Antibodies are not the only standard part of first relapse ...€¦ · 1 Antibodies are not the only standard part of first relapse management in myeloma Jonathan L. Kaufman, MD Associate

1

Antibodies are not the only standard part of first relapse management in myeloma

Jonathan L. Kaufman, MDAssociate ProfessorDepartment of Hematology and Medical OncologyWinship Cancer InstituteEmory University School of Medicine

2Winship Cancer Institute | Emory University

Considerations for using antibodies in myeloma• When

• Smoldering: Dara as single agent: Nooka PI• Induction: Elo RVD: Nooka PI• Consolidation/Maintenance: Elo Len: Nooka PI• First Relapse• Later relapse• Retreatment with pom/dara: Nooka PI

• Applicability of clinical trial data to our patients

• Non antibody based treatment options

• Optimal partner


TOURMALINE-MM1: Phase 3 Study of Weekly Oral Ixazomib Plus Lenalidomide-dexamethasone

Ran

dom

izat

ion

Ixazomib + Lenalidomide + DexamethasoneIxazomib: 4 mg on days 1, 8, and 15Lenalidomide: 25 mg* on days 1-21

Dexamethasone: 40 mg on days 1, 8, 15, 22

N=722

1:1

Placebo + Lenalidomide + DexamethasonePlacebo: on days 1, 8, and 15

Lenalidomide: 25 mg* on days 1-21Dexamethasone: 40 mg on days 1, 8, 15, 22

Repeat every 28 days until progression, or unacceptable toxicity

Stratification:• Prior therapy: 1 vs 2 or 3• ISS: I or II vs III• PI exposure: yes vs no

Global, double-blind, randomized, placebo-controlled study design

Response and progression (IMWG 2011 criteria1) assessed by an independent review committee (IRC) blinded to both treatment and investigator assessment

Primary endpoint: • PFSKey secondary endpoints: • OS • OS in patients with del(17p)

Moreau P, et al. N Engl Med. 2016;374(17):1621-1634.

Outcomes by cytogenetic risk group

Median OS could not be estimated

In the IRd arm, median PFS in high-risk patients was similar to that in the overall patient population and in patients with standard-risk cytogenetics

ORR, % ≥VGPR, % ≥CR, % Median PFS, months

IRd Placebo-Rd IRd Placebo-Rd IRd Placebo-Rd IRd Placebo-RdHR

All patients 78.3* 71.5 48.1* 39 11.7* 6.6 20.6 14.7 0.742*

Standard-risk patients 80 73 51 44 12 7 20.6 15.6 0.640*

All high-risk patients 79* 60 45* 21 12* 2 21.4 9.7 0.543

Patients with del(17p)† 72 48 39 15 11* 0 21.4 9.7 0.596

Patients with t(4;14) alone 89 76 53 28 14 4 18.5 12.0 0.645

*p<0.05 for comparison between regimens. †Alone or in combination with t(4;14 or t(14;16). Data not included on patients with t(14:16) alone due to small numbers (n=7).

Moreau P, et al. N Engl Med. 2016;374(17):1621-1634.


PFS results based on different cut-offs for del(17p)

Cut-off for del(17p)

Number of patients Median PFS, mos IRd vs placebo-Rd

HR p-value

5% 69 21.4 vs 9.7 0.596 0.162

20% 59 21.4 vs 6.7 0.611 0.2049

60% 33 15.7 vs 5.1 0.49 0.2481

10% of patients had tumors harboring the del(17p) abnormality The outcomes for del17-positive patients, in the control arm (Rd), were

similar to what has been reported for Rd therapy in different trialsMoreau P, et al. N Engl Med. 2016;374(17):1621-1634.


Final PFS analysis: A significant, 35% improvement in PFS with IRd vs placebo-Rd

Number of patients at risk:

IRdPlacebo-Rd

360 345 332 315 298 283 270 248 233 224 206 182 145 119 111 95 72 58 44 34 26 14 9 1 0

362 340 325 308 288 274 254 237 218 208 188 157 130 101 85 71 58 46 31 22 15 5 3 0 0

1.0

0.8

0.6

0.4

0.2

0.00 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24

Prob

abili

ty o

f pro

gres

sion

-fr

ee s

urvi

val

Time from randomization (months)

Log-rank test p=0.012Hazard ratio (95% CI): 0.742 (0.587, 0.939)Number of events: IRd 129; placebo-Rd 157

Median PFS:IRd: 20.6 monthsPlacebo-Rd: 14.7 months

Median follow-up: ~15 monthsMoreau P, et al. N Engl Med. 2016;374(17):1621-1634.


ASPIRE Study Design

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

RdLenalidomide 25 mg days 1–21

Dexamethasone 40 mg days 1, 8, 15, 22

KRdCarfilzomib 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 1–21Dexamethasone 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, 16After cycle 18, carfilzomib discontinued

Stewart AK, et al. N Engl J Med. 2015;372(2):142-152.


Progression-Free Survival Intent-to-Treat Population (n=792)

8

1.0

0.8

0.6

0.4

0.2

0.0

Pro

porti

onSu

rviv

ing

With

out P

rogr

essi

on

KRdRd

0 6 12 18 24 30 36 42 48

Months Since RandomizationNo. at Risk:

KRdRd

396 332 279 222 179 112 24 1396 287 206 151 117 72 18 1

CI, confidence interval; KRd, carfilzomib, lenalidomide, and dexamethasone; Rd, lenalidomide and dexamethasone.

KRdN=396

RdN=396

PFS, median months 26.3 17.6

Hazard ratio (KRd/Rd) (95% CI)

0.69 (0.57-0.83)

P value (one-sided) <.0001



PFS by Cytogenetic Risk Status at Baseline (continued)

KRd, carfilzomib, lenalidomide, and dexamethasone; PFS, progression-free survival; Rd, lenalidomide and dexamethasone.

Pro

porti

on S

urvi

ving

W

ithou

t Pro

gres

sion

0.2

Months Since Randomization

6 12 18 24 30 36 48

KRd HighRd HighKRd StandardRd Standard

420

0

0.4

0.6

0.8

1.0



Eligibility

• Relapsed/refractory MM

• 1-3 prior lines of therapy

• PR to at least 1 line of therapy

Carfilzomib 30-min infusion + Low-dose dexamethasone

RBortezomib IV or SC

+ Low-dose dexamethasone

ENDEAVOR: A Phase III Study of Cd versus Vd

Dimopoulos MA, et al. Lancet Oncol. 2016;17(1):27-38.









HTN: 16/9; Dyspnea; 23/5



CHAMPION-1 Study Design

Carfilzomib (mg/m2)a Dexamethasone (mg)Phase 1 (3+3 dose-escalation schema)

Dose level 1 45 40Dose level 2 56 40Dose level 3 70 40Dose level 4 88 40

Phase 2 MTD from phase 1 40aCarfilzomib 20 mg/m2 was administered to all patients on only cycle 1 day 1.

CarfilzomibDays 1, 8, and 15

Duration of infusion: 30 minutesand

Dexamethasone IV or PODays 1, 8, 15, and 22 (day 22 omitted for cycles 9+)Both drugs given until PD or unacceptable toxicity

IV, intravenous; MTD, maximum tolerated dose; PD, progressive disease: PO, per oral.

Treatment Schedule (Phase 1 and 2)

Dosing28 day cycles:

Berenson JR, et al. Blood. 2016;127(26):3360-3368.


Response Rates

15

CBR, clinical benefit rate; CI, confidence interval; DOR, duration of response; NA, not available; ORR, overall response rate; PR, partial response; TTR, time to response; VGPR, very good partial response.

Phase 1–270 mg/m2

(N=104)Best overall response, n (%)

Stringent complete response 5 (5)Complete response 13 (13)Very good partial response (VGPR) 31 (30)Partial response 31 (30)Minimal response 7 (7)Stable disease 12 (12)Progressive disease 2 (2)Not evaluable 3 (3)

ORR, % (95% CI) 77 (68–85)CBR, % (95% CI) 84 (75–90)DOR (≥PR), median months (95% CI) 16.3 (12.7–NA)TTR (≥PR), median months (range) 1.6 (0.7–7.2)

≥VGPR=47%



AEs of Any Grade Occurring in ≥ 20% of PatientsAE, n (%) Patients

(N=104)Fatigue 55 (53)Nausea 41 (39)Diarrhea 34 (33)Insomnia 33 (32)Upper respiratory tract infection 33 (32)Headache 31 (30)Anemia 29 (28)Cough 29 (28)Pyrexia 29 (28)Dyspnea 28 (27)Thrombocytopenia 25 (24)Peripheral edema 25 (24)Back pain 22 (21)

16

AE, adverse event






DVd vs Vd: Efficacy: 1-3 Prior Lines


POLLUX: Study Design

Cycles: 28 days

DRd (n = 286)Daratumumab 16 mg/kg IV

• Qw in Cycles 1 to 2, q2w in Cycles 3 to 6, then q4w until PD

R 25 mg PO• Days 1 to 21 of each cycle until PD

d 40 mg PO• 40 mg weekly until PDRd (n = 283)

R 25 mg PO• Days 1 to 21 of each cycle until PD

d 40 mg PO • 40 mg weekly until PD

Primary endpoint• PFS

Secondary endpoints• TTP

• OS

• ORR, VGPR, CR

• MRD

• Time to response

• Duration of response

Key eligibility criteria• RRMM

• ≥1 prior line of therapy

• Prior lenalidomide exposure, but not refractory

• Creatinine clearance ≥30 mL/min

Multicenter, randomized (1:1), open-label, active-controlled, phase 3 study

Stratification factors• No. of prior lines of therapy

• ISS stage at study entry

• Prior lenalidomide

RANDOMIZE

1:1

Statistical analyses• Primary analysis:

~177 PFS eventsISS, International Staging System; DRd, daratumumab/lenalidomide/dexamethasone; IV, intravenous; qw, weekly; q2w, every 2 weeks; q4w, every 4 weeks; R, lenalidomide; PO, oral; PD, progressive disease; d, dexamethasone; Rd, lenalidomide/dexamethasone; TTP, time to progression; OS, overall survival; MRD, minimal residual disease.

Dimopoulos MA, et al. N Engl J Med. 2016;375(14):1319-1331.

20Winship Cancer Institute | Emory UniversityDimopoulos MA, et al. N Engl J Med. 2016;375(14):1319-1331.

21Winship Cancer Institute | Emory UniversityDimopoulos MA, et al. N Engl J Med. 2016;375(14):1319-1331.

Differential Effects the Same Target

Myeloma Cell Death

T-cellsNK-cells

T-Cell and NK cell

activation

IMID AgentPom>Len>Thal

IKZF1/3

↓ IRF4↓ MYC

IKZF1/3↑ IL-2↓ TNF

ORRa: DARA + POM-D

ORR Subgroup Analysis: DARA + POM-D

Emory (Nooka) Approach to Early Relapse

Slow indolent relapse Aggressive relapse+ Len maintenance - Len maintenance + Len maintenance - Len maintenance

Consider adding Ixazomib/Dex*

Consider Adding Elo/Dex*

* Increase len dose

Consider Dara/Len/Dex

Consider Elo/Len/Dex

Consider Car/Len/Dex

Consider Dara/Pom/Dex

Consider Car/Pom/Dex


Consider Dara/Vel/Dex


Emory (exanded)Approach to Early Relapse

Slow indolent relapse Aggressive relapse+ Len maintenance - Len maintenance + Len maintenance - Len maintenance

Consider adding Ixazomib/Dex*

Consider Adding Elo/Dex*

Car/dex



Consider Elo/Len/Dex

Car/dex


Consider Dara/Pom/Dex








Documents

Antibodies are not the only standard part of first relapse ...€¦ · 1 Antibodies are not the only standard part of first relapse management in myeloma Jonathan L. Kaufman, MD Associate