Clinical research in Multiple Myeloma COMy awardcme-utilities.com/mailshotcme/Material for...
Transcript of Clinical research in Multiple Myeloma COMy awardcme-utilities.com/mailshotcme/Material for...
María-Victoria Mateos
IBSAL-University Hospital of Salamanca
Spain
Clinical research in Multiple Myeloma
COMy award
University of Salamanca
Sagar Lonial CV
Nikil Munshi CV
95 pages
Maria Victoria Mateos CV
Dr. Maria-Victoria Mateos, MD, PhD, is Consultant Physician in the Haematology
Department and Associate Professor of Medicine at the University of Salamanca,
Spain. She is the director of the Myeloma Program and coordinates the Clinical
Trials Unit in Salamanca’s University Hospital Haematology Department.
She serves as coordinator of GEM (Spanish Myeloma Group), with direct
involvement in the design and development of clinical trials. She has coordinated
many clinical trials in elderly and smouldering MM patients that have profoundly
influenced current options for treating these patient populations.
She has published over 200 original papers in international journals. Her areas of
interest include multiple myeloma, the biology of plasma cells and the news drugs
development.
Short document
María-Victoria Mateos
IBSAL-University Hospital of Salamanca
Spain
University of Salamanca
Contributions to the diagnostic and
management of Multiple Myeloma patients
PET:VEL 2004-> velcade-melfalan-prednisone*
MM1S Cell line: In vitro anti-myeloma activity of Bortezomib
+ melphalan + dexamethasone
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
MT
T u
pta
ke (
A5
70)
Dex 100 nM
Melphalan 1 uM
Bortezomib 2 nM
V-MP : Treatment scheduleDay
1 2 3 4 8 11 22 25 29 32 33–42
█ █ █ █ █ █ █ █
█ █ █ █
█ █ █ █
Day
1 2 3 4 8 15 22 23–35
█ █ █ █
█ █ █ █
█ █ █ █
Bortezomib
Melphalan 9 mg/m2
Prednisone 60 mg/m2
• Four 6-week cycles
• Five 5-week cycles
Bortezomib
Melphalan 9 mg/m2
Prednisone 60 mg/m2
Rest p
erio
d
Rest p
erio
d
• Total = 49 weeks of treatmentMateos et al. Blood 2006;108:2165–72
V-MP: Response rates (n=53)
Analysis of the best response so far achieved
1st cycle V-MP
70%
0%
10%
20%
30%
40%
50%
60%
70%
CR IF- CRIF+ PR MR SD
6% 2%
62%
6%
24%
Best response: median 5 cycles (2-9)
86%
30%
13%
43%
13%
0%
10%
20%
30%
40%
50%
60%
70%
CR IF- CR IF+ PR SD
Mateos et al. Blood 2006;108:2165–72
Conclusions
High efficacy of V-MP:
- 43% CR/nCR (30% CR IF-, half of them by immunophenotype)
- Early responses (1-3 cycles)
- Response is not influenced by cytogenetic abnormalities
Acceptable toxicity:
– Similar to the one described in previous studies in refractory MM
– More hematological toxicity (attributable to Melphalan)
– Higher in patients >75 years
– Toxicity decreases from the 3rd cycle
Rationale for experimental arm of Phase III VISTA Trial: V-MP vs MP
VISTA: VELCADE as Initial Standard Therapy in multiple
myeloma: Assessment with melphalan and prednisone
VMPCycles 1-4
Bortezomib 1.3 mg/m2 IV: days 1,4,8,11,22,25,29,32
Melphalan 9 mg/m2 and prednisone 60 mg/m2 days 1-4
Cycles 5-9
Bortezomib 1.3 mg/m2 IV: days 1,8,22,29
Melphalan 9 mg/m2 and prednisone 60 mg/m2 days 1-4
MPCycles 1-9
Melphalan 9 mg/m2 and prednisone 60 mg/m2 days 1-4
R
A
N
D
O
M
I
Z
E
9 x 6-week cycles (54 weeks) in both arms
Randomized, international, phase III trial of VMP vs MP in previously
untreated MM patients who were not candidates for HDT-ASCT
Patients: Symptomatic multiple myeloma/end organ damage with
measurable disease (N, 682)
▪ ≥65 yrs or <65 yrs and not transplant-eligible; KPS ≥60%
Primary Endpoint: TTP
Secondary Endpoints: CR rate, ORR, TTR, DOR, PFS, TNT, OS, QoL (PRO)
San Miguel et al. JCO 2013; 31(4):448-55
TTP OS
0 3 6 9 12
Time (months)
15 18 21 24 27
0
20
40
60
80
100
VMP
MP
Patie
nts
withou
t even
t (%
)
VMP: 24.0 months
MP: 16.6 months, P<0.000001
MP + Bortezomib (VMP) vs MP: VISTA
RR (CR) (%): 71(30) vs 35(4)
0 6 12 18 24 30 36 42 48 54 60 66 72 78
Patie
nts
withou
t even
t (%
)
Median follow-up 60 months
Median OS:
VMP: 56m
MP: 43m, P=0.0008
Median OS benefit: 13.3 m100
90
80
70
60
50
40
30
20
10
0
Time (months)
G3-4 AEs: GI (19%), PN (13%), VVZ react (3%)
Bortezomib twice a week x 4cycles + weekly x 5cycles
VMP is one standard of care
VISTA trial: 682 patients 151 investigators in 22 countries
What was the next step?
Modified VMP vs VTP followed by maintenance with VT or VP in
newly diagnosed elderly MM patients (PETHEMA/GEM05 >65y study)
Aim: To reduce the toxicity of standard VMP (by using a weekly schedule of Bz and only 6
cycles) & to maintain the efficacy ( with a prolonged maintenance)
Induction
x6 cyclesBz weekly
except in the 1st
Bort/Mel/Pred
(VMP)
Bort/Thal/Pred
(VTP)vs
Mateos et al. ASH 2009 (abstract (3)
Mateos MV et al. Lancet Oncology 2010
Maintenance
x3 yearsBz / 3m *
Bort/Thal
(VT)
Bort/Pred
(VP)
Bort/Thal
(VT)
Bort/Pred
(VP)
2ª Aim at maintenance: to compare VT vs VP
*Bz: 1,3mg d 1,4,8,11 / 3m; Thal: 50mg d; Pr: 50mg alternting days
Comparison between GEM 2005 and VISTA
1. More discontinuations with VTP (17%) and more SAEs (15%VMP/ 30%VTP).
2. No differences in RR between VMP & VTP
3. Increase in CR from 23% after induction to 42% with Maintenance
4. TTP/PFS are bodeline superior for VT > VP (p 0,05).
GEM 2005 (260 pts) VISTA (344 pts)
Neuropathy (G3) 5% 13%
G-I (G3) 7% 19%
Discontinuations 11%1 17%
PR 80%2 75%
CR 42%3 30%
PFS 314 21 m
OS (at 3 y) 70% 67%
Mateos et al. Lancet Oncology 2010; 10(11): 934-41 San Miguel et al. N Engl J Med 2008; 359(9):906-17
ASH2009: Plenary session
Conclusions
• Alkylating agents should remain as important drugs in the treatment
armamentarium of elderly untreated elderly MM patients
• The weekly shedule of Bort significantly reduced the incidence of PN
• Maintenance therapy was able to increase the CR rate with a low toxicity
profile. VT was superior in terms of TTEvents.
(GEM05>65)
What else we did?
New standards of care for elderly MM patients
MPT
MP
VMP
Alkylators-based
regimens
Alkylators-free
regimens
Len-dex
IMiD’s
Six randomized trials:
Benefit in PFS&OS...6mOne randomized trial:
Benefit in PFS...8m
OS...13m
Fayers PM et al. Blood 2011; 118(5): 1239-47San Miguel. N Engl J Med 2008;359:906-17
San Miguel . J Clin Oncol. 2013; 31: 448-55
One randomized trial:
Benefit in PFS&OS vs MPT
Benboubker L, et al. NEJM 2014; 371: 906-17
Study design and hypothesis: VMP/Rd
Symptomatic newly diagnosed MM pt > 65 y
* Half of the patients will start by VMP and half by Rd
MPV x 9cycles Lendex x 9 cycles
MPV Rd MPV Rd MPV Rd MPV Rd MPV Rd MPV Rd MPV Rd MPV Rd MPV Rd
Sequential scheme
Alternating scheme*
N: 240 pts74 weeks
Hypothesis: - Higher efficacy for the alternating scheme
- Less probability of cell tumor scape
- Lower cumulative toxicity
Mateos MV et al. Blood 2016
Outcome in terms of PFS and OS in patients who
completed 18 cycles (n:138)
Median follow-up: 30 m (9-43)
OS
Sequential : 91% at 3 yrs
Alternating: 95% at 3 yrs
PFS
Sequential: 52% at 3y
Alternating: 60% at 3y
p=NS
20,0010,000,00
0,2
454035302520151050
1,0
0,8
0,6
0,4
0,2
0,0
454035302520151050
1,0
0,8
0,6
0,4
0,2
0,0 p=NS
Mateos MV et al. Blood 2016
Future of the treatment for elderly MM patients
MP
VMP
Alkylators-based
regimens
Alkylators-free
regimens
Len-dex
IMiD’s
Spanish standard of care for ”fit” elderly NDMM patients
It is necessary to individualize the treatment in elderly patients
according to the frailty
GEM2017FIT
2
aDuring the first cycle (6 weeks), bortezomib is given on D1, 4, 8, 11, 22, 25, 29, and 32.; GAH: J Geriatr Oncol. 2015 Sep;6(5):353-61; R1: first randomization; R2:
second randomization ; IMF imnunofenotipic response NGF ( next generation flow)
NDMM
patients
NS CTC
>65 y
n= 462
elderly
Fit
Patients
(GHA) ARM 2a KRd .N=154
CFZ: 20/70 mg/m2, d1, 8, 15
LEN: 25 mg, d1–21
DEX: 20/10 mg, d1, 2, 8, 9, 15, 16, 22, 23
18 28-day cycles
N=159
ARM 1 VMP N=154
Mel: 9mg/m2 D1-4
Pred: 60mg/m2 D1-4
BTZ: 1.3mg/m2 D1, 8,15,22ª
One 6 week cycle followed
by eight 4-week cycle
N=159
Rd
LEN: 25 mg, d1–21
DEX: 20/10 mg, d1, 2, 8, 9,
15, 16, 22, 23
Nine 28-day cycles
(R1) Induction 18 cycles (R2) MaintenanceConsolidation
Rd
LEN: 25 mg, d1–
21
DEX: 20/10 mg,
d1, 2, 8, 9, 15,
16, 22, 23
Dara 16 mg/Kg
Days 1, 8, 15, 22
of cycles 1-2; Days
1 and 15 of cycles
3 and 4
Four 28-day
cycles
Dara 16 mg/Kg IV Day 1 of cycles 1-24
+
R 15 mg, d1–21
Until progresion
No maintenance
MRD
9 cy
MRD
18 cy
MRD
22 cy
Dara 16 mg/Kg IV Day 1 of cycles 1-24
+
R 15 mg, d1–21
Until progresionARM 2b KRD- DARA n=154
CFZ: 20/70 mg/m2, d1, 8, 15
LEN: 25 mg, d1–21
DEX: 20/10 mg, d1, 2, 8, 9, 15, 16, 22, 23
Dara 16 mg/Kg IV Days 1, 8, 15, 22 of cycles 1-2; Days 1 and 15
of cycles 3 and 4; Day 1 of cycles 5 to 18
No maintenance
Primary endpoint immonuphenotipic complete response Secondary exploratory outcome: PFS
MRD+
MRD-
Directly to the R2
maintenance fase
*
*
* Patientes in Biological relapse will be rechallenge by Dra + R
MGUS or
smouldering
myeloma
Asymptomatic Symptomatic
ACTIVE
MYELOMA
M p
rote
in (
g/L
)
20
50
100
1st RELAPSE
2nd RELAPSE
REFRACTORY
RELAPSE
First-line therapy
Plateau
remission
Second-line therapy Third-line therapy
Multiple myeloma:
natural history of disease
Durie BGM, ed. Multiple Myeloma Concise Review 2007. International
Myeloma Foundation. American Cancer Society.
Cancer Facts & Figures, 2008.MGUS, monoclonal gammopathy of unknown significance; M protein, myeloma protein.
Does make sense thinking in early treatment for asymptomatic myeloma?
Smoldering Multiple Myeloma: Management
AgentsORR (%)
TTP OS Reference
Early MP* vs
Deferred MP
52
55
No
benefit
No
benefit
Hjorth M, et al. Eur J Haematol. 1993
Grignani G, et al. Br J Cancer. 1996
Riccardi A, et al. Br J Cancer. 2000
Thal+Zol vs
Zol**
37
0
No
benefit
No
benefitWitzig TE, et al. Leukemia 2013
Bisphosphonates***vs
observation0
No
benefit
No
benefit
Martin A, et al. Br J Haematol. 2002
D’arena et al. Leuk Lymphoma. 2011
Musto P, et al. Cancer. 2008
*Abandon: No differences in survival and potential risk of secondary leukemias
**Low efficacy&high rates of discontinuation due to PN
***Skeletal related events lower in the bisphosphonate groups (39% vs 73% and 55% vs 78%)
Smoldering Multiple Myeloma: Management
AgentsORR (%)
TTP OS Reference
Early MP* vs
Deferred MP
52
55
No
benefit
No
benefit
Hjorth M, et al. Eur J Haematol. 1993
Grignani G, et al. Br J Cancer. 1996
Riccardi A, et al. Br J Cancer. 2000
Thal+Zol vs
Zol**
37
0
No
benefit
No
benefitWitzig TE, et al. Leukemia 2013
Bisphosphonates***vs
observation0
No
benefit
No
benefit
Martin A, et al. Br J Haematol. 2002
D’arena et al. Leuk Lymphoma. 2011
Musto P, et al. Cancer. 2008
*Abandon: No differences in survival and potential risk of secondary leukemias
**Low efficacy&high rates of discontinuation due to PN
***Skeletal related events lower in the bisphosphonate groups (39% vs 73% and 55% vs 78%)
Low, intermediate and high risk patients were included
QuiRedex: Study Design
• Multicenter, open-label, randomized phase III trial
Patients with
high-risk
smouldering
MM
(N = 125)
Lenalidomide 25 mg/day on
Days 1-21 +
Dexamethasone 20 mg/day on
Days 1-4, 12-15
No Treatment No Treatment
Lenalidomide
10 mg/day on Days 1-21
(Low-dose dexamethasone
added at time of
biologic progression)
Induction
9 x 28-day cycles
Maintenance
28-day cycles
2 yrs
High-risk was defined according to the Mayo and/or Spanish models
In both arms, blood counts, biochemical analysis (including creatinine and calcium) and
serum/urine levels of MC were performed monthly. Skeletal survey was performed during the
screening phase and thereafter only if clinical symptoms emerged.
Mateos MV, et al. NEJM 2013; 369:438-47
Len-dex vs no treatment: TTP to active disease (n = 119)
Per-protocol Patients population
Mateos MV, et al. NEJM 2013
Median follow-up: 40 m
Mateos MV, et al. Lancet Oncology 2016
Median follow-up: 75 m
Treatment Group
Observation Group
Hazard ratio for progression: 0·24, p<0·0001
Len-dex vs no treatment: OS from inclusion
(n = 119)
Median follow-up: 40 m
Mateos MV, et al. NEJM 2013 Mateos MV, et al. Lancet Oncology 2016
Median follow-up: 75 m
Treatment Group
Observation Group
Hazard ratio for death: 0·43, p=0·024
Rajkumar et al. Lancet Oncology 2014; 15: e538-48
Subgroup of SMM patients that require be treated
Current studies in High-risk Smouldering Multiple
Myeloma
• Numerous clinical trials (51 in clinicaltrials.gov) with several
drugs are currently ongoing in this group of patients
• To prevent the progression to Myeloma
- R alone, Elo-Rd, Daratumumab, KRd, Ixazomib-Rd,
pembrolizumab, nivolumab-Rd, isatuximab,…
• To completely erradicate the tumor clone
- CESAR trial
- ASCENT trial
Curative Estrategia Smouldering Alto Riesgo (CESAR trial)(n:90)
Induction 6 cycles of KRd
ASCT (melphalan 200)
Maintenance (Len-dex for 2yrs)
Consolidation (2 cycles of KRd)
Primary objective: To evaluate the proportion of patients in sustained
immunophenotypic response at 5 years
Hypothesis: At least 50% of patients will achieve the objective20 centers
MRD
MRD
MRD
MRD
Role of depth of response
Depth of response is related to TTP, PFS and OS
Depth of response Time to progression
MR
PR
VGPR
nCR
CR
sCR
Treatment Initiation
Time
MR, minimal response; sCR, stringent complete response; iCR, immunophenotypic CR; TTP, time to progression.
CR is a typical endpoint and one of the most
powerful prognostic markers in MM
Pro
gre
ssio
n-f
ree s
urv
ival (%
)
Time from diagnosis (months)
CR (n=578) median PFS: 54 months
nCR (n=273) median PFS: 43
months
PR (n=553) median PFS: 33 months
<PR (217) median PFS: 15 months
100
80
60
40
20
0
0 50 100 150 200
P <.001
CR vs nCR: P
=.002
nCR vs PR: P =.001
PR vs <PR: P <.001
Overa
ll surv
ival (%
)Time from diagnosis (months)
CR (n=578) median OS: 103 months
nCR (n=273) median OS: 86 months
PR (n=553) median OS: 72 months
<PR (217) median OS: 25 months
P <.001
CR vs nCR: P
=.124
nCR vs PR: P =.001
PR vs <PR: P <.001
100
80
60
40
20
0
0 50 100 150 200
GEM2000, GEM2005MENOS65, GEM2005MAS65,
GEM2010MAS65
But the true value of CR relies in the MRD
status, and CR w/o MRD is no better than PR
Pro
gre
ssio
n-f
ree s
urv
ival (%
)
Time from diagnosis (months)
MRD- (n=326) median PFS: 71 months
CR (n=133) median PFS: 36 months
nCR (n=99) median PFS: 32 months
PR (n=211) median PFS: 35 months
<PR (48) median PFS: 21 months
P <.001
MRD- vs CR: P
<.001
CR vs nCR: P =.149
nCR vs PR: P =.607
PR vs <PR: P =.001
Overa
ll surv
ival (%
)Time from diagnosis (months)
MRD- (n=326) median OS: Not
reached
CR (n=133) median OS: 68 months
nCR (n=99) median OS: 73 months
PR (n=211) median OS: 68 months
<PR (48) median OS: 46 months
P <.001
MRD- vs CR: P <.001
CR vs nCR: P =.701
nCR vs PR: P =.667
PR vs <PR: P =.037
100
80
60
40
20
0
0 50 100 150 200
100
80
60
40
20
0
0 50 100 150 200
GEM2000, GEM2005MENOS65, GEM2005MAS65,
GEM2010MAS65
MRD was evaluated by flow cytometry
Martinez-Lopez J, et al. Blood. 2014;123:3073-3079
Tim
e-t
o p
rogre
ssio
n (
%)
100
80
60
40
20
0
100 1500 50
P = .001
CR & MRD –( n = 26)
CR & MRD + (n = 36)
Months
median 131m
median 35m
MRD monitoring using NGS is relevant
58% of the patients in conventionally-defined CR had positive MRD by NGS
Kumar S et al. Lancet 2016
Acknowledgments: Investigators of GEM
Chairs: MVM, Jesús San Miguel, Joan Bladé and JJ Lahuerta
Acknowledgments: GEM/Pethema
Support for data management: Arturo Touchard/Roberto Maldonado
Acknowledgments: Patients
Asociaciones locales de
cada ciudad/region por
el soporte
Acknowledgments: pharmaceutical companies
SAR650984Isatuximab
IxazomibNinlaro®
ElotuzumabEmpliciti™
PanobinostatFarydak®
DaratumumabPembrolizumab
Keytruda
MK-3475
Durvalumab
Carfilzomib
Nivolumab
Acknowledgments: Hematology Department
Acknowledgments: Hematology Department
Acknowledgments: Myeloma team
Norma Gutiérrez, Ramón Garcia-Sanz, Verónica González, Noemi Puig, Mercedes
Garayoa,Teresa Paino,…..
Acknowledgments: family
Acknowledgments: Rafa, Rafa, Marta y Juan