Co-Chairs:
Brian Durie
Vincent Rajkumar
Antonio Palumbo
Group Reports
June 9, 2011
Group 1: Diagnosis & Management of High Risk Smoldering Myeloma
Group 2: Sequential vs. Curative Strategies: Testing 2 vs. 3 vs. 4 drug combos
Group 3: Role of Early Transplant
Group 4: Maintenance or Consolidation
Group 5: Integrating New & Existing Drugs into the Myeloma Treatment Paradigm
Group 6: Risk Stratification in Myeloma
Session 2: Group 1
Group 1
Diagnosis & Management
of High-Risk SMM
Group 1
Dina Ben-Yehuda
Hou Jian
Ramon Garcia-Sanz
Roman Hajek
Amara Nouel
Evangelos Terpos
Doug Joshua
Niels Abilgaard
Robert Kyle
GiamPaolo Merlini
Vincent Rajkumar
What are the best risk factors today to
identify patients with high risk SMM?
Goal
identify patients with high-risk SMM with 90%
chance to develop symptomatic MM at 2 years in
order to:
- prevent end-organ damage
- possibly extend survival
- avoid unnecessary treatment in low-risk SMM
What are the best risk factors today to
identify patients with high risk SMM?
Parameters
Authors
Plasma cell mass
Kyle et al, NEJM 2007
M-protein concentration
BMPC%
FLC ratio 0.125 or 8
Dispenzieri et al, Blood 2008
Aberrant immunophenotype and
Pérez-Persona et al, Blood
immunoparesis
2007
95% BMPC with abnormal phenotype*
decrease of 1 or 2 uninvolved Igs
Evolution pattern: evolving vs nonevolving
Rosinol et al, BJH 2003
Focal lesions at wbMRI
Hillengass, JCO 2010
* absence of CD19 and/or CD45, decreased expression of CD38, and
overexpression of CD56
What are potential new risk factors that we
should look for?
o Bone imaging (wbMRI, PET-CT)
o Changes in dFLC and e GFR
o Total concentration FLC (i.e. > 1000 mg/L)
o BMPCs (i.e. 60%)
o Number of circulating plasma cells
Does the survival benefit seen in the Spanish trial
outweigh the risks? Should we change practice?
The present data of the QuiRedex trial do not support change
of practice
High risk patients are encouraged to enroll into clinical trials
QuiRedex
Schedule of therapy
Treatment arm
Control arm
Lenalidomide
Induction:
25 mg/daily during 21d every 28 d
Nine 4-wks cycles
Dexamethasone
Therapeutic Abstention
20 mg D1-D4 and D12-D15 every 28 d
Lenalidomide
Maintenance
Therapeutic Abstention
10 mg/daily during 21 d
every month*
*Low dose Dex will be added at the moment of biological
progression
Courtesy Dr. MV Mateos
Len-dex vs no treatment: TTP to active disease
(n = 118)
Median follow-up: 22 months (range 542)
Lenalidomide + dex
1.0
Median TTP: NR
6 Progressions (10%)
0.8
2 pts:early disc followed by progression
4 pts:symptomatic progressions
0.6
No treatment
HR: 6.2; 95% IC (2.615); p < 0.0001
0.4
Median TTP: 25m
28 Progressions (46%)
13 patients: bone disease
0.2
5 patients: renal failure
0.0
0
5
10
15
20
25
30
35
40
45
Courtesy Dr. MV Mateos
Time from inclusion
Len-dex vs no treatment: OS from inclusion
(n = 118)
Median follow-up: 22 months (range 542)
Lenalidomide + Dex
1.0
alive
0.8
No treatment
0.6
patients
of
p=0.05
0.4
0.2
Lenalidomide + Dex: 98% at 3 years
Proportion
No treatment: 82% at 3 years
0.0
0
5
10
15
20
25
30
35
40
Time from inclusion
Courtesy Dr. MV Mateos
Should we treat some patients with SMM?
· Len-dex is a promising and atractive option
· All efforts to plan an early treatment in asymptomatic MM
patients should be focused on high-risk patients
· Long term follow-up is required to actually confirm the
benefit, especially in OS
· Results of other trials that they are being conducted are
needed
In the near future, we could offer early treatment to a selected high-risk of
patients with the confidence that they are going to obtain a significant benefit
Courtesy Dr. MV Mateos
What would be endpoints, short of the usual CRAB features,
that would make us consider therapy in clinical practice?
o Bone imaging
·wbMRI 3 focal lesions outside the skull,
· PET-CT or wbLD-CT 3 focal lesions
o Changes in dFLC and eGFR 25%
What should be the endpoint for regulatory
purposes?
Better definition of active multiple myeloma
GROUP 2
Induction Therapy: Sequential vs. curative
strategies: 2 vs. 3 vs. 4 drug combinations
Consensus!
Key Questions
Role of free light chain testing
· Prognostication (limited clinical applicability)
· For response assessment in patients with less than
measurable disease by SPEP (< 1 gm/dl) and UPEP
(<200mg/24 hrs)
· Replacement for 24 hour urine? Need more evidence with
serial data
· Use as a marker for early change in therapy? Need
validation in prospective studies
How do we minimize risk of neuropathy?
· Decrease risk of onset:
· Use once weekly dosing
· Use subcutaneous administration
· Proactive surveillance and early dose modification
· Dose decrease
· Dosing frequency
· Once weekly dosing in upfront setting in combinations
Should we treat to best response prior to
harvest?
· Increasingly becoming less of an issue given the activity
of current induction regimens and increasing use of post
transplant interventions
· Consensus was treatment for 4 to 6 cycles prior to harvest
and SCT
· Clearly patients with progressive/ non-responding disease
should have alteration of therapy
What is the role of risk stratification?
· Depends on what risk we are looking at:
· Risk of toxicity/ early mortality:
· Age
· Frail patient/ poor performance status
· Renal failure
· Risk of early relapse/ resistance
· Genomic risk (FISH, GEP etc.) (The approach here is tightly related
to treatment philosophy: next slides)
Frail patients: treatment algorithm
RISK FACTORS
- Age over 75 years
- Mild, moderate or severe frailty: help needed for self care (a.k.a
Performance status)
- Comorbidities and organ dysfunction
Cardiac
Pulmonary
Hepatic
Renal
Go-go
moderate-go
slow-go
DOSE LEVEL 0
DOSE LEVEL 1
DOSE LEVEL 2
At least one risk factor
No risk factors
At least one risk factor
+
any G 3-4 non hematologic AE
Palumbo personal communication
What kind of evidence do we need to
embrace a new combination?
· Price of success! With median OS of 6+ years, overall
survival is becoming a more and more difficult endpoint
with the trial sizes we can afford
· To accept a combination as a treatment option:
· Comparable response rates and progression free survival in trials
where QOL component has been studied would be enough
· To consider a combination as the "standard of care":
· OS improvement has to be shown
· In the context of the magnitude of benefit and toxicity/ QOL
So what should we use for induction?
· There are three general approaches (philosophy driven
rather than data driven at this point): No absolute right or
wrong way
1. Sequential use of all drugs in different phases: Velcade
based induction SCT (1 or 2) Velcade based
consolidation revlimid or velcade maintenance
2. Response adapted strategies: Starting with a doublet
and adding a third drug based on response SCT
3. Risk based strategies: Len based induction for standard
risk vs. Velcade based triplets for high risk Early or
delayed SCT
What should we use for a trial design?
· Difficult question; ideally we need to compare the different
strategies of `philosophies'
· Trials should specifically ask the questions in high risk
and standard risk patients in separate trials or trials with
appropriate stratification for the risk groups
· QOL parameters very important
· Need development of composite endpoints or scores that
incorporate response depth, toxicity and QOL estimates,
which can be used while waiting for OS differences
More than one way to get a consensus
Group 3
Role of Early
Transplant
Should early transplant still be considered
standard of care?
YES Early autologous transplantation remains a standard of care
It should be considered the control arm for clinical trials aimed at challenging this regimen
Is there an upper-age limit?
Most phase 3 studies conducted in Europe considered patients eligible to autotransplant up
to the age of 65
The panel agreed that patients aged between 65 and 70 could be proposed with Early
autologous transplantation if they are deemed fit to the procedure by their
hematologist. It remains a patient per patient evaluation.
Best Induction regimen
The panel believes that there is no Evidence-based data showing that Bortezomib-
based regimens (VTD, VCD, PAD, VRD) demonstrated superiority to
Thalidomide (CTD) or Lenalidomide-based (Rd CRD) regimens
The panel recommends, however, a TRIPLE-based combination including at least
one novel agent and dexamethasone.
Induction: Number of cycles
The goal of induction is to obtain the Maximum/Best Response (toxicity !!)
In the context of clinical trial, a fixed number must be proposed in order for patients
to be comparable, and trials have used 4 to 6 cycles, so far (maximum of 6
cycles).
There are no data to support that 6 cycles should be performed at induction rather
than to split the number of cycles between induction and consolidation.
Is VGPR at induction an end-point
The best end-point in induction is Maximum / Best response (at least PR)
VGPR : not at any cost (prognostic factor in some studies, CR in other)
Patients that reach CR during Induction, must undergo autotransplant as it is the
standard of care for eligible patients irrespective of the response rate
How to deal with NON responders
Non Responders: patients who failed to obtain at least a PR at the end of induction
as per the IMWG response criteria
The panel recommended for these patients to either
Change to alternative induction or
To go directly to autotransplant, if possible (availability of stem cells)
What is the role of double transplant?
Not a standard of care
Can be considered for patients that did not reach VGPR after autotransplant
Best consolidation ?
What is the role of allo transplant?
No clear answer
If to perform, preferably in clinical trial
Must discuss maintenance post allo transplant
What are the main transplant-related
questions today?
- Questions around the conditioning regimen, that could be improved
The current standard is HDM 200
Some clinical trials to improve the conditioning is welcome: Bu HDM, Vel HDM,
Bcnu HDM, Benda HDM
- Is there a room for clinical trial asking the questions of transplant in
elderly patients? (transplant in the setting of novel agents)
NO
Participants of Group 3
Philippe Moreau
Nantes, France
Gareth Morgan
Royal Marsden, London, UK
Xavier Leleu
Lille, France
Christina Gasparetto
Duke University, USA
Gosta Gahrton
Karolinska, Sweden
David Vesole
New Jersey, USA
Elena Zamagni
Torino, Italy
Anders Waage
Norway
Jenny Bird
Bristol, UK
Stephen Russell
Mayo Clinic, US
Group 4
Maintenance or
Consolidation
Should the concept of maintenance be
pursued?
· Is concept of maintenance OK and should it be
pursued
Yes (100% agree)
Maintenance versus consolidation: Defined
· Consolidation is for short duration with the aim of
improving quality of response
· Maintenance is for prolonged duration with the
intention of prolonging PFS and OS
Should maintenance post-transplant be
standard?
Response:
Yes - 0
No - 0
Not enough evidence for clear decision: Unanimous
Recognize response may be different depending on
the US vs. European perspective
Thalidomide maintenance
· Should thalidomide be offered to everyone post
ASCT?
Unanimous against giving to everyone but consider patients:
· Not in complete response
· Without cytogenetic high-risk (exclude del13; t[4:14]; del17p)
· Without pre-existing neuropathy
· Doesn't matter if induced with thalidomide
· Starting dose of thalidomide is 100
· Duration is 6m-12m depending on tolerance
Lenalidomide post-transplant
·Should patients be selected by quality of response to
induction therapy?
· No include all patients with stable disease or better
·Should lenalidomide maintenance be standard of care?
·Not enough evidence for a clear decision at this time
What are the alternatives to IMiDs?
Bortezomib Maintenance:
No evidence to support bortezomib as
maintenance therapy
Bortezomib Consolidation:
Data from one study
bortezomib improves quality of response
and PFS
What is the optimal dose and duration for
lenalidomide maintenance?
Dose:
10 mg
Regimen: 21/28 days
Duration:
Only data from maintenance studies until PD
available
- May be possible to shorten duration
- Needs to be evaluated in future studies
- Recognize some patient are cured without
maintenance
- risk to overtreat approximately 20% patients
Recognize that many questions remain about validity of
What is the role of consolidation?
To improve quality of response:
Should be standard post transplant
- improves quality of response
- improves PFS
- note that currently no change in OS
- need to prove impact on survival
How do we address the issue of Second
Primary Malignancies (SPMs)?
Define risk factors in current trials need meta-
analysis
- age at dx (> 55 years),
- gender,
- pre-treatment with DCEP
Meta-analysis needs to focus on duration and dose
(cumulative and/or current), and different induction
regimens
High dose melphalan itself doesn't appear to be risk
factor with double transplant
How do we address the issue of Second
Primary Malignancies (SPMs)? ... cont'd
Continuous melphalan may be synergistic with
lenalidomide for SPM development
It would be helpful to have DNA available on all
patients starting on therapy to later identify those
who developed SPMs
How do we address the issue of Second
Primary Malignancies (SPMs)?
Continuous melphalan may be synergistic with
lenalidomide for SPM development
It would be helpful to have DNA available on all
patients starting on therapy to later identify those
who developed SPMs
What are the best clinical trial designs to
consider?
Association and duration
Lenalidomide + proteasome inhibitor
Thalidomide vs. lenalidomide
Lenalidomide vs. proteasome inhibitor
Clinical endpoint hierarchy (from slides):
OS > QoL > PFS with QoL > PFS without good
QoL
QoL should be very important
- what is the best instrument?
Group 5
Integrating New
& Existing Drugs
Committee Members
Sundar Jagannath
Pieter Sonneveld
Ben Van Camp
Morie Gertz
Paul Richardson
David Siegal
Chaim Shustik
Faith Davies
Andrew Spencer
Jatin Shah
Promising New Drugs and Targets
Stage of
Agent
Mechanism of action
Development
Carfilzomib
Proteasome inhibitor
Phase II/III
Pomalidomide
Immunomodulator
Phase I/II
Vorinostat
HDAC inhibitor
Phase III
Panobinostat
HDAC inhibitor
Phase III
Perifosine
Akt inhibitor
Phase II/III
Temsirolimus
mTOR inhibitor
Phase I/II
Jun N-terminal Kinase (JNK) activator,
Plitidepsin
Phase II/III
antiangiogenic activity
Siltuximab
Human MCAB against interleukin-6
Phase III
Elotuzumab
Humanized MCAB against CS1
Phase III
Promising New Drugs and Targets
Stage of
Agent
Mechanism of action
Development
ONX-0912
Oral Proteasome inhibitor
Phase I
ONX-0912
Oral Proteasome inhibitor
Phase I/II
PCI-32765
BTK inhibitor
Phase I
PD 0332991
CDK4,6/cyclin D
CDK2/cyclin A ,E CDK7/cyclin H
Seliciclib
CDK9/cyclinT1
CDK1/cyclin B, CDK4/cyclin D
P276-00
CDK9/cyclinT1
CDK1/cyclin B, CDK2/cyclin A, E
AT-7519
CDK4,6/cyclin D, CDK7,9/cyclin H, T
Perifosine
AKT
Everolimus
mTORC1
Temsirolimus
mTORC1
What are the new drug targets?
Monoclonal target:
1. CD 74-dox conjugate
2. CD 138 immunotoxin
3. CD 38
4. CD 56 conjugate
5. PD1 target
6. Kappa isotype B cell MDX 10 monoclonal
Immuno therapy:
Dendritic Cells, NK cells
CD40 ligand
CTLA4
Targeting tumor cells
1. HSP 70 and 90 inhibitors
2. MDM2 (p53 stabilization)I
Targeting Microenviroment
CXCR in combination with AMD3100
Heperanase
Can bone therapies improve survival
outcome?
Bone therapies improve survival - Yes
Do future agents targeting bone need survival endpoint? - Yes
New Targets and drugs:
ACE-1011
Anti-RANKL
Anti-DDK1
What kind of preclinical study designs do
we need?
good models; these are informative but not predictive
Xenograft models: improving and can help guide combinations
Murine models with intact immune system ( specifically monoclonal and
Vaccine therapies, dendritic cells, NK cells )
Murine models with humanized hematopoietic system
What is the expected efficacy of a new
drug?
Many drugs have less than 20% single agent activity
Cant set a general standard and must look at class of drug and expected MOA
Based on the MOA: epigenetic change ( expect no activity and best with
combo data) vs. cytotoxic agent need single agent activity
If drug sensitization strategy
Antibodies
If there is a preclinical rationale for combination study - may not expect single agent
activity
What are the best trial designs to test new
drugs?
Issue of limitations on 3 or 4 lines of therapy and good performance (relapsed
after prior exposure to alkylators, IMiDs, PI and Steroids)
Start with lower hurdle in relapse and then progress to more refractory patients.
Biomarker Driven: incorporate for targeted modulation
Enrich pt population: with high target expression ( Pi3k mutation)
Group 6
Risk
Stratification
Is it time for risk-adapted therapy?
· We are already practicing risk-adapted therapy e.g. for elderly
patients and patients with renal impairment
· Trials have been designed in the past to see if different treatment
e.g. mini-allo can improve outcome of patients with higher risk
disease e.g. 13 del plus high B2M in the IFM study
· Difference now is that the goal post for high-risk disease is shifting
I.e. what is high-risk before is no longer high-risk now
· We are generally uncomfortable to recommend different treatment
for different risk groups at present except for the specific group of
t(4;14) that may particularly benefit from Velcade and also
perhaps alkylating agent should be avoided
Why Risk Stratify?
· For Clinical Trial and Research design
· For community physician
Prognosis
Velcade-based treatment for t(4;14)
Who are good and poor-risk patients?
· Poor-Risk - survival < 2yrs despite novel agent
induction treatment
· Good Risk - OS at 8 years exceeds 70%
How to define them?
· Poor-Risk (15% of patients, survival < 2yrs despite
novel agent induction treatment)
ISS II or III (available for all patients) plus
t(4;14), 17p13 del, (available for 90% of patients
GEP (available for 60% of patients)
PCL + EMP
For exploration
· Good Risk (30% of patients OS at 8 years 73%)
ISS I plus
No t(4;14), No 17p del, No t(14;16) and No 1q gain
Prognostic impact of t(4;14)/del(17p) with ISS
Overall survival by ISS and t(4;14) or del17 by FISH
P-values: a v b<0.0001, a v c<0.0001, b v c<0.0001
100%
80%
60%
40%
20%
0% 0
5
10
15
Years from start of treatment
4-year
Deaths/N
estimate
a ISS I or ISS II and Normal FISH
193/610
76% (72,79)
b ISS I and Abnormal FISH/ISS III and Normal FISH 140/252
52% (45,58)
c ISS II or ISS III and Abnormal FISH
146/196
32% (26,39)
Avet-loiseau et al. ASH 2009
Which tests should be used for
stratification/outcome assessment?
· For now, ISS plus FISH
· Next step to accumulate GEP data from large
cooperative group prospective trial and integrate GEP
with ISS and FISH using multivariate modeling (MyPI -
Myeloma Prognostic Index)
Which trials are best?
· Can take 2 approaches
One is to design trial that will include all comers but cater for
adequate power to compare risk groups [prospective
validation of high-risk factors]
Design good trial for specific risk groups [pre-requisite is
agreed upon criteria for defining risk groups]. While waiting
for initial test results, treat everyone similarly e.g. VRD for 1st
cycle. Once results are available, divide patients into good and
poor risk groups for different treatment.
· Recognize the critical importance of incorporating
whole genome GEP into clinical trials for validation of
prognostic signatures and discovery of predictive
signatures.
Conclusion
· The group has defined what constitute poor-risk and
good-risk patients
· We can agree on high risk-factors but also agree on
the need to continue to evolve and include GEP data
into the next prognostic model
· In general, we are not in position to recommend
different treatment for the different risk group except
for t(4;14).