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Disclosures

• The relevant financial relationships reported by faculty that they or their spouse/partner have with commercial interests are located on page 5 of your syllabus

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Off-label Discussion Disclosure

This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the Food and Drug Administration. PCME does not recommend the use of any agent outside of the labeled indications. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications and warnings. The opinions expressed are those of the presenters and are not to be construed as those of the publisher or grantors.

Pre-activity Survey

• Please take out the Pre-activity Survey from your packet• It is important that you fill out the demographic information

at the top of the form• Your answers are important to us and will be used to help

shape future CME activities

Polling QuestionPre-activity Survey

Please rate your level of confidence in your ability to treat and manage patients with multiple myeloma (MM):

1 2 3 4 5

Not at all confident Expert


A 55-year-old patient presents with a progressive mild decrease in hemoglobin, but is asymptomatic for MM. His workup revealed a hemoglobin of 11, calcium of 9.2, paraprotein peak of 2.6 with a beta-2 microglobulin of 3.7, and 30% plasma cells with diploid cytogenetics and no high-risk FISH. What further workup would you recommend at this time?

A. No further work-up recommended

B. MRI and/or PET/CT

C. Gene expression profiling

D. Immune spectrotyping


Over a 4-month period, a patient receives 5 cycles of lenalidomide/dexamethasone and bortezomib and achieves a partial response. What is your treatment recommendation for this patient?

A. Continue on RVD

B. Change to other treatment

C. Proceed to stem-cell harvest and autograft consolidation


A patient relapses after an 18-month complete response following consolidation with melphalan, autologous stem-cell rescue, and lenalidomide daily maintenance. She is treated with 6 cycles of bortezomib/dexamethasone; however, a month later, kappa-light chains and FDG avid bone lesions on PET/CT increase. Which treatment is most suitable for this patient?

A. Cyclophosphamide/bortezomib/dexamethasone

B. Salvage melphalan 200 mg/m2 with autologous stem-cell rescue

C. Bortezomib/lenalidomide/dexamethasone

D. Carfilzomib-based combinations OR pomalidomide/low-dose dexamethasone

E. Lenalidomide/dexamethasone


Which of the following factors would NOT impact treatment selection for relapsed/refractory MM:

A. Prior lines of therapy

B. Myeloma genomics

C. Comorbidities

D. Personal lifestyle

E. Clinical trial option

F. None of the above, since all these factors would impact treatment selection

Educational Objectives

• Discuss the role of cytogenetic and molecular analyses in personalizing care in MM

• Review the treatment course for patients with smoldering MM

• Assess the optimal use of induction therapy and transplant to improve patient survival in MM

• Evaluate the use of high-dose chemotherapy vs novel agents for relapsed/refractory MM

Smoldering Multiple Myeloma

• How do I treat a patient who presents with none of the common symptoms for myeloma (bone marrow clonal plasma cells just greater than 10, monoclonal peak barely at 3, mild anemia and no other symptoms related to the disease)?

• Do I really have to wait for a patient to have a calcium level of 11, creatinine level of 2, or less than 12 grams of hemoglobin or to get infected before I initiate treatment?

FAQs Regarding Smoldering Myeloma

Case Presentation

54-year-old male2/11 progressive mild decrease in hemoglobin. No symptoms and normal exam. W/up reveals Hb 11; Ca 9.2; IgG 3786; albumin 4.2; mpeak 2.6; B2M 3.7 BMA 30% plasma cellsDiploid cytogenetic no high-risk FISH

What further work-up is recommended?

1. No further work-up recommended

2. MRI and PET CT

3. Gene expression profiling

4. Immune spectrotyping

Case Question

• Laboratory analysis – Complete blood count and complete metabolic panel

• β2M, LDH– M proteins

• Radiologic imaging – Skeletal survey, MRI/CT, PET

• Bone marrow biopsy• Specific tests to rule out other • Causes of anemia, renal insufficiency, • Hypercalcemia, etc.

Specific Diagnostic Tests

National Comprehensive Cancer Network (NCCN) Guidelines for Diagnosis of Multiple Myeloma.

MGUS1-4

(Monoclonal Gammopathy of Undetermined Significance)

SmolderingMultiple

Myeloma1-5

MultipleMyeloma6-7

Symptoms Asymptomatic Asymptomatic Symptomatic (~89%)

Active treatment No No or clinical trial Yes

M-protein (per dL) <3 g >3 g M-spike orplasmacytoma

Clonal plasma cells in bone marrow <10% >10% >10%

End-organ damage None None 1 or more CRAB criteria

Likelihood of progression 1% per year

10% per year for first 5 years;

73% by 15 yearsNot Applicable

1. Kyle RA et al. N Engl J Med. 2007;356:2582-2590.2. International Myeloma Working Group. Br J Haematol. 2003;121:749-757.3. Jagannath S et al. Clin Lymphoma Myeloma Leuk. 2010;10:28-43.4. Kyle RA et al. Curr Hematol Malig Rep. 2010;5:62-69.

5. Mateos M-V et al. Blood. 2009;114:Abstract 614. 6. Durie BG Salmon SE. Cancer. 1975;36:842-854. 7. Durie BG et al. Leukemia. 2006;20:1467-1473.

Plasma cell malignancy Premalignant condition

Differential Diagnosis

CRAB CRITERIA

HyperCalcemia

Renal dysfunction

Anemia

Bone lesions

Increased Infections

Case Presentation

MRI no lesionsPET CT negativeMarrow 30% plasma cells diploid cytogeneticsDxd with asymptomatic myeloma

What is the risk of this patient to progress to symptomatic myeloma?

Risk Factors For Progression

Reference Wisloff Dimop Witzig Facon Dipenz Rajkumar KastritisFactor% BM/PC >20 >20 >10% >60%Lytic Lesions +M peak

>3 gm >3gm>2gm (IgA) >3 gm

Preoteinuria >50 mg/24h

Circulating PC +

Hb <12FLC ratio >8 >100FISH Low riskInt riskHigh risk

NormalOthers

T4,14 orDel17

TTP 0 Risk 39 m 61 m 9 m >50 m > 60 m >60 m 73 mTTP All Risk 10m 10 m 30 m 6 m 24 m 24 m 8 m

• First year: screen every 3 to 6 months• After first year: screen at least

every 1 to 2 years• 3% of people older than 50 years• 5% of people older than 70 years

10% risk of progression per year*

• Screen every 4-6 weeks*For first 5 years, ~3% per year for next 5 years, ~1% per year thereafter

1% risk of progression per yearMGUS

Smoldering Multiple Myeloma

Disease Progression in SMM and MGUS Patients

Kyle RA et al. N Engl J Med. 2007;356:2582-2590.

Jagannath S et al. Clin Lymphoma Myeloma Leuk. 2010;10:28-43.

Kyle RA et al. Curr Hematol Malig Rep. 2010;5:62-69.

ARajkumar et al, 2014, Lancet Oncology, 15(12), e538-e548; Dispenzieri A et al. Blood. 2013;122:4172-4181.

Algorithm for Reclassifying SMM and Active MM

*Consider including patients with the following FISH: deletion 17p, t(4;14), and 1q21 gains as active MM; this population could account for as many as 30% of SMM patients. §Consider using more than 1 fluorodeox.

Proposed Guidelines on Follow-up and Management of SMM Patients suspected to have MM should first be defined as having MGUS, SMM, or myeloma requiring therapy.

Ghobrial IM, Landgren O. Blood. 2014;124:3380-3388. © 2014 American Society of Hematology.

Evidence for Early Treatment of High-risk SMM with Lenalidomide plus Dexamethasone Survival Outcomes in the Per-Protocol Population

• Major Pitfalls of Mateos Study– Control group DID NOT receive lenalidomide– Control group did not receive uniform

treatment (some actually may have received MP)

• Notwithstanding• Magnitude of benefit dramatic

Mateos et al. N Engl J Med. 2013;369:438-447.

A B

C

Main Limitation of the Mateos Study

“…One limitation of the study was that patients received treatment off-protocol at the time of disease progression to symptomatic myeloma. It would have been informative to examine early treatment with lenalidomide and dexamethasone versus treatment with lenalidomide and dexamethasone that was deferred until the time of progression. However, the combination of lenalidomide and dexamethasone is not an approved first-line regimen for newly diagnosed multiple myeloma, and most patients in this study (81%) were treated with either bortezomib-based regimens (53% of patients) or induction therapy followed by autologous stem-cell transplantation (28%) at the time of progression…”

• Asymptomatic myeloma is an entity that needs to be better defined– All patients with newly diagnosed asymptomatic myeloma

need to be followed closely for the first 2-3 years (every 6-12 week visits)

– All patients should be encouraged to participate in clinical trials

– Patients with high-risk disease should be treated as symptomatic myeloma

Summary

Case Presentation

Over the next 6 months develops progressive anemia to a Hb of 10gm/dLBone marrow now shows 60% plasma cells15% show deletion 17 by FISHKaryotype normalNo lytic lesionsIs there an optimal induction regimen?

FAQs for Induction

• Have we fully defined the role of molecular and cytogenetic classifications in myeloma?

• What is the optimal induction regimen?• How much induction treatment should a transplant-eligible

patient receive?• Should I recommend SCT for a patient who has failed to

achieve a PR or CR after receiving 5 cycles of induction therapy?

• Is allogeneic transplant a reasonable option for a patient with standard-risk disease?

Multiple Myeloma Treatment Linesa

Induction Consolidation

Front-line treatment

Maintenance

Maintenance

Rescue

Relapsed

IMiD: Thal-LenProteasome Inhibitor: Bor-Car

Steroids: Dex-PredAlkylator: Cyclo-Mel

Anthracycline: LipoDnr-Adr

SCT ObservationIMiD: Thal-Len

Proteasome Inh-BorSteroids: Dex-Pred

IMiD: Thal-Len-PomProteasome Inh: Bor-Car

Steroids: Dex-PredAlkylators: Mel-Cy-Benda

InvestigationalaTransplant-eligible patients.

Bor/Dex = bortezomib, dexamethasone; Bor/Dex/Dox = bortezomib, dexamethasone, doxorubicin; Bor/Thal/Dex = bortezomib, thalidomide, dexamethasone;

Len/Dex = lenalidomide, dexamethasone; SCT = stem-cell transplant; Thal/pred = thalidomide, prednisone;

Bor/Liposomal/Dox = bortezomib, liposomal doxorubicin.NCCN, 2009.

Impact of Chromosomal Abnormalities on Survival Outcomes in MM (cont.)

ISS = International Staging SystemAvet-Loisseau H et al. J Clin Oncol. 2009;27:4585-4590.

IMWG AnalysisGenetic Abnormalities

4-year Estimated OSMinus vs Plus Abnormality

Log Rank P Value

Any 73% vs 57% <0.0001

t(4;14)ISSIISS2ISS3

64% vs 36%81% vs 52%63% vs 30%44% vs 22%

<0.0001<0.0001<0.0001<0.007

Del(17)ISSIISS2ISS3

68% vs 44%81% vs 64%68% vs 42%48% vs 28%

<0.0001<0.020

<0.0001<0.020

a. ISSI or ISS2, normal FISH 193/610 deaths (76%)a vs b <0.0001a vs c <0.0001b vs c <0.0001

b. ISSI + abnormal FISH/ISS3 + normal FISH

140/252 deaths (52%)

c. ISS2 or ISS3 + abnormal FISH 146/196 deaths (32%)

Goals of TherapyLongest life with best quality of life with

minimal burden of treatment

A Meta-analysis of Phase III Studies Comparing Bortezomib-based vs Non-bortezomib-based Induction Treatment Before ASCT

100

80

0

Prog

ress

ion-

Free

Sur

vival

(%)

20

60

No. at riskNon-bortezomib basedBortezomib based

Time (months)12 24 36 42 48 54 60

Bortezomib basedNon-bortezomib based

P=0.0001

A

40

6 18 30

785787

604675

429491

178212

98101

5458

2531

1010

671722

527609

306360

100

80

0

Ove

rall S

urviv

al (%

)20

60

No. at riskNon-bortezomib basedBortezomib based

Time (months)12 24 36 42 48 54 60

Bortezomib basedNon-bortezomib based

P=0.0402

B

40

6 18 30

785787

694722

614641

309338

174191

100117

5260

1820

727746

662698

486515

Michele Cavo, MD. Presented at: ASH2013, Abstract #767. Sonneveld P. J Clin Oncol. 2013;31:3279-3287.

Non-bortezomib based

Bortezomib based

Non-bortezomib based

Bortezomib based

Case Presentation

Over the next 3 months receives 4 cycles of lenalidomide / dexamethasone and bortezomib and achieves a PRStem cells are collected

Case Question

What would you recommend for this patient?

• Continue on RVD?• Change to other treatment?• Proceed to autograft consolidation?

Autologous Bone Marrow Transplant – Long-term Results

Barlogie B et al. Bone Marrow Transplant. 1998;21:1101-1107.

Role of High-dose Melphalan in Myeloma in

the Era of IMiDs and Proteasome Inhibitors

Figure 2

Koreth J et al. Biol Blood Marrow Transplant. 2007;13:183-196. (DOI:10.1016/j.bbmt.2006.09.010).Copyright © 2007 American Society for Blood and Marrow Transplantation. Terms and Conditions.

Benefit of Autografting for Myeloma

http://www.bbmt.org/misc/terms

http://www.bbmt.org/misc/terms

VRD x 5

CY (3g/m2)MOBILIZATIONGoal: 5 x106 cells/kg

Lenalidomide 12 mos

VRD x 2

Melphalan 200mg/m2* + ASCT

CY (3g/m2) MOBILIZATIONGoal: 5 x106 cells/kg

IFM/DFCI 2009 StudyNewly Diagnosed MM Patients (SCT Candidates)

VRD x 3

Lenalidomide 12 mos

Induction

Consolidation

Maintenance

VRD x 3

Randomize, stratification ISS & FISH

Collection

SCT at relapse MEL 200 mg/m2 if <65 yrs,

≥65 yrs 140mg/m2

http://www.clinicaltrials.gov/ct2/show/NCT01208662?term=nct01208662&rank=1.

Mel200-ASCT vs CC+R: PFS1Median Follow-up from Randomization: 4 Years

Gay et al, Blood, 2014 124(21). Abstract 198.

Mel200-ASCT vs CC+R: Second-line Therapy


Mel200-ASCT vs CC+R: OSMedian Follow-up from Randomization: 4 Years


Mel200-ASCT vs CC+R

Age <60

Age ≥60

KPS 60-70%

KPS 80-100%

ISS I/II

ISS III

No del17, t(4;14), t(14;16)

Del17, t(4;14), t(14,16)

LDH < ULN

LDH ≥ ULN

HR (95% CI) P value

0.67 (0.41-1.11) 0.117

0.44 (0.23-0.86) 0.015

0.76 (0.33-1.72) 0.506

0.54 (0.34-0.85) 0.008

0.55 (0.34-0.89) 0.016

0.75 (0.38-1.45) 0.376

0.57 (0.34-0.94) 0.029

0.60 (0.31-1.14) 0.118

0.62 (0.41-0.95) 0.027

0.23 (0.03-1.92) 0.177

Favors CC+RFavors Mel200-ASCT

Mel200-ASCT vs CC+ROS Subgroup analysis

OS, overall survival; KPS, Karnofsky Performance Status; ISS, International Staging System; LDH, lactate dehydrogenase; ULN, upper limit of normal; Mel200-ASCT, melphalan 200 mg/m2 followed by autologous stem cell transplantation; CC+R, conventional chemotherapy + lenalidomideGay et al, Blood, 2014 124(21). Abstract 198.

1st Autologous Transplant

n=710

No Sibling DonorAuto-Auto

n=484

Sibling DonorAuto-Allo

n=226

High Riskn=48

Standard Risk

n=189

Standard Risk

n=436

High Riskn=37

Main groups compared

Progression-free Survival Overall Survival

Survival Outcomes after the First Transplant Auto-Auto vs Auto-Allo: Intent-to-treat analysis

Prob

abilit

y, %

100

0

20

40

60

80

90

10

30

50

70

Auto/Allo, 43% @ 3yr

Auto/Auto, 46% @ 3yr

P-value = 0.67 P-value = 0.19

Auto/Allo, 77% @ 3yr

Auto/Auto, 80% @ 3yr 100

0

20

40

60

80

90

10

30

50

70

0 6 12 18 24 30 36 42 48

436 424 406 395 370 348 305 107 79189 183 167 160 156 143 124 43 27

Months 0 6 12 18 24 30 36 42 48# at risk:Auto/Auto 436 395 348 292 242 213 178 54 42Auto/Allo 189 165 138 117 105 89 71 23 16

D-S Stage 1-3, ≤70 years≥2 cycles of induction Attained SD or better≤1 yr from start of therapy≥2 x 106 CD34 cells/kg

Placebo

Lenalidomide*10 mg/d with ↑↓

(5–15 mg)

Lenalidomide*10 mg/d with ↑↓

(5–15 mg)

RestagingDays 90–100

Registration

CALGB 100104 Schema

CRPRSD

Stratification based on registration -2M level and prior thalidomide and lenalidomide use during Induction. Primary Endpoint: powered to determine a prolongation of TTP from 24 months to 33.6 months (9.6 months)

Mel 200

ASCT

* provided by Celgene Corp, Summit, NJ

Randomization

CALGB 100104; N Engl J Med. 2012.

Time to Progression

Multivariate Analysis of Prognostic Factors for PFS

Variable PFS

HR 95% CI P

< CR at induction 1.80 1.29-2.51 0.001

Del(17p) and/or t(4;14) 1.56 1.18-2.05 0.002

ISS > 2 1.57 1.14-2.17 0.006

Plts <150 (109/L) 1.48 1.05-2.08 0.025

Hb <10.5 (g/dL) 1.32 1.03-1.70 0.028

Del(13q) 1.20 0.94-1.54 0.145

IgA isotype 1.13 0.85-1.50 0.393

Creat >1.2 (mg/dL) 0.87 0.64-1.19 0.391

Michele Cavo, MD. Presented at: ASH2013, Abstract #767.

1 2Hazard Ratio

PFS According to Preplanned ASCT(s) for Patients with del(17p) and/or t(4;14) and Who Failed CR after B-based Induction Regimens


ScorePrognostic factors

N° of pts (%)ISS Cytogenetic abnormalities Response at induction2 141 (23.27%)

1-2 Del(17p) ± t(4;14) < CR 70 (11.55%)3 Del(17p) – t(4;14)- < CR 65 (10.73%)3 Del(17p) ± t(4;14) CR 6 (0.99%)

Kaplan-Meier survival estimates

Log rank test: HR 0.41 (0.22 - 0.77)P=0.004 P=0.006

Months

1.00

0.75

0.00

0.25

0.50

0 12 24 36 48

42 mo2 ASCT

21 mo

1 ASCT

OS According to Preplanned ASCT(s) for Pts With del(17p) and/or t(4;14) and Who Failed CR After B-based Induction Regimens

Log rank test: HR 0.22 (0.10 - 0.50)P=0.0001 P<0.001

Months

1.00

0.75

0.00

0.25

0.50

0 12 24 36 48

76%2 ASCT

33%1 ASCT

Kaplan-Meier survival estimates

ScorePrognostic factors

N° of pts (%)ISS Cytogenetic abnormalities Response at induction2 141 (23.27%)

1-2 Del(17p) ± t(4;14) < CR 70 (11.55%)3 Del(17p) – t(4;14)- < CR 65 (10.73%)3 Del(17p) ± t(4;14) CR 6 (0.99%)


Lenalidomide Maintenance**

Lenalidomide Maintenance**

MEL 200mg/m2 VRD x 4*

Lenalidomide Maintenance

MEL 200mg/m2

**Lenalidomide 15 mg daily x 3years

* Bortezomib 1.3mg /m2 days 1, 4, 8,11 Lenalidomide 15mg days 1-15 Dexamethasone 40mg days 1, 8, 15

*

BMT CTN 0702: SCHEMA

Register and Randomize

Relapsed/Refractory Multiple Myeloma

FAQs Regarding Relapsed/Refractory Multiple Myeloma

• Is there a role for high-dose chemotherapy consolidation in the era of novel, more effective agents and strategies? Do we know the optimal timing for HD chemotherapy?

• What are the pros and cons of emerging therapies and novel treatment strategies based on recent clinical data?

• 54-year-old male with progressive anemia to Hb of 10gm/dL; Ca 9.2; IgG 6800; albumin 4.2; mpeak 4.5; B2M 5.5. No lytic lesions, but bone marrow 60% plasma cells, normal karyotype with 15% deletion 17 by FISH

• Receives 4 cycles of lenalidomide/dexamethasone and bortezomib and achieves a PR, followed by consolidation with melphalan 200 mg/m2 with autologous stem cell rescue and len 10 mg po daily maintenance (along with monthly zoledronic acid) with a CR for 1.5 years and then relapses by free light chains with a kappa of 150 mg/L and KLR of 162

Case Presentation

• Treated with bortezomib/dexamethasone for 6 cycles with a PR and then was off therapy for a preplanned trip. The kappa light chains increased again 35 days later to 205 and a KLR of 232 along with asymptomatic but new FDG avid bone lesions on PET-CT.

Case Presentation

Case Question

Which treatment would you choose for this patient at this time?

1. Cyclophosphamide/bortezomib/dexamethasone

2. Salvage melphalan 200 mg/m2 with autologous stem cell rescue

3. Bortezomib/lenalidomide/dexamethasone

4. Carfilzomib-based combinations

5. Pomalidomide/low-dose dexamethasone

6. Lenalidomide/dexamethasone

7. Unsure

• CRAB symptoms, disease burden, and rate of progression• Prior therapies

– Depth and duration of prior response– Side effects– Time since therapy

• Myeloma genomics• General health – diabetes, CBC, cardiac/hepatic/renal function,

neuropathy, VTE• Personal lifestyle and preferences• Option for clinical trial

Factors to Consider in Treatment Selection

MM-003 Final Analysis: Pomalidomide/LoDex vs HiDex in Relapsed/Refractory MM: Efficacy Data

• ORR (overall): 31% (26% PR) Pom/LoDex vs 10% (9% PR) HiDex

San Miguel J et al. Lancet Oncol. 2013;14:1055-1066. Dimopoulos MA et al. Presented at: ASH 2013, Abstract #408. Reproduced with permission.

Median PFS, Mos

Pom + LoDex (n = 302) 4.0

HiDex† (n = 153) 1.9

PFS* OS1.0

0.8

0.6

0.4

0.2

00 4 8 12 16 20 24

PFS (Mos)

Prop

ortio

n of

Pat

ient

s

HR: 0.50P <0.001

1.0

0.8

0.6

0.4

0.2

00 4 8 12 16 20 24 28

OS (Mos)Pr

opor

tion

of P

atie

nts

HR: 0.72P =0.009

Median OS, Mos

Pom + LoDex (n = 302) 13.1

HiDex† (n = 153) 8.1

*Primary endpoint.†85 pts (56%) on the HiDex arm received subsequent Pom.

Pomalidomide/LoDex vs HiDex: Safety

• AEs generally similar between arms and across subgroups– Most common grade 3/4 AEs: neutropenia, anemia, thrombocytopenia– ≥ grade 3 PN in 15% with Pom plus LoDex vs 11% with HiDex

San Miguel J et al. Lancet Oncol. 2013;14:1055-1066.

AE, %Pom + LoDex

(n = 300)HiDex

(n = 150)

Grade 3 Grade 4 Grade 5 Grade 3 Grade 4 Grade 5

Infections and infestations 24 6 4 19 5 9

Anemia 31 2 -- 32 5 --

Neutropenia 26 22 -- 9 7 --

Fatigue 5 -- -- 6 -- --

Thrombocytopenia 9 13 -- 9 17 --

Pyrexia 3 < 1 -- 3 1 --

Diarrhea 1 -- -- 1 -- --

Constipation 2 -- -- -- -- --

Cough < 1 < 1 -- < 1 -- --

Back pain 4 1 -- 3 < 1 --

Dyspnea 4 1 -- 5 -- --

Febrile neutropenia 8 2 -- -- -- --

Carfilzomib, an Irreversible Proteasome Inhibitor, in Relapsed/Refractory MM

• Carfilzomib FDA approved in 2012 for treatment of MM after ≥2 previous therapies, including bortezomib and an IMiD, and with progression on or within 60 days of treatment– Approval based on

single-arm phase II PX-171-003 study (n = 266): ORR of 23.7% and median DOR of 7.8 mos[1]

1. Siegel DS et al. Blood. 2012;120:2817-2825.2. NCCN. Clinical practice guidelines in oncology: multiple myeloma. v.1.2014.

PFS

0 2.5 5.0 7.5 10.0 12.5 15.0 17.5

100

75

50

25

0

Median PFS: 3.7 mos (95% Cl: 2.8-4.6)

Mos From Start of Treatment

Pts

Aliv

e an

d W

ithou

t Pro

gres

sion

(%)

Censored observationsConfidence band

Integrated Safety Profile of Single-agent Carfilzomib: Experience from 526 Patients

• 4 phase II studies (PX-171-003-A0, PX-171-003-A1, PX-171-004, and PX-171-005)

Siegel D et al. Hematologica. 2013;98:1753-1761.

Select AEs, % All Grades Related Grade 3/4 Serious AEFatigue 55.5 41.4 7.6 0Anemia 46.8 26.8 22.4 1.3Nausea 44.9 35.2 1.3 0Any cardiac event

Cardiac failure 22.17.2

NR 9.55.7

7.84.9

Any respiratory event Dyspnea

69.042.2

NR 10.34.9

6.52.1

Any renal impairment Serum creatinine Acute renal failure

33.124.15.3

NR 7.22.74.4

6.11.34.2

Peripheral neuropathy 13.9 NR 1.3 NR

• Tolerable safety profile allows for administration of full-dose carfilzomib with low discontinuation rates

Single Agent and Doublet Efficacy

Trial Phase n IMiD exposed

PI exposed ORR PFS

(months)OS

(months)

Thalidomide 2 169 0% 0% 30% 2y : 20% 2y : 48%

BTZ vs DEX 3 669 49% 0% 38% 6.22 30

BTZ + doxil vs BTZ 3 646 41% 0% 43% 9 33

Len Dex MM009 3 177 41% 10% 61% 11.1 29.6

Len Dex MM010 3 349 30% 4.5% 60% 11.3 38

CFZ (+dex 8) 2 266 100% 99% 23.7% 3.7 15.6

Pom D vs Dex 3 302 100% 95% 31% 4.2 13.1

Barlogie B. Blood. 2001;98:492-494.Richardson P. N Engl J Med. 2005;352:2487-2498. Orlowski RZ. J Clin Oncol. 2007;25:3892-3901.Weber D. N Engl J Med. 2007;357:2133-2142.

Dimopoulos M. N Engl J Med. 2007;357:2123-2132.Siegel DS. Blood. 2012;120:2817-2825.San Miguel J. Lancet Oncol. 2013;14:1055-1066.

RdLenalidomide 25 mg Days 1–21

Dexamethasone 40 mg Days 1, 8, 15, 22

CarRdCarfilzomib 27 mg/m2 IV (10 min)

Days 1, 2, 8, 9, 15, 16 (20 mg/m2 days 1, 2, cycle 1 only) Lenalidomide 25 mg Days 1–21

Dexamethasone 40 mg Days 1, 8, 15, 22

Phase III CarRd vs Rd (ASPIRE) Study Design

Key inclusion criteria:

• 1–3 prior treatments

• Relapsed or PD

• ≥PR to at least 1 prior regimen

Key exclusion criteria:

• CrCl <50 mL/min

• PD on BTZ

• PD on Rd

• Len or dex intolerance

After C12, carfilzomib given D 1, 2, 15, 16

After C18, carfilzomib discontinued

28-day cycles

Randomization n=792

Primary Endpoint: Progression-free SurvivalITT Population (n=792)

Primary Endpoint: Progression-free Survival by Subgroup

23.1 vs 13.9 mos (P 0.083)29.6 vs 19.5 mos (P 0.004)

• Unadjusted P value from the stratified log-rank test comparing the overall survival curves up to 24 months was 0.0046

Kaplan-Meier 24-Month Overall Survival Rates

0

10

20

30

40

50

60

70

80

73.3%65.0%

CarRd

Rd

Perc

enta

ge o

f Pat

ient

s

Adverse Events in the Safety Population

Stewart AK et al. N Engl J Med. 2014. DOI: 10.1056/NEJMoa1411321.

PI + IMiD + Dex (Triplet) Efficacy

Trial Phase n IMiD exposed

IMiD refractory

PI exposed

PI refractory

ORR PFS(mos)

OS(mos)

Bort Thal Dex 1-2 85 74% most 0% 0% 65% 6 22

Bort Len Dex 2 64 73%T

6% L 3% 53% 8% 64% 9.5 30

Bort Pom Dex 1 28 100% 100% 100% NA 71% NA NA

Car-Len-Dex 2 52 73% 44% 80% 25% 77% 15.4 NA

Car-Pom-Dex 1/2 79 100% 100% 89% 91% in

ph 1 70% 9.7 NR

Wang M et al. Blood. 2013;122:3122-3128. Shah JJ et al. Presented at: ASH 2013. Abstract 690.

Pineda-Roman M. Leukemia. 2008;22:1419-1427.Richardson PG et al. Blood. 2014;123:1461-1469. Richardson PG et al. Presented at: ASCO 2014.

PANORAMA 1: Phase III Study of Panobinostat + Bortezomib + Dexamethasone in Relapsed or Relapsed and Refractory MM Panobinostat significantly extended progression-free survival

San-Miguel JF et al. Lancet Oncol. 2014;15:1195-1206.

• Median PFS was significantly longer in the panobinostat group• There is also a trend toward better OS in the panobinostat group• ORRs were similar for the two groups; however, the CR/nCR rate was significantly higher for

panobinostat• Common grade 3-4 laboratory abnormalities and adverse events included thrombocytopenia (67% vs

31%), lymphopenia (53% vs 40%), diarrhea (26% vs 8%), asthenia or fatigue (24% vs 12%), and peripheral neuropathy (18% vs 15%)

PBDn = 387

Pbo-BDn = 381 P

Median PFS, mo 11.99 8.08 <0.0001

Median OS, mo 33.64 30.39 0.26

ORR, % 60.7 54.6 0.09

CR/nCR, % 27.6 15.7 0.00006

Median DOR, mo (range)

13.14 (11.76-14.92)

10.87 (9.23-11.76)

Median TTR, mo (range)

1.51 (1.41-1.64)

2.00 (1.61-2.79)Time (months)

Prog

ress

ion-

free

surv

ival

(%)

Panobinostat, bortezomib, and dexamethasonePlacebo, bortezomib, and dexamethasone

HR 0.63, 95% CI 0.52-0.76; P<0.0001

Overall (n=768)Cytogenetic risk group- Normal risk (n=167)- Poor risk (n=37)

0.25 0.5 0.75 1 1.25 1.5 1.75 2 2.25

PAN-BTZ-Dex Pbo-BTZ-Dex

Hazard Ratio (95% CI)

0.63 (0.52-0.76)

0.88 (0.60-1.29)0.47 (0.18-1.25)

Pan + Btz + Dex Relapsed or Refractory MM Efficacy in Patients with High-risk Cytogenetics

San-Miguel JF et al. Lancet Oncol. 2014;15:1195-1206.

Summary of Combo Therapy with HDACIs

Regimen Phase (N) Outcomes

Panobinostat or placebo + VD III(768)

ORR: 60.7% vs 54.6%PFS: 12.0 vs 8.1 mos (P <0.0001) (9.9 vs 7.7)OS: 33.6 vs 30.4 mos

Panobinostat + VD II (55 BTZ ref) ORR 34.5%, CBR 52.7%

Panobinostat + RD II(19)

ORR of 31%, CBR of 52 %n=14 Len Ref: ORR 21%, CBR 42%

Panobinostat + Carfilzomib I/II(26)

ORR of 46%, CBR of 52 %n=16 Btz Ref: ORR 44%

Vorinostat or placebo + V (no dex)

III(637)

ORR: 54% vs 41% (P <0.0001)PFS: 7.6 vs 6.8 mos (P <0.01); OS no diff

Ricolinostat ± VD I (20) ORR: 25% (heavily pretreated); CBR: 60%

Ricolinostat + RD I (22) ORR: 64%, CBR: 100%

San-Miguel JF et al. Lancet Oncol. 2014;15:1195-1206. Richardson PG et al. Blood. 2013;122:2331-2337.Chari A. Presented at: ASH 2014. Kaufman. Presented at: ASH Abstract #32.

Dimopoulos M et al. Lancet Oncol. 2013;14:1129-1140.Raje N et al. Presented at: ASH 2013. Abstract #759.Raje N et al. Presented at: EHA 2014. Abstract #P358.

CD38 Monoclonal Antibodies

• CD38 - transmembrane glycoprotein & ectoenzyme with high-receptor density on MM cells1 (80%-100%) vs NHL2,3 (30%-80%) vs AML4 58% vs B-CLL5 20%-25%

• Also expressed on precursor B-cells• Daratumumab and SAR650984 : humanized IgG1 monoclonal antibodies

1. Lin et al. Am J Clin Pathol. 2004;121:482-488. 2. Angelopoulou et al. Eur J Haematol. 2002;68:12-21. 3. Schwonzen et al. Brit J Haematol. 1993;83:232-239.4. Keyhani et al. Leukemia Res. 1999;24:153-159.

5. Domingo-Domènech et al. Haematologica. 2002;87:1021-1027.

Daratumumab

• Part 1 (n=32): phase I, first in human– Main toxicity grade 1 or 2 infusional toxicity– 5 of 12 (42%) of patients dosed at 4-24 mg/mg achieved

PR as best response

• Part 2 (n= 50): expansion cohort

Patient Characteristics

All AEs Grade 3/4 and SAEs per Dose Group

Infusion Related Reactions (IRR)

Response

Daratumumab Status

• Breakthrough designation by FDA: May 2013 for >3 lines of therapy or PI and IMiD refractory

• Newly Diagnosed

– Phase III (SCT eligible): DVTD vs VTD

– Phase III (non-SCT eligible): DRd vs Rd

– Phase III (non-SCT eligible): DVMP vs VMP

• Relapse (1+ lines of therapy)

– Phase III: DRd vs Rd

– Phase III: DVD vs VD

• Relapsed/Refractory

– Phase II: Dara

– Phase II: Dara + [VD, VMP, VTD, PomD]

Indatuximab Ravtansine (BT062): Antibody-drug Conjugate vs CD138

Jagannath et al. Abstract #305.

• An anti-CD138 chimerized monoclonal IgG4, covalently linked to thecytotoxic agent maytansinoid (DM4)

• CD138 is highly expressed on MM cells but not other hematopoietic and marrow stromal cell• To a lesser extent CD138 can also be found on epithelial cells • BT062 is stable and non-toxic in circulation

1. Binding to CD138

2. Receptor (CD138)-mediated internalization

3. Lysosomal processing of SPDB linker leads to lipophilic DM4 metabolites(DM4 + S-methyl-DM4)

4. Inhibition of tubulin polymerization

5. Cell cycle arrest and apoptosis

6. Bystander killing of neighboring cells

Best Response in Study 969

*Stabilized for at least 11 weeks (C4D15)Number of patients Total Percentage

Objective Response

Rate

Clinical Benefit

Response

Stable Disease or better

treated with BT062 32

evaluable for response 28 100%

- PD 14 50%

- SD 11 39%50%

- Minor response 2 7%11%

- Partial response 1 4% 4%

• Median # cycles for patients with ≥SD: 5 (105 days), range 4-25• Patient with MR ongoing, progression free >18 months• Related SAEs and DLTs in highest dose levels and CD138+ tissues; resolved after 10-52 days - DLTs: elevated ggt, mucositis, HFS- SAE: as above + GIB, blurred vision/dry eyes/photophobia due to corneal epithelial damage,

acneiform rash

Jagannath et al. Abstract #305.

Summary of Efficacy of Monoclonal Antibodies (@ R2P2/Ph3 Doses)

Treatment n Eligibility (% Refractory)

Response Rate

PFS DOR (mos)

OS (mos)

Elotuzumab Rd 36 NA -R sens 92% 33 mos 17.8 NRDaratumumab 20 50/75/38

(% Ref: B/L/BL35% (n=20) NR NR NR

Sar650984 13 69% C&P exposed 30.8% NA 5+ NADara RD 30 6.7% L ref 87% NA NA NSSar RD 24 80%L/20%P

~60 B/~50%Car63%

(48% L ref, n25)5.8 mos NA NA

BT062 RD 21 100%Bort, 87%L 73%(75% L ref, n8)

NA NA NA

1. Lonial S et al. ASCO 2013. Abstract 8542. 2. Lokhorst HM et al. ASCO 2014. Abstract 8513. 3. Martin T et al. ASCO 2014. Abstract 8532. 4. Plesner T et al. ASH 2014. Abstract 84. 5. Martin T et al. ASH 2014. Abstract 83. 6. Kelly K et al. ASH 2013. Abstract 758.

Dara Breakthrough designation May 2013 for >3 lines of therapy or PI and IMiD refractoryElo Breakthrough designation by FDA: May 19 2014 for >1 line of therapy given with Rd

Kinesin Spindle Protein – A New Drug Target in Multiple Myeloma (MM)

• Kinesin Spindle Protein (KSP, eg5) is a microtubule motor protein required for mitosis and separation of spindle pole– KSP inhibition prevents formation of

bipolar spindle, leading to cell death

• Rapid onset of apoptosis occurs in Mcl-1 Dependent MM

• Expected Differentiated AE profile– No expected neuropathy– Minimal non-hematological toxicity

Tunquist BJ et al. Mol Cancer Ther. 2010;9:2046-2056.

Hematologic ToxicityWorst Grade On-Study

Febrile Neutropenia

Bleeding

Hemoglobin

Platelets

Neutrophils

0 25 50 75 100 0 25 50 75 100

N=32 N=55

Filanesib Single-agent Filanesib + Dex

Grade 3Grade 4

Hematological toxicity predicted based on mechanism of action• Managed with supportive care• Low incidence of febrile neutropenia or bleeding events

Filanesib Activity

Filanesib granted orphan drug approval by FDA in May 2014.

Treatment n Eligibility ORR PFS DOR (mos)

OS (mos)

ixazomib + dex 33 88% Lexp; B sens 34% 12.4 96% @ 6 mo

filanesib in low AAG

32 21

75% IMiD Ref53% PI ref

16% 24%

3.75.3

8.68.6

19 23.3

filanesib + dex in low AAG

55 36

100% IMiD Ref98% PI ref

15% 19%

3.45.1

5.15.1

10.510.8

afuresertib 34 97% I; 88% PI 8.8%selinexor + dex 8 Ref to all classes 50% NR NR NRLGH 447 59 NR 10.5% NR 5.8 NR

Filanesib granted orphan drug approval by FDA in May 2014.

Kumar S et al. ASH 2013. Lonial S. ASH 2013.Voorhees et al. ASH 2013.

Summary of Novel Agents with Single-agent Activity

Chen C et al. EHA 2014. Spencer A et al. Blood. 2014.Raab et al. ASH 2014. Abstract 301.

Participant CME Evaluation

• Please take out the Participant CME Post-survey and Evaluation Form from the back of your packet.

• If you are not seeking credit, we ask that you fill out the information pertaining to your degree and specialty, as well as the few post-activity survey questions measuring the knowledge and competence you have garnered from this program. The post-survey begins on page 1 of the evaluation form.

• Your participation will help shape future CME activities.

Polling QuestionPost-activity Survey

A 55-year-old patient presents with a progressive mild decrease in hemoglobin, but is asymptomatic for MM. His workup revealed a hemoglobin of 11, calcium of 9.2, paraprotein peak of 2.6 with a beta-2 microglobulin of 3.7, and 30% plasma cells with diploid cytogenetics and no high-risk FISH. What further workup would you recommend at this time?

A. No further work-up recommended

B. MRI and/or PET/CT

C. Gene expression profiling

D. Immune spectrotyping


Over a 4-month period, a patient receives 5 cycles of lenalidomide/dexamethasone and bortezomib and achieves a partial response. What is your treatment recommendation for this patient?

A. Continue on RVD

B. Change to other treatment

C. Proceed to stem-cell harvest and autograft consolidation


A patient relapses after an 18-month complete response following consolidation with melphalan, autologous stem-cell rescue, and lenalidomide daily maintenance. She is treated with 6 cycles of bortezomib/dexamethasone; however, a month later, kappa-light chains and FDG avid bone lesions on PET/CT increase. Which treatment is most suitable for this patient?

A. Cyclophosphamide/bortezomib/dexamethasone

B. Salvage melphalan 200 mg/m2 with autologous stem-cell rescue

C. Bortezomib/lenalidomide/dexamethasone

D. Carfilzomib-based combinations OR pomalidomide/low-dose dexamethasone

E. Lenalidomide/dexamethasone


Which of the following factors would NOT impact treatment selection for relapsed/refractory MM:

A. Prior lines of therapy

B. Myeloma genomics

C. Comorbidities

D. Personal lifestyle

E. Clinical trial option

F. None of the above, since all these factors would impact treatment selection

Thank you for joining us today!

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