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.

Months

10 20 30 50 0 60

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.

4 8 12 16

HR = 0.50 P<0.001

20 24 0

PFS (months)

OS (months)

4 8 12 16

HR = 0.72 P=0.009

20 24 28 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.

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

≥25 % (n = 163) 7.4 mos.

<25% (n = 96) 2.3 mos.

≥50% (n = 113) 8.4 mos.

PFS (months)

4 8 12 16 20 24 0

OS (months)

4 8 12 16 20 28 0 24 0.0

4 8 12 16 20 24 0

M-Protein

Reduction

Median

≥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-

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

20/56 mg/m2 20/27 mg/m2 20/27–20/56

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.

Lenalidomide 25 mg (days 1–21)

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

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

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

≥CR ≥VGPR ORR (≥PR)

P<.001

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)

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

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

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).

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

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

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)

Months Since Randomization

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.

≥CR ≥VGPR ORR (≥PR)

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

(95% CI, 73–81)

(95% CI, 58–67)

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

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)

Months Since Randomization

6 12 18 24 30

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)

–100

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

Patient number Re

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

07 01 08

03 02 04 05 06 09 12 10 13

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

Patient number Re

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

42 45 21 35 14

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)

20.0 20.0

33.3 38.1

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

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)

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%

sCR VGPR

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

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

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%

Elotuzumab group

Control group

Months

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

N = 73

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)

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

(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

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

Maintenance versus no

maintenance

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

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

tive p

0 12 24 36 48 60

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

Overall survival Treatment arm

tive p

0 12 24 36 48 60

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

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

12 24 36 48 60 72

Progression-free survival (months)

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

P = 0.40

Maintenance, N = 408

No maintenance, N = 410

12 24 36 48 60 72

Overall survival (months)

Thalidomide maintenance improves PFS with no OS advantage

PFS 20 vs 15 mo

Median OS 58 mo

Maintenance with Lenalidomide

Initial

Time of

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.

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)

(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

regimen PFS OS

Mateos et al.1

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

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.

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

• 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%

• 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...

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