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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)
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