imedex 2-27-14 frontline therapy and maintenance for newly diagnosed multiple myeloma –transplant...
TRANSCRIPT
Imedex 2-27-14
• Frontline Therapy and Maintenance for Newly Diagnosed Multiple Myeloma
– Transplant eligible vs transplant ineligible– Doublets vs triplets– Integrating Novel Agents into Frontline Therapy
• Carfilzomib• Elotuzumab• Pomalidomide• Oral PI’s
– Maintenance
Myeloma Survival by Decade
Current OS and High Risk Myeloma
A good risk stratification system should allow identification of this ~25% patients
Current Paradigm of Initial Treatment
The Concept of Dividing Myeloma Patients into Transplant Eligible vs Transplant
Ineligible
• Arguments for making this distinction:– The use of melphalan impedes the ability to collect PBSC’s– Older patients cannot tolerate more aggressive regimens– Older patients don’t need to achieve a deeper response
since they don’t have as long to live anyway
• Arguments against making this distinction:– More and more we have been able to collect stem cells after
melphalan– There are data that older patients benefit just as much from
deeper responses and would appreciate the added longevity (I would)
– Most US oncologists don’t use melphalan-based regimens anyway (prefer Vd and Rd)
Should CR be Our Goal in All Patients
Martinez-Lopez et al Blood. 2011;118(3):529-534
Prognostic effect of Patients in CR vs those in (nCR or VGPR or PR) vs those with (SD or PD) after
HDT/ASCT
In non-transplant candidates, achievement of CR is also associated with improved
PFS and OS
Gay F et al. Blood. 2011;117:3025.
Shouldn’t the achievement of deeper response be also a goal in non-transplant candidates?
PFS
Frontline TherapyTransplant Eligible Patients
Are Triplets the Standard of Care?
Improving Response Rates with Combination Therapies
Frontline TherapyTransplant Ineligible Patients
Increasing Options
Initial Treatment of Transplant - Ineligible Candidates
Continue initial therapy?
Initial therapy Maintenance?
Duration?
MP-based regimens MPT > MP
VMP > MP VMP = VTP
MPR-R>MPR=MP VMPT> VMP
Duration?
First Trial:MPT vs Rd vs Rd Continuous
Plenary
FIRST: Lenalidomide/Dexamethasone vs MPT in NDDM SCT-Ineligible Patients[1]
Ran
dom
izat
ion
1:1:
1
Arm BRd18
Arm CMPT
Len + LoDex 18 cycles (72 wks) Lenalidomide 25 mg Days 1-21/28LoDex 40 mg Days 1, 8, 15, 22/28
Mel + Pred + Thal 12 cycles[2] (72 wks)Melphalan 0.25 mg/kg Days 1-4/42Prednisone 2 mg/kg Days 1-4/42Thalidomide 200 mg Days 1-42/42
PD
, OS
, and
subs
eque
nt a
nti-M
M T
x
PD
or
unac
cept
able
toxi
city
Active treatment + PFS follow-up phase
Pts > 75 yrs: LoDex 20 mg Days 1, 8, 15, 22/28; Thal[3] 100 mg Days 1-42/42; Mel[3] 0.2 mg/kg Days 1-4. Stratification: age, country, and ISS stage.
Len + LoDex ContinuouslyLenalidomide 25 mg Days 1-21/28LoDex 40 mg Days 1, 8, 15, 22/28
Arm AContinuous Rd
1. Facon T, et al. ASH 2013. Abstract 2. 2. Facon T, et al. Lancet. 2007;370:1209-1218. 3. Hulin C, et al. J Clin Oncol. 2009;27:3664-3670.
Phase IIIN = 1623
FIRST Trial: Progression-Free Survival
Median PFS
Rd (n = 535)
25.5 mos
Rd18 (n = 541)
20.7 mos
MPT (n = 547)
21.2 mos
HR: Rd vs MPT: 0.72 (P = .00006) Rd vs Rd18: 0.70 (P = .00001) Rd18 vs MPT: 1.03 (P = .70349)
Mos
Pat
ien
ts (
%)
100
80
60
40
20
00 6 12 18 24 30 36 42 48 54 60
72 w
ks
1. Facon T, et al. ASH 2013. Abstract 2. Reproduced with permission.
Integrating Approved Newer Agents into Frontline Regimens
Transplant Eligible
Cycles 1–8• CFZ 20-27-36 mg/m2 Days
1–2, 8–9, 15–161
• LEN 25 mg Days 1–21• DEX 40 mg weekly
Cycles 1-4, 20 mg weekly Cycles 5–8
Carfilzomib, Lenalidomide, dexamethasone (CRd) Treatment Schema
Jakubowiak AJ, et al. Blood. 2012;120(9):1801-1809.
Stem cell collection
≥PR
CRd Cycles 9–24
CRdInduction
CRdMaintenance
CRd Cycles 1–4 CRd Cycles 5–8
ASCT
LEN Cycles 25+
Lenalidomide (off protocol)
Transplant-eligible
Transplant-eligible and --ineligible patients
Until disease progression or unacceptable toxicity
Cycles 9–24• CFZ on Days 1–2 and
15–16 only• CFZ, LEN, DEX at last
best tolerated doses
Cycles 25+• LEN at last best
tolerated dose
CRd - Best Response (n=53)*
*ITT, including patients who discontinued treatment early (eg, proceed to transplant)†iCR is an estimate of MRD-negative disease (10 color flow), based on percentage of patients in sCR evaluated for MRD at 12 months (18 of 19) and at 22 months (22 of 24)
†
Jakubowiak et al, ASCO 2013
CRd – Survival
N=53Median follow-up of 25 months (range 5-37)
Jakubowiak et al, ASCO 2013
0 5 10 15 20 25 30 35 400.0
0.2
0.4
0.6
0.8
1.0
Months
PF
S P
rob
abil
ity
0 10 20 30 400.0
0.2
0.4
0.6
0.8
1.0
Months
Su
rviv
al P
rob
abil
ity 24-month rate 98%
24-month rate 94%
Progression-free Survival Overall Survival
Patients receive 8 cycles of CRd Induction then 16 cycles of CRd maintenance then LEN maintenance until progression
CRd - Time to Response
0 4 8 12 16 20 24 28 32
0.0
0.2
0.4
0.6
0.8
1.0
PR
CR
nCR
VGPR
Months
Pro
ba
bili
ty
sCR
Median Time to Response, mo0.9 3.7
6.7 11.0 13.1
Jakubowiak et al, ASCO 2013
Integrating Approved Newer Agents into Frontline Regimens
Transplant Ineligible Patients
Carfilzomib, Melphalan, Prednisone (CMP)
MTD defined at CFZ 36 mg/m2Patients receive 9 cycles then stop treatment
68 patients have been enrolled in Phase 1 +2 Median age 72 years (61 – 86)High risk 17%After a median of 7 cycles (1 – 9)CR 6%VGPR 50% PR 35%SD 9%PD 0
Moreau et al, ASCO 2013, Courtesy P. Moreau
>VGPR 56%
93.9%
PFS
OS
Median follow-up = 12 months
>PR 91%
Median PFS = 22 months
OS= 87%
Carfilzomib, Cyclophosphamide, dex (CCd)
Time to EventProgression-Free and Overall Survival
Time (months)
Pat
ien
ts (
%)
0.00
0.25
0.50
0.75
1.00
0.0 2.5 5.0 7.5 10.0 12.5 15.0
Time (months)
Pat
ien
ts (
%)
0.00
0.25
0.50
0.75
1.00
0.0 2.5 5.0 7.5 10.0 12.5 15.0
0.00
0.25
0.50
0.75
1.00
0.0 2.5 5.0 7.5 10.0 12.5 15.0
0.00
0.25
0.50
0.75
1.00
0.0 2.5 5.0 7.5 10.0 12.5 15.0
1-year PFS
88%
1-year PFS
88%
0.00
0.25
0.50
0.75
1.00
0.0 2.5 5.0 7.5 10.0 12.5 15.0
Time (months)
0.00
0.25
0.50
0.75
1.00
0.0 2.5 5.0 7.5 10.0 12.5 15.0
Time (months)
1-year OS
87%
1-year OS
87%
PFS OS
Palumbo et al, ASH 2012, Courtesy A. Palumbo
Patients receive 9 cycles of CCD then CFZ maintenance until progression
Yet to be Approved New Agents with Potential
Ixazomib (weekly), Lenalidomide, dexamethasone
Patients treated at RP2D (2.23 mg/m2 / 4.0 mg)
4537 32
30
26 35
1932 23
0
10
20
30
40
50
60
70
80
90
100
After 4 cycles(n=47)
After 8 cycles(n=19)
Overall(n=52)
CRVGPRPR
%
≥VGPR58%
≥VGPR49% ≥VGPR
58%
Of 3 response-evaluable patients who completed 12 cycles, 2 achieved CR and 1 VGPR
ORR 94% ORR 95% ORR 90%
Kumar et al, ASH 2012, Courtesy S. Kumar
Oprozomib (ONX 0912)
• Oprozomib (OPZ, formerly ONX 0912) is a structural analog of carfilzomib (CFZ)
– It is an orally bioavailable, next-generation PI
– Similar to CFZ, OPZ is a potent, selective, and irreversible proteasome inhibitor
• Being evaluated in hematologic malignancies and solid tumors
Savona MR, et al. Blood. 2012;120. Abstract 203.
Monoclonal antibodies
• Anti CS 1– Elotuzumab
• Anti CD 38– Daratumumab – SAR 650984
Elotuzumab 10 mg/kg
Elotuzumab 20 mg/kg Total
Patients, n 36 37 73
ORR (≥PR), n (%) 33 (92) 28 (76) 61 (84)
CR/stringent CR, n (%) 5 (14) 4 (11) 9 (12)
VGPR, n (%) 17 (47) 13 (35) 30 (41)
PR, n (%) 11 (31) 11 (30) 22 (30)
<PR, n (%) 3 (8) 9 (24) 12 (16)
Efficacy: Best ResponsePhase II (Study 1703)
1. Lonial S et al. Blood 2011;Abstract 303
• Overall median time to response: 1 mo (range, 0.7-19.2); 1 new and 3 deepening responses were observed since the previous data cut (October, 2011)1
• Overall median time to best response: 2.5 mo (range, 0.7-21.4)
• Median duration of objective response: 15 mo
Progression-free Survival from the Phase II Cohort
10 mg/kg (n=36): 33 mos (95% CI:14.883-NA)20 mg/kg (n=37): 18.6 mos (95% CI: 12.912-32.361)Total (n=73): 25.8 mos (95% CI: 15.376-35.713)
In the 10 mg/kg cohort, median PFS was 33 months In the 20 mg/kg cohort, the median PFS was 18 months
Lonial et al, ASCO 2013
Ongoing Studies with Elotuzumab
Phase Treatment Primary Endpoint
MM Patient Population
ELOQUENT - 1 IIIRD +/– Elotuzumab
PFSPreviously Untreated
ELOQUENT - 2 IIIRD +/– Elotuzumab
PFSRelapsed or Refractory
http://www.clinicaltrial.gov/ct2/show/NCT01239797http://www.clinicaltrial.gov/ct2/show/NCT01335399
Daratumumab Phase I/IIMaximal Change in Paraprotein
≤1 mg/kg 2 mg/kg 4 mg/kg 8 mg/kg 16 mg/kg
• Data at baseline below limits for measurable disease
Results are before database lock
*
SAR650984: Maximal Change in Paraprotein
Myeloma Patients Treated at Doses of 1 mg/kg Q2W or Higher
One patient at 3.0 mg/kg and 20 mg/kg with 0% change; One patient at 20 mg/kg not evaluable
5 mg/kg Q2W10 mg/kg Q2W10 mg/kg QW20 mg/kg Q2W
3 mg/kg Q2W1 mg/kg Q2W
-100
% C
han
ge
in P
arap
rote
in
-75
-50
-25
0
25
50
75
100
125
150
Stem Cell Transplantation
Conventional Chemotherapy vs ASCT RANDOMIZED STUDIES
Median OS
Patients(n) Age
Median Follow
UpConventional
Chemotherapy ASCT
IFM90[1] 200 <65 7 y 44 57
MAG91[2] 190 55-65 56 m 50 55
MRC7[3] 403 <65 42 m 42 55
PETHEMA[4]* 164 <65 42 m 64 72
1. Attal M et al. N Engl J Med. 1996;335:91.2. Fermand JP et al. J Clin Oncol. 2005;23:9227.
3. Child A et al. N Engl J Med. 2003;348:1875.4. Blade J et al. Blood. 2005;106:3755.
*in patients responding to conventional chemotherapy
Len-Bz-Dex ×3
Len-Bz-Dex ×5
Len ×12m (IFM)
Len until relpase (US
Stem collection
Len-Bz-Dex ×3
ASCT
Len ×12m (IFM)Len until relapse (US)
Stem collection
Len-Bz-Dex ×2
ASCT at relapse
NCI Clinical Trial Identifier NCT01191060.
The Debate…ASCT:Up-Front or at Relapse
Maintenance Therapy
Not as Simple as We Thought
ITT Analysis with a median follow-up from transplant of ~48 months p<0.001 Median TTP: 50 months versus 27 months.
146 events on placebo104 events on lenalidomide
Post-Transplant Lenalidomide MaintenanceCALGB 100104
Estimated HR=0.51 (95% CI = 0.39 to 0.66),
McCarthy, IMW Kyoto, April 2013
Updated TTP Updated OSIncludes pts crossing over
Analysis including placebo patients crossing over within 12 months of randomization on lenalidomide arm with a median follow-up of ~48 months. p= 0.003
Cut-off date January 7, 2013
CALGB 100104: Event-Free Survival & SPM
ASCT: autologous stem cell transplant; CALGB: Cancer and Leukemia Group B; EFS: event-free survival; HR: hazard ratio; LEN: lenalidomide; N/A: not applicable; PBO: placebo; PD: progressive disease; SPM: second primary malignancy.
McCarthy PL. N Engl J Med. 2012;366:1770-1781.
•
– Hematologic SPM: 8 (LEN; 3.5%) vs. 1 (PBO; 0.4%)
– Solid-tumor SPM: 10 (LEN; 4.3%) vs. 5 (PBO; 2.2%)
IFM 2005-02: Progression-Free Survival
ASCT: autologous stem cell transplant; β2-M: β2-microglobulin; del: deletion; HR: hazard ratio; IFM: Intergroupe Francophone du Myélome; LEN: lenalidomide; PBO: placebo; PFS: progression-free survival; VGPR: very good partial response.
Attal M. N Engl J Med. 2012;366:1782-1791
IFM 2005-02: Overall Survival
• With a median follow-up of 45 months, no differences in OS has been observed across treatment arms
– 4 year OS (post-randomization): 73% (LEN) vs. 75% (placebo)
IFM: Intergroupe Francophone du Myélome; LEN: lenalidomide; N/A: not applicable; OS: overall survival; PBO: placebo.
Attal M. N Engl J Med. 2012;366:1782-1791
IFM 2005-02: Event-Free Survival & SPM*
* Data as of Oct 2011, including events during consolidation and maintenance.
EFS: event-free survival; IFM: Intergroupe Francophone du Myélome; LEN: lenalidomide; N/A: not applicable; PBO: placebo; PD: progressive disease; SPM: second primary malignancy.
Attal M. N Engl J Med. 2012;366:1782-1791
– Hematologic SPM: 13 (LEN) vs. 5 (placebo) (18 v 7)
– Solid tumor SPM: 10 (LEN) vs. 4 (placebo) (13 v 11)
Bortezomib MaintenanceHOVON-65/GMMG-HD4 Trial
PFS OS
Sonneveld et al, J Clin Oncol 2012;30:2946-55
Bortezomib was used both pre- and post-transplantBenefits mostly in patients with high risk disease
MM-015: Study Design
Dex: dexamethasone; ISS: International Staging System; MP: melphalan-prednisone; MPR: melphalan-prednisone-lenalidomide; MPR-R: melphalan-prednisone-lenalidomide followed by lenalidomide maintenance; PBO: placebo; po: orally.
Palumbo A. N Engl J Med. 2012;366:1759-1769.
MM-015: Progression-Free Survival
HR: hazard ratio; MP: melphalan-prednisone; MPR: melphalan-prednisone-lenalidomide; MPR-R: melphalan-prednisone-lenalidomide followed by lenalidomide maintenance; N/A: not applicable; PFS: progression-free survival.
Palumbo A. N Engl J Med. 2012;366:1759-1769.
• MPR-R significantly extended median PFS vs. MP and MPR
MM-015: Overall Survival
HR: hazard ratio; MP: melphalan-prednisone; MPR: melphalan-prednisone-lenalidomide; MPR-R: melphalan-prednisone-lenalidomide followed by lenalidomide maintenance; N/A: not applicable; OS: overall survival.
Palumbo A. N Engl J Med. 2012;366:1759-1769.
• The number of deaths is low and comparable across treatment groups
Controversies in Maintenance Therapy
• Should everyone (anyone) receive it?• Should everyone receive the same drug(s)?
– Lenalidomide?– VRd for high risk? Who is high risk?
• What should be the duration of therapy– Is there a way to measure this (MRD)?– Does more therapy result in more SPM’s and less
effect?• Would some patients be better off with just
“consolidation?”• At least those of us who work in this area will
not be at a loss for new studies.