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Multiple Myeloma Update CHC 2015 Rafael Fonseca, MD
Chair, Department of Medicine Mayo Clinic in AZ
Rafael Fonseca MD
Chair, Department of Medicine Mayo Clinic in AZ
Multiple Myeloma Update CHC 2015
Scottsdale, Arizona Rochester, Minnesota Jacksonville, Florida
Mayo Clinic College of Medicine Mayo Clinic Comprehensive Cancer Center
Sarah Newbury (Solby 1844)
Progression of the Disease
MGUS Smoldering
MM
Active
MM
Extramedullary
MM Cell line
Clonal cells
> 10%
End organ damage
BM independence
Risk Assessment and Stratification
Delta
Proliferation/Resistan
ce
New Genetic Changes
Drug Resistance
Changes
COMORBIDITIES
Immunity
Microenvironment
Host
Genetic
Epigenetic
Changes
Normal Plasma
cell Biology
ACTGCCGTA
Selection of clones
Creation of clones
Risk Assessment and Stratification
Delta
Proliferation/Resistan
ce
New Genetic Changes
Drug Resistance
Changes
COMORBIDITIES
Immunity
Microenvironment
Host
Genetic
Epigenetic
Changes
Normal Plasma
cell Biology
ACTGCCGTA
Selection of clones
Creation of clones
Su
rviv
al p
rob
ab
ilit
y
Months
P<0.001
t(4;14)
t(14;16)
-17p13
D13
All others including
t(11;14)
Poor 24.7 mos
Intermediate 42.3 mos
Good 51.0 mos
Fonseca et al Blood 101:4569, 2003
Molecular Prognostic Model
Revised International Staging System
Paulmbo et al J Clin Oncol 33:2863-2869.
Truncating Mutation of Cereblon in Drug Resistant patient
CRBN Role in IMID Activity
MS Lawrence et al. Nature 000, 1-5 (2013) doi:10.1038/nature12213
Somatic mutation frequencies in exomes from 3,083
tumour–normal pairs.
Survival by Genomic Instability
Chung T-H, et al (2013) A Novel Measure of Chromosome Instability Can Account for
Prognostic Difference in Multiple Myeloma. PLoS ONE 8(6): e66361
Evolutionary Principles
• Ultimately ability to adapt dictates outcomes
• Diversity = resistance
• Genomic instability drives genomic complexity
• Predictive versus prognostic
Importance of progression events
13
Importance of progression events
Can you predict progression to MM in some patients with “benign” disease
IMWG: About 80% risk of progression in 2 years would be acceptable
Rajkumar et al Lancet Oncology 2014
Importance of progression events
• Extreme plasmacytosis
• Abnormal sFLC ratio of more than 100
• More than one focal lesion in MRI
Rajkumar et al Lancet Oncology 2014
0.1
1
10
100
1000
10000
Lig
ht
ch
ain
co
ncen
trati
on
(m
g/L
)
SPE
CZE IFE
Total
k & l
Normal range in serum
FLC
UPE
Sensitivity of methods for detection of FLCs
Renal Metabolism of FLCs
Smoldering Myeloma
Kyle R. N Engl J Med 2007; 356:2582-90
10%
3% 1%
mSMART SCT Eligible
Long Term Outcomes after SCT in MM
Martinez-Lopez et al Blood. 2011;118(3):529-534
Martinez-Lopez et al Blood. 2011;118(3):529-534
CR vs nCR/VGPR/PR vs less
IMIDs
Thalidomide Lenalidomide Pomalidomide
b1 Post-
glutamyl Tryptic
Chymo-
tryptic
NPI
b2
b3
b4
b5
b6
b7
NPI NPI
Post-
glutamyl Tryptic
Chymo-
tryptic
b3
b4
b5
b6
b7
NPI-0052 (irreversible)
Proteasome Inhibitors
Bortezomib
b1
Bortezomib (reversible)
Carfilzomib (irreversible)
ONX 0912
MLN9708 (reversible)
Single-Agent Carfilzomib:
Response Rates
*IRC-determined; 11 patients had unconfirmed response
0.4%
5.1%
18.3%
13.2%
31.5%
26.8%
0
5
10
15
20
25
30
35
CR* (n=1)
VGPR (n=13)
PR (n=47)
MR (n=34)
SD (n=81)
PD (n=69)
Pe
rce
nta
ge o
f P
atie
nts
ORR = 24%
CBR = 37%
DCR = 69%
TTR: 1.9 mo (≥PR) and 1.0 mo (≥MR) DOR: 7.8 mo (≥PR) and 8.3 mo (≥MR)
Subset analyses of higher risk populations showed similar response rates (e.g., unfavorable cytogenetics, baseline peripheral neuropathy)
Siegel D, et al. Blood. 2012;120:2817-25.
N = 257 response-
evaluable population
CR = complete response; PD = progressive disease; PR = partial response; SD =
stable disease; TTR = time to response; VGPR = very good partial response
CHAMPION 1: Phase 1/2 Dose-
Escalation of Weekly Carfilzomib + Dex
• Enrolled 27 patients with relapsing or progressive MM treated
with 1-3 prior regimens
• Dose-escalation of weekly carfilzomib + dexamethasone
• Established carfilzomib MTD as 70 mg/m2
• Carfilzomib 70 mg/m2 infused over 30 min had mean terminal
half-life similar to approved twice-weekly dosing
• ORR 63%; median time to response 1.0 mo
• Phase 2 portion plans to enroll 127 patients at the 70-mg/m2
carfilzomib dosing level
Berenson JR, et al. ASH 2013. Abstract 1934.
Carfilzomib Extension Study Shows Activity of
Multiple Regimens, Dose changes
• 91 pts received carfilzomib for extended periods – Median treatment duration, 22.5 cycles
– 60% of patients had ≥ 1 regimen change
• Best response after PD during study among evaluable pts:
• No late-onset, severe, or serious cumulative toxicity
Siegel D, et al. ASH 2012. Abstract 2962.
Best response,
%
After 1st PD
(n=30)
After 2nd PD
(n=12)
After 3rd PD
(n=5)
After 4th PD
(n=3)
VGPR 6.7 8.3 0 0
PR 10.0 14.3 25.0 0
MR 10.0 7.1 20.0 16.7
SD 46.7 50.0 25.0 16.7
ORR (≥ PR) 16.7 25.0 40.0 0
CBR (ORR+MR) 26.7 33.3 60.0 33.3
28
Carfilzomib, Lenalidomide, and Dexamethasone vs Lenalidomide and
Dexamethasone in Patients with Relapsed Multiple Myeloma:
Interim Results from ASPIRE, a Randomized, Open-Label, Multicenter
Phase 3 Study
A. Keith Stewart, S. Vincent Rajkumar, Meletios A. Dimopoulos, Tamás Masszi, Ivan Spicka, Albert Oriol, Roman Hájek, Laura Rosiñol, David S.
Siegel, Georgi G. Mihaylov, Vesselina Goranova-Marinova, Péter Rajnics, Aleksandr Suvorov, Ruben Niesvizky, Andrzej Jakubowiak, Jesus F. San Miguel, Heinz Ludwig, Naseem Zojwalla, Margaret E. Tonda, Biao Xing,
Philippe Moreau and Antonio Palumbo
ASPIRE Study Design
29
Rd
Lenalidomide 25 mg Days 1–21
Dexamethasone 40 mg Days 1, 8, 15, 22
KRd
Carfilzomib 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
Randomization
N=792
Stratification:
•β2-microglobulin
•Prior bortezomib
•Prior lenalidomide
After cycle 12, carfilzomib given on days 1, 2, 15, 16
After cycle 18, carfilzomib discontinued
28-day cycles
Primary Endpoint: Progression-Free Survival ITT Population (N=792)
30
1.0
0.8
0.6
0.4
0.2
0.0
Pro
port
ion S
urv
ivin
g
Without P
rogre
ssio
n
KRd
Rd
0 6 12 18 24 30 36 42 48
Months Since Randomization
KRd Rd
(n=396) (n=396)
Median PFS, mo 26.3 17.6
HR (KRd/Rd) (95% CI) 0.69 (0.57–0.83)
P value (one-sided) <0.0001
No. at Risk:
KRd
Rd
396 332 279 222 179 112 24 1
396 287 206 151 117 72 18 1
Secondary Endpoints: Response P
erc
enta
ge o
f P
atients
31
P<.0001
P<.0001
sCR
14.1% vs 4.3%
P<.0001
Median duration of response was 28.6 months in the KRd group and 21.2 months in
the Rd group
Adverse Events (AEs), Treatment Discontinuations, and Deaths Safety Population (n=781)
32
Category KRd
(n=392)
Rd
(n=389)
Median treatment duration, weeks (range) 88.0 57.0
Any AE, %
Grade ≥3 treatment-emergent AE
96.9
83.7
97.2
80.7
Treatment discontinuations, %
Discontinuation due to disease progression
Discontinuation due to AE
69.9
39.8
15.3
77.9
50.1
17.7
Serious AE, % 59.7 53.7
Deaths within 30 days of last dose, %
Deaths due to disease progression
Deaths due to AEs
7.7
0.5
6.9
8.5
1.3
6.9
Other AEs of Interest Safety Population (n=781)
33
AE, %
KRd (n=392) Rd (n=389)
All Grade Grade ≥3 All Grade Grade ≥3
Dyspnea 19.4 2.8 14.9 1.8
Peripheral neuropathy* 17.1 2.6 17.0 3.1
Hypertension 14.3 4.3 6.9 1.8
Acute renal failure* 8.4 3.3 7.2 3.1
Cardiac failure* 6.4 3.8 4.1 1.8
Deep vein thrombosis 6.6 1.8 3.9 1.0
Ischemic heart disease* 5.9 3.3 4.6 2.1
Pulmonary embolism 3.6 3.1 2.3 2.3
Second primary malignancy* 2.8 2.3 3.3 2.8
*Grouped term.
34
Abstract 538 and Abstract 3220 Carfilzomib, Lenalidomide, dexamethasone (CRd)
Response 2 cycles
n/N (%)
8 cycles
n/N (%)
*Best
response
n/N (%)
ORR (>PR) 42/43 (98) 32/33 (97) 42/43 (98)
>VGPR 22/43 (51) 30/33 (91) 38/43 (88)
nCR/CR/sCR 7/43 (16) 24/33 (73) 29/43 (67)
CR/sCR 3/43 (7) 14/33 (42) 22/43 (51)
VGPR 15/43 (35) 6/33 (18) 9/43 (21)
PR 20/43 (47) 2/33 (6) 4/43 (9)
SD 1/43 (2) 1/33 (3) 1/43 (2)
NIH CRd-R Phase II Trial CRd x 8 cycle then 24 cycles of Len Maint
Phase I/II CRd MMRC Trial
CRd x 24 cycles then Len Maint
100
0
20
40
60
80
≥PR ≥VGPR ≥nCR ≥CR sCR iCR
Median 24 CRd cycles (range, 2-24)
Pa
tie
nts
(%
)
98
87
72
64
55 51†
1.0
0.0
0.2
0.4
0.6
0.8
0 10 20 30 40 50
N=53
Median follow-up, 31 months (range, 16-43)
Su
rviv
al
Pro
ba
bilit
y
Months
OS (3-year OS: 96%)
PFS (3-year PFS: 79%)
Among 27 nCR/sCR* patients assessed by flow, all
27 are MRD negative
Response rates based on FISH/cytogenetics are
non-differential
Korde et al, ASH 2013, Abstract #538
OS (3-year OS: 96%)*
PFS (3-year PFS: 79%)
*30% of pts with IMWG high-risk cyto
15% patients with del p53
Jasielec et al, ASH 2013, Abstract #3220
Response
Mikhael et al, ASH 2013 Abstract 3179
ENDEAVOR Study Design
Presented By Meletios Dimopoulos at 2015 ASCO Annual Meeting
Primary End Point: Progression-Free Survival<br />Intent-to-Treat Population (N=929)
Presented By Meletios Dimopoulos at 2015 ASCO Annual Meeting
Secondary End Point: Grade ≥2 Peripheral Neuropathy*
Presented By Meletios Dimopoulos at 2015 ASCO Annual Meeting
Progression-Free Survival and Overall Response Rates by Prior Bortezomib Exposure
Presented By Meletios Dimopoulos at 2015 ASCO Annual Meeting
ELOQUENT-2 Study Design
Presented By Sagar Lonial at 2015 ASCO Annual Meeting
Co-Primary Endpoint: Progression-Free Survival
Presented By Sagar Lonial at 2015 ASCO Annual Meeting
Co-Primary Endpoint: Overall Response Rate
Presented By Sagar Lonial at 2015 ASCO Annual Meeting
Daratumumab A human CD38 mAb with broad-spectrum killing activity
44 Slides courtesy of Dr. Torben
Phase 2 Study of Daratumumab (DARA) in Patients with ≥3 Lines of Prior Therapy or Double Refractory Multiple Myeloma: 54767414MMY2002 (Sirius)*
Presented By Sagar Lonial at 2015 ASCO Annual Meeting
Change in Paraprotein From Baseline
Presented By Sagar Lonial at 2015 ASCO Annual Meeting
1960-65
1965-70
1970-75
1975-80
1980-85
1985-90
1990-95
1995-00
2000-05
2005-10
“The best interest of the patient is the only interest to be
considered, and in order that the sick may have the
benefit of advancing knowledge, union of forces is
necessary”
1844
William J Mayo 1910
