Hematology Highlights 2013
Frontline Therapy and Maintenance for Newly
Diagnosed Multiple Myeloma
P. Leif Bergsagel, M.D.
Professor of Medicine
March 14, 2013
Scottsdale, Arizona
Rochester, Minnesota
Mayo Clinic College of Medicine
Mayo Clinic Comprehensive Cancer Center
Jacksonville, Florida
Frontline Therapy and Maintenance for
Newly Diagnosed Multiple Myeloma
•
•
•
•
•
•
•
Smoldering multiple myeloma
Transplant ineligible patients
Transplant eligible patients
Doublets versus Triplets
Integrating Novel Agents into Frontline
Regimens
Proteasome inhibitors and
immunomodulatory agents
Duration of maintenance
SMOLDERING MULTIPLE MYELOMA AT HIGH-RISK OF
PROGRESSION TO SYMPTOMATIC DISEASE: A RANDOMIZED TRIAL
OF LEN-DEX AS INDUCTION FOLLOWED BY MAINTENANCE
THERAPY WITH LEN ALONE VS NO TREATMENT
• High risk smoldering MM
• Both
 Bone marrow plasma cells >10%
 High M-spike
 IgG >3g/dL, IgA >2g/dL, Bence Jones >1g/day
• Or one of the above plus both:
• 95% phenotypically aberrant PCs by flow cytometry
• Immunoparesis
• Reductions in 1 or more uninvolved immunoglobulins of
>25%
Mateos et al, EHA 2012 abstract 283
SMOLDERING MULTIPLE MYELOMA AT HIGH-RISK OF
PROGRESSION TO SYMPTOMATIC DISEASE: A RANDOMIZED TRIAL
OF LEN-DEX AS INDUCTION FOLLOWED BY MAINTENANCE
THERAPY WITH LEN ALONE VS NO TREATMENT
Group A (57 patients)
• Lenalidomide 25mg d1-21
• Dexamethasone 20mg d1-4, 12-15
• Lenalidomide 10mg d1-21
• Addition of Dex 20mg d1-4 for
x 9 cycles
x 15 cycles
biochemical progression
Group B (62 patients)
• No treatment
Mateos et al, EHA 2012 abstract 283
SMOLDERING MULTIPLE MYELOMA AT HIGH-RISK OF
PROGRESSION TO SYMPTOMATIC DISEASE: A RANDOMIZED TRIAL
OF LEN-DEX AS INDUCTION FOLLOWED BY MAINTENANCE
THERAPY WITH LEN ALONE VS NO TREATMENT
Induction
After maintenance
ORR
81%
PR
56%
VGPR
11%
CR
7%
sCR
7%
sCR
16%
Mateos et al, EHA 2012 abstract 283
SMOLDERING MULTIPLE MYELOMA AT HIGH-RISK OF
PROGRESSION TO SYMPTOMATIC DISEASE: A RANDOMIZED TRIAL
OF LEN-DEX AS INDUCTION FOLLOWED BY MAINTENANCE
THERAPY WITH LEN ALONE VS NO TREATMENT
Progression
Median TTP
3-year OS
Median f/u 32m
Len-dex
9/57 (16%)
Not reached
93%
Observation
37/61 (59%)
23 months
76% (p<0.04)
Conclusion: High-risk SMM has a high mortality with
observation that can be abrogated by early treatment
Mateos et al, EHA 2012 abstract 283
Proposed future state definition of multiple myeloma
• Current revised definition of multiple myeloma
•
Clonal bone marrow plasma cells ≥10% (or biopsy proven plasmacytoma) and
Evidence of end-organ damage or bone marrow plasma cell percentage ≥60%
• Future state definition of multiple myeloma
•
Clonal bone marrow plasma cells ≥10% (or biopsy proven plasmacytoma)
At least one of the following:
•
•
•
•
•
•
•
•
•
•
Evidence of end-organ damage
Bone marrow plasma cell percentage ≥60%
High involved over uninvolved free light chain ratio (≥100)
High levels of circulating plasma cells
Absence (<5%) of normal plasma cells by immunophenotyping
High bone marrow plasma cell proliferative rate by S-phase assessment on flow
cytometry
Deletion 17p on cytogenetic studies
≥3 focal lesions on MRI studies
Evolving pattern: significant increases in monoclonal protein or light chain
levels over time
Unexplained decrease in creatinine clearance by ≥25% accompanied by a rise
in urinary M protein or serum free light chain levels
Rajkumar, Merlini, San Miguel, Nat Rev Clin Oncol 2012 (9) 494
Newly diagnosed
• Elderly non-transplant
• VMPT trial
• CarCtxDex
• Transplant candidates
•
•
•
•
•
CarLenDex
CarThalDex
MLN9708-LenDex
CyCarThalDex
R2V2
Overall Survival Benefit for Bortezomib-Melphalan-PrednisoneThalidomide Followed by Maintenance with Bortezomib-Thalidomide
(VMPT-VT) Versus Bortezomib-Melphalan-Prednisone (VMP) in Newly
Diagnosed Multiple Myeloma Patients
Palumbo Blood 120(21) 2012, abstract 200
VMPT+VT versus VMP for Elderly
Palumbo Blood 120(21) 2012, abstract 200
VMPT+VT versus VMP for Elderly
PFS
OS
VMPT+VT
VMPT+VT
VMP
Palumbo Blood 120(21) 2012, abstract 200
VMP
VMPT+VT versus VMP for Elderly
OS: Landmark Analysis
VMPT+VT
VMP
VMPT+VT
VMPT+VT
VMP
VMP
VMPT+VT
VMPT+VT
VMPT+VT
VMP
VMP
VMP
Palumbo Blood 120(21) 2012, abstract 200
What happens in 1st 12 months?
MP vs VMP
VTP vs VMP
MP vs MPT
Fayers pooled
Len-Dex v.
Len-dex
MP vs TD
VMP vs
VMPT
Carfilzomib, Cyclophosphamide and
Dexamethasone (CCd) for Newly Diagnosed
Multiple Myeloma (MM) Patients.
Palumbo Blood 120(21) 2012, abstract 730
Carfilzomib, Cyclophosphamide and Dexamethasone (CCd)
for Newly Diagnosed Multiple Myeloma (MM) Patients.
Palumbo Blood 120(21) 2012, abstract 730
Carfilzomib, Cyclophosphamide and Dexamethasone (CCd)
for Newly Diagnosed Multiple Myeloma (MM) Patients.
Palumbo Blood 120(21) 2012, abstract 730
Carfilzomib, Cyclophosphamide and Dexamethasone (CCd) for
Newly Diagnosed Multiple Myeloma (MM) Patients.
Palumbo Blood 120(21) 2012, abstract 730
Newly diagnosed
• Elderly non-transplant
• VMPT trial
• CarCtxDex
• Transplant candidates
•
•
•
•
•
CarLenDex
CarThalDex
MLN9708-LenDex
CyCarThalDex
R2V2
Induction Regimens
Response Rates (%) & Survival
1
Trial
N
nCR/sC
R
>=VGPR >=PR
PFS
OS
CarLenDex
20
75
85
95
NA
NA
CarThalDex1
50
18
60
92
1 yr 88% NA
MLN9708Len-Dex
65
23
58
90
1 yr 93% NA
CyCarThalDex 27
26
74
96
1 yr 90% NA
R2V2
40
73
97
1 yr 97% 1 yr
100%
30
Induction portion of CTD x 4 followed by HDM and consolidation with CTD x 4
Blood 120(21) 2012:
Korde, Abstract 732
Sonneveld Abs 333
Kumar Abs 332
Mikhael Abs 445
Kaufman Abs 336: Lenalidomide, Bortezomib, Dexamethasone, and Vorinostat
The Overall, ≥ VGPR, and nCR/CR Rates for a Selection of
Phase 2 and Phase 3 Trials
Do we pick the therapy with the biggest green bar and call it a day?
Stewart A K et al. Blood 2009;114:5436-5443
©2009 by American Society of Hematology
In RCT, bortezomib, but not thalidomide, is
associated with improved OS in high-risk MM
Bergsagel, Mateos, Gutierrez, Rajkumar, San Miguel. Blood 2013 121:884
Standard Risk*†
FISH
Transplant
Ineligible
Transplant
Eligible
Other
Intermediate*
High Risk
t(11;14)§
t(6;14)
Hyperdiploid
t(4;14)‡
del17p
t(14;16)
t(14;20)
All others
Cytogenetic deletion 13
Or hypodiploidy
Or PCLI>3%
GEP High Risk Signature
4 cycles of Rd| or CyBorD
4 cycles of CyBorD
4 cycles of VRd
Autologous stem cell tx
Autologous stem cell tx
especially if not in CR
Bortezomib based therapy for
minimum of 1 year
VRd for minimum of 1 year
Rd or MPT|#
MP + weekly Bortezomib
or weekly CyBorD
VRd
Observation
Bortezomib maintenance
Autologous stem cell tx
Collect Stem Cells¶
#
Continue Rd
www.mSMART.org
Less is more for patients with high-risk cytogenetics
No Cytogenic Abnormality
CA13 or Hypodiploidy
Other CA
TT1
TT2-Thal
TT2+Thal
TT3a
TT3b
TT4
TT4-Lite
12
24
36
12
24
36
12
24
36
Overall Survival
TT4
MVTD-PACE x 2, HDM200 x 2,
VTD-PACE x 2, VRD x 3 years
TT4-Lite
MVTD-PACE x 1, MEL50 qd x 4d with VTD,
VTD-PACE x 1, VRD x 3 years
Van Rhee Blood 120(21) 2012, abstract 193
Transplant
• Effect of Pre-transplant Salvage Therapy Prior to Autologous
Transplant (AHCT) in Patients Not Responding to Initial Induction
for Multiple Myeloma (MM)
• Trends in Utilization and Outcomes of Autologous Hematopoietic
Cell Transplantation (AHCT) in the Upfront Management of Patients
with Multiple Myeloma:
A CIBMTR Analysis
• Second Primary Malignancies (SPM) following Autologous
Hematopoietic Cell Transplantation (AHCT) for
Multiple Myeloma (CIBMTR)
• Secondary Myelodysplasia-Associated Metaphase Cytogenetic
Abnormalities in Newly Diagnosed Multiple Myeloma Treated On
Total Therapies 2 & 3– Influence of Cumulative Dosing of
Maintenance Drugs
Effect of Pre-transplant Salvage Therapy Prior to
Autologous Transplant (AHCT) in Patients Not
Responding to Initial Induction for MM
• Planned upfront AHCT after initial induction improves both
overall and progression free survival (OS and PFS) for patients
with MM.
• However, it is unknown if patients with less than partial
response (PR) after a finite period of initial induction:
• should receive AHCT immediately or
• undergo salvage therapy to improve the level of response
pre-AHCT
Vij Blood 120(21) 2012, abstract 597
MM06-04-12_3.ppt
Effect of Pre-transplant Salvage Therapy Prior to
Autologous Transplant (AHCT) in Patients Not
Responding to Initial Induction for MM
Salvage Cohort
Salvage
Chemotherapy
Diagnosis and
Initial Induction
Autologous
Transplant
< PR to
induction
No Salvage Cohort
Autologous
Transplant
Diagnosis
12 months from diagnosis to AHCT
Vij Blood 120(21) 2012, abstract 597
AHCT
MM06-04-12_6.ppt
Status at Time of HCT
Characteristics
Disease status prior to transplant
CR
PR
MR/NR/SD
PROG
Sensitivity for chemotherapy
(overall)
Sensitive
Time from Dx to AHCT,
median (range)
<4 months
4-8 months
8-12 months
Vij Blood 120(21) 2012, abstract 597
No Salvage
0 (0)
0 (0)
234 (93)
17 (7)
0 (0)
7 (2-12)
86 (34)
101 (40)
64 (26)
Salvage
25 (8)
152 (47)
146 (45)
1 (<1)
177 (55)
8 (3-12)
57 (18)
85 (26)
182 (56)
P
<0.001
0.001
<0.001
MM06-04-12_10.ppt
Probability of Survival, based on Response to
Initial Chemotherapy (Reality Check)
PFS
100
OS
100
4yr PFS – p = 0.0014
90
90
80
80
CR/PR to induction
therapy (n=2326)
70
70
60
60
50
CR/PR to induction
therapy (n=2326)
40
50
<PR to induction
therapy (n=575)
40
30
30
P = 0.0001
<PR to induction
therapy (n=575)
20
20
10
10
0
0
0
2
4
6
Years
Vij Blood 120(21) 2012, abstract 597
8
10 0
2
4
6
8
10
Years
(Source: Txz12_19 & _20) MM06-04-12_13.ppt
Outcomes with/without Pre-AHCT Salvage
PFS
100
OS
100
90
90
P = NS
80
P = NS
70
80
NO SALVAGE
(n=251)
60
50
70
60
50
SALVAGE
(n=324)
40
SALVAGE
(n=324)
30
40
30
20
20
NO SLAVAGE
(n=251)
10
10
0
0
0
2
4
6
Years
Vij Blood 120(21) 2012, abstract 597
8
10 0
2
4
6
Years
8
10
Median follow-up Salvage
No Salvage
Months
61 (9-181)
68 (110-180)
(Source: Txz12_23 & _24) MM06-04-12_15.ppt
Effect of Pre-transplant Salvage Therapy Prior to
Autologous Transplant (AHCT) in Patients Not
Responding to Initial Induction for MM
Multivariate Analysis: Cox proportional hazard models (left truncated to
reduce waiting time bias in the SALVAGE group)
•
•
•
•
•
•
•
Age
Gender
Karnofsky PS
Immunoglobulin isotype
Stage
Serum creatinine at Dx
•
•
•
•
•
•
Salvage vs. no Salvage
Dz status pre-ASCT
Conditioning regimen
Time from Dx to ASCT
Single or Tandem ASCT
Use of thal, bort, or len
Year of transplant
Vij Blood 120(21) 2012, abstract 597
MM06-04-12_6.ppt
Effect of Pre-transplant Salvage Therapy Prior to
AHCT in Patients Not Responding to Initial
Induction for MM: Multivariate Analysis
Reference
Group*
NRM
HR P
Relapse/PD
HR P
Mortality/OS
HR P
SALVAGE vs
NO SALVAGE
1.03 0.93
Creatinine at
diagnosis >1.5
2.68 0.008 1.09 0.4417
1.51 0.003
Novel agent use
prior to AHCT
0.37 0.04
0.79 0.1091
Vij Blood 120(21) 2012, abstract 597
1.01 0.3429
1.11 0.3207
0.87 0.2622
MM06-04-12_17.ppt
Effect of Pre-transplant Salvage Therapy
Prior to Autologous Transplant (AHCT) in
Patients Not Responding to Initial Induction
for MM: Conclusions
• In patients achieving a less than partial response
(PR) after a finite period of initial induction,
additional salvage therapy prior to AHCT
improves the depth of response
• However additional salvage therapy prior to AHCT
was not associated with an improvement in PFS
or OS
Vij Blood 120(21) 2012, abstract 597
MM06-04-12_19.ppt
Trends in Utilization and Outcomes of Autologous
Hematopoietic Cell Transplantation (AHCT) in the Upfront
Management of Patients with Multiple Myeloma:
A CIBMTR Analysis: Inclusion Criteria
• Recipients of first AHCT in US or Canada
• First autologous transplant 1995-2010
• First autologous transplant <1 year from diagnosis (“upfront”)
• Registered at CIBMTR (TED dataset)
• Reported to CIBMTR (CRF dataset)
• At least 100 days of follow up
Costa Blood 120(21) 2012, abstract 596
Utilization 1995-2010
(US data only)
• Estimated new cases of MM 238,235*
• Estimated 32,151 AHCT performed in the period
(23,725 registered)
• 68.3% performed < 1 year from diagnosis
• Estimated 13.4% of new cases of MM received
AHCT
• 9.2% within one year of diagnosis
Costa Blood 120(21) 2012, abstract 596
* SEER database
Utilization (US data only)
≥ 65 years
50-64 years
<50 years
60000
40000
40000
Number of newly
diagnosed patients
30000
30000
30000
20000
20000
20000
10000
10000
10000
0
0
0
40000
2005-2009
2000-2004
1995-1999
Costa Blood 120(21) 2012, abstract 596
2005-2009
First transplant at
any time
2000-2004
50000
1995-1999
50000
50000
2005-2009
First transplant in
12 months
2000-2004
60000
1995-1999
60000
Characteristics of AHCT Recipients
•
<1 year from diagnosis (US and Canada)
Two datasets:
• Transplant essential data (TED N= 29,489)
• Case report forms (CRF N= 4,373)
1995-1999
2000-2004
2005-2010
P
Median age*
54
57
58
<0.001
≥65*
8%
19%
24%
<0.001
Stage 3 (DSS or ISS)
64%
64%
44%
<0.001
1 line of therapy
70%
63%
63%
<0.001
Thalidomide use
<1%
22%
52%
<0.001
Lenalidomide use
0%
<1%
21%
<0.001
Bortezomib use
0%
2%
35%
<0.001
CR/PR prior to AHCT
79%
87%
Costa Blood 120(21) 2012, abstract 596
*TED dataset
88% #CRF dataset
<0.001
Progression-free Survival (PFS) after Auto-HCT
Stratified by Period of Transplant (CRF)
100
100
90
80
Probability, %
90
Does this convergence
suggest that improved
induction not buying
more in overall PFS?
70
80
70
60
60
50
1995-1999
(n=686)
40
50
2000-2004 (n=1,464)
40
30
30
20
20
2005-2010 (n=2,218)
10
Years
10
0
0
0
1
1995-99
2000-04
2005-10
Costa Blood 120(21) 2012, abstract 596
2
3
4
50%
55%*
57%*
5
26%
27%
23%
* vs. 1995-1999, P<0.05
Txz12_17a.ppt
Overall Survival (OS) after REL/PROG Stratified by Period of
Transplant (CRF)
100
100
90
90
Probability, %
80
Years
80
2005-2010(n=1,190)
70
70
60
60
50
50
40
1995-1999 (n=499)
30
40
2000-2004(n=1,021)
30
20
20
10
10
0
0
0
1
1995-99
2000-04
2005-10
Costa Blood 120(21) 2012, abstract 596
2
58%
65%*
72%*#
3
* vs. 1995-1999, P<0.05
4
5
22%
24%
24%
#
vs. 2000-2004, P<0.05
Probability of Overall Survival (OS) after Auto-HCT
Stratified by Period of Transplant (CRF)
Probability, %
100
100
90
90
80
80
2005-2010 (n=2,223)
70
60
60
2000-2004 (n=1,464)
50
40
40
FDA allowances
30
30
1998 Thalidomide Rx permitted,
but no MM indication
5/03 Bortezomib approved
6/06 Lenalidomide approved
6/06 Thalidomide MM indication
10
0
1995-99
2000-04
55%*
2005-10
57%*
50
1995-1999 (n=686)
20
Years
70
0
1
Costa Blood 120(21) 2012, abstract 596
2
72%
20
10
0
3
4
47%
81%*
86%*#
* vs. 1995-1999, P<0.05
5
#
vs. 2000-2004, P<0.05
Bortezomib maintenance
• UAMS: TT3 vs TT2: Bortezomib induction and
maintenance improved t(4;14) OS
• IFM: BzD vs VAD induction: Improved t(4;14)
OS
• HOVON: Bz induction and maintenance vs
Thal induction and maintenance: Improved
del17p OS
• PETHEMA: TV vs T vs IFNa maintenance –
bortezomib did not overcome impact of
adverse genetics
Rosiñol, Blood 120(21) 2012, abstract 334
Secondary Primary Malignancies Post Transplant, with an
focus on lenalidomide maintenance
Study
(Median follow-up)
Treatment
Schedule
% SPM
% t-MDS/t-AL
IFM 2005-02, Attal et al NEJM 2012
(45 months)
Len
Placebo
8%
4%
2.6%
1.3%
CALGB 100104, McCarthy et al NEJM 2012
(34 months)
Len
Placebo
7.8%
2.6%
3%
0%
MM-015, Palumbo et al NEJM 2012
(30 months)
MPL-L/MPL
Placebo
7%
3%
3.6%
0.6%
Usmani Blood 2012, abstr 324
TT3A (VTD)
TT3B (VRD)
NA
3%
10%
Raval CIBMTR, Blood 2012, abstr 946
Mostly no
maintenance
3%
0.6%
SPM-second primary malignancies, t-MDS: therapy related MDS, t-AL: therapy related acute leukemia
Usmani, Blood 120(21) 2012, abstract 324 and Raval abstract 946
Secondary Myelodysplasia-Associated Metaphase
Cytogenetic Abnormalities in Patients On Total Therapies 2 &
3– Influence of Cumulative Dosing of Maintenance Drugs
Total Therapy Trials Schema
TT3b4
TT21
TT3a2,3
n=177
n=668
n=303
INDUCTION
D-PACE + T
X 4 Cycles
VTD-PACE
x 2 Cycles
VTD-PACE
x 2 Cycles
TRANSPLANT
MEL200 x 2
MEL200 x 2
MEL200 x 2
CONSOLIDATION
D-PACE + T
X 4 Cycles
VTD-PACE
x 2 Cycles
VTD-PACE
x 2 Cycles
MAINTENANCE
T vs. Control
VTD x 1 year
TD x 2 years
VRD x 3 years
118 months
78 months
48 months
MEDIAN FOLLOW-UP
(1) Barlogie et al, NEJM 2003
(2) Barlogie et al, Br J Haematol 2007
Usmani, Blood 120(21) 2012, abstract 324
(3) van Rhee F et al, Blood 2010
(4) Nair et al, Blood 2010
Pronounced Higher Cumulative Incidence of
Persistent MDS-CA in TT3B from Onset of
Maintenance
Incidence of any persistent MDS-CA
by protocol at start of maintenance therapy
25%
TT2+Thal
TT2-Thal
TT3a
TT3b
20%
Events / N
7 / 174
6 / 157
7 / 214
7 / 120
2-Year
Estimate
0.6% (0.6, 0.6)
0.7% (0.7, 0.7)
1.0% (1.0, 1.0)
0.9% (0.9, 0.9)
15%
10%
5%
0%
0
3
6
9
Years from onset of maintenance therapy
12
TT3b vs. TT3a:
p= 0.004
TT3b vs. TT2-Thal: p= 0.01
TT3b vs. TT2+Thal: p= 0.0009
TT3a vs. TT2-Thal:
p= NS
TT3a vs. TT2+Thal:
p= NS
TT2-Thal vs. TT2+Thal:p= NS
Usmani, Blood 120(21) 2012, abstract 324
Thanks for inviting me
Myeloma group at Mayo
Rochester
Arizona
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Vincent Rajkumar, MD
Francis Buadi, MD
Jane Case
David Dingli, MD
Angela Dispenzieri, MD
Morie Gertz, MD
Suzanne Hayman, MD
Lisa Hwa
Shaji Kumar, MD
Robert Kyle, MD
Martha Lacy, MD
Nelson Leung, MD
John Lust, MD
Arleigh McCurdy, MD
Steve Russell, MD
Teresa Russell
Steve Zeldenrust, MD
Leif Bergsagel, MD
Rafael Fonseca, MD
Joseph Mikhael, MD
Craig Reeder, MD
Keith Stewart, MD
Jacksonville
 Asher Chanan-Khan, MD
 Vivek Roy, MD
 Tamur Sher, MD