Relapsed Multiple Myeloma and the dilemma of maintenance ... · –Bortezomib, carfilzomib, MLN...

A Practical Approach to

Relapsed Multiple Myeloma and the

dilemma of maintenance therapy

Israel Nov 2015

Scottsdale, Arizona Rochester, Minnesota Jacksonville, Florida

Introduction

• With improved therapeutic strategies, namely through novel agents and ASCT, patients are living longer with MM

– Median survival approaches 10 years in standard risk patients1

• With prolonged survival, most patients will undergo many lines of therapy

• This will require a long term approach, that balances clone elimination vs control2

1. Mikhael et al Management of Newly Diagnosed Symptomatic Multiple Myeloma: Updated Mayo Stratification of Myeloma and Risk-Adapted

Therapy (mSMART) Consensus Guidelines 2013 Mayo Clin Proc April 2013;88:360-376

2. Rajkumar SV et al Approach to the treatment of multiple myeloma: a clash of philosophies. Blood 2011;118(12):3205-3211

The Benefit of Combinations

Nooka AK et al. Leukemia. 2014;28:690-693.

N = 256 patients All received RVD; all risks groups included early and delayed transplant.

0.2

0.5

0.6

0.8

100

Cu

mu

lati

ve s

urv

ival

Months

10 20 30 50 0 60

0.9

0.7

0.4

0.3

0.1

0.0

40

RVD = lenalidomide (Revlimid®), bortezomib (Velcade®), and dexamethasone.

Current Treatment Algorithms for Relapsed/Refractory Multiple Myeloma

Patients with indolent disease, first relapse

Patients with aggressive disease, rapid progression, and multi-relapse

Patients relapsing from non-SCT tx or those with long duration of benefit from first SCT or those in whom response likely to be short lived

Options include: • Bortezomib or lenalidomide, depending on

response to and composition of initial tx, presence of renal dysfunction, or underlying peripheral neuropathy

• Watch and wait for low-level M protein (0.2/0.3)

Combination therapy preferred; do not wait for symptomatic relapse • Combinations of novel agents with

chemotherapy/dexamethasone an option

New additions: carfilzomib, pomalidomide Emerging agents: elotuzumab, ixazomib, panobinostat

Transplant-based salvage therapy a potential option in eligible patients

Selecting Salvage Therapy: General Principles

NCCN Clinical Practice Guidelines in Oncology: Multiple Myeloma. V.2.2014.

SCT = stem cell transplant.

Drugs Used in Relapse

• Proteasome inhibitors

– Bortezomib, carfilzomib, MLN 9708, oprozomib

• IMiDs

– Lenalidomide, pomalidomide

• HDACi agents

– Panobinostat, Acy-2115

• Antibodies

– Elotuzumab, daratumomab, SAR

• Other

– KSP, CDK, KPT

HDACi = histone deacetylase inhibitor; KSP = kinesin spindle protein; CDK = cyclin-dependent kinase;

MM-003: PFS and OS (ITT) Median Follow-up: 15.4 Months

San Miguel J et al. Lancet Oncol. 2013;14:1055-1066.

0.0

0.2

0.4

0.6

0.8

1.0

4 8 12 16

HR = 0.50 P<0.001

20 24 0

PFS (months)

Pro

po

rtio

n o

f p

atie

nts

0.2

0.4

0.6

0.8

1.0

OS (months)

Pro

po

rtio

n o

f p

atie

nts

4 8 12 16

HR = 0.72 P=0.009

20 24 28 0.0

0

Median PFS

POM + LoDEX (n = 302) 4.0 mos.

HiDEX (n = 153) 1.9 mos.

Median OS

POM + LoDEX (n = 302) 13.1 mos.

HiDEX (n = 153) 8.1 mos.

x

85 patients (56%) on the HiDEX arm received subsequent POM.

MM-003: PFS and OS by M-Protein Reduction Depth of Response Less Critical in Refractory Relapse

Median PFS was 4.0 months; median OS was 13.1 months overall for POM + LoDEX.

M-Protein

Reduction

Median

PFS

≥25 % (n = 163) 7.4 mos.

<25% (n = 96) 2.3 mos.

≥50% (n = 113) 8.4 mos.

PFS (months)

0.0

0.2

0.4

0.6

0.8

1.0

4 8 12 16 20 24 0

Pro

po

rtio

n o

f p

atie

nts

OS (months)

0.0

0.2

0.4

0.6

0.8

1.0

4 8 12 16 20 28 0 24 0.0

0.2

0.4

0.6

0.8

1.0

4 8 12 16 20 28 0 24 0.0

0.2

0.4

0.6

0.8

1.0

4 8 12 16 20 24 0

M-Protein

Reduction

Median

OS

≥25 % (n = 163) 17.2 mos.

<25% (n = 96) 7.5 mos.

≥50% (n = 113) 19.9 mos.

San Miguel J et al. Lancet Oncol. 2013;14:1055-1066.

Conclusions: Pomalidomide With Low-Dose Dexamethasone

• Pom/dex is an active agent, even among double- refractory MM patients

• Response is independent of prior therapy.

• Has activity in high-risk MM, specifically in del17p patients

• Potential for combination therapy is high.

Summary of Carfilzomib Activity in Phase II Trials

PX-171-003-

A0

PX-171-003-

A1

PX-171-004 PX-171-004

(BTZ-naïve)

PX-171-007 IST-CAR-512 PX-171-006 Car-Pom-d

Patients

reported

46 266 35 67 24 34 50 32

Median lines of

treatment

(range)

5 (2–16) 5 (1–20) 3 (1–13) 2 (1–4) 4 (1–9) 5 (1–11) 2 6 (2–15)

Refractory to

last line

Yes Yes No No No No No Yes

Carfilzomib

dose (QD x 2)

20 mg/m2

27 mg/m2

20 mg/m2 27 mg/m2 20/45–20/56

mg/m2

20/56 mg/m2 20/27 mg/m2 20/27–20/56

mg/m2

Other agents —

—

—

—

—

—

Len 25 mg

D1–21; Dex

40 mg weekly

Pom 3-4 mg

D1–21; Dex

40 mg weekly

ORR, % 16.7 23.7 17.1 52.2 55 53 78 50

CR, % 0 0 2.8 1.5 0 3 18 —

≥VGPR, % 0 5.1 5.6 28.4 25 27 40 13

OS, months 15.6 29.9 — — NR — NR

PFS, months 3.5 3.7 4.6 NR — 7.6 — 7.4

DOR, months 7.2 8 10.6 NR — 10 — —

Carfilzomib Early Data—Dose?

Gupta VA et al. Blood Lymphatic Cancer Targets Ther. 2013;3:41-51.

CR = complete response; Len = lenalidomide; ORR = overall response rate; Pom = pomalidomide; VGPR = very good partial response; NR = not reached; PFS = progression-free survival; OS = overall survival; QD x 2 = days 1, 2, 8, 9, 15, and 16 of a 28-day cycle; D, day(s).

Champion Study: Weekly Carfilzomib With Dexamethasone in RRMM

• Multicenter, single-arm, phase 1/2 study: safety and efficacy of once-weekly carfilzomib with dexamethasone in patients with relapsed or refractory multiple myeloma (1 to 3 prior)

Treatment

• Patients received carfilzomib at 20 mg/m2 on day 1 of cycle 1, stepped up to a target dose of 45, 56, 70, or 88 mg/m2 beginning on day 8 of cycle 1 as 30-minute IV infusion on days 1, 8, and 15 of a 28-day cycle

• Dexamethasone 40 mg (IV or oral) on days 1, 8, 15, and 22 of cycles 1–8; the dose administered on day 22 was omitted beginning in cycle 9

Berenson J, et al. J Clin Oncol 2015;32:5s, 2014 (suppl; abstr 8594^).

Efficacy/Toxicity of Weekly Carfilzomib

• N=104 patients

• Overall response rate: 77%

• Clinical benefit rate, 84 %

• In bortezomib-refractory patients (n=50), the ORR was 62% and the clinical benefit rate was 76%

• Median PFS was 10.6 months (95% CI, 9.0–16.1) median f/u 9.7 months

Berenson J, et al. J Clin Oncol 2015;32:5s, 2014 (suppl; abstr 8594^).

Patients (n=104)

Adverse event, n (%) Any Grade Grade >3

Fatigue 54 (52) 11 (11)

Nausea 36 (35) 2 (2)

Headache 32 (31) 3 (3)

Diarrhea 32 (31) 3 (3)

Insomnia 31 (30) 1 (1)

Upper respiratory tract infection 31 (30) 1 (1)

Cough 27 (26) 0 (0)

Dyspnea 26 (25) 5 (5)

Anemia 25 (24) 5 (5)

Thrombocytopenia 23 (22) 6 (6)

Pyrexia 23 (22) 0 (0)

Peripheral edema 21 (20) 0 (0)

Back pain 18 (17) 5 (5)

Hypertension 14 (13) 6 )6)

Asthenia 11 (11) 5 (5)

Pneumonia 9 (9) 7 (7)

Acute renal failure 7 (7) 6 (6)

Chronic obstructive pulmonary disease

5 (5) 5 (5) Car once weekly Not approved in Israel

ASPIRE Study Design

Dimopoulos M, et al. J Clin Oncol 2015; 33(suppl; abstr 8525).

IV, intravenous; KRd, carfilzomib, lenalidomide, and dexamethasone; Rd, lenalidomide and dexamethasone.

Rd

Lenalidomide 25 mg (days 1–21)

Dexamethasone 40 mg (days 1, 8, 15, 22)

KRd

Carfilzomib 27 mg/m2 IV (10 min) (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)

Randomization

(1:1)

N=792

Stratification:

• β2-microglobulin

• Prior bortezomib

• Prior lenalidomide

28-day cycles

After cycle 12, carfilzomib given on days 1, 2, 15, 16

After cycle 18, carfilzomib discontinued

• Primary endpoint: PFS

• Secondary endpoints: OS, ORR, DOR, HRQOL, safety

Key inclusion criteria: • Symptomatic MM • Measurable disease • 1–3 prior treatments • Relapsed or progressive disease • ≥PR to at least 1 prior regimen

KRd Not approved in Israel

Secondary Endpoints: Response

31.8

69.9

87.1

9.3

40.4

66.7

0

10

20

30

40

50

60

70

80

90

100

≥CR ≥VGPR ORR (≥PR)

KRd

Rd

Perc

enta

ge o

f Pa

tien

ts

P<.001

P<.001

sCR

14.1% vs 4.3%

P<.001

Median duration of response was 28.6 months in the KRd group and 21.2 months in

the Rd group

Stewart AK et al. N Engl J Med 2015;372:142-52

Primary Endpoint: Progression-Free Survival ITT Population (N=792)


1.0

0.8

0.6

0.4

0.2

0.0

Pro

po

rtio

n S

urv

ivin

g W

ith

ou

t P

rogr

ess

ion

KRd Rd

0 6 12 18 24 30 36 42 48

Months Since Randomization No. at Risk:

KRd Rd

396 332 279 222 179 112 24 1 396 287 206 151 117 72 18 1

KRd (n=396)

Rd (n=396)

Median OS, mo 26.3 17.6

HR (KRd/Rd) (95% CI) 0.69 (0.57–0.83)

P value (one-sided) <0.0001

PFS by Risk Group


KRd (n=396)

Rd (n=396)

Risk Group by FISH

N Median, months

N Median, months

HR P-value

(one-sided)

High 48 23.1 52 13.9 0.70 0.083

Standard 147 29.6 170 19.5 0.66 0.004

Secondary Endpoints: Interim Overall Survival Analysis Median Follow-Up 32 Months

Median OS was not reached; results did not cross the prespecified stopping boundary (P=0.005)

at the interim analysis

Months Since Randomization No. at Risk:

KRd Rd

396 369 343 315 280 191 52 2 396 356 313 281 237 144 39 3

1.0

0.8

0.6

0.4

0.2

0.0

Pro

po

rtio

n S

urv

ivin

g

KRd Rd

0 6 12 18 24 30 36 42 48

KRd (n=396)

Rd (n=396)

Median OS, mo NE NE

HR (KRd/Rd) (95% CI) 0.79 (0.63–0.99)

P value (one-sided) 0.018


ENDEAVOR Study Design

Dimopoulos M, et al. J Clin Oncol. 2015;33 (suppl; abstr 8509).

Vd

Bortezomib 1.3 mg/m2 (IV bolus or subcutaneous injection) Days 1, 4, 8, 11

Dexamethasone 20 mg Days 1, 2, 4, 5, 8, 9, 11, 12

21-day cycles until PD or unacceptable toxicity

Kd

Carfilzomib 56 mg/m2 IV Days 1, 2, 8, 9, 15, 16 (20 mg/m2 days 1, 2, cycle 1 only)

Infusion duration: 30 minutes for all doses Dexamethasone 20 mg

Days 1, 2, 8, 9, 15, 16, 22, 23 28-day cycles until PD or unacceptable toxicity

Randomization 1:1

N=929

Stratification:

• Prior proteasome inhibitor therapy

• Prior lines of treatment

• ISS stage

• Route of V administration

ISS, International Staging System; IV, intravenous; Kd, carfilzomib and dexamethasone; PD, progressive disease; Vd, bortezomib and dexamethasone; V, bortezomib.

Kd in 2nd line Not approved in Israel

Primary End Point: Progression-Free Survival Intent-to-Treat Population (N=929)


32

1.0

0.8

0.6

0.4

0.2

0

Pro

po

rtio

n S

urv

ivin

g

Wit

ho

ut

Pro

gre

ssio

n

0

Months Since Randomization

Kd Vd

Kd (n=464)

171 (37) 18.7

Vd (n=465)

243 (52) 9.4

0.53 (0.44–0.65) 1-sided P<0.0001

Disease progression or death – n (%) Median PFS – months HR for Kd vs Vd (95% CI)

CI, confidence interval; HR, hazard ratio; ITT, intent-to-treat; Kd, carfilzomib and dexamethasone; PFS, progression-free survival; Vd, bortezomib and dexamethasone.

• Median follow-up: 11.2 months

6 12 18 24 30

Secondary End Point: Response Rates


CI, confidence interval; CR, complete response; DOR, duration of response; ORR, overall response rate; Kd, carfilzomib and dexamethasone; NE, not estimable; PR, partial response; Vd, bortezomib and dexamethasone; VGPR, very good partial response.

13%

54%

77%

6%

29%

63%

0

10

20

30

40

50

60

70

80

90

≥CR ≥VGPR ORR (≥PR)

Kd

P<0.0001

P<0.0001

P<0.0001

• Median DOR: 21.3 months (95% CI, 21.3–NE) for Kd vs 10.4 months (95% CI, 9.3–13.8) for Vd

n=58 n=29 n=252 n=133 n=357 n=291

Pat

ien

ts (

%)

(95% CI, 73–81)

(95% CI, 58–67)

Vd

OS data were immature; the study will continue until the final OS analysis is performed

Pro

po

rtio

n S

urv

ivin

g

CI, confidence interval; HR, hazard ratio; ITT, intent to treat; Kd, carfilzomib and dexamethasone; NE, not estimable; OS, overall survival; Vd, bortezomib and dexamethasone.

Secondary End Point: Overall Survival Intent-to-Treat Population (N=929)


0

Months Since Randomization

Kd Vd

6 12 18 24 30

1.0

0.8

0.6

0.4

0.2

0

Kd (n=464)

75 (16) NE

Death – n (%) Median OS – months HR for Kd vs. Vd (95% CI) 0.79 (0.58–1.08)

1-sided P=0.066

Vd (n=465)

88 (19) 24.3

Conclusions

• ENDEAVOR is the first head-to-head study comparing 2 proteasome inhibitors

• Carfilzomib resulted in a 2-fold decrease in the risk of progression or death compared with BTZ

– Median PFS of 18.7 months (Kd) vs 9.4 months (Vd)

– ORR was significantly higher with Kd than Vd (77% vs 63%)

– Twice as many patients achieved a complete response (13% vs 6%) or a very good partial response or better (54% vs 29%)

Dimopoulos M, et al. J Clin Oncol 2015;33 (suppl; abstr 8509)

Future Approaches to RRMM

GEN501: Dose-Dependent Efficacy of Daratumumab as Monotherapy in Patients with RRMM

Lokhorst H et al. Haematologica. 2013;98(suppl1):241 (abstract S576). Lokhorst HM et al. J Clin Oncol. 2014;32(5 suppl):Abstract 8513.

• Part 1: first-in-human, dose escalation

– Results from part 1:

• Daratumumab well-tolerated

• Twelve patients dosed 4–24 mg/kg

– 5/12 (42%) achieved a PR as best response

• Part 2: ongoing, cohort expansion

– 8 weekly doses, followed by 8 doses twice monthly and monthly dosing up to 24 months

– Preliminary data from the first 50 patients; cut-off May 2, 2014

– Primary objective: establish the safety profile of daratumumab as monotherapy in RRMM

Part 2: Efficacy Results

Lokhorst HM et al. J Clin Oncol. 2014;32(5 suppl): Abstract 8513.

IMWG criteria (for measurable disease at baseline)

Ch

ange

in p

arap

rote

in (

%)

100

80

60

20

0

–20

–60

–80

–100

40

–40

Cohort A—8mg/kg Cohort B—8 mg/kg Cohort C—8 mg/kg Cohort D—16mg/kg

Best change in response paraprotein (%)

U S S S S S S S

S S S S U S S F S S S S S S U S F S S S U S U S U F S U S U F U U U U U U S

S = serum; U = urine; F = FLC

Study Design

• Part 1: dose escalation study (3X3 design) of 2–16 mg/kg dose; N = 13

• Part 2: expansion cohort—16 mg/kg dose; N = 32

Daratumumab infusions (First infusion includes pre-dose the day before)

Dexamethasone weekly 40 mg

Lenalidomide treatment day 1–21, 25 mg po

2–16 mg/kg Cycle 1 Cycle 2 Cycle 3–6 Cycle 7–24 Follow-up


Maximum % Change in M Protein from Baseline

Majority had >50% reduction of M protein.

Part 1 Dose-escalation study

2-, 4-, 8-, and 16-mg/kg dose N = 13

Part 2 Expansion-cohort study

16 mg/kg dose N=30

S

-25

-50

-75

-100

Patient number Re

lati

ve c

han

ge f

rom

bas

elin

e in

M p

rote

in (

%)

S S S S S S S S S U U U

11

07 01 08

03 02 04 05 06 09 12 10 13

2 mg/kg 4 mg/kg 8 mg/kg 16 mg/kg

S

-25

-50

-75

-100

Patient number Re

lati

ve c

han

ge f

rom

bas

elin

e in

M p

rote

in (

%)

S U S S S S S S S U U S

36 44

23 40

29

34 28

42 45 21 35 14

39

F S S S S F S S S S S U S S S S S

20 24 32 43 31 32 26 25 17 38 37 33 30 19 18 16 15

16 mg/kg


Infusion-Related Reactions (IRR)

• Majority grade 1 and 2

• 19/45 patients reported infusion-related reactions

• Most infusion-related reactions (86%) occurred during first infusion.

• 18/19 patients with infusion-related reactions recovered and were able to continue the subsequent infusion

≤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)

Pe

rce

nt

(%)

60

40

20

0

20.0 20.0

33.3 38.1

4.8

63.6 First infusion Subsequent infusion


A Phase Ib Dose-Escalation Trial of SAR650984 (Anti-CD38 mAb) in Combination With

Lenalidomide and Dexamethasone in RRMM

• Objectives: Determine the maximum tolerated dose of SAR650984 in combination with lenalidomide and dexamethasone (Len/Dex) in patients with relapsed MM or RRMM, disease response, and progression-free survival.

• Patient population: 31 patients

– 95% prior lenalidomide (Len) and/or pomalidomide (Pom)

– 85% relapse/refractory to either Len or Pom

– 90% prior bortezomib

Martin T G et al. Blood. 2014;124:Abstract 83. Available at www.bloodjournal.org/content/124/21/83

Response Summary (IMWG Criteria)

Martin T G et al. Blood. 2014;124:Abstract 83. Available at www.bloodjournal.org/content/124/21/83

All Treated Patients

n = 31

% (n)

Overall response rate 58 (18)

Stringent complete response 6 (2)

Very good partial response 23 (7)

Partial response 29 (9)

Clinical benefit rate 65 (20)

Minimal response 6 (2)

Stable disease 19 (6)

Progressive disease 13 (4)

Not evaluable 3 (1)

All responses were confirmed by a subsequent assessment. SAR650984 dose level, mg/kg Q2W

3 (n = 4)

80

40

20

0

60

100

5 (n = 3)

10 (n = 24)

Overall (n = 31)

ORR 25% CBR 50%

ORR 67% CBR 67%

ORR 63% CBR 67%

ORR 58% CBR 65%

67%

25%

25%

8%

29%

25%

4%

29%

23%

6%

6%

sCR VGPR

PR MR

Eloquent 2 Study: Progression-free Survival

Lonial S et al. N Engl J Med 2015. DOI: 10.1056/NEJMoa1505654

Subgroup Analysis

Subgroup Elotuzumab Control Hazard Ratio (95% CI) Age

<65 yr 78 (134) 87 (142) 0.75 (0.55-1.02)

>65 yr 101 (187) 118 (183) 0.65 (0.50-0.85)

Baseline β2-microglobulin

<3.5 mg/liter 82 (173) 107 (179) 0.61 (0.46-0.81)

>3.5 mg/liter 97 (147) 98 (146) 0.79 (0.60-1.05) ISS stage at enrollment

I 68 (141) 80 (138) 0.63 (0.46-0.87)

II 60 (102) 67 (105) 0.86 (0.61-1.22)

III 48 (66) 50 (68) 0.70 (0.47-1.04)

Response to most recent line of therapy

Resistance 67 (113) 77 (114) 0.56 (0.40-0.78)

Relapse 112 (207) 128 (211) 0.77 (0.60-1.00)

No. of lines of previous therapy

1 85 (151) 101 (159) 0.75 (0.56-1.00)

2 or 3 94 (170) 104 (166) 0.65 (0.49-0.87) Previous IMID therapy

None 85 (155) 91 (151) 0.78 (0.58-1.05)

Thalidomide only 85 (150) 101 (153) 0.64 (0.48-0.85)

Other 9 (16) 13 (21) 0.59 (0.25-1.40) Previous bortezomid

Yes 132 (219) 150 (231) 0.68 (0.54-0.86)

No 47 (102) 55 (94) 0.72 (0.49-1.07) Previous lenalidomide

Yes 9 (16) 13 (21) 0.59 (0.25-1.40)

No 170 (305) 192 (304) 0.70 (0.57-0.87)

Previous stem-cell transplantation

Yes 102 (167) 117 (185) 0.75 (0.58-0.99)

No 77 (154) 88 (140) 0.63 (0.46-0.86) Mutations

del(17p) 50 (102) 61 (104) 056 (0.45-0.94)

1q21 88 (147) 105 (163) 0.75 (0.56-0.99)

t(4:14) 21 (30) 25 (31) 0.53 (0.29-0.95)

Baseline creatinine clearance

<60 mL/min 53 (96) 55 (75) 0.56 (0.39-0.82)

>60 mL/min 126 (225) 150 (250) 074 (0.58-0.94)

No. at Risk Elotuzumab group Control group

0.25 4.00 0.50 2.00 1.25 0.80

1.00

321 303 279 259 232 215 195 178 157 143 128 117 85 59 42 32 12 7 1 0

325 295 249 216 192 173 158 141 123 106 89 72 48 36 21 13 7 2 0 0

Progression-free Survival

Pro

bab

ility

of

Pro

gres

sio

n-f

ree

Surv

ival

1-Yr progression-free

survival

2-Yr progression-free

survival

Hazard ratio, 0.70 (95% CI, 0.57-0.85) P<0.001 68%

57% 41%

27%

Elotuzumab group

Control group

Months

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38

Treatment-emergent AEs: Phase II (Study 1703) (Any Grade ≥25% or Grade 3/4 ≥5%)

Preferred Term, n (%)

Elotuzumab

10 mg/kg, n = 36

Elotuzumab

20 mg/kg, n = 37

Total

N = 73

Any Grade Grade 3/4

Any Grade Grade 3/4

Any Grade Grade ¾*

Diarrhea 20 (56) 3 (8) 21 (57) 2 (5) 41 (56) 5 (7)

Muscle spasms 19 (53) 2 (6) 22 (60) 0 41 (56) 2 (3)

Fatigue 21 (58) 3 (8) 16 (43) 2 (5) 37 (51) 5 (7)

Constipation 17 (47) 0 19 (51) 0 36 (49) 0

Nausea 16 (44) 0 15 (41) 1 (3) 31 (42) 1 (1)

Upper respiratory tract infection 17 (47) 1 (3) 13 (35) 1 (3) 30 (41) 2 (3)

Pyrexia 14 (39) 1 (3) 15 (41) 0 29 (40) 1 (1)

Anemia 14 (39) 4 (11) 12 (32) 5 (14) 26 (36) 9 (12)

Insomnia 9 (25) 0 13 (35) 1 (3) 22 (30) 1 (1)

Peripheral edema 13 (36) 0 9 (24) 1 (3) 22 (30) 1 (1)

Back pain 12 (33) 1 (3) 8 (22) 1 (3) 20 (27) 2 (3)

Hyperglycemia 8 (22) 2 (6) 12 (32) 5 (14) 20 (27) 7 (10)

Lymphopenia 11 (31) 9 (25) 8 (22) 5 (14) 19 (26) 14 (19)

Neutropenia 11 (31) 5 (14) 8 (22) 7 (19) 19 (26) 12 (16)

Thrombocytopenia 12 (33) 6 (17) 7 (19) 6 (16) 19 (26) 12 (16)

Leukopenia 8 (22) 2 (6) 5 (14) 4 (11) 13 (18) 6 (8)

Hypokalemia 6 (17) 3 (8) 6 (16) 1 (3) 12 (16) 4 (5)

Infusion reactions† 5 (14) 1 (3) Rash

3 (8) 0 8 (11) 1 (1)

*Grade 5: 1 patient, pneumonia complicated by cellulitis and sepsis leading to multi-organ failure; †AEs identified by the investigator as likely to be infusion reactions. Patients were premedicated with a steroid-based regimen to reduce the frequency and severity of infusion reactions. The 4 most common AEs of any Grade and Grade 3/4 are highlighted SPM, 4 cases (1 prostate, 1 bladder, 1 MDS, 1 nasal squamous cell)

Lonial S et al. J Clin Oncol. 2013;31(suppl):Abstract 8542.

Antibody Treatment of Myeloma (Each combined with lenalidomide/dex)*

* non-randomized, historical comparison from ASH 2014 reports.

Antibody No. ORR ≥PR PFS (mos)

BT062

(anti-CD138) 41 32 (78%) Too early

SAR

(anti-CD38) 31 18 (58%) 6.2

Daratumumab

(anti-CD38) 32 28 (87%) Too early

Elotuzumab

(anti-SLAMF7) 73 61 (84%) 28

HDAC Inhibitors in REL/REF MM

1. Dimopoulos M et al. Lancet Oncol. 2013;14:1129-1140. 2. Richardson PG et al. ASH 2013. Abstract 1970 available at https://ash.confex.com/ash/2013/webprogram/Paper56209.html

Vorinostat1 Panobinostat2

Study

details

Phase 3: Vorinostat + BTZ vs BTZ

(VANTAGE 088)

Phase 2: Panobinostat + BTZ + Dex

(PANORAMA 2)

Patients n = 317 vs 320

not resistant to BTZ

n = 55, median age 61 yrs.

all BTZ-refractory (all RRMM)

Results • Median PFS: Vorinostat + BTZ

7.63 vs BTZ 6.83 mos. (P=0.01)

• Most common grade 3/4 AEs

(vorinostat group):

thrombocytopenia (45%),

neutropenia (28%), anemia (17%)

• Fatigue, GI toxicity noted; multiple

dose reductions/discontinuations

• ≥PR 35% (1 CR)

• ≥MR 53%

• ≥PR 43% in high risk pts.

• Median PFS 5.4 months

• Median OS 17.5 months

• Common grade 3/4 AEs:

thrombocytopenia (64%), diarrhea

(20%), fatigue (20%), anemia (15%),

neutropenia (15%), pneumonia (15%)

Conclusions

• Treatment for relapse using existing agents requires a thorough review of prior therapy, toxicities, and response duration.

• Combination therapy (3 or more drugs) in the relapsed setting may be useful in the context of high-risk disease.

• Ongoing studies test the benefit of combination in early relapse (Aspire, Panorama 1, Eloquent 2).

• In truly refractory disease, doublets with MR may benefit the same as combinations; therefore, PS needs to be accounted for when managing refractory disease.

• Additional targets and agents are needed to offer options for patients who have progressed on available therapy.

Maintenance Therapy MM

What are the appropriate study endpoints?

• PFS is certainly appropriate as a surrogate in RRMM to hasten market approval; Td vs D, Vd vs D, Rd vs D, DVD vs Vd

• Patients with multiply relapsed disease that have longer plateaus clearly translate to improved OS the endpoint of greatest interest.

• For newly diagnosed patients OS needs to be considered MPV vs MP, MPT vs MP

Questions to Evaluate Maint. Trials

• In maintenance studies does PFS predict improved OS?

• Have QOL studies been done?

• What fraction of patients on no maint get diarrhea, skin rashes DVT

• In patients that progress was the maintenance agent available to placebo patients-this is a key for study design

• Were induction arms identical in maint trial

Interferon Meta-analysis of >750 Patients--12 Trials

BJH 2001, 113, 1020-1034.

PFS OS

Thalidomide Maintenance after Conventional

Chemotherapy (CC)

No Trial comparing Thal vs no maintenance after the

same Induction Therapy.

The only Maintenance experience with Thal is

provided by the 7 MP vs MPT trials: 5 used Thal maintenance after MPT:

OS benefit of the MPT arm: 1/5. 2 did not use Thal maintenance after MPT:

OS benefit of the MPT arm: 2/2.

Thal is not required to improve OS after MPT

N

Maintenance versus no

maintenance

CR +

VGPR, %

Med PFS,

months

Med OS,

months GIMEMA6

MPT vs MP 255 36 vs 12 22 vs 14 45 v 48

HOVON 497

MPT vs MP 344 23 vs 8 33 vs 21 40 v 31

Nordic8

MPT vs MP 363 6 vs 3* 15 vs 14 29 vs 32

Maintenance therapy in

non-ASCT Pts

6. Palumbo A, Blood 2008;112:3107-14. 7. Wijermans. JCO 2010;28(19):3160-6. 8. Waage Blood. 2010;116(9):1405-12.

* CR rate only.

N Initial

dose, mg

Maintenance versus no maintenance

FU, mo EFS or PFS OS, %

Barlogie1 668 400 72 5-yr 56 vs 44% 8-yr 57 vs 44

Abn Cyto 5yr: 56 v 43

Attal2 597 400 36 3-yr 52 vs 36% 4-yr 87 vs 77

Spencer3 243 200 24 3-yr 42 vs 23% 3-yr 86 vs 75

Morgan4 100 38 ~21 vs 15 m† 2-yr ~58 vs

58†

Stewart5 332 200 (+pred) 48 28 vs 17 m NR vs 60m

Lokhorst6 536 50 (vs IFN) 52 34 vs 25 m 73 vs 60 m

Krishnan7 366 200 (+dex) 36 3-yr 49 v 80% 3-yr 80 v 81%

Maintenance after ASCT with thali

* CR rate only. † Pooled ASCT and nonASCT patients

1. Barlogie B, N Engl J Med. 2006;354:1021-30, updated Blood. 2008;112(8):3115-21. 2. Attal M, Blood. 2006;108:3289-94. 3.

Spencer A, J Clin Oncol; 2009;27:1788-93. 4. Morgan GJ, ASH. 2010;abs 623. 5. Stewart ASH 2010, Abs 39; 6. Lokhorst Blood

(2010); 115:1113-1120 7. Krishnan. ASH 2010;#41-

83% received salvage thalidomide



HOVON 50 Best response on protocol

VAD+IFN TAD+Thal p

≥ PR 79 % 88% 0.005

≥ VGPR 54 % 66% 0.005

≥ CR 23 % 31% 0.04

EFS with censoring at RIC allo-SCT Treatment arm

C

um

ula

tive p

erce

nta

ge

0 12 24 36 48 60

0

25

50

75

100

months

4 Jun 2008 - 17:11:36

A:noThal

B:+Thal

At risk:

A:noThal 267 138 84 44 15 3

B:+Thal 269 163 123 74 34 9

Logrank P<.001

A:noThal 267 168

B:+Thal 269 134

N E

Overall survival Treatment arm

C

um

ula

tive p

erce

nta

ge

0 12 24 36 48 60

0

25

50

75

100

months

4 Jun 2008 - 17:11:38

A:noThal B:+Thal

At risk:

A:noThal 267 227 204 151 65 20

B:+Thal 269 233 201 148 80 24

Logrank P=.96

A:noThal 267 98

B:+Thal 269 101

N D

EFS OS

Lokhorst Blood (2010); 115:1113-1120 Median fu is 52 months

PFS and OS according to maintenance randomization

Median follow-up from maintenance randomization

was 38 months (range 12–66 months)

Morgan Lancet MRC IX

HR [95% CI] = 1.45 [1.22,

1.73], P = 0.0003

Maintenance, N = 407

No maintenance, N = 410

20

40

60

80

100

12 24 36 48 60 72

Pati

en

ts (

%)

Progression-free survival (months)

HR [95% CI] = 0.91 [0.72, 1.17],

P = 0.40

Maintenance, N = 408

No maintenance, N = 410

20

40

60

80

100

12 24 36 48 60 72

Pati

en

ts (

%)

Overall survival (months)

Thalidomide maintenance improves PFS with no OS advantage

0 0

PFS 20 vs 15 mo

Median OS 58 mo

Maintenance with Lenalidomide

Initial

TT N

Time of

Rando

Lenalidomide versus Placebo

Median PFS

after Rando OS after Rando

Attal et al.1 SCT 614 3 m post

SCT 41 m vs 23 m***

4-year OS

73% vs 75%

McCarthy et al.2 SCT 460 SCT 39 m vs 21 m*** 3-year OS

88% vs 80%*

Palumbo et al.3 MPR 305 Diagnosis 31 m vs 14 m** 3-year OS

70% vs 62%

1. Attal M, et al. NEJM 2012 2. McCarthy et al, NEJM 2012. 3. Palumbo et al, NEJM 2012

Randomization, Treatment, and Follow-up of the Enrolled

Patients.

Palumbo A et al. N Engl J Med 2014;371:895-905.

Rdx4

MPRx6 tSCT

R vs 0

Kaplan–Meier Estimates of

Progression-free

Survival and Overall Survival.

Palumbo A et al. N Engl J Med 2014;371:895-905.

Post Rd

SCT produces RFS & OS benefit

R produces RFS but no OS benefit

SCT, as compared with MPR, significantly prolonged PFS & OS

AE Placebo Lenalidomide

Anemia 2% 3%

Thrombocytopenia 7% 14%

Neutropenia 18% 51%

Febrile Neutropenia 1% 1%

Infections 5% 13%

DVT/PE 2% 6%

Skin disorders 4% 7%

Fatigue 2% 5%

Peripheral Neuropathy 1% 1%

Attal et al N Engl J Med 2012

IFM 2005-02: Grade 3–4 AEs (unblinding)

.

Lenalidomide toxicity

Max Non-Hematologic Len 73 32 8 3 <0.001

Placebo 37 16 6 3

N N % %

Grade 3 Non

Hematologic AE

Grade 4

Non Hematologic AE

McCarthy PL, N Engl J Med 2012;366:1770-81.

Number of patients with at least one SPM (10/2011)

Lenalidomide

(N= 306)

Placebo

(N= 302)

Total

(N= 608)

Hematologic malignancies (%) 13 (4.2) 5 (1.7) 18 (3.0)

AML/MDS 5 4

ALL 3 0

Hodgkin lymphoma / Non-HL 4 / 1 0 / 1

Solid tumours (%) 10 (3.3) 4 (1.3) 14 (2.3)

Esophageal / Colon 4 0

Breast 2 0

Lung / Sinus 1 1

Kidney / Prostate 3 2

Melanoma 0 1

Non-Melanoma skin cancers (%) 5 (1.6) 3 (1.0) 8 (1.3)

Total (%) 26* (8.5) 11** (3.6) 37 (6.1)

. Attal et al N Engl J Med 2012

McCarthy PL, N Engl J Med 2012;366:1770-81.

Maintenance with Bortezomib

Initial

therapy

Maintenance

Maintenance

regimen PFS OS

Mateos et al.1

VMP

vs

VTP

VT 32 m 2-year: 86%

VP 24 m 2-year: 81%

Palumbo et al.2

VMPT VT 3-year: 60% 3-year: 89%

VMP 0 3-year: 42%* 3-year: 89%

Sonneveld et

al.3

PAD + SCT V 3-year: 48% 3-year: 78%

VAD + SCT T 3-year: 42%* 3-year: 71%*

1. Mateos mv, lancet oncol 2010 2. Palumbo a, J Clin Onco 2010 3. Sonneveld p, JCO 30:2946;2012

Kaplan-Meier survival curves among patients with multiple myeloma, according to randomly assigned treatment arm.

Sonneveld P et al. JCO 2012;30:2946-2955 ©2012 by American Society of Clinical Oncology

3 yr OS 78

vs 71 %

Kaplan-Meier survival curves of progression-free survival (PFS) and overall survival (OS)

according to treatment arm within subgroups according to del(13/13q) or t(4;14) or

according to del(17p).

Sonneveld P et al. JCO 2012;30:2946-2955

©2012 by American Society of Clinical Oncology

But

• Study not designed to evaluate role of maintainance. i.e. NO random assignment to maintainance

• None of patients in the VAD arm ever saw bortezomib (planned)

• Bortezomib maintainance all had 3 cycles bortezomib induction

• Post induction Bortezomib CR 36% vs VAD CR 24%; CR + nCR 49 vs 34%

But

• Completion of Bortezomib maintainance occurred in 47 %. Completion of Thalidomide in 27%

Conclusion

• Maint therapy may or may not have value for survival prolongation in myeloma but data at this time insufficient to incorporate into routine practice outside of protocols

Maintenance Therapy: Conclusions.

Maintenance cannot be considered as a “Standard

Practice” in 2015.

Indeed, to be considered as a “Standard Practice”

Maintenance should :

• Delay relapse

• But also improve overall survival

• With an acceptable toxicity.

Currently, Lenalidomide is the most “promising

candidate”. However, we still need to:

• Confirm the CLGB survival with the IFM follow-up

• And to better define the duration of maintenance.

• ¾ trials do not demonstrate survival benefit

Relapsed Multiple Myeloma and the dilemma of maintenance ... · –Bortezomib, carfilzomib, MLN...

Documents

Transcript of Relapsed Multiple Myeloma and the dilemma of maintenance ... · –Bortezomib, carfilzomib, MLN...