Understanding Recent Progress in Multiple Myeloma:

Clinical Implications and PerspectivesCarol Ann Huff, MD

Director, Myeloma ProgramAssociate Professor of Oncology

John Hopkins Sidney Kimmel Comprehensive Cancer Center

Disclosures

Dr. Huff discloses the following commercial relationships:

Advisory Board: Celgene, Janssen, MedImmune

Learning Objectives

Distinguish therapeutic strategies for patients with low- versus high-risk MM

Evaluate safety and efficacy data on novel therapies for newly diagnosed and relapsed/refractory MM

Assess disease monitoring and supportive care strategies for patients with MM

MM = multiple myeloma.

Overall Survival From Time of Diagnosis in 6-Year Intervals

Kumar et al, 2008.

Myeloma: Scope of the Problem

Median time to first relapse with current therapies: 3-4 years

Kumar, Dispenzieri, et al, 2014.

> 100,000 patients living with myeloma

Melphalan/Prednisone

FDA Approval Bortezomib

2006

FDA ApprovalLenalidomide Thalidomide

1980s

Autologous Stem Cell Transplant

1990s

IntravenousBisphosphonates –

Reduction in Skeletal Events

1968 20041998 2013

FDA Approval Carfilzomib

2012

Initial Data onThalidomide

2015

FDA Approval Pomalidomide

FDA Approval PanobinostatDaratumumab

Ixazomib Elotuzumab

Multiple Myeloma: Evolution of Treatment

Diagnosis, Staging, and Risk Stratification

Updated IMWG Criteria for Diagnosis of Multiple Myeloma

C: Calcium elevation (>11 mg/dL or >1mg/dL higher than ULN)R: Renal insufficiency (CrCl <40 mL/min or serum creatinine >2 mg/dL)A: Anemia (Hb <10 g/dL or 2 g/dL < normal)B: Bone disease (≥1 lytic lesions on skeletal radiography, CT, or PET-CT)

IMWG = International Myeloma Working Group; BM = bone marrow; CrCl = creatinine clearance; CT = computed tomography; Hb = hemoglobin; MGUS = monoclonal gammopathy of undetermined significance; M protein = monoclonal protein; MRI = magnetic resonance imaging; PET/CT = positron emission tomography/computed tomography; ULN = upper limit of normal. Rajkumar, 2014.

MGUS

M protein <3 g/dL Clonal plasma cells in

BM <10% No myeloma-defining

events

Smoldering Myeloma

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

Clonal plasma cells in BM ≥10% to 60%

No myeloma-defining events

Multiple Myeloma Underlying plasma cell

proliferative disorder AND 1 or more myeloma-

defining events ≥1 CRAB feature Clonal plasma cells in

BM ≥60% Serum free light chain

ratio ≥100 >1 MRI focal lesion

Revised International Staging System

B2M = beta-2-microglobulin; LDH = lactate dehydrogenase; NR = no response; OS = overall survival; R-ISS = revised International Staging System.Palumbo et al, 2015.

Stage Definition

I

Serum albumin ≥3.5 g/dL AND B2M ≤3.5 mg/L

Normal LDH No t(4;14), t(14;16), or

del(17p)

II Not stage I or III

III B2M ≥5.5 mg/dL PLUS Elevated LDH OR t(4;14), t(14;16), or del(17p)

1.0

0.8

0.6

0.4

0.2

00 12 24 36 48 60 72

R-ISS I NRR-ISS II 83R-ISS III 43

Median OS, Mo

MonthsPr

obab

ility

of O

S

Current Clinical Controversies

Defining high-risk disease How best to do this? Are there better therapies?

SCT indications Optimal therapy for non-SCT candidates Implications of CR vs very good partial response Minimal residual disease: Therapeutic goal or prognostic

marker? Role of consolidation/maintenance therapy Optimal sequence/combinations for relapsed/refractory

MM Aggressiveness of relapse

SCT = stem cell transplant..

Defining Risk

Are There High-Risk Features?

International Staging System Stage III Genetic abnormalities

del(13), hypodiploidy t(4;14), t(14;16), or del(17p) by FISH 1q+

Elevated LDH Gene expression profiles

FISH = fluorescent in situ hybridization.

Risk Stratification

High Risk

FISH: 17p

deletion t(14;16) t(14;20)

GEP: High risk

signature

Standard Risk

Trisomies t(11;14)

Intermediate Risk

FISH: t(4;14) 1q +

Complex karyotype

del 13 metaphase

GEP = gene expression profile. Dispenzieri et al, 2007; Kumar et al, 2009; Mikhael et al, 2013.

Survival Based on Risk

High-risk myeloma: Survival remains lower even in the era of novel

therapies

↑ risk of early mortality with ↑ risk factors: age >70 yrs, albumin <3.5 g/dL, B2M >6.5

µg/mL

Kumar, Dispenzieri et al, 2014.

SCT Considerations

Factors Affecting Transplantation Eligibility

Age >70 years of age may not be eligible Older patients more sensitive to toxicity; less physical

reserve Performance status Comorbidities

Renal impairment Cardiovascular disease Pulmonary disease Hepatic disease

High-Dose Melphalan + ASCT vs MPR in Newly Diagnosed MM

Randomized, controlled phase III trial exploring utility of high-dose melphalan + ASCT consolidation ± lenalidomide maintenance vs MPR consolidation ± lenalidomide maintenance in newly diagnosed MM

ASCT = autologous stem cell transplant; Mel = melphalan; Len = lenalidomide; MPR = melphalan, prednisone, lenalidomide; PFS = progression-free survival.Palumbo, Cavallo et al, 2014.

PFS, OS From Time of Diagnosis

Mel + ASCT + Len maintenanceMel + ASCT with no maintenance

MPR + Len maintenanceMPR with no maintenance

100

75

50

25

00 6 1

218

24

30

36

42

48

54

66

Months

PFS

(%)

21.8

60

54.737.434.2

100

75

50

25

00 6 1

218

24

30

36

42

48

54

66

Months

OS

(%)

60

(N=273)

IFM/DFCI 2009: Frontline RVd ± ASCT in Younger Patients (<65 Yrs) With MM

Outcome, % RVd + ASCT(n=350)

RVd Only(n=350) HR (95% CI), P Value

4-Yr PFS 47 35 0.69 (0.56-0.84), <0.001

4-Yr OS 81 83 1.2 (0.7-1.8), NS

SPM 5 3

ORR 99 98

≥VGPR 88 78 0.001

ORR = overall response rate; RVd = lenalidomide, bortezomib, dexamethasone; SPM = second primary malignancy; NS = not significant.Attal et al, 2015.

N=700 previously untreated patients <65 years of age

PFS benefit in ASCT arm uniform across subgroups Age ≤ or >60 years), sex, lg isotype (IgG or others), ISS stage (I, II, or III),

cytogenetics (standard or high risk), and response after the first 3 cycles of RVd (complete response or not)

Induction Therapy

Case Presentation

79-year-old man presents with nausea, lower abdominal pain, and fatigue

Physical examination: T 36.4 ˚C, BP 196/95 mmHg, P 75 beats/min,R 20 breaths/min, weight 70 kg – unremarkable

Assessments Hb 9.6 g/dL Serum creatinine 1.5 mg/dL Calcium 9.9 mg/dL IgG 907 mg/dL, IgA 43 mg/dL, IgM 9 mg/dL,

lambda light chain 20,200 mg/dL B2M 20.9 mg/L Albumin 4.9 g/dL Bone marrow examination:

– 60% monoclonal plasma cells– del(13q) by cytogenetic analysis– t(4;14) by FISH

Skeletal survey shows multiple lytic lesions throughout axial skeletonT = temperature; BP = blood pressure; P = pulse rate; R = respiration rate.

Goals of Induction Therapy

Deep, rapid, and durable responses Improve performance status and quality of life Not limit PBSC mobilization in younger patients 3-drug combinations preferred Maximize the duration of response

Current questions: Optimal regimen and duration of therapy? Do these differ in

non-transplant candidates?

PBSC = peripheral blood stem cells.

Regimens Survival

Bortezomib/lenalidomide/dexamethasone (RVd)

18-mo PFS: 75% 18-mo OS: 97%

Carfilzomib/lenalidomide/dexamethasone (KRd)

12-mo PFS: 97%24-mo PFS: 92%3-yr PFS: 79%3-yr OS: 96%

Carfilzomib/thalidomide/dexamethasone (KTd) 3-yr PFS: 72%

Bortezomib/cyclophosphamide/dexamethasone (CyBorD)

5-yr PFS: 42%5-yr OS: 70%

Ixazomib/lenalidomide/dexamethasone

12-mo PFS: 88%12-mo OS: 94%

Earlier Phase Studies: Induction Regimens for Transplant-Eligible Patients

Richardson et al, 2010; Jakubowiak et al, 2012; Jasielec & Jakubowiak, 2013; Sonneveld et al, 2015; Reeder et al, 2014; Kumar, Berdeja et al, 2014.

RVdPt

s A

chie

ving

≥VG

PR (%

)KRd

KTd

CyBorD

Ixazo

mib/RD

67

81

6862 58

100

80

60

40

20

0

EVOLUTION Trial: Combinations of VD With Cyclophosphamide or Lenalidomide

Randomized phase II trial of VDC vs VDR vs VDCR in previously untreated MM

V = bortezomib; D = dexamethasone; R = lenalidomide; C = cyclophosphamide. Kumar, Flinn et al, 2012.

900

720

600

480

420

180

840

300

240

VDCR (n=48) VDR (n=42) VDC (n=33) VDC-mod (n=17)

1.0

0.8

0.6

0.4

0.2

0

Prop

ortio

n of

Pat

ient

s

Days

0 60 120

360

540

660

780

PFS, Not Censored for ASCTVDC-mod

VDR

VCDR

VDC

1.0

0.8

0.6

0.4

0.2

0

OS

VDR

VCDR

VDC

900

720

600

480

420

180

840

300

240

Days

0 60 120

360

540

660

780

Prop

ortio

n of

Pat

ient

s

MMRC: Extended KRd Treatment With ASCT in Newly Diagnosed Myeloma

Open-label, single arm phase II trial exploring utility of extended KRd treatment with transplant in NDMM (N=62) Treatment: KRd induction (4 cycles) → ASCT and KRd consolidation and maintenance

(cycles 5-18); further R maintenance off-protocol

KRd + ASCT produced a higher sCR rate at 8 cycles vs historical controls without ASCT (71% vs 30%); AEs similar to historical controls

NDMM = newly diagnosed multiple myeloma; AEs = adverse events; nCR = near complete response; sCR = serum complete response.Zimmerman et al, 2016.

Res

pons

e (%

)

100

80

60

40

20

0

85

2112 8

97

3224 22

100 100 100

717587 87 87

≥VGPR≥nCR≥CRsCR

Induction(n=48)

ASCT(n=37)

Consolidation(n=24)

End of KRd(n=8)

Modified Lenalidomide, Bortezomib, and Dexamethasone in ASCT-Ineligible Patients

Phase II trial exploring utility of modified RVd (RVd lite); N=53 Lenalidomide: single daily oral dose of 15 mg D 1-21 Bortezomib: 1.3 mg/m2 SC once weekly on D 1, 8, 15, 22 Dexamethasone: 20 mg twice weekly if ≤75 yrs or

once weekly if >75 yrs RVd lite resulted in 90% ORR (≥PR), 43% ≥VGPR

5 patients discontinued study after <4 cycles; reasons included worsening adrenal insufficiency, rash attributed to lenalidomide, travel distance

AEs manageable in an older population Grade ≥3 AEs: hypophosphatemia (31%), rash (10%)

PR = partial response; SC = subcutaneously.O’Donnell et al, 2015.

Suggested Empiric Age-Adjusted Dose Reduction in Patients With Myeloma

Agent Younger Than 65 Yrs 65-75 Yrs Older Than 75 Yrs

Dexamethasone40 mg/d D 1-4, 15-18 q4w or D 1, 8, 15, 22 q4w

40 mg/d D 1, 8,1 5, 22 q4w

20 mg/dDays 1, 8, 15, 22 q4w

Melphalan 0.25 mg/kg D 1-4 q6w 0.25 mg/kg D 1-4 q6w or 0.18 mg/kg D 1-4 q4w

0.18 mg/kg D 1-4 q6w or 0.13 mg/kg D 1-4 q4w

Cyclophosphamide300 mg/d D 1, 8, 15, 22 q4w 300 mg/d D 1, 8, 15 q4w

or 50 mg/d D 1-21 q4w

50 mg/d D 1-21 q4w or 50 mg/d QOD D 1-21 q4w

Thalidomide 200 mg/d 100 mg/d or 200 mg/d 50 mg/d to 100 mg/d

Lenalidomide 25 mg/d D 1-21 q4w 15-25 mg/d D 1-21 q4w 10-25 mg/d D 1-21 q4w

Bortezomib 1.3 mg/m2 bolus D 1, 4, 8, 11 q3w

1.3 mg/m2 bolus D 1, 4, 8, 11 q3w orD 1, 8, 15, 22 q5w

1.0-1.3 mg/m2 bolus D 1, 8, 15, 22 q5w

Palumbo et al, 2011.

Risk-Based Decision Making

Bortezomib Partially overcomes adverse effect of t(4;14) and possibly

del(17p) Lenalidomide

May improve PFS of t(4;14) and del(17p) (conflicting data) but does not improve overall survival

Pomalidomide May improve outcomes in del(17p)

Combined lenalidomide and proteasome inhibition RVd – reduces adverse effect of t(4;14) and del(17p) on PFS KRd – ASPIRE trial suggests benefit across cytogenetic groups

Sonneveld et al, 2013; Avet-Loiseau et al, 2010; Palumbo, Bringhen et al, 2014; Attal et al, 2012; Palumbo et al, 2012; McCarthy et al, 2012; Benboubker et al, 2014; Dimopoulos et al, 2015; Leleu et al, 2015; Richardson et al, 2010; Roussel et al, 2014; Stewart et al, 2015.

Other Considerations Lenalidomide

Embryo-fetal toxicity warning: – Lenalidomide, a thalidomide analogue, caused limb abnormalities in a developmental monkey study

similar to birth defects caused by thalidomide in humans. If lenalidomide is used during pregnancy, it may cause birth defects or embryo-fetal death

Venous thromboembolism (VTE) warning: – Significantly increased risk for deep vein thrombosis and pulmonary embolism, as well as risk for

myocardial infarction and stroke in MM patients receiving lenalidomide with dexamethasone. Antithrombotic prophylaxis is recommended

Bortezomib Drug interactions:

– Coadministration with strong CYP3A4 inhibitors may increase bortezomib exposure. Closely monitor patients receiving bortezomib in combination with strong CYP3A4 inhibitors

– Coadministration with strong CYP3A4 inducers may decrease bortezomib exposure. Avoid concomitant use of strong CPY3A4 inducers

Pomalidomide Embryo-fetal toxicity warning:

– Pomalidomide is contraindicated during pregnancy. Pomalidomide is a thalidomide analogue. Thalidomide is a known human teratogen that causes severe life-threatening birth defects

VTE warning:– Deep vein thrombosis and pulmonary embolism occur in MM patients receiving pomalidomide

Ixazomib Drug interactions: Avoid concomitant use with strong CYP3A inducers (eg, rifampin,

phenytoin, carbamazepine, St. John’s Wort)

Revlimid® prescribing information, 2015; Velcade® prescribing information, 2014; Pomalyst® prescribing information, 2013; Ninlaro® prescribing information, 2015.

Case Presentation

79-year-old man presents with nausea, lower abdominal pain, and fatigue

Physical examination: T 36.4 ˚C, BP 196/95 mmHg, P 75 beats/min, R 20 breaths/min, weight 70 kg – unremarkable

Assessments Hb 9.6 g/dL Serum creatinine 1.5 mg/dL Calcium 9.9 mg/dL IgG 907 mg/dL, IgA 43 mg/dL, IgM 9 mg/dL,

lambda light chain: 20,200 mg/dL B2M 20.9 mg/L Albumin 4.9 g/dL Bone marrow examination:

– 60% monoclonal plasma cells– del(13q) by cytogenetic analysis– t(4;14) by FISH

Skeletal survey shows multiple lytic lesions throughout axial skeleton

Case Presentation (cont.)

What would you choose as the optimal initial therapy? Cyclophosphamide/bortezomib/dexamethasone Lenalidomide/bortezomib/dexamethasone Carfilzomib/lenalidomide/dexamethasone Lenalidomide/dexamethasone

What factors do you take into consideration? Would your decision differ:

If the patient was 59 years old? If the patient had cardiac disease? If the patient had renal failure? If the genetics differed?

Depth of Response

Achieving ≥VGPR or CR Should Be the Goal of Therapy

Achieving ≥ VGPR

CR = complete response; PD = progressive disease; SD = stable disease.Harousseau et al, 2009; Kapoor et al, 2013.

Patients with sCR have a significantly improved outcome Estimated 5-yr OS 80% with sCR vs 53% with CR or 47% with

nCR

Prob

abili

ty o

f OS

1.00

0.8

0.4

0.2

04 5 6 7

Years Since Transplant

CR or betterVGPR

1 2 3

0.6

PRSD

PD

Achieving CR

1.00

0.75

0.50

0.25

0

Prob

abili

ty o

f OS

Years Since Transplant

CR + VGPR (n=445)

PR (n=288)

P=0.0017

4 5 6 7 81 2 30

CR Correlates With Long-Term Survival in Elderly Patients Treated With Novel Agents

Retrospective analysis: 3 randomized trials of GIMEMA and HOVON (N=1,175) First-line treatment: MP (n=332), MPT (n=332), VMP (n=257), VMPT-VT

(n=254)

MP = melphalan, prednisone; MPT = melphalan, prednisone, thalidomide; VMP = bortezomib, melphalan, prednisone; VMPT-VT = bortezomib, melphalan, prednisone, thalidomide plus maintenance bortezomib/thalidomide.Gay et al, 2011.

PFS

P<0.001 P<0 .001

Pts Older Than 75

Yrs of Age

P=0.001 P=0.004

All Pts

OS

Prob

abili

ty o

f PF

S

1.0

0.8

0.6

0.4

0.2

0

CRVGPRPR

0 24 48 72

Prob

abili

ty o

f OS

1.0

0.8

0.6

0.4

0.2

0

CRVGPRPR

0 24 48 72

Prob

abili

ty o

f PF

S

0.8

0.6

0.4

0.2

0

CRVGPRPR

0 24 48 72Months

1.0

Prob

abili

ty o

f OS

1.00.8

0.6

0.4

0.2

0

CRVGPRPR

0 24 48 72Months

Minimal Residual Disease:

Role in Myeloma

How Do We Define MRD?

Flow cytometry Next-generation sequencing Imaging – PET/CT

0 12 24 36 48 60 72

1.0

0.8

0.6

0.4

0.2

00 6 12 18 24 30 36 42

8-Color Flow Next-Gen Sequencing PET/CT

TTP

(%)

100

80

60

40

20

0100 1500 50

P=0.001

n=26

n=36

TTP (CR Pts)

MRD- MRD+

MRD-MRD+Overall

Months

PFS

(Pro

port

ion)

Months

1.0

0.8

0.6

0.4

0.2

0P=.010

PFS (CR Pts After First-line Therapy)

PET CRmedian: 90 mo

NO PET CRmedian: 50 mos

Months

PFS

PFS

(Pro

port

ion)

MRD Assessment/Outcome

TTP = time to progression.Roussel et al, 2014; Martinez-Lopez et al, 2014; Zamagni et al, 2011; Zamagni et al, 2013.

IFM 2009: Frontline RVd ± ASCT: MRD Negativity Predicts PFS

Avet-Loiseau et al, 2015.

Role of MRD Assessment

Currently a research tool but progressing rapidly toward clinical approval New IMWG response criteria forthcoming Lower levels of MRD predictive of better outcomes Potential to monitor efficacy of therapy and improve definition

of response Relapse occurs even in MRD-negative patients Many questions remain:

Optimal approach? Should therapy be changed based on results of MRD testing?

Maintenance Therapy

Lenalidomide Maintenance After ASCT in MM: Meta-Analyses

IFM = Intergroupe Francophone du Myélome; NCI = National Cancer Institute.Attal et al, 2016; McCarthy et al, 2012; Attal et al, 2012; Palumbo et al, 2014.

Study Treatment Arms Pts, n

CALGB 100104 Lenalidomide maintenancePlacebo

231229

IFM 2005-02 Lenalidomide maintenancePlacebo

307307

GIMEMA(RV-MM-PI-209)

Lenalidomide maintenanceNo maintenance

6768

3 of 17 identified studies fulfilled criteria

Lenalidomide maintenance given until progression IFM elected to discontinue lenalidomide in 2010 following

second primary malignancy signal CALGB and GIMEMA continued until progression

Cumulative Incidence of Second Primary Malignancies by Treatment

Cum Incidence, %

Solids SPM Hematological SPM3 Yrs 5 Yrs 3 Yrs 5 Yrs

Len + Mel 2.7 4.4 1.8 3.9

Len + Cyclo 3.5 NE 0.3 NE

Len + Dex 2.2 2.6 0.3 1.3

No Len 2.9 3.4 0.4 1.4

Cyclo = cyclophosphamide; Dex = dexamethasone; NE = not evaluable. Palumbo et al, 2014.

10

5

70

1 2 3 4 5 60 1 2 3 4 5 6 70

Len + MelLen + CycloLen + DexNo Len (Mel regimens)

Solid SPMs Hematological SPMsLen + MelLen + CycloLen + DexNo Len (Mel regimens)

Cum

ulat

ive

Inci

denc

e (%

)

Cum

ulat

ive

Inci

denc

e (%

) 10

5

0

Years Years

Lenalidomide Maintenance After ASCT in MM: Conclusions

Meta-analysis: Lenalidomide maintenance significantly increased OS post-ASCT in MM Effect seen in all studies; magnitude varied Estimated median OS improvement 2.5 yrs Benefit seen in most subgroups except high-risk cytogenetics HR 1.18 (95% CI:0.66-2.10)

Survival benefit outweighs risk for second primary malignancies

Evidence suggests lenalidomide maintenance post-ASCT should be standard of care in MM MRD may have role in guiding treatment decisions Unclear whether all patients benefit from maintenance

Attal et al, 2016.

FIRST Trial: Efficacy Analysis of Len/Dex vs MPT in SCT-Ineligible Patients

Rd18 = 18 weeks of lenalidomide, low-dose dexamethasone.Benboubker et al, 2014.

Median PFS, Mo

Rd (n=535) 25.5Rd18 (n=541) 20.7MPT (n=547) 21.2

HR (P Value)Rd vs MPT: 0.72 (0.00006)Rd vs Rd18: 0.70 (0.00001) Rd18 vs MPT: 1.03 (0.70349)

4-Yr OS, %Rd (n=535) 59.4Rd18 (n=541) 55.7MPT (n=547) 51.4

HR (P Value)Rd vs MPT: 0.78 (0.0168)Rd vs Rd18: 0.90 (0.307) Rd18 vs MPT: 0.88 (0.184)

100

80

60

40

20

0

100

80

60

40

20

0

Progression-Free Survival (Mo)

Prog

ress

ion-

Free

Sur

viva

l (%

)

0 6 12 18 24 30 36 42 48 54 60

72 w

ks

Overall Survival (Mo)

Ove

rall

Surv

ival

(%)

0 6 12 18 24 30 36 42 48 54 60

Overall response (continuous Rd vs MPT): 75% vs 62% (P <0.00001) Similar, tolerable safety profiles between treatment groups Incidence of second primary malignancies: 3% with continuous Rd vs 6% with Rd18 vs

5% with MPT

Relapsed and Relapsed/Refractory

Myeloma

Case Presentation

72-year-old man diagnosed with ISS stage III MM in 2010. At presentation, FISH showed hyperdiploid MM Enrolled in a clinical trial and received RVd x 8 cycles followed

by ASCT Achieved CR (MRD testing was not performed) and began

lenalidomide maintenance (10 mg) Is 5.5 years post-SCT with evidence of relapsed disease based

on emergent M spike of 0.5 g/dL What would you do next?

Case Presentation (cont.)

52-year-old man who was diagnosed with ISS stage III MM in 2015. At presentation, FISH showed 1q+, t(4;14), and del(17p). Enrolled in a clinical trial and received KRd x 8 cycles followed

by ASCT Achieved CR and began lenalidomide maintenance (10 mg) Is 1 year post-SCT with evidence of relapsed disease based on

emergent M spike of 0.5 g/dL What would you do next?

Confronting Disease Relapse in Myeloma

EFS = event-free survival.Kumar et al, 2004; Kumar, Lee et al, 2012.

Patie

nts

(%)

100

80

60

40

0

20

0 12 24 36 48 60

Months From Time Zero

OSEFS

Events/N170/286217/286

Median, Mo

9 (7-11)5 (4-6)

12

10

8

6

0

2

First Second Third Fourth Fifth Sixth

Treatment Regimen

Med

ian

Res

pons

e D

urat

ion

(Mo)

4

Considerations in Relapsed Myeloma

Does this patient need treatment? Are there new high-risk features? What drugs have been used thus far? Response to

previous treatments? (efficacy, duration of response, toxicity)

How fit is the patient (PS, marrow reserve)? What are the patient’s goals/preferences?

PS = performance status.

ASPIRE: KRd vs Rd: Interim OS Analysis

OS results did not meet prespecified statistical boundary (P=0.005) at interim AEs consistent with previous studies; no unexpected toxicities observed

Grade ≥3 cardiac failure and ischemic heart disease: 3.8% and 3.3% in KRd arm vs 1.8% and 2.1% in Rd arm, respectively

NR = not reached.Stewart et al, 2015.

KRd Rd(n=396) (n=396)

Median OS, mo NR NRHR (KRd/Rd) (95% CI) 0.79 (0.63-0.99)P value .04

Median follow-up: 32 mo

1.0

0.8

0.6

0.4

0.2

0

Pro

porti

on S

urvi

ving

KRdRd

0 6 12 18 24 30 36 42 48Months Since Randomization

Pomalidomide + Low-Dose Dexamethasone in Relapsed/Refractory MM

Pom + LoDex approved for relapsed MM following ≥2 lines of therapy

Phase II MM-002 study (N=221): ORR of 33% with Pom + LoDex vs

18% with Pom DoR of 8.3 mo with Pom +

LoDex vs 10.7 mo with Pom Low rates of discontinuations

due to AEs– Grade 3/4 neutropenia occurred in

41% of Pom + LoDex patients, and 48% of Pom patients

– No grade 3/4 peripheral neuropathy reported

LoDex = low dose dexamethasone.Richardson et al, 2014.

PFS

Median PFS, Mo4.22.7

Pom + LoDexPom

100

80

60

40

20

0

Patie

nts

(%)

0 5 2010 15 25 30

PFS (Mo)

HR: 0.68P= 0.003

Phase I/II Study of KPd in Relapsed/Refractory Multiple Myeloma

Relapsed/refractory MM with measurable disease after ≥1 prior therapy MTD: Carfilzomib 27 mg/m2/dose D 1,2,8,9,15,16 every 28 d,

Pomalidomide 4 mg x 21 d, Dexamethasone 40 mg D 1,8,15 Median follow-up 17.9 mo (range 0.3–40.6)

KPd = carfilzomib, pomalidomide, dexamethasone.Rosenbaum et al, 2016.

Outcome PFS (n=56) OS (n=56)Median duration, mo 12.9 NR1-yr rate, % 53 912-yr rate, % 22 78

ITT Response, % All Evaluable Pts Primary Study Population*

Best response (n=55) (n=45)

• CR/nCR 16 13

• ≥VGPR 47 44

• ≥PR 84 84

• ≥MR 93 96

60

100

Bort/Dex ± Panobinostat in RR Myeloma: Pts who Received Prior Bort and IMiDs

Subgroup analysis of patients who received ≥2 previous treatments, including bortezomib and an IMiD FDA approved indication based on subgroup analysis

PFS

Pro

babi

lity,

(%)

RR = relapsed/refractory; IMiD = immunomodulatory drug.Richardson et al, 2016.

Time (months)

80

40

20

00 2 4 6 8 10 12 14 16 18 20 22 24 26 28

Pan/bort/dexPlacebo/bort/dex

Median PFS, Mos (95% CI)

Events, n/N

44/7354/74

12.5 (7.3-14.0)4.7 (3.7-6.1)

HR(95% CI)

0.47 (0.31-0.72)

Phase II SIRIUS: Daratumumab Showed Activity in Heavily Pretreated MM

Median PFS: 3.7 mo (95% CI: 2.8-4.6); 1-yr OS: 65% (95% CI: 51.2-75%) Most common grade 3/4 AEs: thrombocytopenia (25%), anemia (24%), and

neutropenia (14%); infusion-related reactions occurred in 43% (most grade 1/2)

Lonial, Weiss et al, 2015.

sCR 3%

VGPR 9%

PR 17%

Overall Pt

Population

0

15

20

25

30

35

Pts

Ach

ievi

ng

Obj

ectiv

e R

espo

nse

(%) 29

Age ≥75

yr

10

5

CrCl ≥

60 m

L/min

>3 Lines

of Tx

Extram

edulla

ry

High-Risk

Cytogen

etics

PIs an

d IMiD

Carfilz

omib

Pomalidomide

Carfilz

omib/

Pomalidomide

Bortezo

mib/

Lenolid

omide

Bortezo

mib/

Lenolid

omide/

Carfilz

omib/

Pomalidomide

33 3330

21 20

30 29 28 28 26

21

ORR by Subgroup ORR by Refractory Status

0.8

CASTOR: Daratumumab Improves PFS

Pro

gres

sion

-Fre

e S

urvi

val (

%)

0

0.2

0.4

0.6

1.0

0 3 6 9 12 15Months

1-Yr PFS*

60.7%

26.9%DVdVd

Median (mo)NR7.2

HR: 0.39 (95% CI: 0.28-0.53; P<0.0001)

DVd = daratumumab/bortezomib/dexamethasone; Vd = bortezomib/dexamethasone;VGPR = very good partial response.Palumbo et al, 2016.

ELOQUENT-2: Anti-SLAMF7 Monoclonal Antibody Elotuzumab + Rd vs Rd

PFS benefit seen with elotuzumab in all predefined subgroups

Lonial, Dimopoulos et al, 2015.

Outcome Elotuzumab + Rd(n=321)

Rd(n=325) HR (95% CI)

PFS Median, mo 1 Yr, % 2 Yrs, % 3 Yrs, %

19.4684126

14.9572718

0.73 (0.60-0.89;P=0.0014)

Median time to next treatment, mo 33 21 0.62 (0.50-0.77)

ORR, % 79 66

Interim OS, mo 43.7 39.6 0.77 (0.61-0.97;P=0.0257)

TOURMALINE-MM1: Ixazomib Efficacy

PFS benefit with ixazomib seen in all prespecified subgroups, including cytogenetic high risk, PI, and IMiD exposed

Grade 3/4 AEs occurred in 74% of the ixazomib group and 69% of the placebo group Thrombocytopenia: 19% in ixazomib group, 9% in placebo group Rash: 36% in ixazomib group, 23% of placebo group Peripheral neuropathy: 27% in ixazomib group, 22% in placebo group

aHR: 0.742; bHR: 0.712.PI = proteasome inhibitor.Moreau et al, 2016.

Characteristic Ixazomib + Rd(n=360)

Placebo + Rd(n=362) P Value

Median PFS, mos 20.6 14.7 0.012a

ORR, % CR VGPR PR

78.311.736.466.7

71.56.6

32.364.9

0.0350.019

Median time to response, mos 1.1 1.9

Median DoR, mos 20.5 15.0

Median TTP, mos 21.4 15.7 0.007b

Case Presentation

72-year-old man diagnosed with ISS stage III MM in 2010. At presentation, FISH showed hyperdiploid MM Enrolled in a clinical trial and received RVd x 8 cycles followed

by ASCT Achieved CR (MRD testing was not performed) and began

lenalidomide maintenance (10 mg) Is 5.5 years post-SCT with evidence of relapsed disease based

on emergent M spike of 0.5 g/dL What would you do next?

Case Presentation: Next Steps

Repeat staging including: Bone marrow aspirate and genetic testing Skeletal imaging Serum and urine assessment of disease

Treatment considerations: Genetic changes Prior therapy Comorbid illnesses Patient preference

Case Presentation

52-year-old man diagnosed with ISS stage III MM in 2015. At presentation, FISH showed 1q+, t(4;14) and del(17p) Enrolled in a clinical trial and received KRd x 8 cycles followed

by ASCT Achieved CR and began lenalidomide maintenance (10 mg) Is 1 year post-SCT with evidence of relapsed disease based on

emergent M spike of 0.5 g/dL What would you do next?

Case Presentation: Next Steps

Repeat staging including: BM aspirate and genetic testing Skeletal imaging Serum and urine assessment of disease

Treatment Considerations: Genetic changes Prior therapy Comorbid illnesses Patient preference

Key Takeaways

Treatment landscape in myeloma is rapidly evolving with many emerging therapies that have translated into improved survival

Patients should be risk stratified based on clinical and genetic features that can help guide therapeutic decisions

Depth of response matters and is generally associated with superior outcomes

MRD testing is rapidly moving to clinical application offering the potential of recognizing deeper remissions, raising questions as to what to do for those who remain MRD positive

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