD after 4 cycles– At this time, improved early depth of response does not translate into different

survival outcomes– High-risk patients continue to relapse sooner with all regimens– Promising, 82% of patients treated with these modern therapeutic approaches

are alive at 4 years!

Lenalidomide is not currently approved by the FDA for use as first-line therapy in multiple myeloma.Khan ML, et al. J Clin Oncol. 2010;28:15s (abstr 8131) .


Cybord Once-weekly Bortezomib and Low-dose Dexamethasone Regimen: Trend Towards

Seeking Lower Toxicities Continues

Cybord Once-weekly Bortezomib and Low-dose Dexamethasone Regimen: Trend Towards

Seeking Lower Toxicities Continues

Cohort 1:CyBorD Cyclophosphamide 300 mg by mouth once weekly; Twice-weekly bortezomib (1.3 mg/m2) and regular dose dexamethasone (40 mg 1-4, 9-12, 17-20)

Cohort 2:Cybord with once-weeklybortezomib (1.5 mg/m2 once weekly) and low-dose dexamethasone (40 mg 1-4, 9-12, 17-20 cycles 1 and 2, then 40 mg once weekly, cycles 3 and 4).

Phase II Trial

Reeder CB, et al. Blood. 2010;115(16):3416-3417.

Neuropathy rates were the same in both cohorts even though the total bortezomib dose per cycle was higher in the weekly versus the twice weekly schedule (6.0 mg/m2 vs. 5.2 mg/m2)Lenalidomide is not currently approved by the FDA for use as first-line therapy in multiple myeloma.

Safety and Efficacy of Lenalidomide, Bortezomib, and Dexamethasone (RVD)

[Phase II]


[Phase II]

Pre-ASCT responses to RVD, overall and by cycle

PatientsAll patients, n=35

ORR, % CR/nCR, % VGPR, %

Response at cycle 4 (n=31) 78 12 12

Response at cycle 8 (n=24)

100 33 67

Best response 100 54 69

After median follow-up of 19.3 months, median time to progression (TTP), progression-free survival (PFS), and overall survival (OS) have not been reached;

the estimated 1-year TTP and PFS are 76% and the estimated OS is 100%.

Richardson PG, et al. Blood (ASH Annual Meeting Abstracts). 2009;114:1218. Lenalidomide is not currently approved by the FDA for use as first-line therapy in multiple myeloma.


[Phase II]


[Phase II]

n=2 (6%)Neutropenia

n=2 (6%)Fatigue

n=3 (9%)Hypokalemia

n=7 (20%)Lymphopenia

Number of patients;

%

Treatment-emergent grade 3 and 4 adverse events (>1 patient)

n=1 (--%)Grade 3

n=0 (--%)Grade 4

n=8 (30%)Grade 2

n=18 (67%)Grade 1

n=27 (77%)Of any grade

Number of patients;

%

Sensory PNY

• PNY was reversible with dose reduction, supportive care, and/or completion of therapy

• Thrombosis/thromboembolism was reported in two (6%) patients• No treatment-related mortality was seen

PNY= peripheral neuropathyLenalidomide is not currently approved by the FDA for use as first-line therapy in multiple myeloma.

Richardson PG, et al. Blood (ASH Annual Meeting Abstracts). 2009;114:1218.

Stem Cell TransplantStem Cell Transplant

ASCT vs. Conventional CTResults of Randomized Studies

ASCT vs. Conventional CTResults of Randomized Studies

Attal, et al. 1996 IFM90CT

Auto Tx

Fermand, et al. 2005 MAG91CT

Auto Tx

Child, et al. 2003 MRC7CT

Auto Tx

Palumbo, et al. 2004 IMMSGCT

Auto Tx

Blade, et al. 2005 PETHEMACT

Auto Tx

Barlogie, Kyle, et al. 2006 USIGCT

Auto Tx

100

100

96

94

200

201

98

97

83

81

255

261

5

22

18

27

20

36

19

25a

9

44

20

32

6

25

16

28

11

30

33

42

11

11

16%at 7

years17%

44

57

48

48

42.3

54.1

43

58+

66

61

38%at 7

years38%

.03

.03

< .001

Patients(n)

OS(months) P Value

EFS(months)

CR(%)

CT = chemotherapy; Auto Tx = autologous therapy; IFM = Intergroupe Francais du Myelome; IMMSG = Italian Multiple Myeloma Study Group; MAG = Group Myelome Autographe; MRC = Medical Research Council; USIG = US Intergroup

aP = .07

Author Regimen VGPR after induction, %

VGPR after ASCT, %

EFS or PFS

Macro VADThal+Dex

1335

4244

NS

Harousseau VADBort+Dex

1639

4768

0.01

Lokhorst VADTAD

1533

3249

<0.01

Sonneveld VADPAD

1542

5080

?

Cavo Thal + DexBTD

2962

5876

0.009

Richardson RVD 69 ? ?

Cavo M, et al. 2007.; Harousseau JL, et al. 2007.; Lokhorst HM, et al. 2008.; Macro M, et al. 2006.; Morgan GJ, et al. 2007.; Sonneveld P, et al. 2008.; Richardson PG, et al. 2009.

Transplant Related Inductions: Improved VGPR Rates Post-ASCT

Transplant Related Inductions: Improved VGPR Rates Post-ASCT

Study(N)

Median age (yrs)

Regimen

RR (Post-induction) RR1 (Post-ASCT1) SurvivalCR%

>VGPR%

>PR%

CR1%

>VGPR1%

>PR1%

Median EFS

Harousseau IFM (424)

<65 VDVAD

21 8

CR+nCR

3916

82 65

3719

CR+nCR

5738

8479

69%*60%

Cavo (474)

<65 VTDTD

195

6231

4432

8065

----

85%* 75%

RajkumarE4A03 (445)

65 RDRd

54

71 26

8170

----

----

----

63%* 65%

Harousseau IFM (199)

58 vTDVD

3122

CR+nCR

5036

9081

6047

CR+nCR

6654

9284

NR

Transplant Related Inductions: Improved Survival Post-ASCT

Transplant Related Inductions: Improved Survival Post-ASCT

*significant difference

Transplant Eligible Data from ASH Transplant Eligible Data from ASH

34/35 pts had successful harvesting ASCT

8673975933RVDD60Jakubowiak Phase I/II (72)

93939193

59554760

20242240

CVRDVRDVCDmod-CVD

61Kumar EVOLUTION Phase I/II (140)

100100

7467

5739

NRRVDPhase IPhase II

Richardson Phase I/II (66/35)

Bortezomib dosing 1 mg/m2 in vTD arm

NRNR9284

6654

6047

CR+nCR

9081

5036

3122

CR+nCR

vTDVD

58HarousseauIFM (199)

*2 yr PFS Double ASCT performed

NS85%* 75%

8065

4432

6231

195

NRVTDTD

<65Cavo(474)

*2 yr PFS±1 yr OS

95.3%± 91.7%

69%*60%

8479

5738

3719

CR+nCR

82 65

3916

21 8

CR+nCR

NRVDVAD

<65HarousseauIFM (424)

Median OS

Median EFS

>PR1%

>VGPR1 %

CR1%

>PR%

>VGPR%

CR%

CommentsSurvivalRR1 (Post-ASCT1)RR (Post-induction)Median follow

up

Regimen

Median age (yrs)

Study(N)

Harousseau JL, et al. 2007; Cavo M et al. 2009, Abs 351; Harousseau J-L, et al. 2009, Abs 354;Richardson PG, et al. 2009, Abs 1218; Kumar S, et al. 2009, Abs 127

Single vs. Tandem Auto TxSingle vs. Tandem Auto Tx

Attal, et al. 2003 IFM94 Single

Tandem

Cavo, et al. 2007 Bologna96 Single

Tandem

Sonneveld, et al. 2007 HOVON24

Single

Tandem

< 61

< 61

< 66

199

200

163

158

148

155

42

50

33

47

13

32

7-year

25

30

7-year

23

35

21

22

7-year

48

58

7-year

65

71

55

50

Patients(n)

OS(months)

EFS(months)

CR(%)

Age(years)

Yellow: P Value significantHOVON = Hematology Oncology Cooperative Group

Transplant in the Novel Therapy EraTransplant in the Novel Therapy Era

• High-dose melphalan is superior to standard MP & VAD– Randomized trials– Population-based results

• Transplant improves CR/VGPR rate– CR/VGPR correlates with improved PFS and OS– CR/VGPR pre- and post-transplant improves PFS and OS

• Tandem transplant benefits a subgroup of patients• Novel agents improve induction CR/VGPR rate• Post-transplant maintenance may improve CR/VGPR

and thereby PFS and OS

MP = melphalan, prednisoneBensinger, 2008.; Mehta, et al. 2008.

Impact of Therapy in Poor Prognosis Patients

Impact of Therapy in Poor Prognosis Patients

Prognostic FactorsPrognostic Factors

• β2m

• Del(13) or other chromosomal abnormalities t(11;14) or t(4;14)

• CRP

• LDH

• Circulating plasma cells– Plasma cell labeling index

• Plasmablastic morphology

• Increased angiogenesis

β2m = β2microglobulin; Del(13) = deletion 13; CRP = C-reactive protein

NCCN. 2009 Guidelines. Multiple Myeloma.; Jakob C, et al. Blood. 2007;109:2100-2105.

IFM Analysis of Cytogenetics/β2m on Survival After Tandem ASCT

IFM Analysis of Cytogenetics/β2m on Survival After Tandem ASCT

FISH−, β2m <4

del13, β2m <4

FISH−, β2m >4

del13, β2m >44;14,17p, β2m <4

4;14,17p, β2m >4

Avet-Loiseau H, et al. Blood. 2007;109:3489-3495.

0 10 20 30 40 50 60 70

0.00

0.25

0.50

0.75

1.00

Months

Pro

bab

ility

of

Su

rviv

al

BMP: Consistent Efficacy in Patients With Poor Prognostic CharacteristicsBMP: Consistent Efficacy in Patients With Poor Prognostic Characteristics

CrCl < 60 vs. ≥ 60 mL/min

Age ≥ 75 vs. < 75 years

High-risk t(4;14),

t(14;16), del(17p) vs.

standard-risk cytogenetics

by FISH

TTP OSS

ubje

cts

with

out

eve

nt

(%)

Time (months)

Age < 75 years (N = 237): 23.1 months (59 events)Age ≥ 75 years (N = 107): median not reached (24 events)HR = 0.956 (95% CI: 0.579, 1.579), P = .86

Age < 75 yearsAge ≥ 75 years

Standard risk (N = 142): 23.1 months (34 events)High risk (N = 26): 19.8 months (7 events)HR = 1.297 (95% CI: 0.55, 3.06), P = .55

Standard riskHigh risk

BMP = bortezomib, melphalan, prednisone.Dimopoulos MA, et al. Haematologica. 2008;93:1420-1422.; San Miguel J, et al. J Clin Oncol. 2008;26:2761-2766.

Age < 75 years (N = 237): median not reached (44 events)Age ≥ 75 years (N = 107): median not reached (31 events)HR = 1.572 (95% CI: 0.975, 2.535), P = .0614

Standard risk (N = 142): median not reached (29 events)High risk (N = 26): median not reached (6 events)HR = 1.104 (95% CI: 0.444, 2.743), P = .8311

100

80

60

40

20

00 2 4 6 8 10 12 14 16 18 20 22 24 26

CrCI ³ 60 mL/minCrCI < 60 mL/min

Sub

ject

s w

itho

ute

ven

t (%

)

Time (months)

100

80

60

40

20

00 2 4 6 8 10 12 14 16 18 20 22 24 26

Sub

ject

s w

itho

ute

ven

t (%

)

Time (months)

100

80

60

40

20

00 2 4 6 8 10 12 14 16 18 20 22 24 26

Sur

viva

l dis

trib

utio

nfu

nct

ion

(%

)

Time (months)

Standard riskHigh risk

1.00

0.75

0.50

0.25

0.00

Sur

viva

l dis

trib

utio

nfu

nct

ion

(%

)S

urvi

val d

istr

ibu

tion

fun

ctio

n (

%)

1.00

0.75

0.50

0.25

0.00

1.00

0.75

0.50

0.25

0.00

CrCI ≥ 60 mL/min (N = 159): 21.7 months (43 events)CrCI < 60 mL/min (N = 185): median not reached (40 events)HR = 0.666 (95% CI: 0.416, 1.066), P = .09

0 4 8 12 16 20 24 28 32 36

Time (months)

0 4 8 12 16 20 24 28 32 36

Time (months)0 4 8 12 16 20 24 28 32 36

Age < 75 yearsAge ≥ 75 years

CrCI ≥ 60 mL/min (N = 159): median not reached (31 events)CrCI < 60 mL/min (N = 185): median not reached (44 events)HR = 1.205 (95% CI: 0.725, 2.005), P = .4714

CrCI ³ 60 mL/minCrCI < 60 mL/min

Bortezomib/Thal/Dex vs. Thal/Dex as Induction Therapy: Efficacy in High-Risk Groups

Bortezomib/Thal/Dex vs. Thal/Dex as Induction Therapy: Efficacy in High-Risk Groups

Cavo M, et al. Blood (ASH Annual Meeting Abstracts) 2007;110:73.

0

10

20

30

40

50

Del(13) t(4;14)

TD (N=95)BTD (N=92)

27%

43%

32%

47%43%

4%

47%

8%

- + - +Del(13) t(4;14)+ + + +

P=.06P=.01

P<.001P=.002

% C

R/n

CR

OS After Double Stem Cell TransplantOS After Double Stem Cell Transplant

0 22 44 66 88

Months after 1st transplantation

0

25

50

75

100

OS

(%

)

A. VGPR after 1st transplantation

Double transplant (n = 46)

Single transplant(n = 81)

0 22 44 66 88

Months after 1st transplantation

0

25

50

75

100

OS

(%

)

B. Absence of VGPR after 1st transplantation

Double transplant(n = 128)

Single transplant(n = 84)

Attal, et al. 2003.

P = .7 P < .001

•Tandem transplant only appears to help those who fail to achieve a VGPR with first transplant

Impact of Response on Outcome: OS After 1 or 2 Transplants

Impact of Response on Outcome: OS After 1 or 2 Transplants

N=849

IFM 99 trials courtesy of JL Harousseau.Harousseau JL, et al. Blood. (ASH Annual Meeting Abstracts) 2006;108:3077.

P=0.0002CR

VGPR

PR

<PR

0 1 2 3 4 5 6 7 80.00

0.25

0.50

0.75

1.00

Median follow-up

Summary of Impact of Therapy in Poor Prognosis Patients

Summary of Impact of Therapy in Poor Prognosis Patients

• Therapy with MP plus bortezomib improves outcomes (TTP, OS) for many poor prognostic characteristics– Age– Renal impairment– High-risk cytogenetics

t(4;14), t(14;16), del(17p) vs. standard-risk cytogenetics by FISH

Post-ASCT Maintenance in Newly Diagnosed MM

Post-ASCT Maintenance in Newly Diagnosed MM

• Does maintenance therapy prolong survival (PFS, OS) and does the choice of maintenance therapy make a difference?– If so, who should get treatment, for how long, and at what

dose schedule?

• NCCN Recommended Maintenance therapies [NCCN (v.1.2011)]– Interferon (category 2B) – Lenalidomide (category 2A) – Steroids (category 2B) – Thalidomide (category 1)– Thalidomide + prednisone (category 2B)

InterferonInterferon

• Currently considered a maintenance option in the NCCN Clinical Practice Guidelines in Oncology for MM (v.1.2011)

• The recommendation is based on low-level of evidence and non-uniform consensus (category 2B)

• Given the lack of clear activity and substantial toxicity associated with interferon as well as availability of new agents, research into interferon as maintenance has largely been abandoned (one recent study in combination with thalidomide)

Badros AZ. J Natl Compr Canc Netw. 2010;8 Suppl 1:S21-27.

Thalidomide-based Maintenance Therapy After ASCT

Thalidomide-based Maintenance Therapy After ASCT

• Thalidomide is the best studied of the novel agents in the post-ASCT maintenance setting

• Four randomized phase III trials have been completed to establish the role of thalidomide based maintenance after ASCT

Barlogie B, et al. N Engl J Med. 2006;354:1021-1030.; Attal M, et al. Blood. 2006;108:3289-3294.; Abdelkefi A, et al. Blood. 2008;111:1805-1810.; Spencer A, et al. J Clin Oncol. 2009;27:1788-1793.

Four Trials Have Evaluated Thalidomide as Maintenance Therapy After ASCT

Four Trials Have Evaluated Thalidomide as Maintenance Therapy After ASCT


Overall Survival with Maintenance Thalidomide Post-ASCT

Overall Survival with Maintenance Thalidomide Post-ASCT

A= All trialsB= All trials excluding Barlogie 2006

Adapted from Hicks LK, Haynes AE, Reece DE, et al. A meta-analysis and systematic review of thalidomide for patients with previously untreated multiple myeloma. Cancer Treat Rev. 2008;34:442-452, with permission from Elsevier.


Summary of Four Published Trials Examining Thal Maintenance Post-ASCT

Summary of Four Published Trials Examining Thal Maintenance Post-ASCT

• Improvements in response, and PFS in all 4 trials• Of the 4 trials, 3 also reported significant improvements

in OS– Meta-analysis showed trend toward improved survival1

• TiPN complicated the treatment course of all 4 studies– Incidence of peripheral neuropathy increased with prolonged tx

• Update to one trial (median f/u 6 years: may benefit high- risk patients2

– OS 56% in patients with cytogenetic abnormalities treated with thal vs. 43% with abnormalities in the control group (P =.02)

• Most benefit in patients who achieved only a PR3

– If thalidomide used in induction therapy, consider different maintenance therapy

1Hicks LK, et al. Cancer Treat Rev. 2008;34:442-452. 2Barlogie B, et al. Blood. 2008;112:3115-3121. 3Attal M, et al. Blood. 2006;108:3289-3294.

More Recent Trials Examining Thalidomide Maintenance After ASCT

More Recent Trials Examining Thalidomide Maintenance After ASCT

• Results from other randomized trials with thalidomide maintenance reported over the past 1.5 years have not supported improvement in OS– The United Kingdom Medical Research Council

(MRC) Myeloma IX study (largest study to date) Two arms: thalidomide maintenance (100 mg/d) or no

maintenance until relapse after primary treatment of myeloma (either ASCT or conventional chemotherapy, depending on the clinical situation) (n=820)

Morgan GJ, et al. (ASH Annual Meeting Abstracts). Blood. 2008;656.

Thalidomide Maintenance After ASCT MRC Myeloma IX Study

Thalidomide Maintenance After ASCT MRC Myeloma IX Study

• PFS was numerically higher in the thalidomide arm, but the improvement was statistically significant only among patients who experienced less than a VGPR with induction therapy (HR, 1.9; P =.007)

• OS was not significantly improved in any subgroup• Subgroup analyses showed that patients with 17p

deletions had a significantly worse OS when treated with thalidomide maintenance (HR, 4.55; P =.02)– Researchers concluded that 17p deletion is a contraindication to

thalidomide maintenance

Morgan GJ, et al. (ASH Annual Meeting Abstracts). Blood. 2008;656.

• Two small studies presented at the XII International Myeloma Workshop in 2009 showed significant improvements in PFS, but not OS, with thalidomide-based maintenance – Mounier, et al., compared an intermittent dexamethasone/

thalidomide maintenance regimen with no maintenance after ASCT (n=108)

Median event-free survival of 32 vs. 17 months (P =.02)– Maiolino, et al., compared dexamethasone maintenance with

dexamethasone plus thalidomide, 200 mg daily, after ASCT (n=212)

Thalidomide significantly reduced the risk for progression relative to dexamethasone alone (HR, 2.43; P =.03)

OS was similar in the 2 arms (65% vs. 74% with dexamethasone and dexamethasone/thalidomide, respectively)

Mounier MM, et al. Presented at the XII International Myeloma Workshop; February 26-March 1, 2009; Washington, DC.; Maiolino A, et al. Presented at the XII International Myeloma Workshop; February 26-March 1, 2009; Washington, DC.

Maintenance Therapy in Newly DiagnosedMaintenance Therapy in Newly Diagnosed

• Randomized trials of lenalidomide and bortezomib maintenance therapy are underway

Ongoing Randomized Phase III Trials of Maintenance Therapy After ASCT in Patients

With Newly Diagnosed MM

Ongoing Randomized Phase III Trials of Maintenance Therapy After ASCT in Patients

With Newly Diagnosed MM


ASCO 2010: Two Randomized Trials Examining Lenalidomide After ASCT Show Improved PFS ASCO 2010: Two Randomized Trials Examining Lenalidomide After ASCT Show Improved PFS

• Cancer and Leukemia Group B Study 100104 (CALGB 100104)1 and IFM 2005/022

– CALGB phase III study [n=418] designed to evaluate the efficacy and safety of lenalidomide (10 mg/d escalated to 15 mg/d after 3 months) [n=210] versus placebo [n=208] maintenance therapy following single ASCT in patients with MM until progression (dose-reductions allowed)

Lenalidomide was associated with a 58% reduction in the risk of disease progression

Overall median TTP was 25 months for the placebo group; not reached in the lenalidomide group

Stratification by beta-2 microglobulin and previous thalidomide or lenalidomide exposure during induction demonstrated a benefit for lenalidomide over placebo in each stratification

After a median follow-up of 1 year post-ASCT, there is no difference in overall survival between treatment groups

1McCarthy PL, et al. J Clin Oncol. 2010;28:7s (abstract 8017). 2Attal M, et al. J Clin Oncol. 2010;28:7s (abstract 8018).

ASCO 2010: Two Randomized Trials Examining Lenalidomide After ASCT Show Improved PFSASCO 2010: Two Randomized Trials Examining Lenalidomide After ASCT Show Improved PFS

• IFM 2005/02 [n=614]– Consolidation with lenalidomide (25 mg/d, 21 days/month, for 2 months)

followed by a maintenance with either lenalidomide (10 to 15 mg/d) until relapse (arm A) or placebo (arm B)

– First pre-planned interim analysis (median f/u 24 months) Independent data and safety monitoring committee recommended to unblind

the trial due to the PFS superiority of arm B (primary endpoint) Consolidation improved the response in 20% of patients Maintenance with lenalidomide improved the 3-year PFS from randomization:

35% in arm A vs. 68% in arm B (HR=0.46, P<10-6)– Observed both among patients achieving or not achieving a complete response

after ASCT Multivariate analysis

– PFS was related to response after consolidation, beta-2 microglobulin at diagnosis, and treatment arm

– A strong interaction (P<.04) was found between the efficacy of arm B and beta-2 microglobulin (HR=0.3, P<10-4 for beta-2 microglobulin 3 mg/L; HR=0.58, P<.003 for beta-2 microglobulin > 3 mg/L)

The 2-year survival was similar in both treatment arms (95%)

McCarthy PL, et al. J Clin Oncol. 2010;28:7s (abstract 8017). Attal M, et al. J Clin Oncol. 2010;28:7s (abstract 8018).

ASCO 2010: Two Randomized Trials Examining Lenalidomide After ASCT Show Improved PFSASCO 2010: Two Randomized Trials Examining Lenalidomide After ASCT Show Improved PFS

• Both trials show lenalidomide maintenance after SCT improves PFS

• No improvement in OS observed (yet)• Neither of these studies addressed questions regarding:

1) Duration of therapy

2) Benefit for patients in CR after ASCT

3) Early versus later intervention

4) Issues related to the depth of CR

• Lenalidomide appears to be a reasonable choice if the clinical goal is to improve progression-free survival in post-ASCT patients

McCarthy PL, et al. J Clin Oncol. 2010;28:7s (abstract 8017). Attal M, et al. J Clin Oncol. 2010;28:7s (abstract 8018).

Induction Therapy in Elderly Patients

Induction Therapy in Elderly Patients

•Primary induction therapy for non-transplant candidates–Bortezomib/dexamethasone [BD aka VD] (category 2A)

–Dexamethasone (category 2B)

–Lenalidomide/low-dose dexamethasone (category 1)

–Liposomal doxorubicin/vincristine/dexamethasone [DVD] (category 2B)

–Melphalan/prednisone (category 2A)

–Melphalan/prednisone/bortezomib [MPB] (category 1)

–Melphalan/prednisone/lenalidomide [MPL] (category 2A)

–Melphalan/prednisone/thalidomide [MPT] (category 1)

–Thalidomide/dexamethasone (category 2B)

–Vincristine/doxorubicin/dexamethasone [VAD] (category 2B)

NCCN-listed myeloma therapies (v.1.2011, released 7/2010)

Melphalan in Elderly PatientsMelphalan in Elderly Patients

• Progression-free survival is increased in MPT compared to MP

• OS?– IFM 99-06 trial showed overall survival advantage in MPT

compared to MP1 as did the recently reported IFM 01/01 trial2

– An Italian study did not show OS in MPT compared to MP3 and neither did a second study4

• MPT currently appears to be the therapy of choice for elderly patients not eligible for autologous stem cell transplant, but toxicity must be managed

• Increased toxicity associated with MPT: peripheral neuropathy most frequently reported adverse event

1Facon T, et al. Lancet. 2007;370:1209-1218. 2Hulin C, et al. Clin Oncol. 2009 27:3664-3670. 3Palumbo A, et al. Blood. 2008;112:3107-3114. 4Waage A, et al. Blood (ASH Annual Meeting Abstracts) 2007;110:78.

Induction for Elderly PatientsInduction for Elderly Patients

CommentsSurvivalRR

HR PFS 0.499 MPR+Rm vs. MP P=.001; HR PFS 0.530 MPR+Rm vs. MPR; P=.002*1 yr OS MPR+Rm vs. MP; NS

80%*64%HR 1.4P =.1

34 m23 mHR 1.3P =.1

8083

3237

2027

2473130130

VMP→VTm/VPmVTP→VTm/VPm

Mateos PETHEMA (ASH 2009)

89.2%+88.8%P=NS

60%*42%P =.007

8981

5950

3824

21.671254257

VMPT→VTm MPV

Palumbo (ASH 2009)

92%*NR13.212

776749

323311

18135

9.471152153154

MPR→RmMPRMP

Palumbo (ASH 2009)

8147.623.8

7154MPRPalumbo Phase I/II (2007)

Median OS

Median EFS

?PR%

?VGPR %

CR %

Median follow-up (m)

Median age (yr)

NRegimenStudy Year

Novel Based-Agent Combinations for Elderly MM Patients

Novel Based-Agent Combinations for Elderly MM Patients

Study Regimen N CR (IF-)TTP

PFS/EFSOverall Survival

Palumbo (Blood 2008)

MPT (T maint.)MP (no maint.)

129126

16%4%

21.8m14.5m

NS (45m vs. 47.6m P=.79)

Facon (Lancet 2007)

MPT (72 weeks)MP (72 weeks)

125196

13%2%

27.5m17.8m

51.6m vs. 33.2mHR = 0.59, P=.0006

Hulin (JCO 2009)

MPT (72 weeks)MP (72 weeks)

113116

7%1%

24.1m19m

45.3m vs. 27.7mHR n/a, P=.03

Wijermans (ASH 2008)


165168

2%2%

13m10m

NS (37m vs. 30mP=.16)

Gulbrandsen (EHA 2007)


363 6%3%

20m18m

NS (29m vs. 33mP=.46)

Palumbo (JCO 2007)

LenMP (Phase I/II) 54 24% 1-y EFS: 92% 1-y OS: 100%

Rajkumar (Lancet Onc 2009)

RDRd

445 13%10%

19m25m

1-y OS: 83% vs. 94%In elderly patients

San Miguel (ASH 2009)

VMP (54 weeks)MP (54 weeks)

344338

30%4%

24.0m16.6m

NR vs. 43 monthsHR 0.653P=.0008

The Weekly Infusion of Bortezomib Reduces Peripheral Neuropathy in Elderly Patients

The Weekly Infusion of Bortezomib Reduces Peripheral Neuropathy in Elderly Patients

Bortezomib twice weekly

( N = 135)

Bortezomib once weekly

(N = 315)

P-value

All grade PN (%) 45 27 0.0002

Grade 3-4 PN (%) 16 3 <0.0001

Drug discontinuation (%) 13 3 0.001

Dose reduction (%) 39 12 <0.001

CR rate (%) 33 25 0.07

2-years PFS (%) 68 60 0.31

2-years OS (%) 91 89 0.44

Gay F, et al. Blood (ASH Annual Meeting Abstracts) 2009;114(22):3887.

• Safety and efficacy for the twice-weekly or weekly bortezomib schedule. The VMPT and VMP groups are together

MV Mateos, A Oriol, J Martínez, MT Cibeira, R de Paz, MJ Terol, J García-Laraña,

E Bengoechea, R Martínez, A Martín, F de Arriba, L Palomera, JM Hernández,

JL Bello, ML Martín, Y González, JJ Lahuerta, J Bladé, JF San Miguel.

On behalf of Spanish Myeloma Group (PETHEMA/GEM)

Multicenter, Randomized Trial in Newly Diagnosed Multiple Myeloma Patients Older

Than 65 Years (GEM05>65)

Multicenter, Randomized Trial in Newly Diagnosed Multiple Myeloma Patients Older

Than 65 Years (GEM05>65)

Rationale and Key QuestionRationale and Key Question

• Phase I/II study: bortezomib plus MP (VMP)– 89% ≥PR with 32% CR rate1

– Median progression-free survival (PFS) was 25 months2

– Median OS was 50 months (vs. 29 months for historical MP)– VMP was well tolerated: G3-4 peripheral neuropathy: 17%1,2

1Mateos, et al. Blood. 2006;108:2165-2172.2Mateos, et al. Haematologica. 2008;93:560-565.

Can we maintain the efficacy and reduce the toxicity

with a less intensive bortezomib-based approach?

(GEM05>65)

Maintenance

Bort/Thal

(VT)

Bort/Pred

(VP)Bort/Thal

(VT)

Bort/Pred

(VP)

Induction Bort/Mel/Pred

(VMP)

Bort/Thal/Pred

(VTP)vs.

Multicenter, Two-Stage Randomized Trial in Newly Diagnosed MM Patients Older Than 65 Years

Multicenter, Two-Stage Randomized Trial in Newly Diagnosed MM Patients Older Than 65 Years

(GEM05>65)

Bortezomib 1.3 mg/m2

Melphalan 9 mg/m2

Prednisone 60 mg/m2

Day

1 2 3 4 8 11 22 25 29 32 33–42

█ █ █ █ █ █ █ █

█ █ █ █

█ █ █ █

Rest period

One 6-week cycle

Five 5-week cycles


Melphalan 9 mg/m2

Prednisone 60 mg/m2

Day

1 2 3 4 8 15 22 23–35

█ █ █ █

█ █ █ █

█ █ █ █

Rest period

31 weeks

Induction A: VMP (n:130) Induction A: VMP (n:130)

(GEM05>65)

Day

1 2 3 4 8 11 15 22 25 29 32 33–42

█ █ █ █ █ █ █ █

█ █ █ █

Day

1 2 3 4 8 15 22 23–35

█ █ █ █

█ █ █ █

31 weeks


Thalidomide

Prednisone 60 mg/m2

Rest period

One 6-week cycle

Five 5-week cycles


Thalidomide

Prednisone 60 mg/m2

Rest period

50 mg 100 mg

100 mg

Induction B: VTP (n:130) Induction B: VTP (n:130)

(GEM05>65)

Efficacy: Response Rate After Induction Therapy (ITT Analysis in 260 Patients)

Efficacy: Response Rate After Induction Therapy (ITT Analysis in 260 Patients)

20%

12%

48%

10%8%

46%

6%11%

27%

10%

0%

10%

20%

30%

40%

50%

60%

CRIF- CRIF+ PR MR SD

VMP

VTP

ORR: 80% vs. 81%

*EBMT criteria

• Responses to VMP/VTP were rapid: Median time to achieve first response: 1.6 m

• Prolonged therapy improves the quality of response: Median time to achieve CR:

VMP: 4.4 / VTP: 4.9 m

Only two patients in each arm progressed during induction

(GEM05>65)

VMP vs. VTP: Toxicity Profile (G3-4 AEs) (n:260)

VMP vs. VTP: Toxicity Profile (G3-4 AEs) (n:260)

Hematologic toxicity

- Anemia 15 (11%) 10 (8%) P NS

- Neutropenia 51 (39%) 29 (22%) P=.008

- Thrombocytopenia 35 (27%) 16 (12%) P=.0001

Non-hematologic toxicity

- GI toxicities 9 (7%) 2 (2%) P NS

- PN 9 (5%) 12 (9%) P NS

- Infections 9 (7%) 1 (<1%) P=.01

- DVT/thromboembolism 1(<1%) 3 (2%) P NS

- Cardiologic events* _ 11 (8%) P=.001

VMP (n:130) VTP (n:130)

Patients discontinuing due to SAEs, n (%) 15 (11%) 22 (17%) P=.03

Deaths, n (%) 7* (5%) 7** (5%) P NS

*5/7 in VMP: infections**5/7 in VTP: cardiac complications (GEM05>65)

Conclusions from this StudyConclusions from this Study

• Alkylating agents should remain as important drugs in the treatment armamentarium of elderly untreated elderly MM patients

• The weekly schedule of bortezomib reduced the incidence of PN

• Maintenance therapy was able to increase the CR rate with a low toxicity profile. VT was superior in terms of TT events

• The combination of VMP followed by VT is significantly superior to VTP/VP

• These novel bortezomib-based schemes appear to overcome the poor prognosis of high-risk cytogenetic abnormalities

Mateos M-V, et al. Blood (ASH Annual Meeting Abstracts) 2009;114(22):3. (GEM05>65)

MPL (MPR) +/- L (R) in Newly Diagnosed Elderly Patients (MM-015)


• Ongoing study, first interim intent to treat (ITT) analysis reported at ASH 2009 (n=469), <10 months examining upfront, MPL-L, MPL-placebo vs. MP-placebo– MPL (9-cycles) followed by L (lenalidomide 10 mg/day until progression)– MPR with no continuous R– MP with no maintenance therapy

All patients ≥65, median age of 71 years– 25% were older than age 75

The three treatment arms were well matched for baseline characteristics, with about half the subjects in each arm considered at high risk

Received aspirin thromboprophylaxis, lenalidomide extension phase of trial was open label

• Primary endpoint: PFS– Secondary endpoint: OS, TTP, RR, TTR, DoR, time to next therapy,

safety, QoL, assessment of cytogenetic abnormalities

Palumbo A, et al. Blood (ASH Annual Meeting Abstracts). 2009;114(22):613.



• MPR-R reduced the risk of progression by 47% compared with MPR (f/u 9.4 months)

• Median PFS for MPR-R (not reached); 13.2 months with MPR (P=.002)

• MPR-R vs. MP: risk of progression reduced by 50% (P<.001), and need for next treatment was reduced by 63% (P<.001)

• No significant differences in PFS between MPL-placebo and MP (more time needed)

P<.001 for MPL-L vs. MP

NS for MPL vs. MP

77%67%49%ORR

(P<.001 for MPR-R vs. MP) 32%33%11% ≥VGPR

P<.001 for MPL-L vs. MP 18%13%5%CR

P-ValueMPR-LMPLMPTreatment

Palumbo A, et al. Blood (ASH Annual Meeting Abstracts). 2009;114(22):613.



• Grade 3 or 4 thrombocytopenia occurred in 10% and grade 4 neutropenia in 36% (7% febrile neutropenia) with MPL-L (not seen with MP)

• No grade 3 or 4 peripheral neuropathy was observed in any of the arms– 1% of MPR-R subjects developed grade 2 neuropathy

• Granulocyte colony-stimulating factor (G-CSF) was given to 50% of patients in the MPR-R arm versus 29% of those who got MP

• Discontinuation due to adverse events was reported in 16% of MPR-R patients versus 7% of MP patients– Discontinuations due to hematologic adverse events were seen in 7%

and 2%, respectively

Summary of Recent Updates on Myeloma

With Impact on Clinical Practice

Summary of Recent Updates on Myeloma

With Impact on Clinical Practice• What is the best therapy for newly diagnosed MM?

– Transplant eligible: three-drug combinations, ie, BTD (VTD), LBD (RVD), CyBorD

– Transplant ineligible: MPB, MPL or MPT (MPB provides more rapid and higher response rates than MPT) extended tx with lenalidomide in MPL significantly increases PFS; BD after MPB?

– BD and Ld are acceptable alternatives – MP and TD suboptimal

• Does choice of initial therapy matter? Yes– Age, high-risk patients, renal impairment

• Have novel therapies improved the outcome of transplant? Yes

Case ofNewly Diagnosed Multiple Myeloma: The Low-Risk Patient

Case ofNewly Diagnosed Multiple Myeloma: The Low-Risk Patient

Newly Diagnosed PatientNewly Diagnosed Patient

• The patient is a 61-year-old Caucasian female • History of high blood pressure which is under

control with diuretic, but otherwise in good general health

• The disease was detected after the patient tripped on a curb and suffered a vertebral compression fracture– Patient is now ambulatory after kyphoplasty and is on

treatment with bisphosphonates


• Laboratory Results– β2-microglobulin: 3.8 mg/L– Serum albumin 3.6 g/dL

– Hemoglobin 11 g/dL– Calcium 8.0 mg/dL– Creatinine 1.1 mg/dL– Multiple lytic bone lesions on bone survey, magnetic resonance imaging

shows multiple heterogeneous marrow lesions– SPEP 4.3 g/dL M-component protein IgG λ

– 21% plasma cells by bone aspirate with diploid cytogenetics– FISH: Showed 30% t(11;14)

Durie-Salmon Stage IIIa

ISS Stage II

ISS CriteriaStage Iβ2-microglobulin <3.5 g/dLSerum albumin ≥3.5 g/dL stage II:Serum β2-microglobulin <3.5 mg/LButSerum albumin <3.5 g/dLOrSerum β2-microglobulin 3.5-5.5 mg/L irrespective of the serum albumin level Stage IIIβ2-microglobulin ≥5.5 g/dL


• How would you manage this patient’s myeloma?– Consider whether the patient is a transplant candidate

Stem cell harvest and transplant: timing Choice of induction therapy

– These are only examples: bortezomib/dexamethasone; lenalidomide/dexamethasone†*; bortezomib/thalidomide/dexamethasone, lenalidomide/bortezomib/dexamethasone

Maintenance therapy–If yes–which, how long, dose?

– Risk factors, comorbidities and MM associated sequelae and management of potential treatment-related side effects

*Lenalidomide is not currently approved by the FDA for use as first-line therapy in multiple myeloma

†Lenalidomide/dexamethasone recommendation category I: NCCN guidelines for myeloma (v.3.2010)

• Outline your prognosis, risk-assessment, and response criteria

Case ofNewly Diagnosed Multiple Myeloma: The High-Risk Patient

Case ofNewly Diagnosed Multiple Myeloma: The High-Risk Patient



• 58-year-old black man seen in the ER after awakening with headache followed by diffuse bony aches and pains – Hematocrit 20

• Admitted for further evaluation• History past six months:

– 30 pound weight loss– Increasing fatigue– Nausea and malaise– Mild nosebleeds

• Previous health good except for hypertension• No siblings



• Laboratory results– β2-microglobulin 3.4 mg/L– Albumin 2.2 g/dL

– Hemoglobin 10.8 g/dL– Calcium 8.0 mg/dL– Creatinine 1.0 mg/dL– SPEP 6.2 g/dL M-component protein IgA λ– Skeletal survey normal

– Nucleated RBC, rouleaux– Circulating plasma cells– Platelets 120,000/L– Urine 1+ protein, 2+ RBC – PT/PTT normal

– Marrow 90% plasma cells– Conventional cytogenetics hypodiploid – FISH positive for t (4;14)

ISS Stage II

Durie-Salmon Stage IIIa

Stage II:Serum β2-m <3.5 mg/LButSerum albumin <3.5 g/dL

• How would you manage this patient’s myeloma?– Consider whether the patient is a transplant candidate

Stem cell harvest and transplant: timing

Choice of induction therapy

Maintenance

– Risk factors, comorbidities and MM associated sequelae and management of potential treatment-related side effects



• Receives bortezomib, cyclophosphamide and dexamethasone on a research study [Phase II V-CTD NCT00438841)

– Patients receive bortezomib 1.3 mg/m2 IV on days 1, 4, 8, and 11; cyclophosphamide 300 mg/m2 IV on days 1 and 8 of courses 1-3; beginning cycle 4 bortezomib reduced to 1.0 mg/m2 oral thalidomide 100 mg once daily on days 1-21 beginning in course 4; and dexamethasone 40 mg IV or orally once daily on days 1, 2, 4, 5, 8, 9, 11, and 12. Treatment repeats every 21 days for up to six courses in the absence of disease progression or unacceptable toxicity

• After cycle 1 creatinine jumps to 2.2 mg/dL (due to tumor lysis)– With hydration, alkalinization and allopurinol falls to normal

• After two more cycles M-component protein has fallen from 6.1 to 0.5 g/dL

• Per protocol receives bortezomib 1.0 mg/m2, thalidomide 100 mg/day with dexamethasone

– Dexamethasone is reduced from 40 to 12 mg due to hyperglycemia

• After completing 3 cycles of BTD, his M-component protein is undetectable

BTD=bortezomib, thalidomide, dexamethasone; V-CTD=bortezomib, cyclophosphamide, thalidomide, dexamethasone


• At this point, how would you manage this patient?– Observe

– Refer for stem cell collection Follow with autologous transplant? When, under what

circumstances, and why?

– Consolidation/maintenance therapy? Which, for how long, What dose schedule, What side effects to watch for?

– How is this patient different than the first patient?

• What therapeutic plan would you follow if this patient were 78?

DeliberationDeliberation

Participant Presentation of Management Summary

Participant Presentation of Management Summary

Question and Answer SessionQuestion and Answer Session

Update Impact on Practice: Novel Agents in Younger Patients

Update Impact on Practice: Novel Agents in Younger Patients

• Novel agents should be incorporated into induction regimen– Compared with VAD: Bort+Dex and Thal+Dex improve response

after induction; VAD is a suboptimal induction therapy no longer considered to be standard of care

– TD: Suboptimal induction therapy; Bort+Dex but not Thal+Dex improve response after ASCT and improves EFS; most evidence for Bort+Thal+Dex, Bort+Dex, Len+Dex better than Thal+Dex

– BD (VD): Good induction regimen; improved with addition of doxorubicin; excellent for high-risk patients, ie, adverse cytogenetics, renal failure, age etc; must monitor and dose-adjust as appropriate for PN

– LD (RD): Good induction regimen and convenient oral route; less data in adverse cytogenetic patients than bortezomib but accepted in high risk; requires dose adjustment in patients with renal impairment; affects stem cell collection; low G3/4 PN but need thromboprophylaxis


Update Impact on Practice: Novel Agents and SCT in Younger Patients


– BTD (VTD): Very good induction regimen, effective in high-risk patients; once-weekly bortezomib schedule maintains efficacy with reduced peripheral neuropathy

– LBD (RVD): Very good induction regimen, highest response rates to date, awaiting survival data

– BiRD: Very good induction regimen, high response rates, some promising survival data, need large, randomized trials

– Cyclophosphamide with BD or LD: Very good induction regimens; high response rates, CyBorD showed rapid and higher response prior to ASCT; post-ASCT both comparable with LD with current trial results, CRD may be more toxic

– Modified dosages and dose schedules of Cybord and BiRd maintain high response rates with improved toxicities–need survival data but these response rates approach those of LBD!

– Triple therapies containing novel drugs induce higher ORRs and CRs




• Transplant remains an important treatment option for eligible patients!– Tandem transplant – benefit seen only with patients who fail to

achieve a VGPR with first transplant

• Triple therapies and transplant – if it works for the bad, shouldn’t it be even better for the good…Can you make a CR even better? – Remember Rate, Depth, Durability of Response as well as

Improved Functional Status – Not Just CR!


Summary of Recent Updates on Myeloma With Impact on Clinical Practice-

Maintenance Therapy

Summary of Recent Updates on Myeloma With Impact on Clinical Practice-

Maintenance Therapy• Does maintenance therapy make a difference and if so, which one?

– Yes and No depending on your treatment goals, patient risk factors etc., so safe answer is TBD but initial response to therapy should not be used to guide maintenance treatment decisions at this time

Does improve PFS There is either no evidence (Len, Bort) or no consistent evidence (Thal) of OS

improvement– In some patients, thal (del p17, side effects) may do harm

Thal only appears to benefit those who do not achieve a VGPR post-ASCT– Maintenance still appears cytoreductive – Not convincingly getting at eradication of

minimal residual disease– Do we stop maintenance when we achieve a VGPR?

Lenalidomide may prove preferable to thalidomide (lower incidence of peripheral neuropathy, PFS may prove longer, OS ?)

Bortezomib-containing maintenance therapy regimens are also undergoing clinical trials

Optimal dose schedule, duration of therapy and selection of patients who may benefit most remain to be determined

Renal Complications:Considerations in Practice Update

Renal Complications:Considerations in Practice UpdateAnn F. Mohrbacher, MD Associate Professor of Clinical MedicineKeck School of MedicineUniversity of Southern California Los Angeles, California

Renal FailureRenal Failure

• Myeloma kidney: proximal and distal tubules obstructed by protein casts*

• Monoclonal deposition disease

• Hypercalcemia• Hyperuricemia: primary vs.

secondary to renal failure; tumor lysis rare

• Myeloma cells in the kidney• NSAIDs, ACE inhibitors• Infection• Amyloidosis• IV contrast dye

*Iggo N, et al. QJM. 1997;90:653-656.

Precipitating Events of Renal Failure in Multiple Myeloma

Precipitating Events of Renal Failure in Multiple Myeloma

Irish AB, et al. QJM. 1997;90:773-780.

N=56

Reversibility of Renal Failure and Outcome

Reversibility of Renal Failure and Outcome

• 25% recovered renal function Cr <1.3– Average recovered 1.6 months, 90% in <4 months

• 48% patients with Cr <3.5 recovered

• 8% patients with Cr >3.5 recovered

• Patients with hypercalcemia of Bence Jones Protein (BJP) <1 gm/24 hours more likely to recover

• Factors associated with renal function recovery– Degree of renal failure

– Presence of hypercalcemia

– Amount of proteinuria

• Response to chemotherapy and severity of renal failure were the only independent factors associated with survival

Bladé J, et al. Arch Intern Med. 1998;158:1889-1893.

N=94 (renal failure); N=329 (normal renal function)

Survival by Renal FunctionSurvival by Renal Function

RetrospectiveBladé J, et al. Arch Intern Med. 1998;158:1889-1893.

Summary Summary

• Response to chemotherapy and severity of renal failure affect survival

• Factors associated with renal function recovery– Degree of renal failure– Presence of hypercalcemia– Amount of proteinuria

• Patients with hypercalcemia more likely to recover renal function with treatment

• Patients with creatinine <3.5 are more likely to recover with treatment

Probability of RF Reversal According to Treatment High-Dose Dexamethasone Plus New Agents

Probability of RF Reversal According to Treatment High-Dose Dexamethasone Plus New Agents

• Renal failure (RF) was reversed in 73% of all patients within a median of 1.9 months

• In patients treated with dexamethasone and novel agents (thalidomide and/or bortezomib) the reversibility rate was 80% within a median of 0.8 months

• Severe RF and significant BJP were associated with a lower probability of RF reversal

• Patients who responded to treatment achieved RF reversal more often than in those who did not (85% versus 56%, P=.046)

Kastritis E, et al. Haematologica. 2007;92:546-549.

N=41

Thalidomide and/or Bortezomib

Impact of Renal Insufficiency on Time to Progression and Overall Survival*

Impact of Renal Insufficiency on Time to Progression and Overall Survival*

1Weber D, et al. J Clin Oncol. 2008;26:Abstract 8542. 2San Miguel JF, et al. Haematologica. 2007;Abstract PO-114.

*Not a head-to-head trial comparison

Patients with relapsed MM with varying degrees of renal impairment

None(ClCr > 80 mL/min)

Mild(50 ≤ ClCr ≤ 80

mL/min)

Moderate(30 ≤ ClCr < 50

mL/min)

Severe(ClCr < 30 mL/min)

Len+ Dex1

Bort2 Len + Dex1

Bort2 Len + Dex1

Bort2 Len + Dex1

Bort2

Patients, n 158 118 125 137 42 43 16 15

TTP median, months

11.3 6.3 12.1 6.2 11.4 5.6 7.9 4.2

OS median, months

NR NR 34.7 30.0 30.4 22.8 18.6 22.0

Reversing Renal Insufficiency in Newly Diagnosed MM with Novel Agents

Reversing Renal Insufficiency in Newly Diagnosed MM with Novel Agents

• Single center, 96 consecutive, newly diagnosed, patients with MM and RI, over 10 years, were evaluated.

• RI was defined as a sustained estimated creatinine clearance (CrCl) < 50 ml/min, calculated by the Cockroft-Gault formula, despite volume replacement and reversal of hypercalcemia

-Group A (n= 32) conventional chemo plus dexamethasone (VAD, VAD-like regimens, melphalan plus dexamethasone)-Group B (n=47) received IMiD-based regimens (Thal or Len with high-dose dexamethasone and/or cyclophosphamide or melphalan)-Group C (n=17) received bortezomib- and dexamethasone-containing regimens

High-dose dexamethasone was given at the standard dosage in all regimens and no low-dose dexamethasone was used in the study population. Besides antimyeloma treatment, all patients received supportive care: rigorous intravenous hydration, alkalization of urine, correction of hypercalcemia and discontinuation of all nephrotoxic agents. Renal dialysis was offered to all patients with an appropriate indication.

Roussou M, et al. Leuk Res. 2010 May 24. [Epub ahead of print].

Effect of ESRD on MM DrugsEffect of ESRD on MM Drugs

• Thalidomide toxicity unaltered except risk of severe thalidomide-associated hyperkalemia, especially in dialysis

– Pharmacokinetics of thalidomide in patients with renal failure similar to that in normal renal function

– Although clearance during dialysis is doubled, thalidomide dose need not be changed and no need for a supplementary dose due to dialysis

• Lenalidomide – can be used but careful dose adjustment and observation required

– Substantially excreted by the kidney; observation of the complete blood count (CBC) to minimize the potential for hematologic toxicity

– Dose adjustment recommendations are provided in PI

• Bortezomib – no need to dose adjust, clearance is independent of renal function

– Viable treatment option regardless of degree of renal impairment, including dialysis dependence

– Since dialysis may reduce bortezomib concentrations, the drug should be administered after the dialysis procedure

Mulkerin D, et al. Blood (ASH Annual Meeting Abstracts) 2007;110:3477.

Lenalidomide Starting Dose Adjustment for Renal Impairment

Lenalidomide Starting Dose Adjustment for Renal Impairment

Lenalidomide FDA Label.

Phase II Study Bortezomib-Doxorubicin-Dexamethasone

Phase II Study Bortezomib-Doxorubicin-Dexamethasone

• Recovery of renal function – 37 patients with MM-induced acute renal failure

17 patients with de novo MM; 20 with progressive disease

• Treatment: 21-day cycle: bortezomib 1.0 mg/m2, days 1, 4 ,8 ,11; doxorubicin 9 mg/m2, days 1, 4, 8, 11 (until safety analysis), then 9 mg/m2, days 1, 4; dex 40 mg, days 1, 4, 8, 11

Results

Evaluable Patients (n=22)

(GFR) (mL/min)

Tumor Response Baseline Best ResponseCR/nCR 12 18.2 (13-45) 62.5 (20-134)PR 4 25 (15-44) 81 (16-114)MR 3 17 (10-45) 35 (33-45)NC/PD 3 13 (4-15) 18 (11-25)

CR + PR 16 (73%) GFR > 75 mL/min: 9 (56%)

Ludwig H, et al. Blood (ASH Annual Meeting Abstracts) 2007;110:Abstract 3603.

Bortezomib Can Rapidly Reverse Renal Failure in Up to 50% of Patients

Bortezomib Can Rapidly Reverse Renal Failure in Up to 50% of Patients

Mohrbacher A, et al. 2005.; ASCO Annual Meeting Proceedings. 2005.

Ludwig H, et al. Haematologica. 2007.• Paraprotein induced renal failure is a frequent

complication of multiple myeloma and is associated with poor survival

• Above, shows reversal of acute paraprotein-induced renal failure by bortezomib-based therapy in 5 out of 8 newly diagnosed patients

See also case report: Gladney SP, et al. Clin Lymphoma Myeloma. 2008;8:52-54.

http://meeting.ascopubs.org/content/vol23/16_suppl/images/large/zlj113050341451t.jpeg

Treatment to Reverse Kidney ComplicationsTreatment to Reverse Kidney Complications

• Check uric acid– If elevated, administer allopurinol

• Rapid control of hypercalcemia with IV bisphosphonates and rehydration

• Initiation of rapidly acting chemo Rx, in combination with bortezomib and/or pulse Dex

• Colchicine? Reduces THP-BJP in lab• Plasmapheresis in acute renal of MM of

questionable value• Treat the disease with novel agents

Bone Complications:Appropriate Practices

Bone Complications:Appropriate Practices


Normal Bone Remodeling is a Coupled Process

Normal Bone Remodeling is a Coupled Process

New Directions for Preventing Bone LossNew Directions for Preventing Bone Loss

• Multiple myeloma– Cells responsible for bone resorption, osteoclasts,

are activated– Cells responsible for bone formation, osteoblasts

are inhibited

Osteoclasts Osteoblasts

Clinical Consequences of Myeloma Bone Disease


• Pathological fractures– Non-vertebral– Vertebral compression

• Spinal cord compression/collapse

• Radiation therapy• Surgery to bone• Hypercalcemia• Bone pain • Use of analgesics • Quality-of-life effects• Survival

Prevalence of Skeletal Complications in 21 Months Among MM Patients

Prevalence of Skeletal Complications in 21 Months Among MM Patients

†9-month data; ‡Placebo arm of pamidronate randomized trialBerenson JR, et al. N Engl J Med. 1996;334:488-493.; Berenson JR, et al. J Clin Oncol. 1998;16:593-602.

Patients With SREs, %‡

†

†

N=198 pamidronateN=179 placebo

0 10 20 30 40 50 60

Spinal cordcompression

Surgery to bone

Hypercalcemia ofmalignancy

Radiation tobone

Pathologicfracture

Total

Risk of Fracture at Specific SitesRisk of Fracture at Specific Sites

Thoracic/lumbar vertebrae 33

Ribs 15

Clavicle/scapula/sternum 13

Cervical vertebrae 7.4

Arm (other than humerus) 6.9

Pelvis 6.1

Humerus 1.8

Proximal femur 1.7

Site RR*

*RR = relative risk

Melton, et al. J Bone Mineral Res. 2004;20:3:487-493.

Tumor-Related VCFsSurgical Treatment

Tumor-Related VCFsSurgical Treatment

• Operative management– Vertebral column reconstruction– A or P decompression with internal fixation– Oncology patients are generally poor candidates

for open surgery due to soft bone/tumor mass and comorbidities

• Minimally invasive procedures– Vertebroplasty– Balloon kyphoplasty

VertebroplastyVertebroplasty

Source: Fourney DR, et al. J Neurosurg (Spine 1). 2003;98:21-30.

Kyphoplasty: A Minimally Invasive Fracture Reduction Procedure

Kyphoplasty: A Minimally Invasive Fracture Reduction Procedure

KyphX Introducer Tool Kit: • Allows precise, minimally invasive access to the vertebral body • Provides working channel

KyphX IBT inflation:• Reduces the fracture• Compacts the bone• May elevate endplates

KyphX IBT Removal:• Leaves a defined cavity and trabecular dam that can be filled with an approved bone void filler of the physician’s choice

CAFE:CAncer Patient Fracture Evaluation

CAFE:CAncer Patient Fracture Evaluation

• Randomized trial of balloon kyphoplasty vs. non-surgical management in patients with cancer-related vertebral compression fractures (VCFs)

• Patients enrolled within three months of diagnosis of VCF

• One year follow-up, optional crossover at one month

• Data is from preplanned one month interim analysis of this ongoing study

Berenson, et al. ASH 2008.

Roland-Morris Back DisabilityRoland-Morris Back Disability

• BKP showed significantly greater improvement– Mean improvement from baseline, -8.3 points (95% CI -6.2, -10.5; P<.0001)– Change exceeded the 2.5 point minimally clinically important difference

• No significant change with the control group – Mean improvement from (-0.1 points, 95% CI 0.9, -1.0)

0

4

8

12

16

20

24

Baseline 1 Month

Ro

lan

d-M

orr

is S

co

re

BKP

NSM

Roland-Morris Back Disability

0

4

8

12

16

20

24

Baseline 1 Month

Ro

lan

d-M

orr

is S

co

re

BKP

NSM

Roland-Morris Back Disabilityp<0.0001

N=56N=59 N=47N=53

Level for the 2.5 MCID from baseline

Back Pain (VAS)Back Pain (VAS)

• BKP provided statistically significant reduction of pain within 7 days– Mean improvement from baseline, -4.1 points (95%CI -3.2, -4.9; P<.0001) at

one month– Change exceeded the 2-point minimally clinically important difference

• Pain scores in control patients did not improve– Mean improvement from baseline, -0.5 points (95%CI 0.04, -1.0) at one month

0

2

4

6

8

10

0 30Days

NR

S P

ain p<0.0001 p<0.0001

Back Pain

70

2

4

6

8

10

0 30

NSM

BKP

p<0.0001 p<0.0001

Back Pain

70

2

4

6

8

10

0 30

NSM

BKP

7

Level for the 2-point MCID from baseline

p<0.0001

p<0.0001



• Pathological fractures– Non-vertebral– Vertebral compression

• Spinal cord compression/collapse• Radiation therapy• Surgery to bone• Hypercalcemia• Bone pain • Use of analgesics • Quality-of-life effects• Survival

SREs*

*SREs = skeletal-related events

Potential Mechanisms of Action of Bisphosphonates

Potential Mechanisms of Action of Bisphosphonates

Osteoclast Bisphosphonate

Plasma cell

Stroma

IL-6

Apoptosis Blocks maturation Recruitment

OH R1 OH

OH R2 OH

P C P OO

Apoptosis

Mevalonate

Isoprenylation of proteins

Savage A. Blood. 1996;88:105a.; Hyghes DE. J Bone Min Res. 1995;10:1478.

Relative R1 R2

potency

Etidronate OH – CH3 1

Clodronate Cl – Cl 10

Tiludronate H – S – – Cl 10

Pamidronate* OH –(CH2)2 – NH2 100

Alendronate OH –(CH2)3 – NH2 1,000

Risedronate H –CH2 – N

5,000

Ibandronate OH (CH2)2-N-(CH2)4-CH3 10,000

CH3

Zoledronic acid* OH –N N 100,000

no N

N

Inhibitors of bone loss; potency varies greatly depending upon R1 & R2 side chains

OH R1

OH R2 OH

P C P O

OH

O

BisphosphonatesBisphosphonates

*FDA approved for hypercalcemia of malignancy and patients with osteolytic lesions of multiple myeloma in conjunction with standard antineoplastic therapy

Two Bisphosphonates are Approved in the US for Use in the MM Treatment Setting

Two Bisphosphonates are Approved in the US for Use in the MM Treatment Setting

• Approved– Pamidronate*– Zoledronic acid*

*FDA approved for hypercalcemia of malignancy and patients with osteolytic lesions of multiple myeloma in conjunction with standard antineoplastic therapy

• Not Approved – Etidronate– Clodronate– Tiludronate– Alendronate– Risedronate– Ibandronate

Berenson JR, et al. N Engl J Med. 1996;334:488-493.

• Any SRE• Pathologic fractures• XRT to bone • Decrease in pain scores• 21 month f/u • SRE 51 vs. 38%

PamidronatePamidronate

http://www.ncbi.nlm.nih.gov/entrez/utils/fref.fcgi?PrId=3051&itool=AbstractPlus-def&uid=8559201&nlmid=0255562&db=pubmed&url=http://content.nejm.org/cgi/pmidlookup?view=short&pmid=8559201&promo=ONFLNS19

http://content.nejm.org/content/vol334/issue8/images/large/02f1.jpeg

http://content.nejm.org/content/vol334/issue8/images/large/02f2.jpeg

Berenson JR, et al. N Engl J Med. 1996;334(8):488-493.

Effect of Monthly Intravenous Pamidronate (90 mg) in Reducing Skeletal Events in Patients

with Advanced Multiple Myeloma

Effect of Monthly Intravenous Pamidronate (90 mg) in Reducing Skeletal Events in Patients

with Advanced Multiple Myeloma

Phase III Trial

Zoledronic AcidZoledronic Acid

• Zoledronic acid belongs to a different class of highly potent bisphosphonates1,2

• Heterocyclic, nitrogen-containing bisphosphonate composed of:– A core bisphosphonate moiety – An imidazole-ring side chain

containing two critically positioned nitrogen atoms

1Green J, et al. J Bone Miner Res. 1994;9:745-751. 2Green J, et al. Pharmacol Toxicol. 1997;80:225-230.

NN

O

O

P

P

HO OH

OH

OH

OH

Breast Cancer and Multiple Myeloma Breast Cancer and Multiple Myeloma

Time to Multiple-Proportion first SRE Mean skeletal event analysis

with SRE, % (median)* morbidity rate* hazard ratio*

Zol acid 4 mg 47 376 1.04 0.841

Pam 90 mg 51 356 1.39 —

P value .243 .151 .084 .030

*Hypercalcemia of malignancy is included as a skeletal-related event.

Extension data

Efficacy Summary

Zoledronic Acid vs. PamidronateZoledronic Acid vs. Pamidronate

0

20

40

60

80

100

0 120 240 360 480 600 720

Time, days†

Pat

ien

ts w

ith

ou

t in

crea

se,

%

n Hazard ratio P value

Zol 4 mg 272 1.057 .839Pam 90 mg 268

†After start of study drug.

Zol 4 mg 272 226 197 152 81 68 30Pam 90 mg 268 213 182 138 73 59 27

Rosen LS, et al. Cancer. 2003;98:1735-1744.

Zoledronic acid infused over 15 minutes compared to pamidronate given over 2 hours shows a similar time to first serum creatinine increase in breast cancer and MM

Prescribing Information: Zoledronic acid: 4 mg as a single-dose intravenous infusion over no less than 15 minutesPamidronate: 90 mg administered as a 4-hour infusion

Use of Zoledronic Acid: Renal IssuesUse of Zoledronic Acid: Renal Issues

• Monitor renal function prior to each dose• Maintain hydration status• If serum creatinine increases, resume therapy

only after it returns to within 10% of baseline

Renal Function and the Use of Bisphosphonates Renal Function and the

Use of Bisphosphonates

• Guidelines recommend dose reduction of zoledronic acid in patients with renal impairment

*Doses calculated assuming target AUC of 0.66(mg•hr/L) (CrCl = 75 mL/min)

• Zoledronic acid and pamidronate disodium affect different parts of the kidney– Zoledronic acid – tubular

– Pamidronate disodium – glomerular

Thus, if a renal issue occurs with zoledronic acid or pamidronate disodium, you can try the other bisphosphonate

3.3 mg40-49

3 mg30-39

3.5 mg50-60

4 mg>60

Zoledronic Acid Recommended Dose*Baseline Creatinine Clearance (mL/min)

Zometa (zoledronic acid) injection Prescribing Information (Novartis).

Use of BPs for Patients With Renal Dysfunction

Use of BPs for Patients With Renal Dysfunction

• Use among patients with worse function (Cr >3) minimally assessed– Pamidronate1

– Zoledronic acid2

• However, if patient is on dialysis (irreversibly), may use either zoledronic acid or pamidronate at same dose, infusion time and interval

• Poor renal function at diagnosis– Initially, treat MM without BPs unless hypercalcemia or severe bone

disease is also present

– When renal function improves, IV BPs may be initiated

• If hypercalcemia occurs, use zoledronic acid even with renal dysfunction3

1Berenson JR, et al. J Clin Pharmacol. 1997;37:285-290. 2Novartis, data on file. 3Major P, et al. J Clin Oncol. 2001;19:558-567.

IV Bisphosphonates for Patients With Metastatic Bone Disease – Benefits vs. Risks

IV Bisphosphonates for Patients With Metastatic Bone Disease – Benefits vs. Risks

Benefits Risks

Fractures

Radiotherapy

Bone pain

ONJ

Renal (infrequent)

Humeral fracture in a myeloma patient

ONJ = osteonecrosis of jaw

BP-Osteonecrosis of the Jaw (ONJ)BP-Osteonecrosis of the Jaw (ONJ)

• Linked to long-term use of bisphosphonates– Adynamic bone, angiogenesis, microbial infections

• Reported incidence vary, but recent evidence suggest it has been underestimated

– Manufacturer-sponsored epidemiologic studies report an incidence ranging from 0.1% to 1.8%

– Independent epidemiologic reports from clinicians and the International Myeloma Foundation (IMF) estimates are higher: 5% to 10%

– Selected trials in homogenous MM patients, incidence ranged from 3.2% to 10%– Recent study in two neighboring German cities comparison between retrospective data

and cross-sectional study data showed large differences in reported incidences among multiple myeloma patients

Cross-sectional study showed 16/78 (20.5%) incidence of BP-ONJ compared to the retrospective data 4/81 (4.9%) - Authors conclude that BP-ONJ has been underestimated

All patients with BP-ONJ had received zoledronate; 12 of these had had additional bisphosphonates. All except one had an additional trigger factor (tooth extraction [n = 14], dental surgical procedure [n = 2], sharp mylohyoid ridge [n = 3]).

• Typically occurs after dental procedures or local trauma, but also shown to occur spontaneously

Badros A, et al. J Clin Oncol. 2006;24:945-952.; Migliorati CA, et al. J Am Dent Assoc. 2005;136:1658-1668.Walter C, et al. Head Face Med. 2010;6:11.; Picture: Kuehn BM. JAMA. 2006;295:2833-2836.

Diagnosis and Natural History of ONJDiagnosis and Natural History of ONJ

• Can be defined as an area of exposed bone in the maxillofacial region that has not healed 8 weeks from time of identification by practitioner in a patient who:– Has been exposed to bisphosphonate

No evidence of malignancy, no prior radiotherapy to the affected region

• Patient may present with pain or feelings of numbness or heaviness of the jaw– Other symptoms:

Soft tissue swelling, loosening of teeth, and infection

• Often asymptomatic and only identified by physician who finds an exposed bone in the jaw– Mandible is the main affected site– Most lesions occur posterior to the cuspid teeth

Migliorati CA, et al. J Am Dent Assoc. 2005;136:1658-1668.; Badros A, et al. J Clin Oncol. 2008;26:5904-5909.; Mehrotra B. Am Soc Hematol Educ Program. 2006;1:356-360.

Diagnosis and Natural History of ONJDiagnosis and Natural History of ONJ

• Recent longitudinal study of the natural history of ONJ [n=96 US and Greece] followed 3.9 years after ONJ diagnosis– Dental extractions preceded 47% of cases

More common in patients with a single episode of ONJ than in those with recurrent and nonhealing disease (58% vs. 30%)

ONJ resolved in 62% of cases and recurred after healing in 12% (same or new site)

Did not resolve in 26% of cases during 9 months of f/u

– Recurrence higher among US patients than Greek (22% vs. 7%)– Discontinuation of bisphosphonates correlated with increased bone pain

in Greek patients and increased fracture rates in US cohort US patients more likely to resume bisphosphonates than Greek counterparts

– Reinitiation of bisphosphonate in six cases and dental treatment in four cases

– The rate of MM relapse was higher in patients with recurrent or unresolved ONJ than in those who experienced single episode

Badros A. J Clin Oncol. 2008;26:5904-5909.

Management of ONJ and Risk-reduction Strategies


• Prevention:– Good dental hygiene– Avoidance of unnecessary dental procedures while on bisphosphonate

therapy Comprehensive dental exam with attention to active oral infections or sites at

high risk for infection Ask your patient at every visit about any planned dental procedure, and

educate your patient to report any planned dental procedure directly to you prior to any procedures

Discontinue bisphosphonate use prior to dental procedures

– Limit duration of therapy ASCO guidelines recommend limiting the use of bisphosphonates (BP)

to two years in patients with responsive or stable MM, with BP resumption in patients with new-onset skeletal related events

Preliminary data suggest ONJ incidence may be reduced in patients receiving 3-monthly bisphosphonate therapy vs. monthly infusions but further studies needed

Kyle RA, et al. J Clin Oncol. 2007;25:2464-2472.Wilde F, et al. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2010 Jul 29. [Epub ahead of print].



• No evidence-based consensus guidelines exist for management of ONJ once it occurs– Conservative, “supportive,” non-surgical approach recommended

Chlorhexidine 0.12%, oral rinses, intermittent systemic antibiotics, and careful sequestrectomy

Avoidance of bone curettage and surgical debridement advised since most cases worsen after surgery

– However, see recent article by Wilde F, et al. 2010.

Ozone therapy, hyperbaric oxygen, and laser therapy have been used in several cases of ONJ with mixed results

Kyle RA, et al. J Clin Oncol. 2007;25:2464-2472.Wilde F, et al. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2010 Jul 29. [Epub ahead of print].

Myeloma Bone DiseaseMyeloma Bone Disease

Derived from Roodman GD. N Engl J Med. 2004;32:290-292.

Myeloma Cell/Stromal Cell Interactions Induce RANKL and IL-6

Myeloma Cell/Stromal Cell Interactions Induce RANKL and IL-6

Targeting RANK-LigandTargeting RANK-Ligand

• Denosumab (AMG-162): fully human monoclonal antibody, designed to bind to and inhibit an activating factor in the blood (termed a ligand) RANKL (Receptor Activator of Nuclear Factor-Kappa Beta Ligand) that stimulates the function of osteoclasts (the cells breaking down bone), thus providing a novel way of decreasing bone resorption

Concept:

Inhibit RANK-ligand and thus osteoclast precursor maturation to osteoclasts

X

An Open-label, Phase II Trial of Denosumab in the Treatment of Relapsed

or Plateau-phase Multiple Myeloma

An Open-label, Phase II Trial of Denosumab in the Treatment of Relapsed

or Plateau-phase Multiple Myeloma

• Effective for myeloma bone disease– Median changes in bone resorption markers were

-70% and -52% for relapsed and plateau-phase patients, respectively

Vij R, et al. Blood. 2007;118:1054A.

1. Kyle R, et al. J Clin Oncol. 2007;25: 2464-2472.

SummarySummary

• Bisphosphonates1

Indicated for MM patients w/ lytic bone disease Osteopenia

– Useful as an adjunct for patients with bone pain– The bisphosphonates recommended are either

Zoledronic acid: 4 mg over ≥ 15 minutes, IV q 3-4 weeks Pamidronate: 90 mg over ≥ 2 hours, IV q 3-4 weeks

– Monitoring with serum creatinine (both BPs) and/or urine albumin (for pamidronate only)

– PAM preferred in setting of renal dysfunction but zoledronic acid can be used, particularly in instances of hypercalcemia but dose adjustment may be required

– Re-evaluate after two years and consider stopping if stable disease

• RANKL (denosumab)– Promising data, studies are ongoing

Case of Renal and Bone Complications

Case of Renal and Bone Complications


Renal and Bone ComplicationsRenal and Bone Complications

• 68-year-old male • Presents with:

– Lower back pain– Swelling of the right clavicular head for the past

two months– Back pain has progressed

No longer able to take morning walk of two miles Having difficulty sleeping at night

– No weakness or urinary incontinence– Was taking ibuprofen intermittently at first

Now taking 400 mg 3-4 times a day

• Hypertension, coronary disease and associated risk factors– Hypertension: on ACE inhibitor

– Diabetes: on metformin

– CAD

• Tired

• Past three weeks:

– Four pound weight loss

– Daytime sleepiness

– Moderate anorexia

• Past two weeks:– Slightly ↓ urine volume

– Foaming of the urine in the toilet


• Blood tests (ordered by his internist)– WBC: 6,200/μL; normal differential– Hemoglobin: 9.0 g/dL– Platelets: 174,000/μL– BUN: 48 mg/dL– Creatinine: 3.6 mg/dL– Calcium: 11.0 mg/dL – Total protein: 10.5 g/dL– Albumin: 3.2 g/dL

• Urinalysis– Specific gravity 1.030 with 1+ protein, no blood, no WBC


• Evaluation of skeletal problems– Internist ordered chest X-ray and lumbosacral spine films

Multiple lytic lesions of the clavicles, ribs Compression fractures of T12 and L2 (50% height loss)

– Internist ordered a whole spine MRI Extensive signal abnormality of the marrow Compression fractures T12 and L2 Erosion of posterior elements of T4 and T6 by expansile masses No evidence of cord compression


• Hospitalization: renal failure and elevated calcium

• Bone marrow biopsy recommended for the next day– Cellular marrow with 50% plasma cells with some binucleate forms

• Complete bone survey: multiple lytic lesions throughout axial skeleton and long bones

• Cytogenetics, SPEP, and UPEP (24-hour urine), IFE, and serum free light chains sent, results pending

• Ultrasound of the kidneys: normal size, no evidence of obstruction

• β2-microglobulin 9.8 mg/L


ISS Stage III

Durie-Salmon Stage IIIB

• SPEP: 5.6 g/dL M-component protein IgA λ • Twenty-four hour urine collection: excretion of 2.3 g/day• UPEP protein assessment

– 80% lambda light chain– 20% albumin

• Serum free light chain assay – Kappa 18 mg/L– Lambda 2,500 mg/L– Ratio 0.008

• Cytogenetics still pending


• What would be the initial interventions and choice of supportive treatments on admission?


• After 72 hours of hydration with saline, dexamethasone, and IV bisphosphonate– Calcium ↓ to 9.9 mg/dL– BUN ↓ to 30 mg/dL– Creatinine ↓ to 3.0 mg/dL

• Urine output 800 cc past 24 hours• Blood pressure 150/89 mmHg• Anorexia and somnolence improved


• What initial therapy of his newly diagnosed myeloma might be appropriate to initiate at this time?

• Could it wait until after discharge to outpatient?• Would doses need to be adjusted for the

creatinine clearance (estimated < 15 cc/min)?


• Conventional cytogenetics and myeloma FISH panel [13q-, 17p-, rearrangement (14q32)] came back 10 days later– Both negative for recognized high-risk abnormalities

• Karyotype: diploid


• What other consultation might be requested regarding the vertebral and other bone lesions?

• How would the bone disease affect the therapeutic plan, and how would it be monitored?



• Would stem cell transplant be an option for this patient in the future?

• How long should the initial course of therapy continue and what measures can be taken to avoid toxicity of the regimen?

DeliberationDeliberation

Participant Presentation of Management Summary- Critical Expert Analysis

Participant Presentation of Management Summary- Critical Expert Analysis

• What initial therapy of his newly diagnosed myeloma might be appropriate to initiate at this time? Could it wait until after discharge to outpatient? Would doses need to be adjusted for the creatinine clearance (estimated <15 cc/min)?

a. A bortezomib-based regimen would make sense as bortezomib is not renally excreted to any significant extent, and bortezomib has been reported to rapidly reverse renal failure in myeloma, especially when associated with light chain proteinuria

b. Dexamethasone would be helpful to continue both for the bone pain, hypercalcemia, and for optimal activity of the bortezomib-based regimen. Dexamethasone would commonly be given on the day of and day after bortezomib, at 20 to 40 mg

c. Lenalidomide would be difficult to adjust given the advanced renal failure and likely changing creatinine clearance, but could be added later when creatinine improved or stabilized if the BLD regimen was a planned treatment

• How would the bone disease affect the therapeutic plan, and how would it be monitored?

a. Extensive lytic lesions would prompt consideration of continued bisphosphonate therapy

b. While some groups would also use PET scan to follow patient’s bone disease, patients with a clear paraprotein to follow should have minimal risk of new skeletal events when response is ongoing by SPEP or UPEP monitoring

• What other consultation might be requested regarding the vertebral and other bone lesions?a. Radiation oncology might evaluate for radiation but unless the

pain location indicates the expansile lesions at T4 and T6 are contributing significantly to his pain, there is no evidence of cord compression at any level. Given there is no neurologic emergency, pulse steroids and early initiation of therapy after diagnosis is made might give similar and rapid relief of pain, as would a supportive brace

b. Interventional radiology might evaluate the compression fractures at T12 and L2 for eligibility for vertebroplasty or kyphoplasty, with bone biopsy done through the needle at the time of this procedure

Question and Answer SessionQuestion and Answer Session

10-minute Break10-minute Break


---------- X, 2010


---------- X, 2010

a live training program for the multidisciplinary myeloma care team ---------- x, 2010

Documents

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minutes attendees

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