multiple myeloma experimental therapy except monoclonal...

Multiple MyelomaExperimental therapy except monoclonal

antibodies

Francesca Gay, MD, PhDMyeloma Unit, Division of Hematology

University of Torino, AOU Città della Salute e della Scienza di TorinoTorino, Italy, EU

대한혈액학회 Korean Society of Hematology

COI disclosureName of author： Francesca Gay

I currently have, or I have had in the past two years, an affiliation or financial interest with business corporation(s):

(1) Consulting fees, patent royalties, licensing fees ： No

(2) Research fundings： No

(3) Others Yes:

Honoraria: Amgen, Bristol-Myers Squibb, Celgene, Janssen, Takeda

Advisory board: Amgen, Bristol-Myers Squibb, Celgene, Janssen, Roche, Takeda

Outline

• Treatment of patients in first relapse: current and future options

• Treatment of patients in second and subsequent relapse

• How to choose the best treatment for each patient

DoubletsKd or Vd

Triplets based on bortezomib

DaraVD, PanoVD,EVD, or VCD

First relapse after IMiD-based induction

RD

Triplets(with Rd as backbone)

DaraRd, KRd, IRd, or ERD

First relapse after bortezomib-based induction

ESMO Clinical Practice Guidelines for the managementof relapsed/refractory multiple myeloma

GENERAL PRINCIPLES:1. New combos in early phases of the disease

2. Switch Drug Classes

Moreau P, et al. Ann Oncol. 2017;28 Suppl 4:iv52-61. Dara, daratumumab; ERD, elotuzumab, lenalidomide, dexamethasone; IRd, isatuximab, Rd; KRd, carfilzomib, Rd; Pano, panobinostat.

Bortezomib Carfilzomib Ixazomib Marizomib

Structure & chemical class

Boronate3 Epoxyketone3 Boronate3 Lactam/β-lactone3

Type of Inhibition Reversible4 Irreversible4 Reversible4 Irreversible4

Mechanism of Action

• Inhibits preferentially β5, but also β1 and β22

•Formation of tetrahedral intermediate with side-chain hydroxyl groups (with proteasome and other classes of proteases)6


•Formation of covalent adduct with N-terminal threonine active site (exclusively within the proteasome)6


• Inhibits all threeproteolytic activities, with IC50 values in the nM range5

Route of Administration Intravenous, subcutaneous4 Intravenous3 Oral4 Intravenous4

Treatment landscape: Second Generation Proteasome inhibitors

1 Mujtaba and Dou. Discov Med 2011;12(67):471-80; 2 Muz et al., Drug Des Devel Ther 2016;10:217-26; 3 Wang. Oncology (Williston Park) 2011; 25 Suppl 2:19-24; 4 Kurtin and Bilotti. J Adv Pract Oncol 2013;4(5):307-21; 5 Potts et al.,

Curr Cancer Drug Targets 2011;11(3):254-84; 6 Arastu-Kapur et al. Clin Cancer Res 2011;17:2734-43.

Proteasome inhibitors vary by chemical class, mechanism of action, type of inhibition1-6

KRd Rd(n=396) (n=396)

Median PFS, mo 26.1 16.6HR (KRd/Rd) (95% CI) 0.66 (0.55–0.78)One-sided P value <0.001

Proteasome Inhibitors + Rd

KRD : progression-free survival KRD : overall survival

Stewart AK, et al. N Engl J Med. 2015;372:142-52; Siegel DS, et al. J Clin Oncol 2018;36(8):728-734; Moreau P, et al. N Engl J Med. 2016;374:1621-34.

R, lenalidomide; d, dexamethasone; K, carfilzomib; I, ixazomib; PFS, progression-free survival; OS, overall survival; n, number; Mo, months; HR, hazard ratio; CI, confidence interval.

1813 1514

IRD : progression-free survival

IRd Rd(n=360) (n=362)

Median PFS, mo 20.6 14.7HR (Rd/IRd) (95% CI) 0.74 (0.59–0.94)P value 0.01

1.0

0.8

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0.00 1 2 3 4 5 6 7 8 9 10 1112 1617 1920212223 24

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Time from randomization (months)

IRdRd

KRd Rd(n=396) (n=396)

Median OS, mo 48.3 40.4HR (KRd/Rd) (95% CI) 0.79 (0.67–0.94)One-sided P value 0.0045

Carfilzomib Ixazomib

Proteasome inhibitors plus steroids: Kd versus Vd

K, carfilzomib; d, dexamethasone; V, bortezomib; PFS, progression-free survival; Mo, months; HR, hazard ratio; CI, confidence interval.Dimopoulos MA, et al. Lancet Oncology 2016; 17: 27-38; Dimopoulos MA Lancet oncology 2017; 18: 1327-37.

1.0

0.8

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Prop

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rogr

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0Months since randomization

KdVd

6 12 18 24 30

1.0

0.8

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0Months

KdVd

12 18 246 4830 36 42

Kd Vd(n=396) (n=396)

Median PFS, mo 18.7 9.4HR (Vd/Kd) (95% CI) 0.53 (0.44–0.65)P value <0.0001

Kd Vd(n=396) (n=396)

Median PFS, mo 47.6 40.0HR (Vd/Kd) (95% CI) 0.79 (0.65–0.96)P value 0.01

Progression-free survival Overall Survival

EfficacyPOLLUX

DaraRd vs Rd2,3ASPIRE

KRd vs Rd4,5ELOQUENT-2ERd vs Rd6

TOURMALINE-MM1IRd vs Rd7

PFS HR (95% CI) 0.44 (0.35–0.55)44.5 m vs 17.5 m

0.66 (0.55-0.78)26.3 vs 17.6 m

0.71 (0.59–0.86)19.4 vs 14.9 m

0.74 (0.59–0.94)20.6 vs 14.7 m

ORR, % 93 87 79 78≥ CR, % 57 (MRDneg 30%) 32 5 14DOR, months NE 28.6 21.2 20.5

OS HR (95% CI) 0.63 (0.42–0.95) 0.79 (0.63–0.99)48 vs. 40 m

0.78 (0.63–0.96)48.3 vs 39.6 m NE

1st line• Bortezomib-based combinations• Exposed or not to lenalidomide but not progressing under lenalidomide therapy

Which patients fit today in the ESMO guidelines 2017?

First relapse after Bortezomib-based induction1

Triplets based on RdDaraRd or KRd or IxaRd or EloRd

DoubletsRdX

R, lenalidomide; d, dexamethasone; Dara, daratumumab; K, carfilzomib; Ixa, I, ixazomib; Elo, E, elotuzumab; PFS, progression-free survival; HR, hazard ratio; m, months; ORR, overall response rate; CR, complete response;DOR, duration of response; OS, overall survival; CI, confidence interval; NE, not expressed.1. Moreau P et al. Ann Oncol 2017;28(suppl_4):iv52-iv61; 2. Bahlis NJ, et al. ASH 2018, abstract 1996, poster presentation. 3. Usmani SZ, et al. ASH 2016, abstract 1151, oral presentation; 4. Stewart AK, et al. N Engl J Med.2015;372:142-52 ; 5. Siegel DS, et al. J Clin Oncol 2018;36(8):728-734; 6. Dimopoulos MA, et al., Cancer 2018;124(20):4032-4043; 7. Moreau P, et al. N Engl J Med. 2016;374:1621-34.

EfficacyPOLLUX

DaraRd vs Rd2,3ASPIRE

KRd vs Rd4,5ELOQUENT-2ERd vs Rd6

TOURMALINE-MM1IRd vs Rd7

PFS HR (95% CI) 0.44 (0.35–0.55)44.5 m vs 17.5 m

0.66 (0.55-0.78)26.3 vs 17.6 m

0.71 (0.59–0.86)19.4 vs 14.9 m

0.74 (0.59–0.94)20.6 vs 14.7 m

ORR, % 93 87 79 78≥ CR, % 57 (MRDneg 30%) 32 5 14DOR, months NE 28.6 21.2 20.5

OS HR (95% CI) 0.63 (0.42–0.95) 0.79 (0.63–0.99)48 vs. 40 m

0.78 (0.63–0.96)48.3 vs 39.6 m NE

PFS HR (95% CI), medianIn len-exposed

0.38 (0.21–0.66)38.8 m vs 18.6 m

0.796 (0.522–1.215)19.4 m vs 13.9 m Only 5 pts 0.58

NR vs 17.5 m

1st line• Bortezomib-based combinations• Exposed or not to lenalidomide but not progressing under lenalidomide therapy


First relapse after Bortezomib-based induction1

Triplets based on RdDaraRd or KRd or IxaRd or EloRd

DoubletsRdX

R, lenalidomide; d, dexamethasone; Dara, daratumumab; K, carfilzomib; Ixa, I, ixazomib; Elo, E, elotuzumab; PFS, progression-free survival; HR, hazard ratio; m, months; ORR, overall response rate; CR, complete response;DOR, duration of response; OS, overall survival; CI, confidence interval; NE, not expressed.1. Moreau P et al. Ann Oncol 2017;28(suppl_4):iv52-iv61; 2. Bahlis NJ, et al. ASH 2018, abstract 1996, poster presentation. 3. Usmani SZ, et al. ASH 2016, abstract 1151, oral presentation; 4. Stewart AK, et al. N Engl J Med.2015;372:142-52 ; 5. Siegel DS, et al. J Clin Oncol 2018;36(8):728-734; 6. Dimopoulos MA, et al., Cancer 2018;124(20):4032-4043; 7. Moreau P, et al. N Engl J Med. 2016;374:1621-34.

EfficacyENDEAVOR (n=929)

Kd vs Vd2-4CASTOR (n=499)

DaraVd vs Vd5

PFS HR (95% CI) 0.53 (0.44 – 0.63)18.7 vs 9.4 m

0.31 (0.25 – 0.40)16.7 vs 7.1 m

ORR, % 77 92≥ CR, % 13 43 (MRD neg 20%) (sustMRD 6%)

OS HR (95% CI) 0.76 (0.63–0.92)47.8 vs 38.8 m --

1st line• Bortezomib-based combinations followed by TFI• Exposed to lenalidomide and/or progressing under lenalidomide therapy


First relapse after IMiD-based induction1

Triplets based on bortezomibDaraVD or PanoVD or EloVD or VCD

DoubletsKd, VdX X XX

TFI, treatment-free interval; V, bortezomib; Len, lenalidomide; d, dexamethasone; Dara, daratumumab; K, carfilzomib; Pano, panobinostat; Elo, E, elotuzumab; C, cyclophosphamide; PFS, progression-free survival; HR, hazardratio; m, months; ORR, overall response rate; CR, complete response; OS, overall survival; CI, confidence interval; NE, not expressed; MRD, minimal residual disease.1. Moreau P et al. Ann Oncol 2017;28(suppl_4):iv52-iv61; 2. Dimopoulos MA, et al. Lancet Oncology 2016; 17: 27-38; 3. Dimopoulos MA, et al. Lancet Oncol 2017;18:1327-1337; 4. Orlowski RZ, et al, EHA 2018, abstractPF561, poster presentation; 5. Mateos M et al. ASH 2018, abstract 3270, poster presentation; 6. Usmani et. al., ASH 2018, abstract 3288, poster presentation.

EfficacyENDEAVOR (n=929)

Kd vs Vd2-4CASTOR (n=499)DaraVd vs Vd5-6

PFS HR (95% CI) 0.53 (0.44 – 0.63)18.7 vs 9.4 m

0.31 (0.25 – 0.40)16.7 vs 7.1 m

ORR, % 77 92≥ CR, % 13 43 (MRD neg 20%) (sustMRD 6%)

OS HR (95% CI) 0.76 (0.63–0.92)47.8 vs 38.8 m --

PFS HR (95% CI), medianIn Len-exposed

0.69 (0.52 – 0.92)12.9 m vs 7.3 m

0.40 (0.28 – 0.58) 9.5 m vs 6.1 m

PFS HR (95% CI), medianIn Len-refractory

0.36 (0.22 – 0.58)8.6 m vs 6.6 m

0.44 (0.28 – 0.68)7.8 m vs 4.9 m

1st line• Bortezomib-based combinations followed by TFI• Exposed to lenalidomide and/or progressing under lenalidomide therapy


First relapse after IMiD-based induction1

Triplets based on bortezomibDaraVD or PanoVD or EloVD or VCD

DoubletsKd, VdX

TFI, treatment-free interval; V, bortezomib; Len, lenalidomide; d, dexamethasone; Dara, daratumumab; K, carfilzomib; Pano, panobinostat; Elo, E, elotuzumab; C, cyclophosphamide; PFS, progression-free survival; HR, hazardratio; m, months; ORR, overall response rate; CR, complete response; OS, overall survival; CI, confidence interval; NE, not expressed; MRD, minimal residual disease.1. Moreau P et al. Ann Oncol 2017;28(suppl_4):iv52-iv61; 2. Dimopoulos MA, et al. Lancet Oncology 2016; 17: 27-38; 3. Dimopoulos MA, et al. Lancet Oncol 2017;18:1327-1337; 4. Orlowski RZ, et al, EHA 2018, abstractPF561, poster presentation; 5. Mateos M et al. ASH 2018, abstract 3270, poster presentation; 6. Usmani et. al., ASH 2018, abstract 3288, poster presentation.

X XX

What other options could we consider in the future?- Pomalidomide in earlier lines, in patients

refractory to lenalidomide- Newer combinations

PFS : Len-refractory in first relapseMedian, months

95% CI

PVd 17.84 12.02–NE

Vd 9.49 6.34–16.20

OptimisMM Ph3 trial: PVd versus Vd in RRMM patients559 pts; Median 2 prior lines of therapy

100% Len-exposed; 70% Len-refractory and 63% Len-refractory as part of the last line of therapy

0 3 6 9 12 15 18 21 24 27 30 33 36 39

65 42 30 20 13 10 6 3 1 1 1 1 1 064 55 41 31 24 19 11 8 5 4 3 1 0 0

PFS

(%)

MonthsNo. at riskPVd Vd

100

90

80

70

60

50

40

30

20

10

0

HR 0.55 (95% CI 0.33–0.94); P = .0276

Ph, phase; pts, patients; Len, lenalidomide; PFS, progression-free survival; P,pomalidomide; V, bortezomib; d, dexamethasone; n, number; N, total number;HR, hazard ratio; CI, confidence interval; NE, not expressed; p, p value.Dimopoulos MA et al. ASH 2018, abstract 3278

Subgroup PFS PVd Vd

LEN-refractory

n/N 120/200 118/191

Median, months 9.53 5.59

HR (95% CI)

P Value0.65 (0.50-0.84)

< .001

Efficacy of PI and Pomalidomide-based regimens in Len-refractory ptsENDEAVOR1 CASTOR2 OPTIMISMM3

KD Vd DVdN=251

VdN=247 PVd Vd

Prior Len,exposure % 38 38 36 49 100 100

Median PFS,

months12.9 7.3 9.5 6.1 11.2 7.1

HR 95% CI;p-value

0.69 (0.52 – 0.92)< 0.0052

HR 0.40 (0.28 – 0.58) <0.0001

0.61 (0.49 – 0.77)<0.001

Prior Len, refractory % 24 26 24 33 71 69

Median PFS,

months8.6 6.6 7.8 4.9 9.53 5.59

HR 95% CI;p-value

0.36 (0.22 – 0.58)< 0.001

HR 0.44 (0.28 – 0.68)0.0002

0.65 (0.50-0.84)< .001

Median PFS in LenR and

2L

Pooled analysis4

(n=32)15.6 (9.6 – NE) for Kd

21.2 m vs 7 m HR 0.30 (0.11-0.82)

P=0.0117.8 m for PVd

PI, proteasome inhibitor; Len, lenalidomide; pts, patients; K, carfilzomib; D, d, dexamethasone; D, daratumumab; V, bortezomib; P, pomalidomide; K, carfilzomib; C, cyclophosphamide; PFS, progression-freesurvival; HR, hazard ratio; CI, confidence interval; LenR, len-refractory; 2L; second line.1Dimopoulos MA et al. Lancet Oncology 2016. 2Mateos MV, et al. ASH 2018 poster 3270. 3Dimopoulos MA, et al. ASH 2018. Poster 3278. 4Mateos MV, et al. ASH 2018. Abstract 1963. 5Sonneveld P et al. ASH 2018#801 6. Garderet et al Blood 2018 132(24):2555-2563 7 Usmani SZ, et al. ASH 2018 Abs3288.

Efficacy of PI and Pomalidomide-based regimens in Len-refractory ptsENDEAVOR1 CASTOR2 OPTIMISMM3 EMN-11 MMY10017

KD Vd DVdN=251

VdN=247 PVd Vd KPd5 PCd6 DKd DPd

Prior Len,exposure % 38 38 36 49 100 100 95 100% 95% 100%

Median PFS,

months12.9 7.3 9.5 6.1 11.2 7.1 18 34.2 - 9.9

HR 95% CI;p-value

0.69 (0.52 – 0.92)< 0.0052

HR 0.40 (0.28 – 0.58) <0.0001

0.61 (0.49 – 0.77)<0.001

- - - -

Prior Len, refractory % 24 26 24 33 71 69 95 0 60 89

Median PFS,

months8.6 6.6 7.8 4.9 9.53 5.59 18 - 25.7 10.1

HR 95% CI;p-value

0.36 (0.22 – 0.58)< 0.001

HR 0.44 (0.28 – 0.68)0.0002

0.65 (0.50-0.84)< .001

-- - - -

Median PFS in LenR and

2L

Pooled analysis4

(n=32)15.6 (9.6 – NE) for Kd

21.2 m vs 7 m HR 0.30 (0.11-0.82)

P=0.0117.8 m for PVd 18 - - -

PI, proteasome inhibitor; Len, lenalidomide; pts, patients; K, carfilzomib; D, d, dexamethasone; D, daratumumab; V, bortezomib; P, pomalidomide; K, carfilzomib; C, cyclophosphamide; PFS, progression-freesurvival; HR, hazard ratio; CI, confidence interval; LenR, len-refractory; 2L, second line.1Dimopoulos MA et al. Lancet Oncology 2016. 2Mateos MV, et al. ASH 2018 poster 3270. 3Dimopoulos MA, et al. ASH 2018. Poster 3278. 4Mateos MV, et al. ASH 2018. Abstract 1963. 5Sonneveld P et al. ASH 2018#801 6. Garderet et al Blood 2018 132(24):2555-2563 7 Usmani SZ, et al. ASH 2018 Abs3288.

Sequential regimensWill the first line of therapy guide the subsequent

lines of therapy?

1192 pts4 × VCD +

Stem cell apheresis

4 × VMP HDM 1/2

2 × VRD None

Lenalidomide Lenalidomide

28-days cyclesPom 4 mg, days 1-21Carf 20/36mg/m2 twice wDex 40 mg/w

Melphalan (HDM) 200 mg/m2

Pom 21 d until PDR

Pom 21 d until PD

Dex 21 d until PD

60 pts

• ORR after 8 cycles: 87%, 31% ≥CR rate• Best Overall Response rate: 92%, 42% ≥CR rate

Median PFS: 18 months

All pts len-refractory after 1st line

Pts, patients; V, bortezomib; C, cyclophosphamide; Dex, D, dexamethasone; M,melphalan; P, prednisone; HDM, high-dose melphalan; R, lenalidomide; Pom,pomalidomide; Carf, carfilzomib; ORR, overall response rate; CR, complete response.

Sonneveld P et al. ASH2018, abstract 801

Carfilzomib-pomalidomide and dexamethasone as rescue therapy for patients treated upfront with bortezomib and lenalidomide (EMN011 trial)

N57

F26

At risk: 57 46 36 16 3

0

25

50

75

100

Cum

ulat

ive

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enta

ge

months0 6 12 18 24

R2

R1

Relapse/Refractory MM patients

IMiD, immunomodulatory drug; K, carfilzomib; d, dexamethasone; Dara, daratumumab; Pano, panobinostat; Elo, elotuzumab;V, bortezomib; Cyclo, C, cyclophosphamide; R, lenalidomide; Ixa, ixazomib; Poma, pomalidomide.

Moreau P et al. Ann Oncol 2017;28(suppl_4):iv52-iv61

Kd backboneKd + DaraKd + Cyclo

Kd + venetoclax

Vd BackboneVd+ daratumumab

Vd + selinexorVd + venetoclax

Pd backbonePoma-VdPoma-Cd

Poma-dex-DaraPoma-dex-K

DoubletsKd, Vd

Triplets based on Bortezomib

DaraVD or PanoVD or EloVD or VCD

RdTriplets based on Rd

DaraRd or KRd or IxaRd or EloRd

First relapse after PI and/or IMiD-based induction and len-refractory


First relapseafter bortezomib-based induction

Relapse/Refractory MM patients : ESMO guidelines 2017

IMiD, immunomodulatory drug; K, carfilzomib; Dex, d, dexamethasone; Dara, daratumumab; Pano, panobinostat; Elo, elotuzumab; V, bortezomib; Cyclo, C, cyclophosphamide; R, lenalidomide; Ixa, ixazomib; Poma, pomalidomide.

Moreau P et al. Ann Oncol 2017;28(suppl_4):iv52-iv61

DoubletsKd, Vd

Triplets based on Bortezomib

DaraVD or PanoVD or EloVD or VCD

RdTriplets based on Rd

DaraRd or KRd or IxaRd or EloRd

Daratumumab (single agent or

combination)

Pomalidomide-Dex(as a backbone)

+ Cyclo or Ixa or Bort or Dara or Elo

Clinical trial

At the 2nd or subsequent relapse


First relapseafter bortezomib-based induction

Other options?


Carf, carfilzomib; Dex, d, dexamethasone; Dara, daratumumab; Bort, bortezomib; Cyclo, C, cyclophosphamide; R, lenalidomide; Ixa, ixazomib; Poma, pomalidomide.

Moreau P et al. Ann Oncol 2017;28(suppl_4):iv52-iv61; Costa et al., ASH 2018; abstract 303.


combination)



Clinical trial


Other CD38 mAbsIsatuximabMOR 202

Poma-dex + BortPoma-dex + CycloPoma-dex + DaraPoma-dex + Carf

Poma-dex + isatuximab


Carf, carfilzomib; Dex, d, dexamethasone; Dara, daratumumab; Bort, bortezomib; Cyclo, C, cyclophosphamide; R, lenalidomide; Ixa, ixazomib; Poma, pomalidomide.

Moreau P et al. Ann Oncol 2017;28(suppl_4):iv52-iv61; Costa et al., ASH 2018; abstract 303.


combination)



Clinical trial


Other CD38 mAbsIsatuximabMOR 202



SelinexorVenetoclaxMelflufen

Venetoclax (bcl-2 inhibitor) in RRMM Venetoclax is a selective, orally available small molecule BCL-2 inhibitor1, induces cell death in multiple myeloma

(MM) cell lines and primary samples, particularly those positive for the translocation t(11;14), which correlates withhigher ratios of BCL2 to MCL1 and BCL2 to BCL2L1 (BCL-XL) mRNA1

RRMM, relapsed/refractory multiple myeloma; ORR, overall response rate; K, carfilzomib; Len, lenalidomide; Bort, bortezomib; Sd, syndrome; CR, complete response; Bort-R/Len-R, Bort/Len-refractory; AEs, adverse events.

1. Kumar, et al. Blood 2017;130(22):2401-2409; 2. Kaufman et al, ASH 2017, abstract 3131; 3. Moreau, et al. Blood. 2017;130(22):2392-2400; 4. Costa et al. ASH 2018, abstract 303.

Monotherapy (n=66)1

(median 5 prior lines)

+ Dex in t(11;14) (n=20)2

+Bort-Dex(n=66)3

(median 3 prior lines)

+K-dex(n=42)4

(median 2 priorlines)

ORR 21% (40% in t(11;14))

ORR 65% (ORR 82% in Bort-R

& 71% in Len-R)

ORR 67% (97% in Bort-sensitive & 94% in BCL2 high)

ORR 79% (≥CR 38%) (1-3

prior lines) non-t(11;14) (n=34): CR 32%; in t(11;14),

n=8; CR 63%)

G 3-4 AEs: Thrombocytopenia

(26%), Neutropenia (21%),

Anemia (14%), Leukopenia (14%),

Lymphopenia (15%)

G3-4 AEs in ≥10% pts: Lymphopenia

(15%),Hypophosphatemia

(15%),Hyperuricemia (10%), Tumor lysis Sd (10%)

G3-4 AEs: Thrombocytopenia

(29%), Anemia (15%),

Neutropenia (14%)

G3/4 AEs:Lymphopenia 31%;Neutropenia 17%;

Hypertension (14%);Thrombocytopenia

(12%);Pneumonia (12%)

XPO1-Inhibitor Selinexor in RRMM : Summary of Ph1 data First-in-class, oral Selective Inhibitor of Nuclear Export (SINE) that inhibits XPO1 and activates Tumor Suppressor Proteins & reduces Oncoproteins

• Cancer cells (and MM) overexpress XPO1, causing increased export of tumor suppressors and growth of regulatory proteins from the nucleus

• Selinexor inhibits XPO1 mediated nuclear-cytoplasmic transport by transiently binding to XPO1 cargo binding site

• Accumulation of tumor suppressors in the nucleus amplifies the natural apoptotic function in cancer cells with damaged DNA Tai YT et al. Leukemia 2014;28(1):155-65

RRMM, relapsed/refractory multiple myeloma; ORR, overall response rate; Len, lenalidomide; Bort, bortezomib; CR, complete response; Pom-R/Len-R, Pom/Len-refractory; AEs, adverse events; Pom, pomalidomide; Dara, daratumumab.

1. Chen et al, Blood. 2018;131(8):855-863; 2. Chari et alJ Clin Oncol. 2018;36(9):859-86; 3. Bahlis NJ, Blood 2018;132(24):2546-2554; 4. Chen et al, ASH 2017, abstract 3136; 5. Gasparetto et al., ASH 2018, abstract 599.

Single agent1

(n=84)+Dex2

(n=79)+Bort/dex3

(n=40)+Pom/dex4

(n=24)+ Dara/dex5

(n=25)15% MR 20% ORR (Penta-

Refractory). Median PFS 2.3 m. OS: 9.3 m

ORR: 63% (43% in Btz Rfct), (PH III BOSTON trial ongoing)

ORR 29% in Pom/Len-R & ORR 65% in Pom-Naive/Len-R

ORR 79% (VGPR 29%)

Main AEs: nausea/vomiting 75%, fatigue 70%, anorexia 64%, thrombocytopenia 52% (G3-4 45%).

Main AEs:nausea 73%, anorexia 49%, fatigue 63%, vomiting 44%, thrombocytopenia 75% (G3-4 59%).

AEs: decreased appetite 60%, nausea 62%, thrombocytopenia 50%

AEs: gr 1/2: nausea 55%, anorexia 48%. Gr 3/4: neutropenia 48%, thrombocytopenia 31%

Gr 3/4 AEs: thrombocytopenia (44%), anemia (28%), neutropenia (24%)

Bort-Dex +/- Venetoclax or Selinexor for RRMM patientsM14-031 and KCP-330-023 phase III multicenter trials

RRMM, relapsed/refractory multiple myeloma; Bort, bortezomib, Dex, dexamethasone, Sel, selinexor; Vel, venetoclax; QW, weekly; TW, twice weekly; d, day/s; PR, partial response; SC, sub cute; PD, progressive disease.

M14-031 - Venetoclax-Vd vs Vd KCP-330-023 - Selinexor-Vd vs Vd

R2:1

Prior lines: 1 to 3(N=280)

Vel-Bort-Dex (N=~187)Cycles 1–8, 21-DayVen: 800 mg QD d 1–21Bort: 1.3 mg/m2 d 1,4,8,11Dex: 20 mg d 1,2,4,5,8,9,11,12

Cycles ≥ 9, 35-DayVen: 800 mg d 1–35Bort: 1.3 mg/m2 d 1,8,15,22Dex: 20 mg d 1,2,8,9,15,16,22,23

Placebo-Bort-Dex (N=~93)Cycles 1–8, 21-DayPlacebo: 800 mg QD d 1–21Bort: 1.3 mg/m2 d 1,4,8,11Dex: 20 mg d 1,2,4,5,8,9,11,12

Cycles ≥ 9, 35-DayPlacebo: 800 mg d 1–35Bort: 1.3 mg/m2 d 1,8,15,22Dex: 20 mg d 1,2,8,9,15,16,22,23

R1:1

Prior lines: 1 to 3(N=364)

Sel-Bort-Dex (N=~182)Cycles, 35-DaySel: 100 mg QW d 1,8,15,22,29Bort: 1.3 mg/m2 SC d 1,8,15,22Dex: 20 mg d 1,2,8,9,15,16,22,23,29,30

Sel dose escalation:Cycles ≥3, 35 day 60 mg TW, weeks 1-5If 1) no ≥PR within cycles 1-2; 2) SVd well tolerated; no G>2 study-related AEs.

Bort-Dex (N=~182)Cycles 1–8, 21-DayBort: 1.3 mg/m2 SC d 1,4,8,11Dex: 20 mg d 1,2,4,5,8,9,11,12

Cycles ≥ 9, 35-DayBort: 1.3 mg/m2 d 1,8,15,22Dex: 20 mg d 1,2,8,9,15,16,22,23,29,30

After PD crossover is allowed to a Sel-based regimen (Sel-Bort-Dex or Sel-Dex).

Melflufen therapy in RRMM patientsPhase 2 OP-106 Horizon study

Melflufen – a Novel Targeted Alkylating Peptide:Selectively targeting MM as a first-in-class Aminopeptidase Enhanced Compound

MM-directed cytotoxicity

Cell Death

Drug efflux

Myeloma Cell

MYELOMA CELLS

Drug influx

Patients refractory to pomalidomide and/or daratumumab; ≥2 prior therapies including an IMiD and a PI

Median 5 prior lines of therapy

n %Overall response 27 33

sCR 1 1CR 0 0VGPR 9 11PR 17 21

MR 5 6SD 37 45PD 12 15

Median PFS: 4.0 months (95% CI: 3.3-5.1)

Melflufen-dex was generally well tolerated with manageable toxicity: thrombocytopenia is the most challenging AERRMM, relapsed/refractory multiple myeloma; IMiD, immunomodulatory drug; PI, proteasome inhibitor; CR, complete response; sCR, stringent CR;

Richardson et al., ASH 2018, abstract 600.

Relapse/Refractory MM patients

Carf, carfilzomib; Dex, d, dexamethasone; Dara, daratumumab; Bort, bortezomib; Cyclo, C,cyclophosphamide; R, lenalidomide; Ixa, ixazomib; Poma, pomalidomide; mAbs, monoclonal antibodies.

Moreau P et al. Ann Oncol 2017;28(suppl_4):iv52-iv61.

Daratumumab (as single agent

or in combination)



Clinical trialNovel agents


Other CD38 mAbs

IsatuximabMOR 202

New mAbs



SelinexorVenetoclaxMelflufen

Cell therapy

CAR-T cellsCAR-NK cells

CAR-T cell therapy

Mikkilineni Blood 2017 Dec 14;130(24):2594-2602

Extracellular domain that can bind specifically to a target molecule expressed on the tumor cell surface-Single-chain antibody or ligand of cell surface receptor-Recognize tumor-associated antigens in a non-MHC-specific manner

Molecular hinge region derived from CD8 provides flexibilityto allow reorientation to bind antigen

Costimulatory domain: CD28 or 4-1BBMore robust cytokine production and enhanced cytolytic activity of CAR-Ts

T-cell activation domain: CD3ζ

Immune cells engineered to possess high-affinity receptors specific for particular antigens expressed on tumor cells

Adapted from Kershaw MH et al. 2013.

bb2121 Anti-BCMA CAR T Cell Therapy in RRMM patients

BCMA, B cell maturation antigen; RRMM, relapsed/refrctory multiple myeloma; CAR T, chimeric antigen receptor T; TEAE, treatment-emergent adverse events; CRS, Cytokinerelease syndrome; PFS, progression-free survival; CR, complete response; sCR, stringent CR; PR, partial response; ORR, overall response rate; mDOR, median duration of

response; NE, not expressed; CI, confidence interval; Noopur R. et al., ASCO 2018, Abstract 8007.

CAR T Treatment-EmergentAdverse Events

All Infused Patients (N=43)TEAE, n (%) Overall Grade≥3

CRS 27 (63) 2 (5)

Neurotoxicity 14 (33) 1 (2)

Neutropenia 35 (81) 34 (79)

Thrombocytopenia

26 (61) 22 (51)

Anemia 24 (56) 19 (44)

Infection

o Overall 26 (61) 9 (21)

o First Month

10 (23) 2 (5)

No grade 4 CRS events

No fatal CRS or neurotoxicity events

PFS at inactive (50 x 106) and active(150-800 x 106) dose levels

Tumor response by dose

Phase 1 Open-Label Study of LCAR-B38M, a CAR-T Against BCMA in RRMM Patients

PFS, progression-free survival; OS, overall survival; MRD, minimal residual disease; neg, negative; CR, complete response; m, median; mo, months. Zhao et al., ASH 2018; abstract 955

PFS OS

a30/39 patients still in remission

Patients Not AchievingMRD-neg CRmPFS: 6 mo(95% CI, 3–8)12-mo PFS: 6%

All PatientsmPFS: 15 mo(95% CI, 11–NR)12-mo PFS: 61%

Patients Achieving MRD-neg CRamPFS: 24 mo(95% CI, 15–NR)12-mo PFS: 87%

Patients Achieving MRD-neg CRmOS: not reached12-mo survival: 94%

All PatientsmOS: not reached12-mo survival: 75%

Patients Not Achieving MRD-neg CRmOS: 8 mo (95% CI, 4–14)12-mo survival: 29%

How to make the right choice?Tailoring treatment for the patient and the disease

Diseasecharacteristics

PatientCharacteristics

1) Fitness

2) Comorbidities : - Cardiovascular- Pulmonary functions- Prior neuropathy- Baseline blood cell count

3) Compliance and patient preference

4) Family/caregiver

1) Disease Presentation- renal failure- extramedullary disease- spinal cord compression- Speed of increase in tumorload

2) Risk stratification

3) Duration of remission afterprior line

DrugAvailability

*HR in pts >70 was 0.75. °over 65. PFS, progression-free survival; HR, hazard ratio, CI, confidence interval; m, months; d, low dose dexamethasone; D, daratumumab;K, carfilzomib; V, bortezomib; E, elotuzumab; I, Ixazomib; K, carfilzomib; R, lenalidomide; NR, not reported.

Novel combinations: Age

Rd continuous as a back bone Vd as a backbonePOLLUX1–3

DRd vs RdELOQUENT-24,5

ERd vs RdASPIRE6–8

KRd vs RdTOURMALINE-19

IRd vs RdCASTOR3,10,11

DVd vs VdENDEAVOR12,13

Kd vs VD

Median PFS (m)HRP valueMedian follow-up, m

NR vs 17.5HR 0.44

P<0.000132.9

19.4 vs 14.9HR 0.71

P=0.0004Min. 48

26.1 vs 16.6HR 0.66

P<0.000148.8 (KRd)/48.0 (Rd)

20.6 vs 14.7HR 0.74P=0.01

14.8 (IRd)/14.6 (Rd)

16.7 vs 7.1HR 0.32

P<0.000126.9

18.7 vs 9.4HR 0.53

P<0.000111.9 (Kd)/11.1 (Vd)

Age (years)MedianRange

65(34–89)

66(37–91)

64(31–91)

66(30–91)

64(30–88)

65(30–89)

65–75 years, %HRMedian follow-up, m

41%HR 0.43

17.3

57%†

HR 0.75†

Min. 48

50%†

HR 0.85†*

not specified

37%HR 0.83‡

14.8 (IRd) / 14.6 (Rd)

37%HR 0.26

13.0

38%0.53

not specified

>75, %HRMedian follow-up

11%HR 0.19

17.3

20%HR 0.63

Min. 48

12%HR 0.62

not specified

15%HR 0.87§

14.8 (IRd) / 14.6 (Rd)

12%HR 0.27

13.0

15%HR 0.38

not specified

1. Dimopoulos MA, et al. ASH 2017 (Abstract 739), oral presentation; 2. Dimopoulos MA et al. N Engl J Med. 2016;375(14):1319–1331; 3. Mateos MV et al. ASCO 2017 (Abstract 8033), poster presentation; 4. Dimopoulos MA, et al. EHA 2017 (Abstract S456), oral presentation; 5. Lonial S et al. N Engl J Med. 2015;373 (7):621–631; 6. Stewart AK, et al. ASH 2017 (Abstract 743), oral presentation; 7. Stewart AK et al. N Engl J Med. 2015;372(2):142–

152; 8. Dimopoulos MA et al. Brit J Haematol 2017.177: 404–413; 9. Moreau P et al. N Engl J Med. 2016;374 (17):1621–1634; 10. Spencer A, et al. ASH 2017 (Abstract 3145), poster presentation; 11. Palumbo A et al. N Engl J Med. 2016;375(8):754–766; 12. Dimopoulos MA et al. Lancet Oncol. 2016;17(1):27–38; 13. Ludwig H, et al. Leuk Lymphoma 2017;58(10):2501-2504.

Over 75 under-represented in clinical trials

Practical management considerationsRenal Failure

IMiDs PIs MoABs

Len Pom Vel Ixa Carf Elotuzumab Daratumumab

Dose adjustmentaccording to ClCr

- Non dialysis pts: CrCl: 30-50 ml/min

- CrCl: <30 ml/min

10 mg/day

15 mg eod

none

none

none none

3 mg

none

none

none

none

none

none

Dialysis pts 5 mg* none * none* 3 mg* none* none none

Renal AdverseEvents

AKI, AIN, Fanconi Syndrome, minimal change disease, TLS

AKI, Crystal nephropathyTLS

TMA,TLS

TLS Pre-renal,TLS,TMA,ATN

AKI None reported

Ludwig H, et al. Leukemia 2018;18 [epubahead of print] doi: 10.1038/leu.2017.353

*administer after dialysis; AIN, Acute interstitial nephritis; AKI, acute kidney injury; ATN, Acute tubular necrosis; Carf,carfilzomib; CrCl, creatinine clearance; eod, every other day; IMiD, immunomodulatory drug, PI, proteasome inhibitor; MoAB,monoclonal antibody; Ixa, ixazomib; Len, lenalidomide; Pom, pomalidomide; TLS, tumor lysis syndrome; TMA, thromboticmicroangiopathy; Vel, bortezomib.

Practical management considerations: adverse events

IMIDs PIs MoABs General consideration

Neutropenia

Thrombocytopenia

Len/Pom

Len/Pom all

More frequent at the beginning of treatment in case of active disease and high BMPC infiltration (considertransfusions and G-CSF + continue full dose treatment in case of active disease; dose reduction in case of diseaseunder control)

Hypertension KRd

Kd

DVd Grade 3-4: KRd and Kd 9%; DVd 6%Consider baseline evaluation and management beforestarting treatmentConsider correlation with steroids and dose reductions

Cardiac KRd/IRdKd

Grade 3-4: 7% KRd and IRd; 6% KdConsider baseline evaluation and risk factors for cardiovascular events before starting treatment

Thrombosis All Recommended Prophilaxys in all patientsASA/LMWH based on risk factors (active disease, high-tumor burden, reduced mobility, etc.)

Stewart AK et al. N Engl J Med. 2015;372(2):142–152; Dimopoulos MA et al. Brit J Haematol 2017. 177: 404–413; Dimopoulos et al., The Lancet Oncology. 2016; 17(1):27-38; Moreau P et al. N Engl J Med.

2016;374 (17):1621–1634; Palumbo et al., N Engl J Med. 2016;375:754-66.

IMiD, immunomodulatory drug, PI, proteasome inhibitor; MoAB, monoclonal antibody; K,carfilzomib; I, ixazomib; Len, R, lenalidomide; Pom, pomalidomide; d, low-dosedexamethasone; V, bortezomib; BMPC, bone marrow plasma cell; G-CSF, granulocytestimulating factor; ASA, low-dose aspirin; LMWH, low-molecular-wight heparin.

IMIDs PIs MoABs General consideration

Gastrointestinal LEN: diarrhoea

Bort: constipationIxa: diarrhoea/nausea

Supportive care essential to continue long-termtreatment. Diarrhoea: Consider loperamide; in pts treatedwith len consider coleseveram

Neuropathy Bort Grade 3-4: 4% DVd. Treatment with PI/PIs combo generally feasiblein pts with previous neuropathy

Dermatologic Len/Pom Ixa Supportive care essential to continue long-termtreatment. Consider adding antihistamine after mildreactions

Infusionreactions

ElotuzumabDaratumumab

Grade 3-4: DVd 9%; DRd 5%; ERd 1%Anti CD38: mainly respiratory

• Evaluation of baseline pulmonaryfunction in pt with COPD

• Management of COPD• Consider additional post infusionmedications

Palumbo et al., N Engl J Med. 2016;375:754-66; Dimopoulos MA et al. N Engl J Med.2016;375(14):1319–1331; Lonial S et al. N Engl J Med. 2015;373 (7):621–631;Moreau P et al. N Engl J Med. 2016;374 (17):1621–1634.

IMiD, immunomodulatory drug, PI, proteasome inhibitor; MoAB, monoclonal antibody; I,ixaixazomib; Len, R, lenalidomide; Pom, pomalidomide; d, low-dose dexamethasone; Bort, V,bortezomib; D, daratumumab; COPD, chronic obstructive pulmonary disease.

Practical management considerations: adverse events

Newer AgentsVenetoclax Selinexor

Main toxicities Grade 3/4

HematologicThrombocytopenia 26%

Neutropenia 21%

Non-hematologicNausea 3%

Diarrhea 3%

Fatigue 5%

Vomiting 3%

Main toxicities Grade 3/4

HematologicThrombocytopenia 59%

Neutropenia 23%

Non-hematologicNausea 8%

Diarrhea 5%

Fatigue 15%

Vomiting 4%

AEs, adverse events; G, grade. Kumar S, et al. Blood 2017;130:2401–2409; Vogl DT, et al. J Clin Oncol 2018;36(9):859-866. Richardson et al., ASH 2018, abstract 600.

No tumor lysis syndrome in MM

Melflufen

Main Toxicities Grade 3/G4

Hematologic

Neutropenia 61%

Thrombocytopenia 59%

Non-Hematologic

Febrile neutropenia 6%

Infections and infestations 7%

Pneumonia 2%

CAR-T Cell Issues

• Tumor Lysis Syndrome

• Cytokine release syndromeFevers, Flu like symptoms hypotension, hypoxiaSteroids, Tocilizumab (anti-IL6 receptor MoABs)

• Neurotoxicity/encephalopathyHeadache, delirium, obtundation, seizure, aphasiaRare cerebral edemaSteroids (Grade 2); Anti IL6 (grade 1)

• LogisticsLimited accessDelays for manufacturingCost

Adequate monitoring and timely institution of

supportive care

Neelapu Nat Rev Clin Oncol 2018 Jan;15(1):47-62; Drent PloS One 2018

ConclusionsProteasome inhibitors, immunomodulatory agents and Monoclonalantibodies are the corner-stones of multiple myeloma treatment

Treatment strategy: Multifactorial decision process

Many combo available:• Possibility to choose the most suitable according to patient fitness and age• Possibility to choose the most suitable according to patient comorbidities

and expected toxicities • Possibility to choose the most suitable according to aggressiveness

Prevention and prompt management of adverse events is essential to maximize treatment efficacy

Gay F., personal communication.

Future perspectives

Newer agents, with different mechanism of actions

We need to understand which patients may benefit more from newer drugs, when they should be administered during the course of the disease, and in which combination

Newer potential toxicities

We need to understand how to optimally manage and prevent potential adverse events

Aggress-iveness

Thank you for your attention

JCARH125 – BCMA CAR-T in RRMM Phase I/II multicenter EVOLVE trial

RRMM, relapsed/refractory multiple myeloma; IMiD, immunomodulatory drug; PI, proteasome inhibitor; BCMA, BCMA, B Cell Maturation Antigen; s-, soluble; CRS, cytokine release syndrome; ORR, overall response rate; CR, complete response, n, number. Mailankody S et al. ASH 2018, abstract 957.

Key eligibility criteria: • RRMM, ≥ 3 prior lines, IMiD, PI and anti-CD38. • Refractory to the last line. • No selection based on BCMA expression.

Design and manufacturing features• Fully human binder with low affinity for sBCMA• Minimized tonic signaling to reduce antigen-independent exhaustion. Active on low BCMA cells • Cell product with purified CD4 & CD8 CAR+ T cells enriched for CM phenotype cells

CAR-T cell doseOverall (n=44) 50 x 106 (n=14) 150 x 106 (n=28) 450 x 106 (n=2)

CRS 35 (80) 11 (79) 22 (79) 2 (100) (1 gr 4)Neurological tox 11 (25) 1 (7) 8 (29) 2 (100)ORR, % (CR, %) 79 (43) 86 (18) 50 (50) 82 (27)

• Cytopenia gr 3 & 4 lasting > 29 days: 28/42 (67%) patients• JCARH125 was highly active (ORR 82%) but with a limited follow-up (11 weeks)• Robust expansion in all dose levels. Trend of increasing persistence at higher doses• JCARH125 was active in patients with high sBCMA

42 (74%)

2 (3%)6 (11%) 4 (7%)

1 (2%) 2 (3%)

CR VGPR PR SD PD NE

Best Overall Response (N=57)

39 (68%)MRD-nega

Phase 1 Open-Label Study of LCAR-B38M, a CAR-T Against BCMA in RRMM Patients

VH

VL

Typical CAR LCAR-B38M CAR

VHVH

Binding domains

• 2 BCMA targeting domains– Confers high avidity binding and

distinguishes LCAR-B38M from other BCMA-targeted CAR T cell therapies

• n=57. Median n of prior lines: 3 (1-9)• Prior Bort 68%. Prior Len 44%. Prior PI +

IMiD 60%. Prior SCT: 18%a8-color flow cytometry with cell count up to 500,000 cells; bBCMA expression data available for 53 patients.

RRMM, relapesed/refractory multiple myeloma; n, number; Bort, bortezomib; Len, lenalidomide; PI, proteasome inhibitor; IMiD, immunomodulatory drug; SCT, stem-celltransplantation; pts, patients; RRMM, relapesed/refractory multiple myeloma; N, number; pts, patients; mDOR, median duration of response; BCMA, B Cell Maturation Antigen;

MRD, minimal residual disease; neg; negative; CR, complete response; PR, partial response; VGPR, very good partial response; SD, stable disease; PD, partial disease; NE, not expressed; ORR, overall response rate. Zhao et al., ASH 2018; abstract 955

• mDOR = 16 mo(95% CI, 12–NR)

• mDOR for MRD-neg CR = 22 mo(95% CI, 14–NR)

• Median time to initial response = 1 mo (0.4–3.6)

ORR = 88%

• Responses were maintained regardless the dose of T cells infused as well as the BCMA expression

Toxicity profile• 35% G2 CRS. 7% G3. No G4. • Tocilizumab use: 46%

Treatment goals in elderly MM patients

FIT INTERMEDIATE FRAIL

Co-morbidities, organ disfunction

Life expectancy

Impaired functional status

Deep remission Balance efficacy/safety Do not harm

Goal CR/MRD-negativity Good response Quality of life

Priority Efficacy Combination of efficacy/safety Low toxicity

CR, complete response; MRD, minimum residual disease.

Pom-dex combinations+ Chemo + proteasome inhibitor + MoAbs

Pom-dex1

Cyclo + Pom-Dex3

Bort + Pom-dex4

Carf + Pom-dex5

Ixa + Pom-dex6

Isat + Pom-dex7

Dara +Pom-dex8

MOR202 +Pom-dex10

Elo +Pom-dex9

Prior lines After2L.

Len-refracto

ry as last line

1 2 (1–3)

6(2-12)

2(1–5)

3(1-10)

After 1 or 2L 3 3(2-8)

Len: - exp- ref

-100%

100%-

100%71%

95%95%

100%100%

-82%

100%78%

100%100%

98%90%

PI: - exp- refr

73% 100%-

75%13%

100%-

100%59%*

-84%

--

--

100%78%

ORR/VGPR 32%/13% 85%/34% 82%/53% 92%/76% 48%/20% 62%/27% 72%/22 48%/14% 53%/12%

Median PFS 13.8 m - 11.2 m 18 m 8.6 17.6 77%@1 year - 10.3 m

1. Siegel DSDS et al., ASH 2017 Abstract 1812; 2. Baz R.C. et al., Blood 2016, 127:2561-2568; 3. Garderet Let al. Blood. 2018 Dec 13;132(24):2555-2563; 4. Richardson P. et al. ASCO 2018, Abstract 8001, oralpresentation;. 5. Sonneveld P..et al., ASH 2018 Abstract 801 Oral presentation; 6. Krishnan A. et al.Leukemia 2018 32 1567-1574; 7. Mikhael J. et al. EHA 2018 Abstract S 850, oral presentation; 8. SiegelDSDS. et al., ASCO 2018, Abstract 8027, poster presentation.9. Dimopoulus MA. et al, N Engl J Med. 2018Nov 8;379(19):1811-1822. 10. Raab M t al. ASH 2018 Abstract 153.

Exp, exposed; refr, refractory; MoAb, immunomodulatory drug; Chemo,chemotherapy; PI, proteasome inhibitor; Dara, daratumumab; Carf, carfilzomib;Cyclo, cyclophosphamide; Bort, bortezomib; Isat, isatuximab; Len, lenalidomide;ORR, overall response rate; VGPR, very good partial response; PFS, progression-free survival; pts, patients; NR, not reached; mo, months.*bortezomib refractory

Practical management considerationsInfections Prophylaxis

Prophylaxis

VirusHSV VZV

Mandatory- PIs- MoABs

AciclovirValaciclovir*°Penciclovir*

HBV Recommended:-latent/previous infection Nucleoside/nucleotide analogues

Bacteria To be considered:- Active MM- Elderly/frail patients- Previous Infections- Neutropenia

Trimethoprim-sulfamethoxazoleQuinoloneAmoxicillineIv Ig

Fungi To be considered:- Active MM- Elderly/frail patients- Previous Infections- Neutropenia

FluconazoleItraconazole

Ludwig H et al., Leukemia 2018;18 [epub ahead of print] doi: 10.1038/leu.2017.353.

*greater bioavailability; °reduced incidence of post herpetic neuralgiaPI, proteasome inhibitor; MoAB, monoclonal antibody; MM, multiple myeloma; HBV, hepatitis B virus; HSV, herpes simplex virus; VZV, varicella zoster virus; Iv Ig, Intravenous Immunoglobulin.

0.00

0.25

0.50

0.75

1.00

0 6 12 18 24 30 36 42 48Months

Overall Survival

0.00

0.25

0.50

0.75

1.00

0 6 12 18 24 30 36 42 48Months

Progression-free Survival

0.00

0.25

0.50

0.75

1.00

0 6 12 18 24Months

Cumulative Incidence Non-hematologic AEs

0.00

0.25

0.50

0.75

1.00

0 6 12 18 24Months

Cumulative Incidence Drug Discontinuation

@12 mo P-valueFit 22% -Intermediate 26% 0.217Frail 34% <0.001

@12 mo P-valueFit 16% -Intermediate 21% 0.026Frail 31% <0.001

IMWG Frailty Score: long-term outcome

Palumbo A et al, Blood 25(13):2068-74, 2015.

@3 yrs P-valueFit 84% -Intermediate 76% 0.042Frail 57% <0.001

@3 yrs P-valueFit 48% -Intermediate 41% 0.211Frail 33% <0.001

multiple myeloma experimental therapy except monoclonal...

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