Post on 06-Aug-2020
Recent Updates in Multiple
Myeloma: Newly Diagnosed MM
Keith Stewart
Mayo Clinic
Goals of Initial Therapy
• High response rate; rapid response
• Depth of response
• Improve performance status and QOL
• PBSC mobilization (for younger patients)
Continuous Improvement in Response
Seen With Combinations of Newer
Agents
Stewart AK et al. Blood. 2009;114:5436-5443. Jakubowiak A et al. Blood. 2012;120:1801-1809.
100
90
80
70
60
50
40
30
20
10
0TDVAD VTDRD CVDPAD CVRDRVD
CR/nCR
Res
po
nse
(%
)
Induction Regimen
KRD
ORR VGPR
RVd has become the standard where available
Log-rank P value = 0.0018 (one sided)*
HR = 0.712 (0.560, 0.906)*Log-rank P value = 0.0250 (two sided)*
HR = 0.709 (0.516, 0.973)*
Durie at al, Lancet 2017
Triplet is better than a doublet
KRd in Newly Diagnosed MM: Responses
Pati
ents
(%
)
N = 53; Median 12 Cycles (Range 1-25)
Initial Response Best Response
Jakubowiak AJ et al. Blood 2012;120:1801-1809.
100
75
50
25
0
M-P
rote
in L
evel
(%
of
Bas
elin
e)
100
75
50
25
00 121110987654321Cycle
≥ nCR sCR M-protein
100
80
60
40
0
20
≥ PR
≥ nCR
≥ VGPR
sCR
42
62
81
98
CRd = carfilzomib/lenalidomide/dexamethasone
R
Eligibility
• Newly diagnosed, symptomatic standard-risk MM
• No prior history of Grade 2 or higher peripheral neuropathy
Carfilzomib + lenalidomide +
low-dose dexamethasone limited OR indefinite lenalidomide maintenance
Bortezomib + lenalidomide +
low-dose dexamethasone limited OR indefinitelenalidomide maintenance
Protocol ID: NCT01863550
Target Accrual: 756 (open)
www.clinicaltrials.gov; Accessed December 2014
ECOG-E1A11: A Phase III Study of Bortezomibor Carfilzomib with Lenalidomide and
Dexamethasone for Newly Diagnosed MM
Primary endpoint: Overall survival
Select secondary endpoints: Progression-free survival, overall response rate, duration of response, incidence of Grade ≥2 peripheral neuropathy and cardiac toxicity
IFM 2009: RVd beats Rd for PFS
but Transplant Still required
RVD armN=350
Transplant arm
N=350p-value
CR 49% 59%
VGPR 29% 29% 0.02
PR 20% 11%
<PR 2% 1%
At least VGPR 78% 88% 0.001
Neg MRD by FCM n (%)
228 (65%)
280 (80%) 0.001
Attal et al Abstract 391 ASH 2015
If 3 is good is 4 better?
ORR 81% 93% 96% 96%
96% ORRCR in 42% post SCT
Daratumumab + KRd in Newly Diagnosed MM: Response
Jakubowiak AJ, et al. ASCO 2017. Abstract 8000.
Median follow-up: 10.8 mos (range: 4.0-12.5)
OS: 100% at follow-up
Median number of treatment cycles: 11.5 (range: 1.0-13.0)
100
80
60
40
20
0Resp
on
se r
ate
(%
)
After 4 Cycles, n = 21
100
71
5 5
100
80
60
40
20
0Resp
on
se r
ate
(%
)
After 8 Cycles, n = 15*
10087
27 27
100
80
60
40
20
0Resp
on
se r
ate
(%
)
Best Response, n = 21
10091
4329
Depth of response improved with duration of treatment
*5 pts who proceeded to ASCT before cycle 8 and 1 pt who discontinued due to PD at cycle 7 were excluded.
14
• Median (range) follow-up: 16.8 (15.9-18.7) months
Responses continued to deepen over time
50
38
6
6
38
31
25
63
0
10
20
30
40
50
60
70
80
90
100
End ofinduction
End ofconsolidation
Duringmaintenance(4-13 cycles)
OR
R, %
PR VGPR CR sCR
≥VGPR
56%
≥CR
6%
≥VGPR
100%
≥CR
63% ≥CR
94%
≥VGPR
100%
ORR = 94%
ORR = 100% ORR = 100%
VRD-Dara
ORR, overall response rate; CR, complete response; VGPR, very good partial response; PR, partial response.
38
Maintenance ?
Overall Survival: LenalidomideMaintenance Meta analysis
0.00 10 20 30 40 50 60 70 80 90 100 110 120
0.2
0.4
0.6
0.8
1.0
There is a 26% reduction in risk of death, representing an estimated 2.5-year increase in median survivala
605 578 555 509 474 431 385 282 200 95 20 1 0
604 569 542 505 458 425 350 271 174 71 10 0
Overall Survival, mos
Su
rviv
al P
rob
ab
ilit
y
Patients
at risk
7-yr OS
62%
50%
N = 1209 LENALIDOMIDE CONTROL
Median OS(95% CI), mos
NE(NE-NE)
86.0(79.8-96.0)
HR (95% CI)P value
0.74 (0.62-0.89)
.001
a Median for lenalidomide treatment arm was extrapolated to be 116 months based on median of the control arm and HR (median, 86 months; HR = 0.74). HR, hazard ratio; NE, not estimable; OS, overall survival.
Attal et al ASCO 2016McCarthy et al EHA 2016
39% improvement in overall PFS with ixazomib vs. placebo
• There was a significant 39%
improvement in overall PFS from time of
randomization for patients receiving
ixazomib vs. placebo maintenance:
• HR: 0.72; 95% CI: 0.582–0.890
• p=0.002
• Median 26.5 months vs. 21.3 months
• With only 14% of deaths reported, at a
median follow-up of 31 months, median
OS has not been reached in either
treatment arm and follow up continues
CI, confidence interval; HR, hazard ratio; OS, overall survival.
Pro
bab
ility
of
Pro
gre
ssio
n-F
ree
Su
rviv
al
00
Months from Randomization
3 6 9 12 15 18 21 24 27 30 33 36 39 42 45
0.2
0.4
0.6
0.8
1.0
No. of patients at risk:Ixazomib 395 363 340 311 279 255 238 213 187 135 93 56 35 9 3 0Placebo 261 238 210 195 174 153 130 117 100 69 46 32 15 3 0 0
IxazomibPlacebo
Nontransplant Patient
100
80
60
40
20
0
100
80
60
40
20
0
FIRST Trial: Efficacy Analysis of Len/Dex vs MPT in SCT-Ineligible Pts
With MM
• Overall response (continuous Rd vs MPT): 75% vs 62% (P < .00001)
• Similar, tolerable safety profiles between treatment groups
• Incidence of second primary malignancies: 3% with continuous Rd vs 6% with Rd18 vs 5% with MPT
Benboubker L, et al. N Engl J Med. 2014;371:906-917.
Mos
PFS
(%
)
0 6 12 18 24 30 36 42 48 54 60
72
wks
Median PFS, Mos
Rd (n = 535) 25.5
Rd18 (n = 541) 20.7
MPT (n = 547) 21.2
HR (P Value)
Rd vs MPT: 0.72 (.00006)
Rd vs Rd18: 0.70 (.00001)
Rd18 vs MPT: 1.03 (.70349)
4-Yr OS, %
Rd (n = 535) 59.4
Rd18 (n = 541) 55.7
MPT (n = 547) 51.4
HR (P Value)
Rd vs MPT: 0.78 (.0168)
Rd vs Rd18: 0.90 (.307)
Rd18 vs MPT: 0.88 (.184)
Mos
OS
(%)
0 6 12 18 24 30 36 42 48 54 60
SWOG S0777
Log-rank P value = 0.0018 (one sided)*
HR = 0.712 (0.560, 0.906)*Log-rank P value = 0.0250 (two sided)*
HR = 0.709 (0.516, 0.973)*
Durie at al, Lancet 2017
Triplet is better than a doublet
Overall survival
21Durie BGM, et al. ASH 2018 [abstract 1992].
• Based on current eligibility (N=460)
Deaths/N Median, mos
Rd 125/225 69 (59-88)
RVd 102/235 NR
P = .0114
RVd: 55% OS at 7 years
• Forest plot techniques showed other correlates of improved outcomes (PFS and OS) with RVdwere Sβ2M (< 4), BMPC (60%), hemoglobin (> 10 g/dL), serum creatinine (< 2 mg/dL) i.e. predominantly good risk (early disease) risk features
Impact of age on outcomes
22a For all analyses, both SWOG and IRC assessments have been conducted using the fully updated datasets with current datalock in May 2018.Durie BGM, et al. ASH 2018 [abstract 1992].
Age (yrs) RVd Rd
< 65 48 34
≥ 65 34 24
> 75 34 17
Overall Survival by AgeMedian PFS (mos)
Deaths/N Median, mos
Rd < 65 yrs 56/119 88 (67- )
Rd ≥ 65 yrs 67/106 56 (45-70)
RVd < 65 yrs 46/144 NR
RVd ≥ 65 yrs 50/91 65 (54- )
SWOG S0777: VRd vs. Rd
• Median age 63
• 43% of patients ≥ 65 years old
• ≥ 65 years old 34 month PFS
• 23% in VRd v. 10% in Rd discontinued
induction treatment because of adverse
events
• No treatment-related deaths in the Rd
group and two in the VRd group
23Durie BG, et al. Lancet. 2017;389(10068):519-27
RVD Lite: Results
Best overall response N=50 %
stringent complete response 6 12
complete response 16 32
very good partial response 11 22
partial response 10 20
minimal response 1 2
stable disease 3 6
not evaluable1 3 6
ORR 43 86
VGPR or better 33 661Received less than 4 cycles of therapy
IMWG Criteria; ORR, overall response rate; VGPR,
very good partial response
O’Donnell et al. BJH. 2018 Jul; 182(2): 222-230
Response (n = 64)
Overall response rate 92%
CR 27%
VGPR 31%
PR 34%
≥Grade 3 AEs (n = 65) 63%
Skin/subcutaneous tissue disorders 17%
Neutropenia 12%
Thrombocytopenia 8%
Peripheral neuropathy 6%
ECOG, Eastern Cooperative Oncology Group; ISS, International Staging System; EU, European Union; SC, subcutaneously; PO, oral ly;IV, intravenously; PD, progressive disease; PFS, progression-free survival; ORR, overall response rate; VGPR, very good partial response;
CR, complete response; MRD, minimal residual disease; NGS, next-generation sequencing; OS, overall survival. a8-month PFS improvement over 21-month median PFS of VMP.
ALCYONE Study Design: Updated Results
Key eligibility criteria:
• Transplant-ineligible NDMM
• ECOG 0-2• Creatinine
clearance ≥40 mL/min
• No grade ≥2 peripheral neuropathy or grade ≥2 neuropathic pain
Stratification factors
• ISS (I vs II vs III)
• Region (EU vs other)
• Age (<75 vs ≥75 years)
1:1
Ran
do
miz
atio
n (N
= 7
06
)
D-VMP × 9 cycles (n = 350)
Daratumumab: 16 mg/kg IVCycle 1: once weeklyCycles 2-9: every 3 weeks
+
Same VMP schedule
Follow-up
for PD
and
survival
Primary endpoint:
• PFS
Secondary endpoints:
• ORR
• ≥VGPR rate
• ≥CR rate
• MRD (NGS; 10–5)
• OS
• Safety
VMP × 9 cycles (n = 356)
Bortezomib: 1.3 mg/m2 SC Cycle 1: twice weeklyCycles 2-9: once weekly
Melphalan: 9 mg/m2 PO on Days 1-4 Prednisone: 60 mg/m2 PO on Days 1-4
DCycles 10+
16 mg/kg IV
Every4 weeks: until PD
Statistical analyses
• 360 PFS events: 85% power for
8-month PFS improvementa• Cycles 1-9: 6-week cycles• Cycles 10+: 4-week cycles
27
Efficacy: PFS
57% reduction in the risk of progression or death in patients receiving D-VMP
HR, hazard ratio; CI, confidence interval.aKaplan-Meier estimate.
• Median (range) follow-up: 27.8 (0-39.2) months
No. at riskVMP
D-VMP
VMP Median:19.1 mo
D-VMPMedian: not reached
% s
urv
ivin
g w
ith
ou
t p
rogr
essi
on
0
20
40
60
80
0 3 9 15 18 21 27 39Months
356350
304322
262298
245292
169243
127220
59138
00
30 33
2773
10024-moa
HR, 0.43(95% CI, 0.35-0.54; P <0.0001)
63%
36%
6 12 24 36
277312
206265
102203
531
09
60%
28%
30-moa
Daratumumab monotherapy phase (D-VMP only)
28
Sustained MRD Negativitya
Addition of daratumumab to VMP induced higher rate of sustained MRD negativity
36 (10%)
8 (2%)
0
4
8
12
D-VMP (n = 350) VMP (n = 356)
Su
sta
ine
d M
RD
-ne
ga
tive
ra
te, %
P <0.0001
• Defined as maintenance of MRD negativity for ≥1 year without loss of MRD negativity
aAssessed at time of confirmation of CR/sCR and, if confirmed, at 12, 18, 24, and 30 months after first dose.
MAIA Study Design
• Phase 3 study of D-Rd vs Rd in transplant-ineligible NDMM (N = 737)
Key eligibility criteria:
• Transplant-ineligible NDMM
• ECOG 0-2
• Creatinine clearance ≥30 mL/min
1:1
Ran
do
miz
atio
nPrimary endpoint:
• PFS
Key secondary endpointsc:
• ≥CR rate• ≥VGPR rate• MRD-negative rate (NGS;
10–5)• ORR• OS• Safety
Stratification factors• ISS (I vs II vs III)• Region (NA vs other)• Age (<75 vs ≥75 years)
Cycle: 28 days
Rd (n = 369)
R: 25 mg PO daily on Days 1-21 until PDd: 40 mgb PO or IV weekly until PD
D-Rd (n = 368)
Daratumumab (16 mg/kg IV)a
Cycles 1-2: QW Cycles 3-6: Q2W Cycles 7+: Q4W until PD
R: 25 mg PO daily on Days 1-21 until PD d: 40 mgb PO or IV weekly until PD
aOn days when daratumumab was administered, dexamethasone was administered to patients in the D-Rd arm and served as the treatment dose of steroid for that day, as well as the required pre-infusion medication.bFor patients older than 75 years of age or with BMI <18.5, dexamethasone was administered at a dose of 20 mg weekly. cEfficacy endpoints were sequentially tested in the order shown.
ECOG, Eastern Cooperative Oncology Group; ISS, International Staging System; NA, North America; IV, intravenously; QW, once weekly; Q2W, every 2 weeks; Q4W, every 4 weeks; PD, progressive disease; PO, orally; CR, complete response; VGPR, very good partial response; MRD, minimal residual disease; NGS, next-generation sequencing; ORR, overall response rate; OS, overall survival; BMI, body mass index.
Efficacy: ORR and MRD (NGS; 10–5 Sensitivity Threshold)
Significantly higher ORR, ≥CR rate, ≥VGPR rate, and MRD-negative rate with D-Rd
1428
32
28
17
12
30 12
0
10
20
30
40
50
60
70
80
90
100
D-Rd(n = 368)
Rd(n = 369)
OR
R, %
PR VGPR CR sCR
P <0.0001
ORR = 81%
ORR = 93%
≥CR:
48%c
≥VGPR:
79%c
≥CR:
25%
≥VGPR:
53%
24%
0
5
10
15
20
25
30
D-Rd(n = 368)
Rd(n = 369)
MR
D-n
ega
tive
rate
, %
P <0.0001
3.4X
30 moa
Efficacy: PFS
44% reduction in the risk of progression or death in patients receiving D-Rd
CI, confidence interval.aKaplan-Meier estimate.
Median follow-up: 28 months (range: 0.0-41.4)
% s
urv
ivin
g w
ith
ou
t p
rogr
essi
on
0
20
40
60
80
100
0 3 6 9 12 15 18 42
Months
27
369368
332347
307335
280320
254309
236300
219290
00
149203
No. at riskRd
D-Rd
21 24 30
94146
1835
200271
RdMedian: 31.9 mo
D-RdMedian: not reached
33 36
311
5086
39
21
HR, 0.56;95% CI, 0.43-0.73; P <0.0001
71%
56%
31
Efficacy: PFS by MRD Status
• >3-fold higher MRD negativity achieved with D-Rd
• Lower risk of progression or death with MRD negativity
No. at riskRd MRD negative
D-Rd MRD negativeRd MRD positive
D-Rd MRD positive
2789
342279
% s
urv
ivin
g w
ith
ou
t p
rogr
essi
on
0
20
40
60
80
100
0 3 6 9 12 15 18 42
Months
27
2789
305258
2788
280247
2788
253232
2786
227223
2786
209214
2786
192204
0000
2170
128133
21 24 30
12558291
1121723
2584
175187
Rd MRD negative
Rd MRD positive
D-Rd MRD negative
D-Rd MRD positive
33 36
0536
5334553
0120
39
32
3 Drug Induction now STANDARD
Should we add a 4th drug?
Will ASCT become unnecessary
Is MRD negativity the goal?
The Future: