Smoldering Multiple Myeloma

Kim, Byung-Su MD, PhD

Hallym University Dongtan Sacred Heart Hospital

1

I have no personal or financial interests to declare:

I have no financial support from an industry source at the curre

nt presentation.

대한혈액학회 Korean Society of Hematology

COI disclosure

Name of author ： Byung-Su Kim

The term ‘Smoldering Multiple Myeloma’ was coined in 1980 by RA Kyle.

(Kyle RA, NEJM 1980)

2003 IMWG Criteria of SMM (Kyle RA)

• M-protein in serum ≥3 g/dl and/or BM plasma cells ≥10%

• No end organ damage or symptoms

– Calcium in serum >11 mg/dl or >1 mg/dL higher than ULN

– Renal insufficiency: serum Cr >2 mg/dl

– Anemia: Hb <10 g/dl or >2 g/dL below LLN

– Bone: ≥1 osteolytic lesions (CT or MRI may clarify)

– Other: symptomatic hyperviscosity, amyloidosis, recurrent bacterial

infections (> 2 episodes in 12 months)

Maintained with minor changes until 2010 IMWG recommendation (Kyle RA, Leukemia 2010)

Progression

0.5~1%/year

10%/year (0~5 yr),

3%/year (5~10 yr),

1%/year (10~ yr)

(Kyle RA, NEJM 2007)

Prognostic Model for Progression Risk

Mayo Clinic (Blood 2008)

1 point for meeting each of

– BMPC ≥10%

– Serum M protein ≥3 g/dl

– Serum i/u FLC >8

PETHEMA (Blood 2007)

1 point for meeting each of

– Aberrant PC ≥95% of BMPC on flow cytometry

– Immunoparesis: reduction below the lower normal limit in the levels of 1 or 2 uninvolved Ig

Clinical Features of Korean SMM Patients (KMM172 Study)

• Retrospective study enrolling Korean SMM patients defined by 2003 IMWG criteria

Year of Diagnosis

2003~2005 7

2006~2008 11

2009~2011 12

2012 12

2013 15

2014 17

2015 13

2016~2017 9

Total 96

Age

Median 60.2

Range 35.2 ~ 88.0

≤65 66 (68.3%)

>65 30 (31.3%)

Total 96 (100.0%)

Gender

Male 52 (54.2%)

Female 44 (45.8%)

Total 96 (100.0%)

Time to progression (active MM)

8

TTP 1 yr 2 yr 3 yr 4 yr 5 yr

N=96 8.0% 22.0% 29.2% 35.7% 45.2%

Progression to Active MM

No 64 (66.7%)

Yes 32 (33.3%)

Progression events

Anemia 15 (46.9%)

Bone disease 17 (53.1%)

FLC ratio >100 3 (9.4%)

>1 focal lesions on MRI 3 (9.4%)

Renal failure 3 (9.4%)

~9%/year

TTP: Log-rank test

P=0.034 P=0.002

9

rFLC>100 rFLC≤100 BMPC>35 BMPC≤35

TTP 1 yr 2 yr 3 yr 4 yr 5 yr

rFLC≤100 5.5% 16.5% 21.2% 24.3% 36.7%

rFLC>100 0.0% 48.6% 48.6% 74.3% 74.3%

TTP 1 yr 2 yr 3 yr 4 yr 5 yr

BMPC≤35% 5.5% 16.2% 20.7% 28.8% 37.1%

BMPC>35% 25.0% 50.0% 73.3% 73.3% 73.3%

Risk Models for Stratification of SMM Mayo Clinic # of Factor Median TTP Japanese # of Factor 2-year TTP

≥10% clonal BMPC infiltration 1 10 yr Beta 2-microglobulin ≥2.5 mg/L 2 67.5%

≥3 g/dL of serum M-protein 2 5 yr M-protein increase rate >1 mg/dL/d

sFLC ratio between <0.125 or >8 3 1.9 yr Czech and Heidelberg # of Factor 2-year TTP

Spanish Myeloma # of Factor Median TTP Immunoparesis 0 5.3%

≥95% of aberrant PCs by MFC 0 NR Serum M-protein ≥2.3 g/dL 1 7.5%

Immunoparesis 1 6 yr Involved/uninvolved sFLC >30 2 44.8%

2 1.9 yr 3 81.3%

Heidelberg TM/CA 3-year TTP Barcelona Points 2-year TTP

Tumor mass using the Mayo Model Low/low 15% Evolving pattern = 2 point 0 2.4%

Low/High 42% Serum M-protein ≥3 g/dL = 1 pt 1 31%

t(4;14), del17p, or +1q

High/Low 64% Immunoparesis = 1 point 2 52%

High/High 55% 3 80%

SWOG # of Factor 2-year TTP Mayo Clinic evolving model # of Factor Median TTP

Serum M-protein ≥2 g/dL 0 30% Evolving M protein 0 12.3 yr

Involved FLC >25 mg/dL 1 29% Evolving Hb 1 4.2 yr

GEP risk score >-0.26 ≥2 71% ≥20% BMPC 2 2.8 yr

U Penn # of Factor 2-year TTP 3 1 yr

≥40% clonal BMPC infiltration 0 16% Danish # of Factor 3-year TTP

sFLC ratio ≥50 1 44% Serum M-protein ≥3 g/dL 0 5%

Albumin ≤3.5 mg/dL ≥2 81% Immunoparesis 1 21%

2 50%

Waiting until CRAB Features Develop?

• The ‘waiting’ strategy for SMM has no longer been justified.

– Safer and more effective novel agents

– More sensitive laboratory tests and imaging modalities

Ultra-High Risk SMM

In 2011 summit, IMWG reached a consensus that patients should be

regarded as having active myeloma and offered therapy if they

have risk factors associated with 80% progression risk within 2

years.

2014 Updated IMWG Criteria

(Rajkumar SV, Lancet Oncol 2014)

Smoldering MM: both criteria must be met

• Serum monoclonal protein (IgG or IgA) ≥3 g/dL or urinary monoclonal

protein ≥500 mg per 24 h and/or BM plasma cells 10–60%

• Absence of myeloma defining events or amyloidosis

– CRAB

– BM plasma cells ≥60%

– Involved:uninvolved serum FLC ratio ≥100 (involved ≥100 mg/l)

– >1 focal lesions on MRI

Ultra-High Risk

SMM: Progression to Active Myeloma

High-risk SMM (~50% risk of progression within 2 years): clonal BMPC

≥10% and any one of (Rajkumar SV, Blood 2015)

• Serum M protein ≥3 g/dL

• IgA SMM

• Immunoparesis with reduction (>25%

below LLN) of 2 uninvolved Ig isotypes

• Serum involved/uninvolved FLC ratio ≥8

(but <100)

• Increasing M protein: ≥25% on 2

consecutive measures within 6 month

• B-J protein positive from 24-h urine

• Peripheral blood circulating plasma

cell >5 /mL

• Clonal BMPC 50-60%

• Decrease of Hb in ≥0.5 g/dL within 12

months of diagnosis

• Diffuse or 1 focal lesion (FL) on MRI

• Newly detected FLs or increase in size

of existing FL on FL

• Increased circulating PCs

• High-risk cytogenetics [del 17p, t(4;14) ,

1q gain, hyperdiploidy]

• PET-CT with focal lesion with increased

uptake (no osteolytic bone lesion)

Diagnosis of Smoldering MM

Distinguishing from Active MM

However, Things Are Not

That Straightforward.

BMPC Infiltration

• Based on conventional BM aspiration or biopsy: higher of the two

values

• BMPC enumeration using flow cytometry – not yet

• ‘Clonal’: k/l-light chain restriction on flow cytometry,

immunohistochemistry, or immunoflouresence

• CRAB features cannot be regarded as being attributable to clonal

plasma cell proliferation if BMPC <10% and no biopsy-proven

plasmacytoma repeat BM biopsy showing >10% or presence

of plasmacytoma

Definition of Renal Failure

• Creatinine clearance <40 mL/min or serum creatinine >2 mg/dL

• Measured CrCl or estimated GFR: CKD-EPI (preferred) or MDRD

• eGFR (mL/min) = eGFR (mL/min/1.73m2) x BSA/1.73

• Only renal failure caused by light-chain cast nephropathy fulfils CRAB

– Typical histological changes on kidney biopsy or involved FLC >1500 mg/L

– Selective proteinuria and involved FLC 500-1500 mg/L: a kidney biopsy is probably not

necessary but may be helpful for patients having comorbidities (DM, HT)

– Non-selective proteinuria (albuminuria) or iFLC <500 mg/L: subcutaneous fat biopsy,

kidney biopsy

• Monoclonal gammopathy of renal significance: renal disorders not

regarded as myeloma-defining events

Role of MRI: IMWG Consensus (2015)

• Whole-body MRI or (whole

spine + pelvic) MRI

recommended as initial

assessment (Dimopoulos

MA, JCO 2015)

• Whole-body MRI: T1 &

STIR T2 (head, chest,

abdomen, pelvis, legs) in

coronal + T1 & fsT2 (spine)

in sagittal without Gd

enhance

BM Infiltrations of Plasma Cells

• CT and MRI are equally sensitive and either

test can be used to detect osteolytic bone

lesions

• Most sensitive/specific for detection of BM

infiltration, before mineralized bone is

destroyed

• T1-Low, STIR T2-High, T1-Enhance (+)

• Each focal lesion must be ≥5 mm in size

• Diffuse infiltration, single focal lesion,

equivocal findings f/u in 3-6 months

T1

fsT2

Normal

Focal

Diffuse

Diffuse +

Focal

Variegated

(Dutoit JC, Insights Imaging 2016)

Myeloma Bone Lesions

• One of PET-CT, low-dose whole body CT, or MRI (whole-body or spine)

should be done in all patients with suspected smoldering MM (Kyle RA,

Leukemia 2010)

• One or more sites of osteolytic bone destruction (≥5 mm in size) seen

on CT or the CT portion of PET-CT fulfil the CRAB criteria

• Increased uptake (metabolic focal lesion) on PET-CT: not adequate

• Skeletal survey: still has a role for skull, ribs, clavicles, humeri and femurs

• Care should be taken to avoid over-interpretation of tiny lucencies

correlate with symptoms, repeat in 3-6 months

• ‘Osteoporosis with vertebral compression fracture’ in the absence of lytic

lesions: insufficient for CRAB features

PET-CT: IMWG Consensus (2017)

• Should be considered as part of the initial investigations for newly diagnosed

MM

• The use of PET/CT is mandatory, when whole-body MRI is unavailable

– To confirm a suspected diagnosis of solitary plasmacytoma

– To distinguish between smoldering and active MM

• Optimal to detect extramedullary sites of disease but suboptimal for

detecting diffuse BM plasma cell infiltration and lytic lesions in the skull

• Predicting prognosis (metabolic focal lesions, extramedullary disease)

• Earlier evaluation of response to therapy than MRI scans, particularly helpful

before autologous stem cell transplantation

• Identifies patients who are imaging MRD-negative

(Cavo M, Lancet Oncol 2017)

Treatment of High-Risk Smoldering Myeloma

Len+Dex for High-Risk SMM

PETHEMA (Mateos MV, NEJM 2013)

• Phase 3 study: 119 high-risk SMM

patients randomized to Len + Dex for

9 cycles followed by Len maintenance

for 2 years vs. Observation only

• High-risk SMM defined by the

PETHEMA model

• PR or better in 79% after induction

and 90% during maintenance

• Median TTP: not reached vs. 21

months

• 3yr survival: 94% vs. 80%

Elotuzumab for High-Risk SMM

DFCI (Ghobrial I, ASH 2016)

• Phase 2 study:

Elotuzumab+Rd

• High-risk SMM defined by

Rajkumar (Blood, 2014)

• 51 patients enrolled and 47

patients evaluable

• Response in 82.6% (CR

8.7%, VGPR 26.1%, PR

47.8%)

• No patients had

progressed at 24 months

ASH 2017: Smoldering Myeloma

Phase II GEM-CESAR: KRd + ASCT in

High-Risk Smoldering Myeloma

Integrating New Hematology Findings Into Practice: Independent

Conference Coverage of ASH 2017,* December 9-12, Atlanta, Georgia

*CCO is an independent medical education company that provides state-of-the-art medical information

to healthcare professionals through conference coverage and other educational programs.

This activity is supported by educational grants from AbbVie; AstraZeneca; Celgene Corporation;

Genentech; Janssen Biotech, Inc administered by Janssen Scientific Affairs, LLC; Jazz Pharmaceuticals;

Novartis Pharmaceuticals Corporation; Pharmacyclics Inc; Seattle Genetics; and Takeda Oncology.

GEM-CESAR: Phase II Study Design

Multicenter, open-label trial Induction

6 x 28-day cycle

s

Patients with hig

h-risk* smolderi

ng MM

(N = 90)

Carfilzomib IV 20/36 mg/m2

Days 1, 2, 8, 9, 15, 16

Lenalidomide 25 mg

Days 1-21

Dexamethasone 40 mg

Days 1, 8, 15, 22

High-dose Melphalan

200 mg/m2

followed by ASCT

Carfilzomib IV 20/36 mg/m2

Days 1, 2, 8, 9, 15, 16

Lenalidomide 25 mg

Days 1-21

Dexamethasone 40 mg

Days 1, 8, 15, 22

Consolidation

2 x 28-day cycles

Lenalidomide 10 mg

Days 1-21

Dexamethasone 20 mg

Days 1, 8, 15, 22

Maintenance

24 x 28-day cycles

Mateos MV, et al. ASH 2017. Abstract 402.

Slide credit: clinicaloptions.com

*High risk defined per Mayo and/or Spanish models (pre-2014 diagnostic criteria)

Pts with both BM PCs ≥ 10% and serum M-protein ≥ 3g/dL, or 1 plus > 95% aberrant BM PCs by immunophenotyping plus immunoparesis

Pts w/ bone disease on CT or PET/CT at screening excluded

Primary endpoint: MRD negative rate (by flow cytometry) after induction, ASCT, consolidation/maintenance, and 3 and 5 yrs after maintenance

Secondary endpoints: response, TTP, PFS, OS, safety

GEM-CESAR: Baseline Characteristics

Characteristic Pts (N = 90)

Median age, yrs (range) 59 (33-70)

Serum/urine M protein, g/dL / g/24 hr 2.77 / 0.43

BMPC, % (range) 22 (10-80)

High risk, n (%)

Mayo Clinic model only

Spanish model only

Both

19 (21)

47 (52)

24 (27)

Ultrahigh risk (≥ 1 biomarker), n (%)

sFLC > 100

> 1 focal lesion on MRI

≥ 60% BMPC

30 (33)

18 (20)

11 (12)

7 (8)

PET positive with no lytic lesions, n (%) 5 (6)

Cytogenetic abnormalities, n (%)

Standard risk

High risk

Unknown risk

56 (62)

21 (23)

13 (14)

Mateos MV, et al. ASH 2017. Abstract 402.

Slide credit: clinicaloptions.com

GEM-CESAR: Efficacy at KRd Induction

Mateos MV, et al. ASH 2017. Abstract 402. Slide credit: clinicaloptions.com

Response Category, n (%) Evaluable Pts*

(n = 71)

High Risk

(n = 49)

Ultrahigh

Risk (n = 22)

ORR, n (%) 71 (100) 49 (100) 22 (100)

sCR 21 (30) 17 (34) 4 (18)

CR 11 (15) 5 (10) 6 (27)

VGPR 27 (38) 19 (39) 8 (36)

PR 12 (17) 8 (16) 4 (18)

MRD negative, % 31 25 33

Relapse from CR, n (%) 2 (3)* 1 (2) 1 (4)

Clinical progression, n (%) -- -- --

*2 pts achieved CR but relapsed during induction, 1 pt withdrew from induction.

GEM-CESAR: Efficacy After KRd Consolidation

and Rd Maintenance

Mateos MV, et al. ASH 2017. Abstract 402. Slide credit: clinicaloptions.com

Response Category, n (%) Induction

(n = 71)

HDT ASCT

(n = 42)

Consolidation

(n = 35)

Maintenance

(n = 29)

ORR, n (%) 69 (98) 42 (100) 35 (100) 29 (100)

sCR 21 (30) 22 (52) 24 (69) 24 (83)

CR 9 (13) 2 (5) 2 (6) 2 (7)

VGPR 27 (38) 12 (29) 7 (20) 2 (7)

PR 12 (17) 6 (14) 2 (6) 1 (3)

MRD negative, % 31 50 60 NA

Relapse from CR, n (%) 2 (3) -- -- --

Clinical progression, n (%) -- -- -- --

No pt discontinued consolidation or maintenance.

GEM-CESAR: PFS and OS

Mateos MV, et al. ASH 2017. Abstract 402.

Slide credit: clinicaloptions.com

PFS OS

Median follow-up: 10 mos (range: 1-28)

94% PFS at 28 mos 98% OS at 28 mos

Mos P

rop

ort

ion

Re

ma

inin

g A

live

Pro

po

rtio

n W

ith

ou

t P

rog

ressio

n

2 pts relapsed from CR during induction, proceeded to subseq

uent therapy

2 deaths: 1 due to progression after relapse from CR, 1 due to

ischemic stroke during induction

Mos

1.0

0.

8

0.

6

0.

4

0.

2

0

0 5 10 15 20 25 30 Mos Mos

1.0

0.

8

0.

6

0.

4

0.

2

0

0 5 10 15 20 25 30

GEM-CESAR: Serious AEs and Dose

Modifications

Mateos MV, et al. ASH 2017. Abstract 402. Slide credit: clinicaloptions.com

Treatment-Related Serious AE

(n = 8)

Dose Reductions

(due to Neutropenia, Infection, or Rash)

Pneumonia (n = 1) Carfilzomib: n = 0

Lenalidomide: n = 19

Dexamethasone: n = 10

Melphalan: n = 0

Respiratory infection (n = 1)

Infections (n = 2)

Enterocolitis (n =1)

Cutaneous exanthema (n = 1)

Meningitis (n = 1)

Ischemic stroke (n = 1)

All but 1 serious AE resolved (stroke)

INTENDED FOR INTERNAL USE. ALL MATERIALS/CONTENT ARE SUBJECT TO RELEVANT LOCAL REVIEW PROCESSES (IE, MEDICAL, LEGAL, COMPLIANCE, PRIVACY AND REGULATORY).

Abstract

Daratumumab Monotherapy For Patients With Intermediate or High-risk Smoldering Multiple Myeloma (SMM): CENTAURUS, a Randomized, Open-

label, Multicenter Phase 2 Study*

Craig C. Hofmeister,1 Ajai Chari,2 Yael C. Cohen,3 Andrew Spencer,4 Peter Voorhees,5 Jane Estell,6

Christopher Venner,7 Irwindeep Sandhu,7 Matthew Jenner,8 Catherine Williams,9 Michele Cavo,10

Niels W.C.J. van de Donk,11 Meral Beksac,12 Steven Kuppens,13 Rajesh Bandekar,14 Tobias Neff,14

Christoph Heuck,14 Ming Qi,14 Hartmut Goldschmidt,15 C. Ola Landgren16

1Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, Ohio, USA; 2Tisch Cancer Institute, Mount Sinai School of Medicine, New York, NY, USA; 3Department of Hematology, Tel-Aviv Sourasky (Ichilov) Medical Center, and Sackler

School of Medicine, Tel Aviv University, Israel; 4Malignant Haematology and Stem Cell Transplantation Service, Alfred Health-Monash University, Melbourne, Australia; 5Levine Cancer Institute, Carolinas HealthCare System, Charlotte, NC, USA; 6Haematology Department, Concord Cancer Centre,

Concord Hospital, Concord, NSW, Australia; 7Cross Cancer Institute, University of Alberta, Edmonton, AB, Canada; 8Southampton General Hospital, Southampton, UK; 9Department of Clinical Haematology, Nottingham University Hospitals, Leicestershire, UK; 10“Seràgnoli” Institute of Hematology, Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy; 11Department of Hematology, VU University

Medical Center, Amsterdam, The Netherlands; 12Department of Hematology, Ankara University, Ankara, Turkey; 13Janssen Research & Development, Beerse, Belgium; 14Janssen Research & Development, Spring House, PA, USA; 15University Hospital Heidelberg and German Cancer Research Center,

Heidelberg, Germany; 16Myeloma Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

2*ClinicalTrials.gov Identifier: NCT02316106

CENTAURUS: Study Design

IV, intravenous; QW, once weekly; Q2W, every 2 weeks; Q4W, every 4 weeks; Q8W, every 8 weeks; PD, progressive disease; LPFD,

last patient, first dose; CR, complete response.

1. Rajkumar SV, et al. Lancet Oncol. 2014;15:e538-e548.

Sc

ree

nin

g

1:1

:1 R

AN

DO

MIZ

AT

ION Cycle 1:

QW

Cycles 2 & 3:

Q2W

Cycles 4-7:

Q4W

Cycles 8-20:

Q8W

Cycle 1:

QW

Cycles 2-20:

Q8W

n = 41

n = 41

n = 41

Arm A (16 mg/kg IV; 8-week cycles); Long

Arm B (16 mg/kg IV; 8-week cycles); Intermediate

Arm C (16 mg/kg IV; one 8-week cycle); Short

Following until PD or

end of study

(4 years from LPFD)

Primary endpoints:

• CR

• % patients with

PDa or death per

patient-yearCycle 1:

QW

• CR rate: proportion of subjects who achieve CR in each arm

– First assessed 6 months after last patient randomized

• PD/death rate: ratio of subjects with an event (PD or death) to the total follow-up for all patients

– Assessed 12 months after last patient randomized

– Disease progression to MM assessed according to IMWG guidelines1

• Pre-infusion medication: methylprednisolone 60-100 mg, diphenhydramine 25-50 mg, acetaminophen 650-1,000 mg, montelukast 10 mg (optional)

aAs defined by 2014 IMWG

criteria for SMM.

7

CENTAURUS: Baseline Disease CharacteristicsArm A

Long

(n = 41)

Arm B

Intermediate

(n = 41)

Arm C

Short

(n = 41)

Risk factors at screening,a n (%)

<2

≥2

8 (20)

33 (81)

8 (20)

33 (81)

7 (17)

34 (83)

Type of myeloma, n (%)

IgG

IgA

Others

33 (81)

6 (15)

2 (5)

30 (73)

7 (17)

4 (10)

27 (66)

9 (22)

5 (12)

% plasma cells in bone marrow, n (%)

≥10 to <20%

≥20 to <40%

≥40 to <60%

18 (44)

15 (37)

8 (20)

17 (42)

17 (42)

7 (17)

21 (51)

13 (32)

7 (17)

Median (range) time from SMM diagnosis to

randomization, months 6.47 (0.4-46.2) 5.52 (0.7-46.7) 7.43 (1.0-56.0)

9

aRisk factors include abnormal free light chain ratio (<0.126 or >8), serum M-protein ≥3 g/dL, IgA subtype, urine M-

protein >500 mg/24 hrs, and immunoparesis (at least 1 uninvolved immunoglobulin [IgG, IgA, IgM] decreased more

than 25% below the lower limit of normal).

Baseline disease characteristics are balanced across arms

CENTAURUS: Patient Disposition

Arm A

Long

(n = 41)

Arm B

Intermediate

(n = 41)

Arm C

Short

(n = 41)

Median (range) duration of treatment, months 14.9 (1.0-22.1) 14.8 (1.9-22.1) 1.6 (0-1.9)

Discontinued treatment, n (%)

Adverse eventa

Progressive disease

Refusal of further treatment

Withdrawal of consent

5 (12)

2 (5)

2 (5)

0 (0)

1 (2)

4 (10)

1 (2)

2 (5)

1 (2)

0 (0)

2 (5)

2 (5)

0 (0)

0 (0)

0 (0)

• Prespecified primary analysis: 12 months after randomization of the last patient

• Median follow up: 15.8 (range: 0-23.9) months

aAdverse events included pneumonia, thrombocytopenia, balance disorder, unstable angina, and hypomania (n = 1 each).

10

Low rates of discontinuation

CENTAURUS: Efficacy

aPD/death rate is the ratio of the patients who progressed or died divided

by the total PFS for all patients. bP value for testing the null hypothesis that the PD/death rate

≥0.346/patient-year (corresponding to median PFS ≥24 months).

Co-primary endpoint of CR (>15%) was

not met

PD/Death Ratea

Arm A

Long

(n = 41)

Arm B

Intermediate

(n = 41)

Arm C

Short

(n = 41)

P valueb <0.0001 <0.0001 0.0213

27 2923

27 20

15

25

0

10

20

30

40

50

60

70

80

90

100

Arm ALong Intense

(n = 41)

Arm BIntermediate

(n = 41)

Arm CShort Intense

(n = 40)

OR

R, %

PR VGPR ≥CR

≥VGPR:

29%≥VGPR:

24%≥VGPR:

15%

ORR = 56% ORR = 54%

ORR = 38%

ORR

11

ORR, overall response rate; PR, partial response; VGPR, very good partial response; PFS, progression-free survival.

Arm A

Long

(n = 41)

Arm B

Intermediate

(n = 41)

Arm C

Short

(n = 40)

Co-primary endpoint of median PFS ≥24

months was met

Single-agent daratumumab shows activity in SMM

CENTAURUS: PFS (Biochemical or Diagnostic)

0

20

40

60

80

100

0 3 6 9 12 15 18 24

Months

21

41

41

41

41

41

40

40

34

30

39

33

25

36

28

18

21

16

13

12

7

5

0

0

0

1

1

1

No. at risk

Long

Intermediate

Short

Arm B: Intermediate

Arm A: Long

Arm C: Short

13

•Biochemical/diagnostic PFS is defined

as the earlier of time to biochemical or

diagnostic progression or death

–Biochemical progression:

measurable disease increase

from nadir by ≥25% in 2

subsequent assessments per

IMWG1

–Diagnostic progression: SLiM-

CRAB criteria

•Post-hoc analysis comparing Arm A +

Arm B versus Arm C: P value = 0.0002

93%

75%

56%

Supports the long dosing schedule for the phase 3 study

1. Rajkumar SV, et al. Lancet Oncol. 2014;15:e538-e548.

% s

urv

ivin

g w

ith

ou

t

bio

ch

em

ical/d

iagn

ostic p

rog

ressio

n

NGS Identifies SMM Patients with a High Risk of Disease Progression (ASH 2017;392)

• Methods – WES of 70 tumor-germline matched samples (coverage 50X/100X for

germline/tumor) – Targeted deep sequencing on 116 samples of progressor and non-

progressor SMM (mean target coverage ~500X). – High-risk SMM (HRSMM) and low-risk SMM (LRSMM) were defined

according to the criteria proposed by Rajkumar et al. in Blood 2014.

• Results – Mutation load: LRSMM (0.73 mutations/Mb) vs. HRSMM (1.44

mutations/Mb, p= 0.001) vs. symptomatic MM (1.6 mutations/Mb) – Somatic mutations in known signaling pathways: HR vs. LRSMM

(43.8% vs. 9.5%, p= 0.015) – Mutations in MAPK pathway genes (KRAS, NRAS, BRAF): 21.7% of

HRSMM vs. 0% in LRSMM (p= 0.004). – Mutations in NFkB pathway: HR vs. LRSMM (17.4% vs. 0%, p= 0.018). – Somatic copy number aberrations: HR vs. LRSMM patients (78.1% vs.

42.9%, p= 0.020).

MYC Translocations Predict Rapid Progression

• Methods

– Regions surrounding IgH (0.5Mb), IgK (0.1Mb), IgL (0.1Mb) and MYC loci (1.6Mb) to

identify relevant structural variants (SVs) were included

• Results

– 96 SMM patients included: not progressing >5yr (n=36), progressing 2-5yr (n=23),

progressing <2yr (n=37)

– No MYC SV detected in MGUS (n=32), SMM non-progressing >5yr or SMM progressing

2-5yr

– By contrast, MYC SV were detected in 49% SMM that progressed within 2 years

– SMM with MYC SV had a significantly shorter median TTP (23 vs 50 months; p=0.04)

– Multivariate analysis confirm MYC SV as an independent variable for progression (hazard

ratio=7, 95% confidence interval 3.6-13.7, p=0.00001).

– MYC-Ig translocations may predict high risk of rapid progression to smoldering MM to

MM (100% cases progressed within 2 years)