IMMUNOMODULATORY DRUGS FOR RELAPSE MYELOMAcme-utilities.com/mailshotcme/Material for...

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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