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Meral Beksac
Ankara University
Department of Hematology, Turkey
IMMUNOMODULATORY DRUGS
FOR RELAPSE MYELOMA
+
NDMM
IMID based regimen
Late relapse
Low risk
IMID based regimen
Early relapse on/off maintenance
IMID+PI combination
PI based regimen
Late relapse low risk disease
IMID based regimen
Early relapse/high risk
IMID+PI combination
IMID+PI based regimen
Late relapse/low risk
2nd gen PI + IMID
Early realpse/high risk
Moab+PI+IMID
An algorithm for RRMM : proposal
relapse relapse relapse
relapse
Moab + 2nd/3rd generation IMID+ PI
+
NDMM
IMID based regimen
Late relapse
Low risk
IMID based regimen
Early relapse on/off
maintenance
IMID+PI combination
PI based regimen
Late relapse low risk disease
IMID based regimen
Early relapse/high
risk
IMID+PI combination
IMID+PI based
regimen
Late relapse/low
risk
2nd gen PI + IMID
Early realpse/high
risk
Moab+PI+IMID
Moab+IMID/PI
Moab+ VMP/Rd
standard risk
high risk
An algorithm for RRMM: proposal updated
relapse relapse relapse
relapse
Moab + 2nd/3rd generation IMID+ PI
+PLAN
◼ SEQUENCING OF IMIDs based on clinical trials
◼ REAL LIFE trends
◼ Genetic features of IMID responsive patients (PRECISION Medicine ?)
KRD KD EloRD IRD DRd DVd Pano-VD PomVdOPTIMISM
DPom
APOLLO
IsaPom
ICARIA
IsaKD
IKEMA
DKD
CANDOR
Bortezomib Exposed + + + + + + + + + + + -
Refractory - - + - + - - - - + - -
Lenalidomide Exposure + + + + + + + + + + + -
Refractory - + - - - - + + + + - -
Phase III Regimens for RRMM After 1-3 Prior Lines Based on previous exposure or
refractoriness to bortezomib or lenalidomide
+IMID BASED THERAPIES
COMBINATIONS SINGLE
◼ Monoclonal antibody combinations:
◼ Daratumumab+Len/ Pom/(APOLLO)
◼ Isatuximab+Pom(ICARIA)
◼ Non-monoclonal antibody combinations:
◼ OPTIMISMM
◼ PomCyDex
◼ Other combinations:
◼ Ixazomib vs. Pomalidomide
+
Rios-Tamayo et al Drug Des Devel Ther. 2017 Aug 22;11:2399-2408
+ Selected further combinations under investigation in later
lines of RR MM
24 2833 35.6
23 16
22.2
152.2
52.2
20
0
20
40
60
80
100
Vd +VEN Pom d
+IXA
Pom d
+ELO
Pom d
+ISAT
Pa
tie
nts
(%
)
PR
VGPR
CR
sCR
≥VGPR
44%
53%
ORR: Median 3 prior lines
18
4553 50
9
25
189
9
43
9
93
68
5
93
0
20
40
60
80
100
Pom d
+DARA
Vd + SEL Pom d
+CYC
Pom d
+BENDA
GSK2857916
65% 68%
77%
60%
ORR: Median >3 prior lines
60%
67% 62.2%
Phase 1b 1/2 2 1b
N 66 32 60 45
LEN-
refractory53% 100% 87%
82%
(IMiD)
Median PFS9.5 mos
(TTP)NR 10.3 mos 17.6 mos
1b 1 1/2 1/2 1
103 33 34 38 35
89%91%
(LEN/POM)100% 100%
91%
(IMiDs)
8.8 mos NR 9.5 mos9.6 mos
(N=32)7.9 mos
BENDA, bendamustine; CYC, cyclophosphamide; ELO, elotuzumab; ISAT, isatuximab; IXA, ixazomib; NR, not reported; SEL, selinexor; TTP, time to progression; VEN, venetoclax.1. Moreau P, et al. Blood 2017;130:2392–2400; 2. Krishnan, et al. ASCO 2016; Abstract 8008; 3. Dimopoulos MA et al. EHA 2018, Abstract LB2606; 4. Mikhael J, et al. ASCO 2018; Abstract 8038;5. Chari A, et al. Blood 2017;130:974–981; 6. Bahlis NJ, et al. Blood 2016;128:977; 7. Baz RC, et al. Blood 2016;127:2561–2568; 8. Sivaraj D, et al. ASCO 2017; Abstract 8008 and Oral Presentation; 9. Trudel S, et al. Blood 2017;130:741.
Cyclophosphamide 500 mg/sq.m
intravenously days 1 and 15
>PR: 36% PFS: 6.4 mo
Blood. 2016;127(21):2561-2568)
ORR: 64.7 % vs. 38.9%
PFS: 9.5 mo vs.4.4 mo
Cyclophosphamide (PomCyDex) 400 mg orally on days
1, 8, and 15
Blood. 2018;132(24):2555-2563
After VRD first relapse Cyclophosphamide 300 mg(days 1, 8, 15, and 22)
responding +/-ASCT
>PR: 85% all patients
+Additional combinations investigated for patients
in early RRMM and prior LEN exposure
32 36
1027
33 28
5033
1910
10 17
128
7
0
20
40
60
80
100
Pd
+CARF
Pd
+BORT
Kd
+DARA
Kd
+VENETOCLAX
Pa
tie
nts
(%
)
PR
VGPR
CR
sCR
86%84%
79% 83%
ORR: Median 2 prior lines1–4
Phase 1/21 1/22 1b3 24
N 64 50 51 42 (30 evaluable)
LEN-refractory 91% 100% 100% 62% IMiD refractory
Median PFS 16.8 mos 13.7 mos 14.1 mos NR
1. Jakubowiak AJ, et al. EHA 2017. Abstract P680; 2. Paludo J, et al. Blood 2017;130:1198–1204; 3. Chari A, et al. J Clin Oncol 36, 2018 (suppl; abstr 8002); 4. Costa LJ, et al. J Clin Oncol 36, 2018 (suppl; abstr 8004).
+
71%
29%
63%9%
28%
65%
35%
51%
3%
46% 44%56%
PANORAMA / Pano-Vd5ENDEAVOR / Kd1,2
Non-BORT exposed
BORT refractory
BORT exposed
CASTOR / DVd3
PI-based Phase 3 trials in RRMM (1-3 prior lines): OPTIMISMM is the
first trial with 100% prior LEN exposure
%19
81%
12%
24%
64%
CASTOR / DVd4
14%
24%62%
ENDEAVOR / Kd1,2 PANORAMA / Pano-Vd5
Non-LEN exposed
LEN refractory
LEN exposed
Prior LEN-exposure
Prior BORT-exposure
OPTIMISMM Pom Vd6
OPTIMISMM Pom Vd6
aLEN refractory not reported.1. Dimopoulos MA, et al. Lancet Oncol 2016;17:27–38; 2. Dimopoulos MA, et al. Lancet Oncol 2016;17:27–38 (supplementary appendix); 3. Spencer A et al. J Clin Oncol 2017;35: (suppl, abstr 3145); 4. Lentzsch S, et al. Blood 2017;130:1852 (presented at ASH 2017); 5. San-Miguel JF, et al. Lancet Oncol 2014;15:1195–1206. 6. Richardson PG, et al. J Clin Oncol 2018;36:2018 (suppl; abstr 8001).
+OPTIMISMM: Phase 3 Trial of Pomalidomide, Bortezomib, and
Low-Dose Dexamethasone vs Bortezomib and Low-Dose Dexamethasone
in Lenalidomide-Exposed Patients With Relapsed or Refractory Multiple
Myeloma
Vd (n = 278)
BORT 1.3 mg/m2 SC
Cycles 1-8: days 1, 4, 8, 11
Cycle 9+: days 1 and 8
LoDEX 20 mg (≤ 75 y) or 10 mg (> 75 y)
day of and day after BORT
PD, subsequent
anti-myeloma
Tx,
and survival
PD or
unacceptable
toxicity
PVd (n = 281)
POM 4 mg days 1-14
BORT 1.3 mg/m2 SC
Cycles 1-8: days 1, 4, 8, 11
Cycles 9+: days 1
and 8
LoDEX 20 mg (≤ 75 y) or 10 mg (> 75 y)
day of and day after BORT
RRMM
• 1-3 prior regimens,
≥ 2 cycles of LEN
• ECOG PS ≤ 2
• Prior BORT Tx
allowed (PD with 1.3
mg/m2 twice-
weekly dose
excluded)a
N = 559
R
1:1
LT follow-up
Tx discontinued due to PD
Tx discontinued prior to PD
Follow-up visit
28 days after Tx
discontinuation
Enter PFS
follow-up periodb
21-day cycles
+CLINICAL CHARACTERISTICS
CharacteristicPVd
(n = 281)Vd
(n = 278)
Median age (range), years 67 (29-87) 68 (27-89)
Male, % 55 53
ECOG PS, %012
53434
49438
ISS stage at study entry, %IIIIII
533017
503218
High-risk cytogenetics [del17p, t(4;14), and/or t(14;16)], %
22 18
CrCl < 60 mL/min, % 32 27
Median time since diagnosis (range), years 4.0 (0.2-25.9) 4.3 (0.4-21.8)
16
RESPONSE◼ ORR was significantly higher with PVd vs Vd in the ITT population (P < .001) and in patients with 1
prior line of therapy (P < .001)
◼ PVd led to deeper responses, with higher sCR/CR and ≥ VGPR rates, vs Vd
◼ Median TTR was 0.9 vs 1.4 months, and median DOR was 13.7 vs 10.9 months (ITT)
29.5 31.7 28.8 32.2
37.0
14.4
43.2
16.5
15.7
4.0
18.0
6.1
0
10
20
30
40
50
60
70
80
90
100
PVd Vd PVd Vd
ITT 1 Prior Line of Therapy
PR VGPR sCR/CRORR 82.2%
ORR 50.0%a
ORR 90.1%a
ORR 54.8%≥ VGPR
52.7%
≥ VGPR
18.3%a
≥ VGPR
61.3%a
≥ VGPR
22.6%
Pa
tie
nts
(%
)
Richardson P, Oriol A, Beksac M et al, Lancet Oncol 2019 May
17
PROGRESSION FREE SURVIVAL
Richardson P, et al. Oral presentation at ASCO 2018 [abstract 8001]
Richardson P et al Lancet Oncol 2019.
◼ PVd reduced the risk of progression and death by 39% compared with VdP
rob
ab
ilit
y o
f
Pro
gre
ss
ion
-Fre
e S
ur
viv
al
Events/NMedian PFS,
months
HR (95% CI)
P Value
PVd 154/281 11.20 0.61 (0.49-0.77)
< .0001Vd 162/278 7.10
278 176 112 66 42 30 20 14 4 4 3 2 2 0
281 233 182 128 94 67 47 28 13 7 4 2 1 0
0
1
0
1
No. at Risk
PVd
Vd
0.00 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45
Months
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
49%
32%
36%
22%
Lenalidomide refractory patients After one line of therapy
Subgroup PVd Vd
LEN-refractory,a events/N 120/200 118/191
Median PFS, months 9.53 5.59
HR (95% CI)P value
0.65 (0.50-0.84)< .001
LEN-nonrefractory, events/N 34/81 44/87
Median PFS, months 22.01 11.63
HR (95% CI)P value
0.48 (0.30-0.75).001
Richardson P, Oriol A, Beksac M et al, Lancet Oncol 2019
20
SAFETY
Richardson et al Lancet Oncol 2019
Richardson P, et al. Oral presentation at ASCO 2018 [abstract 8001].
◼ Rates of grade 3 or 4 deep vein thrombosis (0.7% vs 0.4%) and pulmonary embolism (4.0% vs 0.4%) were low with PVd vs Vd; no events were fatal
◼ SPMs occurred in 3.2% of patients (2.7 per 100 person-years) treated with PVd vs 1.5% (1.2 per 100 person-years) treated with Vd
◼ Non-melanoma skin cancer: 2.5% with PVd vs 1.1% with Vd
Selected Grade 3 or 4 TEAEs, n (%)PVd
(n = 278)Vd
(n = 270)
Hematologic
Neutropenia 116 (41.7) 23 (8.5)
Febrile neutropenia 9 (3.2) 0
Thrombocytopenia 76 (27.3) 79 (29.3)
Anemia 39 (14.0) 38 (14.1)
Leukopenia 15 (5.4) 5 (1.9)
Non-hematologic
Infections 86 (30.9) 48 (17.8)
Pneumonia 32 (11.5) 17 (6.3)
Hyperglycemia 25 (9.0) 14 (5.2)
Peripheral sensory neuropathy 23 (8.3) 12 (4.4)
0.00 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45
Months
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
Spencer et al ASH 2018 Richardson et al Lancet Oncol 2019
OPTIMISMM: first report
median follow-up of 15.9 mo
49%
32%
36%
22%
Events/
N
Median
PFS,
months
HR (95%
CI)
P Value
PVd 154/281 11.20 0.61 (0.49-
0.77)
< .0001Vd 162/278 7.10
+
IMIDs and Adherence to treatment
+
+
When to choose IMIDs
Sequencing
Clinical Lymphoma, Myeloma & Leukemia, Vol. 18, No. 7, 480-5, 2018
+Most frequent second line treatments-USA
+
+Age <70 Age >70
Currently, many options exist,
… little consensus on treatment choice
VCd
VRd
Rd
VMP
KRd
VTd
Vd
DVMP
1st line
KRd
Rd
ERd
NRd
Vd
DVd
DRd
Pd
2nd line
Kd
Rd
ERd
NRd
Vd
DVd
DRd/DPd
Pd
3rd line
Courtesy of T.Facon
+
When to choose IMIDs
Prediction of sensitivity
NATURE COMMUNICATIONS | (2018) 9:2943 |
Lancet Haematol 2017;4: e443–51
+Aim & Scope
patients with multiple myeloma who received test doses of
◼ Thalidomide (400 mg per day for 2 days),
◼ lenalidomide (25 mg or 50 mg per day for 2 days), or
◼ pomalidomide (4 mg per day for 2 days)
to identify genes that are altered in response to these IMiDs to build an IMiD-
resistance gene signature predictive of treatment outcome.
PFS OS
+An HR of 0.36 (95% CI: 0.18–0.71, p =0.0031, n = 206) is found between
the treatment arms in the “benefit” class and an HR of 0.71 (95% CI:
0.46–1.10, p =0.13, n = 456) in the “no benefit” class
+IMIDs in RRMM
◼ Non-adherence to treatment is 15-25%
◼ Tolerable, acceptable toxicities, easily manageable
◼ Monotherapy +/- Dexamethasone is effective in low tumor burden & maintenance
◼ Prior IMID exposure and to a lesser degree refractoriness does not mandate switch in class
in the next treatment choice
◼ Aggressive disease mandates triplet & quadriplets