NSSG - Myeloma updatenssg.oxford-haematology.org.uk/education/files/nssg-2015...2015/03/09 · FIRST Trial: PFS by Age Stratification Hulin C, et al. ASH 2014. Abstract 81. Reproduced

Myeloma update

ASH 2014

Updates in Newly Diagnosed Multiple Myeloma

• FIRST: effect of age on lenalidomide/dexamethasone vs MPT in transplantation-ineligible pts

• Phase III: MPT-T vs MPR-R in transplantation-ineligible pts • Weekly vs twice weekly carfilzomib in combination with

cyclophosphamide/dexamethasone

Updates in Relapsed/ Refractory Multiple Myeloma

1st and second relapse • ASPIRE: addition of carfilzomib to lenalidomide/dexamethasone • Pomalidomide/bortezomib/dexamethasone

Double relapsed/refractory setting • Monoclonal antibodies in combination with lenalidomide/

dexamethasone – SAR650984 (anti–CD-38 mAb) – Daratumumab (anti–CD-38 mAb) – Elotuzumab (anti-SLAMF7/CS1 mAb)

Updates in Other Plasma Cell Disorders

• Phase III trial of melphalan/dexamethasone vs

bortezomib/melphalan/dexamethasone for untreated AL amyloidosis

• Phase II trial of lenalidomide/dexamethasone in POEMS syndrome

FIRST Trial: Lenalidomide/Dexamethasone vs MPT in NDMM SCT-Ineligible Pts

Rand

omize

d 1:

1:1

Arm B Rd18

Arm C MPT

Len + LoDex 18 cycles (72 wks) Lenalidomide 25 mg Days 1-21/28 LoDex 40 mg Days 1, 8, 15, 22/28

Mel + Pred + Thal 12 cycles[2] (72 wks) Melphalan 0.25 mg/kg Days 1-4/42 Prednisone 2 mg/kg Days 1-4/42 Thalidomide 200 mg Days 1-42/42

PD, O

S, a

nd

subs

eque

nt a

nti-M

M T

x

PD o

r una

ccep

tabl

e to

xici

ty

Active treatment + PFS follow-up phase

Pts > 75 yrs: LoDex 20 mg Days 1, 8, 15, 22/28; Thal 100 mg Days 1-42/42; Mel 0.2 mg/kg Days 1-4. Stratification: age, country, and ISS stage.

Len + LoDex Continuously Lenalidomide 25 mg Days 1-21/28 LoDex 40 mg Days 1, 8, 15, 22/28

Arm A Continuous Rd

1. Hulin C, et al. ASH 2014. Abstract 81. 2. Facon T, et al. Lancet. 2007;370:1209-1218. 3. Hulin C, et al. J Clin Oncol. 2009;27:3664-3670. 4. Benboubker L, et al. N Engl J Med. 2014;371:906-917

Phase III (N = 1623)

FIRST Trial: PFS by Age Stratification

Hulin C, et al. ASH 2014. Abstract 81. Reproduced with permission.

Aged 75 Yrs or Younger 100

80

60

40

20

0

Pts

(%)

0 6 12 18 24 30 36 42 48 54 60 PFS (Mos)

HR (95% CI) Rd vs MPT: 0.68 (0.56-0.83) Rd vs Rd18: 0.68 (0.55-0.83) Rd18 vs MPT: 1.01 (0.84-1.21)

Rd Rd18 MPT

Median, Mos 27.4 21.3 21.8

46% (Rd)

25% (Rd18)

23% (MPT)

Aged Older Than 75 Yrs 100

80

60

40

20

0

Pts

(%)

0 6 12 18 24 30 36 42 48 54 60 PFS (Mos)


Rd Rd18 MPT

Median, Mos 21.2 19.4 19.2

35% (Rd)

19% (Rd18) 22% (MPT)

571 pts > 75 yrs

FIRST Trial: OS by Age Stratification

Hulin C, et al. ASH 2014. Abstract 81. Reproduced with permission.

Aged 75 Yrs or Younger 100

80

60

40

20

0

Pts

(%)

0 6 12 18 24 30 36 42 48 54 60 OS (Mos)


Rd Rd18 MPT

3-Yr OS, % 74 70 67

Aged Older Than 75 Yrs 100

80

60

40

20

0

Pts

(%)

0 6 12 18 24 30 36 42 48 54 60 OS (Mos)


Rd Rd18 MPT

3-Yr OS, % 63 58 54

Phase III Trial Comparing MPT-T vs MPR-R in SCT-Ineligible Pts with NDMM

• Joint study of the Dutch-Belgian Cooperative Trial Group for Hematology Oncology and the Nordic Myeloma Study Group

MPR Melphalan 0.18 mg/kg on Days 1-4 +

Prednisone 2 mg/kg on Days 1-4 + Lenalidomide 10 mg on Days 1-21

(n = 319)

MPT Melphalan 0.18 mg/kg on Days 1-4 + Prednisone 2 mg/kg on Days 1-4 + Thalidomide 200 mg on Days 1-28

(n = 318)

R Maintenance Lenalidomide 10 mg on Days 1-21 q28d

until PD

T Maintenance Thalidomide 100 mg/day

until PD

Stratified by center and ISS

28-day cycles x 9

Rand

omiza

tion

1:1

Zweegman S, et al. ASH 2014. Abstract 179.

Granulocyte-colony stimulating factor administered if absolute neutrophil count < 0.5 x 109 cells/L or in event of febrile neutropenia during a cycle.

Phase III Trial Comparing MPT-T vs MPR-R in SCT-Ineligible Pts with

NDMM

MPT-T vs MPR-R: Safety Analysis

*Primarily due to peripheral neuropathy in thalidomide arm, hematologic toxicity in lenalidomide arm


Treatment Outcome, % MPR-R MPT-T ≤ 75 Yrs > 75 Yrs ≤ 75 Yrs > 75 Yrs

Completed 6 induction cycles 68 73 76 77 Initiated maintenance therapy 59 58 57 39 Discontinued maintenance 43 88 Due to AEs* 24 31 67 69

Median duration of maintenance, mos (range)

16 (0-53) 15 (1-52) 5 (0-49) 5 (0-44)

• MPT-T associated with significantly higher rate of grade ≥ 2 neuropathy (45% vs 8%; P < .0001); higher rate of grade 3/4 hematologic AEs (including neutropenia [63% vs 27%], thrombocytopenia [28% vs 8%], and anemia [14% vs 5%]) vs MPR-R

MPT-T vs MPR-R: Efficacy Analysis

• Median follow-up: 33.6 mos

• ORR similar between arms: 81% MPT-T vs 83% MPR-R

• No significant difference in PFS or OS


Outcome MPR-R (n = 319)

MPT-T (n = 318) HR (95% CI) P Value

ORR (on protocol), % 83 81 CR 13 10

VGPR 32 38

PR 39 33

Median PFS, mos 22 20 086 (0.72-1.04) .12

Median OS, mos NR NR 0.79 (0.61-1.03) .08

2-yr OS, % 84 73

3-yr OS, % 69 64

4-yr OS, % 55 52

Weekly Carfilzomib + Cyclophosphamide/ Dex: Preliminary Efficacy

MTD: 70mg/m2

Outcome Phase I (n = 12) MTD (n = 19) Total (N = 28) Median cycles received, n (range) 9 (1-9) 4 (1-9) 8 (1-9)

ORR (≥ PR), n (%) 11 (92) 15 (79) 24 (86)

≥ VGPR 9 (75) 11 (58) 18 (64)

sCR + CR + nCR 4 (33) 4 (21) 7(25)

1. Palumbo A, et al. ASH 2014. Abstract 175. 2. Bringhen S, et al. Blood. 2014;124:63-69. Reproduced with permission.

Once weekly[1] Twice weekly[2]

At Least nCR At Least VGPR 50

40

30

20

10

0

Pts

(%)

Cycle 4 Cycle 9

30 24

41 47 100

80

60

40

20

0

Pts

(%)

Cycle 4 Cycle 9

89

57

91 77

ASPIRE: Phase III Trial Comparing Len/ Dexamethasone ± Carfilzomib in R/R MM

• Randomized, open-label, multicenter phase III trial

KRd* (n = 396) Carfilzomib 27 mg/m2 IV

Days 1, 2, 8, 9, 15, 16 (20 mg/m2 days 1, 2, cycle 1 only) Lenalidomide 25 mg Days 1-21

Dexamethasone 40 mg Days 1, 8, 15, 22

Rd (n = 396) Lenalidomide 25 mg Days 1-21

Dexamethasone 40 mg Days 1, 8, 15, 22

Stratified by β2-microglobulin, prior bortezomib, and prior lenalidomide

*After cycle 12, carfilzomib given on Days 1, 2, 15, 16. After cycle 18, carfilzomib discontinued.

Stewart AK, et al. ASH 2014. Abstract 79.

Pts with symptomatic R/R MM after 1-3 prior treatments with ≥ PR to

≥ 1 prior regimen (N = 792)

ASPIRE: Response Rates and PFS by Response

Per

cent

age

of P

ts

1.0

0.8

0.6

0.4

0.2

0.0 Su

rviv

al P

roba

bilit

y

0 10 20 30 40 50

Mos From Randomization

sCR CR VGPR PR MR SD PD

Stewart AK, et al. ASH 2014. Abstract 79. Reproduced with permission.

PFS by Response With KRd Tx

• AEs consistent with previous studies; no unexpected toxicities observed

100

80

60

40

20

0 ≥ CR ≥ VGPR ORR

(≥ PR)

KRd Rd

31.8

9.3

69.9

40.4

87.1

66.7

ASPIRE: PFS in ITT Population (Primary Endpoint)

KRd Rd (n = 396) (n = 396) Median PFS, mos 26.3 17.6 HR (KRd/Rd) (95% CI) 0.69 (0.57-0.83) P value (1 sided) < .0001

1.0

0.8

0.6

0.4

0.2

0.0

Prop

ortio

n Su

rviv

ing

With

out P

rogr

essi

on

KRd Rd

0 6 12 18 24 30 36 42 48 Mos Since Randomization


Risk Group by FISH

KRd (n = 396) Rd (n = 396) HR P Value

n Median PFS, Mos n Median PFS, Mos

High 48 23.1 52 13.9 0.70 .083 Standard 147 29.6 170 19.5 0.66 .004

ASPIRE: Interim OS Analysis

• Median follow-up: 32 mos • Median OS was not reached; results did not meet prespecified statistical

boundary (P = .005) at interim analysis KRd Rd (n = 396) (n = 396) Median OS, mos NR NR HR (KRd/Rd) (95% CI) 0.79 (0.63-0.99) P value (1 sided) .018

1.0

0.8

0.6

0.4

0.2

0.0

Prop

ortio

n Su

rviv

ing

KRd Rd

0 6 12 18 24 30 36 42 48 Mos Since Randomization


Pomalidomide/Bortezomib/Dexamethasone for Lenalidomide Refractory MM

• Phase I/II trial to determine MTD; assess safety and efficacy of pomalidomide/bortezomib/dexamethasone – Included pts with relapsed MM who had 1-4 previous lines of

therapy and were resistant/refractory to lenalidomide. 57% had prior bortezomib

– Accrual: 50 pts (phase I: 3 at dose level 1, 6 at dose level 2; phase II: 41)

• Current analysis: 47 pts treated at MTD (dose level 2 + phase II)

Lacy MQ, et al. ASH 2014. Abstract 304.

Pomalidomide 4 mg/day on Days 1-21

Bortezomib 1.3 mg/m2 (IV or SC) and dexamethasone 40 mg

Day 1 Day 8 Day 15 Day 22

8 cycles

Pomalidomide 4 mg/day until PD

Pomalidomide/Bortezomib/Dexamethasone: Summary of Efficacy

Outcome Pts Treated at MTD (N = 47)

Std-Risk Pts (n = 28)

Int-/High-Risk Pts (n = 19)

Response, n (%)

ORR 40 (85) 24 (86) 16 (84)

sCR 3 (6)

CR 6 (13)

VGPR 12 (26)

PR 19 (40)

Median OS, mos NR NR NR

Event free at 6 mos, % 100 100 100

Event free at 12 mos, % 94 95 92

Median PFS, mos (95% CI) 10.7 (9.4-18.5) 16.3 9.5

Median DoR, mos (95% CI) 13.7 (8.5-16.8)

Lacy MQ, et al. ASH 2014. Abstract 304.

Anxiety Generalized muscle

weakness Edema limbs Constipation

Dyspnea Insomnia Dizziness

Thromboembolic event

Lung infection Vomiting Nausea

Diarrhea Peripheral

neuropathy Fatigue

Pomalidomide/Bortezomib/Dexamethasone: Summary of Adverse Events

Lacy MQ, et al. ASH 2014. Abstract 304. Reproduced with permission.

Hematologic Toxicity

Grade 3+ All grades

2% 70%

2% 81%

89% 68%

Pts (n) 0 10 20 30 40 50

Pts (n) 0 5 10 15 20 35 25 30

Nonhematologic Toxicity

45% 64%

70%

Phase I Trial: SAR650984 in Combination With Len/Dex in Relapsed/Refractory MM

• Phase Ib trial of SAR650984 + len/dex in relapsed/refractory MM – SAR650984 is a humanized IgG1 mAb to the CD38 receptor widely

expressed in many heme malignancies – Dose escalation: SAR650984 3-10 mg/kg on Days 1 and 15 of each 28-

day cycle + lenalidomide 25 mg on Days 1-21 of each 28-day cycle and dexamethasone 40 mg/wk during each 28-day cycle

Martin TG, et al. ASH 2014. Abstract 83.

Previous MM Treatment SAR650984 Dose, mg/kg q2w Overall

(N = 31) 3 (n = 4) 5 (n = 3) 10 (n = 24)

Median prior regimens, n (range) 10 (3-14) 7 (6-7) 6 (2-12) 7 (2-14)

Median prior lines, n (range) 6 (2-11) 6 (4-6) 4 (1-9) 4 (1-11)

Median time on last Len, mos (range) 7 (3-17) 3 (3-10) 10 (1-54) 9 (1-54)

Relapsed/refractory to IMiD 3 (75) 2 (67) 21 (88) 26 (84)

SAR650984 + Len/Dex: Efficacy Analysis

• DoR: 9.13 mo (range: 1.2-15.2)

Martin TG, et al. ASH 2014. Abstract 83. Reproduced with permission.

Response, % Total (N = 31)

ORR 58 sCR 6 VGPR 23 PR 29

CBR 65 MR 6

SD 19 PD 13 Not evaluable 3

Pts

(%)

SAR650984 Dose Level, mg/kg q2w

ORR 25% CBR 50%

ORR 67% CBR 67%

ORR 63% CBR 67%

ORR 58% CBR 65%

100

80

60

40

20

0 3

(n = 4) 5

(n = 3) 10

(n = 24) Overall (n = 31)

25

25

67

8

29

6

29

6 25 23

4

PR sCR VGPR MR

SAR650984 + Len/Dex: PFS by Previous Lines of Therapy

Prob

abili

ty

0

10

20

30

40

50

60

70

80

90

100

Mos 5 0 1 2 3 4 6 7 8 9 10 11 12 13 14 15 16 17

≥ 3 prior lines (n = 24) Overall (N = 31)

Median PFS: NR (95% CI: 6.2-NR)

Median PFS: 6.2 mos (95% CI: 4.80-13.33)

Median PFS: 5.8 mos (95% CI: 2.10-10.30)

1-2 prior lines (n = 7)


SAR650984 plus Len/Dex: Tx-Emergent AEs

• There were 15 incidences of infusion reaction, all occurring in the first 2 cycles – 2 pts discontinued treatment: 1 serious grade 3 anaphylactic reaction in cycle 1 and

1 nonserious grade 3 maculopapular rash in cycle 2 (AEs resolved in both pts) – Remaining incidents were grade 1/2 and did not lead to treatment discontinuation

Pts

(n =

31)

(%)


100

80

60

40

20

0

Grade 1 Grade 2 Grade 3 Grade 4

Phase I Trial: Daratumumab in Combination With Len/Dex in Rel/Ref MM

• Phase I/II dose-escalation trial of daratumumab in combination with len/dex in rel/ref MM (safety cohort: n =45; efficacy cohort: n = 43) – Daratumumab is a human mAb targeting CD38-expressing cells – Dose escalation: daratumumab 2-16 mg/kg/wk for 8 wks, twice monthly

for 16 wks, then once monthly for 24 mos in total or until PD, unmanageable AE

– Lenalidomide 25 mg on Days 1-21 of each 28-day cycle – Dexamethasone 40 mg/wk for of each 28-day cycle

• Median prior lines of therapy: 2 (range: 1-4); most with prior exposure to IMiDs and/or a proteasome inhibitor; 3 pts refractory to len

• MTD: daratumumab 16 mg/kg + len 25 mg and dex 40 mg/wk

Plesner T, et al. ASH 2014. Abstract 84.

Daratumumab in Combination With Len/Dex: Overall Best Response

• Mean follow-up: 12.9 mos (Part 1); 5.6 mos (Part 2) • Median time to response: 1 mo for 16 mg/kg in Part 2; median time to CR: 4.9 mos in Part 2

CR 31% CR 6.7%

VGPR 46%

PR 23%

VGPR 43%

PR 37%

CR 6.7%

CR 8.0% CR

11.8%

VGPR 43.3%

VGPR 52%

VGPR 52.9%

Plesner T, et al. ASH 2014. Abstract 84. Reproduced with permission.

Part 1 0

20

40

60

80

100

Pats

(%)

Overall Best Response

Part 2

PR VGPR CR

100 86.7

50.0

60 64.7

0

20

40

60

Pts (

%)

VGPR or Better Response by Cycles of Treatment (Part 2)

≥ 2 Cycles (n = 30)

≥ 4 Cycles (n = 25)

≥ 6 Cycles (n = 7)

Daratumumab in Combination With Len/Dex: Adverse Events

Most Common (Incidence in > 10% Pts) AEs, % Part 1 (n = 13)

Part 2 (n = 32)

Total (N = 45)

Total number of pts with AEs 100 100 100 Neutropenia 62 65 64 Muscle spasms 62 38 44 Diarrhea 54 18 31 Fatigue 62 16 29 Cough 31 28 29 Constipation 54 13 27 Nausea 38 19 24 Nasopharyngitis 62 3 20 Bone pain 31 13 18 Upper respiratory tract infection 46 3 16 Insomnia 31 6 16 Dyspnea 23 6 11 Anemia 31 19 11

Plesner T, et al. ASH 2014. Abstract 84.

Daratumumab in Combination With Len/Dex: Safety

• Daratumumab related serious AEs

– Pneumonia, neutropenia, diarrhea (1 pt each receiving 16 mg/kg, early infusion program)

– Laryngeal edema (1 pt receiving 16 mg/kg, accelerated infusion program)

• 19/45 pts reported infusion-related reactions; mostly grade 1-2

≤ 8 mg/kg Part 1

(n = 10)

16 mg/kg Part 1 (n = 3)

16 mg/kg Part 2

Current Infusion Program (n = 21)

16 mg/kg Part 2

Accelerated Infusion Program (n = 11)

Plesner T, et al. ASH 2014. Abstract 84. Reproduced with permission.

60

40

20

0

Pts

(%)

20.0 20.0 33.3

38.1

4.8

63.6 Infusion-Related Reactions First Infusion

Subsequent Infusion

Phase I Trial: Elotuzumab in Combination With Len/Dex in RR MM

• Phase Ib/II 1703 trial of elotuzumab + len/dex in relapsed/refractory MM – Elotuzumab is a humanized IgG1 mAb targeting SLAMF7, a glycoprotein

highly expressed on myeloma and NK cells – Elotuzumab 10 or 20 mg/kg on Days 1, 8, 15, 22 for cycles 1-2; Days 1, 15

for subsequent cycles – Lenalidomide 25 mg on Days 1-21 of each 28-day cycle – Dexamethasone 28 mg + 8 mg IV on elotuzumab dosing days, or 40 mg/wk

for of each 28-day cycle • Current analysis on phase II data to assess efficacy and safety of

combination – ~ 60% of pts received previous treatment with bortezomib and/or

thalidomide and 20% to 30% were refractory to previous treatment

Richardson PG, et al. ASH 2014. Abstract 302.

Elotuzumab in Combination With Len/Dex: Final Efficacy Results

Response, % Elotuzumab

10 mg/kg (n = 36)

Elotuzumab 20 mg/kg (n = 36)

Total (N = 73)

ORR 92 76 84

sCR 6 3 4

CR 11 8 10

VGPR 47 38 43

PR 28 27 27

SD 8 19 14

Time to first response, mos 1.0 1.7 1.0

Median DoR, mos 23.0 18.0 20.8

Median PFS, mos 32.5 25.1 28.6


Elotuzumab in Combination With Len/Dex: Final Safety Results

• Infusion reactions: if pts tolerated 2 mL/min, flow rate increased to 5 mL/ min – 33% of infusions were

at rate of 5 mL/min – 11% experienced

infusion reactions • 7 at 2 mL/min rate • 1 at ≥ 2 mL/min rate

– Most common events included pyrexia (3), nausea (1), rash (3)


Preferred term, n (%) Elo 10 mg/kg (n = 36) Elo 20 mg/kg (n = 37) Any Grade Grade 3/4 Any Grade Grade 3/4

Diarrhea 24 (67) 5 (14) 25 (65) 2 (5) Muscle spasms 22 (61) 2 (6) 23 (62) 0 Fatigue 24 (67) 3 (8) 17 (46) 2 (5) Constipation 18 (50) 0 19 (51) 0 Nausea 18 (50) 0 17 (46) 1 (3) URI 19 (53) 1 (3) 15 (41) 1 (3) Pyrexia 14 (39) 1 (3) 17 (46) 1 (3) Back pain 17 (47) 3 (8) 13 (35) 1 (3) Anemia 17 (47) 6 (17) 12 (32) 5 (14) Insomnia 10 (28) 0 15 (41) 2 (5) Cough 12 (33) 0 12 (32) 0 Hyperglycemia 9 (25) 2 (6) 12 (32) 5 (14) Lymphopenia 13 (36) 10 (28) 8 (22) 5 (14) Pain in extremity 9 (25) 0 12 (32) 0 Dyspnea 10 (28) 3 (8) 10 (27) 1 (3) Peripheral edema 12 (33) 0 8 (22) 1 (3) Thrombocytopenia 13 (36) 7 (19) 7 (19) 6 (16) Asthenia 7 (19) 1 (3) 12 (32) 1 (3) Nasopharyngitis 10 (28) 0 9 (24) 0 Neutropenia 11 (31) 7 (19) 8 (22) 7 (19)

• EMN-03: multicenter, randomized phase III trial comparing MDex and BMDex in newly diagnosed AL amyloidosis in Europe and Australia

Phase III Trial: Melphalan/Dexamethasone ± Bortezomib for Untreated AL Amyloidosis

Kastritis E, et al. ASH 2014. Abstract 35.

BMDex (n = 40)

MDex (n = 40)

Treatment-naive pts with systemic AL amyloidosis

(N = 80)

Dosing in BMDex arm Cycles 1, 2 (28 days): bortezomib 1.3 mg/m2 on Days 1, 4, 8, 11; melphalan 0.22 mg/kg on Days 1-4;

dexamethasone 40 mg on Days 1-4

Cycles 3-8 (35 days): bortezomib 1.3 mg/m2 on Days 1, 8, 15, 22; melphalan 0.22 mg/kg on Days 1-4; dexamethasone 40 mg on Days 1-4

Dosing in MDex arm Cycles 1-9 (28 days): melphalan 0.22 mg/kg on Days 1-4; dexamethasone 40 mg on Days 1-4

Continued until any of following: End of planned treatment

(9 or 8 cycles) CR after cycle 6 PR + organ response after

cycle 6 < PR after cycle 3 Progression of clonal

plasma cell disease

Melphalan/Dexamethasone ± Bortezomib in AL Amyloidosis: Efficacy Summary

Kastritis E, et al. ASH 2014. Abstract 35. Reproduced with permission.

Response After Cycle 3, n (%)

Response MDex (29 pts) BMDex (30 pts) P

Overall Hem 15 (52) 22 (73) .086

CR 1 (3) 4 (13) .173

VGPR 9 (31) 11 (37) .648

PR 4 (14) 7 (23) .347

Cardiac 5/23 (22) 4/17 (23) .893

Renal 6/15 (40) 3/16 (19) .193

Best Response (Median 5 Cycles), n (%)

Response MDex (29 pts) BMDex (30 pts) P

Overall Hem 15 (52) 23 (77) .045

CR 6 (21) 7 (23) .807

VGPR 6 (21) 11 (37) .176

PR 3 (10) 5 (17) .478

Cardiac 5/23 (22) 4/17 (23) .893

Renal 7/15 (47) 5/16 (31) .378

100

80

60

40

20

0 Surv

ival

Pro

babi

lity

(%)

PFS

P = .109

BMDex MDex

Mos 0 12 24 36 40

100

80

60

40

20

0 Surv

ival

Pro

babi

lity

(%)

OS

P = .504

BMDex MDex

Mos 0 12 24 36 40

Melphalan/Dexamethasone ± Bortezomib in AL Amyloidosis: Safety

• 14 pts(35%) experienced at least 1 grade ≥ 3 AE in each group

• There were 4 (cardiac) deaths in the first 100 days, 1 in the MDex arm and 3 in the BMDex arm (P = .307)

Kastritis E, et al. ASH 2014. Abstract 35.

Grade ≥ 3 AE, n (%) MDex (n = 40, 163 cycles) BMDex (n = 40, 144 cycles) P Value Overall 19 (12) 39 (27) < .001 Cytopenia 9 (5) 15 (10) .111

Fluid retention 4 (2) 3 (2) .828

Fatigue 2 (1) 1 (0.5) --

cTn increase 1 (0.5) 1 (0.5) --

Diarrhea 1 (0.5) 0 --

Renal failure 1 (0.5) 3 (2) --

Insomnia 0 2 (1) --

Peripheral neuropathy 0 3 (2) --

Injection-site reaction 0 1 (0.5) --

Phase II: Lenalidomide/Dexamethasone in

POEMS Syndrome • Prospective phase II trial of lenalidomide/dexamethasone in pts with

newly diagnosed or relapsing POEMS syndrome

Jaccard A, et al. ASH 2014. Abstract 36.

All eligible pts

Group 1: Pts eligible for

irradiation or ASCT 2 cycles Len/Dex

Group 2: all other pts 9 cycles Len/Dex

Irradiation

ASCT

1 yr low-dose Len only

Lenalidomide: 25 mg 21 days/28 (10 mg if creatinine clearance < 50 ml/min) Dexamethasone: 40 mg/wk (20 mg if older than 75 yrs of age or frail) Low-dose Lenalidomide: 10 mg 28 days/28 for 12 cycles Aspirin or low molecular weight heparin given as venous thromboembolic event prophylaxis

Lenalidomide/Dexamethasone in POEMS Syndrome: Efficacy

Summary

• VEGF normal at inclusion: serum 1 pt, plasma 7 pts • After 2 cycles, VEGF normal: serum 10 pts, plasma 20 pts

– VEGF level with > 50% drop: serum 17 pts, plasma 20 pts

Serum VEGF Plasma VEGF

Normal value

Jaccard A, et al. ASH 2014. Abstract 36. Reproduced with permission.

2000 1800 1600 1400 1200 1000 800 600 400 200

0

Inclusion Post cycle 1 Post cycle 2 300

250

200

150

100

50

0

350

Ser

um V

EG

F, p

g/m

L

Pla

sma

VE

GF,

pg/

mL

Lenalidomide/Dexamethasone in POEMS Syndrome: Efficacy Summary

• Hematologic responses in assessable pts after 2 cycles – Measurable IgG M-spike (n = 9): VGPR (n = 5); PR (n = 1); stable (n = 3) – IgA (n = 12): CR (n = 1); PR (n = 3); stable (n = 9) – FLC λ (n = 21): normalized (n = 9); > 50% reduction (n = 3)

• Neurologic responses after 2 cycles – Improvement with ONLS: n = 11 – Improvement with NIS score: n = 10 – Improvement based on clinical judgment of investigator: n = 16 – 10-meter walking test improved in 5 of 8 evaluable pts


Lenalidomide/Dexamethasone in POEMS Syndrome: Efficacy Last Follow-up


Parameter Group 1: ASCT (n = 8)

Group 1: Radiation (n = 9)

Group 2 (n = 9)

Clinical status No relapses 1 relapse at 6 mos (in pt with BM involvement)

1 PD after 9 cycles 3 pts on therapy 3 pts on maintenance 2 pts off tx

Median VEGF level at baseline, pg/mL (range)

Serum 5237 (1544-8640) 1423 (705-3560) 1606 (162-12,000)

Plasma 384 (17-924) 232 (48-1025) 254 (33-1794)

Median VEGF level at last follow-up, pg/mL (range)

Serum 530 (294-1951) 457 (170-472) 870 (115-6980)

Plasma 75 (19-91) 66 (12-145) 42 (19-844)

• In group 1, ASCT feasible after 2 cycles (8 of 9 pts received ASCT, median follow-up: 10.5 mos)

– No collection failures, engraftment syndrome; 1 death following ASCT (cerebral bleeding after falling)

Documents

NSSG - Myeloma updatenssg.oxford-haematology.org.uk/education/files/nssg-2015...2015/03/09 · FIRST Trial: PFS by Age Stratification Hulin C, et al. ASH 2014. Abstract 81. Reproduced