Should Some patients with Stage I MM
receive treatment: NO
Sagar Lonial, MD
Associate Professor, Winship Cancer Institute
Director of Translational Research,
B-cell Malignancy Program
Disclosures
Consultant for: Millennium, Celgene, BMS,
Novartis, Merck, Onyx
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Disclosures
I can't win this Debate!!
You can't beat Spain
You can't beat PETHEMA
You can't beat Dr Mateos
You Can't Beat Spain
Espania
2
You Can't Beat Spain...
You Can't Beat PETHEMA Investigators
Leader in trials using novel agents in
induction
Leaders in the use of novel methods to re-
define CR
Leaders in Management of EM disease
2 of 5 IMS leaders are from Spain
Leaders in curing patients with MM
Functional cure with interferon?????
Martinez-Lopez et al, Blood 2011
3
Why this debate is intrinsically unfair
VS
Dr Mateos, AKA Mrs Cruz
Dr Lonial , AKA Mr Bean
Internationally renown
Virtually unknown
Won awards in Many different areas
Has been to many different areas
Has many different talents
Still trying to find a useful talent
Key figure in the PETHEMA Group
Can't find his keys....
Will probably vote for Dr Mateos in this debate
Criteria for Diagnosis of Myeloma
MGUS
SMM
Active MM
· < 3 g M spike
· 3 g M spike
· 10% plasma cells
· < 10% plasma cells
· 10% plasma cells
·M spike +
AND
AND
No anemia, bone lesions,
Anemia, bone lesions,
normal calcium, and
high calcium, or
kidney function
abnormal kidney function
MGUS = monoclonal gammopathy of unknown significance; SMM = smoldering multiple myeloma.
Kyle et al, 2009.
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So what is the real question at hand?
Lets rephrase " Should Some patients with Stage
I MM receive treatment" to say
"Should all patients with Asymptomatic
or Smoldering MM (AMM) receive
treatment."
NO....Absolutely Not
Smoldering Multiple Myeloma
27% will convert in 15 years
Roughly 2% per year
Kyle R et al. N Engl J Med 2007;356:2582-2590
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SMM "Conversion"
Clearly not all patients are the same with SMM
Is there a way to identify `Some' of the
patients such that...
"Should patients with high risk Asymptomatic
or Smoldering MM (AMM) receive
treatment as routine care?"
This is the point for discussion
Initial Risk Stratification
2 yr
19 yr
8 yr
Patients with >10% plasma cells and >3gm/dl M protein are at higher risk
Kyle R et al. N Engl J Med 2007;356:2582-2590
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Free Light is Useful for Risk Assessment in AMM
Dispenzeri et al Blood 2008
There are patients with higher risk of
progression to MM
These patients can be defined by the use of
simple testing
There is a subset of high risk AMM patients
that progress to MM on average within 2
years.
Can we change the natural history of their
disease for these patients?
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What are the Elements of Effective
therapy for a patient who HAS NO
SYMPTOMS?
Well tolerated treatment
Reduces depth of disease
Helps all biologic (genetic) subsets of disease
Improves overall survival compared to
observation
Three Themes
Remember the lessons of the past
First do no Harm
Listen to our Elders
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Trials with old treatments
Use of MP was tested in 3 small trials in the
past
No improvement in outcomes was noted
Risk of MDS among early treated patients.
The use of Thalidomide in SMM
3 trials have been done to date (MDACC,
Mayo, UAMS)
2 showed longer TTP for responders to thal,
UAMS trial showed shorter TTP for
responders to thal.
No improvement in OS
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What was the Price of Early Therapy
Toxicity of therapy was significant
Significant PN was noted
Median duration of thal was short in Mayo
study
"Despite our results and those reported by
others, we do not recommend the use of
thalidomide for SMM."
Detweiler-Short et al, AMJ 2010
When is PFS an acceptable endpoint
Initial induction therapy
Too many subsequent therapies that impact OS
Refractory disease
Limited treatment options afterwards and PFS is proven
to be associated with improvement in OS
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When is PFS NOT an acceptable endpoint
Post transplant therapy
Induction and consolidation can impact PFS, but not
always OS
Maintenance therapy
PFS not always or reliably associated with OS
Thal story is instructive, improved PFS, mixed OS,
worse QOL
Smoldering MM
PFS is meaningless among a group of
patients that do not require therapy and
have no symptoms
A Multicenter, Randomised, Open-label, Phase III
Study of Lenalidomide/Dexamethasone versus
Therapeutic Abstention in high-risk Smoldering
MM
MV Mateos, L López-Corraz, MT Hernández, J de la Rubia, JJ Lahuerta, P Giraldo, J Bargay,
L Rosiñol, A Oriol, J García-Laraña, l Palomera, F de Arriba, F Prósper, ML Martino, AI Teruel,
J Hernández, G Estevez, M Mariz, A Alegre, JL Guzman, N Quintana, JL García, JF San
Miguel.
On behalf of Spanish Myeloma Group (PETHEMA/GEM)
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QuiRedex: Time to Progression (n:94)
Median follow-up: 14 m (1-24)
1 pt IC withdrawal during the 1st cycle
1 pt discontinuation after the 8th cycle
Lendex
1,0
0,8
No treatment
0,6
Progressions in abstention arm
Median TTP: 19.3 m
(n=16)
6 pts: lytic lesions
0,4
3 pts: lytic lesions plus anemia
1 pt:lytic lesions renal failure & hypercalcemia
0,2
5 pts: anemia
1pt: PD due to a rapid increase of BJ prot from
p<0,0001
4,5g/24h to 9g/24h in 1 month
0,0
0
3
6
9
12
15
18
21
24
QuiRedex: Overall Survival (n:94)
Median follow-up: 14 m (1-24)
1.0
Lendex
0.8
No treatment
0.6
0.4
0.2
Lendex: 100% at 2 y
No treat: 96% at 2 y
0.0
0
3
6
9
12
15
18
21
24
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Lendex:Toxicity profile (n:47)
G1-2
G3
Anemia, n (%)
8 (17%)
1 (2,6%)
Neutropenia, n (%)
10 (21%)
-
Thrombocytopenia, n (%)
5 (11%)
-
Asthenia
7 (15%)
2 (4.5%)
Anorexia
4 (9%)
Pancreatitis
-
1 (2%)
Constipation
5 (11%)
4 (9%)
Diarrhea
3 (6%)
1 (2%)
Rash
8 (17%)
1 (2%)
Paresthesias
2 (4%)
Infection
9 (19%)
DVT*
3 (6%)
Initial Review of the data
Very impressive effect of a novel treatment
approach
Treatment not without toxicity
Could perhaps overcome lack of OS benefit if
QOL instruments showed improvement
Dex effect?
Preliminary encouraging data that needs
further validation
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Second Cancer Rates
IFM
Len
17/299
5.5%
Placebo
3/292
1.0%
CALGB
Len
15/231
6.5%
Placebo
6/229
2.6%
MM015
MPR
11/355
3.1%
Placebo
2/154
1.3%
*Numbers and % as of 2/6/11
Basal cell cancers excluded
ECOG/SWOG: Phase III ­ Asym
A
p
sym toma
tom tic
a
Myeloma*(PI:
Myelom
SL)
Lenalidomide
Lenalidom
vs. observation
No Dex to isolate the effect of len
R
A
CR/PR/
CR/
Continue therapy
N
Lenalidomide
Stable
Stabl
till prog. or toxicity
D
O
M
IZ
A
Prog.
TI
Observa
Observ tion
Off Rx
anyt
any ime
t
O
N
Control/standard arm
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AMM Trial
· Eligible patients are high or intermediate
risk AMM (Kyle et al, NEJM 2008)
· Initial Pilot study to prove safety and
tolerability of the dose
· No Dexamethasone
· PBSC collection suggested for all patients
· Planned correlatives include GEP, optional
MRI, Immunologic studies (SWOG)
Do No Harm
Risk of PN, DVT, fatigue, cytopenias, and
stem cell reserve cannot be underestimated.
Need to understand what impact (if any) early
intervention has on the natural history of
AMM
Showing delay in developing MM is not
sufficient when treatment at progression may
be compromised by initial therapy.
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What do the experts say....
Leukemia 2010
More Experts....Our Elders..
JCO 2010
You don't have to beat the Spanish if they
agree with you.......
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So Where does that Leave us?
· Preliminary data looks encouraging..This I
will admit..
· Issues of toxicity of therapy and SPM need to
be evaluated before this is a standard
treatment for patients with AMM
· Treatment of High risk AMM patients
CANNOT be recommended for all patients
at this time.
Thanks to:
Jonathan Kaufman
Charise Gleason
Danni Cassabourne
Melanie Watson
Donald Harvey
Renee Smith
Colleen Lewis
Amelia Langston
L.T. Heffner
Ebeneezer David
Claire Torre
S-Y Sun
Jing Chen
Fadlo Khuri
Leon Bernal
Larry Boise
IMS
Golfers Against Cancer
T.J. Martell Foundation
And Many Others who
are part of the B-cell Team
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